HIV-negative African women assigned to take once-daily Truvada for HIV pre-exposure prophylaxis (PrEP) achieved better adherence than those assigned to take PrEP twice weekly or before and after sex, according to findings from the HPTN 067 trial presented at the recent Conference on Retroviruses and Opportunistic Infections (CROI 2015) in Seattle.
Truvada (tenofovir/emtricitabine) PrEP has been shown to dramatically reduce the risk of HIV infection in clinical trials enrolling gay and bisexual men (iPrEx and its Open Label Extension, PROUD and Ipergay) and heterosexual couples (Partners PrEP and TDF2), but results have been less impressive in studies of women, with the FEM-PrEP and VOICE trials both being unable to show a protective effect.
Linda-Gail Bekker from the Institute of Infectious Disease and Molecular Medicine in Cape Town, Robert Grant from the University of California San Francisco and fellow investigators conducted the HIV Prevention Trials Network (HPTN) 067 or ADAPT study to investigate whether once-daily and less frequent Truvada regimens provide equivalent coverage of sex acts, as well as how they compare in terms of pill burden and side-effects.
Findings from the Ipergay trial, also reported at CROI, showed that Truvada taken before and after sex reduced the risk of HIV infection by 86% – the same as in the PROUD trial of once-daily PrEP – but the men in Ipergay had sex often enough that they took Truvada 14 days per month on average, equivalent to the four days per week shown to be highly protective in iPrEx. Thus, it remains unclear whether less frequent PrEP use around the time of sex would be equally effective. In addition, pharmacokinetic studies indicate that PrEP drugs reach higher levels and persist longer in male rectal tissue than in female genital tissue.
The full HPTN 067 trial included women in Cape Town, South Africa, and men who have sex with men and transgender women in Bangkok and New York City. The analysis presented at CROI focused on the 191 women enrolled at the Emavundleni Research Centre in Cape Town. Their median age was 26 years and more than 80% were unmarried and unemployed.
After six weeks of weekly Truvada with directly observed dosing to estimate steady-state drug levels, 179 women were randomly assigned to self-administer Truvada either once daily, twice weekly with an extra booster dose after sex, or before and after sex (event driven), all for 24 weeks.
Pills were dispensed using an electronic device that recorded each time it was opened. The women were interviewed weekly to review pill use and sexual activity, and tenofovir and emtricitabine levels in plasma and peripheral blood mononuclear cells (PBMCs) were measured at weeks 10 and 30.
Women taking daily Truvada reported having sex significantly more often (1954 acts) than those taking twice-weekly (1078 acts) or event-driven PrEP (1533 acts).
Women in the daily arm of the study had significantly more of their sex acts 'covered' by PrEP – defined as at least one pill taken during the four days before and at least one pill during the 24 hours after sex – than those in the twice-weekly and event-driven arms (75%, 56% and 52%, respectively). Further, women assigned to daily PrEP needed significantly more pills to cover their sexual activity than those in the twice-weekly and event-driven arms (9758, 3829 and 2205 pills, respectively).
Adherence was significantly higher among women on daily PrEP compared to those assigned to the twice-weekly or event-driven schedules (76%, 65% and 53%, respectively). In the non-daily arms, adherence was low for the doses that should have been taken after sex.
Expected levels of tenofovir in plasma and intracellular tenofovir diphosphate (its active metabolite) were detected more often among women assigned to daily Truvada compared with those assigned to either of the less frequent regimens. Adherence dropped off over time, with adequate drug levels in plasma and PBMCs being detected in more women in all groups at 10 weeks than at 30 weeks.
There was one new HIV infection in the daily Truvada arm and two each in the twice-weekly and event-driven arms – not a statistically significant difference.
Side-effects were uncommon in the daily PrEP group, but even less frequent in the twice-weekly and event-driven groups (11%, 6% and 8%, respectively, for headache, dizziness or light-headedness; 10%, 8% and 5% for gastrointestinal symptoms).
"The majority of women took oral PrEP when made available in an open-label study," the researchers concluded. "Daily dosing resulted in better coverage of sex acts and adherence, and higher drug levels."
"Daily dosing may foster better habit formation and provide the most forgiveness for missed doses at observed adherence levels," they added. "These findings support current recommendations for daily use of oral [tenofovir/emtricitabine] PrEP in women."
"The regimens used in this trial and the definition of PrEP coverage was based on information that was available when the trial was designed in 2010," according to a fact sheet about the study findings issued by the HIV Prevention Trials Network. "More current information suggests that higher concentrations of PrEP medications are required for protection from vaginal exposure to HIV, as would be afforded by daily oral dosing or any topical dosing."
Bekker LG et al. HPTN 067/ADAPT Cape Town: a comparison of daily and nondaily PrEP dosing in African women. 2015 Conference on Retroviruses and Opportunistic Infections, Seattle, abstract 978LB, 2015.