Skip to main content

It’s Time: The Case for PrEP as an Active Comparator in HIV Biomedical Prevention Trials

Abstract

In July 2012, based on evidence from two major trials, the United States Food and Drug Administration approved the use of combined oral tenofovir/emtricitabine as pre-exposure prophylaxis (PrEP) for people at high risk of HIV acquisition. PrEP effectiveness is marred by poor adherence, however, even in trial populations, thus it is not a magic bullet for HIV prevention. It is, however, the most effective biomedical HIV prevention intervention available for people at high risk of HIV, particularly those who have receptive sex and lack the power to negotiate condom use. Accordingly, there are compelling reasons to compare future experimental HIV prevention interventions against PrEP. The interests both of trial participants and of science are served by using PrEP as comparator: Not only would HIV incidence be reduced, but also the question of whether new interventions were superior to best proven interventions, in a given setting, would be answered comprehensively.

This is a preview of subscription content, access via your institution.

Notes

  1. 1.

    Tenofovir gel works at a biological level as a form of topical pre- and post-exposure prophylaxis, but as taking an oral tablet is distinct from inserting a vaginal gel, the gel form and the oral form are usually seen as separate strategies.

  2. 2.

    Tenofovir (TDF) and emtricitabine (also known as FTC) are antiretroviral drugs that have synergistic action. The drug combination is marketed under the brand name Truvada.

  3. 3.

    Of note, the Bangkok PrEP trial was ethically problematic as it did not supply participants with clean injecting equipment.

  4. 4.

    ARV treatment is defined as “early” when it is administered in people whose CD4 cell levels are above 350.

  5. 5.

    This term was coined in 2007 in the UNAIDS Ethical Considerations document to end the confusion caused my multiple meanings of “standard of care.”

  6. 6.

    It could be argued that given such an effective intervention, the time has come to stop testing new approaches and to fully fund the global roll-out of early treatment for all people with HIV. This approach does not satisfy the requirement for HIV-negative people at high risk to be able to protect themselves, however, and research is likely to continue until this need has been met.

  7. 7.

    While in-depth discussion of these issues is beyond the scope of this paper, conducting a trial in an area where participants are denied access to a proven safe and effective intervention for social or political reasons is both inappropriate and exploitative.

  8. 8.

    At the time of writing, the only demonstration sites launched were in the United States, with others planned in two or three cities in Brazil.

  9. 9.

    Thanks to an anonymous peer reviewer for this point.

References

  1. Abdool Karim, Q., S.S. Abdool Karim, J.A. Frohlich, et al. 2010. Effectiveness and safety of Tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women. Science 329(5996): 1168–1174.

  2. Anderson, P.L., D.V. Glidden, A. Liu, et al. 2012. Emtricitabine-tenofovir concentrations and pre-exposure prophylaxis efficacy in men who have sex with men. Science Translational Medicine 4(151): 151ra125.

    Article  PubMed Central  PubMed  Google Scholar 

  3. Angell, M. 1997. The ethics of clinical research in the third world. The New England Journal of Medicine 337(12): 847–849.

    Article  CAS  PubMed  Google Scholar 

  4. Auvert, B., D. Taljaard, E. Lagarde, J. Sobngwi-Tambekou, R. Sitta, and A. Puren. 2005. Randomized, controlled intervention trial of male circumcision for reduction of HIV infection risk: The ANRS 1265 trial. PLoS Med 2(11): e298. doi:10.1371/journal.pmed.0020298.

  5. Baeten, J.M., D. Donnell, P. Ndase, et al. 2012. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. The New England Journal of Medicine 367(5): 399–410.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Bailey, R.C., S. Moses, C.B. Parker, et al. 2007. Male circumcision for HIV prevention in young men in Kisumu, Kenya: A randomised controlled trial. The Lancet 369(9562): 643–656.

    Article  Google Scholar 

  7. Belsky, L., and H.S. Richardson. 2004. Medical researchers’ ancillary clinical care responsibilities. British Medical Journal 328(7454): 1494–1496.

