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HIV Preexposure Prophylaxis Therapy Trials:
Promote HIV Chemoprophylaxis Research, Don't Prevent It
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Science, Vol 309, Issue 5744, 2170-2171 , 30 September 2005
Policy Forum
..... a balance must be struck between the necessity to conduct trials to very high standards and the need to find ways to prevent the spread of HIV infection....
authors: Robert M. Grant,1,2* Susan Buchbinder,2,3 Willard Cates Jr.,4 Edith Clarke,5 Thomas Coates,6 Myron S. Cohen,7 Martin Delaney,8 Guiselly Flores,9 Pedro Goicochea,10 Gregg Gonsalves,11 Mark Harrington,12 Javier R. Lama,10 Kathleen M. MacQueen,4 John P. Moore,13 Leigh Peterson,4 Jorge Sanchez,10 Melanie Thompson,14 Mark A. Wainberg15
A drawing depicting community discussions of PrEP research. This artwork is being considered for use in information booklets at the Malawi PrEP site.
HIV infects more than 40 million people worldwide, and there are 14,000 new infections per day (1). No preventive vaccine is yet in sight (2). Even as available and proven prevention interventions are used, the HIV pandemic will not be stopped solely by talking to those at risk (3). Chemoprophylaxis with antiretroviral agents is a promising new approach (4). Clinical trials of daily oral antiretroviral dosing as preexposure prophylaxis (PrEP) have been initiated in Africa, Asia, and the United States and are planned in Latin America. Unfortunately, these trials have become controversial.
The first PrEP trials were set up to determine whether administration of tenofovir disoproxl fumarate (TDF) might safely protect high-risk, uninfected individuals from HIV infection. TDF has a long intracellular half-life, which allows once-daily dosing and the possibility of protection even if some doses are missed (5). The lack of drug interactions with hormonal contraceptives, tuberculosis therapy, or opiates makes TDF easier to use in those at highest risk. TDF-resistant strains are not generated easily.
TDF has an excellent safety record, with minimal effects on mitochondrial DNA polymerases that underlie some of the long-term toxicity observed with other antiretroviral drugs (6). The safety profile of TDF has been established in HIV-infected populations (7), and TDF was well tolerated in small-scale studies of uninfected persons (8). To confirm safety in diverse populations and to protect individual participants, monitoring of biomedical parameters is planned in all PrEP trials. The trials also involve frequent testing for HIV infection to allow the study drug to be stopped before there is a substantial chance of drug resistance occurring (9). Safety is of paramount importance for PrEP, because tolerability standards must be extremely high for any drug that is administered to uninfected individuals.
TDF can partially prevent infection of macaques by simian immunodeficiency virus (SIV) when administered at and after viral challenge (10, 11, 12). This effect may be overcome by repeated exposures to virus (13). Given the limitations of animal models, only clinical trials can determine the safety and efficacy of PrEP for humans.
Concerns about PrEP trials first came to international attention at the 2004 International AIDS Conference in Bangkok, when activists destroyed an exhibition booth of the drug developer that was donating drug and placebo for the trials (14). Shortly afterward, the Cambodian prime minister spoke against PrEP trials, and preparations for a trial in Cambodia were suspended (15). In February of 2005, the Cameroon government suspended administration of a study drug after a PrEP trial had full enrollment in that country. Reporting of these events and the underlying issues has been inconsistent and sometimes inaccurate, which contributed further to the controversy (16).
It is not the idea of PrEP itself, but how the research should be carried out, that is most controversial. How can participants be assured provision of the best preventive practices in a way that allows detection of additional protective effects by PrEP? Which populations are most appropriate for trials? How should community organizations be involved? How can treatment be provided during and after the trial, including treatment for HIV-1 infections that may occur? How should research populations be assured access to PrEP if it is shown to be useful? The importance of these issues was highlighted at a recent meeting organized by the International AIDS Society, which brought together sponsors, investigators, and community leaders from North and South to discuss solutions (17). There was a clear commitment to candid dialog that addresses these issues.
