Many Trials Indicate Benefit of HIV Preexposure Prophylaxis

Daniel M. Keller, PhD

October 17, 2011

October 17, 2011 (Belgrade, Serbia) — Several trials of oral or topical antiretroviral compounds as preexposure prophylaxis (PrEP) to prevent the transmission of human immunodeficiency virus (HIV) through sexual intercourse have produced proof of concept.

Charles Lacey, MBBS, MD, professor of genitourinary medicine at the Hull York Medical School at the University of York, United Kingdom, reviewed the latest results in the biomedical prevention research field in a noncommercial satellite session here at the 13th European AIDS Conference of the European AIDS Clinical Society.

Effect sizes have ranged from 31% to 96% in preventing HIV transmission, with 1 outlying trial showing no effect. Medical male circumcision in Africa appears to be about 54% effective (95% confidence interval [CI], 38 to 66).

The HIV Prevention Trials Network (HPTN) 052 study enrolled healthy, stable, sexually active serodiscordant couples (n = 1763 couples) in Africa, Asia, India, and the United States, in which the HIV-positive partner had a CD4 count of 350 to 550 cells/mm3. The HIV-positive partners were randomly assigned to immediate antiretroviral therapy or to delayed therapy, which was initiated only after their CD4 count dropped to 250 cells/mm3 or below. The trial rationale is referred to as "treatment as prevention."

"All together, there were 39 transmission events; only 4 were in the immediate treatment arm and 35 were in the delayed arm, giving an overall 90% reduction in transmission," Dr. Lacey explained (P < .0001). Of the 39 events, 28 were virologically linked to the HIV-positive partner's strain (11 were not linked; they were from a source outside the couple or from an undetermined source). Of these 28 events, only 1 was in the immediate group; 27 were in the delayed group (96% reduction; P < .001). Sixty-four percent of the transmissions were from infected participants with CD4 counts higher than 350 cells/mm3.

The 3-group Partners PrEP study, which looked at serodiscordant couples in Africa (n = 4758), tried to protect the HIV-negative partner directly with tenofovir, emtricitabine/tenofovir (Truvada, Gilead), or placebo, all given once daily. All couples received comprehensive HIV prevention services and were followed for 36 months.

"The protection efficacy is 62% for tenofovir and 73% for [emtricitabine/tenofovir], and they are both significant," Dr. Lacey reported. The HIV incidence was 0.74/100 person-years and 0.53/100 person-years, respectively, compared with 1.92/100 person-years with placebo (P = .0003 and P < .0001, respectively, vs placebo). The 2 active treatment groups were statistically similar (P = .18).

Emtricitabine/tenofovir might have been slightly more effective than tenofovir for men, but there was no clear sex difference between the 2 regimens, and the study was not powered to show one.

The TDF2 study compared daily oral emtricitabine/tenofovir (n = 601; 395 completed study) with placebo (n = 599; 414 completed study) for the prevention of HIV infection in higher-risk heterosexually active young adults not in stable partnerships in Botswana.

"In the primary analysis of the study, there is an overall protective efficacy of about 63%, which was significant," Dr. Lacey reported (95% CI, 21.5% to 83.4%; P = .0133). An analysis by sex showed a protective effect of the intervention for men (P = .026) but not for women (P = .107), but again, the study was not powered to show such an effect.

FEMPrEP was a phase 3 PrEP trial comparing once-daily emtricitabine/tenofovir with placebo in high-risk, HIV-negative heterosexual women for 1 year in eastern and southern Africa. Of the 3752 potential participants screened, 21% were HIV-positive, indicating that this was a high-risk population. The trial enrolled 1951 women (mean age, 24 years), engaging in 3.7 sex acts/week, and reporting 95% adherence to the regimens. There was 95% retention of participants at 1 year.

Surprisingly, there were 28 seroconversions in each group (incidence of 5.1/100 person-years), causing the data monitoring committee to end the trial in April 2011 because it would be unlikely to be able to show a benefit of the active therapy if carried to completion. A full analysis of the results will appear late this year or early next year.

Researchers expected emtricitabine/tenofovir to be effective in FEMPrEP because the results of the Chemoprophylaxis for HIV Prevention in Men (iPrEX) study of high-risk men who have sex with men, announced late last year, showed a 44% reduction in the incidence of HIV with the daily oral combination, with blood levels of the drug strongly correlating with the protective effect.

Topical Microbicides Also Show Efficacy in Prevention

The Centre for AIDS Programme for Research in South Africa (CAPRISA) trial tested tenofovir in a vaginal gel formulation. The gel, used before and after sex, was associated with an overall 39% reduction in acquiring HIV and a 54% reduction in risk for women who had the best adherence.

Another study, the large Vaginal and Oral Interventions to Control the Epidemic (VOICE) phase 2B trial of high-risk women in eastern and southern Africa, looked a 5 treatment groups: daily oral tenofovir, oral emtricitabine/tenofovir, oral placebo, tenofovir vaginal gel, and vaginal placebo. In September, the Data and Safety Monitoring Board recommended discontinuing the oral tenofovir group because of a lack of likelihood of effectiveness.

In the studies of serodiscordant couples, "it's quite clear that treating the infected partner to prevent transmission is a highly effective strategy, more so in terms of stable couples," Dr. Lacey concluded. "The effect size goes down if you look at transmissions from outside of the primary partnership."

In general, the trials showed positive results from PrEP. What happened in FEMPrEP is still something of a mystery. "In the United Kingdom, we've made a position statement saying that we think ad hoc prescribing of PrEP should be avoided until we know more, until we've conducted more trials."

One proposed PrEP study in England and Wales is the PROUD trial of high-risk HIV-negative men who have sex with men, randomized to immediate or delayed emtricitabine/tenofovir. Besides measuring antiviral prophylaxis, the study will involve regular testing for sexually transmitted infections and measurements of sexual behavior to see if there is any behavioral risk enhancement in the trial.

Charles Kelly, PhD, professor of oral immunology at King's College London, United Kingdom, told Medscape Medical News that it is clear that antiretroviral drugs are going to make good microbicides. "That's been a change in the past few years in the field. For women, it looks as though the best option at the moment is topically applied microbicides. I guess for men that may be the case, but clearly the oral PrEP is working," he said.

Different treatments and strategies will most likely be needed for different populations, he said, "whether it's topically applied or orally administered. Within that, there may be different formulations, of course." Sustained-release formulations are gaining quite a lot of interest, such as "the intravaginal rings...that can be inserted and left for a significant period, perhaps weeks," Dr. Kelly explained.

He advised that biomedical trial protocols need to be designed with behavioral components in mind, and trialists need to consider whether a drug and its formulation will be a practical product and will be accepted and used.

Dr. Lacey and Dr. Kelly have disclosed no relevant financial relationships. Both serve on the Combined Highly Active Anti-Retroviral Microbicides (CHAARM) project, a multinational partnership of universities, research institutions, and industries, with the aim of developing combinations of highly active microbicides for the prevention of HIV through sexual intercourse. CHAARM is funded by the European Commission.

13th European AIDS Conference of the European AIDS Clinical Society (EACS). Presented October 12, 2011.

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