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#242 From: PoWeRTX@...
Date: Thu Jun 28, 2007 12:29 am
Subject: Tipranavir before darunavir increases susceptibility to darunavir 		nelsonvergel
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"Tipranavir (Aptivus) before darunavir (Prezista)  increases susceptibility to darunavir for the circulating virus population. The impact of archived mutations on durable response to subsequent treatment with darunavir is unknown and can only be determined by clinical investigation."
 

Regards,

Nelson Vergel
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#243 From: PoWeRTX@...
Date: Thu Jun 28, 2007 12:50 am
Subject: FDA grants speedy review for new class of HIV drug 		nelsonvergel
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FDA grants speedy review for new class of HIV drug

Wed Jun 27, 2007 1:25PM EDT

NEW YORK (Reuters Health) - U.S. regulators will review Isentress, an investigational drug for HIV infection, on a priority basis, and a decision is anticipated by mid-October, Merck & Co. said on Wednesday.

The oral drug is the first in an HIV drug class called integrase inhibitors. It is generically known as raltegravir, and formerly known as MK-0518. The drug blocks the insertion of HIV's genetic material into human DNA and thereby prevents the virus from replicating. It should be taken twice daily, and can be taken with or without food.

The preliminary results of two phase III trials, presented earlier this year at 14th Annual Retroviral Conference, showed that raltegravir is active against HIV in patients resistant to all three previously approved drug classes for HIV infection.

Merck said the drug, if approved, will be used alongside standard oral HIV drugs by patients who are no longer adequately protected by their current treatments because of viral resistance.

The agency grants priority review to products that are considered to be potentially significant therapeutic advancements over existing therapies.

With priority review status, the U.S. Food and Drug Administration will make its decision on whether to approve the drug within 6 months, rather than the usual 10- to 12-month review period.

Merck tested Isentress in patients who continued to take a standard HIV drug regimen, although they were infected with strains of the virus that had become resistant to at least one drug in each drug class.

Merck added that it is also moving forward with marketing applications for the drug outside of the United States.

© Reuters 2006. All rights reserved. Republication or redistribution of Reuters content, including by caching, framing or similar means, is expressly prohibited without the prior written consent of Reuters. Reuters and the Reuters sphere logo are registered trademarks and trademarks of the Reuters group of companies around the world.

 

Regards,

Nelson Vergel
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#244 From: PoWeRTX@...
Date: Fri Jun 29, 2007 11:14 am
Subject: HIV Research Group Calls for Improving System of Patient Access to Investigation 		nelsonvergel
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I was part of this meeting and was very happy with the outcome. I hope the FDA and pharma listen to us. Representatives from the FDA, industry (Merck, Pfizer, Tibotec, Panacos and BI) , physician groups, Kaiser Permanente, researchers, and others were part of the discussion.
 
 
**************************************

HIV Research Group Calls for Improving System of Patient Access to Investigational Drugs

With the first agents from 2 new classes of antiretroviral drugs poised to receive regulatory approval this year, the Forum for Collaborative HIV Research, an independent advocacy group, has called for reassessment of the way investigational new drugs are made available to patients in need.

Below is the text of the group's June 14 press release:

HIV Research Group Calls for Improving System of Patient Access to Cutting-Edge Investigational HIV Drugs

With New Treatments in the Pipeline, Scientists, Industry, Patient Groups Say Change is Needed if All are to Benefit

WASHINGTON, DC (June 14, 2007) -- With at least three promising new HIV drugs in development, radical reform is needed of "expanded access programs" that allow patients to take new drugs before final federal approval.

Such programs can be critically important to HIV patients who no longer respond to current treatments. However, the system for providing access to experimental drugs is fragmented and under-funded, and discourages academic health centers and private physicians from participating, according to a report released today by the Forum for Collaborative HIV Research, an independent public-private partnership comprised of academic researchers, patient advocates, government officials and industry representatives.

The report reviews these problems and recommends guidelines for fixing the system, including a recommendation that drug companies consider reimbursing health care providers for Expanded Access Program (EAP) costs.

"The goal of expanded access programs is to make promising drugs in the late stages of clinical trials available to patients who urgently need treatment and have exhausted all currently approved therapies," said Ben Cheng, Deputy Director of the Forum. "Unfortunately, the current mechanism for early access to these promising drugs serves neither patients, companies, nor regulators."

The United States lacks data regarding the extent to which patients have run out of treatment options, but one estimate in the report suggests that as many as 13 percent of HIV patients have run out of treatment options. EAPs have provided critical medical options for such patients since the early years of HIV treatment, when HIV activists first pressed the Food and Drug Administration [FDA] for such options. But today EAPs are riddled with problems, according to the report, "Rethinking the Approach to Expanded Access Programs."

Among the main problems, EAPs are:

• Expensive to administer, limiting the ability of many healthcare sites to participate, as they must cover such costs themselves. The costs of administration are currently not reimbursed by drug companies, though they are when drugs are provided to patients in clinical trials.

• Poorly advertised;

• Usually dependent on only one novel drug in treating patients. Though policies may recommend using at least two active therapies, many patients are resistant to the other drugs that are available. This can lead to virtual monotherapy, and to the risk of developing resistance to the new treatment.

• Relatively inaccessible to minorities, women and rural residents;

• Failing to take advantage on a valuable opportunity to gather useful safety data on emerging drugs.

The associated expenses and administrative obstacles can be particularly onerous at academic medical centers, where financial and bureaucratic hurdles are greater than in private practices or community-based clinics.

As a result, many academic centers have opted out of participation in EAPs. But treatment opportunities offered by the emergence of simultaneous EAPs for three new drugs (raltegravir [Isentress, formerly MK-0518], etravirine [TMC125], and maraviroc [Celsentri]) are leading some of these institutions to reconsider their decisions so they can offer the new drugs to patients who need them.

But, according to the report, administrators warn that the programs will remain in jeopardy until reliable sources of funding are found to cover high expenses related to data collection requirements and approval processes from internal review boards.

The report is being released at a pivotal moment in the history of HIV drug development, according to its authors. There are a number of drugs in the development pipeline that offer novel approaches to treating HIV. Among these are: a new protease inhibitor, new entry inhibitor drugs that block the CCR5 receptor on immune cells, and new integrase inhibitors.

"Patients groups are particularly excited that so many new options are becoming available," said Veronica Miller, Director of the Forum. "But it is clear that changes must be implemented to make sure that we can expand access to these new therapies as they are proven basically safe and effective."

The report's recommendations are based on the outcome of a recent Forum workshop, which brought together representatives of academic health centers, advocacy groups, pharmaceutical companies, and the Food and Drug Administration. It is particularly timely, given that the United States Food and Drug Administration is in the midst of revising its rules for the regulation of EAPs for other diseases.

Report Recommendations

The HIV Forum report identifies several key directions for improving the EAP system, suggesting that:

• Policymakers explore a two-tiered approach to EAPs. One would be an actual research protocol designed to answer specific questions leading to drug approval. The other would be a simplified system, with fewer data requirements. Both would be would eligible for reimbursement from drug companies, as are traditional clinical trials;

• Pharmaceutical companies work together and with regulatory agencies to design EAPs that simultaneously use several different new drugs in order to limit the use of "virtual monotherapy" and lessen the chance of developing drug-resistant strains of HIV;

• Changes be implemented to decrease the burden of paperwork, among them, standardization of EAP data collection requirements and safety reporting;

• Pharmaceutical companies collaborate to standardize their case report forms and adverse events reporting for their EAPs;

• Develop a centralized electronic database, and other technological tools, to provide real-time access to analyse results, including adverse events for the EAP.

"Every time there is an adverse event, physicians have to report it," Cheng said. "But there is no way to find out whether this is happening in five or 50 percent of patients. None of the information is being analyzed until the program is finished."

Since EAPs were first initiated for HIV drugs in the 1980s, they have saved or prolonged the lives of thousands of HIV patients. Since 1998, however, the use of EAPs for HIV drugs has decreased, and that the size of the patient population that currently needs access to investigational antiretroviral drugs is difficult to estimate. Refining this estimate will be an important aspect of reforming EAPs, according to the study.

