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#12395 From: simon collins <simon.collins@...>
Date: Thu Jun 30, 2005 10:45 pm
Subject: Re: Question on Treatment Interruption 		simoninbrixt...
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Hi Steve

US treatment guidelines say that you are in a group a patients who can safely
stop you treatment.

You started with a CD4 count that is much higher than todays guidelines, and
unless you had an AIDS-related complication, many doctor would not understand
why you are on treatment now - especially if you are getting side effects. You
are likely to get several years off-treatment. Your quality of life will improve
and you can monitor CD4 for when to restart.

You must continue to use a drug that is active against your HBV though. This is
very important. Adefovir is probably much better than 3TC to use for this
though, and newer HBV drugs will become available that are also not active
against HIV in the future. If you have been using 3TC for 8 years also for your
HBV you may already have HBV-related 3TC-resistance - or be at risk of
developing this very soon (over 40% people get resistance over a few years of
HBV monotherapy to 3TC).

Using 3TC monotherapy after a treatment interruption is only recommended once
you have 3TC resistance to HIV. If your viral load has been undetectable onthe
same combination for 8 years, you probably don't have this mutation (M184V) and
it is probably best to stay that way. ie although this is the advantage of 3TC
resistance, the benefits aren't so great that is worth trying to active develop
this resistance. Data on this comes from one study presented at Bangkok last
year, with some follow-up at this years resistance meeting.

Let me know off-list if you'd like further details of the studies.

Simon
simon.collins@...

........


Steve wrote:

I have had excellent results on my cocktail (Viracept, a PI and Combivir, 3TC
and AZT, both NRTIs) for 8 years.  My pre-treatment numbers were good too,
t-cells over 500 and viral load about 60,000.

However, the side effects are taking their toll.  I cannot control the diarrhea,
bloating, and gas.  Plus, I am getting "the look" from body shape changes and
veiny legs (my face is fine for now).

I know that a return to normal might not be guaranteed with a treatment
interruption, but I am willing to try.

Here are my questions:
1.  Has anyone chosen a treatment interruption and chosen to stay on 3TC as a
single drug treatment during the interrruption?  My reasoning is that 3TC
resistance is prevalent and very likely, so I don't loose anything on
monotherapy.  Plus, I need it along with Hepsera for my Hep-B, and 3TC resistant
HIV virus is much weaker and may allow me on a longer interruption.

2.  Has anyone used genotype testing to help decide about a treatment
interruption?

Thanks for your considerations, Steve.

Reply | Forward | Messages in this Topic (4)
#12394 From: John Barrow <pozbod@...>
Date: Thu Jun 30, 2005 2:20 pm
Subject: Has anyone chosen a treatment interruption and chosen to stay on 3TC as a single drug treatment 		johnftl59
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On Jun 30, 2005, at 9:21 AM, PozHealth@yahoogroups.com wrote:

> I have had excellent results on my cocktail (Viracept, a PI and
> Combivir, 3TC and AZT, both NRTIs) for 8 years.  My pre-treatment
> numbers were good too, t-cells over 500 and viral load about 60,000.

Are you undetectable?  If your viral load is less than a thousand or
so, it is difficult to do a viral load test.

>
> However, the side effects are taking their toll.  I cannot control the
> diarrhea, bloating, and gas.  Plus, I am getting "the look" from body
> shape changes and veiny legs (my face is fine for now).

Very distressing.  Nelfinavir is partcularly known for GI problems.
Have you tried adding fiber supplements to your daily routine?
Methycellulose tablets are easy to take, and really help me in this
department.
>
> I know that a return to normal might not be guaranteed with a
> treatment interruption, but I am willing to try.

A "return to normal," alas, is not only "not guaranteed," it is highly
unlikely.
>
> Here are my questions:
> 1.  Has anyone chosen a treatment interruption and chosen to stay on
> 3TC as a single drug treatment during the interrruption?  My reasoning
> is that 3TC resistance is prevalent and very likely, so I don't loose
> anything on monotherapy.  Plus, I need it along with Hepsera for my
> Hep-B, and 3TC resistant HIV virus is much weaker and may allow me on
> a longer interruption.

If you need it for Heb b control, I would continue it.
>
> 2.  Has anyone used genotype testing to help decide about a treatment
> interruption?

A very good idea.

I really think a better idea would be to try to change your
medications, if you have other options.    I find less and less
enthusiasm for treatment interruptions every day, though there are some
individuals who have had good experiences.

JB
>

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#12393 From: "akousen" <akousen@...>
Date: Thu Jun 30, 2005 3:32 pm
Subject: Treatment Interruption- guidance thoughts 		akousen
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Your post said....

Question on Treatment Interruption

I have had excellent results on my cocktail (Viracept, a PI and
Combivir, 3TC and AZT, both NRTIs) for 8 years.  My pre-treatment
numbers were
good too, t-cells over 500 and viral load about 60,000.

However, the side effects are taking their toll.  I cannot control the
diarrhea, bloating, and gas.  Plus, I am getting "the look" from body
shape changes and veiny legs (my face is fine for now).

I know that a return to normal might not be guaranteed with a treatment
interruption, but I am willing to try.

ANSWER.....

Since your health is being impacted by MULTIPLE problems, there are no
easy answers. Your HIV doc is in the position to give you advice.

I used same combo as you, did an interruption at 3 years, for one
month, and just completed a second interruption of 18 months. My
numbers were excellent; VL never went above 50,000, and T cell were
above 700. I went back on a NEW treatment regimin that has less of a
problem with facial wasting- which I DO have.

I have No other medical complications. Assuming I maintain zero VL for
several years, I will likely go off again for another period,
determined by my results of testing.

I never had any side effects to the original medications. I do not have
any to my curent medication regimen. My new regimin is once a day with
a 3 drug combo- total of 5 tabs. I'd be glad to share with anyone my
personal experiences with this and other combo's.

Reply | Forward | Messages in this Topic (1)
#12392 From: JuLev@...
Date: Thu Jun 30, 2005 8:34 am
Subject: [NATAP] The Maze of Treatments for Hepatitis B 		JuLev@...
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NATAP - http://www.natap.org

The Maze of Treatments for Hepatitis B

New England Journal of Medicine
June 30, 2005

Anna Suk-Fong Lok, M.D.
From the Division of Gastroenterology, University of Michigan Medical Center, Ann Arbor.

Worldwide, there are approximately 350 million carriers of hepatitis B virus (HBV), of whom half a million to 1 million die from liver disease each year. The goal of treatment for chronic hepatitis B is to prevent cirrhosis, hepatic failure, and hepatocellular carcinoma. This goal is best achieved by eradicating HBV before irreversible liver damage occurs. However, the eradication of HBV is impossible to achieve because of the presence of extrahepatic reservoirs of HBV, the integration of HBV DNA into the host genome, and the presence of an intracellular conversion pathway that replenishes the pool of transcriptional templates (covalently closed circular HBV DNA) in the hepatocyte nucleus without the need for reinfection. Thus, withdrawal of treatment is usually accompanied by rapid viral rebound.

Currently, there are five approved therapies for chronic hepatitis B in the United States - interferon alfa-2b, lamivudine, adefovir, entecavir, and pegylated interferon (peginterferon) alfa-2a. Table 1 shows a comparison of the efficacy of these treatments.1,2 To approve treatments for hepatitis B, the FDA and other regulatory authorities use criteria that are based on responses after one year of treatment. However, very few patients will have a sustained response after one year of treatment. The benefits versus the risks of long-term treatment of chronic hepatitis B have not been properly studied. Given the variable natural course of HBV infection and the high costs of treatments ($5,000 to $15,000 a year, in U.S. dollars), decisions regarding whom to treat and with what and for how long must be carefully weighed.



In their study in this issue of the Journal, Lau et al. report that a combination of peginterferon alfa-2a and lamivudine was associated with the greatest degree of virus suppression, followed by lamivudine monotherapy and peginterferon alone.3 However, the rates of hepatitis B e antigen (HBeAg) seroconversion at the end of 48 weeks of treatment were similar among the three groups.

Unlike lamivudine and other nucleoside or nucleotide analogues, interferon has immune modulatory as well as antiviral effects. Previous studies involving three-to-six-month courses of conventional interferon showed that HBeAg seroconversion frequently occurred a few months after cessation of treatment, presumably because of the lag between immune priming and the decrease in the expression of viral proteins. The study by Lau et al. used a longer duration of peginterferon therapy; nonetheless, a small increment in the rate of HBeAg seroconversion was observed after treatment was stopped, so that at week 72, the two groups that received peginterferon had significantly higher rates of HBeAg seroconversion than the group that received lamivudine monotherapy.

The study reported by Hadziyannis et al. in this issue of the Journal showed the results at week 96 and week 144 of a phase 3 clinical trial of adefovir dipivoxil in patients with HBeAg-negative chronic hepatitis B.6 An earlier report on this trial showed that at week 48, adefovir was associated with significantly higher rates of virologic, biochemical, and histologic responses than was placebo.4 The study by Hadziyannis et al. showed that these responses were negated in virtually all patients after treatment was stopped at week 48. These disappointing results confirm that current treatments suppress but do not eradicate HBV. They also highlight the inadequacies of the end points of trials used for the approval of treatments for HBV.

Among the patients who continued to receive adefovir from week 49 through week 96 or from week 97 through week 144, the rates of virologic response (defined as a serum HBV DNA level that was undetectable with the use of polymerase-chain-reaction assay) and biochemical response (normalization of levels of aminotransferases) were slightly higher than the rates after 48 weeks. However, 20 to 30 percent of the patients did not meet these criteria after 144 weeks of continuous therapy.

The main concerns with long-term treatment are side effects, drug resistance, and costs. Adefovir at high doses (≥30 mg per day) has been associated with nephrotoxicity.4 In the study by Hadziyannis et al., nephrotoxicity was observed in 3 of 70 patients who received adefovir for three years, necessitating discontinuation of the treatment in two patients. Unlike resistance to lamivudine, resistance to adefovir is considered to be uncommon and to emerge later in the course of treatment. In the current analysis, adefovir-resistance mutations were detected in 6 of 70 patients who received adefovir for three years.6 Thus, although response was maintained in most patients who continued treatment, nephrotoxicity and drug resistance will be of increasing concern with longer durations of treatment.

Ten years ago, conventional interferon was the only approved treatment for chronic hepatitis B. Since then, three orally administered nucleoside or nucleotide analogues and a long-acting (pegylated) interferon have been approved in the United States. Patients with chronic hepatitis B now have more treatment options that have fewer side effects and are more easily administered. This has broadened the indications for treatment for hepatitis B to include patients with decompensated HBV cirrhosis7 and patients who require HBV prophylaxis during chemotherapy for cancer.8 In addition, long-term treatment with lamivudine has been shown to decrease the risk of hepatic failure and hepatocellular carcinoma among patients with cirrhosis and high levels of HBV DNA.9

However, these new therapies have brought along new problems. Foremost is drug-resistance mutations.10 Selection of drug-resistance mutations is accompanied by virologic breakthrough (increased serum HBV DNA levels after initial suppression) and in some patients biochemical breakthrough (increased levels of aminotransferases after initial normalization) and, rarely, hepatic failure and death. In addition, resistance to one antiviral agent may confer resistance to other agents and may limit future treatment options. Another problem is the high rate of relapse when treatment is discontinued. Studies that compared peginterferon and lamivudine all showed a higher rate of virologic relapse when treatment with lamivudine was stopped.3,5,11 Although adefovir and entecavir have not been directly compared with interferon, existing data suggest that relapse is more common than with interferon.

Given multiple treatment options that are less than ideal, who should be treated, with what, and when can treatment be stopped? The decision to treat or not to treat and the choice of treatment should be made jointly by the physician and the patient and should balance the benefits and the risks (e.g., the likelihood of a sustained response after a defined course of treatment or a maintained response during long-term treatment vs. the risk of progressive liver disease, side effects, drug resistance, and costs). For HBeAg-positive patients, viral suppression without HBeAg clearance is invariably associated with relapse, whereas viral suppression with HBeAg clearance is associated with sustained responses in 50 to 90 percent of patients.1 For HBeAg-negative patients, relapse is frequent even when the virus has been suppressed to undetectable levels for more than a year.12 Patients who opt for interferon must be aware of the wide array of potential side effects, whereas those who opt for oral antiviral therapy must be aware of the need for long-term treatment and the risks of drug resistance.

For patients with HBeAg-positive chronic hepatitis B who do not yet have cirrhosis, the goal is to achieve HBeAg seroconversion. Because pretreatment aminotransferase levels are a strong predictor of HBeAg seroconversion (except in the study by Lau et al.),13 current guidelines do not recommend treatment of patients with normal aminotransferase levels unless liver biopsy shows substantial inflammation or fibrosis.1,14,15 For patients with HBeAg-negative chronic hepatitis B who do not yet have cirrhosis, a one-year course of treatment is associated with a 15 to 35 percent chance of sustained response after interferon therapy but a less than 10 percent chance after treatment with lamivudine or adefovir.1,6,10 Given the need for long-term treatment, current guidelines recommend treatment only for patients with elevated aminotransferase levels or histologic evidence of moderate or severe inflammation or advanced fibrosis.1,14,15 For patients with cirrhosis, the potential gains are higher. Treatment is recommended for patients with high HBV DNA levels, but it is unclear whether patients with low HBV DNA levels will derive the same benefits. It is also unknown whether treatment should be lifelong or whether clinical benefit can be maintained after several years of treatment. Given the propensity for HBV to persist, patients should be closely monitored when treatment is stopped, to avoid fatal flares.

Substantial progress has been made in treatments for hepatitis B in the past decade. However, finding an exit through the maze of new therapies remains a challenge, underscoring the need for careful deliberation before initiating treatment.

Dr. Lok reports having served as a paid consultant to and having received grant support from Roche, Gilead Sciences, GlaxoSmithKline, and Bristol-Myers Squibb.

References

   1. Lok AS, McMahon BJ. Chronic hepatitis B: update of recommendations. Hepatology 2004;39:857-861. [CrossRef][ISI][Medline]
   2. Entecavir Review Team. Briefing document for NDA 21-797, entecavir 0.5 and 1 mg tablets and NDA 21-798, entecavir oral solution 0.05 mg/mL. February 10, 2005 (memorandum). (Accessed June 9, 2005, at http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4094B1_02_FDA-Background-Memo.pdf.)
   3. Lau GKK, Piratvisuth T, Xian Luo K, et al. Peginterferon alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B. N Engl J Med 2005;352:2682-2695. [CrossRef]
   4. Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B. N Engl J Med 2003;348:800-807. [Erratum, N Engl J Med 2003;348:1192.] [Abstract/Full Text]
   5. Marcellin P, Lau GKK, Bonino F, et al. Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B. N Engl J Med 2004;351:1206-1217. [Abstract/Full Text]
   6. Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, et al. Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B. N Engl J Med 2005;352:2673-2681. [CrossRef]
   7. Fontana RJ, Hann HW, Perrillo RP, et al. Determinants of early mortality in patients with decompensated chronic hepatitis B treated with antiviral therapy. Gastroenterology 2002;123:719-727. [CrossRef][ISI][Medline]
   8. Lau GK, Yiu HH, Fong DY, et al. Early is superior to deferred preemptive lamivudine therapy for hepatitis B patients undergoing chemotherapy. Gastroenterology 2003;125:1742-1749. [ISI][Medline]
   9. Liaw Y-F, Sung JJY, Chow WC, et al. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med 2004;351:1521-1531. [Abstract/Full Text]
  10. Fung SK, Lok AS. Management of hepatitis B patients with antiviral resistance. Antivir Ther 2004;9:1013-1026. [Medline]
  11. Chan HL, Leung NW, Hui AY, et al. A randomized, controlled trial of combination therapy for chronic hepatitis B: comparing pegylated interferon-alpha2b and lamivudine with lamivudine alone. Ann Intern Med 2005;142:240-250. [Abstract/Full Text]
  12. Fung SK, Wong F, Hussain M, Lok AS. Sustained response after a 2-year course of lamivudine treatment of hepatitis B e antigen-negative chronic hepatitis B. J Viral Hepat 2004;11:432-438. [CrossRef][ISI][Medline]
  13. Perrillo RP, Lai CL, Liaw YF, et al. Predictors of HBeAg loss after lamivudine treatment for chronic hepatitis B. Hepatology 2002;36:186-194. [CrossRef][ISI][Medline]
  14. de Franchis R, Hadengue A, Lau G, et al. EASL International Consensus Conference on Hepatitis B: 13-14 September, 2002 Geneva, Switzerland: consensus statement (long version). J Hepatol 2003;39:Suppl 1:S3-S25. [CrossRef][ISI][Medline]
  15. Liaw YF, Leung N, Guan R, Lau GK, Merican I. Asian-Pacific consensus statement on the management of chronic hepatitis B: an update. J Gastroenterol Hepatol 2003;18:239-245. [CrossRef][ISI][Medline]





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#12391 From: Thandie THANDO <thandiee@...>
Date: Thu Jun 30, 2005 2:05 am
Subject: Re: Surgeon won't perfor Butt implant coz i'm poz 		thandiee
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Hello All

I'd like to thank everyone who responded to my email.
I got a lot of feed back, advise and good leads. i
will definitely check out the clinic estetica
procedures and also the Rio Dejaneiro clinic
procedures with Dr Serra.
I wanted to write individually to everyone who
responded to my email but i somehow accidentally
deleted yr emails.

I'd like to hear from the person who gave me info on
Dr. Serra, pse get in touch I hv some questions.

And, to those who hv been treated at clinic
estetica,pse tell me how the treated area feels. I
mean, is it hard or soft?

Once again thanks y'all for yr feed back.

Thandiee




__________________________________________________
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#12390 From: Roscoeismydog@...
Date: Thu Jun 30, 2005 1:53 pm
Subject: Hey group, question on treatments to tighten loose skin due to Lipodystrophy 		Roscoeismydog@...
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I have had pretty good success looking more normal with newfill, and now microdroplets of silicone. However it will only take me so far, and I am looking for something that will tighten up some of the slack still left in my skin other than surgery.  Its minor but still bothers me.
 I have had a TCA peel which helps slightly and a laser peel, but am still wondering if anyone has had success with something else. I know there is a lot of new procedures out there and am hoping someone has had success with something.
                                                            Thanks, Al

Reply | Forward | Messages in this Topic (1)
#12389 From: "egenagain" <egenegis@...>
Date: Thu Jun 30, 2005 12:51 pm
Subject: Re: Fat atrophy and deposition in HIV 		egenagain
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This is pretty awful.  Up until now studies showed that switching
from zerit/stavudine to abacavir/ziagen prevented or reversed
lipoatrophy but this study finds that ziagen also causes
lipoatrophy.  Whats a poz person to do??

<..The risk of developing fat atrophy was higher in those with low
triceps skin-fold values, smaller hips, a higher nadir HIV load. The
risk was also increased in subjects treated with abacavir, stavudine
or highly active antiretroviral therapy.>>

Reply | Forward | Messages in this Topic (2)
#12388 From: JuLev@...
Date: Thu Jun 30, 2005 7:26 am
Subject: Is Milk thistle Useful in HCV? 		JuLev@...
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Milk thistle and chronic liver disease: NIH invites applications to fund studies of milk thistle

Jay H. Hoofnagle, M.D.
NIDDK, NIH, Bethesda, MD

Jnl of Hepatology
July 2005

There have been numerous studies to examine whether or not milk thistle can be of clinical or 'real' benefit for patients with HCV. At this time it has not been established that milk thistle is beneficial to HCV+ patients. However, many patients take milk thistle. The NIH held a meeting regarding the study of milk thistle to attempt to answer the question of whether milk thistle is beneficial & if it's worth taking. Following a brief introduction are excerpts from the discussions which review studies already conducted in humans and animals and the study findings, and plans to study milk thistle in an attempt to get answers for doctors and patients. Jules Levin

Article Text

“………silymarin is quite different from other new drugs under development. Millions of people are already taking this product, believing that it will help their liver disease. Thus, the usual concerns involved in the step-wise drug development process should be abbreviated. There is a certain urgency to demonstrating whether silymarin has clinical utility in liver disease. Thus, clinical studies should not be slowed for the sake of identifying all of the mechanisms of action of the drug and their relative importance…..”


Milk thistle has been used for centuries to treat acute and chronic liver diseases and, even today, is one of the most widely used herbal medications. Its active ingredients appear to be several closely related flavinoids, collectively known as silymarin. Most silymarin preparations have at least a dozen molecular components and their isomers, including silybin, isosilybin, cis-silybin, silydianin, and silychristine. It is not clear whether one, several, or all of these components are the active ingredient(s), and most commercial preparations represent rough extracts of the milk thistle plant (Silybum Marianum) rather than a purified subcomponent.