    Article  PubMed Central  PubMed  Google Scholar 

  8. Choopanya, K., M. Martin, P. Suntharasamai, et al. 2013. Antiretroviral prophylaxis for HIV infection in injecting drug users in Bangkok, Thailand (the Bangkok Tenofovir Study): A randomised, double-blind, placebo-controlled phase 3 trial. The Lancet 381(9883): 2083–2090.

    Article  Google Scholar 

  9. Cohen, M.S., Y.Q. Chen, M. McCauley, et al. 2011. Prevention of HIV-1 infection with early antiretroviral therapy. The New England Journal of Medicine 365(6): 493–505.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Council for International Organizations of Medical Sciences [CIOMS]. 2002. International ethical guidelines for biomedical research involving human subjects. Geneva: CIOMS and WHO. http://www.cioms.ch/images/stories/CIOMS/guidelines/guidelines_nov_2002_blurb.htm. Accessed July 30, 2013.

  11. Fleming, T. 2013. Non-inferiority clinical trials: Some key consideration in PrEP and microbicide studies. Presentation at the meeting on the Future of PrEP and Microbicide Research: Trial Design and Regulatory Issues, January 7, in Washington, DC. http://www.hivforum.org/storage/hivforum/documents/FutureofPrEP/session_2_fleming.pdf. Accessed February 1, 2013.

  12. Follow-on African Consortium for Tenofovir Studies [FACTS]. No date. FACTS 001 study. http://www.facts-consortium.co.za/?page_id=83. Accessed July 30, 2013.

  13. Food and Drug Administration [FDA]. 2012. FDA approves first drug for reducing the risk of sexually acquired HIV infection: Evidence-based approach enhances existing prevention strategies. U.S. Food and Drug Administration, July 16. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm312210.htm. Accessed September 10, 2012.

  14. Forbes, A., and S. Mudaliar. 2009. Preventing prevention trial failures: A case study and lessons learned for future trials from the 2004 tenofovir trial in Cambodia. Washington, DC: Global Campaign for Microbicides. http://www.global-campaign.org/clientfiles/Cambodia.pdf.

  15. Grant, R.M., J.R. Lama, P.L. Anderson, et al. 2010. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. The New England Journal of Medicine 363(27): 2587–2599.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Gray, R.H., G. Kigozi, D. Serwadda, et al. 2007. Male circumcision for HIV prevention in men in Rakai, Uganda: A randomised trial. The Lancet 369(9562): 657–666.

    Article  Google Scholar 

  17. Haire, B.G. 2011. Because we can: Clashes of perspective over researcher obligation in the failed PrEP trials. Developing World Bioethics 11(2): 63–74.

    Article  PubMed  Google Scholar 

  18. Haire, B., J. Kaldor, and C.F.C. Jordens. 2012. How good is “good enough”? The case for varying standards of evidence according to need for new interventions in HIV prevention. The American Journal of Bioethics 12(6): 21–30.

    Article  PubMed  Google Scholar 

  19. HIV Prevention Trials Network [HPTN]. No date. HPTN 071: The PopART study. http://www.hptn.org/web%20documents/IndexDocs/071StudyAnnouncement14Sep11.pdf. Accessed December 18, 201.

  20. Holt M., Murphy D.A., Callander D., et al. 2011. Willingness to use HIV pre-exposure prophylaxis and the likelihood of decreased condom use are both associated with unprotected anal intercourse and the perceived likelihood of becoming HIV positive among Australian gay and bisexual men. Sexually Transmitted Infections 88(4): 258–263.

  21. IRIN Humanitarian News and Analysis. 2013. Thousands still missing HIV treatment following CAR coup. IRIN Humanitarian News and Analysis, June 11. http://www.irinnews.org/report/98208/thousands-still-missing-hiv-treatment-following-car-coup. Accessed July 30, 2013.

