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Researchers Criticize NIH AIDS Vaccine $119 Million Study; What About ADAP
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--Leading HIV scientists criticize NIH AIDS vaccine study that will cost $119 million: study is “doomed to fail” and “should never been started”
--ADAP has no money
Values & Goals gone screwy.
Commentary by
Jules Levin
Executive Director/Founder, NATAP
http://www.natap.org
HAART, HIV therapy, is clearly established and proven to save lives. Yet thousands of HIV patients cannot access HIV care and treatment through ADAP due to inadequate funding from Congress and the Adminstration. As well, Hepatitis C treatment with pegylated interferon plus ribavirin has been established as therapy that can save lives. Hepatitis appears to be the leading cause of death among people with HIV. Yet, most ADAPs do not provide this treatment for ADAP clients despite the fact that this therapy is the Standard of Care.
In these times we are so underfunded for ADAP that HIV+ individuals needing HIV therapy cannot access life-saving therapy for HIV and hepatitis. Each US state has an ADAP (AIDS Drug Assistance Program), which provides life-saving HIV and hepatitis treatment for patients who lack the finances to access treatment through private insurance or are unable to qualify for Medicaid. In order to provide adequate access to care and treatment for ADAP we need this $119 million but Congress and the Administration are offering $20 to $40 million. For several years ADAP has been severely underfunded and States are starting waiting lists and cutting patients off access to treatment through ADAP due to this underfunding. ADAP advocates have been asking for several hundred million dollars for several years to make ADAP whole but are repeatedly turned away. Is something screwy that we would spend $119 million on this vaccine study but not provide adequate funding to ADAP?
ADAPs are unable to provide Fuzeon, due to financial constraints, despite this new therapy being clearly established as a crucial drug needed for HIV treatment for patients with few or no treatment options remaining. Studies clearly establish Fuzeon as perhaps the only remaining therapy for many patients with drug resistance to the 3 main classes of HIV drugs: protease inhibitors, nucleosides, and NNRTIs. Patients with resistance to these classes of drugs are fully sensitive to Fuzeon, the first in a new class of drugs called entry inhibitors. Fuzeon is a fusion inhibitor, a type of entry inhibitor. This drug is expensive due to being difficult to manufacture, as it is the first in the new class of drugs.
It is clearly established that at the very least hepatitis is a leading cause of death in HIV. We invest millions of dollars in care and live-saving treatments for HIV, yet there is no firm commitment to provide equally needed care and treatment to address hepatitis C to patients co-infected with HIV and the hepatitis C virus. Not only do ADAPs not provide hepatitis C treatments for their clients but there is no commitment in Washington DC or in the States to address Hepatitis C. 30% of HIV-infected individuals have HCV, that is 300,000 HIV+ individuals. 60-90% of those infected with HIV by injection drug use, also have HCV. HIV therapy, HAART, does not slow or resolve HCV. Many HIV+ individuals with HIV well under control are dying of end stage liver disease due to hepatitis C.
In these times of competing political goals in the world of HIV, advocates and activists, government officials, and researchers all have competing demands related to AIDS vaccines, ADAP, HIV drug pricing, and more. What about the patients and their immediate needs?
Leading researchers and others clearly think that this $119 million expenditure on an AIDS vaccine trial is not productive. Perhaps the competing factions can consider that many individuals suffering with HIV and the leading cause of death in HIV, hepatitis, are not able to access care and treatment for therapies that are proven & established to save lives. Something appears screwy to me.
Experts: Thailand AIDS Vaccine Will Fail
By PAUL ELIAS
.c The Associated Press
SAN FRANCISCO (AP) - A $119 million federally funded experiment in which an AIDS vaccine is being tested on 16,000 volunteers in Thailand is doomed to fail and should never have been started, 22 leading HIV researchers charge.
The scientists allege the Thai volunteers are receiving a crude cocktail made of two antiquated AIDS vaccines, each of which failed previous human tests.
"They are taking two failed products and hoping that if they are combined that they are going to work," said Dennis Burton, an AIDS researcher at the Scripps Research Institute in La Jolla. "Everything I've seen about the Thai trial suggests that it doesn't have a prayer."
Burton and 21 other researchers - including Robert Gallo, co-discoverer of the AIDS virus - signed a short opinion piece published in Friday's issue of the journal Science.
The experiment is funded by the National Institutes of Health and the Pentagon and is being carried out by the Thai government.
U.S. government officials defended the research, saying it could yield a new weapon against a disease that has killed 28 million people and infected 42 million more, most of them in Africa.