Results of studies in experimental animal models suggest that silymarin has a broad spectrum of hepatoprotective effects. Thus, silymarin can protect experimental animals against injury from several toxins, including amanita phalloides, carbon tetrachloride, ethanol, and galactosamine. Silymarin is partially protective even when given after exposure. The basis for this hepatoprotective activity may be the antioxidant qualities of the several flavinoids, but antifibrotic, antiinflammatory and immune modulatory actions of silymarin may also be important.

A safe and effective, broad-spectrum hepatoprotective agent would likely be very useful in the management of liver disease. Yet, despite its clear effects in experimental animal models, silymarin has yet to be proven effective in ameliorating human liver disease. Part of the problem is that silymarin has never been adequately evaluated using objective and clinically meaningful endpoints in well-characterized cohorts of patients with well-defined forms of liver disease.

Because of its safety, lack of side effects, activity in animal models, and centuries-long traditional use in liver disease, milk thistle has been introduced and is widely used as an herbal preparation in the United States. It is available in most health food stores and in many conventional grocery stores where it is advertised as beneficial for the liver or for liver wellness. Food and Drug Administration (FDA) rules prohibit the advertisement of any agent as a specific therapy for liver disease, unless it has been proven to be safe and effective, in which case it would be regulated as a drug rather than an herbal preparation. In surveys conducted in liver disease clinics, between 10% and 15% of patients report taking milk thistle, almost entirely on the basis of advice from friends, magazine articles, or the Internet rather than on advice of a physician. Clearly, proof of the efficacy of milk thistle preparations (or lack thereof) and further documentation of its safety are critical needs in improving management of liver disease. In the recently published Action Plan for Liver Disease Research (http://liverplan.niddk.nih.gov), evaluation of nonspecific hepatoprotective agents such as silymarin was listed as an unmet and important research goal.

To address these issues, the National Center for Complementary and Alternative Medicine (NCCAM) in collaboration with the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) held a research workshop entitled Silymarin for Chronic Liver Disease (http://www.niddk.nih.gov/federal/ddicc/meetings.htm).

In this workshop, two critical first steps for development of silymarin as a therapy for liver disease were defined: (1) to identify a standard, reliable silymarin product that could be used in clinical investigation and (2) to initiate phase I/II trials of this product in liver disease. Disease conditions that were considered most appropriate for evaluation were nonalcoholic steatohepatitis (NASH) and chronic hepatitis C, with particular focus on patients who were nonresponders to conventional therapy. The goals for pilot, phase I/II studies were to define the optimal dose and dosing regimen for silymarin and to identify the appropriate patient cohorts and surrogate markers for assessment of efficacy and safety. These elements were considered critical, before expensive, definitive trials of silymarin therapy were initiated that might depend upon more long-term therapy and more critical clinical endpoints.

Accordingly, in March 2005, NCCAM published an announcement of availability of an industry collaboration for the development and evaluation of a commercial form of silymarin (http://nccam.nih.gov/research/announcements/active.htm). This announcement requested a partnership with a commercial entity that could provide a well-characterized, standard formulation of silymarin that could be evaluated in humans under an FDA-approved Investigational New Drug (IND) Application. Finally, in June 2005, NCCAM and NIDDK published a Request for Applications for a Silymarin Clinical Research Consortium. The Consortium will consist of approximately four Clinical Centers and a single Data Coordinating Center, which would be charged with the design and conduct of phase I/II clinical trials of silymarin in NASH and chronic hepatitis C. Each applicant for a Clinical Center is asked to document their experience in participating in multi-center clinical trials, experience in evaluation and follow-up of patients with liver disease, and insight and knowledge about design and conduct of phase I/II clinical trials. Applicants for the Data Coordinating Center are asked to document experience with managing multi-center clinical trials and data acquisition, management and analysis. A letter of intent is requested by August 15, 2005 and final applications by September 12, 2005. Applicants are limited to the United States. Details of the RFA are available at: http://grants.nih.gov/grants/guide/rfa-files/RFA-AT-05-006.html.

Digestive Diseases Interagency Coordinating Committee
Liver Disease Subcommittee

Silymarin as Therapy of Liver Disease

A Workshop Sponsored by the
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK),
National Center for Complementary and Alternative Medicine (NCCAM), and
National Institute on Alcohol Abuse and Alcoholism (NIAAA)

March 22, 2004

EXCERPTS

Discussion

Moderators: Sam Zakhari, Ph.D., Director, Division of Basic Research, NIAAA,
NIH and Jose Serrano, M.D., Ph.D., Program Director, Liver, Biliary, and
Pancreas Programs, NIDDK, NIH, Bethesda, MD

Dr. Sam Zakhari (Director, Division of Basic Research, NIAAA, NIH) asked how
the compounds used in the in vitro studies compared in activity to standard antioxidants, such as vitamin E. Dr. Lee responded that no side-by-side comparisons have been made as these are preliminary data and further work needs to be done using different assays and conditions.

Dr. Serrano asked whether there were differences between the two milk thistle
plants, the pink versus the white flowered plant and how timing of harvest was
standardized. Dr. Lee stated that his group has focused solely on seeds from the pink flowered herbal and that harvesting at different seasons resulted only in changes of total concentration of silymarin in the seeds but that the components remain the same.

Dr. Mark Zern (Professor, Internal Medicine/Transplantation, University of
California, Davis) raised the issue of the incidental removal of beneficial components from the seeds through the purification process. Dr. Lee agreed that this is an area for further study, albeit a difficult one due to the high water solubility of those minor components.

Dr. Hoofnagle commented that the HPLC results suggested that the majority of
milk thistle products on the market are fairly well patterned. Dr. Lee agreed but stated that a few products have considerable impurities. Dr. Hoofnagle asked whether they intended to produce a highly purified silybin A for clinical use. Dr. Lee stated that they were not developing a product with a single silymarin component, but believed that a final product will contain all of the major and minor components in their natural ratios.

Dr. Strauss expressed interest in the issue of extracting, purifying, and
characterizing individual constituents, and emphasized the importance of understanding which components are active and whether they synergize or compete with each other in some way, both in terms of efficacy and toxicity. Milk thistle is so well characterized and so devoid of other constituents that it may well provide an ideal setting to determine whether the compound as a whole is advantageous. Dr. Lee added that subsequent studies would be conducted to compare the standard with individual products.

Silymarin as Treatment of Hepatitis C

Kris Kowdley, MD, University of Washington, Seattle, WA

Use of complementary and alternative medications (CAM) is frequent among
patients with chronic liver diseases including hepatitis C. In surveys of patients attending liver disease clinics, an average of 40% of patients admit to use of CAM and 15% use of herbal products, the most frequent of which is milk thistle or silymarin. Most patients take silymarin on their own initiative without professional medical advice. Unfortunately, there is often poor documentation of the ingredients of commercial silymarin products that are used and little information on its efficacy in hepatitis C or chronic liver disease.
There are a number of reasons why silymarin might be useful in the treatment of
liver disease. Silymarin has antioxidant properties and influences both free radical mediated cytotoxicity and lipid peroxidation in in vitro and in vivo models of liver disease. Silymarin may also have antifibriotic effects.

Silymarin has activity against iron-related liver injury. In a study of carbonyl
iron-fed rats, silybin significantly reduced production of malondialdehyde-protein
adducts and improved mitochondrial energy efficiency and ATP stores (Pietrangelo et al. Gastroenterology 1995:109:1941-9). Silybin has multiple potential beneficial effects in liver injury, including reduction of lipid peroxidation, scavenging of free radicals, and prevention of iron accumulation. In addition, silybin may restore glutathione levels, which may have a significant impact on iron-mediated fibrogenesis and oxidative stress.

The effects of silymarin on hepatic fibrosis have been studied in a gerbil model of
iron overload. Animals were given intramuscular iron dextran and either placebo or silybin. There were no differences in hepatic iron accumulation, however silybin treated animals had less hepatic fibrosis as shown by collagen staining. Hepatocytes also had reduced staining for heme oxygenase suggested reduced oxidative stress (Pietrangelo et al. J Bioenergetics and Biomembranes 2002;34:67-69)

In large scale meta-analyses of silymarin as therapy of liver disease, there was a
slight trend towards improved serum ALT in the silymarin-treated group but a less difference in serum AST levels and no differences in albumin levels (Jacobs et al, Am J Med 2003:13-506-15). There was a trend towards improvement in prothrombin time levels in patients treated with silymarin.

The problem with interpreting clinical studies of silymarin is that few studies have
focused on a homogenous patient population with a specific, well defined liver disease. Perhaps as a consequence, studies have had varying results. In an exhaustive search of both electronic and manual resources, the Cochrane review identified only 14 randomized trials that could be considered useful for evaluating the effectiveness of silymarin therapy for hepatitis C (Liu et al, Am J Gastroenterol 2001:98:538-44). This review concluded that there is no evidence for benefit of silymarin therapy.

A series of small clinical trials have been conducted using a standardized
silymarin product - IdB1016 - which has a standardized concentration of silybin and has undergone extensive pre-clinical anlaysis. In a study of 10 patients with chronic hepatitis C who had failed to respond to a course of interferon-alfa, silymarin was given in a dose equivalent to 360 mg per day of silybinin for 2 months, followed by a 1-month washout and 2-month placebo treatment period. The placebo group was treated in inverse sequence. Compared to the placebo-treated patients, the 10 silymarin treated subjects had an 18% reduction in serum ALT, a 17% reduction in serum AST (which approached statistical significance), but no change in serum bilirubin and alkaline phosphatase levels. Similar results were observed in a pilot study in patients with chronic hepatitis given 120
mg of silybin equivalence twice daily (Moscarella et al, Curr Therap Res 1993; 53: 98-102).

In a subsequent Phase II placebo-controlled, 3-month study, 31 patients with
chronic hepatitis were given 120 mg silybinin and 34 patients were treated with placebo twice daily for 3 months. IdB1016 treatment was associated with a significant decrease in both serum ALT and AST levels (Marcelli et al, Eur Bull Drug Res 1992; 1:131-5).

In an uncontrolled, dose-escalation study, patients with hepatitis C and alcoholinduced liver disease had significant reductions in serum ALT, AST and GGTP levels (Vailati et al. Fitoterapia, 1993. 64:219-28).

In a short term, randomized controlled study in chronic hepatitis C, 20 patients
were given 240 mg silybinin daily (IdB1016) or placebo. Compared to placebo, there were signficant decreases in serum bilirubin, GGT, ALT, and AST levels within 7 days of starting therapy with silybinin (Buzzelli et al, Int J Clin Pharmacol Ther Toxicol 1993;31:56-60).

Supported by a small grant from the NCCAM, the University of Washington has
designed a phase I/II study of IdB1016 in patients with chronic hepatitis C. A total of 36 patients will be stratified on the basis of histological stage (fibrosis scores of 2, 3 or 4) and randomized into one of 3 different doses of drug, ranging from 360 to 1890 mg of silymarin three times daily for 12 weeks followed by a 12-week observation period. Endpoints of therapy include tolerance and serum ALT levels with secondary endpoints being plasma TGF-_1, serum hyaluronic acid (HA), procollagen III peptide (PIIIP), YKL-40 (chondrex), ferritin, and iron saturation levels. Compliance, adverse effects, and health-related quality of life will also be measured. The study has received IRB approval, an IND is in place, and the first patients have been enrolled. No results are available.

Discussion
In response to questions from Drs. Berman (NCCAM) and McClain (Univ
Louisville), Dr. Kowdley stated that the study is not placebo-controlled because it was considered a dose-finding trial and focuses on safety and evaluation of surrogate markers. In addition, patients receive a fixed dose and sequential cohorts are given higher doses.

Dr. John Senior (FDA) recommended that, if the pilot study yields adequate
results leading to a larger randomized study, investigators ought to consider other measures of liver function (e.g., INR, direct and total bilirubin). Dr. Kowdley agreed, stating that the next step would involve a randomized, placebo-controlled trial with liver biopsy as an endpoint, looking at progression vs regression or stabilization of fibrosis. Dr. Leonard Seeff (NIDDK) asked for clarification regarding the status of previous interferon therapy in the patients with chronic hepatitis C who would be enrolled in these studies. Dr. Kowdley explained enrolled patients will have received interferon in the past or have contraindications to interferon therapy. Dr. Kowdley suggested that the beneficial effect of silybin should be independent of responsiveness to the antiviral effects of interferon.

Silymarin as Therapy of Non-alcoholic Steatohepatitis (NASH)

Paul Angulo, Mayo Clinic

NASH is a common and frequently silent liver disease marked by fat
accumulation in the liver along with inflammation, hepatocellular injury and fibrosis. Patients typically have few symptoms but can have mild to moderate elevations in serum ALT levels and evidence of fat in the liver by ultrasound. A liver biopsy is required to diagnose NASH, separating simple hepatic steatosis (fatty liver) from steatohepatitis. NASH resembles alcoholic liver disease histologically but by definition occurs in persons who drink little or no alcohol. NASH is a potentially progressive liver disease, and a proportion of patients eventually develop cirrhosis, end-stage liver disease and, in some instances, hepatocellular carcinoma.

The etiology of NASH is only partially understood. The disease occurs largely in
persons who are overweight or obese, particularly if there is concurrent type 2 diabetes and/or hyperlipidemia. Only a small proportion of people with normal body mass index(BMI of 20 to 25) have either simple hepatic steatosis or NASH. In contrast, more than 60% of obese persons have hepatic steatosis, and approximately 20% have NASH. In patients with severe obesity (BMI above 40), more than 80% have hepatic steatosis and almost half have some degree of NASH. With the rising rates of obesity and diabetes in America, NASH has become the most common cause of abnormal liver tests found in otherwise asymptomatic individuals.

The pathogenesis of NASH is not completely understood, but the most well
accepted hypothesis postulates that the disease is caused by “two-hits” - the first causing steatosis and the second leading to injury and fibrosis. Insulin resistance is likely to account for the first hit in most patients, while oxidative stress and lipid peroxidation or proinflammatory cytokine injury is believed to account for the second.

There is no therapy of proven long-term benefit for NASH. Achieving and
maintaining appropriate control of body weight appears to lead to improvement in NASH histologically. Weight control, however, is a difficult task to accomplish by most overweight or obese individuals. For patients with diabetes or hyperlipidemia, glucose and lipid level control are recommended, but do not always lead to improvements in liver tests associated with NASH. Finally, some patients with NASH are not overweight and do not have diabetes or hyperlipidemia. These considerations have led to the search for pharmacological therapies for this disease.

Several medications have been proposed as therapies for NASH. These
medications include hepatoprotective agents such as ursodiol (ursodeoxycholic acid, UDCA), antioxidants such as vitamin E and betaine and anti-diabetic medications that improve insulin resistance such as metformin and the thiazolidinediones (TZDs).

Ursodiol is the only medication that has been evaluated in a adequately-sized, prospective randomized controlled trial (Lindor et al. Hepatology 2004;39:770). While ursodiol therapy was associated with mild improvements in serum aminotransferases and hepatic steatosis, similar improvements occurred in the control group and there was no improvement in hepatic inflammatory activity or fibrosis. Other medications have been evaluated in small, uncontrolled clinical trials with some evidence of benefit. The most promising results have been reported with the TZDs pioglitazone (Promrat et al. Hepatology 2004;39:188) and rosiglitazone (Neuschwander-Tetri et al. Hepatology 2003;38:1008) and antioxidants (Lavine et al. J Pediatr 2002;136:734; Hasegawa et al. Aliment Pharmacol Ther 2001;15:1667).

Based on these results, two large, multicenter randomized controlled trials of vitamin E versus metformin or pioglitazone have been initiated recently under the auspices of the NASH Clinical Research Network.

Patients with NASH often have evidence of oxidative stress and lipid
peroxidation suggesting that antioxidant therapy may be beneficial. Thus, in several clinical studies, patients with NASH were found to have significantly greater evidence of lipid peroxidation compared to patients with fatty liver alone and normal controls (Seki et al. J Hepatol 2002;37:56; Sanyal et al. Gastroenterology 2001;120:1183). Other evidence that oxidative stress plays a role in progression of NASH include findings of malondialdehyde adducts (MDA) in the liver in patients with NASH which correlates with degree of fibrosis (McDonald et al. J Gastro Hepatol, 2001;16:599) and the finding that CYP2E1 is highly expressed in patients with NASH compared to individuals with steatosis alone and those with normal livers (Videla et al. Clinical Science 2004;61:2035). Silymarin has not been studied prospectively and specifically in patients with NASH. Undoubtedly, some patients with cirrhosis due to NASH were included in the several studies of silymarin in patients with cirrhosis (Saller et al. Drugs 2001;61:2035).

Those studies have demonstrated some evidence of benefit of silymarin although metaanalyses and Cochrane reviews have concluded that the overall evidence of benefit is lacking.

Investigators at the Mayo Clinic Foundation have designed a phase II, open-label
pilot study of silymarin in patients with NASH. Thirty patients with liver biopsy-proven NASH will be treated for 2 years with 600 mg silymarin daily, a dosage level chosen because it has been proven safe in patients with liver disease (Velssi et al. J Hepatol 1997;26:871), and some animal models have shown that higher dosages may produce greater antioxidant and antifibrotic effects (Boigk et al. Hepatology 1987;26:643).

Patients will be followed at 3 month intervals with clinical evaluation and routine blood tests for serum aminotransferase levels. Serum markers of lipid peroxidation, including thiobarbituric acid reacting substances (TBARS) and oxidized LDL (ox-LDL), and markers of liver fibrosis (aminoterminal procollagen III peptide, collagen IV, and hyaluronic acid) will be measured annually. Liver biopsies will be taken at baseline and again after 2 years of treatment. At present, however, the study is on hold because the pharmaceutical company that prepares the silymarin has not been willing to provide the drug for clinical trials.

Discussion
Dr. Josh Berman (NCCAM) asked whether liver biopsies were necessary as an
endpoint for efficacy. Dr. Jay Hoofnagle (NIDDK) responded that histological
confirmation of benefit is required in evaluating many liver diseases and particularly in NASH. There is a poor correlation between the height of serum aminotransferase elevations and the severity of the underlying liver disease in NASH that makes liver biopsies necessary to demonstrate clinical benefit. Serum aminotransferase levels and other blood test results might be adequate surrogate endpoints for phase I studies assessing tolerance and dose regimens and may be adequate in phase II studies when assessing benign drugs such as silymarin. However, for definitive phase III studies, liver biopsies will be necessary to demonstrate meaningful clinical benefit. To date, imaging studies that measure hepatic fat have not been shown to be reliable enough to use as a
clinical endpoint in studies of NASH, but ultimately may be very helpful.
Dr. Kris Kowdley (U Washington, Seattle) commented that liver biopsies are
complicated by sampling variability and reproducibility, and suggested that the
algorithms using markers currently being developed by commercial and research
laboratories may, in the future, be useful for the prognostication of patients or as a surrogate for liver biopsy. Dr. Angulo remarked that one problem with serum markers of fibrosis in NASH is determining a standard to be used for the comparison of serum marker accuracy.


Antioxidants and Liver Disease

Silymarin as Therapy of Liver Disease Workshop
March 22, 2004

Craig J. McClain, M.D., Professor, Division of Gastroenterology/Hepatology, Vice Chair for Research, University of Louisville, Louisville, KY

Oxidative stress is defined as the imbalance between endogenous, intraccellular
prooxidants and antioxidants. Oxidative stress is a frequent finding in liver disease which suggests that antioxidant therapy may be of value. The major reactive oxygen species include superoxide anion, hydrogen peroxide, hydroxyl radical; the reactive nitrogen species are nitric oxide (NO), and peroxynitrite (ONOO-); and reactive halide species are the hypohalous acids (e.g., HOCl). These molecules are important in oxidative stress either directly or as messengers or signaling molecules. Endogenous sources of reactive
oxygen species include mitochondrial dysfunction in alcoholic liver disease, nonalcoholic steatohepatitis (NASH), and, to a lesser extent, hepatitis C. Transition metals (such as copper and iron), myeloperoxidase from infiltrating neutrophils, and increased CYP2E1 are also important in diseases such as alcoholic hepatitis and NASH. Markers used to assess reactive oxygen species and their damage, including biomarkers of DNA oxidation and antioxidant defense systems, are potentially clinically useful in assessing the severity
of liver disease and need for treatment.

A study using a methionine-restricted, choline-deficient rat or mouse model
showed that animals placed on the diet for 4 weeks developed fibrosis, cirrhosis, stellate cell activation, increased TBARS, and increased 4HNE, results which indicate  a progression of simple fatty liver to fibrosis and ultimately cirrhosis, with some cases ultimately developing liver cancer (Chawla et al. Am J Physiol 275:G125-G129). Many of these changes can be prevented by pretreatment with antioxidants including S-adenysl methionine (SAMe), vitamin E and procysteine.