The Forum for Collaborative HIV Research is an independent public-private partnership whose mission is to facilitate discussion on emerging issues in HIV clinical research and the transfer of research results into care. It is comprised of international experts from government agencies, pharmaceutical companies, academia, advocacy and community organizations, and private foundations. The Forum is housed in the Department of Prevention and Community Health at The George Washington University School of Public Health and Health Services. For further information, visit: www.hivforum.org and click on "Rethinking the Approach to Expanded Access Programs"

06/29/07

Source
Forum for Collaborative HIV Research. HIV Research Group Calls for Improving System of Patient Access to Cutting-Edge Investigational HIV Drugs. Press release. June 14, 2007.

 
 

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Nelson Vergel
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#245 From: PoWeRTX@...
Date: Tue Jul 10, 2007 12:10 pm
Subject: Report from the XVI International HIV Drug Resistance Workshop 		nelsonvergel
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Meeting Report

Report from the XVI International HIV Drug Resistance Workshop

An expert’s take on the most clinically relevant findings from this year’s resistance meeting

Many new agents from novel drug classes are now available through expanded access and are expected to gain FDA approval within the next year. Having so many new agents available at the same time means that clinicians can finally construct salvage regimens that maximize the likelihood of full virologic suppression while minimizing further resistance. Still, resistance to these new agents is inevitable, as indicated by many presentations at this year’s International HIV Drug Resistance Workshop, which took place in mid-June in Barbados. The findings described herein are all from industry-supported studies.

CCR5 Antagonists
Two CCR5 antagonists are currently in the late stages of clinical development: Maraviroc is available through expanded-access programs, with FDA approval seemingly imminent, and vicriviroc is entering phase III investigation. Because these drugs bind to host receptors rather than to the virus itself, patterns of efficacy and resistance will likely differ from those of other antiretrovirals.

Tsibris and colleagues analyzed the characteristics of a virus that developed resistance to vicriviroc in ACTG 5211, a phase IIb trial in highly treatment-experienced patients (ACC Jul 9 2007) [Abstract 13]. Similarly, Mori and colleagues characterized four viruses that developed resistance to maraviroc in the phase III MOTIVATE trials [Abstract 10]. Several findings from these studies were notable.

First, the mutations responsible for CCR5-antagonist resistance were in the V3 loop, but their positions and specific amino-acid substitutions varied from one virus to the next. Consequently, clinicians will need to rely on phenotypic testing, rather than genotypic testing, to identify viruses that are resistant to this drug class.

Second, phenotypic tests did not reveal the classic pattern of resistance: The 50% inhibitory concentration did not change, as it does with resistance to other antiretroviral drug classes. Instead, a plateau effect was seen, such that no amount of drug could maximally suppress the virus. This unusual pattern complicates the definition of drug resistance, even with phenotypic testing.

Finally, the mutations observed in the V3 loop seemed to reduce viral fitness in the absence of the drug, such that wild-type virus had the advantage when the drug was withdrawn. Interestingly, the virus that showed the greatest degree of resistance to vicriviroc grew better when the drug was present rather than absent, indicating that the resistant virus had developed a degree of dependence on the drug for optimal replication.

In another analysis from the MOTIVATE trials, Lewis and colleagues explored the development of CXCR4-using virus during treatment [Abstract 56]. Surprisingly, they found that viruses that started using CXCR4 receptors during treatment were often phylogenetically unrelated to the predominant viruses present at baseline. In some cases, the virus found during treatment was a minor variant in the starting population. These findings suggest that, in some patients, the baseline virus is not evolving into a dual/mixed CXCR4-using virus through the accumulation of mutations; instead, a pre-existing dual/mixed or CXCR4-using virus might be present at baseline that goes undetected by the phenotypic assay and then gets selected by CCR5 antagonists during treatment. This pathway of viral escape seems to be fairly common, accounting for two thirds of virologic failures with maraviroc and 40% of failures with vicriviroc. Thus, the emergence of true resistance (in which mutations accumulate and render the drug ineffective) appears to be relatively less common.

Integrase Inhibitors
The integrase inhibitors furthest along in clinical development are raltegravir, which is available through expanded-access programs, and elvitegravir, which is being investigated in phase II studies. In separate presentations, Hazuda and McColl described resistance patterns in patients who experienced virologic failure in phase II trials of these two drugs [Abstracts 8 and 9]. Both reports implicated the same set of mutations (at positions 148 and 155 of the integrase) and demonstrated that a mutation at either position could confer cross-resistance to both compounds. These findings underscore the importance of using integrase inhibitors in combination with other active drugs.

Etravirine
The novel NNRTI etravirine (formerly TMC125) has been studied in the phase III DUET trials (Lancet 2007; 370:29, 39) and is available by expanded access. Vingerhoets and colleagues reported on resistance patterns among DUET participants, all of whom had NNRTI-resistant virus and were randomized to receive optimized background regimens, the new PI darunavir, and either etravirine or placebo [Abstract 32]. The likelihood of virologic response to etravirine was inversely related to the number of NNRTI mutations present at baseline. Notably, when present alone, the 181C mutation did not confer resistance to etravirine; only when it was combined with at least three other NNRTI mutations did it have any major detrimental effect on virologic response to etravirine.

Lopinavir
Resistance to lopinavir is fairly uncommon in patients who receive the drug as part of a first PI-containing regimen. Two research groups documented a new pathway to such resistance, involving the L76V mutation [Abstracts 127 and 75]. This mutation emerged most commonly in people who had nonsubtype-B virus (predominantly African immigrants to Europe).

Additional information about lopinavir resistance came from a report on ACTG 5142, a large randomized trial that compared three regimens: an efavirenz-based regimen (with 2 NRTIs), a lopinavir/ritonavir-based regimen (with 2 NRTIs), and a nucleoside-sparing regimen (with efavirenz + lopinavir/r). As previously reported, the efavirenz-based regimen performed slightly better than the lopinavir-based regimen, and the nucleoside-sparing arm did about as well as the efavirenz-based arm (ACC Sep 18 2006). Now, Haubrich and colleagues have analyzed the prevalence and patterns of resistance in 180 of the trial participants who experienced virologic failure [Abstract 57]. Seventy percent of these patients demonstrated evidence of resistance to one or more drugs, with distinct patterns seen in each treatment arm. Among patients who experienced failure on efavirenz-based regimens, 44% had evidence of resistance to efavirenz, and 30% had evidence of resistance to an NRTI, mainly 3TC. In contrast, among patients who experienced failure on lopinavir-based regimens, only 19% had resistance to NRTIs, and none had resistance to lopinavir. In the nucleoside-sparing arm, two thirds of patients with treatment failure had evidence of efavirenz resistance, but only 4% had evidence of lopinavir resistance. Overall, these findings highlight an important trade-off between efavirenz and lopinavir: Efavirenz-based regimens are slightly more successful in terms of maintaining virologic suppression, but when these regimens fail, the chances of resistance are greater than those seen with lopinavir-based regimens. The reason for the difference in performance of the efavirenz- and lopinavir-based regimens is not clear but may be related to minor differences in tolerability of the two regimens (patients in this study used the older gel formulation of lopinavir/r, which has since been replaced by a tablet formulation that may be better tolerated).

— Daniel R. Kuritzkes, MD

Dr. Kuritzkes is a Professor of Medicine at Harvard Medical School and Director of AIDS Research at Brigham and Women’s Hospital in Boston. He was co-chair of ACTG 5211 and directed the related analysis described in Abstract 13. He is a consultant to and has received honoraria and/or research support from Abbott, Gilead, Merck, Pfizer, Schering-Plough, and Tibotec, all of which produce drugs discussed in this report.

Published in AIDS Clinical Care July 9, 2007

 

Regards,

Nelson Vergel
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#246 From: Nelson Vergel <PoWeRTX@...>
Date: Mon Jul 23, 2007 10:56 pm
Subject: Fwd: NAAP/Sydney: Reyataz-Raltegravir PK levels 		nelsonvergel
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Although Merck does not think there is virologic benefit of using Reyataz to boost raltegravir,  I have seen reduction in VL myself (and reported by others) when we use Reyataz and raltegravir together


I think if someone with extensive treatment experience is to start Raltegravir, it would not hurt to add Reyataz to the background therapy to ensure sustained undetectable viral load with higher raltegravir concentrations. This is just a suggestion and it is not supported by Merck.

