CROI 2012Viread (tenofovir) and Truvada (tenofovir plus emtricitabine), when either was used as daily pre-exposure prophylaxis (PrEP), reduced the risk of contracting HIV by more than two thirds among mixed-status heterosexual couples—and up to 90 percent among those with laboratory evidence of having actually taken their allotted preventive treatment—according to new results from the Partners PrEP study reported on Tuesday, March 6, at the 19th Conference on Retroviruses and Opportunistic Infections (CROI) in Seattle.

The encouraging Partners PrEP results, reported by Jared Baeten, MD, PhD, of the University of Washington in Seattle, contrast those of another study reported at CROI, dubbed FEM-PrEP, focusing specifically on women at risk for HIV infection.

Full Results

Baeten presented full results on behalf of the Partners PrEP study team.

The trial enrolled 4,758 HIV-serodiscordant couples, in which one partner was HIV positive and the other partner was HIV negative. Study sites included four centers in Kenya and five centers in Uganda.

Provided that the HIV-negative partners had normal liver, kidney and blood markers, they were randomized to receive Viread once a day, Truvada once a day or placebo once a day. Couples were to be followed by the researchers for up to 36 months.

Comprehensive care was provided to the study participants. HIV-negative volunteers received monthly HIV and pregnancy testing, monthly symptom and quarterly laboratory safety monitoring and monthly provisions of study medications along with individualized adherence counseling, which included instructions not to share study drugs. HIV-positive participants were seen quarterly and received semi-annual CD4 count testing. They also received ongoing HIV primary care and, depending on their CD4 counts, referrals to receive antiretroviral treatment.

In addition, all participants received risk reduction counseling, free condoms and condom counseling, contraception counseling and provision, screening and treatment for other sexually transmitted infections (STIs), and counseling and referral for other HIV prevention interventions, including male circumcision where applicable.

The study, as designed, was halted July 10, 2011, after safety monitors noted key efficacy differences between the two groups. They recommended that the data be shared publicly and the placebo group be discontinued.

More than 60 percent of those enrolled in the study were men, and the average age of the volunteers was 33. Ninety-eight percent were married couples who had been together for an average of seven years. CD4 counts among the HIV-positive partners averaged 495 upon entering the study, and viral loads were low, around 8,000 copies.

Nineteen percent of the HIV-positive volunteers started ARV treatment during the study.

There were 96 infections in the study, 14 of which were documented at enrollment and were likely acute infections that weren’t detected during the screening process. This left 82 confirmed HIV cases during the study itself—45 infections were documented among women in the study, and 37 were confirmed in men.

Fifty-two of the confirmed study infections occurred in the placebo group, compared with 17 in the Viread group and 13 in the Truvada group. These findings translated into 67 percent fewer HIV infections among those using Viread and 75 percent fewer infections among those using Truvada. Statistically speaking, however, the effects of Viread and Truvada were similar—there was no significant difference between the two groups, meaning that the difference could have been due to chance.

Men and women in Partners PrEP benefited more or less equally. There were 71 percent fewer infections among women and 63 percent fewer infections among men who received Viread. As for those receiving Truvada, there were 66 percent fewer infections among women and 84 percent fewer infections among men. Neither of these differences was statistically significant.

HIV drug resistance rates were rare. According to Baeten, none of the study volunteers with confirmed infection during the study had HIV with either the K65R or the M184V mutation, which confers resistance to tenofovir or emtricitabine respectively. Among the eight study volunteers infected with HIV around the time they entered the study and who were inadvertently treated with Truvada, one developed the K65R mutation and another developed the M184V mutation. Drug resistance mutations were found in four individuals who were conclusively infected with HIV during the trial, but these mutations were tied to non-nucleoside reverse transcriptase inhibitor resistance and were likely transmitted sexually.

No statistically significant differences in the number of deaths, serious side effects or laboratory-documented adverse events were reported. Diarrhea was statistically more likely among those taking Truvada compared with placebo, though this was documented in less than 5 percent of the study participants after one month of PrEP.

As for sexual behavior, 27 percent of couples reported unprotected sex in the month before enrollment. There was a decline in this behavior during the follow-up period in both study groups. Of note, however, one third of the study volunteers—both HIV positive and HIV negative—reported having extramarital sex during the trial.

Adherence Is Key

The adherence rate, primarily determined through monthly pill counts, was high, with 97 percent of dispensed doses taken. Baeten also noted a very high retention rate in the study—more than 96 percent of the volunteers followed through with scheduled clinic visits for as long as they were enrolled.

Pill counts, however, do not tell the whole story when it comes to adherence rates. In turn, Deborah Donnell, PhD, of Fred Hutchinson Cancer Research Center in Seattle and her Partners PrEP colleagues measured blood levels of Viread—the common medication used in both active treatment groups—in a subset of study volunteers to further explore adherence levels in relation to the trial’s efficacy findings.

Donnell’s group compared tenofovir drug levels in 29 study volunteers who seroconverted—17 in the Viread group and 12 in the Truvada group—to 198 randomly selected participants who didn’t become infected while taking either drug.

Among the 29 study volunteers who were allotted to receive PrEP and who became infected during the trial, 35 percent of those assigned to Viread and 25 percent of those assigned to Truvada had detectable tenofovir in their blood samples collected at the clinic visit in which their seroconversion was confirmed. Conversely, 83 percent of samples from those who didn’t became infected in the Viread group and 81 percent of those who didn’t become infected in the Truvada group had detectable levels of tenofovir.

For those randomized to Viread, Donnell and her team determined, having a detectable level of tenofovir, as opposed to an undetectable level, was associated with an 86 percent reduction in the risk of being infected with HIV. Among those who were randomized to Truvada and had detectable tenofovir levels, compared with those with undetectable levels, the HIV risk reduction was 90 percent.

“Among persons taking [Viread] and [Truvada] PrEP,” Donnell’s team concludes, “detection of tenofovir in [blood samples] was strongly predictive of high protection from HIV acquisition. Drug detection and levels over multiple visits in the [uninfected] cohort suggest that a majority consistently used PrEP, supporting the high level of protection for HIV acquisition observed in the Partners PrEP Study.”

Partners PrEP is continuing, albeit with those originally assigned to receive placebo now being offered active PrEP.