In studies of normal volunteers fed alcohol, markers of lipid peroxidation
appeared in the serum ( Meagher et al. J Clin Invest 1999; 104:805-13). Similarly, patients with alcoholic hepatitis have elevated markers of lipid peroxidation compared to controls. Stable alcoholic cirrhotics and patients with chronic hepatitis C have elevations in these markers as well. Patients with NASH also had footprints of oxidative stress as shown by peroxinitrate staining of hepatocytes in patients with fatty liver and NASH compared to individuals with normal livers (Sanyal et al. Gastro 2001;120:1183-92).

In an effort to examine the effectiveness of antioxidant intervention for the downregulation of oxidative stress or pro-inflammatory cytokines, stable alcoholic cirrhotics were treated with procysteine. Glutathione levels rose and pheripheral blood monocyte production of pro-inflammatory cytokines such as IL-8 and TNF was decreased (Pena et al. JPEN 1999;23:1-6). These results, combined with studies cited earlier, provide a rationale for utilizing antioxidant therapy, especially since there are biomarkers that can be assayed in alcoholic liver disease. At present, a large multicenter trial of SAMe in alcoholic liver disease is about to be intiated funded by the Department of Veterans Affairs.

Several studies have suggested a role of antioxidant therapy for NASH. An open
label trial of vitamin E in children demonstrated consistent improvements in serum aminotransferase levels (Lavine J. J Ped 2000:136;734-8). A 6-month period of diet followed by the addition of vitamin E for a year was shown to result in improvements in ALT and TGF_1 levels as well as liver histology (Hasegawa et al. Aliment Pharmacol Ther 15:2001;1667-72). Finally, a lifestyle modification and vitamin E study in which 14 patients with biopsy-proven NASH were randomized to diet and exercise, with or without vitamin E, showed that the interventions resulted in decreased liver enzymes and markedly improved hyaluronic acid levels (a marker for fibrosis and sinusoidal endothelial cell dysfunction) over control individuals (Kugelmas et al. Hepatology 2003;
38:413-9). None of these studies were fully controlled or of adequate size and duration to prove the efficacy of antioxidant therapy of NASH. Two multicenter, large-scale randomized controlled trials of vitamin E versus insulin-sensitizing agents have been developed by the NASH Clinical Research Network which may help define the role of antioxidant therapy of nonalcoholic fatty liver disease.

Thus, oxidative stress plays an etiologic role in liver injury and fibrosis. While
antioxidants are promising interventions, the types, combinations, dosing, and targeting remain important questions to be answered.

Discussion
Dr. Stephen Straus (NCCAM) remarked that the diseases under discussion could
cause injury other than oxidative stress to the liver, and that the benefits of milk thistle, if any, may be due to effects on those other injuries. If solely an oxidant is needed, Dr. Strauss suggested that there may be much more potent, cost effective, and simpler antioxidants than milk thistle suitable for study. Dr. McClain agreed and recommended using animal models or in vitro studies to compare milk thistle to vitamin E or SAMe. Dr. John Senior (FDA) asked whether the methionine-restricted diet model of fatty liver disease was reliable in causing chronic injury and fibrosis. Dr. McClain responded that methionine-restricted animals do not lose weight, but by 2 weeks have severe fatty liver, and by 4 weeks have fibrosis. After 3 months, most animals have cirrhosis. The model occasionally fails because there is too much methionine in the regular diet, which must be carefully controlled to produce the desired results.

Silymarin and Cell Injury

Mark Zern, M.D., Professor, Internal Medicine/Transplant, University of California, Davis, Sacramento, CA

Milk thistle earned its common name from the milky veins in its leaves. Extracts
of milk thistle have been reported to protect liver cells in vitro from a wide variety of toxins, including acetaminophen, ethanol, carbon tetrachloride, galactosamine, and iron, as well as ischemic injury, radiation, and viral hepatitis. Strong evidence from both human studies and animal studies in mice and dogs suggests that silymarin and its components are effective in countering Amanita phalloides mushroom poisoning. Furthermore, several controlled trials of silymarin have suggested that it has a beneficial effect in alcoholic liver disease and cirrhosis. The mechanism of action of silymarin has not been proven, in vitro and in vivo evidence indicating that it has distinct antioxidant, antifibrogenic, anti-inflammatory, and other hepatoprotective actions.

The major effects of silymarin are believed to be mediated through the antioxidant actions of this flavinoid. In large numbers of studies, silymarin has been shown to decrease oxidative injury from a variety of sources, inhibiting lipid peroxidation and membrane damage. Several studies have suggested that silymarin inhibits activation of NF-_B, a selective effect in that the drug does not affect AP1 activation. Silymarin blocks the activation of NF-_B by phorbol ester, lipopolysaccharide, okadaic acid, and ceramide, but not from H2O2. It appears to inhibit phosphorylation and degradation of I_B, and inhibits the translocation of p65 to the nucleus. Silymarin also inhibits TNF-_-induced activation of MAP kinase and its activation of caspases (Manna et al, J Immunol 1999;163:6800). In a study in mice, silybin inhibited the oxidative CYP 450 enzymes 1A1, 1A2 which may limit hepatotoxicity through inhibition of activation to reactive
intermediates (Baer-Dubowska et al, Xenobiotica 1998; 28: 735).

In humans, silybinin has been shown to have oxygen radical scavenging effects
and to inhibit the arachidonic acid pathway (Dehmlow et al, Life Sciences 1996;58:1591). The most significant effect observed was inhibition of perchlorate release by neutrophils, but silybinin also appeared to interfere directly with 5-lipoxygenase activity. Silybinin also had inhibitory effects on PG2 production, which may also be hepatoprotective. Human studies in patients with alcoholic cirrhosis, indicate that silymarin decreases lymphocyte expression of superoxidase dismutase (Feher et al, Acta Med Hung 1988;45:265).

Silymarin has been shown in a variety of different studies to affect liver cell
injury by toxins by pathways other than antioxidant effects. Silymarin blocks the uptake of phalloidin by hepatocytes and may affect other transmembrane transport systems. The regulatory action of silymarin on cellular and mitochondrial membrane permeability associated with increased membrane stability against xenobiotic injury is supported by a number of studies. (Munter et al, Biochem Biophy Acta 1986;860:91). In a rat model of ischemia/reperfusion injury, silymarin reversed the severe impairment of mitochondrial bioenergetics, including increasing ATP levels, decreasing susceptibility to mitochondrial
permeability transition (MPT), and improving defects in mitochondrial respiration (Rolo et al, Hepatol Research 2003;26:217).

Silymarin may also have direct effects on fibrogenesis. In a mouse model of
biliary fibrosis without significant inflammation, silymarin inhibited collagen
accumulation, even when administered late, inhibiting increases in serum PIIINP levels (Boigk et al, Hepatology 1997;26:643). Silymarin downregulated type 1 collagen, TIMP- 1 and TGF-_1 mRNA levels in treated animals (Jia et al, J Hepatol 2001;35:392), suggesting that it has an effect on collagen-related genes which is separate from its antioxidant effect. Lieber and colleagues showed improvement in a 3-year study in alcohol-fed baboons, including decreases in serum ALT and 4-hydroxynoneal levels and suppresion of type 1 procollagen mRNA levels in liver (J Clin Gastroent 2003;4:336). Evaluation of the relative antifibrogenic and antioxidant effects of silymarin in humans warrants further and more careful investigation.

Silymarin has also been reported to have anti-inflammatory actions. Purta et al.
demonstrated decreased edema and neutrophil infiltration in mice treated with silymarin following xylene (ear) or carrageenan (paw or peritoneal) administration. (J Pharm Pharmacol 1995;48:968). In rat Kupffer cells, silybinin decreased superoxide anion radical formation and production of nitric oxide and leukotriene B4 (Dehmlow et al, Hepatology 1996;23:749). Two studies from Hungary have suggested that improvement in immune function is a mechanism for beneficial effects of silymarin in alcoholic liver disease in humans. Silymarin reduced lectin-dependent and natural killer cell-mediated cytotoxicity by lymphocytes, but not antigen-dependent cytotoxicity (Deak et al, Orv
Hetil 1990;131:1291, and Lang et al, Tokai, J Exp Clin Med; 1990; 15:123). Concurrent with the normalization of ALT, AST and bilirubin levels in patients with alcoholic liver disease receiving silymarin, there were decreases in the percentage of OKT8+ cells andlymphocyte toxicity. In a more recent study, Schuman et al (J Hepatol 2003;39:333) showed that silybinin abrogated ConA-induced liver disease in mice by inhibiting TNF-_, IFN-_, IL-2, IL-4, NF-_B, and iNOS, while augmenting IL-10 expression, which again, may be more of an immunomodulatory effect than has been shown in other studies.
A recent study of patients with alcoholic cirrhosis who were treated with
silymarin MZ 80 for 6 months had statistically significant increases in total GSH and decreases in MDA, as well as decreases in PIIINP (Lucena et al, Int J Clin Pharm Ther 2002;40:2). However, not all studies showed improvement of oxidative stress with silymarin therapy. Halim and coworkers (Ann Clin Biochem 1997;34:656) showed a marked decrease in liver enzymes, and improvement in histology and survival with silymarin administration to CCl4-treated rats, but no significant change in MDA levels, suggesting an improvement in perhaps a mechanism other than antioxidant effects.

Silymarin was shown to reduce the ethanol- or acetaminophen-enhanced,
CYP2E1-mediated cytotoxicity of methotrexate in human hepatocytes, but at a relatively high dose (Neuman et al, Clin Biochem 1999;32:519), although other studies have not shown an effect on CYP2E1. In another study, liver microsomes from human donors showed inhibition of CYP3A4 and CYP2C9 activity with silybinin (Bechmann-Knopp et al, Pharmacol Toxicol 2000;86:250).

Thus the potential mechanisms of action of silymarin include:

o Antioxidant properties and the inhibition of lipid peroxidation; and
o Inhibition of NF-_B activation.
o Inhibition of fibrosis;
o Inhibition of inflammation;
o Enhancement of RNA, DNA, and protein synthesis;
o Regulation of cell permeability;
o Inhibition of mitochondrial injury;
o Immunomodulation; and
o Inhibition of P450 activity.

Discussion
Dr. Kris Kowdley (University of Washington) stressed the importance of using
surrogate markers for actions of silymarin in clinical trials. Thus, use of serum,
lymphyocyte and urine markers for oxidative stress, fibrosis, cytokine production and immune function are important during clinical studies seeking to elucidate the efficacy of milk thistle in liver disease. Serum markers of fibrosis, while not proven to be highly sensitive or specific, can be used to help identify the mechanism of action of silymarin and assess its activity in individual patients. Similarly, studies of lymphocyte subsets and function during therapy may help identify the dose and regimen most appropriate in humans. Thus, while ALT, AST and GGTP are commonly used as surrogate markers for improvement in liver disease, markers of fibrosis, oxidative stress and immune function
can supplement these tests while the ultimate criteria for benefit needs to be clinical (death, transplantation, decompensation) and histological.

Dr. Stephen Straus (NCCAM) suggested that animal models should provide some direction to use of indirect surrogate markers for the actions of silymarin and for changes in liver disease activity and grade.

Dr. Jay Hoofnagle (NIDDK) remarked that studies of silymarin suggested that it
had multiple effects on cells that are potentially protective against injury and asked why the focus has been liver disease and not other forms of injury. Why also was it considered a superior antioxidant for liver disease than others such as vitamin E, selenium and SAMe.

Dr. Josh Berman (NCCAM) remarked that his Center will soon engage in an
investigation of the relative antioxidant strengths of many natural products, with an aim to determine whether or not a certain natural product has potential as either a specific or more general antioxidant. He hypothesized that the most likely reason for the use of milk thistle in liver disease is a combination of inherent antioxidant actions and other more liver specific activities. These issues should be resolved in animal models, but ultimately, researchers will have to recognize the realistic limits of the pace of preclinical investigation versus the desire to help patients and initiate clinical trials early.

Dr. Straus (NCCAM) added that having a sense of at least the top three or four
most reasonable mechanisms and the ability to discern at which time the product has the strongest activity allows one to begin to consider a dosing schedule to optimize the effects. He also pointed out that it is probably fairly optimistic to assume that researchers can identify a single effect; rather, it might be more beneficial to separate the major effect from more minor ones, and there are model systems available to do so.

Dr. David Lee (NPI) commented that most herbal remedies have multiple actions
and targets. Nevertheless, it is convenient to focus on a single mechanism of action as this helps to guide clinical studies and to determine appropriate dose-regimens.

Dr. John Senior (FDA) commented that it was important to distinguish effects on
models of acute versus chronic liver disease. The major interest in milk thistle has been on therapy of chronic liver diseases and cell injury. Important endpoints are prevention of fibrosis and clinical deterioration. Use of these endpoints requires large studies conducted over many years. A reasonable surrogate would be to focus on serious acute liver injury. Amelioration of acute injury has been demonstrated in animal models and deserves to be studied in humans as well.

Dr. Jay Hoofnagle (NIDDK) added that an important first step is to identify the
appropriate dose of silymarin and this is best done using short-term surrogate markers for activity. Long-term outcome is the most appropriate endpoint for ultimate decisions on the benefit of silymarin therapy, but intermediate term endpoints or surrogate markers are needed to evaluate what dose needs to be given at what intervals for how long in which patients. Dr. Hoofnagle asked the cell biologists in attendance to suggest what surrogate markers would be best to evaluate in patients receiving silymarin. Drs. Craig McClain and Mark Zern both recommended use of lymphocyte levels of NF-_B or markers of oxidative injury. They also recommended use of a simple animal model to develop these markers and stressed the need to use normal volunteers in early studies of changes of
these markers in humans given silymarin.

Dr. Kowdley stated that although the points raised are very relevant, silymarin is
quite different from other new drugs under development. Millions of people are already taking this product, believing that it will help their liver disease. Thus, the usual concerns involved in the step-wise drug development process should be abbreviated. There is a certain urgency to demonstrating whether silymarin has clinical utility in liver disease. Thus, clinical studies should not be slowed for the sake of identifying all of the mechanisms of action of the drug and their relative importance.


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#12387 From: tim pearce <munkybizness37@...>
Date: Thu Jun 30, 2005 12:59 am
Subject: bioalcamid in NYC 		munkybizness37
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Does anyone know if  a Dr. S White in NYC is doing Bioalcamid?
 
Is it the same stuff as in the clinic in Mexico and how is he able to do that when it is not FDA approved?
 
Has anyone gone there to have it done?
 
Responses appreciated.
 
Tim in
Louisiana

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#12386 From: "Jim" <keysjim2002@...>
Date: Wed Jun 29, 2005 3:17 pm
Subject: IDIG 		keysjim2002
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Hello, I am a 47 yo M who was diagnosed in 1997 as being HIV positive,
one of the most recurring problems I have is my peripheral neuropathy
in my legs. My neurologist now wants me to begin IDIG , which is some
sort of imuno globulin infusion @ 400mg/kilo, and I was wondering if
anyone else has had this done and what I might expect as far as
repercussions to my viral load as well as my overall well being. I
would appreciate a response from anyone with any experiences in this
type of treatment...thank you for your time , Jim

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#12385 From: Steve <simonadyjf@...>
Date: Wed Jun 29, 2005 2:01 pm
Subject: Question on Treatment Interruption 		simonadyjf
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I have had excellent results on my cocktail (Viracept, a PI and Combivir, 3TC and AZT, both NRTIs) for 8 years.  My pre-treatment numbers were good too, t-cells over 500 and viral load about 60,000.
 
However, the side effects are taking their toll.  I cannot control the diarrhea, bloating, and gas.  Plus, I am getting "the look" from body shape changes and veiny legs (my face is fine for now).
 
I know that a return to normal might not be guaranteed with a treatment interruption, but I am willing to try. 
 
Here are my questions:
1.  Has anyone chosen a treatment interruption and chosen to stay on 3TC as a single drug treatment during the interrruption?  My reasoning is that 3TC resistance is prevalent and very likely, so I don't loose anything on monotherapy.  Plus, I need it along with Hepsera for my Hep-B, and 3TC resistant HIV virus is much weaker and may allow me on a longer interruption.
 
2.  Has anyone used genotype testing to help decide about a treatment interruption?
 
Thanks for your considerations, Steve.

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#12384 From: PoWeRTX@...
Date: Wed Jun 29, 2005 7:15 pm
Subject: “Cure to HIV Doldrums Found at Sea” 		nelsonvergel
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FOR IMMEDIATE RELEASE

 

CONTACT:

Sheri Kaplan

305-891-2066

skaplan@...

 

 

 â€śCure to HIV Doldrums Found at Sea”

 

Miami, FL – June 30, 2005 – In an interview for the Positive Voices newsletter, celebrated author and HIV Treatment advocate Nelson Vergel affirmed: “the cure for the HIV doldrums can be found at sea”.  He explained that upon being diagnosed with HIV many people experience a sometimes prolonged period of inaction, emotional paralysis and even outright depression – the HIV Doldrums.  “People living with HIV need to understand that there is life after an HIV+ diagnosis, and that with the right regimen of nutrition, exercise and medical treatment people with HIV can live long, productive and happy lives.  Life-affirming events like the POZ Cruise can help people living with HIV or AIDS find the right balance and get the information they require to survive HIV and thrive” said Vergel.

 

Sponsored by The Center for Positive Connections, the 8th Annual POZ Cruise departs Fort Lauderdale’s Port Everglades at 5:00 PM on Saturday, October 15, 2005 for seven days of fun filled activities on board Holland American Cruise line’s ship the Zuiderdam.  With ports of call in Tortola (British Virgin Islands), St Thomas (US Virgin Islands), Nassau & Half Moon Cay (Bahamas) and a series of educational workshops by Vergel, this cruise offers HIV+ individuals, their family and friends a unique learning opportunity, a supportive environment, rest and relaxation and a venue to make new friends.  Starting at around $530 per person plus $189 port taxes, the trip can be booked by August 1st  by contacting the travel agent Paul Stalbaum at Universal Travel 1424C SE 17th St, Ft Lauderdale, FL  33316 - telephone 1-800-735-0401 ext 241 or by email paul@....  Remember to mention the POZ Cruise to receive our special group discount rate.  The pre-cruise party will be held on October 14th at the Blue Moon Hotel at 944 Collins Ave. on South Beach. Special room rates are available through the travel agent.

 

The Center for Positive Connections (TCPC) is a progressive grassroots non-profit HIV services organization serving the South Florida region since 1995.  Our mission is to provide HIV prevention, health education, emotional and social support, mental health, holistic health and housing services for people for at risk for or living with HIV/AIDS in South Florida.  Our goal is to educate and empower HIV+ individuals to heal in body, mind and spirit and to prevent others from becoming infected with HIV.  Today TCPC is a nationally recognized model for peer/consumer-driven HIV prevention & health education and a leader in the provision of holistic health services.  For more information regarding The Center for Positive Connections, its services or the POZ Cruise please call 305-891-2066 or visit our website:  www.positiveconnections.org.

 

 

 

 
Nelson Vergel
Program for Wellness Restoration
powerusa.org

 Join a 1700 people HIV discussion group by sending a blank email to pozhealth-subscribe@yahoogroups.com
Please email me at nelsonvergel@... if you have problems with this email address. Thanks

Lecture Dates:
Chicago June 30, El Paso- July 7, Miami-Ft Lauderdale- July 18 & 19 (Spanish), Atlanta July 21, Phily Aug 24 /Sept 14, Long Beach Aug 31, NY Sept 8, LA Sept 21, Salt Lake- Nov 5, AIDS Nutritionist Conf- DC Sept 15-17,San Francisco Oct 26, POZ Cruise- Miami- Oct 15-21


Disclaimer

This information (and any accompanying printed material) is not intended to replace the attention or advice of a physician or other health care professional. Anyone who wishes to embark on any dietary, drug, exercise, or other lifestyle change intended to prevent or treat a specific disease or condition should first consult with and seek clearance from a qualified health care professional.

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#12383 From: "Michael Mooney" <mmooney@...>
Date: Wed Jun 29, 2005 4:43 pm
Subject: Article saying that "Vitamin C May Not Fight Colds" 		michaelmoone...
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Funny, they didn't mention the first placebo-controlled study on Vitamin C and colds that showed that 1000 to 6000 mg per day reduced the duration of cold symptoms an average of 21 percent in healthy adults. These guys' publication said that 8 percent was the best.
 
They appear to be guilty of omission, which I almost always see in the articles about studies that say vitamins don't work in the press. They neglect to include all the data that is available, like the data that show the most benefit, and say that this is all there is.......
 
Hmmm. Wotmean??
 
I guess that they figure that since almost no one goes to the sources and checks on them, most people will just read this and believe it. I note that a recent study showed that about 90 percent of doctors only read the headlines, and don't read the studies to see what's really going on.
 