Nelson Vergel
powerusa dot org

also at nelsonvergel@...


-----Original Message-----
From: nataphcvhiv@...
To: hiv@...; nataphcvhiv@...; natapindustry@...; natapdoctors@...
Sent: Mon, 23 Jul 2007 5:31 pm
Subject: NATAP/Sydney: Reyataz-Raltegravir PK levels

NATAP http://natap.org/
_______________________________________________
Atazanavir modestly increases plasma levels of MK-0518

Reported by Jules Levin
4th IAS Conference, 22-25, july 2007, Sydney, Australia

G Mistry1, L Wenning1, A Petry1, S Liou1, S Merschman1, K Ghosh1, M Gutierrez2, J Stone1,
K Gottesdiener1, J Wagner1, M Iwamoto1
1Merck & Co., Inc., Whitehouse Station, NJ, and
2Comprehensive Neuroscience Inc., Fort Lauderdale, FL, United States

AUTHORS CONCLUDE:
--Multiple doses of ATV modestly increase plasma levels of MK-0518.
--MK-0518 is generally well tolerated when coadministered with ATV.
--Based on the safety and tolerability profile of MK-0518 to date, no dose adjustment of MK-0518 is anticipated.


ABSTRACT
Objective
MK-0518 is a novel HIV-1 integrase inhibitor with potent in vitro activity against HIV-1 (IC95 = 33 nM in 50% human serum). MK-0518 is primarily metabolized by UGT1A1 mediated glucuronidation and has no inhibitory or inductive potential in vitro. The protease inhibitor (PI) atazanavir (ATV) is known to inhibit UGT1A1. MK-0518 may be coadministered with ATV. The purpose of this study was to examine the effects of ATV on the pharmacokinetics (PK) of MK-0518.

Methods
In this randomized, double-blind, placebo-controlled, sequential, 2-period study, 12 healthy male subjects received a single oral 100-mg dose of MK-0518 in Period 1. In Period 2, 400 mg ATV was administered qd for 9 days and, on Day 7, a 100-mg dose of MK-0518 was coadministered with ATV. There was a 4-day washout interval between the periods. Plasma samples were collected for MK-0518 assay after single dose administration in Period 1 and on Day 7 of Period 2 following coadministration with ATV. Adverse experiences
(AEs) were monitored throughout the study. Geometric mean ratios with 90% confidence intervals (GMR [90% CI]) were reported for the MK-0518 PK parameters.

Results
All subjects completed the study and no serious AEs were reported. MK-0518 trough concentrations (C12 hr) increased by 95% in the presence of ATV (GMR=1.95 [1.30, 2.92]) versus alone.

Higher AUC0-∞ (increased 72%) and Cmax (increased 53%) values were also observed when MK-0518 was coadministered with ATV (GMR= 1.72 [1.47, 2.02] for AUC and 1.53 [1.11, 2.12] for Cmax).

No substantial differences were observed in the Tmax or half-life of MK-0518 in the presence of ATV.

Conclusions
Multiple doses of ATV modestly increase plasma levels of MK-0518. MK-0518 is generally well tolerated when coadministered with ATV. Based on the safety and tolerability profile of MK-0518 to date, no dose adjustment of MK-0518 is anticipated.

INTRODUCTION
MK-0518 (raltegravir) is a novel HIV-1 integrase inhibitor with potent in vitro activity against HIV-1 (IC95 = 33 nM in 50% human serum).

MK-0518 is primarily metabolized by glucuronidation via UGT1A1 and has a low propensity to act as a perpetrator of drug-drug interactions.

Atazanavir (ATV), a protease inhibitor (PI), inhibits UGT1A1, as well as CYP3A, CYP1A2, and CYP2C9.

ATV is a commonly prescribed PI as part of Highly Active Anti-Retroviral Therapy (HAART) used to treat HIV-1 infection. The recommended efficacious dose of ATV is 400 mg once daily with food in treatment-naïve patients and 300 mg ATV + 100 mg ritonavir (RTV) once daily with food in treatment-experienced patients.

MK-0518 may eventually be coadministered with ATV.

Therefore, the purpose of this Phase I study was to examine the effects of ATV on the pharmacokinetics of MK-0518. Effect of MK-0518 on ATV pharmacokinetics was not evaluated since the available data indicates that MK-0518 does not interfere with the CYP pathways mediating metabolism of ATV.


METHODS
Study Design
This was a randomized, double-blind, placebo-controlled, sequential, 2-period study in healthy male subjects.

Twelve (12) subjects, aged 25 to 43 years, received single MK-0518 (or matching placebo) doses alone in Period 1 and then, after a washout interval, MK-0518 (or matching placebo) was coadministered with ATV after multiple doses of ATV in Period 2 as follows:

Summary of Drug Administration

† There was at least a 4-day washout interval between the single dose of MK-0518 (or matching placebo) in Period 1 and the first ATV dose administered in Period 2.
‡ The same 2 subjects received placebo in each period.
N=Sample size.


Blood samples were collected at specified times up to 12 hours postdose after administration of the single dose of MK-0518 in Period 1 and in Period 2, Day 7, when both MK-0518 and ATV were coadministered for MK-0518 assay.


Analytical and Pharmacokinetic Methods
Plasma samples were analyzed for MK-0518 concentrations using a validated HPLC - MS/MS assay with limit of quantitation of 4.5 nM.

Plasma concentrations of MK-0518 were used to calculate pharmacokinetic parameter values: C12 hr, AUC0-∞ (calculated using linear trapezoidal method for ascending concentrations and log trapezoidal method for descending concentrations), Cmax, Tmax, and apparent terminal half-life (t1/2) for each subject in the presence or absence of multiple doses of ATV.

Statistical Analysis
Geometric mean ratios (GMRs) and 90% confidence intervals (CIs) for MK-0518 C12 hr, AUC0-∞, and Cmax were constructed using an appropriate mixed-effects linear model, as applied to the log-transformed data.

RESULTS

Pharmacokinetic Results
The pharmacokinetic profile of MK-0518 in the presence and absence of ATV are given in Figure I and Table I.

Figure I: Arithmetic Mean MK-0518 Plasma Concentrations Following
a Single Oral Dose of 100-mg MK-0518 With or Without Multiple Oral
Doses of 400-mg Atazanavir Once-Daily to Young, Healthy, Male Subjects

(Inset: semilog scale)



Table I: Comparison of MK-0518 Plasma Pharmacokinetics in Young, Healthy, Male Subjects Administered a Single Oral 100-mg Dose of MK-0518 With or Without Multiple Oral Doses of 400-mg Atazanavir Once-Daily

† Harmonic mean reported for t1/2.
‡ Geometric mean computed from least squares estimate from an ANOVA performed on the natural-log transformed values.
§ Median reported for Tmax.
_ Hodges-Lehman estimate of median treatment difference with corresponding 90% CI for true median treatment difference.
CI = Confidence interval; GM= Geometric mean; GMR = Geometric mean ratio.


MK-0518 C12 hr increased by an average of 95% in the presence of ATV (GMR=1.95) and the corresponding 90% CI was (1.30, 2.92).

Higher AUC0-∞ (increased 72%) and Cmax (increased 53%) values were also observed when MK-0518 was coadministered with ATV (GMR= 1.72 [1.47, 2.02] for AUC and 1.53 [1.11, 2.12] for Cmax).

No substantial differences were observed in Tmax or t1/2 of MK-0518 in the presence of ATV. In the current study, the plasma concentrations of MK-0518 resulting from the coadministration with ATV alone were generally similar compared to the coadministration of MK-0518 with ATV and RTV.1

Safety Results
All subjects completed the study and no serious AEs were reported.
Nine (9) subjects reported a total of 12 nonserious clinical AEs in Period 2, 8 of which were considered by the investigator as related to study drug.

