Antiretroviral-drug concentrations in semen: implications for sexual transmission of human immunodeficiency virus type 1.

The majority of human immunodeficiency virus type 1 (HIV-1) infections result from seminal transmission (17, 104). The size of the viral innoculum in seminal fluid is likely the major determinant of transmissibility. Current HIV prevention strategies include comprehensive population interventions promoting condom use, early diagnosis and treatment of sexually transmitted diseases, and education programs to decrease the rate of sexual-partner change and other high-risk sexual behavior (17, 18, 40, 76, 115). However, antiretroviral therapy targeted to reduce viral shedding in genital secretions may also assist in preventing transmission (17, 86). Although the HIV-1 pandemic continues to be driven by transmission of virus in genital fluids, little is known about the pharmacokinetics and pharmacodynamics of antiretroviral drugs in the genital tract (46). Similarly to the effect of antiretroviral therapy on viral burden in blood and lymphoid tissue (6, 14, 41, 42, 120, 132), potent combinations of HIV-1 reverse transcriptase and protease inhibitors which concentrate in semen may lead to marked viral suppression in this compartment (2, 21, 30, 37, 38, 41–43, 58–60, 84, 117, 118, 124, 138). This article reviews the biology of HIV-1 in the male genital tract, the impact of antiretroviral therapy on seminal shedding, and the emergence of drug-resistant variants. Major determinants of drug distribution into semen are discussed, and strategies for using this information to predict antiretroviral concentrations in this compartment are suggested. Finally, a discussion of animal models critical to investigating correlations between seminal antiretroviral concentrations and viral transmission is included.