Shame on them! Shills for the drug companies that know that if people take vitamins, they get healthier and take less drugs.
 
Michael Mooney
 
 
Hemila H, and associates. Vitamin C and the common cold: a retrospective analysis of Chalmers’ review. Journal of the American College of Nutrition 1995;14(2):116-123.

From: BeefyMuscleBud@... [mailto:BeefyMuscleBud@...]
Sent: Wednesday, June 29, 2005 9:04 AM
To: PoWeRTX@...; mmooney@...
Subject: Vitamin C May Not Fight Colds


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#12382 From: david mariner <health@...>
Date: Wed Jun 29, 2005 5:26 am
Subject: Seniors and HIV/AIDS Clinical Trials 		temenos_health
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Hi everyone,

This week's AIDS Research Community Handbook Article is now online at:

Seniors & HIV/AIDS Clinical Trials
http://www.researchadvocates.org/article005.htm

You can download the PDF and share with folks at your local CAB meetings. Also,
if you are having successes with your local CAB, let me know about it. If you
have articles, or tips, or handouts, or even pictures from your local CAB that
you would like to see posted on the www.researchadvocates.org website, send them
to david@....

Thanks!

David Mariner

DAVID MARINER
Silver Spring Office
Phone (301) 628-3390 | Fax: (301) 628-3306
dmariner@...

Washington DC Office
Phone (202) 797-4424 | Fax: (202) 797-4430
dmariner@...

Home
Phone (301) 588-3645 | Mobile (301) 437 2309
david@...

A fo ben, bid bont
He who would be head let him be a bridge
Welsh Proverb


_____________________________________________________________
Get email for your site ---> http://www.everyone.net

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#12381 From: "John Rosenzweig" <johnrsf@...>
Date: Tue Jun 28, 2005 3:48 pm
Subject: Anal Cancer, HIV Vaccine for men 		johnrsf94114
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In San Francisco, UCSF is enrolling young gay men (ages 18-24) in a vaccine
study to test its usefullness in prevention of HPV infection. They are
given the vaccine on the day of their first visit, after screening out
those who have visible signs of infection as seen through anoscopy.


>
> Message: 1
>    Date: Sun, 26 Jun 2005 06:41:23 -0600
>    From: Bob Munk <bobmunk@...>
> Subject: Re: In response to the Anal Cancer story, why are men not
getting HPV vaccine?
>
> Well, probably because my understanding is that in order to be
> effective, the HPV vaccine needs to be used before someone becomes
> sexually active.
>
> Bob
>
>
> On Sat, 25 Jun 2005 12:43:00 EDT, you wrote:
>
> >I asked my Doctor and she said she had not even thought of that before,
she
> >says she will look into using the HPV vaccine on gay men.
> > HPV surely does not care if your male or female, and HPV does cause
both
> >cervical and at times Anal cancer. I think we should make some noise
about this
> >and find out what it takes to get this. Now I do not know if the vaccine
will
> >work therapeutically but its worth asking.
> >                                                                    Al
>
>
>
>
>
>
> ________________________________________________________________________
>

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#12380 From: "Jim" <j.i.m@...>
Date: Tue Jun 28, 2005 1:15 pm
Subject: norvir, truvada and Reyataz 		hcsta
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I'm thinking of changing from my all nuke and non-nuke regime to norvir, truvada
and
Reyataz by the advice of Jon Kaiser in Marin.  Can anyone give me any feedback
on what
their experiences have been on these meds.  I have an appointment with my local
doc
today and would appreciate any info you could share.  Thanks.

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#12379 From: PoWeRTX@...
Date: Tue Jun 28, 2005 10:42 pm
Subject: Can Past Nutritional Sins Affect Your Health? 		nelsonvergel
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Can Past Nutritional Sins Affect Your Health?

By  Jennifer Nelson
WebMD Feature 		Reviewed By Brunilda Nazario, MD

So you may not have made all the right nutrition choices in the past, but it's unlikely you caused any permanent harm, right?

WebMD wanted to be sure, so we took it to the experts to get the scoop on why some of the nutritional missteps you were guilty of in the past are taboo. And what, if any permanent effects, these prior dietary failings have in store for you. Can these past nutritional skeletons haunt your health today?

Yo-Yo Dieting

If your weight has fluctuated up and down the scale -- and your closet houses an array of pant sizes to accommodate your ever-changing waistline, you're not alone.

Yo-yo dieting is one of the most common nutrition mistakes you can get caught up in. Lose a few pounds here, gain them back there. What's the big deal, right? The National Task Force on the Prevention and Treatment of Obesity from the National Institutes of Health looked at whether yo-yoing, also known as weight cycling, had an adverse effect on body composition, energy expenditure, risk factors for cardiovascular disease, or interfered with future efforts at weight loss. Although conclusive data on the long-term health effects of weight cycling are lacking, the task force determined that maintaining a stable weight should be a priority. Anything beyond a 5-pound variation should tip you off.

However the WISE study (Women's Ischema Symptom Evaluation) funded by the National Heart, Lung, and Blood Institute did find that yo-yo dieting actually lowers levels of good cholesterol (HDL).

"One problem with past yo-yoing is that it can mess up your metabolism," says Keri Glassman, MS, RD, a New York City-based dietitian. When you yo-yo diet, you never really learn to eat normally. Weight cycling sets you up for binges. Plus, you probably aren't eating a variety of healthy foods. You're always either getting too many calories, which turn to fat, or your body is in deprivation mode from eating too little, so your metabolism is constantly thrown out of whack and never burns calories efficiently, which hampers any effort at weight loss.

To boost calorie burn and return metabolism to normal, stop the ups and downs and acquire a balanced healthy diet. Eat consistently every three to four hours and never go too long without food. Glassman tells WebMD, "Once you're eating regularly, you can get your metabolism back on track."

Skimping on Carbs

If tallying carbs and keeping them low was your M.O., you might have easily gone overboard. Carbohydrates are a source of concentrated energy so contrary to some beliefs the ideal is not to eliminate them at all costs. Carbs are a rich source of B vitamins and contribute to skin, hair, eye, and liver health. They also help regulate appetite and keep the brain and nervous system running optimally.

"Skimping on carbs can throw the body out of balance because something it needs isn't showing up for work," says Cynthia Sass, MPH, MA, RD, a Florida-based dietitian.

Too few carbs may lead to increased appetite and insatiable cravings. And severely restricting carbohydrates can cause you to eat too much fat -- think a whole jar of nuts in one sitting.

If eating a low-carb diet equals eating lots of saturated fat and cholesterol-heavy foods, these can increase your risk of high cholesterol, heart disease, and cancer, Sass tells WebMD.

It could also up your risk of diverticulitis, an infection in the pouches within the colon, because of the lack of dietary fiber typical on low-carb plans.


The quick fix is to jump on the veggie bandwagon ASAP. Strive for five to nine servings of produce per day to boost intake of disease fighting antioxidants and phytochemicals. This will also increase fiber, as a typical serving of fruit or vegetables contains 2-3 grams of fiber.

Read labels to keep saturated fat, hydrogenated fat, and cholesterol to the USDA Dietary Guidelines limits, which is 300 milligrams of cholesterol per day from food, 10% of total calories from saturated fat (about 22 grams for a 2,000-calorie diet), and as little hydrogenated fat as possible. Hydrogenated fats come from liquid vegetables oils, which are converted into solid form during manufacturing. They are used mostly in processed baked goods, such as cookies and cakes, and can help increase the shelf life of many products. But these fats have a negative effect on cholesterol, increasing "bad" LDL cholesterol while lowering "good" HDL cholesterol.

Breakfast Skipper

Whether you were too busy sleeping in, just not hungry or truly thought this was a good way to keep your weight in check, former breakfast skippers may have wreaked havoc on their metabolisms, too. Research shows skipping the morning meal slows resting metabolism and keeps our bodies from burning calories until lunchtime. A study in the Journal of the American College of Nutrition shows breakfast skippers have a higher body mass index (BMI).

Other research shows people who eat breakfast daily may be less likely to succumb to obesity and diabetes.

"You need breakfast to get your brain and body functioning," says Glassman. If you don't feed your body, it will only hold onto the fuel it has stored and will never budge a pound.

People who skip breakfast are also the type of people who tend to go without eating in general, Glassman tells WebMD. They're the same ones who go until 3 p.m. without lunch or tend to forget to eat all day and then feast on a large dinner.

These behaviors can destroy of the metabolism over time. Also, when you eat fewer foods throughout the day, you eat fewer types of foods and may miss out on vital nutrients, says Glassman. Skipping breakfast may result in a lack of an adequate store of vitamins and minerals as well as missing out on certain phytochemicals and antioxidants that help ward off disease.

Avoid the metabolism roller coaster by regularly downing a healthy breakfast. If you can't eat first thing in the morning, wait an hour or two for your stomach to settle, and then try half an English muffin with peanut butter or a container of yogurt.

Fad Dieter

If you once followed the grapefruit diet, the cabbage soup diet, or a few other not-so-nutrition-savvy plans, you may have this nutritional blunder in your diet repertoire.

But if you were a fad-diet groupie, have you put your health at risk?

"Fad diets aren't science-based and their goal is only weight loss, not long-term disease prevention or even day-to-day energy," says Sass. You also can feel too tired to exercise and irritable and moody during a fad diet.

Depending on how wacky and lacking in nutrients the fad was, you may have lost lean muscle mass and bone density along with body fat.

The good news: Once you've dumped the fad diet, the short-term side effects like irritability and fatigue fade away. However, lost muscle mass and declining bone density can prove more problematic.

While building lean muscle through weight-bearing exercise is the key, building up bone health can be trickier and take longer to accomplish. Eating a diet rich in calcium and regularly lifting weights is a start.

Talk to your doctor about bone mineral density testing, especially if you have other risk factors for osteoporosis, such as a family history, or if you paid homage to many fad diets in the past.

And never relying on a fad diet to slim down again is the best break your bones will get.

Published Sept. 23, 2004.

SOURCES: National Institutes of Health. WISE study (Women's Ischema Symptom Evaluation), The Journal of the American College of Cardiology, November 2002. Keri Glassman, MS, RD, KKG Body Fuel, New York City, N.Y. Cynthia Sass, MPH, MA, RD, American Dietetic Association, Tampa, Fla. Journal of the American College of Nutrition, 2003; vol 22: pp 296-302.



© 2004 WebMD Inc. All rights reserved.
 
Nelson Vergel
Program for Wellness Restoration
powerusa.org

 Join a 1700 people HIV discussion group by sending a blank email to pozhealth-subscribe@yahoogroups.com
Please email me at nelsonvergel@... if you have problems with this email address. Thanks

Lecture Dates:
Chicago June 30, El Paso- July 7, Miami-Ft Lauderdale- July 18 & 19 (Spanish), Atlanta July 21, Phily Aug 24 /Sept 14, Long Beach Aug 31, NY Sept 8, LA Sept 21, Salt Lake- Nov 5, AIDS Nutritionist Conf- DC Sept 15-17,San Francisco Oct 26, POZ Cruise- Miami- Oct 15-21


Disclaimer

This information (and any accompanying printed material) is not intended to replace the attention or advice of a physician or other health care professional. Anyone who wishes to embark on any dietary, drug, exercise, or other lifestyle change intended to prevent or treat a specific disease or condition should first consult with and seek clearance from a qualified health care professional.

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#12378 From: Albenson@...
Date: Tue Jun 28, 2005 8:21 pm
Subject: GH Improves Myocardial Contractile Performance 		Albenson@...
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Tuesday, June 28, 2005

Growth Hormone Improves Myocardial Contractile Performance

Posted by Al Benson

Reuters via Medscape http://www.medscape.com/viewarticle/507439

Jun 27 - In adults with childhood onset growth hormone deficiency, treatment with growth hormone (GH) improves cardiac contractile performance, according to a report in the May 25th International Journal of Cardiology.

“In patients with childhood onset growth hormone deficiency, treatment with GH should be continued after the end of their linear growth,” Dr. Andrzej Minczykowski from University School of Medical Sciences, Poznan, Poland told Reuters Health.

Dr. Minczykowski and colleagues investigated the effects of GH replacement on cardiac structure and functional indices in 16 patients with childhood onset GH deficiency. The mean age was 42.3 years, ranging from 18 to 60. Three of the subjects had been treated with GH several years earlier.

Heart rate and blood pressure did not change significantly after 12 months of GH treatment, the report indicates, and left atrial end-systolic diameter and left ventricular end-diastolic diameter remained the same.

The systolic increase in left ventricular wall thickness increased significantly after treatment, the authors report, but the left ventricular diastolic wall thickness was not altered by GH treatment.

Ejection fraction increased significantly after 12 months, the results indicate, and left ventricular end-systolic volume decreased significantly.

Growth hormone treatment also brought significant improvements in integrated backscatter, another measure of cardiac architecture and performance, the investigators report.

“Therapy with GH in patients with childhood onset GH deficiency is usually discontinued at the end of linear growth,” Dr. Minczykowski explained. “The majority of patients with GH deficiency occurring in adulthood do not receive GH treatment.” The current findings and the results of other studies “have shown that in such situations GH treatment can give some important benefits to patients, but they disappear with GH discontinuation.”

“GH should be administered in supplementing doses,” Dr. Minczykowski concluded. “It is difficult to recommend an endpoint other than the serum IGF-I response to GH treatment. The dose of GH should aim at the low to middle range of the normal age-predicted values of the serum IGF-I levels.”

Int J Cardiol 2005;101:257-263.

Posted by Al Benson at 02:26 PM on June 28, 2005. (0) Comments | (0) Trackbacks | Permalink


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#12377 From: PoWeRTX@...
Date: Tue Jun 28, 2005 4:57 pm
Subject: Brazil set to break patent on Abbott's AIDS drug 		nelsonvergel
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Brazil set to break patent on Abbott's AIDS drug
The Pink Sheet

6/27/05

Brazil announced it would begin producing its own generic version of Abbott Laboratories' AIDS drug Kaletra if the company does not agree to significantly reduce its price for the treatment. Abbott, which has 10 days to respond before Brazil breaks the patent, said the government does not have "a legal basis to issue a compulsory license" for Kaletra, but a spokesperson said the company hopes to work with Brazil to find a "mutually agreeable solution." Brazil also is pressuring Gilead Sciences and Merck to lower prices on their widely used AIDS drugs or face having their patents ignored. The New York Times (free registration) (6/25)

 

 

Brazil Issues AIDS-Drug Ultimatum --- Generic Production to Begin If Abbott Won't Lower Price; Bristol's African Initiative

Matt Moffett and Heather Won Tesoriero
The Wall Street Journal


B4
English
(Copyright (c) 2005, Dow Jones & Company, Inc.)

Amid growing friction between Brazil and the U.S. over trade and AIDS policy, Brazil said Friday it was giving Abbott Laboratories 10 days to lower its price for the AIDS drug Kaletra. If Abbott refuses, Brazil said it would authorize a state-run laboratory to produce a version of Kaletra for a price 58% that charged by Abbott.

Brazil said its action would be based on national and international trade legislation allowing the issuance of compulsory licenses for drug production in emergencies or as a matter of public interest.

Abbott strongly contested the Brazilian ultimatum. "A compulsory license is not in the best interest of Brazilian patients because it puts the government's desire to cut health-care spending ahead of patients' need for new and better treatments," the Abbott Park, Ill., company said. "The discovery and development of innovative new treatments depends on the reasonable return on investment for existing treatments."

Abbott noted that it was already selling Kaletra to Brazil at a lower price than anywhere outside of Africa and other less-developed countries participating in a humanitarian-access program.

Kaletra had $896 million in world-wide sales last year, making it Abbott's third-biggest drug.

In recent years, Brazil has threatened several times to break AIDS drug patents in order to obtain lower prices. But the dispute with Abbott is the most serious standoff to date. Brazil said that almost one-third of the $394 million it has budgeted for antiretroviral drugs this year will be used to purchase Kaletra. While the price the government pays for Kaletra has come down to $1.17 per pill from $1.60 in 2002, Brazilian Health Minister Humberto Costa said Brazil can manufacture the drug for 68 cents, saving $54 million a year.

Brazilian AIDS activists said the country urgently needs to lower drug prices, as the number of people receiving free AIDS drugs is projected to increase to 215,000 in 2008 from 170,000 currently. "We don't have anything against the drug companies, but with thousands of new drug recipients every year, this is a question of survival," says Roberto Pereira, coordinator of the Center for Sexual Education, an AIDS awareness group in Rio de Janeiro.

Brazil said it is continuing negotiations with Gilead Sciences Inc. and Merck & Co. that are aimed at reducing prices on the AIDS drugs they produce.

Separately, Bristol-Myers Squibb Co. and Baylor College of Medicine will send as many as 250 pediatricians from around the world to Africa over the next five years to help care for the burgeoning population of children with AIDS, the organizations plan to announce today. Bristol-Myers, of New York, and Baylor, of Houston, also plan to build four children's HIV/AIDS treatment centers. The drug maker is also set to announce price reductions to its pediatric HIV medicines in some of the least-developed countries.

Pediatricians in the program will commit to one- or two-year stints in the centers and get relief of as much as $40,000 a year in school loans, plus living expenses. The program is meant as an interim measure until there are more Africans trained to provide pediatric HIV/AIDS care, and the corps will train medical professionals as part of its work. Two of the centers will be built in collaboration with local governments in Kampala, Uganda, and Bobo-Dioulasso, Burkina Faso. The developing-world locations of the other two centers haven't been chosen.

According to Unicef, last year about 640,000 children under age 15 became infected with HIV, and about 510,000 children died of AIDS. Since 1999, Bristol-Myers has awarded $120 million in grants for pediatric AIDS work. As part of the latest efforts, it's committing an additional $30 million, and Baylor is donating $10 million.

Leila Abboud and Marilyn Chase contributed to this article

Document J000000020050627e16r0002v

UPDATE 1-Brazil sees licence on U.S. AIDS drug in 10 days

Reuters News

6/27/05


English
(c) 2005 Reuters Limited

GENEVA, June 27 (Reuters) - Brazil expects to issue a compulsory licence order on U.S.-based Abbott Laboratories Inc.'s Kaletra AIDS drug in 10 days' time, the country's Health Minister Humberto Costa said on Monday.

Costa told a news conference during an AIDS conference in Geneva that a ministry lawyer would deliver the order to Abbott's Sao Paulo offices later in the day. The aim was to ensure that Kaletra, a key element in the country's anti-AIDS programme, could be produced and sold more cheaply in Brazil.

"In 10 days time, we will be issuing the compulsory licence order," said Costa.

Costa said in taking this action, the first time it will break a foreign patent, Brazil was using the flexibility allowed under World Trade Organisation (WTO) intellectual property rules covering public health emergencies.

He said his ministry was continuing negotiations with two other U.S. AIDS drug firms -- Gilead Science Inc and Merck & Co Inc -- on a voluntary licence agreement. "That would be the best solution," he declared.

The Brazilian government, which announced that it was planning to break the Abbott patent last Friday, expects to increase the number of patients on AIDS drugs to 180,000 by the end of this year from 150,000 in 2004.

HEALTH-BRAZIL-AIDS (UPDATE 1)|LANGEN|AFA|CSA|LBY|RWSA|RWS|REULB|GNS|RNA|ABX|BNX|FUN|SXNA

Document LBA0000020050627e16r000zs

 

ANTI-RETROVIRAL DRUG KALETRA TO BE PRODUCED IN BRAZIL

Asia Pulse

6/27/05

English
(c) 2005 Asia Pulse Pte Limited

(Full text of statement. Contact details below.)

BRASILIA, Brazil, June 24 /PRNewswire-AsiaNet/ --

The Government declares anti-retroviral Kaletra to be of public interest and will produce it in Brazil

The Ministry of Health of Brazil has declared the anti-retroviral drug Kaletra (Lopinavir/ritonavir), manufactured by Abbott Laboratories, to be of public interest. As such, the Brazilian government will adopt obligatory licensing of the medication, in the case that the manufacturer does not provide the necessary requirements to guarantee the sustainability of the National STD/AIDS Program. An official notice sent this Friday to the Laboratory opens the door for the company to express its opinion on whether it will address this situation in the public's interest.

(Photo: http://www.newscom.com/cgi-bin/prnh/20050623/SPF001 )

The Laboratory will have 10 days from receipt of this notice to inform the Brazilian Ministry of Health that it is prepared to reduce the sales price of Kaletra to national production levels. Its agreement will prevent the adoption of obligatory licensing.

With the licensing, the government will be able to allow Farmanguinhos Laboratory, from Fiocruz, to produce the medicine for exclusive public, and not commercial, use. This measure is necessary to maintain the sustainability and the quality of the National STD/AIDS Program, which is responsible for guaranteeing life for close to 170,000 Brazilians this year.