But the 22 scientists complained the Thai experiment is diverting critical funding and energy from more promising vaccine candidates, including some of their own.
What's more, they said they fear public and political confidence in AIDS vaccine research will be hurt if the Thai experiment fails as they expect. It would be the third major flop of a large-scale AIDS vaccine experiment, and the second failure in Thailand.
Last year, AIDSVAX, a vaccine created by Brisbane, Calif.-based VaxGen Inc., failed to protect volunteers against the disease in a 5,400-person North American trial. The same vaccine failed in a 2,400-volunteer trial in Thailand in November.
Since then, VaxGen essentially has abandoned its pursuit of an AIDS vaccine.
Despite those failures, AIDSVAX is one of the vaccines being used in the current trial. It's the second part of a one-two punch called "prime boost" that its supporters see as the most promising approach to defeat the AIDS virus by provoking several different immune responses.
A VaxGen spokeswoman declined comment.
The prime piece of the Thai vaccine is ALVAC, created by Aventis Pasteur. An Aventis scientist defended the vaccine as worthy of continued development.
But the critics argue the NIH scrubbed a U.S.-based trial with the same two-vaccine cocktail two years ago because of failures in a smaller experiment.
That trial was canceled, in part, because the Thai test was starting, government officials said.
The U.S. trial targeted a different AIDS strain than the Thai test and was more narrowly focused. Still, the 22 scientists argue the two tests are similar enough to warrant cancellation of the Thai experiment.
Researchers already have inoculated about 500 volunteers since the experiment began in September and plan to give shots to 15,500 more people over the next two years. It will take about five years to see results.
U.S. government officials and advocacy groups contend the failed VaxGen vaccine has shown promise when used in combination with the Aventis vaccine in smaller experiments. More elaborate experiments are needed to prove whether the combination is effective, they say.
The National Institute of Allergy and Infectious Disease, the NIH branch managing the test, issued a sharp rebuttal Thursday, declaring "no evidentiary data is provided (by critics) to support the prediction and assertions."
Government officials said positive results from two earlier human tests gave them a scientific reason to proceed.
"That's why you need the trial," said Dr. John McNeil of the U.S. Army Medical Research and Material Command. "I get discouraged when nothing is done."
SCIENCE ARTICLE FULL-TEXT
PUBLIC HEALTH:
Enhanced: A Sound Rationale Needed for Phase III HIV-1 Vaccine Trials
AUTHORS:
Dennis R. Burton,1 Ronald C. Desrosiers,2 Robert W. Doms,3 Mark B. Feinberg,4 Robert C. Gallo,5 Beatrice Hahn,6 James A. Hoxie,3 Eric Hunter,6 Bette Korber,7 Alan Landay,8 Michael M. Lederman,9 Judy Lieberman,2 Joseph M. McCune,10 John P. Moore,11 Neal Nathanson,3 Louis Picker,12 Douglas Richman,13 Charles Rinaldo,14 Mario Stevenson,15 David I. Watkins,16 Steven M. Wolinsky,17 Jerome A. Zack18[HN13]*
1The Scripps Research Institute, La Jolla, CA; 2Harvard Medical School, Boston, MA; 3University of Pennsylvania, Philadelphia, PA; 4Emory University, Atlanta, GA; 5Institute of Human Virology, Baltimore, MD; 6University of Alabama at Birmingham; 7Santa Fe Institute, Santa Fe, NM; 8Rush Medical College, Chicago, IL; 9Case-Western Reserve University, Cleveland, OH; 10The Gladstone Institute for Virology and Immunology, San Francisco, CA; 11Weill Medical College of Cornell University, New York, NY; 12Oregon Health and Science University, Portland, OR; 13University of California, San Diego, and San Diego Veterans Affairs Healthcare System; 14University of Pittsburgh, Pittsburgh, PA; 15University of Massachusetts Medical School, Worcester, MA; 16University of Wisconsin, Madison, WI; 17Northwestern University, Chicago, IL; 18University of California, Los Angeles, CA, USA.
SUMMARY: Concerns are expressed by a group of AIDS researchers about the U.S. government's plans to conduct a phase III trial of a combination HIV-1 vaccine in Thailand despite the cancellation of a trial of a very similar combination vaccine in the U.S.A. last year. One of the vaccine components, recombinant monomeric gp120, has already been shown to be ineffective in phase III trials in Thailand and the United States; the other component, a recombinant canarypox vector, is also poorly immunogenic. The scientific rationale that has been offered for the new trial in Thailand is considered by the authors to be weak.
