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#1166 From: PoWeRTX@...
Date: Fri Oct 12, 2007 3:15 pm
Subject: Fwd: NATAP: Merck Integrase 'Approval Expected Today' 		PoWeRTX@...
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In a message dated 10/12/2007 8:26:15 A.M. Central Daylight Time, nataphcvhiv@... writes:
NATAP http://natap.org/
_______________________________________________


Merck HIV drug 'Approval Expected Friday'

WASHINGTON
http://www.businessweek.com

Merck & Co. is expected to receive approval to market a first-of-kind HIV drug as early as Friday.

The Food and Drug Administration is scheduled to make a decision on the company's drug Isentress to treat HIV patients who have developed a resistance to other medications. Physicians often prescribe a "cocktail" of several HIV drugs to fight the virus because it changes very rapidly.

A panel of outside advisers unanimously recommended FDA rapidly approve the drug at a meeting last month.

The Merck drug targets integrase, one of three enzymes used by the virus to reproduce and infect cells. The FDA previously has approved drugs that target the two other enzymes.

Despite Isentress' innovative HIV-fighting mechanism, the drug could have trouble reaching blockbuster sales. Like most HIV therapies approved in recent years, Isentress will serve as a second-line therapy for patients who have stopped responding to older, more established drugs.

BMO Capital Markets Robert Hazlett predicts sales of $400 million next year and peaking $950 million by 2010. By comparison, Gilead Science's market-leading drug Truvada posted sales of $1.1 billion last year. Gilead is also expected to have a drug similar to Isentress on the market by the end of the decade.

Merck's New AIDS Drug Has Promise -- if It Isn't Too Pricey

Wall St Jnl
By SARAH RUBENSTEIN
October 11, 2007; Page B1

Merck & Co. could break new ground on the AIDS-fighting front this week with the Food and Drug Administration's expected approval of Isentress, a new type of drug that could be especially useful for patients who no longer respond to many existing treatments. Yet despite the continuing need and market for HIV treatments, and doctors' enthusiasm about the drug's prospects, it's no sure thing that Isentress will pay off for Merck.


A major factor is pricing, yet to be determined and especially important because of the recent arrival of several other drugs to fight HIV, the virus that causes AIDS. Pfizer Inc.'s Selzentry, which won regulatory approval this summer, costs about $10,600 a year wholesale. Roche Holding AG's Fuzeon, which came out in 2003, costs about $24,500 a year wholesale, much higher than many other AIDS drugs. And Johnson & Johnson came out with Prezista last year and may win approval of another HIV drug in early 2008.

Merck declines to discuss pricing ahead of an FDA decision. But if the company were to price Isentress at the high end of the range, "there's no way the system could handle that," says Lanny Cross, a former director of the New York AIDS Drug Assistance Program and a consultant for the National Alliance of State and Territorial AIDS Directors.

Martin Delaney, a longtime AIDS activist, who has participated in price negotiations with Merck on behalf of a group called the Fair Pricing Coalition, says the company has shown sensitivity to patients' financial needs in the past. But he says Merck officials have been "arguing they need to get profitability." He says Merck has indicated it wants to price Isentress in the range of relatively new AIDS drugs such as Prezista and Bristol-Myers Squibb Co.'s Reyataz, both of which cost around $9,500 a year wholesale, according to their makers. He also says Merck has told him it has spent close to $2 billion on HIV research.

Isentress arrives at a time when Merck has just one other HIV drug in clinical trials, at the earliest stage of such testing. And it is just weeks after Merck's leading experimental AIDS vaccine collapsed in a clinical trial. Isentress represents a chance for Merck to show it is still a major player in this arena despite a years-long gap since it last brought a new drug to counter HIV to the market. Some doctors are excited by Isentress's potential, in particular because the pill represents a new way to attack a virus that has managed to develop resistance to many other drugs.

An advisory panel of outside medical experts last month said the data support FDA approval of Isentress for patients who have failed treatment with other HIV drugs. The agency isn't required to follow such panels' advice, but usually does.

Merck may find it difficult to sell Isentress at the highest price possible when many public-assistance programs that help pay for HIV treatments are experiencing fiscal strain. In the 2006 fiscal year, 20 out of nearly 60 AIDS Drug Assistance Programs saw their budgets decrease, according to the Kaiser Family Foundation, a nonprofit health-policy research group in Menlo Park, Calif. Such programs bought drugs for nearly 100,000 HIV patients in 2006 and provided insurance coverage for thousands more, according to Kaiser.

Merck declines to specify how much it spent to develop Isentress or to research other HIV drugs, beyond saying it has spent "hundreds of millions of dollars" on such work. "We believe [HIV research] is the right thing to do," says Robin Isaacs, the Whitehouse Station, N.J., company's executive director of infectious-disease clinical research. "We are hopeful that will translate into return on investment for our shareholders."

While Merck is viewed by many in the AIDS community as one of the major drug makers most committed to HIV research, revenue from such products currently represents a modicum of Merck's total revenue, which amounted to $22.64 billion last year. The company drew a combined $327 million from sales of Crixivan, an HIV drug from the mid-1990s that is no longer used widely, and Stocrin, which Merck sells overseas.

Isentress could provide a bottom-line boost, though it doesn't carry the potential of some major Merck products such as asthma-drug Singulair, which had $3.58 billion of sales last year. Credit Suisse drug analyst Catherine Arnold estimates Merck's annual sales of Isentress could be $500 million world-wide by 2012, and likely more if used in a broad swath of patients. Merck is an investment-banking client of Credit Suisse.


Another factor influencing Isentress's prospects is whether doctors will prescribe it for patients in early stages of HIV treatment. The FDA advisory panel debated how early in a patient's treatment to approve Isentress use, given that most patients in Merck's trials had used a number of drugs already. It will be up to the FDA to make that determination -- though doctors would be permitted to prescribe Isentress "off label" at any point in treatment.

About two-dozen HIV drugs are now available, most of which block two enzymes that HIV uses to replicate in the body: protease and reverse transcriptase. Isentress, known generically as raltegravir, would be the first drug on the market to target a third enzyme -- integrase -- that helps the virus insert its DNA into that of human cells.

Because HIV mutates quickly to outwit drugs, cocktails of three medications are typically used to simultaneously attack the virus in different spots. Patients tend to change drugs as their virus adapts. Isentress would be taken along with other drugs.

Merck's late-stage studies of Isentress involved patients who had been receiving HIV treatment for a median of 10 years, had virus resistant to at least one drug in each of three major classes of HIV drugs and showed evidence the virus was continuing to replicate in their bodies. In other words, they were already sick or in danger of becoming sick soon.

"Since this drug seems to be very effective and pretty well tolerated, I think [there is] potential for it to move in and take territory" from some older drugs, says Judith Feinberg, a leader of the AIDS clinical-trials unit at the University of Cincinnati College of Medicine who served on the advisory panel.

However, she said some doctors may be uncomfortable prescribing Isentress more broadly until further studies are complete. Merck is currently conducting late-stage Isentress studies in patients who are new to HIV treatment. The company expects to have the results toward the end of 2008. Dr. Feinberg says she had no ties to Merck at the time of the panel hearing but has since agreed to give talks sponsored by the company.

Isentress will be used principally in "patients who have tried a whole raft of drugs," says Daniel Kuritzkes, director of AIDS research at Brigham and Women's Hospital in Boston, who consults for Merck and other HIV-drug makers. However, "for patients who have earlier stages of disease, there will be some tendency to hold off because it's so useful in patients with extensive treatment experience."


Another potential complication is that Isentress is taken twice a day, while some new patients take a once-a-day pill called Atripla that combines three drugs. That could make it tougher to get patients to take Isentress from the beginning.

While Merck has little else for HIV in clinical trials, research-and-development chief Peter Kim says the company is committed to pursuing HIV treatments, and continues to do research related to the integrase enzyme.

"We really do think that this drug-resistance issue is going to continue to be a significant unmet medical need," Dr. Kim says.


 

Regards,

Nelson Vergel
powerusa dot org



See what's new at AOL.com and Make AOL Your Homepage.
NATAP http://natap.org/
_______________________________________________
Merck HIV drug 'Approval Expected Friday'

WASHINGTON
http://www.businessweek.com

Merck & Co. is expected to receive approval to market a first-of-kind HIV drug as early as Friday.

The Food and Drug Administration is scheduled to make a decision on the company's drug Isentress to treat HIV patients who have developed a resistance to other medications. Physicians often prescribe a "cocktail" of several HIV drugs to fight the virus because it changes very rapidly.

A panel of outside advisers unanimously recommended FDA rapidly approve the drug at a meeting last month.

The Merck drug targets integrase, one of three enzymes used by the virus to reproduce and infect cells. The FDA previously has approved drugs that target the two other enzymes.

Despite Isentress' innovative HIV-fighting mechanism, the drug could have trouble reaching blockbuster sales. Like most HIV therapies approved in recent years, Isentress will serve as a second-line therapy for patients who have stopped responding to older, more established drugs.

BMO Capital Markets Robert Hazlett predicts sales of $400 million next year and peaking $950 million by 2010. By comparison, Gilead Science's market-leading drug Truvada posted sales of $1.1 billion last year. Gilead is also expected to have a drug similar to Isentress on the market by the end of the decade.

Merck's New AIDS Drug Has Promise -- if It Isn't Too Pricey

Wall St Jnl
By SARAH RUBENSTEIN
October 11, 2007; Page B1

Merck & Co. could break new ground on the AIDS-fighting front this week with the Food and Drug Administration's expected approval of Isentress, a new type of drug that could be especially useful for patients who no longer respond to many existing treatments. Yet despite the continuing need and market for HIV treatments, and doctors' enthusiasm about the drug's prospects, it's no sure thing that Isentress will pay off for Merck.


A major factor is pricing, yet to be determined and especially important because of the recent arrival of several other drugs to fight HIV, the virus that causes AIDS. Pfizer Inc.'s Selzentry, which won regulatory approval this summer, costs about $10,600 a year wholesale. Roche Holding AG's Fuzeon, which came out in 2003, costs about $24,500 a year wholesale, much higher than many other AIDS drugs. And Johnson & Johnson came out with Prezista last year and may win approval of another HIV drug in early 2008.

Merck declines to discuss pricing ahead of an FDA decision. But if the company were to price Isentress at the high end of the range, "there's no way the system could handle that," says Lanny Cross, a former director of the New York AIDS Drug Assistance Program and a consultant for the National Alliance of State and Territorial AIDS Directors.

Martin Delaney, a longtime AIDS activist, who has participated in price negotiations with Merck on behalf of a group called the Fair Pricing Coalition, says the company has shown sensitivity to patients' financial needs in the past. But he says Merck officials have been "arguing they need to get profitability." He says Merck has indicated it wants to price Isentress in the range of relatively new AIDS drugs such as Prezista and Bristol-Myers Squibb Co.'s Reyataz, both of which cost around $9,500 a year wholesale, according to their makers. He also says Merck has told him it has spent close to $2 billion on HIV research.

Isentress arrives at a time when Merck has just one other HIV drug in clinical trials, at the earliest stage of such testing. And it is just weeks after Merck's leading experimental AIDS vaccine collapsed in a clinical trial. Isentress represents a chance for Merck to show it is still a major player in this arena despite a years-long gap since it last brought a new drug to counter HIV to the market. Some doctors are excited by Isentress's potential, in particular because the pill represents a new way to attack a virus that has managed to develop resistance to many other drugs.

An advisory panel of outside medical experts last month said the data support FDA approval of Isentress for patients who have failed treatment with other HIV drugs. The agency isn't required to follow such panels' advice, but usually does.

Merck may find it difficult to sell Isentress at the highest price possible when many public-assistance programs that help pay for HIV treatments are experiencing fiscal strain. In the 2006 fiscal year, 20 out of nearly 60 AIDS Drug Assistance Programs saw their budgets decrease, according to the Kaiser Family Foundation, a nonprofit health-policy research group in Menlo Park, Calif. Such programs bought drugs for nearly 100,000 HIV patients in 2006 and provided insurance coverage for thousands more, according to Kaiser.

Merck declines to specify how much it spent to develop Isentress or to research other HIV drugs, beyond saying it has spent "hundreds of millions of dollars" on such work. "We believe [HIV research] is the right thing to do," says Robin Isaacs, the Whitehouse Station, N.J., company's executive director of infectious-disease clinical research. "We are hopeful that will translate into return on investment for our shareholders."

While Merck is viewed by many in the AIDS community as one of the major drug makers most committed to HIV research, revenue from such products currently represents a modicum of Merck's total revenue, which amounted to $22.64 billion last year. The company drew a combined $327 million from sales of Crixivan, an HIV drug from the mid-1990s that is no longer used widely, and Stocrin, which Merck sells overseas.

Isentress could provide a bottom-line boost, though it doesn't carry the potential of some major Merck products such as asthma-drug Singulair, which had $3.58 billion of sales last year. Credit Suisse drug analyst Catherine Arnold estimates Merck's annual sales of Isentress could be $500 million world-wide by 2012, and likely more if used in a broad swath of patients. Merck is an investment-banking client of Credit Suisse.


Another factor influencing Isentress's prospects is whether doctors will prescribe it for patients in early stages of HIV treatment. The FDA advisory panel debated how early in a patient's treatment to approve Isentress use, given that most patients in Merck's trials had used a number of drugs already. It will be up to the FDA to make that determination -- though doctors would be permitted to prescribe Isentress "off label" at any point in treatment.

About two-dozen HIV drugs are now available, most of which block two enzymes that HIV uses to replicate in the body: protease and reverse transcriptase. Isentress, known generically as raltegravir, would be the first drug on the market to target a third enzyme -- integrase -- that helps the virus insert its DNA into that of human cells.

Because HIV mutates quickly to outwit drugs, cocktails of three medications are typically used to simultaneously attack the virus in different spots. Patients tend to change drugs as their virus adapts. Isentress would be taken along with other drugs.

Merck's late-stage studies of Isentress involved patients who had been receiving HIV treatment for a median of 10 years, had virus resistant to at least one drug in each of three major classes of HIV drugs and showed evidence the virus was continuing to replicate in their bodies. In other words, they were already sick or in danger of becoming sick soon.

"Since this drug seems to be very effective and pretty well tolerated, I think [there is] potential for it to move in and take territory" from some older drugs, says Judith Feinberg, a leader of the AIDS clinical-trials unit at the University of Cincinnati College of Medicine who served on the advisory panel.

However, she said some doctors may be uncomfortable prescribing Isentress more broadly until further studies are complete. Merck is currently conducting late-stage Isentress studies in patients who are new to HIV treatment. The company expects to have the results toward the end of 2008. Dr. Feinberg says she had no ties to Merck at the time of the panel hearing but has since agreed to give talks sponsored by the company.

Isentress will be used principally in "patients who have tried a whole raft of drugs," says Daniel Kuritzkes, director of AIDS research at Brigham and Women's Hospital in Boston, who consults for Merck and other HIV-drug makers. However, "for patients who have earlier stages of disease, there will be some tendency to hold off because it's so useful in patients with extensive treatment experience."


Another potential complication is that Isentress is taken twice a day, while some new patients take a once-a-day pill called Atripla that combines three drugs. That could make it tougher to get patients to take Isentress from the beginning.

While Merck has little else for HIV in clinical trials, research-and-development chief Peter Kim says the company is committed to pursuing HIV treatments, and continues to do research related to the integrase enzyme.

"We really do think that this drug-resistance issue is going to continue to be a significant unmet medical need," Dr. Kim says.



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Reply | Forward | Messages in this Topic (1)
#1165 From: PoWeRTX@...
Date: Thu Oct 11, 2007 10:25 pm
Subject: FDA's Expected Approval of Merck's Antiretroviral Raltegravir Could 'Break New G 		PoWeRTX@...
Send Email Send Email
 

Kaiser Daily HIV/AIDS Report

Politics and Policy | FDA's Expected Approval of Merck's Antiretroviral Raltegravir Could 'Break New Ground' in HIV/AIDS Fight, Wall Street Journal Reports
[Oct 11, 2007]

      FDA's expected approval this week of Merck's antiretroviral drug raltegravir could "break new ground" in the fight against HIV/AIDS, the Wall Street Journal reports. However, despite the "continuing need and market for HIV treatments," as well as some physicians' "enthusiasm about the drug's prospects," it is "no sure thing" that raltegravir will "pay off" for the company, according to the Journal (Rubenstein, Wall Street Journal, 10/11).

An independent FDA panel of medical experts last month unanimously recommended accelerated approval of raltegravir, an experimental integrase inhibitor. Raltegravir effectively decreases HIV viral loads after 24 weeks of use among HIV-positive people who have not responded to other treatments, according to a study published in the April 14 online edition of the journal Lancet. Raltegravir works by blocking an HIV enzyme called integrase. Integrase is one of the three enzymes necessary for HIV to replicate in the body, and integrase inhibitors stop HIV from inserting its genes into uninfected DNA. The other two enzymes necessary for viral replication, reverse transcriptase and protease, already are targeted by a variety of antiretrovirals.

According to an FDA review of raltegravir released ahead of the independent panel's meeting, the drug is effective at treating HIV-positive people who have shown resistance to available treatments. Rash and increased levels of creatine in the blood were the most common side effects of the drug, according to the review. Other potential side effects include liver injuries and cancer. In clinical trials, a higher number of cancers was found among people taking raltegravir than among those taking a placebo, but the difference could be because of a lower rate of cancer among people in the placebo group, FDA said.

Merck said that if the drug is approved, it will be used in combination with standard oral antiretrovirals by HIV-positive people who have developed resistance to their current treatments. Raltegravir will be sold under the brand name Isentress. FDA is expected to make a final decision about raltegravir in mid-October (Kaiser Daily HIV/AIDS Report, 9/6).

Pricing, Usage
According to the Journal, a "major factor" in the drug's financial prospects will be its price, which has not been determined but is "especially important" because of the recent availability of other antiretrovirals on the market. Merck has declined to comment on pricing ahead of an FDA decision, but the company said it has spent "hundreds of millions of dollars" to develop the drug. Lanny Cross -- former director of the New York AIDS Drug Assistance Program and a consultant for the National Alliance of State and Territorial AIDS Directors -- said that if Merck places the drug at the high end of the price range, "there's no way the system could handle that."

Martin Delaney, who has participated in price negotiations with Merck on behalf of the Fair Pricing Coalition, said that the company has shown sensitivity to patients' financial needs in the past but that Merck officials have been "arguing they need to get profitability." He added that Merck wants to price the drug in the range of Prezista, sold by the Johnson & Johnson subsidiary Tibotec Pharmaceuticals, and Bristol-Myers Squibb's Reyataz, both of which cost around $9,500 annually wholesale.

An additional factor that will influence the drug's prospects is whether physicians will prescribe it for people living with HIV in the early stages of treatment, the Journal reports. "Since the drug seems to be very effective and pretty well-tolerated, I think (there is) potential for it to move in and take territory" from some older antiretrovirals, Judith Feinberg -- head of the AIDS clinical-trials unit at the University of Cincinnati College of Medicine who served on the FDA advisory panel -- said. She added that some physicians might be uncomfortable prescribing raltegravir more regularly until further studies are complete. According to the Journal, Merck is conducting late-stage studies on the drug among HIV-positive people new to treatment. The company expects to have the results toward the end of 2008, the Journal reports (Wall Street Journal, 10/11).


 

Regards,

Nelson Vergel
powerusa dot org



See what's new at AOL.com and Make AOL Your Homepage.

Reply | Forward | Messages in this Topic (1)
#1164 From: PoWeRTX@...
Date: Thu Oct 11, 2007 9:02 am
Subject: Fwd: NATAP/IDSA: New ART KP-1461 Safety/tolerability 		PoWeRTX@...
Send Email Send Email
 
 
 
This drug works in a completely different process
 
 

Regards,

Nelson Vergel
powerusa dot org



See what's new at AOL.com and Make AOL Your Homepage.
NATAP http://natap.org/
_______________________________________________
Safety and tolerability of KP-1461 in phase 1, dose-ranging study in highly ART-experienced HIV infected persons

Reported by Jules Levin
IDSA Oct 2007

P. G. Clay1, D. E. Sweet2, O. O. Osiyemi3, E. Godofsky4, R. Redfield5, S. E. Smith6, R. Campo7, J. H. Shrank8, J. Parkins9, J. Reno9, S. Becker9
1Kansas City University of Medicine and Biosciences, Kansas City, MO, 2University of Kansas School of Medicine, Wichita, KS, 3Triple O Medical Services, West Palm Beach, FL, 4Bach and Godofsky, MD, PC, Sarasota, FL, 5University of Maryland, Baltimore, MD, 6New Jersey Medical School, Newark, NJ, 7University of Miami, Miami, FL, 8Greenville Hospital System, Greenville, SC, 9Koronis Pharmaceuticals, Inc., Redmond, WA.

SUMMARY
KP-1461 is a novel antiretroviral agent that works as a selective viral mutagen through a process called Viral Decay Acceleration. Unlike conventional ART, KP-1461 demonstrates irreversible viral extinction in vitro. This phase I-b study shows that treatment with KP-1461 is generally safe and well tolerated when administered over 14 days at doses of 400, 800, and 1600 mg every 12 hours to HIV-infected subjects. Whether the notable effect seen in the in vitro studies is replicated in vivo is the subject of an ongoing phase 2 study.

Background
KP-1461 is a novel, first-in-class, therapeutic agent for the treatment of human immunodeficiency virus (HIV) infection. KP-1461 is an oral prodrug of KP-1212, which in vitro irreversibly extinguishes HIV through the process of Viral Decay Acceleration™ (Harris).

KP-1461 is a deoxycytidine analog that acts as a selective viral mutagen. As a result of its flexible structure, KP-1461 induces base pairing errors. This accumulation of errors leads to a progressive reduction of viral fitness and eventual error catastrophe and population collapse. The naturally high error rate in the incorporation of bases during HIV transcription and the information dense genome allow the virus to escape immune system responses and to develop resistance to antiviral drugs. As a result, HIV exists as a quasispecies containing related variants with differing degrees of fitness, virulence and pathogenicity. The high inherent error rate, lack of RT proofreading capability, and no known ability to repair a DNA-RNA heteroduplex make HIV and other viruses particularly vulnerable to additional errors that could adversely affect viral population survival (Overbaugh; Eigen; Anderson).

KP-1461 contains an unmodified sugar, allowing continual chain elongation by RT, with a modified base that appears ambiguous to the complementary base. Through a tautomeric process, KP-1461 can pair with either guanosine or adenosine, thus creating G-to-A and C-to-T errors (Loeb). Base pairing errors are incorporated randomly throughout the viral genome and persist through subsequent replication cycles. Based on in vitro data where HIV was ablated, modeling suggests that at least 8 to 12 weeks of treatment may be required before a significant antiviral effect in humans is noted.

Consequent to its mechanism of action, KP-1461 does not appear to exert the same type of selective pressure on the virus as conventional antiretrovirals. This may reduce, or even preclude, the development of KP-1461-resistant variants. The ability to irreversibly extinguish virus in vitro, a feature that distinguishes KP-1461 from all approved antiretroviral agents, and extensive pre-clinical evaluation conditioned the conduct of the phase I-b study performed in HIV-infected individuals reported here.

Additional Findings
Combining all subjects treated with KP-1461 to evaluate the system organ classes with the highest incidence of events, the most frequently reported adverse events were: Gastrointestinal Disorders (13 subjects, 41%), Investigations (11 subjects, 34%), Blood and Lymphatic Disorders (8 subjects, 25%), Nervous System Disorders (7 subjects, 22%), Infections and Infestations (7 subjects, 22%), and Metabolism and Nutrition Disorders (7 subjects, 22%).

When individual adverse events were evaluated, headache, nausea, neutropenia and fatigue (or increased fatigue) were the most frequent, with 5 events. Other events were thrombocytopenia and diarrhea, each with 4 events, and dizziness, with 3 reported events for the total KP-1461 group.

Discussion
Safety & Tolerability:
These data demonstrate that KP-1461 is generally safe and well tolerated when administered at multiple doses, thus warranting phase 2 efficacy studies.
--Most adverse events were mild to moderate in intensity
--There were no dose-dependency findings to AEs
-- Gradable values for laboratory abnormalities were generally mild to moderate and showed no dose-dependency
--Further evaluation of hematologic findings in longer-term studies is warranted
--No clinically significant changes noted in serial ECG

A total of 3 subjects experienced SAEs. None were attributed to KP-1461
- Thrombocytopenia
- Muscle spasm
- Catheter-related infection

Efficacy:
Despite the expectation that a longer period of dosing would be required, trends are suggestive of antiviral effect by HIV RNA and RT assay at higher doses. (Formal efficacy analysis was not planned as part of this assessment. Descriptive data only is provided.)

Pharmacokinetics:
Findings are supportive of pursuing twice daily dosing. (Full PK data will be presented at European AIDS Conference, Madrid, October 2007.)


Purpose
The purposes of study KP-1461-102 are to determine the safety, tolerability, and pharmacokinetic activity of multiple oral doses of KP-1461 in HIV+ men and women, and to assess any effect of KP-1461 on plasma HIV RNA.

Objectives
To assess the safety and tolerability of oral KP-1461 administered every 12 hours for 14 days (28 doses) to cohorts of HIV+ subjects

To determine the PK profiles of KP-1461 (the inactive prodrug) and KP-1212 (the active drug)

To assess the effects of twice-daily KP-1461 over 14 days on plasma HIV RNA copy number and HIV Reverse Transcriptase activity

STUDY DESIGN
Methods
This was a phase 1-b multi-site, randomized, double-blind, placebo-controlled dose-escalation study. Study population included:
o Men and women 18 to 60 years of age
o CD4+ cell counts >100cells/mm3
o HIV RNA 2,500 to 200,000 copies/mL
o Documented exposure to at least two different HAART regimens containing NRTI(s), NNRTI(s), and at least two (2) PIs, excluding low dose Ritonavir®, for a minimum of four months each OR documented three class resistance by genotype and/or phenotype AND in the opinion of the investigator, have few if any effective treatment options available.

Four cohorts of 10 subjects each were randomized in a ratio of 4:1 to KP-1461 or placebo, respectively. Successive dose cohorts received 400 mg, 800 mg and 1600 mg of KP-1461 every 12 hours. An additional 10 subjects were enrolled at the 1600-mg dose for a total of 20 subjects at the 1600-mg dose. A fifth cohort of 5 subjects was randomized in a ratio of 4:1 to KP-1461 or placebo, respectively, at a KP-1461 dose of 3200 mg every 12 hours. Data on this cohort is not yet complete.

Subjects were off antiretroviral drugs for at least two weeks prior to the first dose of study drug. Each dose was taken on an empty stomach. Subjects in each cohort were treated for 14 days with an additional 14 days of follow-up. Entry into the next higher dose cohort began when the previous cohort completed enrollment and ≥ 80% of subjects completed dosing plus 1 week of observation. Approval to dose escalate was provided by a Safety Review Committee (SRC). If two or more subjects in a cohort experienced a Grade 3 or 4 toxicity, the SRC reviewed the event to determine whether further dose escalation was safe. If the SRC halted escalation, the previous dose level would be considered the maximum tolerated dose (MTD). Blood was collected for a 12-hour PK profile after the first dose and a 24-hour PK profile after the last dose of KP-1461 (Day 14) and at Days 8, 16, 21 and 28 to determine trough drug concentrations. Routine safety assessments were measured at baseline and on Days 4, 6, 8, 10, 12, 14, 16, 21, and 28. Follow-up safety evaluations occurred at Days 16, 18, 21 and 28. Subjects were able to restart antiretroviral medications after the Day 28 visit. If restarted within 2 weeks of the Day 28 visit, blood was to be collected for
viral load and CD4+ count 84 days afterward, if subject agreed to do so.