With the declaration of public interest, the Brazilian government is applying the flexibility laid out in international norms and Brazilian legislation, without breaking a contract. The Ministry of Health is basing its adoption of the licensing on the TRIPs Accords (Trade-Related Aspects of Intellectual Property Rights), the Doha Declaration, and Patent Law (1997) and Decree 4.830/03.

The Brazilian National STD/AIDS Program is a worldwide benchmark for treatment of HIV carriers and has as its goals the universal and free access to all resources available for the treatment of the disease, and for prevention and diagnosis at public hospitals.

The number of patients using anti-retrovirals in Brazil has risen from nearly 36,000 in 1997 to 170,000. Between 2004 and 2005, more than 20,000 people participated in the Program. There are 15 types of anti-retroviral medications that distributed free of charge. Kaletra was introduced in 2002 and is prescribed for patients who have already developed resistance to other medications.

To guarantee the use of the latest generation anti-retrovirals on all people, the Ministry of Health has increased by 50% the resources dedicated to the program, which started in 2004 at R$620.9 million, and in 2005 were increased to R$945 million (US$393.9 million). Of this sum, almost one third (R$257 million) will be used solely for the acquisition of Kaletra.

The projection is that in 2008, close to 215,000 people in Brazil will need the cocktail, which means a budget of R$1.25 million (US$520.8 billion), with one third of this amount being earmarked for the purchase of Kaletra.

Investment increases to maintain the National STD/AIDS Program have been constant. But in the last four years, Brazil has increased investments by 77%, while the number of patients has gone up by 43%.

It is estimated that 600,000 Brazilians carry the HIV virus. There are even more who do not know that they are infected, and will need to be treated in the upcoming years. "Brazil is concerned about doing a good job of treating those Brazilians who need it, with the proper medication, and with updated treatment measures. It is a matter of public interest," explains Minister Humberto Costa.

To guarantee delivery of the ideal medicine to each one of the carriers registered in the program, the Ministry of Health must acquire the latest generation medications. Beginning to be distributed, for example, is Enfuvirtida, which belongs to a new class of anti-retrovirals, at a cost of R$19,000/month (US$7,900 per patient). A total of 1,200 patients are currently signed up to be treated with this new medication.

Negotiation - In March of this year, the Ministry began negotiations for voluntary licensing with Abbott Laboratories, Gilead Science Incorporation, and Merck Sharp & Dohme. The medications produced by these laboratories - Kaletra, Efavirenz (Merck) and Tenofovir (Gilead) - make up 66% of the entire budget for the purchase of anti-retrovirals.

Negotiations with Merck and Gilead continue. Abbott was the only one to oppose both the alternative voluntary licensing as well as a price reduction which guarantees the future sustainability of the program. Since the medication arrived in Brazil in 2002, its price has been reduced by 25%--a percentage that is considered to be low in global terms--because development costs diminish over the years.

Today, the unit price of Kaletra is US$1.17 in contrast to its price of US$1.60 in 2002, and US$0.72 for its generic version. However, in this period, the government costs for the purchase of the medication have gone up from US$35.2 million to $91.6 million annually. This is due to the fact that the number of patients who need the medication in Brazil has increased threefold per year. In 2002, there were 3,200 people who needed it. This year, there will be 23,400.

Legislation - The Ministry of Health's initiative is backed by national and international norms and respects the rights of private companies to make a profit from their inventions. Article 71 of Brazilian patent law (Law 9.279/96) provides for obligatory licensing in the case of public interest. Decrees 3201 of 1999, and 4830 of 2003, also consider those items related to public health to be of public interest.

The Doha Declaration (Catar) in 2001 allows countries to take measures to protect public health. Those measures, according to the Declaration, do not compromise the TRIPs Agreement, which established minimum rights over intellectual property.

Should Abbott Laboratories not follow the Ministry's notice, the medication will be produced in Brazil exclusively for national consumption. Although the obligatory licensing gives Brazilian laboratories the right to produce Liponavir/ritonavir, it does not prevent Abbott from commercializing Kaletra in the country.

National production - With the obligatory licensing, the Institute of Pharmaceutical Technology (Farmanguinhos Laboratory), of the Oswaldo Cruz Foundation would produce the Lopinavir/ritonavir medication while reducing by the current price by almost 50%. Within one year, Farmaguinhos would be able to produce six million capsules/month, the necessary amount to meet domestic demand. The unit price for the medication should be around US$0.68, which would add up to approximately R$130 million/year for the National Program.

Farmaguinhos is the largest official laboratory in Brazil and already produces more than 60 medicines, among them anti-virals. Last year, the Brazilian government invested US$6 million in the acquisition of the GlaxoSmithKline industrial park in Rio de Janeiro in order to convert it into the Medicine Technology Complex (CTM) for Farmaguinhos. The CTM will produce 10 billion pharmaceutical units in 2007.

The Program - Since 1986, the National STD/AIDS Program has guaranteed 100% free treatments to those with HIV/AIDS. Since the program started, the life expectancy of persons with AIDS has increased twelve-fold, from five months to 58 months. Mortality has dropped 50% and the number of pregnant women suffering from the disease who have access to AZT, which helps prevent infection of the newborn, is on the rise. This year, the Ministry of Health will finance 754 disease-fighting projects run by NGOs with a budget of R$60 million.

In 2001, UNESCO (United Nations Educational, Scientific, and Cultural Organization) presented an award to the Brazilian program in the category of Human Rights and Culture of Peace. Last year, the quality of the Brazilian AIDS Program received one more international award: a medal from the U.N. AIDS Program (Unaids) for the leadership that Brazil has exerted in improving the fight against the epidemic.

Brazil has participated in an international HIV and AIDS cooperation program since 1995. Today, 25 countries are involved in that work, which includes prevention, assistance and treatment, epidemiological monitoring, project management, sexually transmitted diseases, human rights, and cooperation with private sector organizations. SOURCE Ministry of Health of Brazil

-0-

06/24/2005

/CONTACT: Press Office of the Ministry of Health: +55-61-315-3825, +55-61-315-2376 or +55-61-315-3721, or Fax: 55-61-225-7338, or presssaude.gov.br/

/Photo: NewsCom: http://www.newscom.com/cgi-bin/prnh/20050623/SPF001

 
Nelson Vergel
Program for Wellness Restoration
powerusa.org

 Join a 1700 people HIV discussion group by sending a blank email to pozhealth-subscribe@yahoogroups.com
Please email me at nelsonvergel@... if you have problems with this email address. Thanks

Lecture Dates:
Chicago June 30, El Paso- July 7, Miami-Ft Lauderdale- July 18 & 19 (Spanish), Atlanta July 21, Phily Aug 24 /Sept 14, Long Beach Aug 31, NY Sept 8, LA Sept 21, Salt Lake- Nov 5, AIDS Nutritionist Conf- DC Sept 15-17,San Francisco Oct 26, POZ Cruise- Miami- Oct 15-21


Disclaimer

This information (and any accompanying printed material) is not intended to replace the attention or advice of a physician or other health care professional. Anyone who wishes to embark on any dietary, drug, exercise, or other lifestyle change intended to prevent or treat a specific disease or condition should first consult with and seek clearance from a qualified health care professional.

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#12376 From: PoWeRTX@...
Date: Tue Jun 28, 2005 1:12 am
Subject: Signs & Symptoms of Kidney Problems 		nelsonvergel
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Signs & Symptoms of Kidney Problems
http://www.privateresults.com/kidneysymptoms.html
 
 
 
 
 
 
 
 
 
 
Kidney Damage, Disease and Failure

In kidney failure, the kidneys lose their ability to filter enough waste products from the blood and to
regulate the body's balance of salt and water. Eventually, the kidneys slow their production of urine, or
stop producing it completely. Waste products and water accumulate in the body. This can lead to a
potentially life-threatening overload of fluids (such as congestive heart failure), a dangerous
accumulation of waste products in the blood, and extreme changes in blood chemistry that eventually
can affect the function of the heart and brain. There are three types of kidney failure (also called renal
failure). The two most common are:

Acute renal failure — In this form of kidney failure, the kidneys stop functioning properly because of a
sudden illness, a medication or medical condition that causes one of the following:

A severe drop in blood pressure or an interruption in the normal blood flow to the kidneys, which can
occur during major surgery, severe burns with fluid loss through burned skin, massive bleeding
(hemorrhage) or a heart attack that severely affects heart function. Blood clots that travel to the kidney
also can cause acute kidney failure.

Direct damage to kidney cells or to the kidneys' filtering units, which can be caused by an inflammation
of the kidneys called glomerulonephritis, toxic chemicals, medications and infections.
Blocked urine flow from the kidney, which can occur because of obstructions outside the kidney, such
as kidney stones, bladder tumors or an enlarged prostate. Blockage of urine flow within the kidney also
can cause sudden kidney failure, as can occur with major muscle injury.

Chronic renal failure — In this form of kidney failure, the functioning of the kidney gradually declines,
usually over a period of years. Most commonly, it is caused by illnesses such as diabetes, uncontrolled
high blood pressure or chronic kidney inflammation (glomerulonephritis or pyelonephritis). It also can
occur because of long-term exposure to lead, mercury or certain drugs, especially painkillers. Some
forms of chronic renal failure run in families, so your doctor will ask you about family members' medical
problems.

Knowing the symptoms of kidney disease can help people detect it early enough to get treatment.
Symptoms can include:

  • Changes in urination -making more or less urine than usual, feeling pressure when urinating,
    changes in the color of urine, foamy or bubbly urine, or having to get up at night to urinate.
  • Swelling of the feet, ankles, hands, or face -fluid the kidneys can't remove may stay in the tissues.
  • Fatigue or weakness -a build-up of wastes or a shortage of red blood cells (anemia) can cause
    these problems when the kidneys begin to fail.
  • Shortness of breath -kidney failure is sometimes confused with asthma or heart failure, because
    fluid can build up in the lungs.
  • Ammonia breath or an ammonia or metal taste in the mouth -waste build-up in the body can
    cause bad breath, changes in taste, or an aversion to protein foods like meat.
  • Back or flank pain -the kidneys are located on either side of the spine in the back.
  • Itching -waste build-up in the body can cause severe itching, especially of the legs.
  • Loss of appetite
  • Nausea and vomiting
  • More hypoglycemic episodes, if diabetic
 
Nelson Vergel
Program for Wellness Restoration
powerusa.org

 Join a 1700 people HIV discussion group by sending a blank email to pozhealth-subscribe@yahoogroups.com
Please email me at nelsonvergel@... if you have problems with this email address. Thanks

Lecture Dates:
Chicago June 30, El Paso- July 7, Miami-Ft Lauderdale- July 18 & 19 (Spanish), Atlanta July 21, Phily Aug 24 /Sept 14, Long Beach Aug 31, NY Sept 8, LA Sept 21, Salt Lake- Nov 5, AIDS Nutritionist Conf- DC Sept 15-17,San Francisco Oct 26, POZ Cruise- Miami- Oct 15-21


Disclaimer

This information (and any accompanying printed material) is not intended to replace the attention or advice of a physician or other health care professional. Anyone who wishes to embark on any dietary, drug, exercise, or other lifestyle change intended to prevent or treat a specific disease or condition should first consult with and seek clearance from a qualified health care professional.







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#12375 From: Albenson@...
Date: Tue Jun 28, 2005 1:27 am
Subject: Bird flu 'as grave a threat as terrorism' 		Albenson@...
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Monday, June 27, 2005

UK: Bird flu 'as grave a threat as terrorism'

Posted by Al Benson
 
I have been telling people to stock up on Tamiflu for months.

The Independent

Bird flu is now as much of a danger to Britain as terrorism, ministers have been told by the Government’s official emergency body.

Top officials from the Civil Contingency Secretariat (CCS), part of the Cabinet Office, told a cabinet subcommittee last week that a flu pandemic - which it believes could kill 700,000 Britons - is now one of the most serious threats facing the country.

more...

Posted by Al Benson at 10:22 PM on June 27, 2005. (0) Comments | (0) Trackbacks | Permalink


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#12374 From: PoWeRTX@...
Date: Tue Jun 28, 2005 1:07 am
Subject: Antiretroviral therapy with tenofovir is associated with mild renal dysfunction. 		nelsonvergel
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AIDS. 2005 Jan 3;19(1):93-5. Related Articles, Links
Click here to read 
Antiretroviral therapy with tenofovir is associated with mild renal dysfunction.

Mauss S, Berger F, Schmutz G.

Center for HIV and Hepatogastroenterology, Duesseldorf, Germany.

A cross-sectional study was conducted to compare patients treated with tenofovir with patients never treated with tenofovir. Patients on tenofovir showed a lower mean glomerular filtration rate estimated by creatinine clearance or cystatin C clearance compared with control patients. In total, 24 patients on tenofovir versus five control patients had proteinuria greater than 130 mg/day. In the majority of patients on tenofovir proteinuria was of tubular origin.
 
Nelson Vergel
Program for Wellness Restoration
powerusa.org

 Join a 1700 people HIV discussion group by sending a blank email to pozhealth-subscribe@yahoogroups.com
Please email me at nelsonvergel@... if you have problems with this email address. Thanks

Lecture Dates:
Chicago June 30, El Paso- July 7, Miami-Ft Lauderdale- July 18 & 19 (Spanish), Atlanta July 21, Phily Aug 24 /Sept 14, Long Beach Aug 31, NY Sept 8, LA Sept 21, Salt Lake- Nov 5, AIDS Nutritionist Conf- DC Sept 15-17,San Francisco Oct 26, POZ Cruise- Miami- Oct 15-21


Disclaimer

This information (and any accompanying printed material) is not intended to replace the attention or advice of a physician or other health care professional. Anyone who wishes to embark on any dietary, drug, exercise, or other lifestyle change intended to prevent or treat a specific disease or condition should first consult with and seek clearance from a qualified health care professional.

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#12373 From: PoWeRTX@...
Date: Mon Jun 27, 2005 12:14 pm
Subject: Peptide T (Lexipafant) and HIV cognitive function 		nelsonvergel
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Where can someone get Peptide T? I remember when it was sold in buyers clubs
 
Randomized Double-blind Placebo-Controlled Trial of Peptide T for HIV-Associated Cognitive Impairment

Peter N. R. Heseltine, MD; Karl Goodkin, MD, PhD; J. Hampton Atkinson, MD; Benedetto Vitiello, MD; James Rochon, PhD; Robert K. Heaton, PhD; Elaine M. Eaton, PhD; Frances L. Wilkie, PhD; Eugene Sobel, PhD; Stephen J. Brown, MD; Dan Feaster; Lon Schneider, PhD; Walter L. Goldschmidts, PhD; Ellen S. Stover, PhD

Arch Neurol. 1998;55:41-51.

Background  Cognitive impairment is a common consequence of human immunodeficiency virus (HIV) infection, and dementia is one of the diseases that defines the acquired immunodeficiency syndrome. Peptide T (d-ala-peptide-T-amide) has been reported to block the binding of gp120 to brain tissue and to protect neurons from the toxic effects of gp120 in vitro. In pilot studies, administration of peptide T to HIV-positive patients with cognitive impairment was associated with improvement in cognition and constitutional symptoms.

Objective  To determine whether the intranasal administration of peptide T would improve cognitive function of HIV-positive patients with cognitive impairment.

Patients and Methods  This was a 3-site, double-blind, placebo-controlled trial of peptide T given intranasally at a dosage of 2 mg 3 times a day for 6 months. Participants were HIV-seropositive persons with evidence of cognitive deficits on a screening test battery. Concomitant antiretroviral therapy was allowed. Randomization to the 2 study arms was balanced according to several stratification variables, such as CD4+ cell count, severity of cognitive impairment, and antiretroviral therapy at study entry. A comprehensive neuropsychological (NP) battery, which yielded 23 scores, was administered at baseline and the study end point. The primary outcome measure was a global NP score derived from the 23 standardized scores. The efficacy end point was the change in NP score at 6 months compared with baseline. Secondary efficacy measures were 7 cognitive domain scores and deficit scores of global and domain performance. The patients who completed the baseline and final NP evaluations (after at least 4 months in the randomized treatment arm) were included in the efficacy analyses. Additional analyses were conducted on subgroups of patients according to the CD4+ count and baseline NP deficit. The incidence of NP improvement in the 2 treatment arms was also compared.

Results  There was no statistically significant difference between the peptide T and placebo groups on the global NP change score, the individual domains, or the deficit scores. Because of an imbalance in the baseline CD4+ cell count between treatment arms, analyses were also adjusted for this variable. These CD4+-adjusted analyses suggested (P=.07; analysis of covariance [ANCOVA]) a greater improvement in the peptide T group. Subgroup analyses indicated a treatment effect for patients whose CD4+ cell count was above 0.200x109/L (200 cells/µL) at baseline. Moreover, peptide T treatment was associated with overall cognitive improvement in patients with baseline global deficit scores of at least 0.5, while overall deterioration was more common among the placebo group (P=.02; Mantel-Haenszel {chi}2 test).

Conclusions  Peptide T was not significantly different from placebo on the study primary end points. However, additional analyses indicated that peptide T may be associated with improved performance in the subgroup of patients with more evident cognitive impairment (ie, NP global deficit score >=0.5) or with relatively preserved immunological status (ie, CD4+ cell count >0.200x109/L).


From the Departments of Medicine (Dr Heseltine), Psychology (Dr Eaton), Epidemiology (Dr Sobel), and Psychiatry (Dr Schneider), University of Southern California, Los Angeles; the Department of Psychiatry, University of Miami, Miami, Fla (Drs Goodkin and Wilkie and Mr Feaster); the Department of Psychiatry, University of California, San Diego (Drs Atkinson, Heaton, and Brown); the Office on AIDS, National Institute of Mental Health (Drs Vitiello, Goldschmidts, and Stover), and the George Washington Biostatistics Center (Dr Rochon), Rockville, Md.


Nelson Vergel
Program for Wellness Restoration
powerusa.org

 Join a 1700 people HIV discussion group by sending a blank email to pozhealth-subscribe@yahoogroups.com
Please email me at nelsonvergel@... if you have problems with this email address. Thanks

Lecture Dates:
Chicago June 30, El Paso- July 7, Miami-Ft Lauderdale- July 18 & 19 (Spanish), Atlanta July 21, Phily Aug 24 /Sept 14, Long Beach Aug 31, NY Sept 8, LA Sept 21, Salt Lake- Nov 5, AIDS Nutritionist Conf- DC Sept 15-17,San Francisco Oct 26, POZ Cruise- Miami- Oct 15-21


Disclaimer

This information (and any accompanying printed material) is not intended to replace the attention or advice of a physician or other health care professional. Anyone who wishes to embark on any dietary, drug, exercise, or other lifestyle change intended to prevent or treat a specific disease or condition should first consult with and seek clearance from a qualified health care professional.

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#12372 From: Albenson@...
Date: Mon Jun 27, 2005 8:38 am
Subject: Medicare to stop covering Anti-anxiety Drugs 		Albenson@...
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Monday, June 27, 2005

Medicare to stop covering Anti-anxiety Drugs: money saved will come in handy for War

Posted by Al Benson

AP via Yahoo

When the federal government’s new prescription drug benefit kicks in next year, it will not cover a category of drugs commonly used to treat anxiety, insomnia and seizures.

That means those disabled and elderly people on Medicare who take Xanax, Valium, Atvian and other types of the drug benzodiazepine will have to look elsewhere for coverage...

This is another atrocity from the Bush Govt. A tiny fraction of what has been spent on the war could provide needed medications to all, but was squandered. In terms of the health needs of People with HIV, Bush now rivals Regan as the worst American president. 

more...

Posted by Al Benson at 05:14 AM on June 27, 2005. (0) Comments | (0) Trackbacks | Permalink


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#12371 From: JuLev@...
Date: Sun Jun 26, 2005 10:58 am
Subject: HPV Vaccine Study: Merck study 		JuLev@...
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NATAP - http://www.natap.org

HPV Vaccine Study: Merck study

“Prophylactic quadrivalent human papillomavirus (types 6, 11, 16, and 18) L1 virus-like particle vaccine in young women: a randomised double-blind placebo-controlled multicentre phase II efficacy trial”

Lancet Oncology April 2005; 6:271-278

Luisa L Villa  a ,   Ronaldo LR Costa b,   Carlos A Petta c,   Rosires P Andrade d,   Kevin A Ault e,   Anna R Giuliano f,   Cosette M Wheeler g,   Laura A Koutsky h,   Christian Malm i,   Matti Lehtinen i,   Finn Egil Skjeldestad j,   Sven-Eric Olsson k,   Margareta Steinwall l,   Darron R Brown m,   Robert J Kurman n,   Brigitte M Ronnett n,   Mark H Stoler o,   Alex Ferenczy p,   Diane M Harper q,   Gretchen M Tamms r,   Jimmy Yu s,   Lisa Lupinacci s,   Radha Railkar s,   Frank J Taddeo t,   Kathrin U Jansen t,   Mark T Esser t,   Heather L Sings u,   Alfred J Saah r   and   Eliav Barr r

Summary
Background
A randomised double-blind placebo-controlled phase II study was done to assess the efficacy of a prophylactic quadrivalent vaccine targeting the human papillomavirus (HPV) types associated with 70% of cervical cancers (types 16 and 18) and with 90% of genital warts (types 6 and 11). Merck Research Laboratories (West Point, PA, USA), a division of Merck & Co, funded this study in its entirety.

