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Translational Approach to Predicting the Efficacy of Maraviroc-Based Regimens as HIV Preexposure Prophylaxis.

ABSTRACT: Maraviroc-based regimens have been explored as preexposure prophylaxis (PrEP) against human immunodeficiency virus (HIV). In this study, we utilized mucosal tissue drug exposure data, combined with target concentrations generated in vitro, in a pharmacokinetic-pharmacodynamic analysis to predict the effects of drug combinations and adherence on PrEP efficacy. Mucosal tissue concentrations of maraviroc were measured in 24 healthy women. The 90% effective concentrations (EC90) of maraviroc (alone and combined with tenofovir and emtricitabine) for protection against HIV were identified in CD4+ T cells. Monte Carlo simulations were performed to identify dosing strategies to protect colorectal and female genital tract (FGT) tissues from HIV infection. Colorectal maraviroc concentrations were 350-fold higher than in the FGT. Under steady-state conditions, our model predicted that one 300-mg dose/week was sufficient to protect colorectal tissue from HIV in 99% of the population, while 300?mg daily would protect the FGT in only 63% of the population. FGT protection increased to >90% when maraviroc was used in combination with tenofovir (5 doses/week) or emtricitabine (3 doses/week). Poor adherence resulted in a drastic decrease in efficacy in the FGT but not colorectal tissue. However, greater forgiveness was seen when maraviroc was combined with tenofovir or emtricitabine, suggesting that maraviroc should not be used alone as PrEP.

SUBMITTER: Srinivas N

PROVIDER: S-EPMC6985753 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Translational Approach to Predicting the Efficacy of Maraviroc-Based Regimens as HIV Preexposure Prophylaxis.

Srinivas Nithya N Cottrell Mackenzie M Maffuid Kaitlyn K Prince Heather A HA Nelson Julie A E JAE White Nicole N Sykes Craig C Dellon Evan S ES Madanick Ryan D RD Shaheen Nicholas J NJ Gonzalez Daniel D Kashuba Angela D M ADM

Antimicrobial agents and chemotherapy 20200127 2

Maraviroc-based regimens have been explored as preexposure prophylaxis (PrEP) against human immunodeficiency virus (HIV). In this study, we utilized mucosal tissue drug exposure data, combined with target concentrations generated <i>in vitro</i>, in a pharmacokinetic-pharmacodynamic analysis to predict the effects of drug combinations and adherence on PrEP efficacy. Mucosal tissue concentrations of maraviroc were measured in 24 healthy women. The 90% effective concentrations (EC<sub>90</sub>) of ...[more]

PMID: 31740561

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Project description:Reproductive-age women need effective interventions to prevent the acquisition of human immunodeficiency virus type 1 (HIV-1) infection.We conducted a randomized, placebo-controlled trial to assess daily treatment with oral tenofovir disoproxil fumarate (TDF), oral tenofovir-emtricitabine (TDF-FTC), or 1% tenofovir (TFV) vaginal gel as preexposure prophylaxis against HIV-1 infection in women in South Africa, Uganda, and Zimbabwe. HIV-1 testing was performed monthly, and plasma TFV levels were assessed quarterly.Of 12,320 women who were screened, 5029 were enrolled in the study. The rate of retention in the study was 91% during 5509 person-years of follow-up. A total of 312 HIV-1 infections occurred; the incidence of HIV-1 infection was 5.7 per 100 person-years. In the modified intention-to-treat analysis, the effectiveness was -49.0% with TDF (hazard ratio for infection, 1.49; 95% confidence interval [CI], 0.97 to 2.29), -4.4% with TDF-FTC (hazard ratio, 1.04; 95% CI, 0.73 to 1.49), and 14.5% with TFV gel (hazard ratio, 0.85; 95% CI, 0.61 to 1.21). In a random sample, TFV was detected in 30%, 29%, and 25% of available plasma samples from participants randomly assigned to receive TDF, TDF-FTC, and TFV gel, respectively. Independent predictors of TFV detection included being married, being older than 25 years of age, and being multiparous. Detection of TFV in plasma was negatively associated with characteristics predictive of HIV-1 acquisition. Elevations of serum creatinine levels were seen more frequently among participants randomly assigned to receive oral TDF-FTC than among those assigned to receive oral placebo (1.3% vs. 0.2%, P=0.004). We observed no significant differences in the frequencies of other adverse events.None of the drug regimens we evaluated reduced the rates of HIV-1 acquisition in an intention-to-treat analysis. Adherence to study drugs was low. (Funded by the National Institutes of Health; VOICE ClinicalTrials.gov number, NCT00705679.).

Dataset Information

Translational Approach to Predicting the Efficacy of Maraviroc-Based Regimens as HIV Preexposure Prophylaxis.

Publications

Translational Approach to Predicting the Efficacy of Maraviroc-Based Regimens as HIV Preexposure Prophylaxis.

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