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PrEP: Is One Drug As Good As Two?

, by Reilly O'Neal

To date, the only product currently approved for pre-exposure prophylaxis (PrEP) is Truvada, a combination of the drugs tenofovir (brand name Viread) and emtricitibine (Emtriva). While Truvada PrEP is highly effective at reducing HIV risk when taken daily, studies are also exploring additional PrEP options, including new formulations and delivery methods.

BluePillsCROPCould PrEP with a single drug work as well as a two-drug combo? At the 21st Conference on Retroviruses and Opportunistic Infections, Jared Baeten of the University of Washington at Seattle reported study results that suggest the answer is yes.

The Partners PrEP study was a randomized, placebo-controlled, double-blinded Phase 3 clinical trial evaluating tenofovir alone and combination tenofovir/emtricitabine as daily oral PrEP in 4,747 mixed-HIV-status heterosexual couples in Kenya and Uganda (abstract 43).

As previously reported, daily oral tenofovir/emtricitabine yielded an HIV risk reduction of 75% and tenofovir alone yielded a 67% risk reduction. This difference between the two study drug arms was not statistically significant, and both tenofovir alone and Truvada were deemed highly effective against HIV infection.

In July 2011, the trial discontinued the placebo arm and offered to “re-randomize” placebo-using participants to receive either tenofovir or tenofovir/emtricitabine PrEP. “This provided both additional information on safety and efficacy of one vs. two drugs for pre-exposure prophylaxis, as well as providing access to effective product for study participants,” Baeten explained.

The current analysis includes data from 2008 through 2012. A total of 4,427 individuals were assigned to take active PrEP during the trial, with an 89% re-randomization rate of eligible participants who switched to active PrEP from the discontinued placebo arm. Nearly 8,800 person-years of follow-up (the number of years all persons were followed throughout the study) were accrued, including 3,569 additional person-years gleaned after July 2011.

A total of 52 new HIV infections occurred among individuals assigned to the active PrEP arms (30 before and 22 after the July 2011 re-randomization). Of these, 31 occurred in the tenofovir-only arm, for an incidence (HIV infection rate) of 0.7 per 100 person-years; 21 occurred in the Truvada arm, for an incidence of 0.5 per 100 person-years. Again, the difference was not statistically significant.

No significant differences in protective effect were seen between the two PrEP arms according to participant characteristics such as age, sex, male circumcision status, and sexual behavior. Safety measures were also comparable between the two PrEP arms.

Analysis of tenofovir drug levels in blood samples—a measure of adherence to the study products—showed that a great majority of those who remained uninfected had detectable tenofovir levels in their blood, whereas only a minority of participants who acquired HIV had detectable blood levels of tenofovir.

“The relative risk reduction associated with detectable levels of tenofovir was 85% for tenofovir alone, and 90% for the combination emtricitabine/tenofovir—both of which were highly statistically significant,” Baeten reported.

Why pursue a single-agent PrEP formulation? First, tenofovir alone is less pricy than either branded or generic tenofovir/emtricitabine, Baeten noted. Also, single-agent tenofovir has the advantage of less risk for HIV resistance mutations in people who take PrEP when they are already HIV-positive or who acquire HIV despite using PrEP.

For example, a closer look at drug resistance mutations showed more resistance associated with emtricitabine than tenofovir in Partners PrEP (abstract 590LB). “The majority of resistance detected in PrEP trials related to PrEP agents has been related to emtricitabine, not to tenofovir,” explained Baeten, “although in all PrEP trials—including our study, and including looking at low-frequency resistance—the rate of resistance is still quite small.”

“Our results continue to inform the discussion about what are the best agents for PrEP, taking into account side effects, resistance, risk, cost, and other considerations,” Baeten concluded.

Reilly O’Neal is a freelance writer and former editor of BETA.

Abstracts

43: Single-Agent TDF Versus Combination FTC/TDF PrEP Among Heterosexual Men and Women
Jared Baeten, Deborah Donnell, Patrick Ndase, Nelly Mugo, Connie Celum, Partners PrEP Study Team