The need for a human immunodeficiency virus-1 (HIV-1) vaccine [HN1] is unquestioned, and we strongly support its development as the highest AIDS research priority. We have a concern about the wisdom of the U.S. government's sponsoring a recently initiated phase III trial [HN2] in Thailand of a vaccine made from the live-replicating canarypox vector ALVAC (from Aventis Pasteur) [HN3] with a boost of monomeric gp120 (from VaxGen) [HN4] (1). The original aim of this trial was to determine whether a combination of immunogens designed to induce cellular immunity (ALVAC) and humoral immunity [HN5] (gp120) could prevent infection and/or lead to the immune control of HIV-1 replication postinfection. These remain questions fundamentally worth addressing, but we doubt whether these immunogens have any prospect of stimulating immune responses anywhere near adequate for these purposes.
A phase III trial of similar design was scheduled to be conducted in the U.S.A. by the HIV Vaccine Trials Network (HVTN) [HN6], the world's largest consortium of AIDS vaccine scientists and clinicians. However, the trial was canceled last year. [HN7] Multiple phase I and II clinical trials have revealed that the ALVAC vector is poorly immunogenic (2). The gp120 component has now been proven in phase III trials in the United States and Thailand to be completely incapable of preventing or ameliorating HIV-1 infection (1, 3). [HN8] There are no persuasive data to suggest that the combination of ALVAC and gp120 could induce better cellular [CD8+ cytotoxic T lymphocyte (CTL)] [HN9] or humoral (neutralizing antibody [HN10]) responses than either component can alone. Instead, the rationale for the Thai trial is reported to have now shifted toward an exploration of the hypothesis that the combination ALVAC + gp120 vaccine might induce an improved CD4+ T helper (TH) cell response [HN11] that would enhance host defenses (1). The evidence underlying this hypothesis is derived from phase I/II trials of the same or very similar vaccines and is, in our opinion, extremely weak (4-6). Moreover, the same data were available to the HVTN. We concur with the HVTN's decision not to proceed with a phase III trial of the ALVAC + gp120 vaccine (2). What scientific reasons mandate a different decision for the Thai trial? We also take issue with the scientific rationale for the revised hypothesis underlying the trial (1). Merely trying to answer a question about the protective role of the TH response does not seem to justify an experiment on this scale. Whether induction of TH responses by the gp120 component could enhance the breadth or magnitude of CTL responses to the ALVAC vector sufficiently could be answered rapidly by a small trial using methodology that was not available at the time of the earlier studies (4-6).
The cost of the phase III trial in Thailand is reported to be $119m, with at least $3m for the purchase of the gp120 component from its commercial manufacturer, itself a controversial point based on past precedent (7). The trial will involve 16,000 volunteers. [HN12] Approval was obtained from several committees, including one from the World Health Organization. But the latter committee's recommendation to proceed was made over a year before the results of the gp120 efficacy trial in Thailand were available, and it was made irrespective of the outcome of that trial (1). Our opinion is that the overall approval process lacked input from independent immunologists and virologists who could have judged whether the trial was scientifically meritorious. The U.S. National Institutes of Health (NIH) investment in basic and applied immunology research has been massive and appropriate over the past 15 years; the cumulative expertise gained should be used when important strategic decisions are made.
Society expects the scientific community to develop a vaccine to counter the AIDS pandemic, but there are adverse consequences to conducting large-scale trials of inadequate HIV-1 vaccines. We have recently seen two large phase III trials of immunogens that, all too predictably, failed to generate protective immunity (1, 2). We seriously question whether it is sensible now to conduct a third trial that, in our opinion, is no more likely to generate a meaningful level of protection against infection or disease. One price for repetitive failure could be crucial erosion of confidence by the public and politicians in our capability of developing an effective AIDS vaccine collectively. This seems to us to be another readily predictable scenario that is best prevented.
Phase III trials are, ultimately, the only way to judge HIV-1 vaccine efficacy, but sometimes a formal end point is not needed. Applying judgment about the value of existing data is an essential part of the scientific process when determining whether or not to move ahead with any experiment. The failure of the gp120-only vaccine was, for example, fully predicted by phase II trial data (8). For a phase III trial to be justifiable, there should be a reasonable prospect that the vaccine will benefit the study population, i.e., that it will protect at least some of the participants from HIV-1 infection or its consequences. The decision about whether or not to proceed with mounting a phase III HIV-1 vaccine trial needs to take into account the likelihood of success and the consequences of failure, the value of what can realistically be learned, and the human and financial costs involved. As a whole, the scientific community must do a better job of bringing truly promising vaccine candidates to this stage of development and beyond. More highly immunogenic HIV-1 vaccines that offer a greater hope of success than the ALVAC-gp120 combination are, in fact, now in early-phase clinical trials.
