Many types of pre-exposure prophylaxis (PrEP) have shown great promise for preventing HIV infection. Some prophylactics, such as male circumcision, require few clinic visits, while others may rely on a patient to take a daily prescription. Whether or not someone takes a prescribed medication is called adherence. The ideal situation is when a person at risk for HIV adheres to the daily regimen 100% of the time. However, in the real world, many factors can affect a patient’s adherence. This issue becomes especially important during PrEP clinical trials; where effectiveness is dictated by both treatment (drug effect) and adherence. Two years ago, the Partners in PrEP phase III double blind clinical trial found two oral treatments, tenofovir (TDF) and tenofovir/emtricitabine combination (TDF-FTC), that exhibited high efficacy against HIV acquisition among serodiscordant couples in Kenya and Uganda. In comparison with placebo, both drugs reduced the risk of HIV infection; by 67% (TDF) and 75% (TDF-FTC).
To determine if PrEP adherence correlated with the observed HIV protection, VIDD Associate Member Dr. Deborah Donnell and colleagues quantitatively measured plasma tenofovir concentrations from participants (who received drug in the Partners trial) who became HIV+ and those who remained uninfected. The presence or absence of tenofovir was chosen because it is present in both of the treatment arms (TDF and TDF-FTC). Tenofovir detection was split into three bins: 1) >0.3 ng/mL, indicative of taking medication within the previous week; 2) >10 ng/mL, within the last 2-3 days; and >40 ng/ml, within the past 24 hours (and also suggestive of daily dosage). When assigning the tenofovir concentration of >0.3 ng/mL as ‘detectable’ and anything lower as ‘undetectable,’ the authors identified a marked difference in adherence between uninfected and subjects who became HIV+.
Among the TDF cohort, tenofovir was detected in 83% of plasma samples from uninfected persons. In comparison, for participants who became HIV+, only 41% of samples had detectable levels (Figure, left graph). These results translated to an 84% risk reduction in acquiring HIV when the subjects adhered, albeit to varying levels. Similar results were found for the TDF-FTC arm: 80% and 17% detectable from uninfected and those who became HIV+, respectively, translating to 92% protection when the subjects adhered to the regimen (Figure, right graph).
Measuring adherence can be a challenging task, based on numerous factors such as individual differences in drug metabolism; whether or not the drug can be detected; whether or not the placebo can be detected (if a trial has a placebo arm); and if participants misreport their level of adherence, such as pill counts. This quantitative study concluded that plasma tenofovir levels positively correlated with HIV prevention. It is imperative that persons at high risk for HIV infection who are receiving PrEP adhere to the prescribed drug regimen.
Donnell D, Baeten JM, Bumpus NN, Brantley J, Bangsberg DR, Haberer JE, Mujugira A, Mugo N, Ndase P, Hendrix C, Celum C. HIV Protective Efficacy and Correlates of Tenofovir Blood Concentrations in a Clinical Trial of PrEP for HIV Prevention. J Acquir Immune Defic Syndr. 2014 Apr 29. [Epub ahead of print]
Baeten JM, Donnell D, Ndase P, et al. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N Engl J Med. 2012 Aug 2;367(5):399-410.