This study was conducted in accordance with the clinical research guidelines defined in the U.S. 21 CFR Parts 50, 56, and 312, the principles enunciated in the World Assembly Declaration of Helsinki and its most recent amendments, and the principles defined by the International Conference on Harmonization.

Results
Subject Demographics

*Includes Cohort 5 (3 Caucasian; 1 Black, non-Hispanic; 1 Hispanic; mean age 43)


Subject Disposition

1Subjects who took at least one dose of study drug and for whom at least one safety evaluation was available.
2Subjects who took at least one dose of study drug and for whom at least one efficacy parameter was recorded.


Treatment-Emergent Adverse Events (all grades) by System Organ Class

This table only includes all events reported with frequency of >15%.

Efficacy Tables
HIV RNA Viral Load (Log10): Mean Change from Baseline for Days 8 and 14
There is little change in viral load during this 14 day study but study authors say above they think it should take 8-12 weeks to see a viral load response.



References
Overbaugh J and Bangham CR. Selection Forces and Constraints on Retroviral Sequence Variation. Science 2001; 292(5519):1106-1109.

Eigen M. Error Catastrophe and Antiviral Strategy. Proc Natl Acad Sci USA 2002; 99(21):13374-6.

Anderson JP, Daifuku R, and Loeb LA. Viral Error Catastrophe by Mutagenic Nucleosides. Annu Rev Microbiol 2004; 58:183-205.

Loeb LA, Essigmann JM, Kazazi F, Zhang J, Rose KD, and Mullins JI. Lethal Mutagenesis of HIV with Mutagenic Nucleoside Analogs. Proc Natl Acad Sci USA 1999; 96(4):1492-1497.

Harris KS, Brabant W, Styrchak S, Gall A, Daifuku R. KP-1212/1461, a nucleoside designed for the treatment of HIV by viral mutagenesis. Antiviral Research 2005;67:1-9.








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#1163 From: PoWeRTX@...
Date: Wed Oct 3, 2007 8:13 pm
Subject: Trimeris gives up on device to inject Fuzeon 		PoWeRTX@...
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Regards,

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#1162 From: PoWeRTX@...
Date: Wed Sep 26, 2007 3:49 pm
Subject: Drs. Joseph J. Eron, Daniel R. Kuritzkes, and Pedro Cahn review latest data 		PoWeRTX@...
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I learn a lot from this printed discussions of experts in clinical care options. I respect Dr Daniel Kuritzkes' opinion the most in the field of HIV. He usually says what he believes without being afraid of pharmaceuticals.

DUET-1 and -2: Assessment of Etravirine (TMC 125- a new non nucleoside) Plus Darunavir/Ritonavir (Prezista) -Based Regimens in Treatment-Experienced Patients

Daniel R. Kuritzkes, MD:
The DUET-1 and -2 studies are a pair of randomized, placebo-controlled, double-blind, phase III trials investigating the use of etravirine (formerly known as TMC125), a next-generation NNRTI, in highly treatment–experienced patients (Capsule Summary).[1,2] The 24-week results from these 2 trials were presented at the International AIDS Society (IAS) Conference on HIV Pathogenesis, Treatment and Prevention and were also recently published in The Lancet.[3,4] To be enrolled in the studies, patients experiencing virologic failure on their current HAART regimen had to have evidence of at least 1 NNRTI resistance mutation either at screening or in a previous genotype, along with 3 or more primary PI resistance mutations at screening. These inclusion criteria ensured that this group of patients was highly treatment experienced. The DUET studies were unique in that all participants received darunavir/ritonavir as part of their optimized background regimen, which was also an investigational agent at the time the study was done. A total of 1203 participants in both DUET trials were randomized to receive etravirine or placebo, each combined with darunavir/ritonavir and optimized background regimen. The primary endpoint of both studies was HIV-1 RNA < 50 copies/mL at Week 24. The DUET-1 trial was conducted in Argentina, Brazil, Chile, France, Mexico, Panama, Puerto Rico, Thailand, and the United States, whereas DUET-2 was conducted in Australia, Belgium, Canada, France, Germany, Italy, the Netherlands, Poland, Portugal, Spain, the United Kingdom, and the United States.

The 24-week results of the studies showed that there was a substantial advantage to receiving etravirine in addition to darunavir/ritonavir and optimized background regimen. The rate of virologic suppression < 50 copies/mL for the etravirine arms vs the placebo arms was 56% vs 39% for patients in DUET-1 (P = .005) and 62% vs 44% for patients in DUET-2 (P = .0003). In addition, patients who received etravirine in DUET-1 demonstrated a significantly greater mean increase in CD4+ cell count from baseline compared with placebo recipients (+89 vs +64 cells/mm3, respectively; P = .0002). Etravirine was well tolerated, with a toxicity profile comparable to that of the placebo arms.

Some very interesting subanalyses assessed the relationship between the number of NNRTI mutations and activity, as well as how the use of enfuvirtide in the background regimen influenced activity. The investigators identified 13 etravirine resistance mutations, which were associated with a reduced response to etravirine. This group of mutations comprised V90I, A98G, L100I, K101E/P, V106I, V179D/F, Y181C/I/V, and G190A/S. Patients with no etravirine resistance–associated mutations at baseline had a virologic response rate (HIV-1 RNA < 50 copies/mL) that approached 80%. This response rate fell to approximately 60% in the presence of 1 or 2 etravirine resistance–associated mutations and fell further to 38%—a virologic response rate similar to the placebo arms—in the presence of 3 or more etravirine resistance–associated mutations. The relatively common Y181C mutation confers resistance to the first-generation NNRTIs but, by itself, had minimal impact on etravirine response rates as demonstrated in a focused subanalysis. A similar proportion of patients with only the Y181C resistance mutation achieved an undetectable HIV-1 RNA compared with the overall virologic response rate for the pooled etravirine arms (65% vs 62%, respectively). Finally, it is important to point out that the K103N mutation does not affect etravirine susceptibility and, as such, is not listed among the 13 etravirine resistance mutations.

Joseph J. Eron, Jr., MD:
Early findings raised concerns that Y181C might have a particularly important influence on etravirine susceptibility, but these data demonstrated that this is only true when Y181C is present together with several additional NNRTI resistance mutations. It was also reassuring to see the most common NNRTI mutation, K103N, did not affect the response to etravirine. The investigators presented data showing that patients who had no etravirine resistance–associated mutations at baseline attained the best virologic response at Week 24 (approximately 80% with HIV-1 RNA < 50 copies/mL), suggesting that the investigators have correctly identified the mutations that contribute to etravirine resistance.

Pedro Cahn, MD, PhD:
It is interesting to note that the placebo arm regimens also performed quite well, which speaks to the efficacy of darunavir/ritonavir in the background regimen. The proportion of patients in the placebo arms who achieved HIV-1 RNA < 50 copies/mL at Week 24 in DUET-1 and DUET-2 was 39% and 44%, respectively. Furthermore, 33% to 34% of patients in the placebo arm who did not receive enfuvirtide or who were not naive to enfuvirtide still achieved HIV-1 RNA < 50 copies/mL at Week 24. In comparison, placebo recipients who did receive enfuvirtide for the first time in combination with darunavir/ritonavir achieved virologic response rates of 56% and 68% in DUET-1 and DUET-2, respectively.

In my opinion, the difference in virologic outcomes between etravirine recipients and placebo recipients who had no active agents in their background regimens was a striking finding. In DUET-1, 47% of etravirine-treated patients with no active agents in their background regimen achieved HIV-1 RNA < 50 copies/mL at Week 24 compared with 9% of placebo-treated patients. In DUET-2, the respective proportions were similar at 44% vs 7%.

Joseph J. Eron, Jr., MD:
Indeed, the difference in response rates between etravirine-treated patients and placebo-treated patients who had no or only 1 active agent in their background regimen ranged from 27% to 38%. However, when there were 2 or more active drugs in the background regimen, there was only a modest difference in response rates between the 2 arms—approximately 7% to 12%. It is not clear to me why etravirine was so effective on its own or in combination with 1 other active agent, and yet it contributed only modest added efficacy once there were multiple active drugs in the regimen.

Another interesting aspect of this study is the adverse effect profile of etravirine compared with placebo. Rash was reported by patients in both study arms, but it was significantly more common in the etravirine arms (P < .0001). The incidence of rash in the etravirine and placebo arms was 20% vs 10% in DUET-1 and 14% vs 9% in DUET-2. However, the reported rashes were usually mild. Only 1% of patients had grade 3 rash, and none had grade 4 rash. A few patients had fever and rash, but there were no patients with fever, rash, and abnormal liver function test results. Of note, 34% of women in the etravirine arms experienced rash compared with only 18% of men (P = .0192). Aside from rash, there were no other noticeable differences between the placebo-treated patients and the etravirine-treated patients regarding the incidence of adverse events. The investigators specifically evaluated the incidence of central nervous system (CNS) events and psychiatric events (sleep disturbances, anxiety, depression) and observed very few differences between the study arms.

Pedro Cahn, MD, PhD:
There were also no significant differences between the etravirine and placebo arms regarding increases in lipid parameters, nor were there any significant differences in liver toxicity.

TMC278 ( another non nucleoside following TMC 125) Metabolic and Safety Substudies: Investigation of Rilpivirine (TMC 278) in Treatment-Naive Patients

Pedro Cahn, MD, PhD:
Rilpivirine, formally known as TMC278, is another next-generation NNRTI with activity against both wild-type and NNRTI-resistant HIV-1 that is currently being developed for use in first-line therapy. TMC278-C204 is an ongoing, randomized, controlled, partially blinded, dose-ranging phase IIb study comparing the efficacy and safety of 3 different doses of rilpivirine (25, 75, and 150 mg once daily) with that of efavirenz (600 mg once daily). According to the preliminary 48-week results of the TMC278-C204 study reported at the 2007 Conference on Retroviruses and Opportunistic Infections (CROI), rilpivirine produced comparable virologic and immunologic activity to efavirenz when both agents were dosed with 2 NRTIs in treatment-naive individuals with no major baseline NNRTI mutations (Capsule Summary).[5] Approximately 80% of patients in the rilpivirine and efavirenz arms achieved HIV-1 RNA < 50 copies/mL at Week 48. In addition, the initial reports suggested that rilpivirine had a better adverse events profile, regarding both CNS effects and lipid abnormalities.

Two studies were presented at IAS that more rigorously compared the metabolic and adverse events profiles of rilpivirine vs efavirenz at 48 weeks in treatment-naive individuals participating in the TMC278-C204 study. Regarding metabolic parameters, rilpivirine was associated with minimal changes in lipid parameters, glucose levels, and insulin sensitivity after 48 weeks of treatment (Capsule Summary).[6] For the combined rilpivirine doses, the changes in total cholesterol (+5 vs +31 mg/dL [+0.13 vs +0.80 mmol/L]; P < .001), low density lipoprotein (LDL) cholesterol (+1 vs +15 mg/dL [+0.03 vs +0.39 mmol/L]; P < .001), triglycerides (-10 vs +18 mg/dL [-0.11 vs +0.20 mmol/L]; P < .05), and glucose (+1 vs +3 mg/dL [+0.05 vs +0.17 mmol/L]; P <.05) were all significantly more favorable in patients treated with rilpivirine vs efavirenz. Interestingly, changes in high density lipoprotein (HDL) cholesterol were significantly more favorable with efavirenz vs rilpivirine (+12 vs +5 mg/dL [+0.31 vs +0.13 mmol/L]; P < .001). The change in the ratio of total cholesterol-to-HDL cholesterol was not significantly different between the rilpivirine and efavirenz arms (-0.5 vs -0.3), nor was the log change in the homeostasis model assessment of insulin resistance (0.2 vs 0.1). In addition, the magnitude of the changes in all metabolic parameters was not related to the rilpivirine dose. Therefore, rilpivirine seemed to perform better than efavirenz regarding many metabolic parameters.

Regarding adverse events, rilpivirine had an adverse events profile very similar to that of efavirenz (Capsule Summary).[7] However, the data did suggest that rilpivirine was associated with fewer CNS adverse events (18% vs 40%; P < .001) and psychiatric adverse events (7% vs 15%; P < .05) than efavirenz. The major differences in CNS adverse events between the rilpivirine and efavirenz arms could be attributed to dizziness (5% vs 27%; P < .001) and somnolence (3% vs 10%; P < .05). There was no difference between the treatment arms in the incidence of headache (8% vs 8%). The difference in psychiatric adverse events between the rilpivirine and efavirenz arms could be attributed to the incidence of abnormal dreams (2% vs 10%; P < .01), as there was no significant difference between the arms in the incidence of insomnia (3% vs 5%) or depression (1% vs 1%).

Joseph J. Eron, Jr., MD:
I was surprised by these results because the data presented at CROI suggested that rilpivirine was generally associated with a lack of CNS adverse effects as was the case with etravirine in the DUET studies. However, in the current rilpivirine presentation, although there were lower rates of CNS and psychiatric adverse effects associated with rilpivirine than with efavirenz, the rates of headache, insomnia, and depression were all similar. Moreover, it is important to note that this was only a partially blinded study; the rilpivirine arms were blinded to dose, but the efavirenz arm was unblinded. Therefore, patients who knew they were receiving efavirenz might have been more likely to report CNS and psychiatric adverse events, as they should have been counseled about the possibility of developing these adverse effects. Therefore, some caution is warranted when interpreting these data.

In conclusion, these 2 substudies provide a little more information about the safety and tolerability of rilpivirine. For additional efficacy and safety data, we must await the results of the double-blind phase III studies of rilpivirine, which are supposed to begin in fall 2007.

Comparable Antiviral Activity and Accelerated Viral Decay of Raltegravir (Isentress, an integrase inhibitor) vs Efavirenz (Sustiva) in Treatment-Naive Patients

Daniel R. Kuritzkes, MD:
Markowitz and colleagues[15] presented the 48-week results from a randomized study of the HIV integrase inhibitor raltegravir conducted in 198 treatment-naive individuals (Capsule Summary). Four different doses of raltegravir—100, 200, 400, and 600 mg twice daily—were compared with efavirenz 600 mg once daily, each combined with tenofovir and lamivudine.

The 24-week results of this study were presented at the 2006 International AIDS Conference and demonstrated that the various doses of raltegravir were associated with comparable virologic and immunologic outcomes to efavirenz (Capsule Summary).[16] For example, the proportion of patients in the raltegravir arms with HIV-1 RNA < 50 copies/mL at Week 24 ranged from 85% to 95%, which was similar to the virologic response rate of 92% observed in the efavirenz arm. At 48 weeks, the virologic responses appeared to be durable in all of the study arms. The proportion of patients with HIV-1 RNA < 50 copies/mL at Week 48 in the raltegravir arms ranged from 83% to 88% compared with a rate of 87% in the efavirenz arm.

An interesting observation in the 24-week data was the rapid decrease in HIV-1 RNA in the raltegravir arms compared with the efavirenz arm. For example, at Day 15, at least 30% of patients in each raltegravir arm had achieved HIV-1 RNA < 50 copies/mL compared with only 11% of patients in the efavirenz arm (all P values < .05). Given that observation, Murray and colleagues[17] performed modeling work, in which they assessed the first-phase viral decay rates and compared those with the decay rates for the efavirenz-containing arm (Capsule Summary). The investigators determined that the first-phase viral decay rate did not significantly differ between the raltegravir and efavirenz arms, and they reported that the half-life of first-phase viral decline across all raltegravir-treated patients was 1.2 days. From this information, the investigators extrapolated that the difference had to be in the second-phase decay rates, but they had difficulty measuring the second-phase decay rates because patients’ HIV-1 RNA had so quickly progressed below the limit of detection of their assays. All raltegravir arms showed a significant reduction in second-phase HIV-1 RNA decline compared with efavirenz, and HIV-1 RNA levels were 70% lower with raltegravir vs efavirenz at the start of the second phase of viral decay (P < .0001). However, it was noted that the half-life of second-phase viral decay was similar between the combined raltegravir arms and the efavirenz arm (15.5 vs 18.3 days, respectively; P = .2). Therefore, although their observations are intriguing, a more comprehensive assessment of the first-phase and second-phase decay rates needs to be performed using more sensitive virologic assays and also using more closely timed samples in the first 48 hours of treatment. In this way, the investigators might be able to tease apart whether there are any differences in virologic decay.

The investigators proposed a hypothetical model to explain these data that seems very plausible, even though there are no data yet to support it. Namely, these findings may be explained by the possibility that raltegravir may be blocking the integration of HIV-1 DNA in latently infected cells, which may allow for an additional day’s worth of virus production in patients receiving efavirenz or a PI, which do not block this integration step.

Irrespective of the mechanism of the accelerated viral dynamics, however, the bottom line is that the faster rate of viral decay associated with raltegravir may have no clinical relevance given that similar rates of undetectable HIV-1 RNA were eventually reached, regardless of whether patients received raltegravir or efavirenz.

Joseph J. Eron, Jr., MD:
The investigators also compared the incidence of adverse events between the efavirenz and raltegravir arms. In this open-label comparison, raltegravir was associated with a much lower incidence of the CNS adverse effects, such as dizziness, headache, and atypical dreams, that are associated with efavirenz. The investigators also compared the changes in lipid parameters between efavirenz-treated patients and raltegravir-treated patients from baseline to Week 48. Raltegravir produced no adverse changes in lipid parameters, whereas efavirenz was associated with significantly greater changes in total cholesterol (-2.3 vs +20.7 mg/dL [-0.06 vs +0.54 mmol/L]; P < .001) and LDL cholesterol (-7.5 vs +3.0 [-0.19 vs +0.08 mmol/L]; P = .016). There was a numeric difference in triglyceride changes (-1.0 vs +49.5; P = .068) and a modest decrease in the total cholesterol–to–HDL cholesterol ratio that did not significantly differ between the raltegravir and efavirenz arms (-0.59 vs -0.47; P = .52).

Daniel R. Kuritzkes, MD:
Data are also starting to accrue on the in vivo patterns of resistance and cross-resistance to raltegravir and elvitegravir, the other integrase inhibitor in late-stage development. In contrast with what was seen in the laboratory, the in vivo resistance patterns of elvitegravir and raltegravir look very similar, with the N155H and the Q148R/K/H mutations representing the predominant mutations for both drugs.[18] At IAS, DeJesus and colleagues[19] presented data from a pilot study designed to assess the response to raltegravir in patients who had failed on elvitegravir/ritonavir (Capsule Summary). They studied 2 patients who had either the N155H or Q148R mutation and who replaced elvitegravir/ritonavir with raltegravir while continuing the rest of their failing regimen. Little or no reduction in HIV-1 RNA was observed after 7 days, therefore reinforcing the impression that it will not be possible to use these 2 drugs sequentially.

 

References

1. Mills A, Cahn P, Grinsztejn B, et al. DUET-1: 24 week results of a phase III randomised double-blind trial to evaluate the efficacy and safety of TMC125 vs placebo in 612 treatment-experienced HIV-1 infected patients. Program and abstracts of the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract WESS204-1. (Capsule Summary)

2. Katlama C, Campbell T, Clotet B, et al. DUET-2: 24-week results of a phase III randomised double-blind trial to evaluate the efficacy and safety of TMC125 vs placebo in 591 treatment-experienced HIV-1 infected patients. Program and abstracts of the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract WESS204-2. (Capsule Summary)

3. Madruga JV, Cahn P, Grinsztejn B, et al. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-1: 24-week results from a randomised, double-blind, placebo-controlled trial. Lancet. 2007;370:29-38.

4. Lazzarin A, Campbell T, Clotet B, et al. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-2: 24-week results from a randomised, double-blind, placebo-controlled trial. Lancet. 2007;370:39-48.

5. Pozniak A, Morales-Ramirez J, Mohapi L, et al. 48-week primary analysis of trial TMC278-C204: TMC278 demonstrates potent and sustained efficacy in ART-naive patients. Program and abstracts of the 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles, California. Abstract 144LB. (Capsule Summary)

6. Ruxrungtham K, Bellos N, Morales-Ramirez J, et al. The metabolic profile of TMC278, an investigational non-nucleoside reverse transcriptase inhibitor (NNRTI). Program and abstracts of the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract TUAB105. (Capsule Summary)

7. Pozniak A, Steyn D, Grinsztejn B, et al. Less frequent reporting of central nervous system and psychiatric adverse events with TMC278 than with efavirenz. Program and abstracts of the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract WEPEA105. (Capsule Summary)

8. Fätkenheuer G, Staszewski S, Plettenburg A, et al. Short-term monotherapy with UK-453,061, a novel NNRTI, reduces viral load in HIV-infected patients. Program and abstracts of the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract WESS202. (Capsule Summary)

9. Saag M, Ive P, Heera J, et al. A multicenter, randomized, double-blind, comparative trial of a novel CCR5 antagonist, maraviroc vs efavirenz, both in combination with Combivir (zidovudine [ZDV]/lamivudine [3TC]), for the treatment of antiretroviral naive patients infected with R5 HIV 1: week 48 results of the MERIT study. Program and abstracts of the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract WESS104. (Capsule Summary)

10. Riddler SA, Haubrich R, DiRienzo G, et al. A prospective, randomized, phase III trial of NRTI-, PI-, and NNRTI-sparing regimens for initial treatment of HIV-1 infection: ACTG 5142. Program and abstracts of the 16th International AIDS Conference; August 13-18, 2006; Toronto, Canada. Abstract THLB0204. (Capsule Summary)

11. Gulick R et al. ACTG 5211: phase II study of the safety and efficacy of vicriviroc (VCV) in HIV+ treatment-experienced subjects: 48-week results. Program and abstracts of the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract TUAB102. (Capsule Summary)

12. Gulick RM, Su Z, Flexner C, et al. Phase 2 study of the safety and efficacy of vicriviroc, a CCR5 inhibitor, in HIV-1-Infected, treatment-experienced patients: AIDS Clinical Trials Group 5211. J Infect Dis. 2007;196:304-312.

13. Cohen C, DeJesus E, Mills A, et al. Potent antiretroviral activity of the once-daily CCR5 antagonist INCB009471 over 14 days of monotherapy. Program and abstracts of the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract TUAB106. (Capsule Summary)

14. Saag MS, Jacobson JM, Thompson M, et al. Antiviral effects and tolerability of the CCR5 monoclonal antibody PRO 140: a proof of concept study in HIV-infected individuals. Program and abstracts of the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract WESS201. (Capsule Summary)

15. Markowitz M, Nguyen BY, Gotuzzo E, et al. Rapid onset and durable antiretroviral effect of raltegravir (MK-0518), a novel HIV-1 integrase inhibitor, as part of combination ART in treatment-naive HIV-1 infected patients: 48-week results. Program and abstracts of the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract TUAB104. (Capsule Summary)

16. Markowitz M, Nguyen B-Y, Gotuzzo F, et al. Potent antiretroviral effect of MK-0518, a novel HIV-1 integrase inhibitor, as part of combination ART in treatment-naive HIV-1 infected patients. Program and abstracts of the 16th International AIDS Conference; August 13-18, 2006; Toronto, Canada. Abstract THLB0214. (Capsule Summary)

17. Murray JM, Emery S, Kelleher A, et al. The integrase inhibitor raltegravir alters viral decay kinetics of HIV, significantly reducing the second phase and challenging current hypotheses of viral replication. Program and abstracts of the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract TUAB103. (Capsule Summary)

18. McColl DJ, Fransen S, Gupta S, et al. Resistance and cross-resistance to first generation integrase inhibitors: insights from a phase II study of elvitegravir (GS-9137). Program and abstracts of the 16th Drug Resistance Workshop; June 12-16, 2007; Barbados, West Indies. Abstract 9.

19. DeJesus E, Cohen C, Elion R, et al. First report of raltegravir (RAL, MK-0518) use after virologic rebound on elvitegravir (EVT, GS 9137). Program and abstracts of the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract TUPEB032. (Capsule Summary)

20. Cahn P, Cassetti I, Wood R, et al. Efficacy and tolerability of 10-day monotherapy with apricitabine in antiretroviral-naive, HIV-infected patients. AIDS. 2006;20:1261-1268.

21. Cahn P, Altclas J, Martins M, Losso M, Cassetti I, Cooper D. Superior activity of apricitabine in treatment experienced HIV-1 infected patients with M184V and NRTI resistance. Program and abstracts of the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract WESS203.


Regards,

Nelson Vergel
powerusa dot org



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#1161 From: PoWeRTX@...
Date: Sat Sep 22, 2007 7:18 pm
Subject: New Classes of Antiretrovirals: The Clinical Role of Integrase Inhibitors and En 		PoWeRTX@...
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Excellent update on new HIV drugs for those of you who like to read and get details..from clinical care options, a great web site that provides treatment education to clinicians.
 
Please feel free to email me back if you do not understand any terms or concepts.

When to Use a New Agent

In recent years, clinical management of treatment-experienced HIV-infected patients has changed. Based on the results of trials incorporating newer agents in the treatment of these patients, the goal of undetectable plasma HIV-1 RNA is achievable in an ever-increasing group of treatment-experienced patients. Both the US Department of Health and Human Services and the International AIDS Society-USA guidelines now state that virologic suppression to < 50 copies/mL is the goal of therapy for all patients, regardless of antiretroviral experience.[1,2] Antiretroviral agents currently in clinical development are expanding the selection of possible options for patients with drug-resistant HIV. These include new “second-generation” agents in current classes, as well as those in novel classes with new mechanisms of action.

Several questions should be addressed before considering the use of a new antiretroviral regimen in HIV-infected patients who have detectable viremia on their current regimen

  • What is the patient’s overall prognosis if they continue on a nonsuppressive regimen?
  • What are the resistance consequences of continuing such a regimen?
  • When will new drugs be available? Will these drugs be active against this particular patient’s virus?
  • Most importantly, are there partner agents available that could be a part of an optimized regimen capable of regaining virologic suppression?

The decision to use a new agent can be challenging. Combination therapy is always required to prevent resistance; however, multiple active agents may not be available simultaneously. A choice must often be made between the lesser of 2 evils

  • Premature use of a new agent in a new regimen that may fail to achieve virologic suppression, which may then result in resistance to that drug and to other agents in the new regimen or
  • Remaining on the current nonsuppressive regimen until sufficient active agents are available to construct a new regimen that is likely to be suppressive; however, while waiting, additional resistance to agents in the current regimen may accrue, which may reduce the likelihood of response to subsequent regimens

Generally, patients will require multiple active agents to achieve full viral suppression. When designing a suppressive regimen, it is important to consider all agents—approved and investigational—to which the patient’s virus might be susceptible. 

 

Antiretroviral Classes and New Agents in These Classes

A number of new antiretroviral agents are now in various stages of clinical development. These include new NRTIs, NNRTIs, PIs, and agents that belong to the “novel classes”—entry inhibitors, integrase inhibitors, and maturation inhibitors. The agents in phase IIb clinical trials and beyond are listed in Table 1. Also included is maraviroc, which was approved for use in multidrug-resistant patients with CCR5-tropic (R5) virus in August 2007. The agents that will be discussed in this review are etravirine, maraviroc, TNX-355, vicriviroc, elvitegravir, and raltegravir.

Table 1. New Agents for Treatment-Experienced Patients

 

Entry Inhibitors

Entry is a multistep process that involves binding of the viral gp120 envelope protein to the host cell’s CD4 receptor, followed by secondary interactions with 1 of 2 chemokine receptors, CCR5 or CXCR4. This leads to fusion of the viral and cell membranes, mediated by a rearrangement in the structure of the HIV envelope transmembrane subunit, gp41. The various groups of entry inhibitors, including CD4 antagonists, chemokine receptor antagonists, and fusion inhibitors, act at various points in the entry process. The first approved agent in this class, enfuvirtide, is a fusion inhibitor that was approved for use in treatment-experienced patients in 2003.