References
1. J. Cohen, Science 302, 1309 (2003).
2. J. Cohen, Science 299, 1290 (2003).
3. J. Cohen, Science 295, 1616 (2002).
4. M. L. Clements-Mann et al., J. Infect. Dis. 177, 1230 (1998) [Medline].
5. G. J. Gorse et al., Vaccine 19, 1806 (2001) [Medline].
6. S. Ratto-Kim et al., J. Acquir. Immune Defic. Syndr. 32, 9 (2003) [Medline].
7. J. Cohen, Shots in the Dark: The Wayward Search for an AIDS Vaccine (Norton, New York, 2001) [publisher's information].
8. R. I. Connor et al., J. Virol. 72, 1552 (1998) [Medline] [Full text].
Numbered Hypernotes (HN)
1. HIV vaccines. Search for a vaccine is a presentation on NOVA Online's Surviving AIDS Web site. AIDSinfo offers a resource page and overview of vaccines. The World Health Organization's HIV/AIDS Web site offers an introduction to HIV vaccines. NIAID makes available a May 2003 fact sheet titled "Challenges in designing HIV vaccines" and a August 2003 fact sheet titled "Clinical research on HIV vaccines," as well as the online brochures Understanding Vaccines and HIV Vaccines Explained (in PDF format). The NIAID Division of AIDS offers a resource page on HIV vaccines. IAVI provides an overview titled "Preventive AIDS vaccine approaches currently in human testing" and the IAVI Database of Preventive AIDS Vaccines in Human Trials. The Pipeline Project, a collaboration of the UCSF Center for HIV Information and the HIV Vaccine Trials Network, provides information about vaccines in development; links to Internet resources on vaccine development are included. HIVandHepatitis.com offers news reports about HIV vaccines. The Body, an AIDS and HIV information resource, provides links to articles about HIV vaccines. The AIDScience archive from Science Online makes available a March 2002 article by H. Köhler, S. Müller, and V. Veljkovic titled "No hope for an AIDS vaccine soon."
2. Phases of clinical trails. Definitions of the phases of clinical trials are provided by the CenterWatch glossary. IAVI provides an introduction to the phases of clinical trials. ClinicalTrials.gov provides an introduction to clinical trials. D. Stevens, Department of Pediatrics, University of South Dakota School of Medicine, provides lecture notes on clinical trials.
3. Canarypox vector ALVAC from Aventis Pasteur. Canarypox, vector, and ALVAC-HIV are defined in the HIV Vaccine Glossary. Aventis Pasteur provides an introduction to its R&D program. Aventis makes available a 8 July 2002 press release titled "Aventis Pasteur and AIDS vaccine research: An overview"; the fact sheets on ALVAC and Prime Boost are also available in PDF format. The IAVI Database of Preventive AIDS Vaccines has an entry for ALVAC vCP1521 (the vector to be used in the phase III trial in Thailand).
4. VaxGen's gp120 vaccine. The NIAID HIV Vaccine Glossary defines gp120. VaxGen provides information about its AIDSVAX HIV vaccine candidates and the associated clinical trials. Information about gp120 vaccines is provided by aidsmap.com.
5. Cellular and humoral immunity. Humoral immunity and cell-mediated immunity are defined by the AIDSinfo glossary. Understanding the Immune System is a presentation of the News Center of the National Cancer Institute. S. Baron's Medical Microbiology includes an immunology overview. Kimball's Biology Pages offers an introduction to cell-mediated immunity. J. Decker offers tutorials on humoral immunity and cell-mediated immunity for an immunology course. P. Bugl provides introductions to cell-mediated immunity and humoral immunity in lecture notes for a course on epidemics and AIDS. HIV InSite provides information on humoral and cellular immune responses in the presentation on the science of HIV vaccine development.
6. The HIV Vaccine Trials Network, formed in 1999 by the NIAID Division of AIDS, conducts all phases of clinical trials, from evaluating candidate vaccines for safety and the ability to stimulate immune responses to testing vaccine efficacy.
