Maximizing Effectiveness of HIV Preexposure Prophylaxis Among Men Who Have Sex with Men

Despite decades of prevention and treatment efforts, human immunodeficiency virus (HIV) infection is a global pandemic, with HIV/acquired immunodeficiency syndrome (AIDS) among the leading causes of death for children and adults in developing countries. HIV/AIDS disproportionately affects men who have sex with men (MSM), including in the United States, where MSM account for over half of all new HIV infections. Existing HIV prevention tools have not been sufficient to curb the pandemic, and biomedical prevention strategies, such as circumcision and microbicides, had not been shown to be effective in preventing HIV infection in MSM until 2010, when the multi-national iPrEx study found that daily oral preexposure prophylaxis (PrEP) using antiretroviral therapy (emtricitabine/tenofovir, or FTC/TDF) prevented HIV infection among MSM and transgender women. Although the success of FTC/TDF PrEP in such trials has given new hope to the HIV prevention field, excitement has been tempered by concerns about low adherence to daily pill use among trial participants. Adherence, as measured by self-reported pill use, was high among participants in the iPrEx trial, but testing for evidence of the drug in blood specimens from a subset of participants indicated that actual pill use was much lower than reported pill use. Adherence is critical for PrEP effectiveness; iPrEx participants in whom antiretroviral drug was detected in blood experienced a substantially greater reduction in HIV risk than was seen overall. The iPrEx results suggest that low adherence may be a barrier to successful implementation of PrEP as an HIV prevention strategy among MSM. Identification of effective strategies for supporting the consistent use of prophylactic medications could provide much needed guidance in the development of interventions to support adherence to PrEP.In addition to concerns about adherence, there is a widespread concern that PrEP could result in an increase in sexual risk behaviors by lowering users' perception of their risk of acquiring HIV infection; such risk compensation could reduce or even negate the benefits of PrEP. Foundational to most models of health behavior is the hypothesis that perceived risk is a primary motivation for self-protective behavior. Based on this theory, when a new prevention strategy, such as PrEP, is introduced, risk compensation could be prevented by sustaining individuals' perceptions of their own HIV risk. While the act of taking PrEP on a daily basis could result in risk compensation, it could also provide a daily opportunity to contemplate and manage HIV risk, thus motivating condom use and other self-protective behaviors. A better understanding of whether, and how, PrEP use affects sexual risk behavior could inform the development of risk-reduction interventions for individuals prescribed PrEP. In addition to preventing HIV infection, there is evidence that FTC/TDF PrEP may also be protective against infection with Herpes simplex virus type 2 (HSV-2). HSV-2 is the primary cause of genital ulcer disease worldwide, and HSV-2 infection is known to increase the risk of sexual transmission and acquisition of HIV infection. In the CAPRISA 004 study, a topical 1% tenofovir gel used as PrEP against HIV infection also reduced the risk of HSV-2 acquisition by 51% in women. In the Partners PrEP study, oral FTC/TDF reduced HSV-2 acquisition by 35% among heterosexual couples. Protection against HSV-2 acquisition or expression could enhance the public health impact of PrEP, but it is unknown whether FTC/TDF has anti-herpetic properties in men who have sex with men. The effectiveness of FTC/TDF PrEP in protecting against HIV infection depends on individual-level behaviors, including adherence and sustained risk reduction, as well as its effect on other sexually transmitted infections (STI) that increase the risk of HIV acquisition. Chapter 1 of this dissertation describes a systematic review that aimed to identify interventions that have been used to support adherence to daily oral medications prescribed to healthy or asymptomatic individuals. This review found evidence of interventions that demonstrated short-term improvements in medication adherence across a variety of prevention settings, thus identifying potential strategies for adherence support among PrEP users. Chapter 2 describes an analysis of data from the randomized phase of the iPrEx study to determine whether sexual risk compensation occurred among trial participants. Consistent with other PrEP studies, this analysis found no evidence of increased sexual risk behavior or STIs among participants who believed they had been assigned to the FTC/TDF arm and that the drug was highly effective. Finally, Chapter 3 describes an analysis that used data from the randomized phase of iPrEx to measure the effect of FTC/TDF on HSV-2 acquisition and expression among men who have sex with men. Although there was no effect of FTC/TDF on HSV-2 acquisition, participants receiving the active drug had a lower prevalence of herpetic ulcers than participants receiving the placebo. Taken together, these papers contribute to the HIV prevention field by providing guidance on behavioral support strategies for daily oral PrEP and identifying anti-herpetic properties of FTC/TDF that could increase its effectiveness as a novel prevention tool