Monoclonal Anti-CD4 Antibody
TNX-355 is a humanized monoclonal antibody that belongs to the immunoglobulin G subtype 4 class. It recognizes the second extracellular domain of the CD4 receptor (notably, not the epitope associated with gp120 binding). The exact mechanism of action of TNX-355 is unknown, but it is thought that this antibody may block viral entry through steric hindrance of the binding of gp120 and the CD4 receptor, preventing the interaction of the V3 loop of gp120 with the chemokine coreceptor. This agent is administered by IV infusion.

A phase II randomized study[3] showed that TNX-355 plus an optimized background regimen (OBR) had substantial activity (Capsule Summary). In a last-observation-carried forward analysis, patients who received TNX-355 plus OBR had a decline in HIV-1 RNA up to 0.96 log10 copies/mL at 48 weeks compared with 0.14 log10 copies/mL with placebo plus OBR (P < .001 for TNX-355 compared with placebo). Adverse events in the group that received TNX-355 were similar to placebo.

CCR5 Antagonists
CCR5 antagonists block viral binding to the CCR5 chemokine coreceptor. Several CCR5 antagonists have been tested in clinical trials.

In August 2007, maraviroc was approved for use in multidrug-resistant patients with R5-only virus. A phase IIb/III trial of this agent in treatment-experienced patients has been reported.[4,5] A phase IIb/III study of maraviroc in treatment‑naive patients with R5 virus has also been performed, and 48-week results were recently reported.[6]

A second CCR5 antagonist in development is vicriviroc. Week 48 phase IIb data from studies in treatment‑experienced patients with R5 virus have been presented.[7] Phase IIb studies in treatment‑naive patients were stopped by the data and safety monitoring board because of decreased efficacy vs efavirenz‑based therapy and an increased rate of viral tropism change among patients receiving vicriviroc.[8]

Clinical data on both of these agents will be discussed further in this module.

CXCR4 Antagonists
CXCR4 antagonists block binding to the CXCR4 chemokine coreceptor. There are currently no CXCR4 antagonists in late clinical development

Viral Tropism and CCR5 Antagonists

As described in the accompanying module of this program by Daniel R. Kuritzkes, MD, HIV variants have long been recognized as being either syncytium-inducing (SI) or nonsyncytium-inducing (NSI) in cell culture. The emergence of an NSI viral population to a predominantly SI population has been shown to be temporally associated with immunologic decline.[9] It is now understood that SI viruses are primarily either dual tropic (use both receptors) or use CXCR4 only (X4); NSI viruses are those that primarily use the CCR5 coreceptor (R5 viruses).  

As outlined in Dr. Kuritzkes’ module, current tropism assays report the viral population as being R5 only, X4 only, or dual or mixed (D/M) tropic. Although there is no proof that D/M or X4 viruses cause disease progression, the association has raised concerns regarding the possibility that CCR5 antagonists might select for such viruses. Moreover, there have been concerns that using CCR5 antagonists in patients with detectable D/M or X4 virus could enrich these viral populations.

To address these concerns, the safety of using maraviroc in patients with detectable D/M or X4 virus was assessed in a randomized, double-blind, phase IIb safety study, A4001029 (Capsule Summary).[10] Patients who were antiretroviral-experienced and/or had multiclass-resistant virus with detectable D/M or X4 virus at the time of screening received maraviroc (150 mg once or twice daily) or placebo, both with an OBR containing at least 1 active drug. There were approximately 60 patients in each arm.

The results of study A4001029 are summarized in Table 2. The study demonstrated no significant difference in change in mean plasma HIV-1 RNA level between the patients randomized to the 2 maraviroc groups or to placebo. By contrast, maraviroc was associated with a greater increase in CD4+ cell count at Week 24 than placebo, even among those patients who had only X4 virus detected at virologic failure. No major adverse events, including malignancies, were seen.

Table 2. HIV-1 RNA and CD4+ Cell Count Change in Patients With D/M or X4 Virus Treated With Maraviroc or Placebo

Although the clinical relevance of these data is not known, it suggests that CCR5 antagonism in patients with X4 or D/M virus is not associated with adverse immunologic outcomes. These results are not definitive, but they suggest that at least over the short term, there is little risk of harm if a CCR5 antagonist is inadvertently given to a patient who has D/M-tropic virus, although no virologic benefit of the CCR5 antagonist can be expected in this setting.

 

Maraviroc: Phase IIb/III Studies

Phase IIb/III Studies of Maraviroc in Treatment-Experienced Patients
In August 2007, the US Food and Drug Administration (FDA) approved maraviroc for use in multidrug-resistant patients with R5-only virus, based on 24-week data from the Maraviroc Plus Optimized Background Therapy in Viremic, ART-Experienced Patients (MOTIVATE) 1 and 2, parallel placebo-controlled phase IIb/III trials. Data from these studies were first presented at the 2007 Conference on Retroviruses and Opportunistic Infections (Capsule Summary).[4,5] MOTIVATE 1 (N = 601) was undertaken in Canada and the United States, and MOTIVATE 2 (N = 475) was performed predominantly in Europe and Australia.

Entry criteria for the study required that patients were triple‑class experienced and did not have detectable X4 or D/M virus by the phenotypic tropism assay at the time of screening. Other inclusion criteria included HIV-1 RNA ≥ 5000 copies/mL, a stable antiretroviral regimen before the study or no antiretroviral therapy for ≥ 4 weeks before enrollment, and resistance to and/or ≥ 6 months of experience with ≥ 1 agent from 3 antiretroviral classes or ≥ 2 PIs. The trial randomized patients either to placebo or to once-daily or twice-daily maraviroc at doses of 150 mg or 300 mg, all with OBR. Because maraviroc is a substrate for CYP450, there are significant drug-drug interactions with other PIs and NNRTIs that serve to increase or decrease the plasma concentration of maraviroc. Consequently, the once-daily or twice-daily 150-mg dose was used if patients were taking any ritonavir-boosted PI-based regimen or delavirdine. The 300-mg dose of maraviroc was used in those patients not receiving ritonavir or in those receiving tipranavir. The OBRs typically included 3-6 antiretroviral agents.

The patients were stratified by HIV-1 RNA < 100,000 or ≥ 100,000 copies/mL and enfuvirtide use. Patients were allowed to use all the available drugs; if they were prescribed efavirenz and nevirapine, they also had to be prescribed a PI. (It should be noted that darunavir was not yet available at the start of this trial.) The primary endpoint was change in HIV-1 RNA at Week 24. The trial is scheduled to continue through 48 weeks.

Baseline characteristics were well balanced across all groups, with median CD4+ cell counts between 150 and 182 cells/mm³; median baseline HIV-1 RNA was between 4.85 and 4.89 log10 copies/mL. Forty-two percent of patients included enfuvirtide as part of their OBRs. Forty-four percent of patients screened had detectable X4 or D/M-tropic virus and were, therefore, not eligible for the trial.

Maraviroc in combination with OBR demonstrated potent activity at each of the doses tested. At Week 24, there was an average decline in HIV-1 RNA of approximately 1.9 log10 copies/mL from baseline in both treatment arms compared with a reduction of 1 log10 copies/mL in the placebo plus OBR arm.

When analyzed for the proportion of patients with HIV-1 RNA < 400 copies/mL in an intent-to-treat, noncompleter-equals-failure analysis, results were very similar across both MOTIVATE 1 and 2, with approximately 60% of patients receiving maraviroc plus OBR achieving this endpoint vs approximately 30% in the placebo arms. There was a slight nonsignificant trend favoring the twice-daily vs once-daily maraviroc arm in this overall analysis. Likewise in both studies, approximately 40% to 50% of the maraviroc-treated patients achieved HIV-1 RNA < 50 copies/mL vs 20% to 25% in the placebo arms (Table 3). The twice-daily maraviroc dose performed slightly better than the once-daily dose but both were significantly better than placebo. The CD4+ cell count increase was also significantly higher in the maraviroc-treated arms than the placebo-treated arms.

Table 3. MOTIVATE 1 and 2: Results at Week 24[4,5]

In a pooled analysis of the 2 studies, stratified by the number of active agents in the OBR as measured by genotype/phenotype analysis at baseline, once-daily and twice-daily maraviroc doses were associated with higher rates of virologic suppression than placebo, except when there were ≥ 3 active agents in the OBR, which resulted in little difference between arms (Figure 1).

Figure 1. MOTIVATE 1 and 2: proportion of patients with HIV-1 RNA < 50 copies/mL stratified by number of active drugs in their OBRs.[4,5]

Slightly better efficacy was observed with twice-daily than with once-daily administration of maraviroc for specific patient subgroups with unfavorable treatment characteristics (Capsule Summary).[11] These subgroups included patients with HIV-1 RNA ≥ 100,000 copies/mL at screening, a CD4+ cell count < 50 cells/mm3 at baseline, or no active agents in the OBR. These results support the twice-daily administration of maraviroc, as indicated in the product labeling.

Among patients with treatment failure in whom the tropism assay was performed, the emergence of detectable D/M or X4 virus was more common among maraviroc than placebo recipients (~ 65% vs 5%, respectively). Using sensitive methods to further characterize baseline and emerging viral populations during therapy, investigators have shown that most D/M or X4 virus present at the time of virologic failure was likely to have pre-existed at low levels prior to the initiation of treatment [12] As noted earlier, one theoretical concern regarding CCR5 antagonist therapy is that selection for D/M-tropic virus in patients with treatment failure might be associated with accelerated CD4+ cell decline and disease progression, as seen in natural history studies. Although the current data are limited to only 24 weeks of follow-up, there was no evidence of a significant decline in CD4+ cell count in patients with treatment failure who had D/M or X4 virus at the time of the analysis.

Approximately 8% of patients initially found to be eligible for the study with R5-only virus at screening subsequently had D/M-tropic virus detected at baseline, before the initiation of maraviroc therapy. Although details have not been presented, investigators have commented that this subset of patients had a limited response to maraviroc therapy, similar to that seen in study A4001029 in patients with D/M-tropic virus.

In addition to the emergence of X4 or D/M virus, HIV-1 can also become resistant to maraviroc and other CCR5 antagonists. The mechanism for resistance to maraviroc has not been clearly defined, but it appears that the virus overcomes the steric hindrance related to drug binding and can use the receptor with maraviroc bound. In patients with R5-only virus who failed treatment, mutations were seen in the V3 loop, but no signature R5 mutations have been identified to date.

Maraviroc in Treatment-Naive Patients

Maraviroc has also been studied in treatment-naive patients in the Maraviroc vs Efavirenz Regimens as Initial Therapy (MERIT) study, a randomized, double-blind, multicenter phase IIb/III trial (Capsule Summary).[6] This study randomized antiretroviral-naive patients with detectable R5-only virus and HIV-1 RNA < 2000 copies/mL in a 1-to-1 fashion to receive maraviroc 300 mg twice daily or efavirenz 600 mg once daily, each combined with tenofovir and lamivudine. A third arm, maraviroc 600 mg once daily plus tenofovir and lamivudine, was discontinued at Week 16 by the data and safety monitoring board when it failed to meet criteria for noninferiority to efavirenz for the coprimary endpoint, HIV-1 RNA < 50 copies/mL.

Patients were well matched at baseline. Mean baseline HIV-1 RNA between the 2 groups was 4.87 log10 copies/mL, and the mean baseline CD4+ cell count was 247 cells/mm3.

The on-treatment noninferiority analysis included all patients who received ≥ 1 dose of study drug, with a noninferiority margin of -10% (lower bound of 1-sided 97.5% confidence interval). The primary endpoints were HIV-1 RNA < 400 and < 50 copies/mL at Week 48. At this time point, noninferiority of twice-daily maraviroc vs efavirenz was shown for the endpoint of HIV-1 RNA < 400 copies/mL (73.1% vs 70.6% [97.5% confidence interval lower bound -9.5%]) but not for the other primary endpoint of HIV-1 RNA < 50 copies/mL (69.3% vs 65.3% [97.5% confidence interval lower bound -10.9%]). Patients in the maraviroc arm had a significantly larger increase in CD4+ cell counts (170 vs 140 cells/mm3). Approximately 25% of patients in each arm discontinued, but the reasons for discontinuation were different: More patients in the efavirenz arm discontinued for adverse events (13.6%), and more in the maraviroc arm discontinued for lack of antiviral efficacy (11.9%).

Additional prespecified analyses evaluated HIV-1 RNA response based on baseline plasma HIV-1 RNA of < 100,000 or > 100,000 copies/mL, and whether the study site was in the Northern or Southern Hemisphere. Although it was reported that a significantly lower proportion of patients with a baseline HIV-1 RNA level > 100,000 achieved a plasma HIV-1 RNA of < 50 copies/mL compared with patients who had a baseline HIV-1 RNA level < 100,000 copies/mL, for reasons yet to be explained, most of the difference was observed in patients from the Southern Hemisphere.

Adverse Events With Maraviroc

In the MOTIVATE trials, there was no difference in the rate of adverse events between the maraviroc and placebo groups. Each group had the same low level of hepatotoxicity. With the CCR5 antagonists, there have concerns about the potential for hepatotoxicity, and one investigational CCR5 antagonist, aplaviroc, was withdrawn from development due to this adverse event. One case of maraviroc-induced hepatotoxicity with allergic features was reported in a study in healthy volunteers, and an increase in hepatic adverse events with maraviroc was observed during studies of treatment-experienced HIV-infected patients, although there was no overall increase in ACTG grade 3/4 liver function test abnormalities. Nevertheless, the complete prescribing information for maraviroc includes a black box warning about the potential for hepatotoxicity.

There was also no evidence of an increased incidence of malignancies, a potential concern raised by recent data on vicriviroc. In MOTIVATE 1 and 2, a total of 11 malignancies were reported: 3 cases of Kaposi’s sarcoma and 3 cases of lymphoma in the maraviroc arms, and 3 cases of Kaposi’s sarcoma and 2 cases of lymphoma in the placebo arms. In analyzing these safety data, one should remember that approximately 4 times as many patients were enrolled in the maraviroc arms as placebo, so the incidence of malignancies was lower in the maraviroc arms.

In the MERIT trial of treatment-naive patients, overall rates of adverse events and serious adverse events were similar in both arms, including a similar low incidence of hepatotoxicity. In this trial, malignancies also occurred at a lower rate in the maraviroc-treated patients: 2.8% vs 4.4% in the efavirenz-treated arm. Lipid elevations were more pronounced in the efavirenz arm.

 

Advantages and Disadvantages of CCR5 Antagonists

Based on the data currently available for treatment with CCR5 antagonists, there appear to be certain advantages and disadvantages associated with their use. At this time, efficacy data for these agents show a clear advantage over placebo in treatment-experienced individuals who have R5-only virus detected at entry. Indeed, there are numerous reasons to consider using CCR5 antagonists in the later stages of disease. There will likely be no cross-resistance with other available agents such as NRTIs, NNRTIs, PIs, or enfuvirtide. CCR5 antagonists seem to be well tolerated and are orally administered.

Despite these advantages, data have shown that treatment-experienced patients who are in later stages of disease are more likely to have D/M or X4 virus, a setting in which these drugs have not shown antiretroviral activity. For any individual patient, there may be only a specific window of opportunity to benefit from one of these agents while he or she has R5 virus only, with the chance that D/M or X4-only virus will emerge over time. By contrast, other classes of antiretroviral drugs typically only lose activity when agents from the class are used and resistance develops. It is important to recognize that although short-term safety has been demonstrated in studies to date, it remains possible that pharmacologic blockade of CCR5 may have adverse consequences that become apparent only after long-term use of these drugs. The safety aspects of these drugs as well as the consequences of resistance development need to be assessed with long-term use. There may also be the concern about the emergence of D/M or X4 virus with CCR5 antagonist therapy. Finally, use of these agents will require a test for viral tropism, incurring additional cost.

Integrase Inhibitors

Integrase inhibitors target the viral integrase enzyme, which plays a critical role in the viral life cycle, as discussed in the accompanying module by Daniel R. Kuritzkes, MD. Although integrase inhibitors focus on a novel target enzyme, the principle of enzyme inhibition has been the most commonly used mechanism of antiretroviral therapy. Therefore, evaluating response to these agents should be more straightforward than evaluating agents with other mechanisms of action.

The integrase inhibitors that are the furthest in clinical trial development are raltegravir (formerly MK-0518) and elvitegravir (formerly GS9137). Currently, phase III trials of raltegravir in treatment‑naive and treatment-experienced patients are ongoing, and at the time of writing is being considered by the US Food and Drug Administration (FDA) for approval for use in treatment-experienced patients. Elvitegravir is in phase II development for treatment‑experienced patients.

There are significant differences between these 2 compounds. Raltegravir is metabolized by glucuronidation; therefore, while there are interactions with drugs that are metabolized by the CYP450 system, interactions with that have been observed with other PIs and NNRTIs are not thought to be clinically relevant. By contrast, elvitegravir is metabolized by CYP3A4 and may therefore have significant interactions with other antiretrovirals including PIs, NNRTIs, and possibly CCR5 antagonists. Elvitegravir can be pharmacologically boosted with ritonavir, allowing once-daily dosing, whereas raltegravir must be administered twice daily.

 

Phase III Studies of Raltegravir in Treatment-Experienced Patients

The results of Blocking Integrase in Treatment Experienced Patients With a Novel Compound against HIV: MeRcK, MK-0518 (BENCHMRK)-1 and -2, two parallel phase III studies of the integrase inhibitor, raltegravir, were presented at the 2007 Conference on Retroviruses and Opportunistic Infections (Capsule Summary).[13,14] These studies were performed in Europe, Australia, and the Pacific Rim (BENCHMRK-1) and in North, Central, and South America (BENCHMRK-2). Inclusion criteria included genotypic or phenotypic resistance to ≥ 1 drug from the PI, NRTI, and NNRTI classes, and HIV-1 RNA > 1000 copies/mL. Patients were randomized 2 to 1 to receive raltegravir 400 mg twice daily or placebo, each combined with an OBR. The primary endpoint was the proportion of patients with HIV-1 RNA < 400 copies/mL at 16 weeks.

Baseline characteristics were similar across arms, with the exception of a greater racial diversity in the BENCHMRK-2 trial. Mean baseline CD4+ cell count across the arms ranged from 146-163 cells/mm³, and mean baseline HIV-1 RNA ranged from 32,000-48,000 copies/mL. Patients had a median previous treatment duration of 11-12 years of antiretroviral therapy and 12 previous agents.

Approximately 60% of patients in each treatment arm had a genotypic sensitivity score of 0 or 1 for the OBR. For the phenotype assay, it should be noted that in the baseline resistance assessment of the drugs in the OBR, patients were considered resistant to a drug if the fold-change in susceptibility to that drug exceeded the lower cutoff in the phenotypic assay. The lower cutoff marks the transition between full activity and reduced activity, rather than no activity, so drugs that had partial activity could have been assigned a score of 0; in other words, the phenotypic susceptibility scores could have slightly underestimated the activity of the OBR. Approximately 20% of patients were naive to enfuvirtide at study entry. When enfuvirtide was used in a previously enfuvirtide-naive patient, a score of 1 was added to the phenotypic susceptibility score. Phenotypic susceptibility testing for darunavir was not available at the study outset, so darunavir was also assigned an activity score of 1 when administered to a patient who had previously been darunavir naive. This approach may have overestimated the activity of darunavir in some patients. Approximately 25% of patients in BENCHMRK‑1 and nearly 50% in BENCHMRK‑2 were darunavir naive and received darunavir as part of their OBR.

The primary endpoint was the proportion of patients with HIV-1 RNA < 400 copies/mL at Week 16 in an intent-to-treat, missing data or noncompleter-equals-failure analysis. In both trials, 77% of patients receiving raltegravir plus OBR had HIV-1 RNA < 400 copies/mL at Week 16 compared with 41% and 43% of patients (in BENCHMRK-1 and BENCHMRK‑2, respectively) who received the OBR with placebo (P < .001 for comparison of raltegravir vs placebo) (Figure 3). Although 24-week data were also reported for some patients, it should be noted that not all patients had reached the 24-week time point at the time of this analysis.

Figure 3. BENCHMRK-1 and -2: proportion of patients with HIV-1 RNA < 400 copies/mL.[13,14]

The percentage of patients with HIV-1 RNA < 50 copies/mL at Week 16 was also reported. In an intent-to-treat, noncompleter-equals-failure analysis, 61% and 62% of patients in BENCHMRK-1 and BENCHMRK‑2, respectively, in the raltegravir plus OBR arm achieved this endpoint compared with 33% and 36%, respectively, in the placebo arm (P < .001 for comparison of raltegravir vs placebo) (Figure 4). The increase in CD4+ cell count at Week 16 was +83 and +86 cells/mm³ in the raltegravir arms in BENCHMRK-1 and BENCHMRK-2, respectively, compared with +31 and +40 cells/mm³, respectively, in the placebo arms (P < .001 for comparison of raltegravir vs placebo).

Figure 4. BENCHMRK-1 and -2: proportion of patients with HIV-1 RNA < 50 copies/mL.[13,14]

Adverse events in patients treated with raltegravir in the 2 studies were similar to placebo. There also did not appear to be an increased incidence of laboratory abnormalities when compared with the placebo arms.

A subset analysis of virologic efficacy in patients who had received enfuvirtide and/or darunavir for the first time as part of their background regimen was also reported. Among those who received both of these agents for the first time in combination with raltegravir (n = 44), 98% had HIV-1 RNA < 400 copies/mL at 16 weeks in a virologic failure–carried-forward analysis. It should be noted that these 44 subjects represent only a small subset (approximately 10%) of the patients treated with raltegravir in the 2 studies (Figure 5). Among those who received either enfuvirtide or darunavir (but not both) as a new agent combined with raltegravir, 90% achieved HIV-1 RNA < 400 copies/mL at 16 weeks. By contrast, 74% of raltegravir-treated patients who received neither enfuvirtide nor darunavir achieved viral suppression. These results illustrate the importance of combining 2-3 active agents into a new regimen rather than adding these agents in a stepwise fashion, and underscore the very real potential to regain virologic suppression in patients who are naive to 2 or more potent agents.

Figure 5. BENCHMRK-1 and -2: proportion of patients with HIV-1 RNA < 400 copies/mL by selected agents in OBR.[13,14]

In a combined analysis stratified by the number of active drugs in the OBR as determined by resistance testing, the virologic efficacy of raltegravir was especially evident in patients with genotypic or phenotypic sensitivity scores of 0 and 1. The high rates of viral suppression observed when raltegravir was given with an OBR for which the genotypic and phenotypic susceptibility scores were 0 suggest that raltegravir has considerable intrinsic activity, recognizing that some of the drugs in the OBR were likely to have partial activity. However, the 16‑week time point is relatively early, and it will be important to evaluate whether patients experience viral breakthrough during longer-term follow-up.

A total of 76 patients on raltegravir in the BENCHMRK trials (16%) experienced virologic failure. Genotype analyses were available for 41 of those who failed. Thirty two of the 41 had changes in the integrase gene that predominantly followed 1 of 2 pathways, characterized by the presence of either N155H or Q148K/R/H. In general, at least 2 mutations were present when resistance was observed at the time of virologic failure. There was no report on resistance to enfuvirtide, darunavir, or other components of the OBR in patients who experienced viral rebound on therapy or who failed to achieve undetectable HIV-1 RNA.

Use of Raltegravir in Treatment-Naive Patients

Protocol 004 is a phase II trial that randomized 203 treatment-naive patients to therapy involving 4 doses of raltegravir (100 mg, 200 mg, 400 mg, and 600 mg) combined with tenofovir plus lamivudine for 48 weeks, compared with a control arm receiving efavirenz, tenofovir, and lamivudine. By Week 24, approximately 80% of patients in each arm had HIV-1 RNA < 50 copies/mL, with no significant differences in response between any of arms (Capsule Summary).[15] This response was maintained through Week 48.[16]

Although there was no difference between the arms in rates of virologic suppression by Week 24, the reduction in viremia occurred more rapidly with raltegravir than with efavirenz. Viral decay observed in response to efavirenz was typical of that seen in other efavirenz trials. However, more than one half of patients in each of the raltegravir arms had HIV-1 RNA levels < 50 copies/mL by Week 4. A mathematical model of this response suggested that second-phase viral decay may be accelerated with raltegravir (Capsule Summary).[17] However, the clinical relevance of this rapid response (if any) has not been defined at this time.

Week 48 results showed similar rates of virologic suppression as seen at Week 24 in each of the arms (Table 5).[16] No raltegravir dose-related toxicities have been identified at this time. Lipid increases were observed with efavirenz but not with raltegravir.

Table 5. Raltegravir in Treatment-Naive Patients: Week 24 and 48 Results

Integrase Inhibitors: Advantages and Disadvantages

The advantages of agents in the integrase inhibitor class are clear. It is a novel class with no known cross‑resistance with other agents. The agents act synergistically in combination with approved agents, at least in vitro. They target the third essential enzyme of HIV. Finally, these drugs can be given orally.

Regarding disadvantages, there are no long‑term data on adverse effects since these agents are relatively new and relatively few patients have been treated to date. Virologic failure appears to be associated with a high likelihood of the emergence of resistance mutations. Moreover, available evidence, although limited to date, suggests that considerable cross-resistance exists between raltegravir and elvitegravir.[20,21] A recent case report described 2 patients who switched from elvitegravir/ritonavir to raltegravir after virologic failure, but experienced no significant reduction in HIV-1 RNA level (Capsule Summary).[22] It is clear that these drugs should be combined with an effective OBR to minimize the risk of resistance and potential cross‑resistance

Etravirine: Second-Generation NNRTI

Recent studies have demonstrated the efficacy of second-generation agents from existing classes that have been designed to retain activity against virus that is resistant to other drugs in that class. The POWER trials[23] and the RESIST trials[24] demonstrated the efficacy of the second-generation PIs darunavir/ritonavir and tipranavir/ritonavir in treatment-experienced patients with multiple protease mutations.

Etravirine is a second-generation NNRTI with demonstrated activity against a wide variety of NNRTI-resistant viruses.[25] In contrast to efavirenz or nevirapine, etravirine has a high genetic barrier to resistance in vitro, and multiple NNRTI resistance mutations are required before significant loss of susceptibility is observed.

In a phase IIb trial, study TMC125-C223, etravirine plus an OBR was associated with significantly greater rates of viral suppression than placebo plus an OBR in highly treatment-experienced patients with a history of at least 1 NNRTI resistance mutation and at least 3 primary protease mutations.[26]

The phase II TMC125-C227 trial compared etravirine vs a PI, each combined with NRTIs, in PI-naive patients with virologic failure on an initial regimen containing efavirenz or nevirapine.[27] Although the etravirine arm had an initial HIV-1 RNA reduction of about 1.5 log10 copies/mL at Week 8, this was not sustained, whereas the PI arm showed sustained viral suppression. Further analysis showed that patients with virologic failure had more NNRTI and NRTI resistance mutations than would be expected in a first-line failure population. A substantial proportion of patients was recruited from resource-limited countries, where these patients had been on their failing regimen for many months, which resulted in the accumulation of multiple NNRTI and NRTI resistance mutations. This study underscores the importance of prompt modification of a failing first-generation NNRTI regimen to avoid the accumulation of mutations that may compromise the activity of a second-generation agent.