No AEs were reported in Period 1 when the subjects received MK-0518 alone.
The most common drug-related AE was hyperbilirubinaemia (7/8 reports), which is a known side effect of ATV, 1 episode of which occurred when the subject received placebo matched to MK-0518 + ATV.

REFERENCE
1. Mistry GC, Wenning LA, Merschman S, Kost JT, Bridson WE, Stone J, Gottesdiener KM, Wagner JA, Iwamoto M. Atazanavir and ritonavir increase plasma levels of MK-0518. Poster presented at: Eighth International Congress on Drug Therapy in HIV Infection. Glasgow, Scotland; 2006. Abstract published in Eighth International Congress on Drug Therapy in HIV Infection: Abstracts. 2006; P291.




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Reply | Messages in this Topic (2)
#247 From: "toddjr99214" <toddjr99214@...>
Date: Wed Jul 25, 2007 3:29 pm
Subject: Question on Merck drug. 		toddjr99214
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Hi,

Any info on the side effect mainly liver toxicity on the new Merck
drug?  Anyone has elevated numbers on liver figures after taking it?

And what are the other options if the Merck drug harms the liver so
much that one has to get off the drug?

I understand from your website that there're three new drugs under the
pipeline for salvage patients, in which Merck's new drug is one of
them.  Any other possible same class of drugs as Merck's one are
undergoing trial that may be possible for access in the next couple
years.

Sorry for so many questions but I would really appreciate if you can
share some valuable information on this issue as your earliest possible.

Sincerely,
YC

Reply | Messages in this Topic (2)
#248 From: Stephen <myotheremail123@...>
Date: Tue Jul 24, 2007 6:41 pm
Subject: Re: Fwd: NAAP/Sydney: Reyataz-Raltegravir PK levels 		myotheremail123
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Nelson,
I am glad you posted this study and added your comment
at the top.  It seems so clear in my case that adding
Reyataz boosted raltegravir.  Without Reyataz, we
measured my VL four times:
- 191 and 149 in mid-April;
- 105 three weeks later;
- 143 three weeks after that (June 6).

These numbers were a great improvement on the 102,000
VL I had before raltegravir and etravirine, but we
were worried that the VL was not dropping below 50
copies.  The ONLY change we then made to my regimen
was adding 300 mg. Reyataz (not 400 because I was
already taking Norvir).  After being on the Reyataz
for four weeks, my VL dropped to undetectable levels
for the first time.  Not scientific proof, but another
individual case that seems to show what the study's
authors propose.
-Stephen



--- Nelson Vergel <PoWeRTX@...> wrote:

>
> Although Merck does not think there is virologic
> benefit of using Reyataz to boost raltegravir,  I
> have seen reduction in VL myself (and reported by
> others) when we use Reyataz and raltegravir together
>
>
> I think if someone with extensive treatment
> experience is to start Raltegravir, it would not
> hurt to add Reyataz to the background therapy to
> ensure sustained undetectable viral load with higher
> raltegravir concentrations. This is just a
> suggestion and it is not supported by Merck.
>
>
> Nelson Vergel
> powerusa dot org
>
> also at nelsonvergel@...
>
>
> -----Original Message-----
> From: nataphcvhiv@...
> To: hiv@...; nataphcvhiv@...;
> natapindustry@...; natapdoctors@...
> Sent: Mon, 23 Jul 2007 5:31 pm
> Subject: NATAP/Sydney: Reyataz-Raltegravir PK levels
>
>
>
> NATAP http://natap.org/
> ______________________________________________
>
>
> Atazanavir modestly increases plasma levels of
> MK-0518
>
> Reported by Jules Levin
> 4th IAS Conference, 22-25, july 2007, Sydney,
> Australia
>
> G Mistry1, L Wenning1, A Petry1, S Liou1, S
> Merschman1, K Ghosh1, M Gutierrez2, J Stone1,
> K Gottesdiener1, J Wagner1, M Iwamoto1
> 1Merck & Co., Inc., Whitehouse Station, NJ, and
> 2Comprehensive Neuroscience Inc., Fort Lauderdale,
> FL, United States
>
> AUTHORS CONCLUDE:
> --Multiple doses of ATV modestly increase plasma
> levels of MK-0518.
> --MK-0518 is generally well tolerated when
> coadministered with ATV.
> --Based on the safety and tolerability profile of
> MK-0518 to date, no dose adjustment of MK-0518 is
> anticipated.
>
>
> ABSTRACT
> Objective
> MK-0518 is a novel HIV-1 integrase inhibitor with
> potent in vitro activity against HIV-1 (IC95 = 33 nM
> in 50% human serum). MK-0518 is primarily
> metabolized by UGT1A1 mediated glucuronidation and
> has no inhibitory or inductive potential in vitro.
> The protease inhibitor (PI) atazanavir (ATV) is
> known to inhibit UGT1A1. MK-0518 may be
> coadministered with ATV. The purpose of this study
> was to examine the effects of ATV on the
> pharmacokinetics (PK) of MK-0518.
>
> Methods
> In this randomized, double-blind,
> placebo-controlled, sequential, 2-period study, 12
> healthy male subjects received a single oral 100-mg
> dose of MK-0518 in Period 1. In Period 2, 400 mg ATV
> was administered qd for 9 days and, on Day 7, a
> 100-mg dose of MK-0518 was coadministered with ATV.
> There was a 4-day washout interval between the
> periods. Plasma samples were collected for MK-0518
> assay after single dose administration in Period 1
> and on Day 7 of Period 2 following coadministration
> with ATV. Adverse experiences
> (AEs) were monitored throughout the study. Geometric
> mean ratios with 90% confidence intervals (GMR [90%
> CI]) were reported for the MK-0518 PK parameters.
>
> Results
> All subjects completed the study and no serious AEs
> were reported. MK-0518 trough concentrations (C12
> hr) increased by 95% in the presence of ATV
> (GMR=1.95 [1.30, 2.92]) versus alone.
>
> Higher AUC0-∞ (increased 72%) and Cmax (increased
> 53%) values were also observed when MK-0518 was
> coadministered with ATV (GMR= 1.72 [1.47, 2.02] for
> AUC and 1.53 [1.11, 2.12] for Cmax).
>
> No substantial differences were observed in the Tmax
> or half-life of MK-0518 in the presence of ATV.
>
> Conclusions
> Multiple doses of ATV modestly increase plasma
> levels of MK-0518. MK-0518 is generally well
> tolerated when coadministered with ATV. Based on the
> safety and tolerability profile of MK-0518 to date,
> no dose adjustment of MK-0518 is anticipated.
>
> INTRODUCTION
> MK-0518 (raltegravir) is a novel HIV-1 integrase
> inhibitor with potent in vitro activity against
> HIV-1 (IC95 = 33 nM in 50% human serum).
>
> MK-0518 is primarily metabolized by glucuronidation
> via UGT1A1 and has a low propensity to act as a
> perpetrator of drug-drug interactions.
>
> Atazanavir (ATV), a protease inhibitor (PI),
> inhibits UGT1A1, as well as CYP3A, CYP1A2, and
> CYP2C9.
>
> ATV is a commonly prescribed PI as part of Highly
> Active Anti-Retroviral Therapy (HAART) used to treat
> HIV-1 infection. The recommended efficacious dose of
> ATV is 400 mg once daily with food in
> treatment-naïve patients and 300 mg ATV + 100 mg
> ritonavir (RTV) once daily with food in
> treatment-experienced patients.
>
> MK-0518 may eventually be coadministered with ATV.
>
> Therefore, the purpose of this Phase I study was to
> examine the effects of ATV on the pharmacokinetics
> of MK-0518. Effect of MK-0518 on ATV
> pharmacokinetics was not evaluated since the
> available data indicates that MK-0518 does not
> interfere with the CYP pathways mediating metabolism
> of ATV.
>
>
> METHODS
> Study Design
> This was a randomized, double-blind,
> placebo-controlled, sequential, 2-period study in
> healthy male subjects.
>
> Twelve (12) subjects, aged 25 to 43 years, received
> single MK-0518 (or matching placebo) doses alone in
> Period 1 and then, after a washout interval, MK-0518
> (or matching placebo) was coadministered with ATV
> after multiple doses of ATV in Period 2 as follows:
>
> Summary of Drug Administration
>
> † There was at least a 4-day washout interval
> between the single dose of MK-0518 (or matching
> placebo) in Period 1 and the first ATV dose
> administered in Period 2.
> ‡ The same 2 subjects received placebo in each
> period.
> N=Sample size.
>
>
> Blood samples were collected at specified times up
> to 12 hours postdose after administration of the
> single dose of MK-0518 in Period 1 and in Period 2,
> Day 7, when both MK-0518 and ATV were coadministered
> for MK-0518 assay.
>
>
> Analytical and Pharmacokinetic Methods
> Plasma samples were analyzed for MK-0518
> concentrations using a validated HPLC - MS/MS assay
> with limit of quantitation of 4.5 nM.
>
> Plasma concentrations of MK-0518 were used to
> calculate pharmacokinetic parameter values: C12 hr,
> AUC0-∞ (calculated using linear trapezoidal method
> for ascending concentrations and log trapezoidal
> method for descending concentrations), Cmax, Tmax,
> and apparent terminal half-life (t1/2) for each
> subject in the presence or absence of multiple doses
> of ATV.
>
> Statistical Analysis
> Geometric mean ratios (GMRs) and 90% confidence
> intervals (CIs) for MK-0518 C12 hr, AUC0-∞, and
> Cmax were constructed using an appropriate
> mixed-effects linear model, as applied to the
> log-transformed data.
>
> RESULTS
>
> Pharmacokinetic Results
> Pharmacokinetic Results
> The pharmacokinetic profile of MK-0518 in the
> presence and absence of ATV are given in Figure I
> and Table I.
>
> Figure I: Arithmetic Mean MK-0518 Plasma
> Concentrations Following
>
=== message truncated ===