Background: Antiretroviral pre-exposure prophylaxis (PrEP), using daily oral tenofovir (TDF) alone or combination emtricitabine/tenofovir (FTC/TDF), has been demonstrated to be an efficacious HIV-1 prevention intervention in four clinical trials. Whether single-agent TDF PrEP has comparable efficacy to dual-agent FTC/TDF PrEP is unknown.
Methodology: The Partners PrEP Study was a randomized, double-blind, placebo-controlled three-arm trial of daily oral TDF and FTC/TDF PrEP among heterosexual HIV-1 uninfected members of HIV-1 serodiscordant couples from Kenya and Uganda. In July 2011, the trial’s placebo arm was discontinued because of clear demonstration of HIV-1 protection from PrEP; compared to placebo, HIV-1 prevention efficacy was 67% for TDF and 75% for FTC/TDF, and TDF and FTC/TDF efficacy were not significantly different (p=0.23). After July 2011, to gather additional comparative information about singleversus dual-agent PrEP, the trial’s active arms were continued in a blinded fashion and the participants initially randomized to placebo were offered rerandomization to TDF or FTC/TDF PrEP. Data collection was completed in December 2012.
Results: 4747 HIV-1 serodiscordant couples were enrolled and followed; for 62%, the HIV-1 uninfected partner was male. A total of 52 post-randomization HIV-1 infections occurred among individuals assigned to the active PrEP arms: 30 prior to and 22 after July 2011. Of these 52 infections, 31 were among those assigned TDF (incidence 0.7 per 100 person-years) and 21 were among those assigned FTC/TDF (incidence 0.5 per 100 person-years); for comparison, HIV 1 incidence in the placebo arm prior to July 2011 was 2.0 per 100 person-years. HIV-1 prevention efficacy for FTC/TDF compared to TDF alone was not statistically significantly different: HR 0.67, 95% 0.39-1.17, p=0.16. Detection of tenofovir in plasma samples, measured in seroconverters and a subset of non-seroconverters, was associated with an 85% relative risk reduction in HIV-1 acquisition for the TDF arm and 93% for the FTC/TDF arm (both p<0.001). By consensus sequencing, no cases of HIV-1 antiretroviral resistance related to TDF or FTC were identified in HIV-1 seroconverters after July 2011.
Conclusions: Among heterosexual men and women, once-daily oral TDF and FTC/TDF are safe and provide high and comparable risk reduction against HIV-1 acquisition.

590LB: PrEP Exposure and the Risk of Low-Frequency Drug Resistance
Dara A. Lehman, Jared Baeten, Connor McCoy, Julie F. Weis, Dylan Peterson, Connie Celum, Nelly Mugo, Julie Overbaugh, Frederick Matsen, the Partners PrEP Study Team

Background: Pre-exposure prophylaxis (PrEP) reduces HIV acquisition. However, for those who acquire HIV while receiving PrEP there is the potential for drug resistance to arise as a result of partial HIV suppression through PrEP medication exposure before HIV seroconversion is detected. The level of resistance selected by PrEP may not be detectable with standard sequencing methods, which only detect resistance present at frequencies above 20% of the viral population. Studies of antiretroviral treatment failure have suggested that resistance as low as 1% may be clinically significant during subsequent antiretroviral use. 454 ultra-deep sequencing can detect resistance at frequencies below 1%.
Methodology: In the Partners PrEP Study, a randomized trial of daily oral tenofovir disproxil fumarate (TDF) or tenofovir plus emtricitabine (FTC), plasma samples from the time of HIV seroconversion were tested for predefined mutations that could be selected by TDF (K65R and K70E) and FTC (K65R and M184IV) using 454 ultra-deep sequencing. Samples were considered resistant if the proportion of mutant sequences was significantly above that observed in wild-type genotype-matched controls using Fisher’s exact test with correction for a 5% false discovery rate. Plasma levels of tenofovir were measured among seroconverters in the active PrEP arms at the time of seroconversion. Fisher’s exact test was used to determine associations with resistance.
Results: A total of 121 seroconverters were tested: 38 had received TDF, 25 FTC-TDF, and 58 placebo. PrEP-related resistance mutations (K65R, K70E and/or M184IV) were detected in 9 (7.4%) at levels >1%, 2 of which had previously been detected by standard sequencing. In the TDF arm, 2 of 38 (5.3%, p=0.65 vs placebo) had resistance >1%: 1 had K65R/K70E and 1 had M184IV. In the FTC-TDF arm, resistance was detected in 5 of 25 (20%, p=0.024 vs placebo): 4 had M184IV alone and 1 had M184IV/K65R. Two of the 58 (3.5%) placebo participants had M184IV resistance. Resistance was detected in 3 individuals retrospectively determined to be HIV infected (seronegative but RNA positive) when PrEP was initiated, and in 6 individuals infected after PrEP start. In seroconverters in the active PrEP arms, PrEP use was associated with higher risk of resistance: 6 of 23 (26%) with measurable drug levels versus only 1 of 39 (2.6%) without evidence of PrEP use had resistance >1% (p=0.009).
Conclusions: High-sensitivity resistance testing detected more resistance than standard sequencing in persons acquiring HIV who were exposed to PrEP, although resistance still occurred in a minority of subjects. More resistance was selected by FTC than TDF, as evidenced by the prevalence of M184IV compared to K65R.

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