The activity of etravirine when combined with active agents in treatment-experienced patients was confirmed by the phase III, randomized, double-blind, placebo-controlled DUET studies, which are evaluating the long-term efficacy, tolerability, and safety of etravirine vs placebo, each combined with a darunavir/ritonavir-containing OBR in treatment-experienced HIV-infected patients (Capsule Summary).[28-31] Inclusion criteria stipulated that the patients be on a stable but virologically failing regimen. The subjects were required to have HIV-1 RNA > 5000 copies/mL at screening, at least 1 documented NNRTI resistance–associated mutation (either at screening or from historical genotype reports), and at least 3 documented primary PI mutations. Patients were randomized in a 1-to-1 ratio to either etravirine (given in the new 200 mg twice-daily formulation) or to placebo, both in combination with darunavir/ritonavir (600/100 mg twice daily), and an investigator-selected OBR of at least 2 antiretroviral medications, consisting of NRTI(s) with or without enfuvirtide. Patients were also stratified by number of active agents in the OBR, enfuvirtide use in the OBR, baseline HIV-1 RNA, and previous darunavir use. The primary endpoint was the proportion of patients achieving HIV-1 RNA < 50 copies/mL at Week 24 by intention-to-treat, time-to-loss-of-virologic-response analysis. Secondary endpoints included proportion of patients with HIV-1 RNA < 400 copies/mL, change in HIV-1 RNA from baseline, change in CD4+ cell count from baseline, safety, and tolerability. Of note, this is the first study in treatment-experienced patients to use viral suppression to < 50 copies/mL as the primary endpoint, consistent with current guidelines that state that this endpoint is an achievable goal of therapy in this patient population.

A total of 612 patients were randomized in DUET-1 (304 in the etravirine group; 308 in the placebo group) and 591 patients were randomized in DUET-2 (295 in the etravirine group; 296 in the placebo group). Baseline characteristics were similar between the treatment groups and between the studies. The mean baseline HIV-1 RNA was approximately 4.8 log10 copies/mL, and the mean CD4+ cell count was approximately 100 cells/mm³. Approximately 65% of patients had ≥ 2 NNRTI mutations at baseline, and a similar proportion had ≥ 5 primary PI mutations. Approximately 5% of subjects were experienced with darunavir, and approximately one third of patients in DUET-1 and one half of patients in DUET-2 had previous experience with enfuvirtide.

A summary of the results of primary and secondary endpoints at Week 24 are shown in Table 6. Significantly more patients in the etravirine arm achieved HIV-1 RNA < 50 copies/mL after 24 weeks compared with those in the placebo group. Higher rates of virologic suppression were seen with etravirine, regardless of the number of active agents in the OBR. Relatively high rates of suppression were seen even among patients receiving etravirine with no active agent in OBR. The difference in virologic suppression between etravirine and placebo was particularly pronounced in those patients with 0 or 1 active agents in the OBR. A greater proportion of patients with a baseline HIV-1 RNA ≥ 100,000 copies/mL achieved HIV-1 RNA < 50 copies/mL in the etravirine arm vs the placebo arm in both DUET-1 (38% vs 27%) and DUET-2 (51% vs 24%). Of interest (and unexplained) is the nonsignificant difference in CD4+ cell count between the arms in DUET-2, although in DUET-1 the immunologic response was significantly superior among etravirine recipients.

Table 6. DUET-1 and -2: Primary and Secondary Endpoint Week 24 Analyses[28,30]

Response was also compared in patients who were enfuvirtide naive and used enfuvirtide in their background regimen (n = 153 in the etravirine arms; n = 160 in the placebo arms) vs those who did not use enfuvirtide or recycled it (n = 446 in the etravirine arms; n = 444 in the placebo arms). Among those who were reusing or not using enfuvirtide, more patients in the etravirine group achieved HIV-1 RNA < 50 copies/mL. Among those who were enfuvirtide naive, there was no significant difference in response to etravirine compared with placebo.

Adverse events were generally mild or moderate and were similar in frequency and severity between the etravirine and placebo groups. Rash was approximately twice as common in the etravirine group vs placebo (14% vs 9% in DUET-1; 20% vs 10% in DUET-2). There was no difference between the arms in the nature, frequency, or severity of neuropsychiatric events.

Etravirine Resistance
Among 406 NNRTI-experienced patients enrolled in the DUET trials, researchers identified 13 NNRTI mutations present at baseline that were associated with reduced response to etravirine¾V90I, A98G, L100I, K101E, K101P, V106I, V179D, V179F, Y181C, Y181I, Y181V, G190A, and G190S.[30] Of interest, K103N, which causes high-level resistance to both efavirenz and nevirapine, was not associated with reduced response to etravirine. The Y181C mutation that frequently occurs in patients failing nevirapine-based therapy was only associated with substantially reduced response to etravirine when accompanied by at least 2 other etravirine-associated mutations. The investigators observed an association between increasing number of etravirine resistance mutations and decreasing virologic response. Study participants with no more than 2 of the 13 identified mutations at baseline did not exhibit a reduced virologic response to etravirine. In subjects with 3 or more of the specified mutations at baseline, however, the rate of virologic response declined to a level similar to that observed in the placebo arm. Of the 406 NNRTI-experienced patients studied, 70% had none or only 1 of the 13 etravirine resistance mutations detected at baseline, and only 14% had 3 or more mutations.

How Will We Use New Agents in Treatment-Experienced Patients?

Maraviroc has been approved for use in treatment-experienced patients; therefore, candidates for therapy will typically be those with more advanced stages of disease who are more likely to have D/M or X4 virus, a setting in which CCR5 antagonists are likely to have reduced or no activity. Another challenge is that it will be difficult to consider switching to maraviroc as a replacement for other agents in patients whose HIV-1 RNA is suppressed, because testing for viral tropism requires detectable viremia. Therefore, maraviroc is most appropriate for the subset of treatment-experienced patients who are experiencing virologic failure on existing therapy, who have no detectable D/M or X4 virus on a screening test for viral tropism, and who have other active agents available to use as part of an OBR.

Individuals who are treatment naive, on the other hand, are less likely to have a D/M-tropic or X4 virus and, therefore, have a better chance of being candidates for CCR5 antagonist therapy. However, in the recently reported results of the MERIT trial, maraviroc failed to meet criteria for noninferiority to efavirenz for the primary endpoint of HIV-1 RNA < 50 copies/mL. Likewise, a trial of vicriviroc was halted because of inferior efficacy compared with efavirenz in treatment-naive patients. These data suggest that further investigation of the use of maraviroc and vicriviroc in treatment-naive patients maybe needed before they can be considered for use in this patient population

Integrase inhibitors will initially be used for treatment-experienced patients because the largest data sets involve this population of patients. Studies in treatment-naive individuals are also under way, and preliminary data certainly suggest that there may be a role for this class of drugs in these patients. Unlike CCR5 antagonists, there appear to be no specific considerations that argue for earlier or later therapy, since agents in this class should be effective regardless of when the agents are used. Dosing issues may affect the use of integrase inhibitors as initial therapy. For example, raltegravir, the drug that is in the most advanced stage of clinical development, is dosed twice daily whereas once‑daily options are generally favored in the earlier stages of disease and, indeed, throughout treatment. Although elvitegravir is a once-daily drug and can be given with ritonavir, the implications of the use of low-dose ritonavir without another PI must be considered. There is little experience with this particular situation, and the potential risk of selecting for PI resistance if virologic failure occurs must be explored in the future. Consistent with general principles, this class of drugs will be most active when used in conjunction with other active drugs. Therefore, strategic thinking is necessary when considering the introduction of novel drugs into treatment regimens. It is crucial to preserve as many active drugs as possible and to combine these with new drugs, hopefully enabling us to achieve undetectable HIV-1 RNA even in the most treatment‑experienced patients, as recommended in the US Department of Health and Human Services and the International AIDS Society-USA guidelines.

Etravirine, a new second-generation NNRTI, has demonstrated potent activity when combined with other active agents in patients who have experienced virologic failure while receiving efavirenz or nevirapine. Patients who may benefit most from this drug are those who stopped NNRTI-based therapy in the past after developing only 1 or 2 NNRTI resistance mutations, or patients who were not considered candidates for NNRTI-based therapy because of transmitted NNRTI-resistant virus. Those with a greater number of NNRTI mutations may derive less benefit from this agent. The recently reported mutation score may help in identifying which individual patients are most appropriate for this agent. Furthermore, the resistance data emphasize the importance of discontinuing the use of currently approved NNRTIs in a failing regimen to minimize the risk of accumulating multiple NNRTI resistance mutations and developing cross-resistance to next-generation agents. Finally, studies of etravirine have underscored the importance of having an adequate background regimen when using any new and potentially active drug.

Summary: Implications for Clinical Practice

  • Significant advances have been made in the development of new antiretroviral agents in existing and new classes that are active against drug-resistant HIV.
  • These drugs have demonstrated enhanced rates of virologic response when combined with other fully and/or partially active agents.
  • Nevertheless, in treatment-experienced patients, the ability to achieve the goal of undetectable HIV-1 RNA is often limited by the lack of other active drugs to combine in a new regimen. This obstacle has recently been diminished by the availability of new agents that exploit novel targets in the viral life cycle, such as entry and integrase inhibitors.
  • The phase IIb/III MOTIVATE trials of maraviroc in treatment-experienced patients with R5 virus demonstrated superior virologic and immunologic efficacy for maraviroc plus OBR vs placebo plus OBR at Week 24. Both once-daily or twice-daily doses were tested. Safety and tolerability of this agent was similar to placebo; although there were some patients who had D/M or X4 virus on failure, this virus was shown to be present at baseline.
  • The MERIT trial of maraviroc vs efavirenz, both with tenofovir plus lamivudine, was not able to demonstrate noninferiority of maraviroc for percentage of patients with suppression of HIV-1 RNA to < 50 copies/mL at Week 48. Noninferiority was demonstrated for HIV-1 RNA < 400 copies/mL. Results of this trial indicate that maraviroc will not immediately be considered for use in treatment-naive patients but will require further investigation.
  • ACTG 5211, a phase IIb trial in treatment-experienced patients, has demonstrated superiority of another CCR5 antagonist, vicriviroc, compared with placebo, each combined with an OBR. A greater number of malignancies occurred in the vicriviroc-treated arm than in the placebo arm but it is unclear that the malignancies are related to vicriviroc use. Patients are now being recruited for phase III trials of vicriviroc in the treatment-experienced population.
  • Trials of 2 integrase inhibitors, raltegravir and elvitegravir, have yielded results in treatment-experienced patients in 2007. A trial of raltegravir in treatment-naive patients has also reported 48-week results.
  • The phase III BENCHMRK trials of raltegravir in treatment-experienced patients demonstrated greater virologic and immunologic efficacy at Week 16 for raltegravir vs placebo, each combined with an OBR. Safety and tolerability were similar to placebo.
  • Raltegravir has also been studied in treatment-naive patients. The phase II Protocol 004 has compared several doses of raltegravir vs efavirenz, each with tenofovir and lamivudine. At Week 48, similar proportions of patients treated with all doses of raltegravir or efavirenz achieved HIV-1 RNA < 50 copies/mL. Safety and tolerability were similar to efavirenz.
  • Week 24 results were reported for a phase II trial of elvitegravir/ritonavir vs comparator PI, each combined with an OBR, in treatment-experienced patients. In the primary endpoint analysis, both of the higher doses of elvitegravir/ritonavir—50/100 mg or 125/100 mg—were shown to be noninferior to comparator PIs.
  • Genotypic data from patients with virologic failure taking raltegravir and elvitegravir, albeit limited, have indicated that there is considerable cross-resistance between these 2 drugs at failure. This may mean that it will not be possible to sequence these 2 integrase inhibitors.
  • Etravirine, a second-generation NNRTI which is active against many virus variants that are resistant to efavirenz and nevirapine, has demonstrated superior efficacy vs placebo, each combined with a darunavir/ritonavir-based OBR, in a pair of phase III trials in treatment-experienced patients, DUET-1 and -2. This new agent, available in expanded access, can be used as an active agent with integrase inhibitors and entry inhibitors to build regimens in multidrug-resistant patients.

References

1. US Department of Health and Human Services. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Available at: http://aidsinfo.nih.gov/guidelines/GuidelineDetail.aspx?MenuItem=Guidelines&Search=Off&GuidelineID=7&ClassID=1. Accessed August 13, 2007.

2. Hammer S, Saag M, Schechter M, et al. Treatment for adult HIV infection: 2006 recommendations of the International AIDS Society-USA panel. JAMA. 2006;296:827-843.

3. Norris D, Morales J, Godofsky E, Garcia F, Hardwicke R, Lewis S. TNX-355, in combination with OBR, achieves statistically significant HIV-1 RNA reduction and CD4 cell count increase when compared with OBR alone in phase II study at 48 weeks. Program and abstracts of the 16th International AIDS Conference; August 13-18, 2006; Toronto, Canada. Abstract THLB0218. (Capsule Summary)

4. Lalezari J, Goodrich J, DeJesus E, et al. Efficacy and safety of maraviroc plus optimized background therapy in viremic, ART-experienced patients infected with CCR5-tropic HIV-1: 24-week results of a phase 2b/3 study in the US and Canada. Program and abstracts of the 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles, California. Abstract 104bLB. (Capsule Summary)

5. Nelson M, Fätkenheuer G, Konourina I, et al. Efficacy and safety of maraviroc plus optimized background therapy in viremic, ART-experienced patients infected with CCR5-tropic HIV-1 in Europe, Australia, and North America: 24-week results. Program and abstracts of the 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles, California. Abstract 104aLB. (Capsule Summary)

6. Saag M, Ive P, Heera J, et al. A multicenter, randomized, double-blind, comparative trial of a novel CCR5 antagonist, maraviroc vs efavirenz, both in combination with Combivir (zidovudine [ZDV]/lamivudine [3TC]), for the treatment of antiretroviral naive patients infected with R5 HIV 1: Week 48 results of the MERIT study. Program and abstracts of the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract WESS104. (Capsule Summary)

7. Gulick R, Su Z, Flexner C, et al. ACTG 5211: phase II study of the safety and efficacy of vicriviroc (VCV) in HIV-infected treatment-experienced subjects: 48-week results. Program and abstracts of the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract TUAB102. (Capsule Summary)

8. Greaves W, Landovitz R, Fatkenheuer G, et al. Late virologic breakthrough in treatment-naïve patients on a regimen of Combivir + vicriviroc. Program and abstracts of the 13th Conference on Retroviruses and Opportunistic Infections; February 5-8, 2006; Denver, Colorado. Abstract 161LB. (Capsule Summary)

9. Koot M, Keet IP, Vos AH, et al. Prognostic value of HIV-1 syncytium-inducing phenotype for rate of CD4+ cell depletion and progression to AIDS. Ann Intern Med. 1993;118:681-688.

10. Mayer H, van der Ryst E, Saag M, et al. Safety and efficacy of maraviroc (MVC), a novel CCR5 antagonist, when used in combination with optimized background therapy (OBT) for the treatment of antiretroviral-experienced subjects infected with dual/mixed-tropic HIV-1: 24-week results of a phase 2b exploratory trial. Program and abstracts of the 16th International AIDS Conference; August 13-18, 2006; Toronto, Canada. Abstract THLB0215. (Capsule Summary)

11. Gulick RM, van der Ryst E, Lampiris H, et al. Efficacy and safety of once-daily (QD) compared with twice-daily (BID) maraviroc plus optimized background therapy (OBT) in treatment-experienced patients infected with CCR5-tropic-HIV-1: 24-week combined analysis of the MOTIVATE 1 and 2 studies. Program and abstracts of the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract WEPEB116LB. (Capsule Summary)

12. Lewis M, Simpson P, Fransen S, et al. CXCR4-using virus detected in patients receiving maraviroc in the phase III studies MOTIVATE 1 and 2 originates from a pre-existing minority of CXCR4-using virus. Program and abstracts of the 16th International HIV Drug Resistance Workshop; June 12-16, 2007; Barbados, West Indies. Abstract 56.

13. Cooper D, Gatell J, Rockstroh J, et al. Results of BENCHMRK-1, a phase III study evaluating the efficacy and safety of MK-0518, a novel HIV-1 integrase inhibitor, in patients with triple-class resistant virus. Program and abstracts of the 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles, California. Abstracts 105aLB. (Capsule Summary)

14. Steigbigel R, Kumar P, Eron J, et al. Results of BENCHMRK-2, a phase III study evaluating the efficacy and safety of MK-0518, a novel HIV-1 integrase inhibitor, in patients with triple-class resistant virus. Program and abstracts of the 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles, California. Abstracts 105bLB. (Capsule Summary)

15. Markowitz M, Nguyen B-Y, Gotuzzo F, et al. Potent antiretroviral effect of MK-0518, a novel HIV-1 integrase inhibitor, as part of combination ART in treatment-naive HIV-1 infected patients. Program and abstracts of the 16th International AIDS Conference; August 13-18, 2006; Toronto, Canada. Abstract THLB0214. (Capsule Summary)

16. Markowitz M, Nguyen B-Y, Gotuzzo F, et al. Rapid and durable antiretroviral effect of the HIV-1 integrase inhibitor raltegravir as part of combination therapy in treatment-naive patients  with HIV-1 infection: results of a 48-week controlled study week data. J Acquir Immune Defic Syndr. 2007 Aug 23; [epub ahead of print]

17. Murray JM, Emery S, Kelleher A, et al. The integrase inhibitor raltegravir alters viral decay kinetics of HIV, significantly reducing the second phase and challenging current hypotheses of viral replication. Program and abstracts of the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract TUAB103. (Capsule Summary)

18. DeJesus E, Berger D, Markowitz M, et al. Antiviral activity, pharmacokinetics, and dose response of the HIV-1 integrase inhibitor GS-9137 (JTK-303) in treatment-naive and treatment-experienced patients. J Acquir Immune Defic Syndr. 2006;43:1-5.

19. Zolopa A, Mullen M, Berger D, et al. The HIV integrase inhibitor GS-9137 demonstrates potent antiretroviral activity in treatment-experienced patients. Program and abstracts of the 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles, California. Abstract 143LB. (Capsule Summary)

20. Hazuda DJ, Miller MD, Nguyen BY, Zhao J. Resistance to the HIV-integrase inhibitor raltegravir: analysis of protocol 005, a phase II study in patients with triple-class-resistant HIV-1 infection. Program and abstracts of the 16th International HIV Drug Resistance Workshop; June 12-16, 2007; Barbados, West Indies. Abstract 8.

21. McColl DJ, Fransen S, Gupta S, et al. Resistance and cross-resistance to first-generation integrase inhibitors: insights from a phase II study of elvitegravir (GS-9137). Program and abstracts of the 16th International HIV Drug Resistance Workshop; June 12-16, 2007; Barbados, West Indies. Abstract 9.

22. DeJesus E, Cohen C, Elion R, et al. First report of raltegravir (RAL, MK-0518) use after virologic rebound on elvitegravir (EVT, GS 9137). Program and abstracts of the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract TUPEB032. (Capsule Summary)

23. Clotet B, Bellos N, Molina JM, et al. Efficacy and safety of darunavir-ritonavir at week 48 in treatment-experienced patients with HIV-1 infection in POWER 1 and 2: a pooled subgroup analysis of data from two randomised trials. Lancet. 2007;369:1169-1178.

24. Hicks CB, Cahn P, Cooper DA, et al. Durable efficacy of tipranavir-ritonavir in combination with an optimised background regimen of antiretroviral drugs for treatment-experienced HIV-1-infected patients at 48 weeks in the Randomized Evaluation of Strategic Intervention in multidrug reSistant patients with Tipranavir (RESIST) studies: an analysis of combined data from two randomised open-label trials. Lancet. 2006;368:466-475.

25. Vingerhoets J, Azijn H, Fransen E, et al. TMC125 displays a high genetic barrier to the development of resistance: evidence from in vitro selection experiments. J Virol. 2005;79:12773-12782.

26. Cohen C, Steinhart C, Ward D, et al. Efficacy and safety results at 48 weeks with the novel NNRTI, TMC125, and impact of baseline resistance on the virologic response in study TMC125-C223. Program and abstracts of the 16th International AIDS Conference; August 13-18, 2006; Toronto, Canada. Abstract TUPE0061.

27. Woodfall B, Vingerhoets J, Peeters M, et al. Impact of NNRTI and NRTI resistance on the response to the regimen of TMC125 plus two NRTIs in study TMC125-C227. Program and abstracts of the 8th International Congress on Drug Therapy in HIV Infection; November 12-16, 2006; Glasgow, Scotland. Abstract PL5.6.

28. Mills A, Cahn P, Grinsztejn B, et al. DUET-1: 24 week results of a phase III randomised double-blind trial to evaluate the efficacy and safety of TMC125 vs placebo in 612 treatment-experienced HIV-1 infected patients. Program and abstracts of the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract WESS204-1. (Capsule Summary)

29. Madruga JV, Cahn P, Grinsztejn B, et al. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-1: 24-week results from a randomised, double-blind, placebo-controlled trial. Lancet. 2007;370:29-38.

30. Katlama C, Campbell T, Clotet B, et al. DUET-2: 24-week results of a phase III randomised double-blind trial to evaluate the efficacy and safety of TMC125 vs placebo in 591 treatment-experienced HIV-1 infected patients. Program and abstracts of the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract WESS204-2.

31. Lazzarin A, Campbell T, Clotet B, et al. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-2: 24-week results from a randomised, double-blind, placebo-controlled trial. Lancet. 2007;370:39-48.

 

Regards,

Nelson Vergel
powerusa dot org



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#1160 From: "nedinsd" <nedinsd@...>
Date: Sat Sep 22, 2007 2:53 pm
Subject: Re: Fuzeon massager. 		nedinsd
Offline Offline
Send Email Send Email
  
We have a Fuzeon Support group here in San Diego that meets every two
months to trade tips on lessening the adverse effects.

      Using a 31ga 1/2 in.insulin needle instead of the 27ga 1 in.
   included in the kit makes a big difference.  I use just the 30ga
needle tips and swap them out on the mixing 23ga mixing needle. Your
Dr. might have to write Rx for new needles or okay it over the phone
with the pharmacy

      Use of the massager before and after injection for a few minutes.

      Use hot compresses before and after (wet wash cloth in a zip-lock
bag microwaved 15-20 sec. or Thermawrap as Wes mentioned)

      When inserting needle, positioning angle cut of needle tip facing
up

      Mixing 2 or 3 at a time and refrigerating the standbys, warming
them in the waistband of your pants, shorts, boxers. Mixing a new one
and rotating premixed and newly mixed as you go.

      Hope some of these tips help.  I will pass on more as they come.
Nurse Connections is a really good resource and advocate.

Good health,
Ned




> Ramon said:
>    "I just got my fuzeon monthly prescription filled. The company
gave me a
> massager. Is there something about using this for the fuzeon bumps?"
>
>
> Yes the massager is suppose to help disperse the fuzeon to help
reduce the injection site reactions (ISR's). I have been using it ever
since I started it about 2 years ago. The "Fuzeon Nurse Educator"
http://www.fuzeon.com/2100NurseConnections.aspx gave it to  me when he
came to show me how to to the injections. It does seem to help to some
degree.
>
> I use some ThermaCare heat wraps to help those stuborn ISR that just
won't go away.
>
> Wes
> ,_._,___
>
>
>
>
________________________________________________________________________________\
____
> Be a better Heartthrob. Get better relationship answers from someone
who knows. Yahoo! Answers - Check it out.
> http://answers.yahoo.com/dir/?link=list&sid=396545433
>

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#1159 From: pozrangr@...
Date: Sat Sep 22, 2007 7:57 am
Subject: Has anybody heard... 		pozrangr
Offline Offline
Send Email Send Email
 
Hi Group:
 
   Has anyone heard about any new developments which will make Fuzeon easier to administer? I ran into a person who told me they were,working on once a month dosing which seems unlikely. Any news for me? Thanks, Ricky in Michigan



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#1158 From: PoWeRTX@...
Date: Thu Sep 20, 2007 8:27 pm
Subject: Fuzeon made Prezista work better even in the presence of Prezista resistance 		PoWeRTX@...
Send Email Send Email
 
Comment: fold change over 40 usually means decreased sensitivity to Prezista (Darunavir). The fold change is the ratio of drug required to control 50% of the (more resistant) virus compared to the amount of drug required to control 50% of wild type (drug sensitive) virus. More on fold change here: http://www.monogramhiv.com/assays/hcp/phenoHIVReport.aspx
 
Too bad this good drug (Fuzeon) is an injectable...
 
 

Baseline Darunavir Sensitivity Does Not Predict Response to Boosted Ritonavir plus Enfuvirtide in Triple-class-experienced Patients: BLQ Study Final Results

Prior studies have suggested that baseline phenotypic resistance to darunavir (Prezista), or fold change in sensitivity, may predict virological response in antiretroviral-experienced patients treated with ritonavir-boosted darunavir plus enfuvirtide (Fuzeon, T-20).

The present analysis, presented at the 47th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) this week in Chicago, assessed the impact of baseline darunavir fold change and other variables on virological response to regimens containing darunavir/ritonavir plus enfuvirtide.

In this prospective, 24-week, open-label, safety and efficacy study, 142 highly treatment-experienced patients received 90 mg twice-daily enfuvirtide plus 600/100 mg twice-daily darunavir/ritonavir with optimized background treatment. Participants had previously taken NRTIs, NNRTIs, and protease inhibitors, but not enfuvirtide.

Of 142 patients enrolled, 140 were included in the safety population and 131 were included in the intention-to-treat (ITT) population (> 1 post-baseline assessment). 11 patients were excluded from the analysis due to missed post-baseline assessments. At baseline, the mean HIV RNA level was 4.69 log copies/mL and the mean CD4 cell count was 162 cells/mm3.

Logistic regression methods were used to assess the relationship of baseline darunavir fold change, genotypic sensitivity score, and CD4 count to Week 24 virological response. Darunavir fold change was defined using standard EC50 scores (50% of the maximum effective drug concentration).

Results

• 4 patients withdrew prematurely for safety reasons (1 non-treatment-related death; 2 adverse event or disease related; 1 due to enfuvirtide injection site reactions).

• At Week 24, in an ITT analysis (n = 131), 60.3% of the patients achieved a viral load below 50 copies/mL and 72.5% had a viral load below 400 copies/mL.

• Among those with a darunavir fold change < 10 (n = 88), the corresponding percentages were 63.6% below 50 copies/mL and 78.4% below 400 copies/mL.

• Among those with a darunavir fold change > 10 but <40 (n = 19), the corresponding percentages were 57.9% and 84.2%.

• Among those with a darunavir fold change > 40 (n = 8), the corresponding percentages were 62.5% and 75.0%.

• Logistic stepwise regression analysis showed that patients with a CD4 count ? 100 cells/mm3 were more likely to achieve a viral load below 50 copies/mL (P = 0.020) or below 400 c/mL (P = 0.015) relative to those with lower CD4 counts.

Conclusion

Based on these findings, the researchers concluded, "The use of darunavir/ritonavir with enfuvirtide and optimized background therapy in highly antiretroviral-experienced patients naive to these two drugs resulted in high levels of virologic responses that appear to persist even in those pts with baseline darunavir fold change > 40."

Orlando Immunology Ctr., Orlando, FL; AIDS Health Care Foundation, Los Angeles, CA; Synergy Hematology Oncology, Los Angeles, CA; Therapeutic Concepts, Houston, TX; Roche Laboratories, Nutley, NJ; Stanford University, Stanford, CA.

09/18/07

Reference
E DeJesus, C Farthing, M Gottlieb and others. Response to Darunavir/Ritonavir (DRV/r) Combined with Enfuvirtide (ENF)-containing ARV in Triple-Class Experienced Patients was not Predicted by Baseline DRV Sensitivity: The BLQ Study Final Results. 47th Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago, September 17-20, 2007. Abstract H-367.


 

Regards,

Nelson Vergel
powerusa dot org



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#1157 From: PoWeRTX@...
Date: Thu Sep 13, 2007 9:49 am
Subject: KP-1461 		PoWeRTX@...
Send Email Send Email
 

Regards,

Nelson Vergel
powerusa dot org



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KP-1461: Novel agent enters phase 2a proof-of-concept study by Jeff Berry

A new type of drug which is based on a completely different approach to treating HIV than those currently on the market began enrollment in late June for a Phase 2a proof-of-concept study.

