Peter L Anderson1, David V Glidden2, Lane R Bushman3, Walid Heneine4, J Gerardo García-Lerma4. 1. The Department of Pharmaceutical Sciences, University of Colorado Denver, 12850 E. Montview Blvd, Aurora, CO 80045, USA peter.anderson@ucdenver.edu. 2. The Department of Epidemiology and Biostatistics, University of California San Francisco, 185 Berry St W., San Francisco, CA 94143, USA. 3. The Department of Pharmaceutical Sciences, University of Colorado Denver, 12850 E. Montview Blvd, Aurora, CO 80045, USA. 4. The Laboratory Branch, Division of HIV/AIDS Prevention, Centers for Disease Control, 1600 Clifton Rd, Atlanta, GA 30329, USA.
Abstract
OBJECTIVES: This study evaluated the relationship between intracellular tenofovir diphosphate concentrations in peripheral blood mononuclear cells and prophylactic efficacy in a macaque model for HIV pre-exposure prophylaxis (PrEP). METHODS: Macaques were challenged with simian HIV (SHIV) via rectal inoculation once weekly for up to 14 weeks. A control group (n=34) received no drug, a second group (n=6) received oral tenofovir disoproxil fumarate/emtricitabine 3 days before each virus challenge and a third group (n=6) received the same dosing plus another dose 2 h after virus challenge. PBMCs were collected just before each weekly virus challenge. The relationship between tenofovir diphosphate in PBMCs and prophylactic efficacy was assessed with a Cox proportional hazards model. RESULTS: The percentages of animals infected in the control, one-dose and two-dose groups were 97, 83 and 17, respectively. The mean (SD) steady-state tenofovir diphosphate concentration (fmol/10(6) cells) was 15.8 (7.6) in the one-dose group and 30.7 (10.1) in the two-dose group. Each 5 fmol tenofovir diphosphate/10(6) cells was associated with a 40% (95% CI 17%-56%) reduction in risk of SHIV acquisition, P=0.002. The tenofovir diphosphate concentration associated with a 90% reduction in risk (EC90) was 22.6 fmol/10(6) cells (95% CI 13.8-60.8). CONCLUSIONS: The prophylactic EC90 for tenofovir diphosphate identified in macaques exposed rectally compares well with the EC90 previously identified in men who have sex with men (MSM; 16 fmol/10(6) cells, 95% CI 3-28). These results highlight the relevance of this model to inform human PrEP studies of oral tenofovir disoproxil fumarate/emtricitabine for MSM.
OBJECTIVES: This study evaluated the relationship between intracellular tenofovir diphosphate concentrations in peripheral blood mononuclear cells and prophylactic efficacy in a macaque model for HIV pre-exposure prophylaxis (PrEP). METHODS: Macaques were challenged with simian HIV (SHIV) via rectal inoculation once weekly for up to 14 weeks. A control group (n=34) received no drug, a second group (n=6) received oral tenofovir disoproxil fumarate/emtricitabine 3 days before each virus challenge and a third group (n=6) received the same dosing plus another dose 2 h after virus challenge. PBMCs were collected just before each weekly virus challenge. The relationship between tenofovir diphosphate in PBMCs and prophylactic efficacy was assessed with a Cox proportional hazards model. RESULTS: The percentages of animals infected in the control, one-dose and two-dose groups were 97, 83 and 17, respectively. The mean (SD) steady-state tenofovir diphosphate concentration (fmol/10(6) cells) was 15.8 (7.6) in the one-dose group and 30.7 (10.1) in the two-dose group. Each 5 fmol tenofovir diphosphate/10(6) cells was associated with a 40% (95% CI 17%-56%) reduction in risk of SHIV acquisition, P=0.002. The tenofovir diphosphate concentration associated with a 90% reduction in risk (EC90) was 22.6 fmol/10(6) cells (95% CI 13.8-60.8). CONCLUSIONS: The prophylactic EC90 for tenofovir diphosphate identified in macaques exposed rectally compares well with the EC90 previously identified in men who have sex with men (MSM; 16 fmol/10(6) cells, 95% CI 3-28). These results highlight the relevance of this model to inform human PrEP studies of oral tenofovir disoproxil fumarate/emtricitabine for MSM.
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