      
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#249 From: PoWeRTX@...
Date: Thu Jul 26, 2007 11:05 am
Subject: Re: Question on Merck drug. 		nelsonvergel
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In a message dated 7/26/2007 12:45:01 A.M. Central Daylight Time, toddjr99214@... writes:

Hi,

Any info on the side effect mainly liver toxicity on the new Merck
drug? Anyone has elevated numbers on liver figures after taking it?

And what are the other options if the Merck drug harms the liver so
much that one has to get off the drug?

I understand from your website that there're three new drugs under the
pipeline for salvage patients, in which Merck's new drug is one of
them. Any other possible same class of drugs as Merck's one are
undergoing trial that may be possible for access in the next couple
years.

Sorry for so many questions but I would really appreciate if you can
share some valuable information on this issue as your earliest possible.

Sincerely,
YC

************************
YC:
 
So far, Merck's integrase inhibitor ( research name: MK 518, generic: raltegravir, brand name: Isentress) does not seem to cause any side effect except a little bloating and gas. It does not seem to increase cholesterol, tryclicerides, liver enzymes, and creatinine.  However, it  is very early to tell.
I have taken raltegravir now for 1.5 years and all I can report is the bloating/gas.  Along with duranavir ( TMC 114 or Prezista, plus Norvir) and Truvada..it brought my viral load to under 50 for the first time ever in 24 years. But those good news only lasted 6 months. My VL rebounded to 20,000 after that. Then I dropped the Prezista/Norvir and added Reyataz to boost the raltegravir and my VL went down again to 6000 where it has stayed for months.
My CD4 cells started at 180 when I started the study, went up to 450  6 months later, and are 350 now....so I am still benefiting from the drug combo. I am concerned about future options, though. I got a tropism test and turned out R5 tropic which makes me a candidate for Maraviroc. But I have to wait for 2 other active agents before I change combos again.  I have my eye on TMC 278 and TNX 355 (if it does not get dropped by Genetech), and possibly if the maturation inhibitor class comes through eventually. Merck also has a second generation integrase MK 2078 that looks good but we have seen no data in those with raltegravir (or elvitegravir) resistance.
 
Sorry for the long answer. Tipranavir (APTIVUS) has a black box warning to warn doctors to monitor liver enzymes closely.  But I have not seen any signals when it comes to liver in all other drugs like the integrase class, Maraviroc (R5 inhibitor) , TMC 125 or 278, yet.....
 
Regards,

Nelson Vergel
Program for Wellness Restoration
PoWeRUSA dot org


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#250 From: PoWeRTX@...
Date: Thu Jul 26, 2007 4:14 pm
Subject: Fwd: NATAP/Sydney: Raltegravir 48-Week Naives-no lipids elevations 		nelsonvergel
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For the person who asked about side effects of the Merck integrase....
 
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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_______________________________________________
Raltegravir 48-week Naives potent; No Lipids Elevations

Reported by Jules Levin
9th IAS Conference, July 22-25, 2007, Sydney, Australia

Today's oral session was a major presentation at IAS Sydney. There were a number of important studies presented: the 48-week raltegravir in naives data was presented showing no lipid elevations, good side effects profile, and potent activity (83-88% <50 copies/ml, 90% <400 c/ml); Incyte presented potent activity from 14 days monotherapy with their CCR5 inhibitor (1.8 log reduction); TMC278 in naives showed a favorable lipids profile; the TITAN  study compared kaletra and TMC114 in an earlier than salvage patient situation; and we saw 48-week data from the CCR5 drug vicriviroc ACTG study 5211.

Rapid Onset and Durable Antiretroviral Effect of Raltegravir, a Novel HIV-1 Integrase Inhibitor, as Part of Combination ART in Treatment-Naïve HIV-1 Infected Patients:
48-Week Results

M. Markowitz1, B.-Y. Nguyen2, E. Gotuzzo3, F. Mendo4, W. Ratanasuwan5, C. Kovacs6, H. Wan2, L. Gilde2, M. Miller2, R. Isaacs2, H. Teppler2, and the Protocol 004 Part II Study Team

1Aaron Diamond AIDS Research Center, New York, NY; 2Merck Research Labs, West Point, PA; 3Hospital Nacionale Cayetano Heredia, Lima, Peru; 4Hospital Nacionale Edgardo Rebagliati, Lima, Peru; 6Maple Leaf Medical Center, Toronto, Canada;  5Siriraj Hospital, Bangkok, Thailand

AUTHOR SAFETY/EFFICACY SUMMARY
Overall AE profiles were generally similar across treatment groups
--No dose-related toxicities
--Drug-related clinical AEs less common with raltegravir (48%) than EFV (71%); no drug-related serious AEs
--Neuropsychiatric symptoms* less common with raltegravir than EFV:  
8% vs 21% at wk 8                                    
13% vs 29% at wk 48 
--Grade 3 / 4 lab abnormalities uncommon
-- Neutral effect of raltegravir on serum lipids

Raltegravir is a promising new HIV integrase inhibitor with rapid and durable antiretroviral effect

In treatment naïve patients with HIV RNA ≥ 5000 copies/ml and CD4 ≥ 100/mm3, raltegravir at all doses studied for 48 weeks:
-- had potent antiretroviral activity
83-88% with HIV RNA < 50 copies/mL
achieved viral suppression faster than EFV

was generally well tolerated


Raltegravir (MK-0518): HIV Integrase Strand-Transfer Inhibitor
--HIV integrase inhibition: a novel mechanism of action
--Raltegravir: potent in vitro activity
--IC95 = 31 nM ± 20 nM in 50% human serum
--Metabolism primarily via glucuronidation (UGT1A1)
--Not a potent inhibitor or inducer of CYP3A4
--Does not require “ritonavir boostingâ€

In Phase I studies,
--Doses up to 800 mg p.o. BID were generally well tolerated
--At 100 mg BID, mean C12hr > mean IC95
No dose adjustment when used with other ARTs

Protocol 004: Study design
This is a phase II study where 8 patients each were randomized to 5 different dosing schemes for a brief monotherapy in Part I and then 30 patients were given 4 different raltegravir doses + TDF/3TC or efavirenz + TDF/3TC in Part II.