The drug, KP-1461, is a mutagen, or a drug that causes mutations. This can be a scary term for some people because you want to make sure that the drug selects for the virus and does not promote mutations in other types of cells, but tests so far have shown it to be safe and generally well tolerated in humans.

This is a small, open-label study of 32 HIV-positive individuals to see whether the drug has activity against the virus in humans. Each study participant will receive the same amount of drug (the dose being studied is 1,600 mg, currently four pills twice-daily). Individuals who are already triple-class resistant and have more than 250 T-cells will receive KP-1461 monotherapy for four months. People interested in joining the study should not go off their therapy, but rather they are looking for those who have already decided for whatever reason to be off drug for at least 16 weeks.

KP-1461 works through a process called Viral Decay Acceleration (VDA), which in the test tube increases the mutation rate of the virus, leading to impaired viral function and eventual collapse of the viral population. VDA has been trademarked by the company developing the drug, Koronis. Stephen Becker, M.D., Chief Medical Officer for Koronis, explains that resistance mutations usually occur in response to drug therapy which inhibits reverse transcriptase or protease, or to the selective pressure of the immune system on the virus.

“It’s almost counter-intuitive, because in the HIV world we’ve lived in up until now, mutations are ‘bad’ things, and now we are talking about a drug that induces mutations, and ‘hyper-mutates’ the virus. So it’s a completely different phenomenon, but when you understand that HIV, like other viruses such as hepatitis B and C, sort of teeters on the brink, if you give it too many mutations it doesn’t survive, then this makes sense. When you take a viral load measurement, most of what we’re measuring is dead virus. HIV has got a lot of dead virus, it’s amazing how much damage it does with so little fully infective progeny. It wreaks havoc with a relatively small volume of live virus. It probably doesn’t take many mutations to collapse HIV or other viral populations that live on the edge.

“If you think of the success of the viral population as being more live births than deaths, just like any other population, if we create a viral population where fitness is impaired to non-viability, and we have a population that is no longer able to produce more infective virions than those that are ineffective, or dead, then that population will collapse. And what that could mean for the HIV-infected patient is that the viral population could collapse, and that the virus could be eradicated.”

Of course we’ve heard the term eradication before, and you’re not going to hear Dr. Becker say that this can cure HIV, because in his words that would be “unfair and far overreaching to say that.” But in vitro (in cell cultures) the drug extinguishes the virus in 14 serial passages, and this could translate to 4-8 weeks of therapy in humans. “If it works in HIV-infected individuals the way it works in the test tube, we think it could eradicate infection. That would distinguish it markedly from other anti-HIV therapies, which as you well know inhibit a viral protein or a viral enzyme, or they inhibit entry into the cell. But those drugs are just inhibitors, they don’t extinguish virus. So the shift in the paradigm would be huge if this in fact works in vivo the way it works in vitro. And I don’t know the answer to that yet, but that’s the purpose of the Phase 2 proof-of-concept study that we’ve just begun.”

While it’s still too early to tell, if this drug is ultimately proven to work in humans, whether or not it would be best used in combination with other drugs, as monotherapy, or even as a “pulsed” therapy remains to be seen. Theoretically it could even be used in someone who has a high CD4+ T-cell count who doesn’t need to start therapy, but could possibly delay the time to when that person would ultimately have to begin therapy.

If you are interested in joining this trial or would like to learn more about KP-1461, contact Jeff Parkins, Koronis Director of Operations at (425) 825-0240, ext. 214, or visit www.clinicaltrials.gov. If you are in Chicago, contact Northstar Healthcare at (773) 296-2400.


Reply | Forward | Messages in this Topic (1)
#1156 From: ramoninez@...
Date: Sun Sep 9, 2007 1:53 pm
Subject: Re: Fuzeon massager. 		ramoninez@...
Send Email Send Email
  
thank you very much for the info. I started to use it after a warm bath
and it seems to work.

Ramon


-----Original Message-----
From: Wes <spruce5@...>
To: FuzeonSupport@yahoogroups.com
Sent: Sat, 8 Sep 2007 11:28:45 -0700 (PDT)
Subject: [FuzeonSupport] Fuzeon massager.























             ----- Original Message ----
From: "ramoninez@..." <ramoninez@...>
To: FuzeonSupport@yahoogroups.com
Sent: Friday, September 7, 2007 11:20:03 PM
Subject: Re: [FuzeonSupport] LUNCH AND LEARN LECTURE IN ATLANTA- SEPT 17

Ramon said:
   "I just got my fuzeon monthly prescription filled. The company gave
me a
massager. Is there something about using this for the fuzeon bumps?"

 
Yes the massager is suppose to help disperse the fuzeon to help reduce
the injection site reactions (ISR's). I have been using it ever since I
started it about 2 years ago. The "Fuzeon Nurse Educator"
http://www.fuzeon.com/2100NurseConnections.aspx gave it to  me when he
came to show me how to to the injections. It does seem to help to some
degree.
 
I use some ThermaCare heat wraps to help those stuborn ISR that just
won't go away.
 
Wes
,_._,___




------------------------------------------------------------
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Reply | Forward | Messages in this Topic (3)
#1155 From: Wes <spruce5@...>
Date: Sat Sep 8, 2007 6:28 pm
Subject: Fuzeon massager. 		spruce5
Offline Offline
Send Email Send Email
 
----- Original Message ----
From: "ramoninez@..." <ramoninez@...>
To: FuzeonSupport@yahoogroups.com
Sent: Friday, September 7, 2007 11:20:03 PM
Subject: Re: [FuzeonSupport] LUNCH AND LEARN LECTURE IN ATLANTA- SEPT 17
Ramon said:
   "I just got my fuzeon monthly prescription filled. The company gave me a
massager. Is there something about using this for the fuzeon bumps?"
 
Yes the massager is suppose to help disperse the fuzeon to help reduce the injection site reactions (ISR's). I have been using it ever since I started it about 2 years ago. The "Fuzeon Nurse Educator" http://www.fuzeon.com/2100NurseConnections.aspx gave it to  me when he came to show me how to to the injections. It does seem to help to some degree.
 
I use some ThermaCare heat wraps to help those stuborn ISR that just won't go away.
 
Wes
,_._,___


Got a little couch potato?
Check out fun summer activities for kids.

Reply | Forward | Messages in this Topic (3)
#1154 From: PoWeRTX@...
Date: Sat Sep 8, 2007 9:31 am
Subject: Re: LUNCH AND LEARN LECTURE IN ATLANTA- SEPT 17 		PoWeRTX@...
Send Email Send Email
 
In a message dated 9/8/2007 1:51:39 AM Central Daylight Time, ramoninez@... writes:
I just got my fuzeon monthly prescription filled. The company gave me a
massager. Is there something about using this for the fuzeon bumps?

ramon
 It realkly helps, specially if you take a hot shower before it



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Reply | Forward | Messages in this Topic (3)
#1153 From: ramoninez@...
Date: Sat Sep 8, 2007 3:20 am
Subject: Re: LUNCH AND LEARN LECTURE IN ATLANTA- SEPT 17 		ramoninez@...
Send Email Send Email
  
I just got my fuzeon monthly prescription filled. The company gave me a
massager. Is there something about using this for the fuzeon bumps?

ramon


-----Original Message-----
From: PoWeRTX@...
To: fuzeinfo@yahoogroups.com
Cc: fuzeonsupport@yahoogroups.com; salvagetherapies@yahoogroups.com
Sent: Fri, 7 Sep 2007 5:17 pm
Subject: [FuzeonSupport] LUNCH AND LEARN LECTURE IN ATLANTA- SEPT 17



























I will be
speaking at the  lunch and learn program sponsored by POSITIVE IMPACT
(http://new.positiveimpact-atl.org) on September
17 from noon to 2 pm at the Grady Infectious Disease Program. The topic
will be
:
How to Survive HIV Resistance : Effective Use of Emerging HIV
Therapies

The
address is 341 Ponce de Leon Ave, Atlanta,
GA 30308.
 Pre-registration will
be required.  Individuals should call Positive Impact at 404-589-9040
to
pre-register prior to September 14
 

Regards,

Nelson Vergel
powerusa dot
org


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________________________________________________________________________
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Reply | Forward | Messages in this Topic (3)
#1152 From: PoWeRTX@...
Date: Fri Sep 7, 2007 5:17 pm
Subject: LUNCH AND LEARN LECTURE IN ATLANTA- SEPT 17 		PoWeRTX@...
Send Email Send Email
 

I will be speaking at the  lunch and learn program sponsored by POSITIVE IMPACT (http://new.positiveimpact-atl.org) on September 17 from noon to 2 pm at the Grady Infectious Disease Program. The topic will be :

How to Survive HIV Resistance : Effective Use of Emerging HIV Therapies

The address is 341 Ponce de Leon Ave, Atlanta, GA 30308.

 Pre-registration will be required.  Individuals should call Positive Impact at 404-589-9040 to pre-register prior to September 14

 

Regards,

Nelson Vergel
powerusa dot org



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Reply | Forward | Messages in this Topic (3)
#1151 From: Nelson Vergel <nelsonvergel@...>
Date: Wed Aug 29, 2007 4:51 pm
Subject: tmc 125 warning 		nelsonvergel
Offline Offline
Send Email Send Email
  
f you are thinking about obtaining TMC 125 (Etravirine, a new non
nucleoside yet to be approved) via Tibotec's expanded access program
(EAP) and you have developed resistance to non nucleosides in the past
(Sustiva, Viramune, Rescriptor), be aware that it is very difficult to
know if TMC 125 will work for your virus since the mutations that
predict its efficacy may not be present in your genotype. Non
nucleoside old mutations are "archived" and may not show up in your
current genotype or phenotype tests. In fact, many people with past non
nucleoside resistance show complete sensitivity to nucleosides years
after developing resistance and not using that drug class. Doctors
sometimes try to go to old charts to see if they can pull old genotype
tests that can give them an indication that TMC 125 may be a good
option for the patient. In most instances, that information is not
found. We are also learning that TMC 125 specific mutations were not
included in genotype tests years ago, so looking for old patient charts
may be a moot subject.

My advise is that if you are going to
start TMC 125, make sure that you are not gambling about assuming drug
sensitivity, so NEVER start it with only one fully active agent but
TWO. This will assure that you have enough of an active background for
viral suppression and sustained response in case that you may not have
sensitivity to TMC 125.

Possible combinations :

No
resistance to Prezista but resistance to Fuzeon: Darunavir (Prezista) +
TMC 125 + Raltegravir (Merck integrase available via expanded access as
of Aug 2007) + nukes (approved agents + two EAPs)

If you have
resistance to Prezista and Fuzeon and have an R5 tropic virus:
Maraviroc+ TMC 125+ Raltegravir + nukes (approved agents + two EAPs)

If you do not have resistance to Fuzeon or Prezista:  Fuzeon + TMC 125 +
Prezista + nukes ( all approved agents + one EAP)

If you have resistance to Prezista but not Fuzeon:  Fuzeon + TMC 125 +
raltegravir (approved agents plus two EAPs)

If
you do not have a R5 only tropic virus and have resistance to Fuzeon
and Prezista: TMC 125 + raltegravir + ???...you may want to wait

If you have resistance to Prezista, Fuzeon, and have a R5 tropic virus: TMC 125
+ Maraviroc + ?? you may want to wait

Message:
a new agent may not be an active agent, so be cautious and combine
agents in such a way that you do not take too many chances.

Regards,
Nelson Vergel
powerusa dot org

Reply | Forward | Messages in this Topic (1)
#1150 From: "Rob" <mntwister@...>
Date: Tue Aug 7, 2007 3:07 am
Subject: Is there any benifit for those with duo-tropic 		mntwister
Offline Offline
Send Email Send Email
  
I have read of this new drug boosting t-cells somewhat better than
others. Has anything been said about its effect on people with CCR5 and
4 (duo tropic) or any studies? I also heard that if the virus changes
completely to using CXCR4, that is a more lethal entry for the virus.

Reply | Forward | Messages in this Topic (1)
#1149 From: PoWeRTX@...
Date: Tue Aug 21, 2007 3:18 pm
Subject: Fwd: NATAP: Monogram Trofile Assay Availability 		nelsonvergel
Offline Offline
Send Email Send Email
 
I hear this test costs $1700 !
 
It takes 3 weeks to get the results
Everyone considering starting maraviroc (Selzentry) needs to get the test
 
I wonder how ADAP systems will pay for this.
 
 
NATAP http://natap.org/
_______________________________________________


Monogram Biosciences Introduces New Co-Receptor Tropism Assay, Trofile™

August 20, 2007

Dear Friends,

On August 6, 2007, the FDA approved Selzentry™ (maraviroc), the first in a new oral class of HIV medicines in more than ten years. This important new approach to treating HIV stops the virus before it enters uninfected CD4 cells by blocking the CCR5 co-receptor, one of two viral entry points.

The FDA points out several important considerations in Selzentry's indication label:
o     Selzentry has been approved for use in combination with other antiretroviral agents for treatment-experienced adult patients who have HIV-1 strains resistant to multiple antiretroviral agents
o     Selzentry is indicated for patients infected with CCR5-tropic HIV-1
o     The drug's antiviral efficacy has not been demonstrated in patients with dual/mixed or CXCR4-tropic HIV-1
o     Tropism testing and treatment history should guide the use of Selzentry

With Selzentry's approval, Monogram has launched our latest HIV diagnostic, the Trofile™ co-receptor tropism assay. Trofile is a highly accurate patient-selection tropism assay that determines which co-receptor an individual's HIV strain uses to enter healthy CD4 cells. Trofile was used to select patients for the pivotal trials leading up to maraviroc's approval, and is being used in all clinical trials of CCR5 antagonists currently in development. Trofile is the only co-receptor tropism assay currently available.

Because Trofile is necessary to select which patients should be prescribed Selzentry, access to the assay is paramount. We take very seriously our charge to make Trofile available so that anyone living with HIV will have the ability to determine whether they are a candidate for Selzentry.

To that end, we have been working directly with insurers and payors to provide reimbursement as quickly as possible. Because this technology is so new, many insurance plans are in the process of setting new policies in order to cover the test. Monogram will work with each patient regarding coverage and reimbursement. For those without insurance, there are multiple programs in place in order to help gain access to Monogram's assays. Information is available through Monogram's Gateway Line at 1-877-436-6243.

Trofile results are reported to the treating physician, and typically take about 14 days from the date Monogram receives a patient's blood sample. Trofile does not replace other laboratory tests. Because Selzentry is to be used in combination with other antiretroviral agents, Trofile's results should be used in conjunction with those of other tests to evaluate an optimized background therapy.

Trofile is now accessible in advance of Selzentry's availability in the pharmacy, so those patients who are good candidates for Selzentry can begin treatment as soon as possible.  Trofile can be ordered directly through Monogram Biosciences at a list price of $1,960. Coverage for molecular tests can take time.  Monogram will work with all physicians and patients and take receipt of patient samples as we work with each payor to determine coverage and reimbursement.  We understand the need for broad access in HIV care and believe our sample collection and billing model meets the concerns of all patients.

We will have more information about Trofile and its use coming your way shortly as well as online at: www.trofileassay.com. Provided there is strong enough interest within the community, we will be hosting a virtual tropism meeting for HIV treatment advocates, allowing you to remotely log on, ask questions and learn more about Trofile, HIV tropism, and what they mean for those living with and treating HIV. If you have any questions in the meantime, please don't hesitate to contact our Virology team at 1-800-777-0177.

Yours truly,
William Young
CEO, Monogram Biosciences

About Trofile
Trofile is a patient selection co-receptor tropism assay that determines which co-receptor a patient's HIV strain or strains use for viral entry- CCR5, CXCR4, or a combination of CCR5 and CXCR4. These “cellular gateways” that a particular HIV strain uses to gain entry into a healthy CD4+ cell is known as the patients “tropism”.  Trofile amplifies a patient's HIV genome (from their blood sample) to make HIV particles specific to that individual patient. The resultant HIV particles are then used to infect CCR5- and CXCR4-expressing cell lines. Once the virus infects the cell and undergoes its single round of replication, a reporter gene expresses its indicator gene (luciferase), giving a visible signal-thus identifying the patient's viral tropism. Viral load must be at least 1000 copies/mL to determine a patient's viral tropism.

About Monogram Biosciences, Inc.
Monogram is advancing individualized medicine by discovering, developing and marketing innovative products to guide and improve treatment of serious infectious diseases and cancer. The Company's products are designed to help doctors optimize treatment regimens for their patients that lead to better outcomes and reduced costs. The Company's technology is also being used by numerous biopharmaceutical companies to develop new and improved antiviral therapeutics and vaccines as well as targeted cancer therapeutics. More information about the Company and its technology can be found on its web site at www.monogrambio.com.



 
Regards,

Nelson Vergel
Program for Wellness Restoration
PoWeRUSA dot org


“I had rather attempt something great and fail, than to attempt nothing at all and succeed.” R. Schuller



Get a sneak peek of the all-new AOL.com.
NATAP http://natap.org/
_______________________________________________
Monogram Biosciences Introduces New Co-Receptor Tropism Assay, Trofile™

August 20, 2007

Dear Friends,

On August 6, 2007, the FDA approved Selzentry™ (maraviroc), the first in a new oral class of HIV medicines in more than ten years. This important new approach to treating HIV stops the virus before it enters uninfected CD4 cells by blocking the CCR5 co-receptor, one of two viral entry points.

The FDA points out several important considerations in Selzentry's indication label:
o     Selzentry has been approved for use in combination with other antiretroviral agents for treatment-experienced adult patients who have HIV-1 strains resistant to multiple antiretroviral agents
o     Selzentry is indicated for patients infected with CCR5-tropic HIV-1
o     The drug's antiviral efficacy has not been demonstrated in patients with dual/mixed or CXCR4-tropic HIV-1
o     Tropism testing and treatment history should guide the use of Selzentry

With Selzentry's approval, Monogram has launched our latest HIV diagnostic, the Trofile™ co-receptor tropism assay. Trofile is a highly accurate patient-selection tropism assay that determines which co-receptor an individual's HIV strain uses to enter healthy CD4 cells. Trofile was used to select patients for the pivotal trials leading up to maraviroc's approval, and is being used in all clinical trials of CCR5 antagonists currently in development. Trofile is the only co-receptor tropism assay currently available.

Because Trofile is necessary to select which patients should be prescribed Selzentry, access to the assay is paramount. We take very seriously our charge to make Trofile available so that anyone living with HIV will have the ability to determine whether they are a candidate for Selzentry.

To that end, we have been working directly with insurers and payors to provide reimbursement as quickly as possible. Because this technology is so new, many insurance plans are in the process of setting new policies in order to cover the test. Monogram will work with each patient regarding coverage and reimbursement. For those without insurance, there are multiple programs in place in order to help gain access to Monogram's assays. Information is available through Monogram's Gateway Line at 1-877-436-6243.

Trofile results are reported to the treating physician, and typically take about 14 days from the date Monogram receives a patient's blood sample. Trofile does not replace other laboratory tests. Because Selzentry is to be used in combination with other antiretroviral agents, Trofile's results should be used in conjunction with those of other tests to evaluate an optimized background therapy.

Trofile is now accessible in advance of Selzentry's availability in the pharmacy, so those patients who are good candidates for Selzentry can begin treatment as soon as possible.  Trofile can be ordered directly through Monogram Biosciences at a list price of $1,960. Coverage for molecular tests can take time.  Monogram will work with all physicians and patients and take receipt of patient samples as we work with each payor to determine coverage and reimbursement.  We understand the need for broad access in HIV care and believe our sample collection and billing model meets the concerns of all patients.

We will have more information about Trofile and its use coming your way shortly as well as online at: www.trofileassay.com. Provided there is strong enough interest within the community, we will be hosting a virtual tropism meeting for HIV treatment advocates, allowing you to remotely log on, ask questions and learn more about Trofile, HIV tropism, and what they mean for those living with and treating HIV. If you have any questions in the meantime, please don't hesitate to contact our Virology team at 1-800-777-0177.

Yours truly,
William Young
CEO, Monogram Biosciences

About Trofile
Trofile is a patient selection co-receptor tropism assay that determines which co-receptor a patient's HIV strain or strains use for viral entry- CCR5, CXCR4, or a combination of CCR5 and CXCR4. These “cellular gateways” that a particular HIV strain uses to gain entry into a healthy CD4+ cell is known as the patients “tropism”.  Trofile amplifies a patient's HIV genome (from their blood sample) to make HIV particles specific to that individual patient. The resultant HIV particles are then used to infect CCR5- and CXCR4-expressing cell lines. Once the virus infects the cell and undergoes its single round of replication, a reporter gene expresses its indicator gene (luciferase), giving a visible signal-thus identifying the patient's viral tropism. Viral load must be at least 1000 copies/mL to determine a patient's viral tropism.

About Monogram Biosciences, Inc.
Monogram is advancing individualized medicine by discovering, developing and marketing innovative products to guide and improve treatment of serious infectious diseases and cancer. The Company's products are designed to help doctors optimize treatment regimens for their patients that lead to better outcomes and reduced costs. The Company's technology is also being used by numerous biopharmaceutical companies to develop new and improved antiviral therapeutics and vaccines as well as targeted cancer therapeutics. More information about the Company and its technology can be found on its web site at www.monogrambio.com.




**************************************
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Reply | Forward | Messages in this Topic (1)
#1148 From: PoWeRTX@...
Date: Tue Aug 14, 2007 9:30 am
Subject: Fwd: NATAP: T20-No Lipid/mtDNA Changes Healthy Volunteers 		nelsonvergel
Offline Offline
Send Email Send Email
 
In a message dated 8/14/2007 5:28:53 A.M. Central Daylight Time, nataphcvhiv@... writes:
NATAP http://natap.org/
_______________________________________________


Lack of metabolic abnormalities and mitochondrial toxicity with enfuvirtide (T-20):
a double-blind, placebo-controlled, crossover study with random sequence assignation in healthy adult volunteers

Reported by Jules Levin
9th Intl Workshop on Adverse Drug Reactions and Lipodystrophy in HIV
July 2007, Sydney, Australia

MC Villarroel, E Martinez, N Riba, A Leon, M Manrique, M Larrousse, JL Blanco, J Mallolas, X Carne, JM Gatell
Hospital Clinic, University of Barcelona
Barcelona, SPAIN

BACKGROUND
Some NRTI and PI have been associated with mitochondrial toxicity that may induce organ-specific diseases including lipoatrophy and metabolic abnormalities such as hyperlipidemia and insulin resistance that result in an increased risk for cardiovascular disease.

Enfuvirtide (T-20) is the first fusion inhibitor available for salvage combination therapy. Local reactions at the injection site have represented its major toxicity. No major systemic adverse effects have been reported so far.
Because the target and the chemical structure of enfuvirtide are different from those ones of the NRTI and PI, we hypothesized that enfuvirtide therapy would not trigger mitochondrial and metabolic toxicities associated with some NRTI and PI.

AUTHOR CONCLUSION
The administration of short-term enfuvirtide to healthy volunteers was not associated with lipid or glucose abnormalities or mitochondrial toxicity.

Overall Safety
Blood cells and chemistry and urine chemistry were within normal ranges and serologies for HIV and hepatitis B and C, and screening for abuse drugs were negative for all volunteers that completed the study.

Injection site reactions were the most common adverse events during the study (n=125, 88%), but all of them mild.

There were 17 (12%) adverse events other than injection site reactions, including headache, odinophagia and other minor flu-like symptoms.
None of adverse events led to drug discontinuation or required any intervention.

PARTICIPANTS
Eligible volunteers had to be males between 18 and 45 years, without a history of drug abuse, and without abnormal blood cell and chemistry tests at entry. Negative plasma serologies for HIV, hepatitis B and C viruses and lack of detection of abuse drugs in urine were also required at entry.

Written informed consent was obtained from all eligible volunteers before selection visit.

Volunteers were randomized in a 1:1 fashion to receive one of the following sequences: enfuvirtide+placebo or placebo+enfuvirtide.

The study was done at the Phase I Unit of Hospital Clínic (Barcelona, Spain).

DESIGN
Volunteers recd WHO diets consisting of 50-60% carbohydrates, 30-50% fat and 10-15% protein. Medication (T20) administered sc every 12 hrs at hospital. Fasting blood analyses included total cholesterol, OGTT, TG, HDL & LDL cholsesterol, PBMC mtDNA.

1 WHO diet consisting of 50-60% carbohydrates, 30-35% fat and 10-15% protein
2 Medication administered sc every 12h at hospital
3 Including glucose, total & HDL- & LDL-cholesterol, triglycerides, 2h OGTT, creatinine, urea, AST/ALT, GGT, bilirubin, ALP, proteins, lactate, Na, K, Ca, and P

OUTCOMES
Major outcome: change in fasting plasma total cholesterol.

Secondary outcomes were changes in LDL-cholesterol, HDL-cholesterol, triglycerides, oral glucose tolerance test, lactate, and mitochondrial DNA.

Safety end-points included any clinical adverse events or abnormal laboratory tests. The adverse events were graded according to the World Health Organization score. Causality was assessed following a standard algorithm.
Injection site reactions were particularly assessed according to persistent pain and discomfort at the injection site, size of the indurations and erythema.

Statistical analysis
Available data suggest that the intraindividual variability of fasting normal plasma total cholesterol is expected to be lower than 10%. Therefore, we assumed that an increase equal to or higher than 25 mg/dL of the total cholesterol in persons with normal plasma values would be considered as an evidence of a real increase. We estimated that 12 volunteers would be needed to detect an increase in fasting plasma total cholesterol ≥ 25 mg/dL with a one-side alpha of 0.025 and a power of 80%.

Mean and standard deviation were used to report normally distributed variables. In case of non-normal distribution we used median and interquartile range. A t-test was used to assess any carryover effect, and an ANOVA test to evaluate the effects of the period, sequence and treatment.

All statistical analyses were done with the STATA package (StataCorp 2005. Release 9.2. College Station, TX).

STUDY POPULATION
202 candidates were invited to participate in the study.

77 received verbal information about the study.

36 accepted to come for the screening visit.

22 finally came. Five volunteers were excluded at the screening visit for any of the following reasons: psychiatric illness (n=1), evidence of drug abuse (n=2), abnormal total cholesterol (n=1), and abnormal bilirubin (n=1).

17 volunteers were included in the study.

15 received at least one dose of study medication and these volunteers were evaluated for safety.

12 volunteers completed the study with 100% compliance and they were evaluated for efficacy.

RESULTS

TOTAL CHOLESTEROL


LDL cholesterol


HDL CHOLESTEROL


TRIGLYCERIDES


LACTATE


ORAL GLUCOSE TOLERANCE TEST


PBMC MITOCHONDRIAL DNA



 
Regards,

Nelson Vergel
Program for Wellness Restoration
PoWeRUSA dot org


“I had rather attempt something great and fail, than to attempt nothing at all and succeed.” R. Schuller



Get a sneak peek of the all-new AOL.com.
NATAP http://natap.org/
_______________________________________________
Lack of metabolic abnormalities and mitochondrial toxicity with enfuvirtide (T-20):
a double-blind, placebo-controlled, crossover study with random sequence assignation in healthy adult volunteers

Reported by Jules Levin
9th Intl Workshop on Adverse Drug Reactions and Lipodystrophy in HIV
July 2007, Sydney, Australia

MC Villarroel, E Martinez, N Riba, A Leon, M Manrique, M Larrousse, JL Blanco, J Mallolas, X Carne, JM Gatell
Hospital Clinic, University of Barcelona
Barcelona, SPAIN

BACKGROUND
Some NRTI and PI have been associated with mitochondrial toxicity that may induce organ-specific diseases including lipoatrophy and metabolic abnormalities such as hyperlipidemia and insulin resistance that result in an increased risk for cardiovascular disease.