  22. Knox, R., and M. Doucleff. 2012. Clinton reveals blueprint for an “AIDS-free generation.” Shots: Health News From National Public Radio, November 29. http://www.npr.org/blogs/health/2012/11/29/166154269/clinton-reveals-blueprint-for-an-aids-free-generation.

  23. Krebs, J. 2008. The importance of public health ethics. Bulletin of the World Health Organization 86(8): 577–656. http://www.who.int/bulletin/volumes/86/8/08-052431/en/.

  24. Lurie, P., and S. M. Wolfe. 1997. Unethical trials of interventions to reduce perinatal transmission of the human immunodeficiency virus in developing countries. The New England Journal of Medicine 337(12): 853–856.

    Article  CAS  PubMed  Google Scholar 

  25. Macklin, R. 2001. After Helsinki: Unresolved issues in international research. Kennedy Institute of Ethics Journal 11(1): 17–36.

    Article  CAS  PubMed  Google Scholar 

  26. Macklin, R. 2006. Changing the presumption: Providing ART to vaccine research participants. The American Journal of Bioethics 6(1): 1–5.

    Article  Google Scholar 

  27. Macklin, R. 2008. Standard of care: An evolution in ethical thinking. The Lancet 372(9635): 284–285.

    Article  Google Scholar 

  28. May, M., M. Gompels, and C. Sabin. 2012. Life expectancy of HIV-1-positive individuals approaches normal, conditional on response to antiretroviral therapy: UK collaborative HIV cohort study. Abstract from the Eleventh International Congress on Drug Therapy in HIV Infection, November 11–15, in Glasgow, Scotland.

  29. Mayer, K. 2013. Future of PrEP and microbicide research: Setting the stage. Presentation at the meeting on the Future of PrEP and Microbicide Research: Trial Design and Regulatory Issues, January 7, in Washington, DC. http://www.hivforum.org/storage/hivforum/documents/FutureofPrEP/session_1_mayer.pdf. Accessed February 2, 2013.

  30. McGrory, E., A. Irvin, and L. Heise. 2009. Research Rashomon: Lessons from the Cameroon pre-exposure prophylaxis trial site. Washington, DC: Global Campaign for Microbicides. www.globalcampaign.org/clientfiles/Cameroon.pdf. Accessed January 8, 2011.

  31. Microbicide Trials Network [MTN]. 2013. Understanding the results of VOICE. http://www.mtnstopshiv.org/news/studies/mtn003. Accessed March 12, 2013.

  32. Miller, P.B., and C. Weijer. 2006. Fiduciary obligation in clinical research. The Journal of Law, Medicine and Ethics 34(2): 424–440.

    Article  PubMed  Google Scholar 

  33. PopART. 2013 About PopART. http://www1.imperial.ac.uk/departmentofmedicine/divisions/infectiousdiseases/infectious_diseases/hiv_trials/hiv_prevention_technologies/popart/about/. Accessed July 30, 2013.

  34. Rennie, S., and J. Sugarman. 2010. Developing ethics guidance for HIV prevention research: The HIV Prevention Trials Network approach. Journal of Medical Ethics 36(12): 810–815.

    Article  PubMed Central  PubMed  Google Scholar 

  35. Rennie S., J. Sugarman, and the HPTN Ethics Working Group. 2009. HIV Prevention Trials Network ethics guidance for research. http://www.hptn.org/web%20documents/EWG/HPTNEthicsGuidanceV10Jun2009.pdf. Accessed July 31, 2012.

  36. Rerks-Ngarm, S., P. Pitisuttithum, S. Nitayaphan, et al. 2009. Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand. The New England Journal of Medicine 361(23): 2209–2220.

    Article  CAS  PubMed  Google Scholar 

  37. Richardson, H.S. 2007. Gradations of researchers’ obligation to provide ancillary care for HIV/AIDS in developing countries. American Journal of Public Health 97(11): 1956–1961.