Protocol 004:  Part II Design
--Part I patients continued at same dose in Part II (pbo_efv)
--About 150 additional patients randomized for Part II
Key inclusion criteria
--Susceptible to EFV, 3TC , TFV  (by genotype)
--No prior ART (<7 days allowed)
-- HIV RNA ≥ 5000 copies/mL
baseline stratification for HIV RNA ≤ or > 50,000 copies/mL
--CD4 ≥ 100 cells/mm3

Endpoints
HIV-1 RNA and CD4 counts, Adverse experiences

Hypotheses:  Raltegravir + TFV/3TC
--will be generally safe and well tolerated 
--will have antiretroviral activity similar to EFV + TFV/3TC

Patient Baseline Characteristics
65% were non-white; HIV RNA: mean 43,000-65,000; CD4: 300; % with AIDS: 30%


Patient Status at Week 48
About 200 patients in study
Discontinued by week 48: 5% in 400mg raltergavir arm, 8% in EFV arm. 0 withdrew for lack of efficacy in both arms.


HIV RNA <400 Copies/mL (95% CI) (Primary Endpoint)
[Non-Completer=Failure]
Appears to be 90%+ <400 in raltegravir arm.



HIV RNA <50 Copies/mL (95% CI)
[Non-Completer=Failure]
83-88% <50 c/ml in raltegravir arm.


Change From Baseline in HIV RNA
[Observed Failures]


Change From Baseline in CD4 Cell Count
[Observed Failures]


Virologic Failure

Definitions:  2 measurements of HIV-1 RNA at least 1 week apart

Non-response:
--  >400 copies/mL at week 24 or early discontinuation, or

Virologic relapse:
-- >400 copies/mL after initial response to <400 copies/mL, or
-- >1.0 log10 increase above nadir level.

Resistance testing in all patients with virologic failure; performed at time of failure, compared with baseline
--5 of 160 (3%) in RAL group
--1 of 38 (3%) in EFV group

Treatment-Emergent Mutations

*S230S/N is a common polymorphism not thought to affect sensitivity to integrase inhibitors.  All other mutations were associated with reduced drug sensitivity.  (--- indicates no mutations)

Adverse Event Summary
(% of patients)

RAL taken twice daily; EFV taken once daily; both with TFV/3TC.
* Determined by investigator to be possibly, probably, or definitely caused by study drug regimen.
No Serious AEs were considered drug related.

Most Common* Drug-Related
Adverse Events (% of patients)


EFFECT ON SERUM LIPIDS
Total cholesterol, LDL-cholesterol, triglycerides not increased by raltegravir
Mean change from baseline (mg/dL) at week 48
* All raltegravir dose groups combined.




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#251 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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_______________________________________________


Nelson Vergel
powerusa dot org

also at nelsonvergel@...


-----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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#252 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/
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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.

 
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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_______________________________________________
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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#253 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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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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#254 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

 
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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#255 From: PoWeRTX@...
Date: Tue Aug 21, 2007 3:18 pm
Subject: Fwd: NATAP: Monogram Trofile Assay Availability 		nelsonvergel
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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, Trofileâ„¢

August 20, 2007

Dear Friends,

On August 6, 2007, the FDA approved Selzentryâ„¢ (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 Trofileâ„¢ 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 “tropismâ€.  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, Trofileâ„¢

August 20, 2007

Dear Friends,

On August 6, 2007, the FDA approved Selzentryâ„¢ (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 Trofileâ„¢ 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 “tropismâ€.  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 | Messages in this Topic (1)
#256 From: PoWeRTX@...
Date: Wed Aug 29, 2007 12:43 pm
Subject: Be Aware of TMC 125 (Etravirine, Tibotec new non nucleoside) limitations 		nelsonvergel
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Be Aware of TMC 125 (Etravirine, Tibotec new non nucleoside) limitations

 
 
Regards,

Nelson Vergel
Program for Wellness Restoration
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“I had rather attempt something great and fail, than to attempt nothing at all and succeed.†R. Schuller



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#257 From: PoWeRTX@...
Date: Sat Sep 1, 2007 7:32 pm
Subject: Raltegravir (Merck integrase inhibitor) FDA Preclinical Development Summary 		nelsonvergel
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I am not a rat,  but no wonder Raltegravir makes me so bloated !
It is a pretty safe drug so far with no increased lipids in naive patients taking it with Truvada. Hopefully, it will get approved in a few weeks. I truly believe it will change the nature of HIV treatment worldwide and will raise the bar for all new drugs coming up after it.
 
****************************
 
"No additional toxicities were noted in juvenile rats, indicating that juvenile rats were not more sensitive to drug effects than adult rats. In mice, the mucosal irritation was manifested as dose-related increases in the incidences of gastrointestinal bloating."
 
FDA Preclinical Development Summary

This was part of the FDA safety-efficacy report.

The safety profile of raltegravir has been extensively characterized in rats, mice, rabbits, and dogs. The absorption, distribution, metabolism, and excretion (ADME) profiles of raltegravir in these species are similar to that in humans making them appropriate animal models for nonclinical safety evaluation. Toxicologic, genotoxic, allergenic, immunologic, and reproductive toxicological potential and potential effects on cardiovascular, neurologic, respiratory, gastrointestinal, renal and other systems were evaluated. Two year carcinogenicity studies in rats and mice are ongoing; the dosing phase is expected to end in the 4th quarter of 2007.

All of the pivotal toxicology studies employed an adequate range of doses and produced sufficient systemic exposures and safety margins over the clinical dose of 400 mg twice daily. Raltegravir was found to readily cross blood-brain and blood-placental barriers. It is not known whether raltegravir is secreted in human milk. The highest doses explored following chronic oral administration of raltegravir were 360 mg/kg/day in dogs (12 month administration) and 600 mg/kg/day in rats (6 month administration). Exposures at these doses were 5- and 3-fold greater than exposures observed with the proposed dose of 400 mg twice daily. At these doses, raltegravir was found to be well tolerated and produced few or no adverse effect; one notable exception was irritation to mucosal surfaces that came in contact with raltegravir.

Mucosal irritation was dose- and duration-related but was independent of age. Raltegravir at doses ≥ 120 mg/kg/day caused dose-related salivation, increases in the incidence of glandular mucosal degeneration/erosions in stomach, and incidence and severity of inflammation in nose and nasopharynx (presumably due to aspiration of drug) in adult rats. Similar irritation to mucosal surfaces was also observed in young rats. No additional toxicities were noted in juvenile rats, indicating that juvenile rats were not more sensitive to drug effects than adult rats. In mice, the mucosal irritation was manifested as dose-related increases in the incidences of gastrointestinal bloating. Irritation to mucosal surfaces is dose-limiting (mortality in rats and mice and >10% reduction in body weight gain in rats) and is independent of formulation. The toxicity was likely related to the local concentration of raltegravir rather than the systemic exposure. In contrast to the findings in rats and mice, no adverse events were observed in dogs, although dogs had the highest and longest duration of systemic exposure to raltegravir.

Raltegravir was evaluated in three in vitro and one in vivo genotoxicity assays and was found not to be mutagenic or clastogenic. The carcinogenic potential of raltegravir is being evaluated in two-year carcinogenicity studies in rats and mice; as noted, studies are ongoing. Histomorphologic examination in all prematurely necropsied animals through Week 76 showed that 5 out of 24 high dose males examined had squamous cell carcinoma in the nasopharynx or nose. In mice, histomorphologic examination in all prematurely necropsied animals through Week 76 did not detect any tumors. However, dose-related increases in the incidence of squamous metaplasia were seen in nose and  nasopharynx of both males and females at doses ≥ 50 mg/kg/day. These results confirm the irritability of raltegravir and suggest that rats are most sensitive to this toxicity. There is no indication of gastrointestinal irritation in clinical studies so far.

The safety of raltegravir was also investigated in a variety of in vitro and local tolerance studies. It is not a dermal sensitizer in the mouse local lymph node assay or a skin irritant in in vivo rabbit dermal irritation model or in vitro EpiDerm Skin Model. It is not phototoxic or hemolytic in vitro to blood cells isolated from rats, dogs, and humans. As expected, because of its irritability to mucosal surfaces, it is considered a severe irritant in the in vitro bovine corneal opacity test with in vitro score higher than that for the positive control, imidazol.

In conclusion, except for the irritation to mucosal surfaces observed in rodents, raltegravir has a favorable safety profile in animals at multiples of exposure in humans.



