Pre-exposure prophylaxis for HIV prevention: how to predict success

Use of antiretroviral drugs to prevent sexual transmission of HIV-1 has been a critical priority since their development. In the past 2 years results from seven important prevention trials have been reported (table). One of the trials, HPTN 052, showed nearly complete prevention of HIV transmission when viraemia was suppressed. The other studies focused on antiretroviral agents for pre-exposure prophylaxis: two used 1% tenofovir gel (CAPRISA 004 and VOICE), four used oral tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) in combination (iPrEX, TDF2, Partners in Prevention [PIP], and Fem-PrEP), and two used oral TDF alone (VOICE and PIP). Somewhat confusingly, the findings of these studies have led to reports both of successful prevention of HIV infection (CAPRISA 004, iPrEx, TDF2, and PIP) and of futility (VOICE and Fem-PrEP)

Population Modeling Highlights Drug Disposition Differences Between Tenofovir Alafenamide and Tenofovir Disoproxil Fumarate in the Blood and Semen

Understanding antiretroviral disposition in the male genital tract, a distinct viral compartment, can provide insight for the eradication of HIV. Population pharmacokinetic modeling was conducted to investigate the disposition of tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF), and emtricitabine and their metabolites in blood and semen. Blood plasma and seminal plasma (SP) concentrations of tenofovir and emtricitabine were measured, as were tenofovir-diphosphate and emtricitabine-triphosphate concentrations in peripheral blood mononuclear cells (PBMCs) and seminal mononuclear cells. Sequential compartmental modeling described drug disposition in blood and semen. Our modeling suggests slower elimination of apparent tenofovir-diphosphate PBMC and faster elimination of tenofovir SP after administration of TAF compared with TDF, likely reflecting flip-flop kinetics. Additionally, TAF metabolism to tenofovir appeared slower in semen compared with blood; however, SP elimination of TAF-derived tenofovir appeared faster than its blood plasma elimination. These findings provide valuable insight for further mechanistic study of cellular entry and drug metabolism in the male genital tract

Differential Extracellular, but Similar Intracellular, Disposition of two Tenofovir Formulations in the Male Genital Tract

Background: The male genital tract (MGT) is a viral sanctuary and likely HIV reservoir; understanding MGT pharmacokinet-ics (PK) of antiretrovirals (ARVs) used for curative strategies is critical to eradication and cure. Tenofovir alafenamide (TAF) is a tenofovir (TFV) formulation designed to maximize efficacy/minimize toxicity with unknown MGT PK. Methods: HIV-positive and HIV-negative men receiving TFV-based regimens provided six paired blood plasma (BP) and semen samples. Extracellular (TFV, TAF, emtricitabine [FTC]) drug concentrations in BP and seminal plasma (SP), and intracellular metabolite (IM) and endogenous nucleotide (EN) concentrations were measured in peripheral blood mononuclear cells (PBMCs) and seminal mononuclear cells (SMCs). Exposure ratios for SP:BP, SMC:PBMC and IM:EN were calculated from PK parameters generated by noncompartmental analysis. HIV viral load was measured in BP and SP. Results: Sixteen HIV-positive (n=8, TDF/FTC; n=8, TAF/FTC) and eight HIV-negative (TDF/FTC) men provided samples. Median TFV SP:BP ratios differed between TDF and TAF (1.5 versus 7.4), due to lower TFV BP concentrations with TAF coupled with TFV SP concentrations similar to TDF. FTC SP:BP ratios were approximately 3. SMC concentrations of IMs and ENs were a fraction of PBMC concentrations (1–22%), though IM:EN ratios exceed a suggested protective threshold. Conclusions: TAF SP PK was unexpected. IM SMC concentrations were low relative to PBMC, as were EN concentrations, suggesting differences in cell phenotype and lineage in the MGT; these differences in phenotype and pharmacology may have an impact on selecting and dosing ARVs used in cure strategies

ANTHROPOLOGY AND PUBLIC POLICY IN ALASKA: RECENT POLICY RELATED TO LEGAL SYSTEMS NATIVE SUBSISTENCE AND COMMERCIAL FISHERIES

The past and potential contributions of anthropology to public policy have been described andlor argued for by numerous writers in the past decade, but the primary application and concern have been at the national and international levels. The present paper continues this discussion, but focuses on state-level policy in Alaska. The work of three Alaskan anthropologists is presented; they have made significant contributions to policy in the areas of law, Native Alaskan subsistence rights and fisheries management. Their work is evaluated in the context of a five-step model for conducting policy analysis which begins with the assessment of policy-making environments and ends with an evaluation of policy alternatives. The primary policy concerns of the anthropologists discussed involved the traditional research focus of anthropology, Native Alaskans; however, the tools they employ and background they bring to their work, the specific kinds of policy issues and problems confronted, are not as traditional. One of the anthropologists discussed is atlingit Indian completing doctoral studies at Harvard University, another is a lawyer-anthropologist, and the third is highly trained in biological and economic theory as well as computer technology. It is argued that the "hyphenated" anthropologist, at least as exemplified in the cases discussed, is most readily equipped to make policy relevant contributions. Copyright 1981 by The Policy Studies Organization.