…..We have shown that a multivalent vaccine is efficacious against HPV types that cause cancer and genital warts. Over 35 months' follow-up, incidence of persistent infection associated with HPV 6, 11, 16, or 18 decreased by 89% in women allocated active vaccine who had at least one dose (ie, the modified intention-to-treat population) compared with those allocated placebo. Vaccine efficacy was 90% in the per-protocol efficacy population, suggesting that the vaccine was protective even during the vaccination period….. The low-dose HPV vaccine was generally well tolerated……There were no vaccine-related serious adverse events…..

Introduction

Up to 70% of sexually active women will become infected with human papillomavirus (HPV) during their lifetime.1 HPV infection causes about 470000 cases of cervical cancer per year.2 Although most cases of cervical cancer arise in the developing world where organised screening programmes with the Pap test have not been implemented, about 35000 women die from this disease every year in the USA and Europe.2 Even though screening reduces the risk of cervical cancer, it does not prevent HPV infection or development of precancerous lesions,3 which need careful follow-up and often need excision.4 Moreover, HPV infections that manifest as genital warts arise in 1-2% of young adults,5 for which treatment is expensive and painful, and recurrences are common.6 A diagnosis of genital warts might also cause sexual dysfunction and emotional disruption.7

More than 35 types of HPV infect the genital tract.8 Of these, types 16 and 18 cause about 70% of cervical cancer and high-grade cervical intraepithelial neoplasia (CIN);1 HPV 6 and 11 cause 90% of anogenital warts.6 A prophylactic vaccine that targets these types should thus substantially reduce the burden of HPV-associated clinical diseases.

HPV is a non-enveloped, encapsulated, double-stranded DNA virus.9 Expression of the L1 protein in heterologous systems (eg, yeast cells) generates non-infectious virus-like-particles (VLP) that resemble HPV virions.9 In a placebo-controlled study,10 a yeast-produced HPV 16 L1 VLP vaccine was 100% efficacious in prevention of CIN caused by HPV 16 infection 17 months after vaccination in women who were HPV 16 naive at the time of vaccination, and results from studies11-15 have also shown HPV 11 or 18 L1 VLP vaccines to be highly immunogenic. These trials thus served as the basis for assessment of a quadrivalent HPV vaccine that targets HPV 6, 11, 16, and 18.

Methods

277 young women (mean age 20·2 years [SD 1·7]) were randomly assigned to quadrivalent HPV (20 É g type 6, 40 É g type 11, 40 É g type 16, and 20 É g type 18) L1 virus-like-particle (VLP) vaccine and 275 (mean age 20·0 years [1·7]) to one of two placebo preparations at day 1, month 2, and month 6. For 36 months, participants underwent regular gynaecological examinations, cervicovaginal sampling for HPV DNA, testing for serum antibodies to HPV, and Pap testing. The primary endpoint was the combined incidence of infection with HPV 6, 11, 16, or 18, or cervical or external genital disease (ie, persistent HPV infection, HPV detection at the last recorded visit, cervical intraepithelial neoplasia, cervical cancer, or external genital lesions caused by the HPV types in the vaccine). Main analyses were done per protocol.

Findings

Combined incidence of persistent infection or disease with HPV 6, 11, 16, or 18 fell by 90% (95% CI 71-97, p<0·0001) in those assigned vaccine compared with those assigned placebo.

Interpretation

A vaccine targeting HPV types 6, 11, 16, 18 could substantially reduce the acquisition of infection and clinical disease caused by common HPV types.

AUTHOR DISCUSSION
We have shown that a multivalent vaccine is efficacious against HPV types that cause cancer and genital warts. Over 35 months' follow-up, incidence of persistent infection associated with HPV 6, 11, 16, or 18 decreased by 89% in women allocated active vaccine who had at least one dose (ie, the modified intention-to-treat population) compared with those allocated placebo. Vaccine efficacy was 90% in the per-protocol efficacy population, suggesting that the vaccine was protective even during the vaccination period. For example, during the course of vaccination (day 1 through month 7), three women assigned active vaccine and five women assigned placebo were detected with HPV 18 DNA. Of these, only one was verifiable persistent infection (in the placebo group). Thus, one woman allocated placebo and no women allocated active vaccine developed persistent HPV 18 infection during the vaccination period. Furthermore, efficacy with regard to clinical disease associated with HPV 6, 11, 16, or 18 was 100%.

This study was not originally powered to assess vaccine efficacy for the disease endpoints or for each HPV type separately. However, the fact that all three women with external genital lesions and all three with CIN were in the placebo group is encouraging in terms of protection against these disease endpoints. Analysis of the incidence of the main efficacy endpoint in the two higher-dose groups supported the decision to select the low dose of quadrivalent HPV L1 VLP vaccine as the final dose for assessment in the phase III programme.

The quadrivalent HPV vaccine was highly immunogenic. All women allocated active vaccine developed higher detectable antibody responses to HPV at month 7 than did those allocated placebo who had natural infection and who remained at higher or similar antibody titres throughout the study. Because women are at risk of HPV infection for as long as they are sexually active, protection induced by a HPV vaccine must be long-lived. At month 36, more than 94% of women were seropositive for HPV 6, 11, and 16; fewer (76%) women had antibody responses against HPV 18 at month 36, although 89% had antibody titres for HPV 18 above the assay's lower limit of quantification. Longer follow-up studies will be needed to assess the duration of efficacy of this quadrivalent HPV vaccine, and to determine whether booster doses will be needed.

Results from a previous study10 found that a prototype yeast-produced HPV 16 L1 VLP vaccine given to women who were HPV 16-negative prevented acquisition of HPV 16 infection and associated CIN.12 A bivalent HPV 16/18 vaccine prepared with AS04 adjuvant was efficacious in preventing persistent infections and associated cervical abnormalities over a 27-month period.25

In the developed world, full implementation of cervical-cancer screening has substantially shifted the burden of HPV infection from cervical-cancer mortality to management of precancerous lesions. In these countries, in addition to further reduction in the incidence of cervical cancer, universal HPV vaccination might decrease the medical, psychological, and economic costs associated with management of abnormalities detected by Pap testing and CIN. Inclusion of HPV 6 and 11 in a vaccine could diminish the incidence of genital warts and low-grade CIN that are prognostically benign, costly,26 and disruptive psychologically.7 In developing countries that have not implemented screening programmes for cervical cancer, the effect of a drop in rates of cervical cancer after implementation of universal HPV vaccination could be substantial. However, such implementation will need definition of the vaccine's effect on public health, cost-effectiveness, the optimum age for vaccination, and the duration of protection.

Universal HPV vaccination might be most effective when implemented in 10-13 year olds, who are likely to be HPV negative.27-29 The expectation that the vaccine will reduce cervical-cancer rates, the fact that HPV infection affects most women, and the lack of an effective means to prevent HPV infection in sexually active people lend support to the vaccination of preadolescents. The benefit of vaccination against oncogenic HPV types 16 and 18 is likely to be negligible in heterosexual men because they rarely develop HPV-associated genital cancers. However, a vaccine against the non-oncogenic HPV types 6 and 11 could be considered in the prophylaxis of genital warts in men and in women.

This study has shown that a candidate HPV 6, 11, 16, and 18 vaccine was generally well tolerated, induced high-titres of serum antibodies to HPV types, and effectively prevented acquisition of infection and clinical disease caused by common HPV types. Large-scale studies are under way.

Results
277 women were randomly assigned to quadrivalent HPV (types 6, 11, 16, and 18) L1 VLP vaccine (20, 40, 40, 20 É g, respectively) and 275 to placebo. 431 (78%) were included in the per-protocol efficacy analyses for HPV types 6/11, 404 (73%) for type 16, and 456 (83%) for type 18. 275 (99%) women assigned low-dose vaccine and 275 (100%) assigned placebo were included in the safety analyses. The main reasons for exclusion from the per-protocol cohort were seropositivity to a vaccine HPV type at day 1 or presence of HPV 6, 11, 16, or 18 DNA before completion of the vaccination regimen. The HPV 6/11, 16, and 18 modified intention-to-treat cohorts included 498, 465, and 521 women, respectively.

The main efficacy analyses were done in the per-protocol efficacy cohort. Over the 30 months' follow-up after vaccination, combined incidence of persistent HPV 6, 11, 16, or 18 infection or associated genital disease decreased by 90% (95% CI 71-97) in women assigned vaccine compared with those assigned placebo. Of the 40 primary HPV endpoint cases, 13 were from detection of HPV 6, 11, 16, or 18 DNA on samples obtained at the last visit of record (three in the vaccination group [all at month 36] and ten in the placebo group [eight of ten at month 36]). HPV 16 DNA was detected in three women in the vaccine group at the last recorded visit, and one woman had verified, persistent HPV 18 infection detected at months 12 and 18 only. In the modified intention-to-treat cohort, the efficacy of the vaccine with regard to the primary endpoint was 89% (95% CI 73-96, p<0·0001).

Findings from interim immunogenicity analysis showed the lowest dose vaccine induced serological antibody responses to HPV 6, 11, 16, or 18 that were much the same as those of the intermediate-dose and high-dose preparations.24 The combined incidence of persistent infection with HPV 6, 11, 16, or 18 or associated genital disease did not differ between the high-dose, intermediate-dose, or low-dose groups (incidence per 100 women-years at risk 0·7, 1·3, and 0·5, respectively). Vaccine efficacy with regard to the composite endpoint of infection or disease associated with HPV 6, 11, 16, or 18 for the three doses pooled (n=701) was 88% (95% CI 76-94).

Vaccine-induced immune responses were assessed in the HPV 6 and 11, HPV 16, and HPV 18 per-protocol immunogenicity cohorts, which included 208, 194, and 219 women assigned vaccine, respectively. Concentrations of antibodies to HPV associated with protection from infection have not been defined.20 The immune response to the vaccine was observationally compared with the serum antibody concentrations to HPV in those assigned placebo who had been infected with vaccine HPV types, had subsequently mounted an immune response, and had apparently cleared infection before enrolment (ie, who were seropositive and PCR negative for the relevant HPV type at enrolment). In those assigned placebo, geometric mean titre of antibodies to HPV remained constant throughout the 3 years of the study.

All women assigned active vaccine in the per-protocol immunogenicity cohorts developed detectable antibody responses to HPV 6, 11, 16, and 18 at completion of the vaccine regimen (ie, month 7). Vaccine-induced geometric mean titres of antibodies were substantially higher in women assigned active vaccine than in those assigned placebo who had a previous history of natural HPV infection. Although mean antibody titres in those assigned quadrivalent HPV L1 VLP vaccine started to decline after month 7 (data not shown), at month 36 they remained at or above the titres recorded for women who had an immune response, presumably associated with clearance of HPV infection. Of women who had a valid immunoassay result at month 36, 173 (94%) of 184 were seropositive for HPV type 6, 176 (96%) of 184 for type 11, all 177 for type 16, and 149 (76%) of 196 for type 18. Furthermore, antibody titres for 174 (89%) of the 196 women positive for HPV 18 were above the assay's lower limit of quantification. Analyses of antibody titres in four women assigned quadrivalent vaccine who developed persistent HPV 18 infection or who were detected with HPV 16 DNA at one visit before loss to follow-up were non-informative because they developed robust antibody responses at month 7. However, antibody titres to HPV 18 after month 7 for the participant who had persistent infection with HPV 18 were slightly lower than for most of those who were allocated active vaccine.

The low-dose HPV vaccine was generally well tolerated. Adverse events at the injection site were higher in women allocated active vaccine than in those allocated placebo. Pain was the most common injection-site adverse event and headache the most common systemic adverse event. Most (94%) adverse events were of mild or moderate intensity. Only one patient (in the placebo group) discontinued treatment, because of hypoaesthesia thought not to be caused by the placebo. There were no vaccine-related serious adverse events. Neither intermediate-dose nor the high-dose quadrivalent HPV vaccine was excluded from assessment in phase III trials on the basis of an unacceptable safety profile. However, a modest increase (from 3% to 6%) in injection-site adverse events was recorded with the higher doses (data not shown).

Methods
Study design

A phase II randomised, multicentre, double-blind placebo-controlled study of a quadrivalent HPV (type 6, 11, 16, and 18) L1 VLP vaccine was done in two parts. Part A was a sequential dose-escalation safety assessment, in which participants, investigators, and staff were blinded as to assignment of vaccine or placebo, but not to assignment of doses in the active-treatment group. Part B was a fully blinded dose-ranging assessment of immunogenicity and efficacy. Study procedures for individuals in part A and part B were identical. The results presented in this article are from part B.

1158 women aged 16-23 years were recruited in Brazil, Europe, and the USA. The study enrolled healthy women, who were not pregnant, had no previous abnormal Pap smears, and reported a lifetime history of four or fewer male sex partners. Enrolment of virgins was restricted to women who were 18 years or older and who were seeking contraception. This study did not exclude women with previous HPV infection. Participants were required to use effective contraception during the trial.

The active quadrivalent vaccine was a mixture of four recombinant HPV type-specific VLPs (Merck Research Laboratories, West Point, PA, USA) consisting of the L1 major capsid proteins of HPV 6, 11, 16, and 18 synthesised in Saccharomyces cerevisiae.10,14,16 The four VLP types were purified and adsorbed onto amorphous aluminium hydroxyphosphate sulfate adjuvant. The placebo consisted of the same adjuvant and was visually indistinguishable from vaccine.

Three preparations of a quadrivalent HPV types 6, 11, 16, and 18 L1 VLP were used. The three preparations were: 20 É g type 6, 40 É g type 11, 40 É g type 16, and 20 É g type 18, with 225 É g aluminium adjuvant; 40 É g type 6, 40 É g type 11, 40 É g type 16, and 40 É g type 18, with 225 É g aluminium adjuvant; and 80 É g type 6, 80 É g type 11, 40 É g type 16, and 80 É g type 18, with 395 É g aluminium adjuvant. The study had two placebo groups with adjuvant doses of 225 É g or 450 É g for appropriate safety comparisons.

0·5 mL vaccine or placebo was given by intramuscular injection at day 1, month 2, and month 6. After vaccination, participants were observed for 30 min. Temperatures were also recorded orally every day in the evening for 5 days after vaccination, and the participant noted adverse events by standard diary card for 14 days after vaccination.

Gynaecological examination was done at day 1 and at months 7, 12, 24, and 36. A ThinPrep™ Pap test (Cytyc, Boxborough, MA, USA) and external genital, lateral vaginal, and cervical swabs for PCR analysis of HPV were obtained from all participants at day 1 and at months 7, 12, 18, 24, 30, and 36. Biopsy samples of external genital lesions identified during the study were taken, and serum samples were obtained at day 1 and months 2, 3, 6, 7, 12, 18, 24, 30, and 36.

This study was done in accordance with national or local requirements for ethics-committee review, informed consent, and other statutes or regulations regarding the protection of the rights and welfare of those participating in biomedical research. All individuals, or their parents or legal guardians, gave written informed consent after review of the protocol procedures.

The aim of the study was to assess a quadrivalent HPV L1 VLP vaccine in terms of the composite primary endpoint of persistent infection associated with HPV 6, 11, 16, or 18, or cervical or external genital disease compared with placebo. Women with persistent infection were defined as those who had the same vaccine-HPV-type DNA in cervicovaginal samples obtained 7 months after vaccination as those obtained from two or more consecutive visits (required to be 4 months or longer apart unless at least one tissue sample was diagnosed as cervical disease by a panel of pathologists), or as those who had vaccine-HPV-type DNA detected in a sample recorded during the last visit before being lost to follow-up. HPV-associated disease was defined as a tissue sample diagnosed as CIN by a panel of pathologists 7 months after vaccination; vulval intraepithelial neoplasia; vaginal intraepithelial neoplasia; external genital warts; or cervical, vulval, or vaginal cancer with vaccine-HPV-type DNA detected in tissue from, or in a swab of, the same lesion and in cervicovaginal samples obtained at the visit before the biopsy visit.


Laboratory analyses

All Pap tests and histological assessment were done in the setting of the study. Pap tests were reported in accordance with the Bethesda 2001 System.17 Women underwent colposcopy if they were diagnosed with atypical squamous cells, in which high-grade squamous epithelial lesions could not be excluded; low-grade squamous intraepithelial lesions; high-grade squamous intraepithelial lesions; or atypical glandular cells. After the release of the American Society for Colposcopy and Cervical Pathology Biopsy Guidelines for management of atypical squamous cells of undetermined importance,18 the protocol was modified so that residual liquid from these Pap tests was analysed by Hybrid Capture II™ (Digene, Gaithersburg, MD, USA) testing. Patients with a positive result on either low-risk or high-risk HPV probes underwent colposcopy.

All participants had colposcopy at the end of the study. At colposcopy, biopsy samples of discrete abnormalities were taken with separate instruments and were processed separately for histopathological analysis to avoid HPV contamination. A sample of the same lesion or a sample adjacent to the biopsied lesion was submitted for HPV typing. Biopsy samples were processed and read by a central laboratory (Diagnostic Cytology Laboratories, Indianapolis, IN, USA) for medical management. Endpoint assignment was done by use of consensus diagnoses from a panel of pathologists (RJK, MHS, BMR, and AF) who were blinded to central-laboratory diagnoses, treatment group, and HPV status.19

Swabs, biopsy samples and, later, thin tissue sections cut adjacent to sections used for histopathological analysis were used to detect HPV DNA with primers specific for HPV 6, 11, 16, or 18. Serum concentrations of antibodies to HPV 6, 11, 16, and 18 were measured with a competitive immunoassay (Luminex Corporation, Austin, TX, USA).20 Antibody titres were determined in a competitive format-ie, known, type specific phycoerythrin-labelled, neutralising antibodies21,22 compete with serum antibodies from the participant for binding to conformationally sensitive, neutralising epitopes on VLPs.

To define the serostatus cutoff (ie, the lowest level of the assay's quantifiable range that can be reliably distinguished from negative samples), positivity rates for about 500 samples were assessed at 11 cutoffs ranging from 8 MU/L to 48 MU/L in increments of 4 MU/L. Before testing, serum samples were classified into panels according to their potential for being a true positive on the basis of clinical history and PCR results. Serostatus cutoff was then selected as the lowest titre so that all, or nearly all, known PCR-negative samples and likely negative samples yielded negative results. Dilution-corrected serostatus cutoffs were 20 MU/L for HPV type 6, 16 MU/L for type 11, 20 MU/L for type 16, and 24 MU/L for type 18. The dilution-corrected limits of detection were 4·1 MU/L for type 6, 3·0 MU/L for type 11, 10·2 MU/L for type 16, and 2·9 MU/L for type 18.


Statistical analysis

Randomisation schedules were computer generated by use of a blocking factor of eight. Subjects were allocated in a 2:2:2:1:1 ratio to: HPV type 6, 11, 16, and 18 at doses of 20, 40, 40, and 20 É g, respectively, doses of 40, 40, 40, 40 É g, respectively, or doses of 80, 80, 40, 80 É g, respectively of quadrivalent L1 VLP vaccine; or to placebo with 225 É g or 450 É g of amorphous aluminium hydroxyphosphate sulfate adjuvant, respectively.

Primary efficacy analyses were done in the HPV 6/11, 16, and 18 per-protocol efficacy cohorts, which consisted of women who were naive for the relevant HPV type at enrolment, remained free of infection with the same vaccine HPV type through completion of the vaccination regimen, had all three doses of vaccine or placebo, and did not violate the protocol. Efficacy cases were counted starting after month 7.

To test the efficacy of the 20, 40, 40, 20 É g dose against persistent infection or disease associated with HPV 6, 11, 16, or 18, a one-sided test of the null hypothesis that the vaccine efficacy was 0 versus the hypothesis that vaccine efficacy was more than 0 at the Éø=0·025 level was done; p values were not adjusted for multiple hypothesis testing. Thus, rejection of the null hypothesis required the lower bound of the two-sided 95% CI for vaccine efficacy to exceed 0%. An exact conditional procedure was used to assess vaccine efficacy with the assumption that the numbers of cases in the vaccine and placebo groups are independent Poisson random variables.23 Individual follow-up was calculated as the number of person-years between the specified starting time and the final visit date, the date the participant became a case (ie, developed an endpoint), or the date the participant underwent definitive treatment (cervical endpoints only). If a woman developed more than one endpoint, her date of becoming a case was the date when the first endpoint was detected.

