CROI 2015: “On-Demand” PrEP Shows High Efficacy in IPERGAY Trial
BETA is attending and reporting from the 2015 Conference on Retroviruses and Opportunistic Infections this week in Seattle from February 23 to 26—bringing you the latest news, updates, and research on HIV treatment and prevention.
On the second day of CROI, Jean-Michel Molina for the French National AIDS Research Institute (ANRS) presented the much-anticipated IPERGAY trial efficacy results. IPERGAY, meaning “a study designed with and for the gay community,” according to Molina, set out to determine how effective on-demand PrEP is for men who have sex with men. On-demand PrEP refers to a dosing schedule where PrEP is taken intermittently, or only around times of sexual activity instead of every day.
“We thought on-demand PrEP could improve adherence, safety, and cost-effectiveness, and make PrEP overall more attractive,” said Molina.
Molina reported promising findings: On-demand PrEP reduced risk of HIV infection by 86% compared to placebo. On-demand PrEP “could be a game-changer,” he said.
In a later press conference, Molina was quick to caution about how the results of IPERGAY should be interpreted. “Like every study, there are limitations. The efficacy percent was 86% but the confidence interval was between 40% and 99%.”
In contrast to how PrEP is now prescribed—as a once-daily pill—men in the IPERGAY study were instructed to take two tablets of Truvada two to 24 hours before sex, and then one Truvada tablet 24 hours later and one final Truvada tablet 48 hours later.
Only two individuals in the on-demand PrEP group acquired HIV during the study compared to 16 people in the placebo group. The two people in the intermittent PrEP group who did get infected with HIV, explained Molina, did so 16 months into the study. He reported that the study team doesn’t believe these infections were due to PrEP failure—but rather, to non-adherence since PrEP drugs weren’t detectable in plasma samples taken around the time of infection.
Robert Grant, MD, of the Gladstone Institutes, the University of California at San Francisco, and medical director for San Francisco AIDS Foundation, explained to BETA that, “There were very few men in the study who had sex less than weekly. Although there were no infections among this small group of men, we are not confident that their levels of drug were sufficient for high-level protection. I still favor daily dosing, as it provides the highest level of protection, the most forgiveness for occasional missed doses, fosters habit formation, and does not require that people plan for all sex.”
On average, men in the study took about 16 pills a month, or about 4 pills per week for an average of one sexual encounter a week.
Since men in the study were taking an average of four doses per week, it’s not clear yet if taking PrEP less often using the same dosing strategy is effective. The results achieved with an average of four pills per week seen in IPERGAY echoes the efficacy achieved during the iPrEx OLE demonstration project—where no participants on a daily PrEP regimen acquired HIV when an average of four doses per week were taken. Because this study was conducted with a population of men who engaged in relatively frequent sexual activity, the results may not translate to situations when dosing falls below an average of four per week.
They key may be how much drug is “on board” at the time of sexual activity. The CDC advises that PrEP needs to be taken for at least seven days before a risk event to provide protection from rectal HIV exposure. The IPERGAY study’s protocol only specifies that two doses must be taken before sex for protection.
“While two pills the day before sex is better than none, the highest level of protection comes after five to seven daily doses for rectally exposed men (and 20 daily doses for women). In the Ipergay study, the average number of pills taken per month was 16, for a median of 10 sex acts per month. Only a few men took PrEP for very infrequent sex. Two tablets before infrequent sex probably does not provide the same high level of protection that we see with daily dosing,” explained Grant.
Molina acknowledged that he understands the messaging around this issue “is complex,” and that, “not a single study can answer all the questions.” He reported that his team will perform a substudy that will add to their understanding of how early protection is provided by PrEP, by analyzing drug levels in rectal tissue after drug is taken.
Evidence of on-demand PrEP’s effectiveness was anticipated from IPERGAY based on a change to the study design that occurred in October of 2014. While specific study data were not released at the time, an early analysis of the unblinded study data by the data safety monitoring board (DSMB) found evidence that the oral Truvada-based on-demand PrEP regimen had significantly reduced HIV risk as compared to placebo. This led the DSMB to recommend that all IPERGAY participants assigned to placebo be offered access to on-demand PrEP.
The beauty of on-demand PrEP, according to Molina, is that it gives men greater choice about when and how to use PrEP. When the IPERGAY team asked participants about their last episode of sex, they found hat 28% of participants did not use PrEP. “So participants were able to select the type of sexual intercourse, and the type of partners, where they would want to use PrEP,” summed Molina.
Previously reported study findings showed that men in the trial were adherent to the intermittent PrEP schedule according to drug levels detected in blood samples and self-reported pill taking. “IPERGAY is an important study that demonstrates how much forgiveness there is with daily dosing,” explained Grant. IPERGAY also adds to our understanding of how best to stop PrEP, according to Grant. “Apparently, two doses after the last exposure is enough if people were taking PrEP consistently beforehand.”
A statement released by the CDC on Tuesday urged people currently taking PrEP to continue daily dosing. Truvada is approved by the U.S. Food and Drug Administration to reduce the risk of HIV infection only when used daily.