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. 2018 Sep 8;218(8):1284-1290.
doi: 10.1093/infdis/jiy301.

Efficacy of Vaginally Administered Gel Containing Emtricitabine and Tenofovir Against Repeated Rectal Simian Human Immunodeficiency Virus Exposures in Macaques

Charles W Dobard  1 , Natalia Makarova  1 , Rolieria West-Deadwyler  1 , Andrew Taylor  2 , Chuong Dinh  1 , Amy Martin  1 , Jonathan Lipscomb  1 , James Mitchell  1 , George Khalil  1 , Gerardo Garcia-Lerma  1 , Walid Heneine  1
Affiliations

Efficacy of Vaginally Administered Gel Containing Emtricitabine and Tenofovir Against Repeated Rectal Simian Human Immunodeficiency Virus Exposures in Macaques

Charles W Dobard et al. J Infect Dis. .

Abstract

Vaginal microbicides containing antiretrovirals (ARVs) have shown to prevent vaginally acquired human immunodeficiency virus (HIV), but these products may not protect women who engage in anal sex. Intravaginal dosing with ARVs has shown to result in drug exposures in rectal tissues, thus raising the possibility of dual compartment protection. To test this concept, we investigated whether intravaginal dosing with emtricitabine (FTC)/tenofovir (TFV) gel, which fully protected macaques against repeated vaginal exposures to simian human immunodeficiency virus (SHIV), protects against rectal SHIV exposures. Pharmacokinetic studies revealed rapid distribution of FTC and TFV to rectal tissues and luminal fluids, albeit at concentrations 1-2 log10 lower than those in the vaginal compartment. Efficacy measurements against repeated rectal SHIV challenges demonstrated a 4.5-fold reduction in risk of infection in macaques that received intravaginal FTC/TFV compared to placebo gel (P = .047; log-rank test). These data support the concept of dual compartment protection by vaginal dosing and warrants developing ARV-based vaginal products with improved bidirectional dosing.

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Figures

Figure 1.
Figure 1.
Pharmacokinetic drug distribution in blood, vaginal, and rectal compartments following intravaginal emtricitabine (FTC)/tenofovir (TFV) gel dosing. A, The data shown are median FTC and TFV concentrations and interquartile ranges in plasma (circles), rectal (squares), and vaginal (diamonds) fluids following intravaginal dosing with FTC/TFV gel. B, Intracellular TFV-diphosphate and FTC-triphosphate concentrations measured in peripheral blood mononuclear cells, vaginal lymphocytes, and rectal lymphocytes 2 hours after intravaginal FTC/TFV dosing. Solid black and gray circles represent individual animals. Abbreviations: DP, diphosphate; FTC, emtricitabine; RF, rectal fluid; TFV, tenofovir; TP, triphosphate; VF, vaginal fluid.
Figure 2.
Figure 2.
Rectal simian human immunodeficiency virus infection delayed in macaques treated with vaginal emtricitabine (FTC)/tenofovir (TFV) gel. Kaplan–Meier plot representing the cumulative percentage of uninfected macaques as a function of the number of rectal challenges. Macaques were challenged twice per week (every 3–4 days) 30 minutes after intravaginal dosing with placebo or FTC/TFV gel.
Figure 3.
Figure 3.
Longitudinal plasma drug concentrations during study period. Emtricitabine (FTC; open squares) and tenofovir (TFV; solid circles) levels in plasma 30 minutes after intravaginal FTC/TFV dosing. Black arrows indicate rectal challenges. Macaques continued to receive twice-weekly intravaginal gel dosing for a median of 7 weeks after the last rectal challenge. Abbreviations: FTC, emtricitabine; PEb, PLj, PNh, PNj, POk, PRf, animal identification; TFV, tenofovir. Abbreviations: TFV, tenofovir; FTC, emtricitabine; PEb, PLj, PNh, PNj, POk, PRf; animal identification.
Figure 4.
Figure 4.
Breakthrough infections have blunted viremia but show no evidence of M184V or K65R emergence. Median plasma simian human immunodeficiency virus (SHIV) RNA levels of controls (gray dashed line) and breakthrough infections (black dashed line) under continued twice-weekly dosing with placebo and emtricitabine (FTC)/tenofovir (TFV) gel, respectively. *Statistically significant differences in peak levels (P = .03, Wilcoxon–Mann–Whitney test). Solid circles (●) indicate plasma samples in breakthrough infections screened for M184V and K65R mutations.
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