All participants receive standard prevention measures and are counseled that they should not feel protected by the "pill." The relevant research question is whether addition of daily oral TDF provides protection in addition to what can be achieved by known prevention strategies, including counseling, condoms (male and female), clean needles (18), and management of sexually transmitted diseases. Provision of these prevention measures is expected to decrease risk behavior during the trial (19) but has never eliminated it completely. The trials are designed to recruit large numbers of participants so that any additional protective benefit of PrEP can be discerned.
Investigators use several procedures to assure adequate counseling and to detect and remedy false optimism. Whether such "pill optimism" can be completely eliminated with counseling is being evaluated in PrEP trials, most directly in San Francisco and Atlanta. The risks of overoptimism are especially important if efficacy is modest or is promoted immodestly in communities. Alternatively, efficacy of PrEP may be high, which could empower a vision for an HIV/AIDS-free life and reinforce healthy behaviors. The challenges are not unique to PrEP and are inherent to HIV treatment programs and vaccine development.
Many prospective participants in Africa, Asia, and Latin America are especially vulnerable to HIV and a wide range of other harms, because they reside in some of the poorest parts of the planet, because they are women, or because their lack of legal status can lead to discrimination, extortion, summary judgment, or even execution. Community and governmental organizations often struggle with very limited resources and with international political forces beyond their control. Yet vulnerable populations are also those in most need of safe and effective ways to protect themselves from HIV infection, providing the ethical basis for studies in such groups.
Research in vulnerable populations is essential to evaluate the safety and efficacy of the intervention in those populations. It cannot always be assumed that the outcome will be the same in different groups; efficacy may differ depending on the route of viral exposure owing to differences in transmission efficiency, drug penetration into tissues, or the types of cells that are first exposed to virus. Body size differs widely and directly affects drug levels that may impinge on efficacy and side effects. Other variables may be gender, genetics, adherence, gray and black markets for drugs, access to safe storage, and social circumstances. Performing prevention research only in Paris, San Francisco, or New York would be a tragic mistake that would perpetuate the situation of antiretroviral therapy, which has been optimized for the richest 2% of those infected.
Involvement of community members and leaders is a proven way to protect vulnerable persons who participate in research. Community advisory boards, community consultations, and independent, local, ethical review boards are well-established mechanisms for fostering community input into research design and implementation. They help to assure that studies provide benefit to study populations, while minimizing risks to individuals, and that there are procedures to obtain and maintain genuine informed consent. Community advisory boards and ethical review boards also address issues that emerge during the trial, including unexpected or serious adverse events, participant complaints, public misperceptions and rumors, and media communications. Access to ombudsmen for participants is warranted and is already provided by some ethical review boards. Local community advisers and ethical review boards should be involved in deliberations early in the development of research projects before sponsors' final approval is sought.
PrEP research was first proposed in 2001, before the advent of a global response for providing antiretroviral therapy (4). Some treatment advocates were angry that participants found to be HIV-infected before or during the trials might not have access to therapy and that antiretroviral drugs might be diverted from life-saving treatment programs. Since 2001, several agencies have been funding antiretroviral therapy on a massive scale. Clinics have opened, or are under development, at all PrEP trial sites, thereby providing access to antiretroviral therapy in these communities.
Community expectations for access to treatment should prompt good-will efforts but should not create ethical obligations that would block prevention research in locations where treatment is not yet available. The basis for collaboration between proponents of treatment and proponents of prevention research is clear: Successful prevention decreases the burden on treatment programs while sparing lives.
Research sponsors will need to ensure that medical care to treat adverse events related to the prevention study can be provided in poor countries. Financial mechanisms may have to be created. Comprehensive medical insurance that pays for treatment regardless of whether the injury was related to the study would increase total research costs manyfold and would be unfair to those not participating in research. Product liability insurance that covers injuries directly related to the study agent requires a process for judging the cause of the injury, which can involve legal systems that may not be accessible to study participants. A common approach of relying on academic medical centers and clinics to provide services to research participants requires that these centers be supported. Local solutions will frequently involve governments.
