Jim Kling

February 25, 2015

SEATTLE — The combination of tenofovir and emtricitabine (Truvada, Gilead) used as prophylaxis is highly effective in reducing the rate of HIV infection in real-world settings, according to two pilot studies.

In both, the incidence of HIV was reduced by 86% with the pre-exposure prophylaxis.

The two studies were stopped early because the treatment was effective, which is very encouraging, said Mauro Schechter, MD, from the Universidade Federal do Rio de Janeiro, who was involved in the IPrEx study in the mid-1990s, which was the first to demonstrate the efficacy of pre-exposure prophylaxis.

"They show that in real life, it really works," he told Medscape Medical News.

The studies were presented here at the Conference on Retroviruses and Opportunistic Infections 2015.

The Pragmatic Open-Label Randomised Trial of Pre-exposure Prophylaxis study, known as PROUD, involved 545 men who have sex with men from 13 sexual health clinics in England and was conducted from November 2012 to April 2014.

The PROUD Study

All men tested negative for HIV in the 4 weeks before study enrollment and had engaged in anal intercourse without a condom in the previous 90 days, with a median of 10 partners (range, 4 - 20). A total of 64% had been diagnosed with a sexually transmitted infection (STI) in the previous 12 months.

The men were randomized to start treatment immediately or to defer initiation for 1 year. Both groups underwent quarterly follow-up.

In the first year, there were three HIV infections in the immediate group and 19 in the deferred group. There was a difference of 7.6 infections per 100 person-years between the immediate and deferred groups (1.3 vs 8.9 per 100 person-years; 90% confidence interval [CI], 4.1 - 11.2). The relative risk reduction with treatment was 86% (90% confidence interval [CI], 62% - 96%; P = .0002).

There was no significant difference in the rate of rectal chlamydia, gonorrhea, or other STIs between the two groups, which suggests that the men in the immediate group who were receiveing prophylaxis were not engaging in riskier behavior, said lead investigator Sheena McCormack, MD, professor of clinical epidemiology at Imperial College in London.

The Action to Prevent Risk Exposure by and for Gay Men, known as IPERGAY, evaluated "on demand" treatment.

The study was prompted by the fact that some people find it difficult to adhere to a daily treatment regimen. In fact, in previous studies in which prophylaxis was shown to be ineffective, poor adherence was the likely culprit.

The IPERGAY Study

IPERGAY involved men who had anal sex without a condom and had creatinine levels above 60 mL/min. The 414 men were randomly assigned to on-demand treatment or placebo. They were asked to take two pills 2 to 24 hours before sexual intercourse, an additional dose 24 hours after the first pills, and another dose 48 hours after the initial dose.

Men in the prophylaxis group used a median of 16 pills per month (interquartile range, 12 - 24), or four per week.

At a median follow-up of 8.8 months, the incidence of HIV infection was lower in the treatment group than in the placebo group (0.94 vs 6.75 per 100 patient-years). The relative risk reduction with treatment was 86% (95% CI, 39.4% - 98.5%; P = .002).

The rate of other STIs during the study period was not significantly different between the treatment and placebo groups (38% vs 32%; P = .22).

The rate of serious adverse events was similar in the two groups, at about 9%. Two patients in the treatment group experienced a temporary reduction in creatinine clearance to below 60 mL/min.

"It's really exciting to see efficacy data showing pre-exposure prophylaxis works just as we thought it did," Darrell Tan, MD, from St. Michael's Hospital in Toronto, told Medscape Medical News.

Dr Tan noted, however, that HIV infection rates in the men who did not receive the prophylaxis in the two studies were higher than expected, and expressed concern about risk compensation, in which subjects increase their risky behavior because they believe they are protected.

"People need to pay attention" to the potential for risk compensation, said Dr Schechter. "Every single study of pre-exposure prophylaxis so far has shown that it has no impact on risk compensation," but if the numbers in this study are related to risk compensation, that would indeed be "bad news."

However, it is also possible that the study attracted volunteers who were already at higher than average risk, in which case the drug is having an impact on the people who need it most, which would be "good news," he explained.

In the PROUD study, "these guys knew they needed something extra," said Dr McCormack. "They already weren't using condoms consistently. They recognized their need, and they were clearly highly motivated to take the tablets in both studies. I think that's why we achieved what we achieved," she told Medscape Medical News.

Brian West, chair of the board of directors of the European AIDS Treatment Group, said he is hoping for information on the cost-effectiveness of treatment so he can sell the idea to public health agencies in Europe.

Questioning the Cost

"We need to be able to assure them that any intervention is cost-effective, especially in healthcare settings that are cash-strapped," he said. "I suspect, at 86% reduction, it will be very cost-effective," he told Medscape Medical News.

He said that his organization will push Gilead, the manufacturer of the drug combination, to get the treatment approved for prophylaxis in Europe, as it is in the United States.

"If it doesn't have it written on the label, it's not easy to get the National Health Service to pay for it," West explained. We need a label change."

Gilead provided the drug for both studies. Dr McCormack and Dr Tan report receiving research support from Gilead. Dr Schechter has consulted for Gilead. Mr West has disclosed no relevant financial relationships.

Conference on Retroviruses and Opportunistic Infections (CROI) 2015: Abstracts 22LB and 23LB. Presented February 24, 2015.

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