Overall, 20 women with the composite endpoint of persistent infection or diseases associated with the vaccine HPV types were needed for the study to have 89·8% power to declare the vaccine efficacious with a two-sided Éø=0·05, assuming a true vaccine efficacy of 80%. Therefore, enrolment of about 250 participants in the placebo group and in the low-dose vaccine group was needed.

Secondary analyses were done for a modified intention-to-treat population that included all participants who were naive (ie, seronegative and PCR negative) to the relevant HPV type at enrolment and who had had at least one vaccination. Efficacy cases in this population were counted from day 30. Immunogenicity was measured in a per-protocol immunogenicity cohort, defined as members of the per-protocol efficacy cohort who were vaccinated and who had had serum samples obtained during the protocol-specified time frames, irrespective of HPV infection or disease status after month 7. This study presents the efficacy, immunogenicity, and tolerability of this low-dose vaccine compared with the pooled placebo groups. This low-dose vaccine was chosen for phase III studies.


Role of the funding source

Sponsor staff and clinical-site investigators designed the study. Sponsor staff were responsible for field monitoring, data entry, data review (including integrity and consistency checks), testing of clinical samples for HPV DNA and HPV immune responses, and analysis of data. All authors provided input into interpretation of the data, and writing and revising of the report. The corresponding author had full access to the data and had final responsibility for the decision to submit for publication.

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#12370 From: JuLev@...
Date: Sun Jun 26, 2005 10:54 am
Subject: [NATAP] HPV Vaccine: end of HPV? 		JuLev@...
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The end for genital human papillomavirus infections?
(2 Editorials follow)
Lancet Oncology 2005; 6:256-257

Margaret Stanley 
Department of Pathology, Cambridge University, Tennis Court Road, Cambridge CB1 2HF, UK

Nearly all cervical cancer and its precursor lesions are thought to arise from infection with one of the human papillomavirus (HPV) types.1 These viruses infect skin and mucosae, inducing epithelial proliferation and resulting in warts. About 30-40 types infect the genital tract. Types 6 and 11 and minor types cause anogenital warts, and are rarely detected in malignant anogenital disease. By contrast, HPV 16, 18, 31, 33, 35, 45, and 58, and about eight to ten other minor types, are oncogenic and are found in almost all cervical-cancer biopsy samples and in 90% of high-grade intraepithelial precursor lesions. HPV types 16 and 18 are the most commonly detected HPV in biopsy samples.2

Vaccines have been a cost-effective way to prevent viral diseases. Candidate vaccines for HPV consist of virus-like particles generated by recombinant expression of the major capsid protein, L1, in eukaryotic yeast or baculovirus expression vectors.3 The L1 virus-like particle is an empty capsid (ie, contains no DNA), that has correct conformation and seems to have identical morphology to, and contains the major neutralising epitopes of, the native virion. Proof-of-principle trials of adjuvant HPV 16 L14 or HPV 16 and 18 L15 virus-like particles have shown that 100% of vaccinees in the per-protocol cohort were protected against persistent infection with the homologous HPV type, whereas the placebo group had persistent infections with both HPV and cervical intraepithelial neoplasia (CIN).

Virus-like particles seem to work by eliciting high titres of neutralising serum antibody, but whether this is the actual mechanism by which the vaccine protects against infection is unknown. Nevertheless, concentrations of serum antibody to L1 and the persistence of the antibody response might be crucial for measuring the amount of protection. However, L1 virus-like particle vaccines give type-specific protection, and the number of types in the vaccine will thus be need to be increased to prevent 80-90% of cancers. But, whether such a polyvalent vaccine would result in immunological equivalence such that each component virus-like particle induced an antibody response that correlated with protection is unclear. In this issue of The Lancet Oncology, Villa and colleagues6 present results of a double-blind, placebo-controlled-efficacy trial of a quadrivalent (HPV types 6, 11, 16, and 18), aluminium-adjuvant vaccine in young women negative for HPV. In this study, concentrations of serum antibody to L1 in those assigned the vaccine were much the same for types 6, 11, and 18, but antibody concentrations against type 16 L1 virus-like particles were up to 1 log higher at both 7 months and 36 months after vaccination. As in previous reports, peak antibody concentrations were much higher in vaccinees than in seropositive non-vaccinated individuals at seroconversion, and these concentrations remained higher 36 months after vaccination, when antibody titres in the vaccinees had decreased. Despite the difference in antibody concentration, patients were protected against persistent infection with HPV 16 and 18, confirming data from previous trials. One patient in the vaccination group had verifiable HPV infection attributable to HPV 18. The antibody concentrations in this patient throughout the 36 months would have been of interest to know, because if this infection is from failure of the vaccine, then this patient could provide useful information of variables that correlate with protection.

Vaccines prevent disease not infection, and in this study no patients in the vaccinated group had CIN, whereas in the placebo group, seven had CIN and four had external genital warts. These results are consistent with previous data for protection against CIN induced by HPV 16 or 18, and raise hope that infections from HPV 6 and 11 can be similarly controlled. The apparent protection against disease induced by HPV 6 and 11 is encouraging, but larger trials will be needed before HPV 6 and 11 L1 virus-like particle vaccination can be confirmed to be protective. Endpoints for the efficacy of HPV 6 and 11 vaccines must, realistically, be disease endpoints, since the difficulties of adequately sampling widespread areas of anogenital skin for accurate assessment of the presence or absence of HPV DNA are formidable.

All trials to date of HPV vaccines have enrolled women, but genital HPV infections are mainly sexually transmitted and men will also need to be vaccinated if the whole population is to develop immunity. Interestingly, seroconversion rates in men with anogenital warts who are infected with HPV 6 or 11 are consistently lower than those in women,7,8 and trials of L1 virus-like-particle vaccines will need to also enrol men to confirm that responses are similar in men and women. Despite these caveats, we must be optimistic that the control of genital HPV infection, and morbidity and mortality associated with resultant disease is achievable-it could be the end of the affair with HPV.

MS is an ad-hoc consultant for Merck Vaccines, West Point, PA, USA; Sanofi Pasteur, France; and GlaxoSmithKline Vaccines, Rixensart, Belgium, but is not a member of their scientific advisory boards and has no stock, share holdings, or patent interests in these companies. MS had a research collaboration with GlaxoSmithKline Immunotherapeutics, Stevenage, UK, 1998-2004, on therapeutic HPV vaccines, which resulted in several publications


The Lancet 2004; 364:1731-1732
Vaccination against human papillomaviruses shows great promise

The Lancet November 2004; 364:1731-1732

Matti Lehtinen  a   and   Jorma Paavonen b
a National Public Health Institute, Department of Infectious Disease Epidemiology, 00300 Helsinki, Finland
b Department of Obstetrics and Gynaecology, University of Helsinki, Helsinki, Finland

It took almost 10 years from the discovery of an association between human papillomavirus (HPV) and cervical cancer1 to the finding of HPV type 16 in cervical cancer tissue.2 It took another 10 years to show that past infection with HPV16 increases the risk for subsequent development of invasive cervical cancer,3 and yet another decade to show that the seven most prevalent HPV types cause 87% of all cervical cancers.4 By comparison, the creation of HPV virus-like-particle (VLP) vaccines has been a rapid breakthrough. VLPs mimic the true structure of the virion and induce a striking antibody response after vaccination.5 2 years ago, Koutsky et al6 showed that vaccination with HPV16 VLPs protected 768 vaccinated women from persistent HPV16 infection.

Lancet, Diane Harper and colleagues now expand this rapid development in a phase 2 trial in just over 1100 participants, a study that lasted 2·5 years. VLPs of the two most important oncogenic HPV types, HPV16 and HPV18, were combined in a preventive vaccine. According-to-protocol and intention-to-treat analyses showed high efficacy for this bivalent vaccine against both the incident and persistent HPV16 and HPV18 infections. This efficacy turned out to be excellent even though the most sensitive method, vaginal self-sampling, was used to define the endpoints.

The efficacy of the bivalent vaccine against HPV18 infection is particularly important. HPV18 is more closely associated with cervical adenocarcinoma, which is more difficult to detect by Pap-smear screening. The target cells of this HPV type (and others such as HPV45) might be endocervical cells. This suggestion is seen in the disease associations-ie, HPV16 is more closely associated with cervical squamous-cell carcinoma, and HPV18 is more closely associated with cervical adenocarcinoma. From the public-health point of view, an intervention effective against cervical adenocarcinoma is indeed needed.

It is also important to emphasise that these oncogenic HPV types are associated with chronic infections, chronic diseases, and neoplasms in many other sites, such as the vulva, vagina, anus, penis, and oropharynx.7,8 The effectiveness of preventive vaccination against the oncogenic HPV types against the non-cervical HPV-associated neoplasms may be as good as against cervical neoplasia.

The cytological endpoints used by Harper and colleagues represent the clinical manifestations of infections with the oncogenic HPVs. It is encouraging that the bivalent vaccine protects against these cytological abnormalities and cervical intraepithelial neoplasia. However, long-term passive follow-up of cohorts of vaccinees and non-vaccinees by population-based cancer registries is needed to prove that HPV vaccination ultimately protects against invasive cervical cancer.9

Licensure of the HPV vaccine is not far away. It will probably be the first licensed vaccine against a common sexually transmitted infection. However, the implementation should be accomplished in a controlled way with community randomised trials. Several questions on the effectiveness and the public-health impact of vaccine implementation remain unanswered.9,10,11 How to implement HPV vaccination in national vaccination programmes to guarantee high coverage in adolescents before they become sexually active? Should both girls and boys be vaccinated? How many oncogenic HPV types should the vaccine contain? Is resurgence of oncogenic HPV types not included in the vaccine a real threat? When is booster vaccination required? Harper and colleagues show, for instance, that the vaccine induces a robust B-cell response, but it is not known whether it induces a significant T-cell response.

While we trust that the remaining questions can be answered, a straightforward message of Harper and colleagues' work is that preventive vaccination against the oncogenic HPV types will soon be available.

We are both principal investigators in phase 3 trials of HPV vaccines for Merck and Co and GSK Biologicals.

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#12369 From: David Phillips <redhotmuslbear@...>
Date: Sun Jun 26, 2005 7:10 pm
Subject: Re: In response to the Anal Cancer story, why are men not getting HPV vaccine? 		pozhotandtmptng
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On 6/26/05, Bob Munk <bobmunk@...> wrote:
> Well, probably because my understanding is that in order to be
> effective, the HPV vaccine needs to be used before someone becomes
> sexually active.


I believed this very same notion until I read this article [posted in
the "I Got Tested" Tribe on tribe.net] and googled other scientific
data to back it up.  The vaccine is effective against HPV 16 that is a
leading cause of squamous cell cancer, cervical and anal;  however,
HPV 16 is not known to be sexually transmitted.  Social conservatives
have lacthed contorted the facts regarding HPV transmission and the
inefficacy of condoms in controlling the spread of certain types of
HPV to develop a lethal message:

http://education.guardian.co.uk/higher/research/story/0,9865,1510717,00.html

Cheers,
David

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#12368 From: JuLev@...
Date: Sun Jun 26, 2005 10:55 am
Subject: HPV Vaccine: GlaxoSmithKline Vaccine 		JuLev@...
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NATAP - http://www.natap.org

HPV Vaccine: GlaxoSmithKline Vaccine

“Efficacy of a bivalent L1 virus-like particle vaccine in prevention of infection with human papillomavirus types 16 and 18 in young women: a randomised controlled trial”

The Lancet November 2004; 364:1757-1765

Diane M Harper
a ,   Eduardo L Franco b,   Cosette Wheeler c,   Daron G Ferris d,   David Jenkins e,   Anne Schuind f,   Toufik Zahaf e,   Bruce Innis f,   Paulo Naud g,   Newton S De Carvalho h,   Cecilia M Roteli-Martins i,   Julio Teixeira j,   Mark M Blatter k,   Abner P Korn l,   Wim Quint m   and   Gary Dubin f,   GlaxoSmithKline HPV Vaccine Study Group

Summary
Background: Vaccination against the most common oncogenic human papillomavirus (HPV) types, HPV-16 and HPV-18, could prevent development of up to 70% of cervical cancers worldwide. We did a randomised, double-blind, controlled trial to assess the efficacy, safety, and immunogenicity of a bivalent HPV-16/18 L1 virus-like particle vaccine for the prevention of incident and persistent infection with these two virus types, associated cervical cytological abnormalities, and precancerous lesions.

Methods: We randomised 1113 women between 15-25 years of age to receive three doses of either the vaccine formulated with AS04 adjuvant or placebo on a 0 month, 1 month, and 6 month schedule in North America and Brazil. Women were assessed for HPV infection by cervical cytology and self-obtained cervicovaginal samples for up to 27 months, and for vaccine safety and immunogenicity. This study was conceived jointly by GlaxoSmithKline Biologicals and consultants, some of whom also served as investigators. GlaxoSmithKline Biologicals funded and coordinated this study.

Findings: In the according-to-protocol analyses, vaccine efficacy was 91.6% (95% CI 64·5-98·0) against incident infection and 100% against persistent infection (47·0-100) with HPV-16/18. In the intention-to-treat analyses, vaccine efficacy was 95·1% (63·5-99·3) against persistent cervical infection with HPV-16/18 and 92·9% (70·0-98·3) against cytological abnormalities associated with HPV-16/18 infection. The vaccine was generally safe, well tolerated, and highly immunogenic.

Interpretation: The bivalent HPV vaccine was efficacious in prevention of incident and persistent cervical infections with HPV-16 and HPV-18, and associated cytological abnormalities and lesions. Vaccination against such infections could substantially reduce incidence of cervical cancer.

AUTHOR DISCUSSION
The results of this trial show that the bivalent HPV-16/18 virus-like particle vaccine was highly efficacious in preventing incident and persistent HPV-16/18 infection in fully vaccinated healthy young women. The vaccine was also highly efficacious in the broader group of women, including those who did not fully comply with the protocol.

The incidence of HPV-16 infection in the placebo group was sufficient to detect significant differences compared with the vaccine arm in all cohorts. However, the incidence of HPV-18 was much lower, as noted in other studies.26 Nonetheless, significant results for vaccine efficacy against HPV-18 were obtained in the intention-to-treat cohort, where there were sufficient numbers of events for analysis. We conclude that the bivalent vaccine shows high efficacy against both incident and persistent HPV-16 and HPV-18 infections.

Incident HPV infection was common in young women in this study, as noted in previous cohort studies.27 Because we used two PCR methods (broad-primer testing and type-specific testing) designed for maximum sensitivity to detect HPV-16/18, many incident infections were detected only on one occasion, particularly in cervicovaginal samples. It is likely that this single timepoint detection represents the presence of very small amounts of HPV DNA, possibly as a result of HPV presence not related to active infection or very low-grade transient infection.28

We provide evidence for the close relation between the development of persistent HPV infection and the concomitant development of cytological abnormalities, followed by the detection of CIN from biopsy. These results are consistent with those of previous epidemiological cohort studies of the natural history of HPV infection. Compared with the subjective readings of cytology and cervical histopathology, detection of persistent infection with a type-specific HPV is a reliable endpoint with high reproducibility.19 Previous studies have established the role of persistent HPV infection as the necessary cause of cervical cancer. Our data lend support to the conclusion that persistent type-specific infection with HPV over 6-12 months should be a recommended endpoint for vaccine efficacy trials.29

Taken together, our data provide compelling evidence that this HPV-16/18 vaccine is highly efficacious against persistent HPV-16/18 cervical infection, cytological abnormalities associated with HPV-16/18, and histological development of HPV-16/18-associated CIN. However, a limitation to our study was that it was not powered to estimate efficacy for histopathologically confirmed cervical lesions.

We have shown that the HPV-16/18 virus-like particle vaccine adjuvanted with AS04 induces a level of antibody production against HPV-16/18 that is much higher than that induced by natural infection. Previous work has shown that combinations of the adjuvants MPL and aluminum salts induce an enhanced immune response compared with antigen alone or adjuvanted with only aluminum, at both the humoral and cellular level.30,31,32 These findings suggest that the immune responses induced in vaccinated women may provide a longer duration of protection than the protective effects induced by natural HPV infection; however, a protective antibody level has not been established nor is there sufficient data currently available to estimate the duration of vaccine-induced protection.

In this trial, the bivalent HPV-16/18 vaccine appeared to be safe and well tolerated. No serious vaccine-related adverse events were reported. Neither local nor general vaccine related symptoms affected overall subject compliance. Greater local reaction rates were observed in the vaccine group, but general symptom rates were equivalent to placebo. The AS04 adjuvant has been used in other vaccine studies and found to be generally safe and well tolerated.32

Our findings indicate that the vaccine could contribute substantially to reducing worldwide rates of cervical cancer. However, large-scale trials with long-term follow-up are needed to extend our findings and confirm that vaccination prevents cervical cancer.

Mathematical modelling predicts that a prophylactic vaccine programme, directed at young adolescent women, is likely to be cost-effective in both screened and unscreened populations, with important long-term implications for cervical cancer prevention, especially in countries where screening is limited or unavailable.33-37 Additional benefits could come from vaccination of older women. In countries with opportunistic or organised screening programmes, the high vaccine efficacy in preventing cytological abnormalities associated with HPV-16/18 shows the potential to reduce the number of women receiving additional cytology or colposcopy, thereby reducing the cost of medical treatments associated with cervical screening programmes. In the USA, these preventable costs are estimated at several billion dollars per year.38

Further studies are in progress to provide additional information to enable the effective implementation of HPV vaccination as a public health measure aimed at reducing the global burden of cervical cancer.

Introduction

Cervical cancer is the most important manifestation of genital human papillomavirus (HPV) infection and is one of the leading causes of cancer mortality in women worldwide. The global disease burden of cervical cancer is estimated at 470000 new cases and 230000 deaths every year; almost 80% of the cases occur in developing countries, where in many regions it is the most common cancer among women.1,2 Cervical cancer is also the leading cause of years-of-life-lost in women in south central Asia, Latin America, and sub-Saharan Africa, results in a greater reduction of a woman's life expectancy compared with AIDS, tuberculosis, or maternal conditions in Latin America and Europe.3

The causal role of some high-risk HPV types in cervical carcinogenesis has now been clearly established by studies that take into account the many molecular, epidemiological, virological, cytological, and histological complexities of the disease's natural history. Molecular studies show high-risk HPV DNA has been detected in 99·7% of an international series of cervical cancers with highly sensitive PCR, and, in 100% of cases, confirmed by expert histological review.4

The odds ratio for cervical cancer associated with high-risk HPV infection has been estimated as greater than 150 in case-control studies.5 Findings from case-control studies and cohort studies together with laboratory evidence of HPV oncogenic expression, have established that persistent infection with high-risk HPV types is the necessary cause of cervical cancer.6-9 The most prevalent HPV types associated with cervical cancer are HPV-16 and HPV-18; HPV-16 accounts for more than 60% of cervical cancers, with HPV-18 adding about another 10%.5,10-13

HPV vaccines based on L1 virus-like particles have shown promise in protecting against infection and development of lesions.14,15 Recently, a monovalent HPV-16 virus-like particle vaccine showed protection against persistent infection with HPV-16 and its associated cervical intraepithelial neoplasia (CIN).16 These data suggest that L1 virus-like particle vaccines have the potential to reduce worldwide cervical cancer rates.

We did a double blind, multi-centre, randomised, placebo-controlled clinical trial to assess the efficacy of a bivalent HPV-16/18 virus-like particle vaccine against incident and persistent infections with HPV-16 and HPV-18. We also assessed vaccine efficacy against cytological abnormalities and CIN, and vaccine immunogenicity, safety, and tolerability.

Introduction

Cervical cancer is the most important manifestation of genital human papillomavirus (HPV) infection and is one of the leading causes of cancer mortality in women worldwide. The global disease burden of cervical cancer is estimated at 470000 new cases and 230000 deaths every year; almost 80% of the cases occur in developing countries, where in many regions it is the most common cancer among women.1,2 Cervical cancer is also the leading cause of years-of-life-lost in women in south central Asia, Latin America, and sub-Saharan Africa, results in a greater reduction of a woman's life expectancy compared with AIDS, tuberculosis, or maternal conditions in Latin America and Europe.3

The causal role of some high-risk HPV types in cervical carcinogenesis has now been clearly established by studies that take into account the many molecular, epidemiological, virological, cytological, and histological complexities of the disease's natural history. Molecular studies show high-risk HPV DNA has been detected in 99·7% of an international series of cervical cancers with highly sensitive PCR, and, in 100% of cases, confirmed by expert histological review.4

The odds ratio for cervical cancer associated with high-risk HPV infection has been estimated as greater than 150 in case-control studies.5 Findings from case-control studies and cohort studies together with laboratory evidence of HPV oncogenic expression, have established that persistent infection with high-risk HPV types is the necessary cause of cervical cancer.