Concerns have been raised about whether PrEP will become available in poor countries (17). Access requires the support of international agencies such as the Global Fund to Fight AIDS, Tuberculosis, and Malaria, which plans to evaluate results from current research. PrEP trials will obtain information about efficacy, safety, drug resistance, risk behavior, and immunological effects that bear directly on costs and benefits. High-quality research is needed as a platform for raising funds for access to PrEP, if it is proven to be useful.
Access also depends on drug prices. Gilead (the company that developed TDF) has established a global access program to allow it to become available at cost in 95 countries (20). Gilead has recently declared its intention to establish a nonexclusive licensing agreement with a drug manufacturer and distributor in South Africa (21). The decision not to seek intellectual property protection in Africa and parts of Asia makes it likelier that TDF will be widely available where it is most needed.
HIV PrEP research, as with all aspects of the fight against HIV/AIDS, is built on partnerships between sponsors, investigators, communities, and governments. Cooperation among such diverse interests is never easy, and coalitions are easily fractured by acts of disrespect, misinformation, or miscommunication. Such acts occurred too frequently in the early days of PrEP research, and hard lessons have been learned on all sides. While good-faith efforts are made to improve the conduct of trials, a balance must be struck between the necessity to conduct trials to very high standards and the need to find ways to prevent the spread of HIV infection.
References and Notes
1. Joint United Nations Programme on HIV/AIDS (UNAIDS), "Report on the global AIDS epidemic" (UNAIDS, 2004).
2. R. Horton, New York Rev. Books 51 (14), 7 (2004).
3. B. Koblin, M. Chesney, T. Coates, Lancet 364, 41 (2004).
4. M. Youle, M. Wainberg, AIDS 17, 937 (2003).
5. T. Hawkins, paper presented at the XV International AIDS Conference, Bangkok, Thailand, 11 to 16 July 2004.
6. G. Birkus, M. J. Hitchcock, T. Cihlar, Antimicrob. Agents Chemother. 46, 716 (2002).
7. J. E. Gallant et al., JAMA 292, 191 (2004).
8. K. Mayer et al., paper presented at the 2004 International AIDS Conference, Bangkok, Thailand, 11 to 16 July 2004.
9. P. Barditch-Crovo et al., Antimicrob. Agents Chemother. 45, 2733 (2001).
10. C.-C. Tsai et al., Science 270, 1197 (1995).
11. K. K. A. Van Rompay et al., J. Infect. Dis. 184, 429 (2001).
12. K. K. A. Van Rompay et al., J. Virol. 74, 1767 (2000).
13. S. Subbarao et al., paper presented at the 12th Conference on Retroviruses and Opportunistic Infections, Boston, MA, 22 to 25 February 2005.
14. J. A. Singh, E. J. Mills, PLoS Med 2, e234 (2005).
15. K. Page-Shafer et al., Lancet 10.1016/S0140-6736(05)67146-2 (2005).
16. E. J. Mills et al., BMC Int. Health Hum. Rights 5, 6 (24 August 2005).
17. Y. Halima, C Collins, International AIDS Society stakeholder consultation to address issues related to tenofovir prophylactic research, Seattle, WA, 19 to 20 May 2005; meeting summary
(www.global-campaign.org/clientfiles/IAS%20TDF%20FINAL.doc).
18. M. Ruiz et al., No Time to Lose: Getting More from HIV Prevention
(Institute of Medicine, National Academy Press, Washington, DC, 2001).
19. B. N. Bartholow et al., J. Acquir. Immune Defic. Syndr. 39, 90 (2005).
20. Gilead Sciences, press release (www.gilead.com/wt/sec/pr_686106).
21. Gilead Sciences, press release (www.gilead.com/wt/sec/pr_700521).
22. The authors thank their colleagues, participants, government and community leaders for informative, interesting, and courageous discussions. R.M.G., S.B., E.C., J.S., J.R.L., P.G., W.C., L.P., K.M.M., M.S.C., and M.T. are investigators involved in PrEP trials. M.A.W. and M.T. have received research grants from Gilead Sciences, but none related to PrEP.
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