    Article  PubMed Central  PubMed  Google Scholar 

  38. Thigpen, M.C., P.M. Kebaabetswe, L.A. Paxton, et al. 2012. Antiretroviral preexposure prophylaxis for heterosexual HIV transmission in Botswana. The New England Journal of Medicine 367(5): 423–434.

    Article  CAS  PubMed  Google Scholar 

  39. Ukpong, M., and K. Peterson, eds. 2009. Oral tenofovir controversy II: Voices from the field. Falomo, Nigeria: New HIV Vaccines and Microbicides Society (NHVMAS)

    Google Scholar 

  40. UNAIDS. 2011. Good participatory practice: Guidelines for biomedical HIV prevention trials 2011, 2nd ed. Geneva: Joint United Nations Programme on HIV/AIDS [UNAIDS]. http://www.unaids.org/en/media/unaids/contentassets/documents/unaidspublication/2011/JC1853_GPP_Guidelines_2011_en.pdf. Accessed February 2, 2013.

  41. UNAIDS. 2012. UNAIDS report on the global AIDS epidemic 2012. Geneva: Joint United Nations Programme on HIV/AIDS [UNAIDS]. http://www.unaids.org/en/media/unaids/contentassets/documents/epidemiology/2012/gr2012/20121120_UNAIDS_Global_Report_2012_with_annexes_en.pdf. Accessed January 30, 2013.

  42. UNAIDS/WHO. 2012. Ethical considerations in biomedical HIV prevention trials. UNAIDS/WHO guidance document. Geneva: Joint United Nations Programme on HIV⁄AIDS [UNAIDS] and the World Health Organization [WHO]. http://www.unaids.org/en/media/unaids/contentassets/documents/unaidspublication/2012/jc1399_ethical_considerations_en.pdf. Accessed January 14, 2013.

  43. Vallely, A., C. Shagi, S. Kasindi, et al. 2007. The benefits of participatory methodologies to develop effective community dialogue in the context of a microbicide trial feasibility study in Mwanza, Tanzania. BMC Public Health 7: 133.

    Article  PubMed Central  PubMed  Google Scholar 

  44. Van Damme, L., A. Corneli, K. Ahmed, et al. 2012. Preexposure prophylaxis for HIV infection among African women. The New England Journal of Medicine 367(5): 411–422.

    Article  PubMed Central  PubMed  Google Scholar 

  45. van der Graaf, R., and J.J.M. van Delden. 2009. What is the best standard for the standard of care in clinical research? The American Journal of Bioethics 9(3): 35–43.

    Article  PubMed  Google Scholar 

  46. Varmus, H., and D. Satcher. 1997. Ethical complexities of conducting research in developing countries. The New England Journal of Medicine 337(14): 1003–1005.

    Article  CAS  PubMed  Google Scholar 

  47. Wheelock, A., A.B.. Eisingerich, J. Ananworanich, et al. 2013. Are Thai MSM willing to take PrEP for HIV prevention? An analysis of attitudes, preferences and acceptance. PLoS ONE 8(1): e54288. doi:10.1371/journal.pone.0054288.

  48. World Health Organization [WHO]. 2013. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: Recommendations for a public health approach. Geneva: WHO. http://www.who.int/hiv/pub/guidelines/arv2013/download/en/index.html. Accessed July 30, 2013.

  49. World Medical Association [WMA]. 1948. WMA Declaration of Geneva. http://www.wma.net/en/30publications/10policies/g1/. Accessed February 6, 2013

  50. World Medical Association [WMA]. 2013. World Medical Association Declaration of Helsinki: Ethical principles for medical research involving human subjects. http://www.wma.net/en/30publications/10policies/b3/17c.pdf. Accessed February 6, 2013.

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Bridget Haire.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Haire, B. It’s Time: The Case for PrEP as an Active Comparator in HIV Biomedical Prevention Trials. Bioethical Inquiry 12, 239–249 (2015). https://doi.org/10.1007/s11673-014-9565-9

Download citation

Keywords

  • AIDS
  • Biomedical research
  • Human subjects research
  • Regulatory issues
  • Research ethics
  • International/global health