 

Regards,

Nelson Vergel
powerusa dot org



Get a sneak peek of the all-new AOL.com.
NATAP http://natap.org/
_______________________________________________
FDA Preclinical Development Summary

This was part of the FDA safety-efficacy report.

The safety profile of raltegravir has been extensively characterized in rats, mice, rabbits, and dogs. The absorption, distribution, metabolism, and excretion (ADME) profiles of raltegravir in these species are similar to that in humans making them appropriate animal models for nonclinical safety evaluation. Toxicologic, genotoxic, allergenic, immunologic, and reproductive toxicological potential and potential effects on cardiovascular, neurologic, respiratory, gastrointestinal, renal and other systems were evaluated. Two year carcinogenicity studies in rats and mice are ongoing; the dosing phase is expected to end in the 4th quarter of 2007.

All of the pivotal toxicology studies employed an adequate range of doses and produced sufficient systemic exposures and safety margins over the clinical dose of 400 mg twice daily. Raltegravir was found to readily cross blood-brain and blood-placental barriers. It is not known whether raltegravir is secreted in human milk. The highest doses explored following chronic oral administration of raltegravir were 360 mg/kg/day in dogs (12 month administration) and 600 mg/kg/day in rats (6 month administration). Exposures at these doses were 5- and 3-fold greater than exposures observed with the proposed dose of 400 mg twice daily. At these doses, raltegravir was found to be well tolerated and produced few or no adverse effect; one notable exception was irritation to mucosal surfaces that came in contact with raltegravir.

Mucosal irritation was dose- and duration-related but was independent of age. Raltegravir at doses ≥ 120 mg/kg/day caused dose-related salivation, increases in the incidence of glandular mucosal degeneration/erosions in stomach, and incidence and severity of inflammation in nose and nasopharynx (presumably due to aspiration of drug) in adult rats. Similar irritation to mucosal surfaces was also observed in young rats. No additional toxicities were noted in juvenile rats, indicating that juvenile rats were not more sensitive to drug effects than adult rats. In mice, the mucosal irritation was manifested as dose-related increases in the incidences of gastrointestinal bloating. Irritation to mucosal surfaces is dose-limiting (mortality in rats and mice and >10% reduction in body weight gain in rats) and is independent of formulation. The toxicity was likely related to the local concentration of raltegravir rather than the systemic exposure. In contrast to the findings in rats and mice, no adverse events were observed in dogs, although dogs had the highest and longest duration of systemic exposure to raltegravir.

Raltegravir was evaluated in three in vitro and one in vivo genotoxicity assays and was found not to be mutagenic or clastogenic. The carcinogenic potential of raltegravir is being evaluated in two-year carcinogenicity studies in rats and mice; as noted, studies are ongoing. Histomorphologic examination in all prematurely necropsied animals through Week 76 showed that 5 out of 24 high dose males examined had squamous cell carcinoma in the nasopharynx or nose. In mice, histomorphologic examination in all prematurely necropsied animals through Week 76 did not detect any tumors. However, dose-related increases in the incidence of squamous metaplasia were seen in nose and  nasopharynx of both males and females at doses ≥ 50 mg/kg/day. These results confirm the irritability of raltegravir and suggest that rats are most sensitive to this toxicity. There is no indication of gastrointestinal irritation in clinical studies so far.

The safety of raltegravir was also investigated in a variety of in vitro and local tolerance studies. It is not a dermal sensitizer in the mouse local lymph node assay or a skin irritant in in vivo rabbit dermal irritation model or in vitro EpiDerm Skin Model. It is not phototoxic or hemolytic in vitro to blood cells isolated from rats, dogs, and humans. As expected, because of its irritability to mucosal surfaces, it is considered a severe irritant in the in vitro bovine corneal opacity test with in vitro score higher than that for the positive control, imidazol.

In conclusion, except for the irritation to mucosal surfaces observed in rodents, raltegravir has a favorable safety profile in animals at multiples of exposure in humans.



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Reply | Messages in this Topic (1)
#258 From: PoWeRTX@...
Date: Fri Sep 7, 2007 5:17 pm
Subject: LUNCH AND LEARN LECTURE IN ATLANTA- SEPT 17 		nelsonvergel
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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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#259 From: PoWeRTX@...
Date: Thu Sep 13, 2007 9:49 am
Subject: KP-1461 		nelsonvergel
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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.â€

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.â€

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.


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#260 From: PoWeRTX@...
Date: Fri Aug 31, 2007 11:45 am
Subject: New Booklet for Salvage Patients by Dr Paul Bellman- NYC 		nelsonvergel
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New Booklet for Salvage Patients by Dr Paul Bellman- NYC

Paul Bellman is one of the most concerned doctors in the US on the subject of how to rescue HIV patients who have ran out of options. Here is a manuscript he wrote for patients and medical students on the subject that I highly recommend for all to read:

http://salvagetherapies.org/articals/salvageTreatment_ManualDrBellmanAug07
 
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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#261 From: PoWeRTX@...
Date: Tue Sep 18, 2007 12:01 pm
Subject: A CONSUMER GUIDE FOR GETTING AND KEEPING HEALTH INSURANCE 		nelsonvergel
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Regards,

Nelson Vergel
powerusa dot org



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The Georgetown University Health Policy Institute has written A CONSUMER GUIDE FOR GETTING AND KEEPING HEALTH INSURANCE for each state and the District of Columbia — fifty-one in all. These Consumer Guides are available at this web site and will be updated periodically as changes in federal and state policy warrant.
 
 
 
I hear this broker may find you an insurance policy under HIPPA is you are losing your insurance (you have 61 days to switch otherwise you will be limited by pre-existing conditions)
 
 
 
Also, president Clinton passed a bill to require high risk pools in different states, but some states like Georgia and Florida decided not to join. Here are the states that provide health insurance to people with pre-existing conditions:
 
 States That Have Risk Pools:  

Alabama  (for portability only)
Alabama Health Insurance Plan
Phone 1-800-513-1384 or (334) 353-8924

Alaska
Alaska Comprehensive Health Insurance Association
Phone 1-800-467-8725 or (907) 269-7900

Arkansas
Arkansas Comprehensive Health Insurance Pool
Phone 1-800-285-6477

California
California Major Risk Medical Insurance Program
Phone 1-800-289-6574 or (916) 324-4695

Colorado
CoverColorado
Phone (303) 863-1960

Connecticut
Connecticut Health Reinsurance Association
Phone 1-800-842-0004

Florida  (not open for new enrollees)
Phone (850) 309-1200  

Idaho
Idaho Individual High Risk Reinsurance Pool

Illinois
Illinois Comprehensive Health Insurance Plan
Phone 1-800-367-6410 or (217) 782-6333

Indiana
Indiana Comprehensive Health  Association
Phone 1-800-552-7921 or (317) 614-2000

Iowa
Iowa Comprehensive Health Association
Phone (877) 793-6880

Kansas
Kansas Health Insurance Association
Phone 1-800-290-1366 or (316) 792-1779

Kentucky
Kentucky Access
Phone (866) 405-6145

Louisiana
Louisiana Health Insurance Association
Phone 1-800-736-0947 or (504) 926-6245  

 Maryland
Maryland Health Insurance Plan
Phone (888) 444-9016

Minnesota
Minnesota Comprehensive Health Association
Phone (952) 593-9609  

Mississippi
Mississippi Comprehensive Health Insurance Risk Pool
Phone (601) 362-0799

Missouri
Missouri Health Insurance Pool
Phone 1-800-843-6447 (All but NW Missouri)
Phone 1-800-645-8346 (NW Missouri)

Montana
Montana Comprehensive Health Insurance Association
Phone (406) 444-8200

Nebraska  
Nebraska Comprehensive Health Association
Phone (402) 343-3574 or (877) 348-4304

New Hampshire
New Hampshire Health Plan
Phone (800) 578-3272

New Mexico
New Mexico Medical Insurance Pool
Phone (505) 622-4711

North Dakota
Comprehensive Health Association Of North Dakota
Phone 1-800-737-0016 or (701) 282-1235