Enfuvirtide (T-20) is the first fusion inhibitor available for salvage combination therapy. Local reactions at the injection site have represented its major toxicity. No major systemic adverse effects have been reported so far.
Because the target and the chemical structure of enfuvirtide are different from those ones of the NRTI and PI, we hypothesized that enfuvirtide therapy would not trigger mitochondrial and metabolic toxicities associated with some NRTI and PI.

AUTHOR CONCLUSION
The administration of short-term enfuvirtide to healthy volunteers was not associated with lipid or glucose abnormalities or mitochondrial toxicity.

Overall Safety
Blood cells and chemistry and urine chemistry were within normal ranges and serologies for HIV and hepatitis B and C, and screening for abuse drugs were negative for all volunteers that completed the study.

Injection site reactions were the most common adverse events during the study (n=125, 88%), but all of them mild.

There were 17 (12%) adverse events other than injection site reactions, including headache, odinophagia and other minor flu-like symptoms.
None of adverse events led to drug discontinuation or required any intervention.

PARTICIPANTS
Eligible volunteers had to be males between 18 and 45 years, without a history of drug abuse, and without abnormal blood cell and chemistry tests at entry. Negative plasma serologies for HIV, hepatitis B and C viruses and lack of detection of abuse drugs in urine were also required at entry.

Written informed consent was obtained from all eligible volunteers before selection visit.

Volunteers were randomized in a 1:1 fashion to receive one of the following sequences: enfuvirtide+placebo or placebo+enfuvirtide.

The study was done at the Phase I Unit of Hospital Clínic (Barcelona, Spain).

DESIGN
Volunteers recd WHO diets consisting of 50-60% carbohydrates, 30-50% fat and 10-15% protein. Medication (T20) administered sc every 12 hrs at hospital. Fasting blood analyses included total cholesterol, OGTT, TG, HDL & LDL cholsesterol, PBMC mtDNA.

1 WHO diet consisting of 50-60% carbohydrates, 30-35% fat and 10-15% protein
2 Medication administered sc every 12h at hospital
3 Including glucose, total & HDL- & LDL-cholesterol, triglycerides, 2h OGTT, creatinine, urea, AST/ALT, GGT, bilirubin, ALP, proteins, lactate, Na, K, Ca, and P

OUTCOMES
Major outcome: change in fasting plasma total cholesterol.

Secondary outcomes were changes in LDL-cholesterol, HDL-cholesterol, triglycerides, oral glucose tolerance test, lactate, and mitochondrial DNA.

Safety end-points included any clinical adverse events or abnormal laboratory tests. The adverse events were graded according to the World Health Organization score. Causality was assessed following a standard algorithm.
Injection site reactions were particularly assessed according to persistent pain and discomfort at the injection site, size of the indurations and erythema.

Statistical analysis
Available data suggest that the intraindividual variability of fasting normal plasma total cholesterol is expected to be lower than 10%. Therefore, we assumed that an increase equal to or higher than 25 mg/dL of the total cholesterol in persons with normal plasma values would be considered as an evidence of a real increase. We estimated that 12 volunteers would be needed to detect an increase in fasting plasma total cholesterol ≥ 25 mg/dL with a one-side alpha of 0.025 and a power of 80%.

Mean and standard deviation were used to report normally distributed variables. In case of non-normal distribution we used median and interquartile range. A t-test was used to assess any carryover effect, and an ANOVA test to evaluate the effects of the period, sequence and treatment.

All statistical analyses were done with the STATA package (StataCorp 2005. Release 9.2. College Station, TX).

STUDY POPULATION
202 candidates were invited to participate in the study.

77 received verbal information about the study.

36 accepted to come for the screening visit.

22 finally came. Five volunteers were excluded at the screening visit for any of the following reasons: psychiatric illness (n=1), evidence of drug abuse (n=2), abnormal total cholesterol (n=1), and abnormal bilirubin (n=1).

17 volunteers were included in the study.

15 received at least one dose of study medication and these volunteers were evaluated for safety.

12 volunteers completed the study with 100% compliance and they were evaluated for efficacy.

RESULTS

TOTAL CHOLESTEROL


LDL cholesterol


HDL CHOLESTEROL


TRIGLYCERIDES


LACTATE


ORAL GLUCOSE TOLERANCE TEST


PBMC MITOCHONDRIAL DNA




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#1147 From: PoWeRTX@...
Date: Wed Aug 15, 2007 10:09 am
Subject: Re: Not Eating with new agents 		nelsonvergel
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Here is your answer about TMC 125 food requirements
 
 
 
 
Prezista gets absorbed better with food
 
 
MK 518 (raltegravir) does not have food requirements
 
 
 
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#1146 From: "Rob" <mntwister@...>
Date: Wed Aug 15, 2007 9:00 am
Subject: Not Eating with new agents 		mntwister
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I started, 30 days ago, on Prezista, TMC125 and MK0518 (int.
inhibitor).  I have taken all of these at 10:30 on the dot every day
(give or take 15 minutes). Yesterday, something popped into my mind
about taking one of these without food. Is this true? I seem to
remember being told this at the meetings when I signed up for the
trial, but according to the internet, what I am finding is that all are
OK with food. If this is true, I am worried that I have harmed my new
regimin, and what I should do....any suggestions on this?

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#1145 From: PoWeRTX@...
Date: Mon Aug 13, 2007 9:27 pm
Subject: Selzentry Information 		nelsonvergel
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Overview of New FDA-approved Entry Inhibitor Maraviroc (Selzentry)

http://www.hivandhepatitis.com/hiv_and_aids/selzentry_maraviroc.html

Brand Name: Selzentry
Generic Name: Maraviroc
Drug Class: Entry and Fusion Inhibitors (CCR5 antagonist)

Maraviroc (Selzentry) is a chemokine receptor antagonist that acts as an HIV entry inhibitor. It is designed to prevent HIV infection of CD4 T cells by blocking chemokine receptor 5 (CCR5), a co-receptor necessary for HIV to enter cells, from binding to HIV.

• Introduction
• Dosing Information
• Pharmacology
• Adverse Events

• Food and Drug Interactions
• Clinical Trials
• Manufacturer Information
• Sources		 • Patient Information
• Medication Guide
• Prescribing Information
 HIV and AIDS - Top New Articles
Monogram Biosciences Launches New "Trofile" HIV Co-receptor Tropism Test to Select Patients Eligible to Use CCR5 Antagonist Maraviroc (Selzentry)
Recent Studies Show HIV RNA Below 50 Copies/mL Should Be the Goal for Both Treatment-naive and Treatment-experienced Patients (AIDS)
 
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#1144 From: PoWeRTX@...
Date: Mon Aug 13, 2007 9:31 pm
Subject: More on Maraviroc (Selzentry) 		nelsonvergel
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Drug Watch

FDA Approval: Maraviroc

The CCR5 antagonist maraviroc is an important new option for treatment-experienced patients — as long as they harbor CCR5-tropic virus.

Background:
On August 6, 2007, the FDA granted accelerated approval for the CCR5 antagonist maraviroc, making it the first approved agent in this drug class.

Indications:
Maraviroc is indicated for treatment-experienced patients who have (1) detectable HIV RNA, (2) evidence of resistance to multiple antiretrovirals, and (3) infection with CCR5-tropic virus. This last criterion requires that patients undergo pretreatment testing with a viral tropism assay, which is currently offered by only one company (Monogram Biosciences). Although the test (Trofile) has been used previously in clinical trials of CCR5 antagonists, it did not become commercially available until maraviroc was approved. Approximately one half of all patients with highly drug-resistant virus are expected to have CCR5-tropic virus and, hence, will be candidates for maraviroc treatment.

Maraviroc’s approval was based primarily on favorable 24-week results from the MOTIVATE studies, which were presented initially at this year’s Retrovirus Conference (ACC Apr 2 2007). In these two identical studies, a total of 1076 triple-class–experienced patients with CCR5-tropic virus at screening received an optimized background regimen plus either placebo, once-daily maraviroc, or twice-daily maraviroc. At 24 weeks, approximately twice as many maraviroc recipients as placebo recipients had undetectable viral loads, and maraviroc treatment also induced a significantly greater mean CD4-cell response. No clinically important differences were observed in the safety and tolerability of maraviroc versus placebo; notably, malignancy incidence was similar in the study arms. Patients who experienced virologic failure during maraviroc treatment often had selection for CXCR4-tropic virus; however, such selection was not associated with any short-term adverse clinical or immunologic consequences.

Maraviroc is not approved for treatment-naive patients. However, as presented at this year’s IAS Conference on HIV Pathogenesis, Treatment and Prevention (Abstract WESS104), more than 700 treatment-naive patients have been randomized to receive AZT/3TC plus either maraviroc or efavirenz. At 48 weeks, 65% of the maraviroc arm and 69% of the efavirenz arm had viral loads <50 copies/mL. Although these virologic response rates were similar, noninferiority could not be established (the lower bound of the 97.5% confidence interval for a 4% difference was 10.9%, which crossed the study-specified threshold for noninferiority). However, maraviroc was associated with a significantly greater CD4-cell response than was efavirenz (mean, 170 vs. 143 cells/mm3).

Pharmacology and dosing:
Maraviroc is available as 150-mg and 300-mg tablets; it is given twice daily, with or without food. Because maraviroc is metabolized in the liver by cytochrome P450 3A (CYP3A), dosing will vary depending on coadministered drugs. Specifically, dosing should be provided as follows:

  • 150 mg twice daily when given with CYP3A inhibitors (with or without a CYP3A inducer), such as PIs (except ritonavir-boosted tipranavir); delavirdine; ketoconazole, itraconazole, or clarithromycin; or other strong CYP3A inhibitors (e.g., nefazadone, telithromycin)
  • 600 mg twice daily when given with potent CYP3A inducers (without a strong CYP3A inhibitor), including efavirenz, etravirine, rifampin, carbamazepine, phenobarbital, and phenytoin
  • 300 mg twice daily when given with other concomitant medications, including ritonavir-boosted tipranavir, nevirapine, all NRTIs, and T-20

Importantly, as noted above, when maraviroc is given with both a potent inhibitor and an inducer — such as the combination of ritonavir-boosted darunavir plus etravirine — then the net effect is inhibition, and the proper dose is 150 mg twice daily.

Although metabolized by the cytochrome P450 system, maraviroc does not inhibit or induce the activity of these enzymes to any clinically relevant degree. According to the package insert, during drug-interaction studies, maraviroc had no clinically relevant effect on the pharmacokinetics of midazolam or of the oral contraceptives ethinylestradiol and levonorgestrel; it also had no effect on the urinary 6ß-hydroxycortisol/cortisol ratio. Together, these findings suggest that the drug does not induce CYP3A in vivo.

Adverse effects:
As noted above, in the MOTIVATE studies, maraviroc had a comparable safety and tolerability profile to placebo. In the study of treatment-naive patients, the maraviroc groups had lower rates of discontinuations due to adverse effects than did the placebo group and also had more favorable lipid profiles.

Cost and availability:
According to Pfizer, maraviroc will be in pharmacies by mid-September 2007. The wholesale cost for either the 150-mg or the 300-mg twice-daily dose is US$29 daily or $870 monthly. The turnaround time for receiving results of the Trofile assay is likely to be similar to the time for receiving results of a resistance phenotype assay (approximately 3 weeks).

Comment: Remarkably, maraviroc is the first oral HIV treatment to become available in a new drug class since 1996, when nevirapine was approved as the first NNRTI. As demonstrated in the MOTIVATE studies, maraviroc greatly augments treatment response when it is given to patients who harbor CCR5-tropic virus that is multidrug-resistant. In addition, maraviroc appears to have a very favorable safety profile, and, thus far, inadvertent selection of CXCR4-tropic virus (which is a consequence of the tropism assay not identifying low levels of such virus at baseline) has not had serious adverse consequences. As with other agents approved for use in this patient population, the likelihood of treatment success will be increased greatly when maraviroc is combined with other active drugs. These regimens will likely include various combinations of darunavir, tipranavir, and T-20 (among approved drugs) and etravirine and raltegravir (among expanded-access drugs).

— Paul E. Sax, MD

Published in AIDS Clinical Care August 10, 2007

 
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Nelson Vergel
Program for Wellness Restoration
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#1143 From: PoWeRTX@...
Date: Mon Aug 13, 2007 9:45 am
Subject: High response rate with enfuvirtide plus darunavir regardless of existing protea 		nelsonvergel
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High response rate with enfuvirtide (Fuzeon) plus darunavir (Prezista) regardless of existing protease inhibitor resistance
Tuesday, August 07, 2007
Almost two-thirds (64%) of 3-class treatment-experienced patients achieved undetectable HIV viral load (<50 copies/mL) at 24 weeks.

Interim results from BLQ (Below the Level of Quantification), an ongoing study evaluating the use of the injectable fusion inhibitor enfuvirtide (Fuzeon, T-20) with the recently-approved ritonavir-boosted oral protease inhibitor (PI) darunavir (Prezista), in combination with other anti-HIV drugs, showed that almost two-thirds (64%) of 3-class treatment-experienced patients achieved undetectable HIV viral load (<50 copies/mL) at 24 weeks. In addition, baseline sensitivity to darunavir did not appear to influence patient response.

Preliminary results of the BLQ study were presented by Andrew Zolopa, MD, of Stanford University in a poster discussion session at the recent 4th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention in Sydney, Australia (July 22-25, 2007).

Co-developed by Roche and Trimeris, enfuvirtide is the first and only fusion inhibitor commercially available for the treatment of HIV, and is also the sole approved drug in the entry inhibitor class. Ritonavir-boosted darunavir, an oral PI approved for use in treatment-experienced HIV patients, was developed by Tibotec Therapeutics. The BLQ study was sponsored by Roche and Trimeris. Patients received darunavir predominantly through co-enrollment in the darunavir compassionate use program.

"Previous studies had provided encouraging - but limited - information on the use of enfuvirtide in combination with darunavir/ritonavir," said Edwin DeJesus, MD, of the Orlando Immunology Center. "Given that attaining undetectable HIV of less than 50 copies has become the standard of care even in treatment-experienced patients, it is encouraging that so many patients can achieve this result with enfuvirtide and darunavir/ritonavir - 2 agents widely available to patients and physicians today. Even patients with significant resistance to darunavir responded well to this combination."

The BLQ Study

The BLQ study is a prospective, open-label, 24-week, single-arm, multicenter, cohort study conducted in the United States and Australia. The trial was designed to explore the impact of baseline variables - including darunavir phenotypic sensitivity (prior drug resistance) - on virological responses in highly treatment-experienced patients receiving regimens containing enfuvirtide and darunavir/ritonavir.

Patients received the approved dosages of enfuvirtide and darunavir/ritonavir, along with other anti-HIV drugs selected on the basis of individual treatment history and resistance testing.

This protocol-defined interim analysis was conducted when the first half of the total enrolled participants completed their week 24 assessments. Of 63 eligible patients enrolled, 62 had taken at least 1 dose of study medication and a safety follow-up at day 7, and were included in the safety analysis.

A total of 58 patients who received at least 1 dose of study medication and received at least 1 post-baseline efficacy assessment at week 4 were included in the intent-to-treat (ITT) efficacy analysis; 5 were excluded due to missed post-baseline assessments.

Results

• At 24 weeks, 64% of patients achieved undetectable HIV viral load less than 50 copies/mL.

• 78% of patients achieved undetectable HIV less than 400 copies/mL.

• 86% of patients achieved a viral load reduction of at least 1 log10.

• The mean reduction in HIV RNA was 2.39 log10.

• When virological response was analyzed as a function of patients' baseline phenotypic sensitivity to darunavir, the percentages of patients achieving less than 50 copies/mL were similar in the 3 groups of patients:

- 67% undetectable for patients with a low levels of resistance (fold change of less than 10);

- 70% undetectable for patients with medium levels of resistance (fold change of 10 or greater and less than or equal to 40);

- 67% undetectable for patients with high levels of resistance (fold change greater than 40).

• Treatment with enfuvirtide and darunavir/ritonavir with other anti-HIV drugs was generally well tolerated.

• 11 serious adverse events were reported in 7 patients.

• 2 of these patients discontinued therapy due to adverse events.

• 1 additional patient discontinued therapy due to an adverse event not considered to be serious.

• 1 death (unrelated to the study drugs) was reported in a patient with sepsis, worsening anemia, and worsening renal insufficiency.

Conclusion

Based on these findings, the investigators concluded, "In this sample [Expanded Access Program] population of treatment-experienced patients, virologic responses at week 24 were uniformly excellent when darunavir/ritonavir and enfuvirtide were combined with optimized background therapy in patients naive to these 2 drugs."


Orlando Immunology Center, Orlando, FL; Stanford University Medical Center, Palo Alto, CA; AIDS Healthcare Foundation, Los Angeles, CA; Synergy Hematology Oncology Med. Assoc., Los Angeles, CA; Therapeutic Concepts, Houston, TX; Trimeris, Inc., Durham, NC; Roche Laboratories, Nutley, NJ.


Reference
E DeJesus, A Zolopa, C Farthing, and others. Response to darunavir/ritonavir (DRV/r) combined with enfuvirtide (ENF)-containing ARV in triple-class experienced patients was not predicted by baseline darunavir (DRV) sensitivity or viral tropism (VT): the BLQ study preliminary results. 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, July 22-25, 2007. Sydney, Australia. Abstract (poster) WEPEB039.


SOURCE: HIVandHepatitis.com
 
Regards,

Nelson Vergel
Program for Wellness Restoration
PoWeRUSA dot org


“I had rather attempt something great and fail, than to attempt nothing at all and succeed.” R. Schuller



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#1142 From: PoWeRTX@...
Date: Mon Aug 13, 2007 10:04 am
Subject: Fwd: NATAP: More Comments-FDA's Maraviroc Approval 		nelsonvergel
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In a message dated 8/7/2007 6:40:50 A.M. Central Daylight Time, nataphcvhiv@... writes:
NATAP http://natap.org/
_______________________________________________


More Comments-Pfizer's AIDS Drug Maraviroc Wins U.S. Approval

By Elizabeth Lopatto and Luke Timmerman

Aug. 6 (Bloomberg) -- Pfizer Inc., the world's biggest drugmaker, won U.S. approval for maraviroc, the first new type of medicine in a decade to treat the virus that causes AIDS, sending the company's shares to their biggest gain in more than a year.

The drug was cleared by the Food and Drug Administration for patients who have failed to reduce the levels of the human immunodeficiency virus with other treatments, Pfizer said today in a statement.

Maraviroc, to be sold under the name Selzentry, will provide an alternative for thousands of Americans with drug-resistant forms of HIV. Analysts say it may generate $145 million in sales next year. The drug will cost about $900 a month wholesale, comparable to other HIV treatments, Pfizer said. The New York- based company said it expects maraviroc to be available in the U.S. by the middle of next month.

``It's clearly an important new medicine for many patients with HIV in need of new therapies,'' said Robert Hazlett, an analyst with BMO Capital Markets in New York, in a telephone interview. He rates Pfizer shares ``market perform'' and doesn't own any.

An FDA advisory panel recommended in April that the agency make the drug available quickly to the 25,000 to 40,000 people who may benefit because their infections resist other treatments. Pfizer also needs to conduct additional studies on maraviroc's side-effects and on which population groups ought to use it, the panel said.

No Unusual Deaths

``This is an important new product for many HIV-infected patients who have not responded to other treatments and have few options,'' said Steven Galson, the director of the FDA's Center for Drug Evaluation and Research, in a statement.

The FDA found no unusual deaths tied to maraviroc. People who took the drug were more likely to develop flu-like illnesses or herpes. The product's prescribing information includes a boxed warning about liver damage and a statement about the possibility of heart attacks, the FDA said in a statement.

Pfizer said on June 20 that the FDA had delayed approval of the drug because of undisclosed issues with its labeling.

The shares rose 60 cents, or 2.6 percent, to $24.11 at 4:01 p.m. in New York Stock Exchange composite trading. The stock hasn't risen that much in a day since July 24, 2006, when the shares gained 4 percent.

The medicine is the first in a new class that blocks the CCR5 receptor, a chemical portal used by HIV to get into healthy cells. The drug changes the shape of the entryway, making it impossible for HIV to get in.

Maraviroc will be given to patients as an oral pill to be taken twice a day, Pfizer spokesman Ray Kerins said by telephone. It must be given in combination with other HIV medications, he said in an e-mail.

Monogram Test

About half of the 1 million people in the U.S. with HIV are infected with a form of the virus that uses the CCR5 entryway. Patients will have to get a test, available from Monogram Biosciences Inc. of South San Francisco, California, to determine whether their type of HIV could be targeted by the drug. The test, called Trofile, is 90 percent accurate.

Monogram retains commercial rights to Trofile in the U.S., and Pfizer will sell it outside the U.S., said Alfred Merriweather, Monogram's chief financial officer, in a telephone interview.

Monogram hasn't announced the price of Trofile, although it sells another HIV diagnostic test for $1,700, Merriweather said. The company's HIV-testing products generated $45 million in 2006.

``This has the potential over a couple years to double our HIV business,'' Merriweather said.

Possible Barrier

The need for a diagnostic test may create a barrier for physicians to prescribe Selzentry, analyst Hazlett said. Another HIV medicine, Isentress from Merck & Co., could be approved by the FDA in October and might appeal to a broader market of patients, Hazlett said.

Two other drugs in the same class as maraviroc were sidetracked by dangerous side effects. GlaxoSmithKline Plc halted trials of its aplaviroc because of liver damage among patients, and Schering-Plough Corp.'s vicriviroc was linked to lymphoma.

Studies ``do not indicate that maraviroc is associated'' with liver damage or with cancers, the FDA staff said in an analysis of the drug.

 
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Nelson Vergel
Program for Wellness Restoration
PoWeRUSA dot org


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NATAP http://natap.org/
_______________________________________________
More Comments-Pfizer's AIDS Drug Maraviroc Wins U.S. Approval

By Elizabeth Lopatto and Luke Timmerman

Aug. 6 (Bloomberg) -- Pfizer Inc., the world's biggest drugmaker, won U.S. approval for maraviroc, the first new type of medicine in a decade to treat the virus that causes AIDS, sending the company's shares to their biggest gain in more than a year.

The drug was cleared by the Food and Drug Administration for patients who have failed to reduce the levels of the human immunodeficiency virus with other treatments, Pfizer said today in a statement.

Maraviroc, to be sold under the name Selzentry, will provide an alternative for thousands of Americans with drug-resistant forms of HIV. Analysts say it may generate $145 million in sales next year. The drug will cost about $900 a month wholesale, comparable to other HIV treatments, Pfizer said. The New York- based company said it expects maraviroc to be available in the U.S. by the middle of next month.

``It's clearly an important new medicine for many patients with HIV in need of new therapies,'' said Robert Hazlett, an analyst with BMO Capital Markets in New York, in a telephone interview. He rates Pfizer shares ``market perform'' and doesn't own any.

An FDA advisory panel recommended in April that the agency make the drug available quickly to the 25,000 to 40,000 people who may benefit because their infections resist other treatments. Pfizer also needs to conduct additional studies on maraviroc's side-effects and on which population groups ought to use it, the panel said.

No Unusual Deaths

``This is an important new product for many HIV-infected patients who have not responded to other treatments and have few options,'' said Steven Galson, the director of the FDA's Center for Drug Evaluation and Research, in a statement.

The FDA found no unusual deaths tied to maraviroc. People who took the drug were more likely to develop flu-like illnesses or herpes. The product's prescribing information includes a boxed warning about liver damage and a statement about the possibility of heart attacks, the FDA said in a statement.

Pfizer said on June 20 that the FDA had delayed approval of the drug because of undisclosed issues with its labeling.

The shares rose 60 cents, or 2.6 percent, to $24.11 at 4:01 p.m. in New York Stock Exchange composite trading. The stock hasn't risen that much in a day since July 24, 2006, when the shares gained 4 percent.

The medicine is the first in a new class that blocks the CCR5 receptor, a chemical portal used by HIV to get into healthy cells. The drug changes the shape of the entryway, making it impossible for HIV to get in.

Maraviroc will be given to patients as an oral pill to be taken twice a day, Pfizer spokesman Ray Kerins said by telephone. It must be given in combination with other HIV medications, he said in an e-mail.

Monogram Test

About half of the 1 million people in the U.S. with HIV are infected with a form of the virus that uses the CCR5 entryway. Patients will have to get a test, available from Monogram Biosciences Inc. of South San Francisco, California, to determine whether their type of HIV could be targeted by the drug. The test, called Trofile, is 90 percent accurate.

Monogram retains commercial rights to Trofile in the U.S., and Pfizer will sell it outside the U.S., said Alfred Merriweather, Monogram's chief financial officer, in a telephone interview.

Monogram hasn't announced the price of Trofile, although it sells another HIV diagnostic test for $1,700, Merriweather said. The company's HIV-testing products generated $45 million in 2006.

``This has the potential over a couple years to double our HIV business,'' Merriweather said.

Possible Barrier

The need for a diagnostic test may create a barrier for physicians to prescribe Selzentry, analyst Hazlett said. Another HIV medicine, Isentress from Merck & Co., could be approved by the FDA in October and might appeal to a broader market of patients, Hazlett said.

Two other drugs in the same class as maraviroc were sidetracked by dangerous side effects. GlaxoSmithKline Plc halted trials of its aplaviroc because of liver damage among patients, and Schering-Plough Corp.'s vicriviroc was linked to lymphoma.

Studies ``do not indicate that maraviroc is associated'' with liver damage or with cancers, the FDA staff said in an analysis of the drug.



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#1141 From: Nelson Vergel <PoWeRTX@...>
Date: Sat Aug 11, 2007 7:04 am
Subject: Fwd: NATAP: CCR5 Maraviroc FDA Review 		nelsonvergel
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FDA Concerns, OKs Maraviroc for drug-resistant AIDS patients

Instead of attacking the deadly virus, the treatment defends human immune cells.

By Jia-Rui Chong, LA Times Staff Writer
August 7, 2007

Providing a new alternative to AIDS patients who have developed resistance to multiple drugs, the Food and Drug Administration on Monday approved the first-ever pill that works by defending human immune cells instead of attacking the deadly virus.

The drug, which will be sold in the United States under the trade name Selzentry, prevents the AIDS virus from entering immune cells by clogging up a cell receptor known as CCR5. All previous drugs have targeted parts of the virus.

The last new class of drugs was approved by the FDA in 2003.

Drug-maker Pfizer Inc. plans to make Selzentry commercially available in September at a wholesale cost of $29 per day. Patients with limited treatment options have been able to apply for the pill through an expanded access program since the end of last year.

The FDA reviewed data on more than 600 patients that showed Selzentry, whose generic name is maraviroc, was effective when used in combination with other AIDS drugs. About 45% of the patients who took Selzentry as part of their regimen saw the amount of HIV in their blood drop to undetectable levels after 24 weeks. About 23% of those who added a placebo to their regimen saw a similar decline.

The agency delayed approval of the drug for about two months because of concerns about liver toxicity, said Dr. Debra B. Birnkrant, who directs the FDA's antiviral products division.

In June, the FDA received a report of a woman who had high levels of a liver enzyme that might have been due to Selzentry, she said.

A similar drug made by GlaxoSmithKline, called aplaviroc, also was linked to severe liver toxicity. Trials for that drug were halted in 2005.

The FDA re-reviewed the data and approved Pfizer's drug on the condition that the label include a black-box warning, the strongest possible advisory. Selzentry also will carry a warning about an increased risk of heart attack.

"I think the benefits of the drug clearly outweigh the risks," Birnkrant said.

To check on the drug's long-term effects, the agency will obtain data on patients for at least five years, she said.

Dr. Helmut Albrecht, who oversees the infectious diseases division at the University of South Carolina and was not involved in the drug's clinical trials, said he was "cautiously optimistic" about Selzentry.

Because the CCR5 site is known to be involved in tumor surveillance and other immune functions, researchers need to keep a close watch for new cases of cancer or other medical problems, said Albrecht, who was involved in an aplaviroc trial.

