Biomedical HIV Prevention, Including Microbicides, Vaccines, Circumcision and PrEP

In this summary, Ronald Gray, M.D., discusses his plenary update on "Biomedical Prevention, Including Microbicides, Vaccines, Circumcision and PrEP." To view his full presentation, click here. To review his slides, click here.

Ronald Gray: I've been asked to discuss 20 years experience with clinical trials via medical prevention of HIV infection¹ and it's been a very sobering experience.

There were 29 completed [biomedical prevention] trials, only four of which showed any efficacy for reduction of HIV and three of those were trials on male circumcision.

One of the things that has been most disappointing to me is that the trials of STD [sexually transmitted disease] control for HIV prevention have been in large part negative, because I sincerely believe that STIs [sexually transmitted infections] or STDs were fueling the epidemic in sub-Saharan Africa, but our efforts to control these infections have not been successful.^2-8

Then we reviewed 11 trials on microbicides, none of which showed efficacy for HIV prevention in an intention-to-treat analysis. One microbicide called PRO 2000 did suggest the possibility of about a 30% reduction in HIV.⁹

HIV vaccine trials, as you well know, have been negative. And there is evidence of one vaccine (the MRK adeno 5 vaccine) that may have increased risk, particularly in men who had prior immunity to the adeno 5 vector, and who were uncircumcised.

The circumcision story is a little better. There are three trials that have shown that circumcision protects men from HIV, and more recently shown that it protects men from herpes and from human papillomavirus [HPV].

Last week we just published a trial in which we circumcised HIV-infected men to determine whether we could reduce transmission to their initially uninfected female partners.¹⁰ Sadly, we did not see protection of the women in the short term. But there are prior studies -- some that we've conducted, and one that we presented at this meeting -- that suggest that men who are circumcised in childhood may have a reduced likelihood of transmitting to their wives.

Craig McClure: Ron, question for you. During your talk, you postulated on why it may be that there are so many negative results recently from a number of biomedical prevention trials, STIs and others. One factor you brought up was the fact that possibly the incremental impact of that intervention may have been so small that the trials weren't powered to pick it up. So given the number of interventions there are now for HIV prevention -- including antiretroviral therapy and the potential next year and the year after if we have positive results of the pre-exposure prophylaxis [PrEP] trials with antiretroviral therapy for HIV-negative people -- what is the future for biomedical prevention trials? And how can some of these challenges you identified be addressed so that we can get the answers that we all so desperately want from these trials in the future?

Ronald Gray: Thank you. That's an impossible question. [Laughs.] I think there are several things. Obviously, we hope that pre-exposure prophylaxis trials are successful. But I think the lesson we have to learn from the trials that have been completed is that we need to do much more fundamental research on immunologic mechanisms to further development of vaccines and potentially of microbicides. I would argue that some of that focus should shift from the effort to develop systemic immunity to working with much more causal barriers, causal immunity, so we can prevent the virus from entering the body. I do believe that that area of research -- though in its early stages -- could ultimately provide new innovative prevention methods.

This transcript has been lightly edited for clarity.

References

1. Gray R. Biomedical prevention, including microbicides, vaccines, circumcision and PrEP. In: Program and abstracts of the 5th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 19-22, 2009; Cape Town, South Africa. Abstract TUPL101.
   View slides: Download PowerPoint
2. Wawer MJ, Sewankambo NK, Serwadda D, et al, and The Rakai Project Study Group. Control of sexually transmitted diseases for AIDS prevention in Uganda: a randomised community trial. Lancet. February 13, 1999;353(9152):525-535.
3. Gray RH, Wabwire-Mangen F, Kigozi G, et al. Randomized trial of presumptive sexually transmitted disease therapy during pregnancy in Rakai, Uganda. Am J Obstet Gynecol. November 2001;185(5):1209-1217.
4. Kamali A, Quigley M, Nakiyingi J, et al. Syndromic management of sexually-transmitted infections and behaviour change interventions on transmission of HIV-1 in rural Uganda: a community randomised trial. Lancet. February 22, 2003;361(9358):645-652.
5. Gregson S, Adamson S, Papaya S, et al. Impact and process evaluation of integrated community and clinic-based HIV-1 control: a cluster-randomised trial in eastern Zimbabwe. PLoS Med. March 27, 2007;4(3):e102.
6. Kaul R, Kimani J, Nagelkerke NJ, et al, for the Kibera HIV Study Group. Monthly antibiotic chemoprophylaxis and incidence of sexually transmitted infections and HIV-1 infection in Kenyan sex workers. JAMA. June 2, 2004;291(21):2555-2562.
7. Watson-Jones D, Weiss HA, Rusizoka M, et al. Effect of herpes simplex suppression on incidence of HIV among women in Tanzania. N Engl J Med. April 10, 2008;358(15):1560-1571.
8. Celum C, Wald A, Hughes J, et al, and the HPTN 039 Protocol Team. Effect of aciclovir on HIV-1 acquisition in herpes simplex virus 2 seropositive women and men who have sex with men: a randomised, double-blind, placebo-controlled trial. Lancet. June 21, 2008;371(9630):2109-2119.
9. Karim SA, Coletti A, Richardson B, et al. Safety and effectiveness of vaginal microbicides BufferGel and 0.5% PRO 2000/5 gel for the prevention of HIV infection in women: results of the HPTN 035 trial. In: Program and abstracts of the 16th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2009; Montréal, Canada. Abstract 48LB.
10. Wawer MJ, Makumbi F, Kigozi G, et al. Circumcision in HIV-infected men and its effect on HIV transmission to female partners in Rakai, Uganda: a randomised controlled trial. Lancet. July 18, 2009;374(9685):229-237.