Oklahoma
Oklahoma Health Insurance High Risk Pool
Phone 1-800-255-6065 or (913) 362-0040

Oregon
Oregon Medical Insurance Pool
Phone (503) 373-1692

South Carolina
South Carolina Health Insurance Pool
Phone 1-800-868-2500, ext. 42757, or 1-803-788-0500,
ext. 42757 

South Dakota
South Dakota Risk Pool

Tennessee
TennCare Program
Contact Tennessee area county medical assistance offices, or
Phone (615) 741-8642

Texas
Texas Health Insurance Risk Pool
Phone 1-888-398-3927 

Utah
Utah Comprehensive Health Insurance Pool
Phone 1-800-705-9173 or (801) 442-6660

Washington
Washington State Health Insurance Pool
Phone 1-800-877-5187

West Virginia
AccessWV
Phone 1-866-445-8491

Wisconsin
Wisconsin Health Insurance Risk Sharing Plan
Phone (608) 441-5777

Wyoming
Wyoming Health Insurance Pool
Phone (307) 634-1393

 


Reply | Messages in this Topic (1)
#262 From: PoWeRTX@...
Date: Sat Sep 22, 2007 7:18 pm
Subject: New Classes of Antiretrovirals: The Clinical Role of Integrase Inhibitors and En 		nelsonvergel
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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 classesâ€â€”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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#263 From: PoWeRTX@...
Date: Wed Sep 26, 2007 3:49 pm
Subject: Drs. Joseph J. Eron, Daniel R. Kuritzkes, and Pedro Cahn review latest data 		nelsonvergel
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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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#264 From: PoWeRTX@...
Date: Thu Oct 11, 2007 10:25 pm
Subject: FDA's Expected Approval of Merck's Antiretroviral Raltegravir Could 'Break New G 		nelsonvergel
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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



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Reply | Messages in this Topic (1)
#265 From: PoWeRTX@...
Date: Fri Oct 26, 2007 9:32 am
Subject: Info on new HIV drugs 		nelsonvergel
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Hi Nelson

I've just started Raltegravir (adding it and T20 into my
current combination of Prezista, 3TC, TMC125 and Ritonavir),
but haven't been given any patient information - my clinic
pharmacy doesn't have any information and say that this is
because it is an unlicensed drug and little is known about
it. Can you suggest any websites which might provide me with
info?
 
Fiona

******************************************
 
Dear Fiona
 
 
What do you need to know? there are no good web sites with a short summary..but here it goes
 
 
Raltegravir- trade name: Isentress. FDA approved now in the US. It is an integrase inhibitor taken twice a day with or without food. It does not need Norvir. It does not have any significant interactions with other HIV meds. Probably the most effective HIV drug so far. We do not know how sustainable the response will be  after 48 weeks and it will depend on how many active medicines you are taking with it. Side effects do not seem to be bad at all: mostly flatulence and bloating during the first weeks
 
TMC 125- Etravirine- a second generation non nucleoside ( same family as Sustiva and Viramune)-  Not FDA approved yet but available via expanded access  if doctors fill out all needed forms.  No Novir boosting required. It may lower some HIV medication blood levels so talk to your doctor about it (You should not have any concerns of adjusting dosage if you are taking it with Prezista, Isentress, Truvada).  Rash is the main side effect.  Tricky drug to know if you have resistance to since the genotype test is not available yet.  If you had resistance to Sustiva or Viramune in the past, the drug may not work as well.  It seems to work OK with the main non nuke resistance mutation L103, however.  It is good that you are starting it with two other active agents.
 
Fuzeon- enfurvitide- T-20. entry inhibitor that works to attempt to block the virus gp41. Injectable under the skin twice a day. Drug with the most data in multidrug resistance.  One side effect: injection side reactions.  Almost doubles efficacy of other drugs studied with it. Do not use the needles that come with the product since they are too wide. Get your pharmacist to provide 31 gauge insulin needles since they are very small and do not cause as many problems. A nurse can come to your house for free as many times as you need to show you best injection techniques (you can find out more in fuzeon.com)
 
Darunavir- Prezista- Second generation protease inhibitor boosted by Novir. Very good results in those with baseline sensitivity to it (around 33% pf patients with Kaletra resistance have resistance to Prezista even if they have not taken it).  Side effects are the same as most protease inhibitors. It is a sulfa based drug so it can cause some problems in sulfa sensitive patients.
 

Regards,

Nelson Vergel
powerusa dot org



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Reply | Messages in this Topic (1)
#266 From: PoWeRTX@...
Date: Thu Jan 17, 2008 7:39 pm
Subject: New Drug Soon to Be Approved: TMC125 (etravirine) Intelence ® 		nelsonvergel
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This is from Rob Camp's blog, a well known treatment activist that sends letters to the FDA before an HIV drug gets approved with his comments and observations about that drug. If you are considering taking this new NNRTI, read this:

Regards,

Nelson Vergel
powerusa dot org



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Reply | Messages in this Topic (2)
#267 From: PoWeRTX@...
Date: Fri Jan 18, 2008 6:33 pm
Subject: I am deleting this group soon 		nelsonvergel
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I just want to tell everyone that I am deleting this group soon. No activity from you guys so I feel no one really needs it . All I get is spammers trying to post

Regards,

Nelson Vergel
powerusa dot org



Start the year off right. Easy ways to stay in shape in the new year.

Reply | Messages in this Topic (1)
#268 From: "dgathers2004" <dgathers2004@...>
Date: Fri Jan 18, 2008 11:30 pm
Subject: Re: New Drug Soon to Be Approved: TMC125 (etravirine) Intelence ® 		dgathers2004
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--- In SalvageTherapies@yahoogroups.com, PoWeRTX@... wrote:
>
> This is from Rob Camp's blog, a well known treatment activist  that
sends
> letters to the FDA before an HIV drug gets approved with his
comments  and
> observations about that drug. If you are considering taking this
new NNRTI,  read
> this:
> _http://mundocamp.vox.com/_ (http://mundocamp.vox.com/)
>
> Regards,
>
> Nelson Vergel
> powerusa dot  org
>
>
>
> **************Start the year off right.  Easy ways to stay in
shape.
> http://body.aol.com/fitness/winter-exercise?
NCID=aolcmp00300000002489
>

Nelson -

      Thanks a BUNCH! for this information.  I will definetly read
this in it's entirity.  Ihave been positive for about 12 years.  I
have had T-cells (under 10) for several years and viral loads as high
as 750,000 copies.  About 3 months ago, I would put on Maravoric, TMC-
125, Isentress as well as Viread & Combivir boosted with Norivir.  I
found out today that my viral load had dropped to 2,225 copies and T-
cells increased to 108.

      I see that some of the reading that you sent touched a little
bit on success or failure as it relates to race & gender.  I will say
that I am a 45 y/o African American male who has had never had any
success with HIV meds.  Going into this regiment I had no idea what
to expect.  I now have very different outlook on my future.  Again,
thanks for this information, this is very helpful.

Daryl representing Houston :)

Reply | Messages in this Topic (2)
#269 From: "steve.white99" <steve.white99@...>
Date: Mon Mar 24, 2008 1:02 pm
Subject: Doctor, Physician and Nurse Jobs 		steve.white99
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Hello,
I have found a website, where Doctor, Physician and Nurse Jobs available.

http://www.thecertifications.com/DoctorJobs

Regards,
Steve

Reply | Messages in this Topic (1)
#270 From: "Tim" <screenwriter41@...>
Date: Fri Mar 13, 2009 6:50 pm
Subject: New Member 		screenwriter41
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I hope this is still a active group, I am just starting out.

Reply | Messages in this Topic (2)
#271 From: PoWeRTX@...
Date: Sun Mar 15, 2009 9:52 pm
Subject: Re: New Member 		nelsonvergel
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It is not really active...you may want to subscribe to pozhealth-subscribe@yahoogroups.com


-----Original Message-----
From: Tim <screenwriter41@...>
To: SalvageTherapies@yahoogroups.com
Sent: Fri, 13 Mar 2009 1:50 pm
Subject: [SalvageTherapies] New Member

I hope this is still a active group, I am just starting out.


Reply | Messages in this Topic (2)
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