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Tuesday, March 6, 2012

Intracellular drug levels and PrEP dosing strategies

PRN Report from 19th CROI:

In a late breaker, Peter Anderson of the University of Colorado Denver reported on a substudy of the iPrEx trial (which has already demonstrated a 42% decrease in HIV acquisition in men who have sex with men (MSM) assigned to daily oral emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF) versus placebo, with ~90% risk reduction estimated for those with drug detected in blood), in which intracellular drug concentrations associated with pre-exposure prophylaxis (PrEP) efficacy in iPrEx, were used to identify dosing regimens likely to achieve high efficacy.

HIV-uninfected active-arm controls were matched to each active-arm HIV-infected case, plasma and/or viably cryopreserved peripheral blood mononuclear cells (v-PBMC) were tested from all available time points; every 3 months for plasma, every 6 months for v-PBMC, and at HIV seroconversion in cases. Multiple imputation inferred drug levels for all active-arm participants based on observed concentrations and subject characteristics. A Cox model was used to estimate HIV incidence relative to placebo with tenofovir-diphosphate (TFV-DP) as a time-dependent covariate. The predicted HIV risk reduction was then estimated for TFV-DP levels (in v-PBMC) arising from 3 dosing strategies from STRAND, a randomized, crossover trial of oral TDF in 23 HIV– subjects assigned to 2, 4, and 7 doses per week (directly observed), for 6 weeks at each dose.

Six hundred and fifteen v-PBMC and 1146 plasma samples were tested from 1212 time points (302 cases, 910 controls). The risk of contracting HIV was reduced by ≥90% relative to placebo among those with a TFV-DP concentration ≥15.6 fmol/M viable cells (95%CI 3.0 to 28.2). Based on this model, estimated HIV risk reduction associated with TFV-DP troughs (median [IQR]) generated in STRAND was 76% for 2 doses per week, 97% for 4 doses per week and 99% for 7 doses per week.

Dr Anderson concluded that an intracellular TFV-DP concentration of 15.6 fmol/M viable cells was associated with 90% reduced risk of HIV acquisition relative to placebo among MSM. Daily and 4 doses per week of oral TDF produced TFV-DP concentrations corresponding with high PrEP efficacy.

Anderson P, Liu A, Buchbinder S, et al. Intracellular Tenofovir-DP Concentrations Associated with PrEP Efficacy in MSM from iPrEx. Presented March 6, 2012 at the 19th CROI, Seattle, WA. Oral Abstract #31LB.

Source: Reporting from Seattle for PRN News: James Braun, DO