Abstract & Commentary

Should We Adopt a Pre-exposure Prophylaxis Approach for HIV Prevention?

By Dean L. Winslow, MD, FACP, FIDSA, Chief, Division of AIDS Medicine, Santa Clara Valley, Medical Center; Clinical Professor, Stanford University School of Medicine, is Associate Editor for Infectious Disease Alert.

Dr. Winslow is a speaker for Cubist Pharmaceuticals and GSK, and is a consultant for Siemens Diagnostic.

Synopsis: In this study, 2,499 HIV-seronegative men or transgender females who have sex with men were randomized to daily tenofovir/emtricitabine (TDF/FTC) vs. placebo. During a median period of follow-up of 1.2 years, TDF/FTC resulted in a 44% reduction in the incidence of HIV.

Source: Grant RM, et al. Pre-exposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med. 2010 Nov. 23 (epub ahead of print).

In this study, 2,499 hiv-seronegative men or transgender females who have sex with men (MSM) were randomized to daily TDF/FTC vs. placebo in a multicenter, controlled trial with clinical sites in North America, Latin America, Thailand, and Africa. In addition to being provided TDF/FTC (or placebo), all subjects received HIV testing, risk-reduction counseling, condoms, and management of sexually transmitted infections. The study subjects were followed for 3324 person-years (median 1.2 years) and were seen every 4 weeks. One hundred subjects became infected during follow-up (36 in the TDF/FTC group and 64 in the placebo group). A subgroup of patients had serum and PBMC's examined for antiretroviral levels.

Of the 2,499 subjects, 10 were found to be infected at study enrollment, and 100 became infected during follow-up (36 in the TDF/FTC group and 64 in the placebo group), indicating a 44% reduction in the incidence of HIV. Study drug was detected in 22/43 seronegative subjects and in 3/34 HIV-infected subjects. Excess nausea was reported in the TDF/FTC treated subjects. No TDF or FTC resistance was detected in either the TDF/FTC or placebo groups who became infected with HIV during the trial.

Commentary

Bob Grant and his team should be congratulated for completing this large international trial and conclusively demonstrating that TDF/FTC prevents many cases of HIV when given as pre-exposure prophylaxis. Several weeks ago when the news of this important study hit the lay press, a lot of enthusiasm was generated, and the press in San Francisco declared this a major breakthrough in HIV prevention. While poor adherence likely contributed to the relatively low efficacy of this intervention (based on non-human primate experiments, I would have predicted > 80% efficacy rather than observed 44% efficacy), the success of this approach will undoubtedly be significantly lower in the real world outside of the context of a clinical trial where the patients received regular monitoring and support.

I have some big issues with adopting this approach more widely for HIV prevention. These include the concern about selecting out NRTI-resistant variants of HIV in the community. While it is gratifying that this was not seen in the short term (median 1.2 years) duration of this trial, the widespread use of this non-fully suppressive regimen will surely drive resistance when many HIV-infected patients will likely get access to TDF/FTC and use it outside of a controlled clinical environment and in the absence of fully suppressive 3-drug HAART.

While I do not lose sleep over the potential renal and bone toxicity of TDF when treating patients with known HIV, I am concerned about exposing millions of HIV-uninfected people (mainly in the developing world) to ARV's for years.

The last concern is simply cost. TDF/FTC currently sells for approximately $40/tablet. Using some back-of-the-envelope calculations, the cost per patient during the 1.2 years of the study would be $16,800. The total drug supply cost for this 2500 person trial was $42 million. Therefore, the cost of preventing each of the 28 cases of HIV was $1.5 million. Is that really an effective use of limited resources? As someone who served as an Air Force physician on the front lines of many of the humanitarian crises our weary world has endured over the last 20 years, I do not think so. $42 million spent digging wells could provide enough safe water to prevent hundreds (if not thousands) of childhood deaths due to diarrheal disease. $42 million could buy permethrin-treated bed nets for just about every child in Africa and prevent thousands of deaths due to malaria. We could certainly provide routine childhood immunizations to millions of children (again preventing thousands of deaths) for that amount as well.