Results

Based on the estimate of appropriate study sample size, 1113 women were enrolled and randomised. We administered the study vaccine to 560 women and the placebo to 553 women. The average age of enrolled women was 20 years (SD 3). We noted similar patterns of risk factors for HPV acquisition among women in each treatment group: about half of the women were current smokers, a large proportion had between two and five previous sexual partners, and most began sexual activity between 15 years and 19 years of age.

The major reasons for elimination from according-to-protocol efficacy analysis were abnormal cytology, high-risk HPV DNA positivity, or seropositivity for HPV-16 or HPV-18 at enrolment; followed by non-compliance with the vaccine schedule and drop-out from the study up to month 18. 958 women (85%) completed the initial phase to month 18, with similar proportions of women from the vaccine and placebo dropping out of the study.

Analyses to assess our primary objective showed significant vaccine efficacy against incident HPV-16 and HPV-16/18 infections (table 3). In the according-to-protocol 18-month cohort, vaccine efficacy against incident HPV-18 infection was not statistically significant; however, in the intention-to-treat cohort, vaccine efficacy was significant (analysis of cervical samples only).

We noted 100% vaccine efficacy in the according-to-protocol cohorts against persistent HPV-16 and HPV-16/18 infections detected in both cervical and combined cervical and cervicovaginal samples. Although no persistent HPV-18 infections were detected in cervical samples from the according-to-protocol 18-month cohort, significant vaccine efficacy against persistent HPV-18 infection was shown in the 27-month cohort for combined cervical and cervicovaginal samples. Additionally, significant vaccine efficacy against persistent HPV-16 and HPV-16/18 infections was noted in the intention-to- treat cohort in analyses of cervical samples only and of combined cervical and cervicovaginal samples.

As shown in table 5, 27 women in the placebo group and two in the vaccine group had HPV-16 and/or HPV-18 associated cytological abnormalities (vaccine group: one woman with ASCUS, and one with LSIL). 15 ASCUS, 14 LSIL, and one HSIL were reported in the placebo group and one ASCUS, two LSIL, and no HSIL in the vaccine group. Vaccine efficacy in the according-to-protocol cohort was 93·5% (95% CI 51·3-99·1; p=0·0002).

We also assessed women with histologically confirmed CIN 1 or 2 lesions, with HPV-16 or HPV-18 infection detected in the cytology specimen before colposcopy. Overall, seven women (six in the placebo group and one in the vaccine group), developed these lesions.

One woman in the vaccine group first tested positive for HPV-51 and HPV-56 at month 9. Her cytology specimen at month 12 tested positive for HPV types 18, 51, and 56. The CIN 1 lesion found in the colposcopically-directed biopsy contained only HPV-51, and not HPV-18. Subsequent HPV testing showed persistent HPV-51 through month 21; therefore, the lesion was finally judged to be associated with HPV-51.

Three women who received placebo developed CIN 1; all had ASCUS or LSIL cytology and a pattern of persistent HPV-16 infection. HPV-16 was detected in the lesions of all three women. Two women remained HPV-16 positive after biopsy and the third woman had a persistent HPV-58 infection in addition to persistent HPV-16 infection.

Consensus diagnosis confirmed CIN 2 diagnoses in three other women in the placebo group with preceding ASCUS, LSIL, and HSIL cytological abnormalities. In each case, HPV-16 was detected in all lesions and persistent HPV-16 infections preceded the lesions.

No serious adverse events related to vaccination occurred in either vaccine or placebo groups. The vaccine group had more injection site symptoms (pain, swelling, redness) than the placebo group (overall injection site symptoms 5·9% difference between proportions, 95% CI 2·1-10·1, Fisher's exact test), but these symptoms tended to be transient and mild. The difference in incidence of injection site reactions between the groups had no effect on compliance with completion of the vaccination course. The general symptoms of fatigue, gastrointestinal complaints, headache, itching, and rash were equally common in both the vaccine and placebo groups. Three women in the placebo group dropped out because of non-serious adverse events; one woman in the vaccine group dropped out because of a serious adverse event (spontaneous abortion) that was not related to vaccination.

Among the vaccinated women in the according-to-protocol cohort from month 0 to month 7, 100% seroconverted to HPV-16-positive and 99·7% seroconverted to HPV-18-positive after three doses of vaccine. By 18 months, 100% of the women had seroconverted for both HPV-16 and HPV-18. Comparison of GMTs at month 7 between vaccine and placebo groups for each antibody type was significant (p<0·0001).

Geometric mean titres for naturally occurring infections were 50 ELISA units/mL (SD 0·5, 95% CI 40·9-60·4) for antibodies against HPV-16 and 41 ELISA units/mL (0·5, 34·2-49·0) for antibodies against HPV-18. Geometric mean titres for vaccine-induced antibodies to HPV antibodies were over 80 and 100 times greater than those seen in natural infections with HPV-18 and HPV-16, respectively. Vaccine-induced titres remained substantially raised at 18 months, and were still 10-16 times higher than those seen in women with natural HPV-16 or HPV-18 infections, respectively.

Methods
Study objectives and participants

The primary objective of this study was to assess vaccine efficacy in the prevention of infection with HPV-16, HPV-18, or both (HPV-16/18), between months 6 and 18 in participants who were initially shown to be seronegative for HPV-16/18 by ELISA and negative for HPV-16/18 DNA by PCR. Secondary objectives included: evaluation of vaccine efficacy in the prevention of persistent infection with HPV-16/18, and the evaluation of vaccine efficacy in the prevention of cytologically confirmed low-grade squamous intraepithelial lesions (LSIL), high-grade squamous intraepithelial lesions (HSIL), and histologically confirmed LSIL (CIN 1), HSIL (CIN 2 or 3) squamous cell cancer, or adenocarcinoma associated with HPV-16/18 infection between months 6 and 18, and months 6 and 27. The prevention of atypical squamous cells of undetermined significance (ASCUS) cytology associated with HPV-16/18 infection was added post-hoc to the outcome analyses.

We also did an exploratory analysis of the histopathological endpoints CIN 1 and 2 associated with HPV-16/18 DNA detected by PCR in lesional tissue. Other objectives included the assessment of vaccine immunogenicity, safety, and tolerability.

Investigators in North America (Canada and the USA) and Brazil recruited women for this efficacy study through advertisements or previous participation in an HPV cross-sectional epidemiology study that took place between July and December, 2000.

For each of the 32 study sites, an institutional review board approved the protocol, consent forms, and amendments. Women signed separate written consents for study participation and colposcopy. For those under 18 years, parental consent and assent from the participant were obligatory.

There were two study phases: an initial phase for vaccination and follow-up that concluded at month 18; and a blinded follow-up extension phase that concluded at month 27.

Women eligible for the initial phase (months 0-18) included healthy women aged 15-25 years, who had had no more than six sexual partners, no history of an abnormal Pap test or ablative or excisional treatment of the cervix, and no ongoing treatment for external condylomata; and who were cytologically negative, seronegative for HPV-16 and HPV-18 antibodies by ELISA, and HPV-DNA-negative by PCR for 14 high-risk HPV types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68) no more than 90 days before study entry.

Women who completed the initial phase of the study earliest, and who did not have ablative or excisional therapy of the cervix, or hysterectomy after enrolment, were eligible to participate in the extension phase of the study (months 18-27).


Procedures

Each dose of the bivalent HPV-16/18 virus-like particle vaccine (GlaxoSmithKline Biologicals, Rixensart, Belgium) contained 20 É g of HPV-16 L1 virus-like particle and 20 É g of HPV-18 L1 virus-like particle. Each type of virus-like particle was produced on Spodoptera frugiperda Sf-9 and Trichoplusia ni Hi-5 cell substrate with AS04 adjuvant containing 500 É g aluminum hydroxide and 50 É g 3-deacylated monophosphoryl lipid A (MPL, Corixa, Montana, USA) provided in a monodose vial. The placebo contained 500 É g of aluminum hydroxide per dose, and was identical in appearance to the HPV-16/18 vaccine. Every study participant received a 0·5 mL dose of vaccine or placebo at 0 months, 1 month, and 6 months.

Health-care providers obtained cervical specimens with a cervical brush and spatula (washed in PreservCyt, Cytyc Corporation, Boxborough, MA, USA) for cytology and HPV DNA testing at screening and months 6, 12, and 18. At months 0 and 6, and subsequently every 3 months, women self-obtained cervicovaginal samples with two sequential swabs (placed in PreservCyt) for HPV DNA testing.17 A central laboratory (Quest Diagnostics, Teterboro, NJ, USA) reported cytology results (ThinPrep, Cytyc Corporation) by use of the 1991 Bethesda classification system.

Protocol guidelines recommended colposcopy after two reports of ASCUS, or one report of atypical glandular cells of undetermined significance, LSIL or HSIL, squamous cell carcinoma, adenocarcinoma in situ, or adenocarcinoma. These guidelines also recommended biopsy for any suspected lesions.

The central histology laboratory made an initial diagnosis from the formalin-fixed tissue specimens for clinical management. A panel of three pathologists made a subsequent consensus diagnosis for HPV-16 and HPV-18 associated lesions with the CIN system. This consensus diagnosis also included review of the sections taken at the time of microdissection for PCR detection of lesional HPV DNA.

HPV DNA isolated from the cytology specimen (MagNaPure Total Nucleic Acid system, Roche Diagnostics, Almere, Netherlands) and from the cervical biopsy specimen (proteinase K extraction) was amplified from an aliquot of purified total DNA with the SPF10 broad-spectrum primers that amplify a 65 bp region of the L1 gene.18-20 The amplification products were detected by a DNA enzyme immunoassay. A line probe assay (LiPA Kit HPV INNO LiPA HPV genotyping assay, SPF-10 system version 1, Innogenetics, Gent, Belgium, manufactured by Labo Bio-medical Products, Rijswijk, Netherlands) detected 25 HPV genotypes (6, 11, 16, 18, 31, 33, 34, 35, 39, 40, 42, 43, 44, 45, 51, 52, 53, 56, 58, 59, 66, 68, 70, and 74).21 Any specimen that was positive by DNA enzyme immunoassay was tested by type-specific HPV-16 and HPV-18 PCR. HPV-16 type-specific PCR primers amplified a 92 bp segment of the E6/E7 gene and HPV-18 type-specific PCR primers amplified a 126 bp segment of the L1 gene.22

We defined incident cervical infection with HPV-16/18 as at least one positive PCR result for HPV-16 or HPV-18 during the trial, and persistent infection with HPV-16/18 as at least two positive HPV-DNA PCR assays for the same viral genotype separated by at least 6 months.23,24 HPV-DNA test results were concealed from investigators during the study and cytological and histological diagnoses were only revealed for clinical management purposes. Analyses included HPV-16/18 DNA results for cervical specimens and combined cervical and self-obtained cervicovaginal specimens.

We collected serum from study participants at months 0, 1, 6, 7, 12, and 18 for assessment of immunogenicity. Serological testing for antibodies to HPV-16 and HPV-18 virus-like particles was by ELISA. Recombinant HPV-16 or HPV-18 virus-like particles were used as coating antigens for antibody detection (see webappendix http://image.thelancet.com/extras/04art10103webappendix.pdf). Seropositivity was defined as a titre greater than or equal to the assay cut-off titre established at 8 ELISA units/mL for HPV-16 and 7 ELISA units/mL for HPV-18. Typical natural titres were determined by use of blood samples obtained from women in the preceding epidemiology study who were found to be seropositive for HPV-16 or HPV-18 by ELISA.

Women recorded symptoms experienced during the first 7 days after vaccination on diary cards with a three-grade scale of symptom intensity. Additionally, they reported to study personnel by interview all adverse events within the first 30 days after vaccination. Information on serious adverse events and pregnancies was collected throughout the study.


Statistical methods

Assuming a 6% cumulative incidence rate of both HPV-16 and HPV-18 type infections over 12 months, we estimated that 500 women per treatment group would provide 80% power to assess a lower limit of the 95% CI of the vaccine efficacy above zero. We assumed an 80% retention rate over 18 months. Interim analyses for efficacy, safety, and immunogenicity were done for future study planning purposes only; the O'Brien and Fleming method was used to adjust the Éø value for the final analysis after interim analyses occurred (overall Éø=0·05; two-sided test).25

Stratified, block randomisation according to validated algorithms was centralised with an internet randomisation system. Stratification was according to age (15-17, 18-21, and 22-25 years) and region (North America and Brazil). Each vaccine dose was attributed a randomly chosen number based on specific participant information entered into the computerised randomisation system by study personnel. Treatment allocation remains concealed from investigators and the women participating in a long-term follow-up study.

The intention-to-treat and according-to-protocol cohorts are shown in the figure, in which the reasons for exclusion from analyses are listed in rank order; women who met more than one exclusion criterion were only counted once according to the highest ranking criterion. We refer to the sets of participants entered in the intention-to-treat and according-to-protocol analyses as cohorts, although the information used to restrict subject inclusion in the according-to-protocol was only known after follow-up.

We did both according-to-protocol and intention-to-treat analyses for efficacy. Calculation of vaccine efficacy in the according-to-protocol 18-month analysis was based on the proportion of participants with HPV-16/18 infection in the vaccinated versus placebo groups. Vaccine efficacy was defined as 1 minus the ratio between these two proportions; 95% CIs measured the precision of the efficacy estimates. p values were calculated with the two-sided Fisher's exact test. Corresponding rates were expressed as the numbers of cases with the outcome divided by the numbers of participants at risk. The according-to-protocol 18-month cohort included enrolled women who received three scheduled doses of vaccine and complied with the protocol as described in the figure

Calculation of vaccine efficacy in the intention-to-treat and according-to-protocol 27-month analyses was based on the Cox proportional hazard model using the time-to-occurrence of cases with HPV-16/18 infection in the vaccinated versus placebo groups. This allowed controlling for the accrued person-time data in each group. Vaccine efficacy was calculated using 1 minus the hazard ratio and p values calculated using the log rank test. Corresponding rates were expressed as the number of cases divided by the total person-time. All enrolled women who received at least one dose of vaccine or placebo, were negative for high-risk HPV-DNA at month 0, and had any data available for outcome measurement were included in the intention-to-treat cohort. The according-to-protocol 27-month cohort included outcome results from the according-to-protocol 18-month cohort and results that occurred during the extension phase (from 18 months to 27 months).

Calculation of p values for the safety analysis was performed using Fisher's exact test comparisons. The cohort for safety analysis included all enrolled women who received at least one dose of vaccine or placebo and complied with specified, minimal protocol requirements.

Immunogenicity was assessed in a subset of the according-to-protocol safety cohort, which included women with serology results at months 0, 7, and 18, who received all three doses of study vaccine or placebo according to schedule, complied with the blood sampling schedule, and did not become positive for HPV-16/18-DNA during the trial. Seropositivity rates between the vaccine and placebo groups were compared with Fisher's exact test (p<0·001 judged significant). Geometric mean titres were compared with ANOVA and Kruskal-Wallis test.

Block randomisation and statistical analyses were done with SAS version 8.2 (SAS Institute, Cary, North Carolina).


Role of the funding source

This study was conceived jointly by GlaxoSmithKline Biologicals and consultants, some of whom also served as investigators. GlaxoSmithKline Biologicals funded and coordinated this study. A publication steering committee was assembled to represent all members of the HPV Vaccine Study group who collected data for the study and cared for the study patients. GlaxoSmithKline Biologicals did all HPV serological testing, Quest Diagnostics processed all cytology and histology specimens, and Delft Diagnostic Laboratory did PCR for HPV types. An independent external statistician worked separately on data analyses to maintain allocation concealment; and the sponsor drafted the clinical study report for regulatory purposes with these data provided. The corresponding author had full access to the data and had final responsibility for submission for publication.

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#12367 From: Bob Munk <bobmunk@...>
Date: Sun Jun 26, 2005 12:41 pm
Subject: Re: In response to the Anal Cancer story, why are men not getting HPV vaccine? 		munkrj
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Well, probably because my understanding is that in order to be
effective, the HPV vaccine needs to be used before someone becomes
sexually active.

Bob


On Sat, 25 Jun 2005 12:43:00 EDT, you wrote:

>I asked my Doctor and she said she had not even thought of that before, she
>says she will look into using the HPV vaccine on gay men.
> HPV surely does not care if your male or female, and HPV does cause both
>cervical and at times Anal cancer. I think we should make some noise about this
>and find out what it takes to get this. Now I do not know if the vaccine will
>work therapeutically but its worth asking.
>                                                                    Al

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#12366 From: PoWeRTX@...
Date: Sat Jun 25, 2005 8:15 pm
Subject: National AIDS activists gather in Ft. Lauderdale to engage the local community 		nelsonvergel
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FOR IMMEDIATE RELEASE

                                                                     CONTACT:     Kristen Lepore

                                                                        E-mail: kristen@...

                                                  Website:  www.atac-usa.org

 

 

National AIDS activists gather in Ft. Lauderdale to engage the local community

 

 

Ft. Lauderdale, June 24, 2005 – Have you felt a strong desire to work with other activists to improve access to life-saving HIV  treatment and insure that HIV activists continue to advocate for ethical and well-designed research of new anti-HIV therapies?  Come meet the AIDS Treatment Activists Coalition (ATAC) !  We are  a national coalition of treatment activists, many living with HIV/AIDS, who are working together to end the AIDS epidemic by ensuring access to treatment, sharing knowledge, and advancing research on HIV/AIDS.  ATAC is an individual membership organization run for and by community activists. Membership is free and open to the public.*

 

 

HIV/AIDS are highly prevalent in South Florida. Come join us and make a difference! The  PALS Project (Positive Action for Living Safely) and the Gay and Lesbian Community Center (GLCC) are hosting a reception and dinner for ATAC on  Saturday, July 16, 2005 from 6:30 pm to 10:00 pm at GLCC (1717 N. Andrews Avenue, Ft. Lauderdale, FL).

 

 

"Getting involved in HIV activism is vital. People living with HIV/AIDS and the community at-large have the power to influence decisions that affect the future of HIV policy. There is no time to waste. ATAC leads the way in providing an organized and effective response to the challenges that we face in HIV today,” said Manuel Rodriguez from the PALS Project.

 

Currently ATAC has more than 400 members, and three active program areas. Program areas, better known as “Working Groups,” are initiated by members and are a direct outgrowth of community interests. Current Working Groups include: the Drug Development Committee (which works with the pharmaceutical industry and regulatory groups like the Food and Drug Administration to provide community input into the development of new therapies), Access to Health Care for Incarcerated Individuals, the Immune Based Therapies Working Group and SAVE ADAP (which seeks to address the current crisis facing the AIDS Drug Assistance Programs).

 

“ATAC has connected me to a great network of fellow activists.  I no longer feel like I am alone in this fight.  They have also helped me stay abreast of new information and issues even before they become known by researchers and physicians,” stated Nelson Vergel, director of the Program for Wellness Restoration and  ATAC steering committee member. 

 

Cathy Olufs, ATAC member since 2002 and HIV-positive since 1995 stated, “Membership in ATAC has allowed me the opportunity to learn the in’s and out’s of activism from some of the best.  The unique structure of our group fosters support and enables a new activist to jump right into the trenches with those who have been doing this work for years.” 

 

Curious how you can help shape the future the HIV/AIDS treatment? Come and learn more about ATAC on July 16.  Seating is limited to the first 100 attendees. Call Manny Rodriguez at the PALS Project 954-537-4111 ext. 110 for more information, email Kristen at kristen@... or visit the ATAC website www.atac-usa.org.

 

* Individuals employed by the pharmaceutical sector are not eligible for Associate membership but are welcome to join ATAC as a Community member.

# # #

 

 
Nelson Vergel
Program for Wellness Restoration
powerusa.org

 Join a 1700 people HIV discussion group by sending a blank email to pozhealth-subscribe@yahoogroups.com
Please email me at nelsonvergel@... if you have problems with this email address. Thanks

Lecture Dates:
Chicago June 30, El Paso- July 7, Miami-Ft Lauderdale- July 18 & 19 (Spanish), Atlanta July 21, Phily Aug 24 /Sept 14, Long Beach Aug 31, NY Sept 8, LA Sept 21, Salt Lake- Nov 5, AIDS Nutritionist Conf- DC Sept 15-17,San Francisco Oct 26, POZ Cruise- Miami- Oct 15-21


Disclaimer

This information (and any accompanying printed material) is not intended to replace the attention or advice of a physician or other health care professional. Anyone who wishes to embark on any dietary, drug, exercise, or other lifestyle change intended to prevent or treat a specific disease or condition should first consult with and seek clearance from a qualified health care professional.

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