HIV Prevention Pill May Not Require Daily Dosing

Researchers Explore a Day-Before-Day-After HIV Prevention Strategy

Man taking pill medicine drug
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On December 1, 2015, researchers with the IPERGAY trials in France and Canada reported that the use of HIV pre-exposure prophylaxis (PrEP) just before and just after sex significantly reduced the risk of HIV in gay men considered to be at high risk.

The study, published in the New England Journal of Medicine, was much anticipated after the early termination of the trial in Octover 2014, at which time interim data showed that only two men on PrEP had become infected versus 14 in the placebo arm.

As a result, all of participants in the placebos were immediately switched to control drug Truvada (tenofovir + emtricitabine).

The IPERGAY trial, which began in February 2014 and recruited 300 men who have sex with men (MSM), asked participants to take two Truvada tablets between two and 24 hours before sex. One tablet would then be taken every 24 hours until the completion of sex, after which one additional tablet would be taken within approximately 24 hour of the last dose.

Results Confirm "On Demand" Effectiveness

Following the closure of the trial in 2014, the IPERGAY scientists spent the better part of the next year analyzing the results, finally concluding  that the "on-demand" strategy reduced the risk of HIV in the study population by between 82% and 86%.

They also reported that the two men on PrEP who were infected with HIV did not take the drugs as prescribed. Both returned more than 95% of their pills unused, with neither having any evidence of Truvada in their blood.

According to the researchers, 43% of the participants took their pills correctly, with only 7% complaining of abdominal pain and 8% reporting nausea. Moreover, participants on PrEP took the pills a median of 15 days per month, strongly suggesting that non-daily use of Truvada may afford high levels of protections in certain populations.

British PrEP Trial Supports IPERGAY Results

The IPERGAY closure came on the back of news that a similar trial, known as the UK PROUD, had also closed their study prematurely. The study, which aimed to determine whether MSM provided daily PrEP might increase high-risk behaviors in such a way as to cancel out  its protective effects, recruited 545 gay and bisexual men, half of whom were provided immediate PrEP, while the other half were deferred treatment for a year.

The UK PROUD trial was designed, in part, to address critics who had suggested that PrEP would increase infection rates by encouraging condomless sex.

In September 2015, investigators with the UK PROUD reported an 86% reduction in the number of infections in the control group versus the placebo group, translating to the avoidance of 17 out of every 20 infection in MSM.

So What Do The Results Mean at This Stage?

While both studies provide further evidence of PrEP efficacy—and will likely provide the foundation for future recommendations—there remain a number of key questions. Among them:

  • Will the strategy work as effectively for those who only take PrEP only a few times a year, as opposed to the study population who took it 15 times per month? It is believed by some that the long half life of Truvada may provide blanket protection in those who take it, say, 50% of the time versus those who only take it periodically.
  • Might the strategy work as effectively in heterosexuals? Recent research has already suggested that key differences in the protective benefit of PrEP in women versus men may limit the benefit of an on-demand strategy in some groups.

In the meantime, both IPERGAY and UK PROUD investigators are likely to expand the scope of their investigation to confirm whether the results hold up in other study populations.


Molina, J.; Capitant, C.; Spire, B.; et al. "On-Demand Preexposure Prophylaxis in Men at High Risk for HIV-1 Infection." New England Journal of Medicine. December 1, 2015; published online in advance of print; DOI: 10.1056/NEJMoa1506373.

Agence National de Recherche sur le Sida et Les Hépatites Virales (ANRS). "A significant breakthrough in the fight against HIV/AIDS – a drug taken at the time of sexual intercourse effectively reduces the risk of infection." Paris, France; press release issued October 29, 2014.

UK PROUD Trial Steering Committee. "PROUD study interim analysis  finds pre- exposure prophylaxis (PrEP) is highly protective against HIV for gay men and other men who have sex with men in the UK." London, England; press release issued October 16, 2014.

McCormack, S.; Dunn, D.; Desai, M.; et al. "Pre-exposure prophylaxis to prevent the acquisition of HIV-1 infection (PROUD): effectiveness results from the pilot phase of a pragmatic open-label randomised trial." The Lancet. September 14, 2015, published online: DOI:

Barro, J. "AIDS Group Wages Lonely Fight Against Pill to Prevent H.I.V." New York Times, published November 16, 2014.

Cottrell, M.; Yang, K.; Prince, H.; et al. "Predicting effective Truvada PrEP dosing strategies with a novel PK–PD model incorporating tissue active metabolites and endogenous nucleotides (EN)." HIV Research for Prevention Conference. 28-31 October, 2014; Cape Town, South Africa; oral abstract 22.06 LB.

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