"It's so completely new that it is sort of difficult to see how well this is going to do over time," Albrecht said.

The FDA accelerated the approval process for Selzentry because it saw a pressing need for patients infected with drug-resistant forms of HIV, the virus that causes AIDS. These patients may use the drug if they have the kind of HIV that uses the CCR5 site to help it enter a cell.

About 50% to 60% of patients with resistant viruses are infected with ones that use the CCR5 site. HIV also can target other cell receptors to gain entry.

The only test for HIV receptor targets is made by Monogram Biosciences of South San Francisco. It was made available to the public Monday and will probably cost about $1,700, said Monogram Chief Financial Officer Alfred G. Merriweather.

A limited group of patients might be appropriate for Selzentry at the moment, said Dr. Malcolm D. John, who directs an HIV clinic at UC San Francisco and was not involved in the study. Patients who are controlling their virus with other regimens should probably stay on those drugs, he said.

He estimated that about 10 to 15% of his patients would be good candidates.

"I'm not going to be rushing to use it, but if I have the right patient, I'll use it," John said.

The approval of Selzentry comes amid a renaissance in the development of AIDS treatments. Promising results on another new class of drugs called integrase inhibitors were announced this year.




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-----Original Message-----
From: nataphcvhiv@...
To: hiv@...; nataphcvhiv@...; natapindustry@...; natapdoctors@...
Sent: Wed, 8 Aug 2007 4:54 am
Subject: NATAP: CCR5 Maraviroc FDA Review

NATAP http://natap.org/
_______________________________________________
FDA Concerns, OKs Maraviroc for drug-resistant AIDS patients

Instead of attacking the deadly virus, the treatment defends human immune cells.

By Jia-Rui Chong, LA Times Staff Writer
August 7, 2007

Providing a new alternative to AIDS patients who have developed resistance to multiple drugs, the Food and Drug Administration on Monday approved the first-ever pill that works by defending human immune cells instead of attacking the deadly virus.

The drug, which will be sold in the United States under the trade name Selzentry, prevents the AIDS virus from entering immune cells by clogging up a cell receptor known as CCR5. All previous drugs have targeted parts of the virus.

The last new class of drugs was approved by the FDA in 2003.

Drug-maker Pfizer Inc. plans to make Selzentry commercially available in September at a wholesale cost of $29 per day. Patients with limited treatment options have been able to apply for the pill through an expanded access program since the end of last year.

The FDA reviewed data on more than 600 patients that showed Selzentry, whose generic name is maraviroc, was effective when used in combination with other AIDS drugs. About 45% of the patients who took Selzentry as part of their regimen saw the amount of HIV in their blood drop to undetectable levels after 24 weeks. About 23% of those who added a placebo to their regimen saw a similar decline.

The agency delayed approval of the drug for about two months because of concerns about liver toxicity, said Dr. Debra B. Birnkrant, who directs the FDA's antiviral products division.

In June, the FDA received a report of a woman who had high levels of a liver enzyme that might have been due to Selzentry, she said.

A similar drug made by GlaxoSmithKline, called aplaviroc, also was linked to severe liver toxicity. Trials for that drug were halted in 2005.

The FDA re-reviewed the data and approved Pfizer's drug on the condition that the label include a black-box warning, the strongest possible advisory. Selzentry also will carry a warning about an increased risk of heart attack.

"I think the benefits of the drug clearly outweigh the risks," Birnkrant said.

To check on the drug's long-term effects, the agency will obtain data on patients for at least five years, she said.

Dr. Helmut Albrecht, who oversees the infectious diseases division at the University of South Carolina and was not involved in the drug's clinical trials, said he was "cautiously optimistic" about Selzentry.

Because the CCR5 site is known to be involved in tumor surveillance and other immune functions, researchers need to keep a close watch for new cases of cancer or other medical problems, said Albrecht, who was involved in an aplaviroc trial.

"It's so completely new that it is sort of difficult to see how well this is going to do over time," Albrecht said.

The FDA accelerated the approval process for Selzentry because it saw a pressing need for patients infected with drug-resistant forms of HIV, the virus that causes AIDS. These patients may use the drug if they have the kind of HIV that uses the CCR5 site to help it enter a cell.

About 50% to 60% of patients with resistant viruses are infected with ones that use the CCR5 site. HIV also can target other cell receptors to gain entry.

The only test for HIV receptor targets is made by Monogram Biosciences of South San Francisco. It was made available to the public Monday and will probably cost about $1,700, said Monogram Chief Financial Officer Alfred G. Merriweather.

A limited group of patients might be appropriate for Selzentry at the moment, said Dr. Malcolm D. John, who directs an HIV clinic at UC San Francisco and was not involved in the study. Patients who are controlling their virus with other regimens should probably stay on those drugs, he said.

He estimated that about 10 to 15% of his patients would be good candidates.

"I'm not going to be rushing to use it, but if I have the right patient, I'll use it," John said.

The approval of Selzentry comes amid a renaissance in the development of AIDS treatments. Promising results on another new class of drugs called integrase inhibitors were announced this year.




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#1140 From: Nelson Vergel <PoWeRTX@...>
Date: Sat Aug 11, 2007 7:14 am
Subject: FDA Approves Maraviroc, First Drug in New Class of Anti-HIV Medications 		nelsonvergel
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FDA Approves Maraviroc, First Drug in New Class of Anti-HIV Medications

On August 6, 2007, the United States Food and Drug Administration (FDA) approved maraviroc (Selzentry), the first drug to be approved in the CCR5 coreceptor antagonist class of anti-HIV medications. Maraviroc has been approved for use in conjunction with other antiretrovirals in treatment-experienced adults who have exclusively CCR5-tropic HIV virus, evidence of viral replication, and resistance to multiple antiretroviral medications.
More information about maraviroc and related topics is also available:
Nelson Vergel
powerusa dot org

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#1139 From: PoWeRTX@...
Date: Mon Jul 30, 2007 7:02 pm
Subject: Fuzeon Improves Maraviroc Response in MOTIVATE- Comments from Nelson 		nelsonvergel
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Comment from Nelson
 
We were eagerly waiting for data of Fuzeon naive patients who started Maraviroc. These two drugs work outside the T cell, so we were expecting some synergy between them. So far, we cannot answer that.
 
May be Pfizer can help us finally answer if Fuzeon is like any other active agent in a background when combined with Maraviroc. They quickly concluded at CROI 2007 that Fuzeon had no added effect virologically over other active agents, but they did not tell us that they had mixed Fuzeon experienced and Fuzeon naives in their analysis. Now we see separated data.
 
It seems from these graphs that 63.7 % of those naive to Fuzeon at baseline and who started it with Maraviroc qd had viral load under 50 copies/ml at 24 weeks (we do not know  how many active agents the Fuzeon naive starters had) . It also seems that 30% of patients in the Maraviroc arms had one active drug left in their background at baseline (Fuzeon?).  46.9% of those who started Maraviroc with only one active agent in their background had viral load under 50 at week 24.
 
It would be nice if we could see how many of the patients with GSS=1 (genotypic score of one active agent in their optimized background therapy-OBT) in both MOTIVATE studies  who started Fuzeon de novo (naive to it, 200 patients) compared to patients with GSS=1 who started something else with Maraviroc (82 patients). Many patients and doctors wait til Fuzeon is the last active agent left to combine with a new drug. I also wonder how many patients with GSS= 0 or 1 have a R5 virus since this would be an advanced population.
 
I have to admit that Pfizer and Merck , the companies with the next two drugs to be approved soon, are doing a better job at separating data for us to make some better sense of the role of the background regimen in treatment experienced patients starting their drugs.  
 
Finally, I hope someone is looking at Maraviroc+ Raltegravir+ or - Fuzeon for advanced patients who have R5 and dual mixed virus.  The MOTIVATE studies were closed when Merck started their BENCHMRK studies and the Maraviroc EAP did not start til after Merck closed their studies, so no data are available for the combination of those two drugs. Only doctors who are dispensing both drugs together via EAP have some experience with this combo but they are usually forbidden to publish EAP pilot data to the world.
 
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Fuzeon or A New Drug (PI) Improved Maraviroc Response in MOTIVATE

Efficacy of Maraviroc in Combination with At Least One Other Potent New Antiretroviral Drug: 24-week Combined Analysis of the MOTIVATE 1 and 2 Studies

“….In all treatment groups, undetectable HIV-1 RNA was achieved by a higher proportion of patients who received ENF as part of their OBT when they were naive to ENF…. Patients who received OBT that included first use of a PI experienced a greater virologic response across…”

Reported by Jules Levin
4th IAS, 22-25 July, Sydney, Australia

Elna van der Ryst1, David Cooper2, Irina Konourina1, Mike Saag3, James Goodrich4, Margaret Tawadrous4, Paul Simpson1, John Sullivan1, Mike Westby1 and Howard Mayer4
1Pfizer Global Research and Development, Sandwich, UK
2University of New South Wales, National Centre in HIV Epidemiology and Clinical Research, Sydney, Australia
3University of Alabama at Birmingham, Birmingham, USA
4Pfizer Global Research and Development, New London, USA

AUTHOR CONCLUSIONS
These results demonstrate the additional treatment benefit of including a potent new drug in a patient's OBT when initiating therapy with maraviroc and are consistent with data from studies of other recently developed ARVs with activity against HIV-1 resistant to established agents,10,11 including raltegravir12,13.

The data on first use of other potent ARVs are consistent with the analysis of virologic response by GSS, which demonstrates that higher numbers of patients achieve virologic suppression on maraviroc treatment in subgroups with more potentially active drugs in their OBT regimen.

In conclusion, these data demonstrate that, in treatment-experienced patients with CCR5-tropic HIV-1, maraviroc combined with at least one other potent new ARV in the background regimen is highly effective in suppressing HIV-1 RNA over 24 weeks, consistent with an additive effect of maraviroc with other ARVs, as predicted by in vitro data.1
SEE RESULTS BELOW

BACKGROUND
Maraviroc (CELSENTRI®) is a highly selective oral CCR5 antagonist that has demonstrated potent activity against R5 viruses resistant to current classes of antiretroviral drugs (ARVs).1-3

In the Phase 3 MOTIVATE studies in treatment-experienced patients with R5 virus, maraviroc plus optimized background therapy (OBT) demonstrated greater efficacy and a similar safety profile compared with placebo
plus OBT at 24 weeks.4-6

Enfuvirtide (ENF) use as part of OBT was one of the stratification factors incorporated into the randomization for the two studies. The rationale for this was to ensure a balance of ENF use between treatment groups, given the demonstrated efficacy of ENF in this treatment-experienced patient population.7,8

As shown in Figure 1, both maraviroc treatment groups maintained superiority over OBT alone, with and without concomitant ENF treatment.

Figure 5. Patients with HIV=1 RNA <50 copies/mL at Week 24 according to Genotypic Susceptibility Score at Baseline 4,5

The more drugs a patient was sensitive to the better their viral response was:

When patients had GSS=0 (genotypically not sensitive to any drugs):
--OBT had 2% <50 c/ml,
--MVC QD+OBT had 28.4% >50 c/ml,
--MVC BID+OBT had 32.7% <50 c/ml.
SENSITIVE TO 1 additional drug, GSS=1:
--OBT had 11% <50 c/ml
--MVC QD+OBT 46.9% <50 c/ml
--MVC bid+OBT 46.7% <50 c/ml
SENSITIVE to 2 additional drugs (GSS=2):
--OBT had 36.6% <50 c/ml
--MVC QD+OBT had 54% <50 c/ml
--MVC bid+OBT had 55.7% <50 c/ml
SENSITIVE TO 3 or more drugs (GSS=3):
--OBT 50.9% <50 c/ml
--MVC qd+OBT 61.7% <50 c/ml
--MVC bid+OBT 59% <50 c/ml


Response by enfuvirtide first use
Thirty-three percent of patients had a history of previous ENF use.

Just over 40% of patients received ENF as part of their OBT.

In all treatment groups, undetectable HIV-1 RNA was achieved by a higher proportion of patients who
received ENF as part of their OBT when they were naive to ENF and had no evidence of resistance to ENF at screening, compared with patients who had previous experience of ENF or evidence of resistance.

For both these subgroups of patients, maraviroc treatment groups maintained superiority over OBT alone (Figure 3).

These findings were consistent across all virologic endpoints analyzed, including the primary endpoint of HIV-1 RNA reduction from baseline at Week 24 (not shown).

Figure 3. Proportion of patients receiving maraviroc plus OBT containing enfuvirtide who achieved HIV-1
RNA suppression to A) <400 copies/mL and B) <50 copies/mL at Week 24 according to first use of enfuvirtide
Fuzeon first use increased percent <400 from 30% taking MVC qd & 49% taking MVC bid to 75%, and percent less than <50 c/ml from 32% to close to 63% taking MVC qd & 53% taking MVC bid among patients with Fuzeon experience/resistance.


Response by protease inhibitor first use
Patients who received OBT that included first use of a PI experienced a greater virologic response across all endpoints in all three treatment groups, compared with those patients who received the same PI in their OBT but who had a history of prior usage or evidence of resistance to it at screening (Figure 4).

Both maraviroc treatment groups maintained superiority over OBT alone, regardless of the first use of individual protease inhibitors (PIs) in the OBT (i.e. a PI received for the first time in a patient with no evidence of genotypic resistance to that PI at screening) (Figure 4).

Figure 4. Proportion of patients receiving maraviroc plus OBT containing A) lopinavir/r, B) (fos)amprenavir, C) atazanavir and D) tipranavir who achieved HIV-1 RNA suppression at week 24 according to first use of these PIs



Figure 1. Week 24 interim efficacy analysis by enfuvirtide use
(stratification factor)4,5


OBJECTIVES
HIV treatment guidelines indicate that adding a drug with a new mechanism of action and/or a drug with activity against drug-resistant virus to an optimized background regimen can provide significant antiretroviral activity in patients with virologic failure due to highly resistant virus.9

The objectives of this analysis were to evaluate the efficacy of maraviroc when combined with an OBT regimen containing at least one potent ARV (ENF, lopinavir [LPV], tipranavir [TPV], amprenavir [APV] or atazanavir [ATV]) used for the first time. Darunavir use was not permitted as it was only available through pre-approval access and no drug-drug interaction data were available in order to allow co-administration.

METHODS
MOTIVATE 1 (North America) and MOTIVATE 2 (Europe/Australia/USA) are ongoing, randomized, double-blind, placebo-controlled Phase 3 studies assessing the safety and efficacy of maraviroc in patients with triple-class experience and/or resistance and harboring R5 virus.4,5

The study design is summarized in Figure 2.

Figure 2. MOTIVATE 1 and 2 study design

* Randomized patients had triple-class drug experience and/or triple-class drug resistance, R5 virus only (Trofile™, Monogram BioSciences), and HIV-1 RNA >5000 copies/mL; patients were stratified by enfuvirtide use and baseline HIV-1 RNA < or >100 000 copies/mL.
† OBT = optimized background therapy: 3-6 ARVs (± low-dose ritonavir) selected by the investigator on the basis of resistance testing at the screening visit (expert interpretation services available to investigators if required), treatment history and safety considerations.
‡ Dose equivalent; patients receiving a protease inhibitor (except TPV) and/or delavirdine in their OBT received 150 mg of maraviroc; all other patients received 300 mg of maraviroc.

Subgroup analyses at Week 24
Subgroup analyses at Week 24 were carried out on data pooled from the two MOTIVATE studies, resulting in larger subgroup sizes.

Pooled analysis was justified since the two studies had identical designs, entry criteria, conduct, monitoring and statistical analyses and only minor differences in baseline characteristics for each study population.

Efficacy of maraviroc in combination with an OBT containing ENF, LPV, ATZ, TPV or APV was assessed on the basis of:
-- first use of the selected OBT drug: patient's usage of the OBT drug was
categorized as 'first use' if the drug history section of the patient's case report form indicated no prior history of the ARV and there was no evidence of drug resistance to the ARV based on the results of the genotypic resistance testing performed at the screening visit. Patients with prior drug history of use or evidence of resistance to it at screening were categorized as 'experienced/resistance'
-- Genotypic Susceptibility Score (GSS): GSS indicates the total number of drugs in the OBT regimen to which a patient's virus isolate showed wildtype genotypic sensitivity at screening.


The pooled analysis of MOTIVATE 1 and 2 included 1049 patients who received at least one dose of study drug. Demographics and baseline characteristics were well balanced across treatment groups (Table 1).

More than 120 different OBT regimens were used in the two studies. The most commonly used ARVs are shown in Table 2.

The majority of patients had two or fewer potentially active drugs in their OBT regimen according to susceptibility testing at screening (Table 1).

Table 1. Demographics and baseline characteristics for MOTIVATE 1 & 2


Table 2. MOTIVATE 1 & 2: OBT drugs used by >10% of patients in anytreatment arm

* PK boosting dose (<200 mg BID).
† Enfuvirtide use in OBT was a randomization stratification factor.
Bold text = ARVs included in subgroup analysis.

References
1. Dorr P, et al. Antimicrob Agents Chemother 2005; 49:4721-4732.
2. Fätkenheuer G, et al. Nat Med 2005; 11:1170-1172.
3. Pfizer. Data on file. Presented as part of the FDA Antiviral Drugs Advisory Committee (AVDAC) meeting, held
24 April 2007. Available at: http://www.fda.gov/ohrms/dockets/ac/cder07.htm#AntiviralDrugs. 2007.
4. Lalezari J, et al. 14th Conference on Retroviruses and Opportunistic Infections. Los Angeles, USA, 25-28 February 2007; Abstract 104bLB.
5. Nelson M, et al. 14th Conference on Retroviruses and Opportunistic Infections. Los Angeles, USA, 25-28 February 2007; Abstract 104aLB.
6. Gulick RM, et al. 4th IAS Conference on HIV Pathogenesis, Treatment and Prevention. Sydney, Australia, 22-25 July 2007; Abstract WEPEB116LB.
7. Lalezari JP, et al. N Engl J Med 2003; 348:2175-2185.
8. Lazzarin A, et al. N Engl J Med 2003; 348:2186-2195.
9. Department of Health and Human Services (DHHS). Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. 2006. Available at: http://aidsinfo.nih.gov/guidelines (accessed June 2007).
10. Cahn P, et al. Clin Infect Dis 2006; 43:1347-1356.
11. Katlama C, et al. AIDS 2007; 21:395-402.
12. Cooper D, et al. 14th Conference on Retroviruses and Opportunistic Infections. Los Angeles, USA, 25-28 February 2007; Abstract 105aLB.
13. Steigbigel R, et al. 14th Conference on Retroviruses and Opportunistic Infections. Los Angeles, USA, 25-28 February 2007; Abstract 105bLB.


 
Regards,

Nelson Vergel
Program for Wellness Restoration
PoWeRUSA dot org


“I had rather attempt something great and fail, than to attempt nothing at all and succeed.” R. Schuller



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Fuzeon or A New Drug (PI) Improved Maraviroc Response in MOTIVATE

Efficacy of Maraviroc in Combination with At Least One Other Potent New Antiretroviral Drug: 24-week Combined Analysis of the MOTIVATE 1 and 2 Studies

“….In all treatment groups, undetectable HIV-1 RNA was achieved by a higher proportion of patients who received ENF as part of their OBT when they were naive to ENF…. Patients who received OBT that included first use of a PI experienced a greater virologic response across…”

Reported by Jules Levin
4th IAS, 22-25 July, Sydney, Australia

Elna van der Ryst1, David Cooper2, Irina Konourina1, Mike Saag3, James Goodrich4, Margaret Tawadrous4, Paul Simpson1, John Sullivan1, Mike Westby1 and Howard Mayer4
1Pfizer Global Research and Development, Sandwich, UK
2University of New South Wales, National Centre in HIV Epidemiology and Clinical Research, Sydney, Australia
3University of Alabama at Birmingham, Birmingham, USA
4Pfizer Global Research and Development, New London, USA

AUTHOR CONCLUSIONS
These results demonstrate the additional treatment benefit of including a potent new drug in a patient's OBT when initiating therapy with maraviroc and are consistent with data from studies of other recently developed ARVs with activity against HIV-1 resistant to established agents,10,11 including raltegravir12,13.

The data on first use of other potent ARVs are consistent with the analysis of virologic response by GSS, which demonstrates that higher numbers of patients achieve virologic suppression on maraviroc treatment in subgroups with more potentially active drugs in their OBT regimen.

In conclusion, these data demonstrate that, in treatment-experienced patients with CCR5-tropic HIV-1, maraviroc combined with at least one other potent new ARV in the background regimen is highly effective in suppressing HIV-1 RNA over 24 weeks, consistent with an additive effect of maraviroc with other ARVs, as predicted by in vitro data.1
SEE RESULTS BELOW

BACKGROUND
Maraviroc (CELSENTRI®) is a highly selective oral CCR5 antagonist that has demonstrated potent activity against R5 viruses resistant to current classes of antiretroviral drugs (ARVs).1-3

In the Phase 3 MOTIVATE studies in treatment-experienced patients with R5 virus, maraviroc plus optimized background therapy (OBT) demonstrated greater efficacy and a similar safety profile compared with placebo
plus OBT at 24 weeks.4-6

Enfuvirtide (ENF) use as part of OBT was one of the stratification factors incorporated into the randomization for the two studies. The rationale for this was to ensure a balance of ENF use between treatment groups, given the demonstrated efficacy of ENF in this treatment-experienced patient population.7,8

As shown in Figure 1, both maraviroc treatment groups maintained superiority over OBT alone, with and without concomitant ENF treatment.

Figure 5. Patients with HIV=1 RNA <50 copies/mL at Week 24 according to Genotypic Susceptibility Score at Baseline 4,5

The more drugs a patient was sensitive to the better their viral response was:

When patients had GSS=0 (genotypically not sensitive to any drugs):
--OBT had 2% <50 c/ml,
--MVC QD+OBT had 28.4% >50 c/ml,
--MVC BID+OBT had 32.7% <50 c/ml.
SENSITIVE TO 1 additional drug, GSS=1:
--OBT had 11% <50 c/ml
--MVC QD+OBT 46.9% <50 c/ml
--MVC bid+OBT 46.7% <50 c/ml
SENSITIVE to 2 additional drugs (GSS=2):
--OBT had 36.6% <50 c/ml
--MVC QD+OBT had 54% <50 c/ml
--MVC bid+OBT had 55.7% <50 c/ml
SENSITIVE TO 3 or more drugs (GSS=3):
--OBT 50.9% <50 c/ml
--MVC qd+OBT 61.7% <50 c/ml
--MVC bid+OBT 59% <50 c/ml


Response by enfuvirtide first use
Thirty-three percent of patients had a history of previous ENF use.

Just over 40% of patients received ENF as part of their OBT.

In all treatment groups, undetectable HIV-1 RNA was achieved by a higher proportion of patients who
received ENF as part of their OBT when they were naive to ENF and had no evidence of resistance to ENF at screening, compared with patients who had previous experience of ENF or evidence of resistance.

For both these subgroups of patients, maraviroc treatment groups maintained superiority over OBT alone (Figure 3).

These findings were consistent across all virologic endpoints analyzed, including the primary endpoint of HIV-1 RNA reduction from baseline at Week 24 (not shown).

Figure 3. Proportion of patients receiving maraviroc plus OBT containing enfuvirtide who achieved HIV-1
RNA suppression to A) <400 copies/mL and B) <50 copies/mL at Week 24 according to first use of enfuvirtide
Fuzeon first use increased percent <400 from 30% taking MVC qd & 49% taking MVC bid to 75%, and percent less than <50 c/ml from 32% to close to 63% taking MVC qd & 53% taking MVC bid among patients with Fuzeon experience/resistance.


Response by protease inhibitor first use
Patients who received OBT that included first use of a PI experienced a greater virologic response across all endpoints in all three treatment groups, compared with those patients who received the same PI in their OBT but who had a history of prior usage or evidence of resistance to it at screening (Figure 4).

Both maraviroc treatment groups maintained superiority over OBT alone, regardless of the first use of individual protease inhibitors (PIs) in the OBT (i.e. a PI received for the first time in a patient with no evidence of genotypic resistance to that PI at screening) (Figure 4).

Figure 4. Proportion of patients receiving maraviroc plus OBT containing A) lopinavir/r, B) (fos)amprenavir, C) atazanavir and D) tipranavir who achieved HIV-1 RNA suppression at week 24 according to first use of these PIs



Figure 1. Week 24 interim efficacy analysis by enfuvirtide use
(stratification factor)4,5


OBJECTIVES
HIV treatment guidelines indicate that adding a drug with a new mechanism of action and/or a drug with activity against drug-resistant virus to an optimized background regimen can provide significant antiretroviral activity in patients with virologic failure due to highly resistant virus.9

The objectives of this analysis were to evaluate the efficacy of maraviroc when combined with an OBT regimen containing at least one potent ARV (ENF, lopinavir [LPV], tipranavir [TPV], amprenavir [APV] or atazanavir [ATV]) used for the first time. Darunavir use was not permitted as it was only available through pre-approval access and no drug-drug interaction data were available in order to allow co-administration.

METHODS
MOTIVATE 1 (North America) and MOTIVATE 2 (Europe/Australia/USA) are ongoing, randomized, double-blind, placebo-controlled Phase 3 studies assessing the safety and efficacy of maraviroc in patients with triple-class experience and/or resistance and harboring R5 virus.4,5

The study design is summarized in Figure 2.

Figure 2. MOTIVATE 1 and 2 study design

* Randomized patients had triple-class drug experience and/or triple-class drug resistance, R5 virus only (Trofile™, Monogram BioSciences), and HIV-1 RNA >5000 copies/mL; patients were stratified by enfuvirtide use and baseline HIV-1 RNA < or >100 000 copies/mL.
† OBT = optimized background therapy: 3-6 ARVs (± low-dose ritonavir) selected by the investigator on the basis of resistance testing at the screening visit (expert interpretation services available to investigators if required), treatment history and safety considerations.
‡ Dose equivalent; patients receiving a protease inhibitor (except TPV) and/or delavirdine in their OBT received 150 mg of maraviroc; all other patients received 300 mg of maraviroc.

Subgroup analyses at Week 24
Subgroup analyses at Week 24 were carried out on data pooled from the two MOTIVATE studies, resulting in larger subgroup sizes.

Pooled analysis was justified since the two studies had identical designs, entry criteria, conduct, monitoring and statistical analyses and only minor differences in baseline characteristics for each study population.

Efficacy of maraviroc in combination with an OBT containing ENF, LPV, ATZ, TPV or APV was assessed on the basis of:
-- first use of the selected OBT drug: patient's usage of the OBT drug was
categorized as 'first use' if the drug history section of the patient's case report form indicated no prior history of the ARV and there was no evidence of drug resistance to the ARV based on the results of the genotypic resistance testing performed at the screening visit. Patients with prior drug history of use or evidence of resistance to it at screening were categorized as 'experienced/resistance'
-- Genotypic Susceptibility Score (GSS): GSS indicates the total number of drugs in the OBT regimen to which a patient's virus isolate showed wildtype genotypic sensitivity at screening.


The pooled analysis of MOTIVATE 1 and 2 included 1049 patients who received at least one dose of study drug. Demographics and baseline characteristics were well balanced across treatment groups (Table 1).

More than 120 different OBT regimens were used in the two studies. The most commonly used ARVs are shown in Table 2.

The majority of patients had two or fewer potentially active drugs in their OBT regimen according to susceptibility testing at screening (Table 1).

Table 1. Demographics and baseline characteristics for MOTIVATE 1 & 2


Table 2. MOTIVATE 1 & 2: OBT drugs used by >10% of patients in anytreatment arm

* PK boosting dose (<200 mg BID).
† Enfuvirtide use in OBT was a randomization stratification factor.
Bold text = ARVs included in subgroup analysis.

