HIV Prophylaxis Fails to Prevent Infection Among Adults

What if you could provide HIV prophylaxis for people at high risk of contracting the disease just as we now provide antibiotic prophylaxis for women at high risk of urinary track infections and kidney infections? Well, you can. It’s called PreExposure Prophylaxis, or PrEP, and it is becoming a viable option in areas of the world where the epidemic is particularly rampant. By starting patients on antiretroviral therapy (ART) before infection, researchers theorize, the drugs may inhibit HIV replication immediately after exposure to the virus, preventing permanent infection just as it prevents transmission from infected mothers to their newborns.¹

Two large government-sponsored studies, the IPrEx (Chemoprophylaxis for HIV Prevention in Men) trial and the TDF2 study, found that PrEP could reduce the risk of transmission among men who have sex with men (MSM) as well as heterosexual men and women. In addition, the Partners PrEP study, conducted among the HIV-negative partners of infected African individuals who received daily oral tenofovir or emtricitabine/tenofovir, showed significant benefits: a 62% and 73% reduction in HIV transmission, respectively.²

The IPrEx trial, sponsored by the US National Institutes of Health, found that daily oral use of tenofovir plus emtrictabine (TDF/FTC [Truvada]) reduced the risk of HIV transmission 44% in the intervention group compared to the placebo group (95% confidence interval [CI], 16-63; P=0.005). In addition, in those on the study drug who were infected, the drug was detected in just 9% of participants, suggesting that nonadherence to the protocol played a significant role in their ultimate infection. The only significant side effect was nausea in the first 4 weeks of the study.³  Researchers are now following participants as part of an open-label extension of the trial.

Another study, called TDF2, tested the same single-pill combination in a different population. In Botswana, 1,219 heterosexual men and women (ages 18-39) who were at high risk of HIV infection were randomized to take Truvada or placebo. Those in the intervention group were 62.6% less likely to become infected, compared to the placebo group (P=0.013). The efficacy was even higher in those who were most adherent to the drug.⁴

However, the trial was not powered to break out the benefits by gender. Another trial designed to do that, the FEM-PrEP trial, compared infection rates among 2,120 women from South Africa, Kenya, and Tanzania who received either placebo or a once-daily oral combination of emtricitabine andtenofovir disoproxil fumarate combination (FTC/DFT).

Interim results, released in April 2011, found it was highly unlikely that the intervention would have any significant benefit, and the trial was halted early. Final analysis of the data, released at the 19th Annual Conference on Retroviruses and Opportunistic Infections (held in Seattle in early March) ,confirmed those results. In the end, 33 infections occurred in the FTC/TDF group (incidence rate [IR], 4.7/100 person-years) and 35 in the placebo group (IR, 5.0/100 person-years), with an estimated hazard ratio (HR) for infection of 0.94 (95% CI, 0.59 to 1.52, P=0.81).

So why was this trial unsuccessful when three previous trials showed positive outcomes? Blame adherence.

In the FEM-PrEP trial, researchers found detectable drug in less than half of the infected and uninfected cases at the time of infection. One possible reason, the lead researcher said during a press conference, could be the participants’ low perceived risk of infection.

These prophylaxis trials continue in other populations, including injection drug users, adolescents, and pregnant or breast-feeding women.⁵  A recent review article on the topic noted that, despite the complexities of such approaches, “the challenge is an exciting one in the field of prevention, an area in which practitioners often contend with a sense of futility or frustration, given the many types of preventive programs that have had relatively little success in the past.” Now, noted the author, there are “evidence-based tools with which to work.”⁵

References:

1 National Institute of Allergy and Infectious Diseases. Questions and Answers: The iPrEx Study: Pre-Exposure Prophylaxis as HIV Prevention Among Men who Have Sex with Men. Available at: http://www.niaid.nih.gov/news/QA/Pages/iPrExQA.aspx. Accessed March 19, 2012.2 Baeten J. Antiretroviral pre-exposure prophylaxis for HIV-1 prevention amongheterosexual African men and women: the Partners PrEP Study. [Abstract MOAX0106.] 6th IAS Conference on HIV Pathogenesis, Treatment and Prevention.July 17-20, 2011; Rome, Italy.3 Grant RM, Lama Jr, Anderson PL, et al. Pre-exposure Chemoprophylaxis for HIV Prevention in Men Who Have Sex with Men. N Engl J Med. 2010;363(27):2587-99.4 Centers for Disease Control and Prevention. TDF2 Study of Pre-Exposure Prophylaxis (PrEP) Among heterosexual Men and Women in Botswana: Key Facts. Available at: http://www.cdc.gov%2Fnchhstp%2Fnewsroom%2Fdocs%2FPrEP-Heterosexuals-Factsheet.doc&ei=GdhnT4veJMnx0gHQp8T2CA&usg=AFQjCNGd8VAmteTu4pbKvJMCSRxsl9uc3w&cad=rja. Accessed March 19, 2012.5 Cellum CL. HIV Preexposure Prophylaxis: New Data nd Potential Use. Top Antivir Med. 2011;19(5):181-185.