HIV Antiretroviral Pre-Exposure Prophylaxis: Development Challenges and Pipeline Promise

Abstract

The US Food and Drug Administration (FDA) approved oral daily tenofovir/emtricitabine (Truvada) for pre-exposure prophylaxis of human immunodeficiency virus (HIV) infection in 2012 on the basis of two randomized controlled trials (RCTs), one in men who have sex with men (MSM) and another in HIV serodiscordant heterosexual couples. Subsequently, even greater efficacy has been demonstrated in MSM with rapid population-level incidence reductions in some locations. In contrast, studies of antiretroviral pre-exposure prophylaxis (PrEP) in heterosexual women showed only modest or no efficacy, largely attributed to low adherence. The mixed results of antiretroviral-based PrEP bear witness to unique drug development challenges at this complicated intersection of sexual behavior, public health, and drug development. Multiple innovative methods and formulation strategies followed to address unmet medical needs of persons struggling with daily oral PrEP adherence or preference for nonsystemic PrEP options. Clinical pharmacology plays essential roles throughout this PrEP development process, especially in early product development and through pharmacologically informed enhancement and interpretation of clinical trials.

Figure 1.

HIV prevention methods include strategies to reduce the infectious burden in the infected partner and reduce susceptibility in the uninfected “at risk” partner. PrEP is one of many highly effective methods to reduce HIV infection working in a complementary manner with these other prevention methods.

Figure 2.

Comparison of the vaginal TFV and rectal TFV microbicide product development pathways. Left column indicates numerous methods developed primarily to enhance rectal product development which later influenced vaginal product development, but not in a timely way for TFV 1% vaginal gel development. Four different TFV microbicide products (middle text indicating VF, RGVF, RF, and EF) were developed in temporal sequence (top to bottom). The traditional development stages for both vaginal (top, tan boxes) and rectal (lower, blue boxes) include a brief list of design elements for PK, safety, and acceptability becoming increasingly complex. Red boxes indicate development “no go” decisions. Light blue boxes indicate needed future studies to advance rectal microbicide products.