References
1. Dorr P, et al. Antimicrob Agents Chemother 2005; 49:4721-4732.
2. Fätkenheuer G, et al. Nat Med 2005; 11:1170-1172.
3. Pfizer. Data on file. Presented as part of the FDA Antiviral Drugs Advisory Committee (AVDAC) meeting, held
24 April 2007. Available at: http://www.fda.gov/ohrms/dockets/ac/cder07.htm#AntiviralDrugs. 2007.
4. Lalezari J, et al. 14th Conference on Retroviruses and Opportunistic Infections. Los Angeles, USA, 25-28 February 2007; Abstract 104bLB.
5. Nelson M, et al. 14th Conference on Retroviruses and Opportunistic Infections. Los Angeles, USA, 25-28 February 2007; Abstract 104aLB.
6. Gulick RM, et al. 4th IAS Conference on HIV Pathogenesis, Treatment and Prevention. Sydney, Australia, 22-25 July 2007; Abstract WEPEB116LB.
7. Lalezari JP, et al. N Engl J Med 2003; 348:2175-2185.
8. Lazzarin A, et al. N Engl J Med 2003; 348:2186-2195.
9. Department of Health and Human Services (DHHS). Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. 2006. Available at: http://aidsinfo.nih.gov/guidelines (accessed June 2007).
10. Cahn P, et al. Clin Infect Dis 2006; 43:1347-1356.
11. Katlama C, et al. AIDS 2007; 21:395-402.
12. Cooper D, et al. 14th Conference on Retroviruses and Opportunistic Infections. Los Angeles, USA, 25-28 February 2007; Abstract 105aLB.
13. Steigbigel R, et al. 14th Conference on Retroviruses and Opportunistic Infections. Los Angeles, USA, 25-28 February 2007; Abstract 105bLB.




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Reply | Forward | Messages in this Topic (1)
#1138 From: PoWeRTX@...
Date: Sat Jul 28, 2007 2:24 pm
Subject: Maraviroc with Fuzeon and/or Kaletra 		nelsonvergel
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Late Breaker Poster WEPEB115LB at IAS 2007

Note from Nelson: No baseline CD4 or VL info was provided for those naive to Fuzeon or Kaletra. The difference in efficacy may be due to a difference in baseline CD4 cell count or baseline viral load in those two groups. Also note that the number of patients in the Kaletra and the Fuzeon group are very different.

Efficacy of Maraviroc in combination with at least one other potent new antiretroviral drug: 24-week combined analysis of the MOTIVATE 1 and 2 studies

Presented by Elna van der Ryst, .

van der Ryst E.1, Cooper D.2, Konourina I.1, Saag M.3, Goodrich J.4, Tawadrous M.4, Simpson P.1, Sullivan J.1, Westby M.1, Mayer H.4

1Pfizer Global Research and Development, Sandwich, United Kingdom, 2University of New South Wales, National Centre in HIV Epidemiology and Clinical Research, Sydney, Australia, 3University of Alabama at Birmingham, Birmingham, United States, 4Pfizer Global Research and Development, New London, United States

Objectives: Maraviroc, a CCR5 antagonist, plus optimized background therapy (OBT) demonstrated statistically significantly greater virologic and immunologic efficacy and a similar safety profile compared to placebo plus OBT at 24 weeks in two double-blind studies in treatment-experienced patients – MOTIVATE 1 (USA/Canada) and MOTIVATE 2 (Europe/Australia/USA). The aim of this analysis was to evaluate efficacy of maraviroc when combined with other active drugs in the OBT.
Methods: Patients with triple-class-experience and/or -resistance, CCR5-tropic HIV-1 (Trofileä), and HIV-1-RNA ³5000 copies/mL were randomized 2:2:1 to OBT (3–6 ARVs +/- low-dose ritonavir) plus maraviroc QD, BID or placebo. Efficacy was evaluated by screening genotypic, phenotypic and overall susceptibility scores to OBT, as well as by first-time use of selected background drugs.
Results: More patients with higher susceptibility scores reached undetectable HIV-1 RNA than those with lower scores. For patients receiving maraviroc whose virus had no enfuvirtide or lopinavir/r resistance mutations detected at screening, first-time use of enfuvirtide or lopinavir/r increased the likelihood of achieving undetectable HIV-1 RNA.


  Placebo + OBT Maraviroc QD + OBT Maraviroc BID + OBT
  <50 / <400 copies/mL <50 / <400 copies/mL <50 / <400 copies/mL
Total population 25% / 30% (N=207) 48% / 61% (N=408) 48% / 65% (N=419)
Enfuvirtide first use/no mutations 36% / 40% (N=58) 64% / 75% (N=91) 53% / 75% (N=109)
Lopinavir/r first use/no mutations 50% / 60% (N=10) 74% / 96% (N=27) 70% / 87% (N=23)

Conclusions: The data demonstrate that maraviroc combined with at least one other potent new antiretroviral in the regimen is highly effective in reducing viral load to below the limit of detection. This is consistent with an additive effect of maraviroc with other antiretroviral drugs, as predicted by in vitro data
 
Regards,

Nelson Vergel
Program for Wellness Restoration
PoWeRUSA dot org


“I had rather attempt something great and fail, than to attempt nothing at all and succeed.” R. Schuller



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#1137 From: PoWeRTX@...
Date: Sat Jul 28, 2007 10:40 am
Subject: Fwd: NATAP/IAS: Fuzeon+TMC114 Response 		nelsonvergel
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Fold Change (FC) is the amount of drug needed  (EC50 or effective concentration to control 50% of the virus) to suppress virus, compared to the amount needed for a wild type (naive ) virus. Prezista works better when the FC is less than 40. Fuzeon seems to make Prezista work better even at higher FC's.
 
NATAP http://natap.org/
_______________________________________________


RESPONSE TO DARUNAVIR/RITONAVIR (DRV/R) COMBINED WITH ENFUVIRTIDE (ENF)-CONTAINING ARV IN TRIPLE-CLASS EXPERIENCED PATIENTS WAS NOT PREDICTED BY BASELINE DARUNAVIR (DRV) SENSITIVITY OR VIRAL TROPISM (VT):
THE BLQ STUDY PRELIMINARY RESULTS

Reported by Jules Levin
4th IAS Conference
on HIV Pathogenesis,
Treatment and Prevention
22-25 July 2007
Sydney, Australia
Poster WePeB039

E DeJesus,1 A Zolopa,2 C Farthing,3 M Gottlieb,4 J Gathe,5 M Greenberg,6 and J Thommes7
1Orlando Immunology Center, Orlando, FL, USA; 2Stanford University Medical Center, Palo Alto, CA, USA; 3AIDS Healthcare Foundation, Los Angeles, CA, USA;
4Synergy Hematology Oncology Med. Assoc., Los Angeles, CA, USA; 5Therapeutic Concepts, Houston, TX, USA; 6Trimeris, Inc., Durham, NC, USA;
7Roche Laboratories, Nutley, NJ, USA.

Subset analyses from phase III studies in triple-class, antiretroviral (ARV)-experienced patients evaluating the efficacy and safety of darunavir/ritonavir (DRV/r) with an optimized background regimen demonstrated high rates
of virologic suppression when DRV/r was used with enfuvirtide (ENF).1

These published studies report that baseline DRV phenotypic sensitivity predicts virologic response in ARV-experienced patients treated with a DRV/r-containing regimen.1

The BLQ cohort study enrolled triple-class experienced patients experiencing virologic failure who had begun a new optimized regimen with ENF and DRV/r obtained before commercial availability through DRV expanded access in a predominantly community clinical setting, and was designed to explore the impact on virologic outcome of baseline factors such as DRV phenotypic sensitivity.

This protocol-defined interim analysis was conducted when the first half of the total cohort completed their week 24 assessments.

AUTHOR CONCLUSIONS
Treatment with ENF and DRV/r with OBT was generally well tolerated in this cohort with overall high 24-week virologic and CD4 responses that are consistent with previously reported 12-week results.3

The small dataset in this interim analysis might limit the power of logistic regression to identify predictors of virologic response other than baseline viral load.

Subsequent and comprehensive analysis of the complete cohort will be necessary to elucidate the potential impact of other factors (such as immune activation) on virologic outcome.

However, in triple-class experienced EAP patients, virologic responses at week 24 were uniformly excellent when DRV/r and ENF were combined with OBT in patients naïve to these two drugs.

In this interim analysis, no differences in virologic response were seen across the range of baseline DRV phenotypes among patients receiving ENF and DRV/r with OBT.


Methods
Prospective, open-label, 24-week, single-arm, multicenter, cohort study conducted in the US and Australia.

Eligible patients (age ≥18 years) meeting the following inclusion criteria were enrolled:
--triple-class ARV-experienced
--ENF-naïve
--DRV-naïve, either enrolled in a DRV early access program or prescribed DRV
--HIV-1 RNA >2,000 copies/mL within 60 days.

At entry all patients switched their current failing ARV treatment to a regimen consisting of:
--ENF 90 mg twice daily (BID) self-administered as a subcutaneous injection
--DRV/r 600/100 mg BID
--other investigator-selected ARVs based on treatment history and resistance testing.

Phenotypic and genotypic resistances were assessed at baseline using the PhenoSense HIV drug susceptibility assay (Monogram Biosciences, South San Francisco, CA) and GeneSeq HIV genotypic assay (Monogram Biosciences). DRV phenotype was defined using EC50 fold-change (FC) standard scores.

CD4 and CD8 activation, analyzing the expression of surrogate immune activation markers CD38+ and HLA-DR+ in plasma samples taken at baseline and week 24, were assessed using multiparameter, polychromatic flow cytometry-based assay strategies conducted at Duke University.

Co-receptor tropism (to CCR5 and CXCR4) was determined using the Trofile Assay (Monogram Biosciences).

Efficacy parameters included:
--virologic responses (percent of patients with HIV-1 RNA <50 copies/mL, <400 copies/mL, and HIV-1 RNA decrease from baseline >1 log10 copies/mL)
--mean change in log HIV-1 RNA from baseline
--mean change in CD4 count (cells/mm3) from baseline.

Safety parameters were assessed using descriptive statistics and focused on adverse events and serious adverse events leading to treatment discontinuation.

Stepwise logistic regression methods assessed the impact of the following baseline variables on week 24 virologic responses: genotypic susceptibility scores for OBT; DRV phenotypic sensitivity (EC50 FC); viral tropism; HIV-1 RNA;
CD4 counts; CD4 and CD8 activation (CD38+ and HLADR+); and number of prior ARVs used.

To better understand virologic response rates over the complete range of baseline DRV sensitivity phenotypes in this small dataset, we characterized responses in two ways:
-- DRV sensitivity utilizing categorical cut-offs previously cited in the literature1 (DRV FC<10, 10 to 40 and >40)
--DRV sensitivity ordered from lowest to highest values and then organized into three equal groups (low, medium and high tertiles).
-- This protocol-defined interim analysis of the efficacy and safety of DRV/r + ENF with optimized background treatment (OBT) was conducted when the first half of total patients enrolled (N = 135) completed their week 24 assessments.

Results
Patient Disposition
Of 63 eligible patients enrolled, 62 had at least one dose of trial medication and a safety follow-up at day 7 and were included in the safety analysis.

Discontinuations occurred among 14/63 (22.2%) patients enrolled.
Non-safety related: 11 (17.5%) due to the following:
--4 (6.3%) withdrew consent
--3 (4.8%) refused treatment
--2 (3.2%) failed to return
--1 (1.6%) entry criteria protocol violation
--1 (1.6%) administrative/other.

Safety related: 3 (4.8%) due to the following:
--2 (3.2%) adverse events - rash, upper gastrointestinal hemorrhage
--1 (1.6%) death (not related to trial medication).
--A total of 58 patients who received at least one dose of trial medication and received at least one post-baseline efficacy assessment at week 4 were included in the intent-to-treat (ITT) analysis.

Of the 58 patients in the ITT population, results for only 52 patients were available for phenotypic resistance to DRV. Six did not have phenotypable samples.

Patient Baseline Characteristics
The baseline characteristics of the first 63 patients enrolled are summarized in Table 1.

Table 1. Patient Baseline Characteristics (All Patients, n = 63).
40% had GSS=0, 27% GSS=1. Phenotypic DRV fold-change median 2.55 (-0.4-58.0). 75% phenotypic DRV fold-change <10, 19% >10- <40, 6% >40. Dual-mixed tropism 36%, CCR5: 24%, CXCR4: 1.7%, 21% not reportable.


Virologic and Immunologic Responses (ITT Population)
Virologic responses after treatment with ENF + DRV with an OBT at week 24 were:
-- 64% of patients achieved <50 copies/mL
--78% of patients achieved <400 copies/mL
--86% of patients achieved >1 log10 unit drop
--mean log10 viral load decrease from baseline of -2.39.

When virologic response was analyzed as a function of DRV phenotype using FC cut-offs previously described,1 the percentage of patients achieving <50 copies/mL were: (Figure 1A)
-- 67% with baseline DRV FC <10
-- 70% with baseline DRV FC ≥10 to ≤40
--67% with baseline DRV FC >40

DRV phenotype was organized into three equal tertiles across the range of low (FC 0.40-1.07); medium (FC 1.17-5.23) and high tertile (FC 6.38-58.0) phenotypes.

The tertile analysis demonstrated response rates <50 copies/mL ranging from 61% to 77%, and <400 copies/mL ranging from 77% to 88% (Figure 1B).

Figure 1. Patients with HIV-1 RNA <50 and <400 Copies/mL, and
>1 Log10 Reduction at Week 24 Categorized by Baseline DRV Fold-change
(ITT Population, Last Observation Carried Forward [LOCF]).



Figure 2. Mean HIV-1 RNA Change from Baseline to Week 24 by
Baseline DRV Phenotype (ITT Population, LOCF)


Viral load and CD4 responses at week 24 by baseline DRV phenotype are summarized in Figures 2 and 3, respectively.

Only 1 patient was found to have X4 tropism at baseline. At 24 weeks, this patient had a >1 log10 reduction in HIV-1 RNA to <50 copies/mL, with a mean log10 change from baseline of -1.33 and an increase from baseline CD4 counts of 95 cells/mm3, respectively. Virologic and CD4 response by co-receptor tropism are summarized in Table 2.

Figure 3. Mean CD4 Change from Baseline to Week 24 by Baseline DRV
Phenotype (ITT Population, LOCF).


Table 2. Summary of Viral Responses and CD4 Counts from Patients
with R5 Tropic Virus.


Multiple stepwise logistic regression of baseline factors demonstrated the impact on virologic response from baseline HIV-1 RNA (≤ or >5 log10 copies/mL) with an odds ratio of 0.101 (p<0.001), 0.165 (p=0.021) and 0.130 (p=0.020) for HIV-1 RNA <50 copies/mL, <400 copies/mL, and decrease of >1 log HIV-1 RNA from baseline, respectively.

Other baseline variables included in the model failed to identify predictors of virologic response: genotypic susceptibility score, DRV fold change, number of prior ARV treatments, CD4+ count, CD4+ activation percentage, CD8+ activation percentage, and viral tropism.

Injection Site Reactions
Although the study was not designed to compare injection site reaction (ISR) risk, the injection devices used were generally safe and well tolerated. No patients discontinued due to ISRs. More detailed information on ISRs has been
presented previously.2

Safety
Of 62 patients included in the safety analysis, a total of 11 serious adverse events occurred in 7 (11%) patients (Table 3). Two of these patients discontinued due to their adverse events (AEs).

An additional patient discontinued due to a rash not judged to be serious.

One death (unrelated to study drug) was reported in a patient with sepsis, worsening anemia, dyspnea, and worsening renal insufficiency.

Table 3. Serious Adverse Events (Safety Population, n = 62).

*One participant had these adverse events.

References
1. Clotet B, Bellos N, Molina J-M, et al. Efficacy and safety of darunavirritonavir at week 48 in treatment-experienced patients with HIV-1 infection in POWER 1 and 2: a pooled subgroup analysis of data from two randomized trials. Lancet. 2007; 369: 1169-78.
2. Gottlieb M, Farthing C, Guittari CJ and DeJesus E. Impact of patientselected
self-injection devices on the development of injection site reactions associated with enfuvirtide use. 9th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV, 19-21 July 2007; Sydney, Australia.
3. Farthing C, Gottlieb M, DeMasi RA, Thommes JA, DeJesus E. Impact of patient-selected self-injection devices on the development of injection site reactions associated with enfuvirtide use. Presented at HIV DART 2006, 10-14 December 2006; Cancun, Mexico.




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_______________________________________________
 
Regards,

Nelson Vergel
Program for Wellness Restoration
PoWeRUSA dot org


“I had rather attempt something great and fail, than to attempt nothing at all and succeed.” R. Schuller



Get a sneak peek of the all-new AOL.com.
NATAP http://natap.org/
_______________________________________________
RESPONSE TO DARUNAVIR/RITONAVIR (DRV/R) COMBINED WITH ENFUVIRTIDE (ENF)-CONTAINING ARV IN TRIPLE-CLASS EXPERIENCED PATIENTS WAS NOT PREDICTED BY BASELINE DARUNAVIR (DRV) SENSITIVITY OR VIRAL TROPISM (VT):
THE BLQ STUDY PRELIMINARY RESULTS

Reported by Jules Levin
4th IAS Conference
on HIV Pathogenesis,
Treatment and Prevention
22-25 July 2007
Sydney, Australia
Poster WePeB039

E DeJesus,1 A Zolopa,2 C Farthing,3 M Gottlieb,4 J Gathe,5 M Greenberg,6 and J Thommes7
1Orlando Immunology Center, Orlando, FL, USA; 2Stanford University Medical Center, Palo Alto, CA, USA; 3AIDS Healthcare Foundation, Los Angeles, CA, USA;
4Synergy Hematology Oncology Med. Assoc., Los Angeles, CA, USA; 5Therapeutic Concepts, Houston, TX, USA; 6Trimeris, Inc., Durham, NC, USA;
7Roche Laboratories, Nutley, NJ, USA.

Subset analyses from phase III studies in triple-class, antiretroviral (ARV)-experienced patients evaluating the efficacy and safety of darunavir/ritonavir (DRV/r) with an optimized background regimen demonstrated high rates
of virologic suppression when DRV/r was used with enfuvirtide (ENF).1

These published studies report that baseline DRV phenotypic sensitivity predicts virologic response in ARV-experienced patients treated with a DRV/r-containing regimen.1

The BLQ cohort study enrolled triple-class experienced patients experiencing virologic failure who had begun a new optimized regimen with ENF and DRV/r obtained before commercial availability through DRV expanded access in a predominantly community clinical setting, and was designed to explore the impact on virologic outcome of baseline factors such as DRV phenotypic sensitivity.

This protocol-defined interim analysis was conducted when the first half of the total cohort completed their week 24 assessments.

AUTHOR CONCLUSIONS
Treatment with ENF and DRV/r with OBT was generally well tolerated in this cohort with overall high 24-week virologic and CD4 responses that are consistent with previously reported 12-week results.3

The small dataset in this interim analysis might limit the power of logistic regression to identify predictors of virologic response other than baseline viral load.

Subsequent and comprehensive analysis of the complete cohort will be necessary to elucidate the potential impact of other factors (such as immune activation) on virologic outcome.

However, in triple-class experienced EAP patients, virologic responses at week 24 were uniformly excellent when DRV/r and ENF were combined with OBT in patients naïve to these two drugs.

In this interim analysis, no differences in virologic response were seen across the range of baseline DRV phenotypes among patients receiving ENF and DRV/r with OBT.


Methods
Prospective, open-label, 24-week, single-arm, multicenter, cohort study conducted in the US and Australia.

Eligible patients (age ≥18 years) meeting the following inclusion criteria were enrolled:
--triple-class ARV-experienced
--ENF-naïve
--DRV-naïve, either enrolled in a DRV early access program or prescribed DRV
--HIV-1 RNA >2,000 copies/mL within 60 days.

At entry all patients switched their current failing ARV treatment to a regimen consisting of:
--ENF 90 mg twice daily (BID) self-administered as a subcutaneous injection
--DRV/r 600/100 mg BID
--other investigator-selected ARVs based on treatment history and resistance testing.

Phenotypic and genotypic resistances were assessed at baseline using the PhenoSense HIV drug susceptibility assay (Monogram Biosciences, South San Francisco, CA) and GeneSeq HIV genotypic assay (Monogram Biosciences). DRV phenotype was defined using EC50 fold-change (FC) standard scores.

CD4 and CD8 activation, analyzing the expression of surrogate immune activation markers CD38+ and HLA-DR+ in plasma samples taken at baseline and week 24, were assessed using multiparameter, polychromatic flow cytometry-based assay strategies conducted at Duke University.

Co-receptor tropism (to CCR5 and CXCR4) was determined using the Trofile Assay (Monogram Biosciences).

Efficacy parameters included:
--virologic responses (percent of patients with HIV-1 RNA <50 copies/mL, <400 copies/mL, and HIV-1 RNA decrease from baseline >1 log10 copies/mL)
--mean change in log HIV-1 RNA from baseline
--mean change in CD4 count (cells/mm3) from baseline.

Safety parameters were assessed using descriptive statistics and focused on adverse events and serious adverse events leading to treatment discontinuation.

Stepwise logistic regression methods assessed the impact of the following baseline variables on week 24 virologic responses: genotypic susceptibility scores for OBT; DRV phenotypic sensitivity (EC50 FC); viral tropism; HIV-1 RNA;
CD4 counts; CD4 and CD8 activation (CD38+ and HLADR+); and number of prior ARVs used.

To better understand virologic response rates over the complete range of baseline DRV sensitivity phenotypes in this small dataset, we characterized responses in two ways:
-- DRV sensitivity utilizing categorical cut-offs previously cited in the literature1 (DRV FC<10, 10 to 40 and >40)
--DRV sensitivity ordered from lowest to highest values and then organized into three equal groups (low, medium and high tertiles).
-- This protocol-defined interim analysis of the efficacy and safety of DRV/r + ENF with optimized background treatment (OBT) was conducted when the first half of total patients enrolled (N = 135) completed their week 24 assessments.

Results
Patient Disposition
Of 63 eligible patients enrolled, 62 had at least one dose of trial medication and a safety follow-up at day 7 and were included in the safety analysis.

Discontinuations occurred among 14/63 (22.2%) patients enrolled.
Non-safety related: 11 (17.5%) due to the following:
--4 (6.3%) withdrew consent
--3 (4.8%) refused treatment
--2 (3.2%) failed to return
--1 (1.6%) entry criteria protocol violation
--1 (1.6%) administrative/other.

Safety related: 3 (4.8%) due to the following:
--2 (3.2%) adverse events - rash, upper gastrointestinal hemorrhage
--1 (1.6%) death (not related to trial medication).
--A total of 58 patients who received at least one dose of trial medication and received at least one post-baseline efficacy assessment at week 4 were included in the intent-to-treat (ITT) analysis.

Of the 58 patients in the ITT population, results for only 52 patients were available for phenotypic resistance to DRV. Six did not have phenotypable samples.

Patient Baseline Characteristics
The baseline characteristics of the first 63 patients enrolled are summarized in Table 1.

Table 1. Patient Baseline Characteristics (All Patients, n = 63).
40% had GSS=0, 27% GSS=1. Phenotypic DRV fold-change median 2.55 (-0.4-58.0). 75% phenotypic DRV fold-change <10, 19% >10- <40, 6% >40. Dual-mixed tropism 36%, CCR5: 24%, CXCR4: 1.7%, 21% not reportable.


Virologic and Immunologic Responses (ITT Population)
Virologic responses after treatment with ENF + DRV with an OBT at week 24 were:
-- 64% of patients achieved <50 copies/mL
--78% of patients achieved <400 copies/mL
--86% of patients achieved >1 log10 unit drop
--mean log10 viral load decrease from baseline of -2.39.

When virologic response was analyzed as a function of DRV phenotype using FC cut-offs previously described,1 the percentage of patients achieving <50 copies/mL were: (Figure 1A)
-- 67% with baseline DRV FC <10
-- 70% with baseline DRV FC ≥10 to ≤40
--67% with baseline DRV FC >40

DRV phenotype was organized into three equal tertiles across the range of low (FC 0.40-1.07); medium (FC 1.17-5.23) and high tertile (FC 6.38-58.0) phenotypes.

The tertile analysis demonstrated response rates <50 copies/mL ranging from 61% to 77%, and <400 copies/mL ranging from 77% to 88% (Figure 1B).

Figure 1. Patients with HIV-1 RNA <50 and <400 Copies/mL, and
>1 Log10 Reduction at Week 24 Categorized by Baseline DRV Fold-change
(ITT Population, Last Observation Carried Forward [LOCF]).



Figure 2. Mean HIV-1 RNA Change from Baseline to Week 24 by
Baseline DRV Phenotype (ITT Population, LOCF)


Viral load and CD4 responses at week 24 by baseline DRV phenotype are summarized in Figures 2 and 3, respectively.

Only 1 patient was found to have X4 tropism at baseline. At 24 weeks, this patient had a >1 log10 reduction in HIV-1 RNA to <50 copies/mL, with a mean log10 change from baseline of -1.33 and an increase from baseline CD4 counts of 95 cells/mm3, respectively. Virologic and CD4 response by co-receptor tropism are summarized in Table 2.

Figure 3. Mean CD4 Change from Baseline to Week 24 by Baseline DRV
Phenotype (ITT Population, LOCF).


Table 2. Summary of Viral Responses and CD4 Counts from Patients
with R5 Tropic Virus.


Multiple stepwise logistic regression of baseline factors demonstrated the impact on virologic response from baseline HIV-1 RNA (≤ or >5 log10 copies/mL) with an odds ratio of 0.101 (p<0.001), 0.165 (p=0.021) and 0.130 (p=0.020) for HIV-1 RNA <50 copies/mL, <400 copies/mL, and decrease of >1 log HIV-1 RNA from baseline, respectively.

Other baseline variables included in the model failed to identify predictors of virologic response: genotypic susceptibility score, DRV fold change, number of prior ARV treatments, CD4+ count, CD4+ activation percentage, CD8+ activation percentage, and viral tropism.

Injection Site Reactions
Although the study was not designed to compare injection site reaction (ISR) risk, the injection devices used were generally safe and well tolerated. No patients discontinued due to ISRs. More detailed information on ISRs has been
presented previously.2

Safety
Of 62 patients included in the safety analysis, a total of 11 serious adverse events occurred in 7 (11%) patients (Table 3). Two of these patients discontinued due to their adverse events (AEs).

An additional patient discontinued due to a rash not judged to be serious.

One death (unrelated to study drug) was reported in a patient with sepsis, worsening anemia, dyspnea, and worsening renal insufficiency.

Table 3. Serious Adverse Events (Safety Population, n = 62).

*One participant had these adverse events.

References
1. Clotet B, Bellos N, Molina J-M, et al. Efficacy and safety of darunavirritonavir at week 48 in treatment-experienced patients with HIV-1 infection in POWER 1 and 2: a pooled subgroup analysis of data from two randomized trials. Lancet. 2007; 369: 1169-78.
2. Gottlieb M, Farthing C, Guittari CJ and DeJesus E. Impact of patientselected
self-injection devices on the development of injection site reactions associated with enfuvirtide use. 9th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV, 19-21 July 2007; Sydney, Australia.
3. Farthing C, Gottlieb M, DeMasi RA, Thommes JA, DeJesus E. Impact of patient-selected self-injection devices on the development of injection site reactions associated with enfuvirtide use. Presented at HIV DART 2006, 10-14 December 2006; Cancun, Mexico.




**************************************
Get a sneak peek of the all-new AOL at http://discover.aol.com/memed/aolcom30tour 
_______________________________________________
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This is an annoucement-only mailing list.  Do not reply.

To unsubscribe: send a blank email to nataphcvhiv-request@... with a
subject of unsubscribe.


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_______________________________________________

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