7. Cancellation of the U.S. phase III trial. NIAID issued a 25 February 2002 press release titled "NIAID phase III HIV vaccine trial to determine correlates of protection will not proceed." The January-February 2002 issue of the IVAI Report had an article by P. Kahn titled "NIH drops plans for phase III trial." The 1 March 2002 issue of Science had a News of the Week article by J. Cohen titled "Disappointing data scuttle plans for large-scale AIDS vaccine trial."
8. Previous trials. The IAVI Database of Preventive AIDS Vaccines provides information on ALVAC vCP1452 and ALVAC vCP205 trials, as well as information on AIDSVAX B/E and AIDSVAX B/B trials. Information about ALVAC trials is provided by aidsmap.com. VaxGen issued a 24 February 2003 press release titled "VaxGen announces initial results of its phase III AIDS vaccine trial" and a 12 November 2003 press release titled "VaxGen announces results of its phase III HIV vaccine trial in Thailand: Vaccine fails to meet endpoints." The 28 February 2003 issue of Science had a News of the Week article by J. Cohen titled "AIDS vaccine trial produces disappointment and confusion." The 7 March 2003 issue had a News of the Week article by J. Cohen titled "Vaccine results lose significance under scrutiny." The 4 April 2003 issue had a News of the Week article by J. Cohen titled "A setback and an advance on the AIDS vaccine front." BioMed Central makes available a 7 November 2003 daily news story (provided by The Scientist) by R. Walgate titled "AIDS answers and questions: Failed vaccine trial in Thailand teaches many lessons, says the UN's José Esparza."
9. CD8+ cytotoxic T lymphocyte. CD8+ T lymphocyte and cytotoxic T lymphocyte (CTL) are defined by the HIV Vaccine Glossary. Dalhousie University School of Medicine's Immunology Book Case provides introductions to cytotoxic T cells and cytotoxic T lymphocyte activity. Kimball's Biology Pages offers an introduction to cytotoxic T lymphocytes.
10. Neutralizing antibody is defined in the HIV vaccine glossary. IAVI issued a 9 July 2002 press release titled "IAVI launches Neutralizing Antibody Consortium to accelerate search for preventive AIDS vaccine."
11. CD4+ T helper cells. CD4+ T lymphocyte is defined by the HIV Vaccine glossary. CD4+ cells are defined in the AIDSinfo glossary. An entry for helper T cell is included in the Wikipedia online encyclopedia. Kimball's Biology Pages offers an introduction to CD4+ T cells and T helper cells.
12. The phase III trial in Thailand. UNAIDS provides a brief on Thailand's response to AIDS. The HIV/AIDS Surveillance Web site of the U.S. Census Bureau makes available in PDF format an HIV/AIDS profile of Thailand. The Thai Prime-Boost HIV Vaccine Phase III Trial Web site provides a FAQ and information about the researchers. The AIDS Vaccine Clearinghouse provides information about the Thailand trial. The IAVI Database of Preventive AIDS Vaccines provides information on the Thailand phase III trial. IVAI provides a 28 February 2002 news report titled "U.S. government announces plans for final stage human trial of ALVAC-AIDSVAX in Thailand." The October-December 2001 issue of the IAVI Report (a special issue on Thailand & AIDS Vaccines) had an article by P. Kahn titled "Thailand prepares for a new phase III trial" and an article titled "Thailand, AIDS and vaccines: An interview with Supachai Rerks Ngarm." The 21 November 2003 issue of Science had a News of the Week article by J. Cohen titled "AIDS vaccine still alive as booster after second failure in Thailand."
13. Dennis R. Burton is at the Scripps Research Institute. Ronald C. Desrosiers and Judy Lieberman are at Harvard Medical School. Robert W. Doms, James A. Hoxie, and Neal Nathanson are at the University of Pennsylvania. Mark B. Feinberg is at Emory University; Robert C. Gallo is at the Institute of Human Virology. Beatrice Hahn and Eric Hunter are at the University of Alabama at Birmingham. Bette Korber is at the Santa Fe Institute. Alan Landay is at the Rush Medical College. Michael M. Lederman is at Case Western Reserve University. Joseph M. McCune is at the Gladstone Institute for Virology and Immunology. John P. Moore is at the Weill Medical College of Cornell University. Louis Picker is at the Oregon Health and Science University. Douglas Richman is at the University of California, San Diego, and San Diego Veterans Affairs Healthcare System. Charles Rinaldo is at the University of Pittsburgh. Mario Stevenson is at the University of Massachusetts Medical School. David I. Watkins is at the University of Wisconsin. Steven M. Wolinsky is at Northwestern University. Jerome A. Zack is at the University of California, Los Angeles.
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