Tenofovir diphosphate concentrations and prophylactic effect in a macaque model of rectal simian HIV transmission
Peter L Anderson1, David V Glidden2, Lane R Bushman3
1The Department of Pharmaceutical Sciences, University of Colorado Denver, 12850 E. Montview Blvd, Aurora, CO 80045, USA peter.anderson@ucdenver.edu.
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.
Insights
This study shows that higher intracellular tenofovir diphosphate levels in macaques correlate with better protection against simian-human immunodeficiency virus (SHIV) infection, informing HIV pre-exposure prophylaxis (PrEP) strategies.
Area of Science:
- Virology
- Pharmacology
- Immunology
Background:
- Pre-exposure prophylaxis (PrEP) is a key strategy for HIV prevention.
- Understanding the relationship between drug concentration and efficacy is crucial for optimizing PrEP.
- Intracellular tenofovir diphosphate is the active metabolite of tenofovir disoproxil fumarate, a component of commonly used PrEP regimens.
Purpose of the Study:
- To evaluate the correlation between intracellular tenofovir diphosphate concentrations in peripheral blood mononuclear cells (PBMCs) and the prophylactic efficacy of tenofovir disoproxil fumarate/emtricitabine.
- To determine the effective concentration for 90% protection (EC90) in a macaque model for rectal HIV exposure.
Main Methods:
- Macaques were administered oral tenofovir disoproxil fumarate/emtricitabine with varying dosing regimens and challenged rectally with simian-human immunodeficiency virus (SHIV).
- Peripheral blood mononuclear cells (PBMCs) were collected weekly to measure intracellular tenofovir diphosphate concentrations.
- A Cox proportional hazards model was used to assess the relationship between tenofovir diphosphate levels and SHIV acquisition risk.
Main Results:
- The two-dose regimen significantly reduced SHIV infection rates (17%) compared to the one-dose (83%) and control (97%) groups.
- A dose-dependent increase in intracellular tenofovir diphosphate concentrations was observed with higher dosing.
- Each 5 fmol/10(6) cells increase in tenofovir diphosphate was associated with a 40% reduction in SHIV acquisition risk.
Conclusions:
- The prophylactic EC90 for tenofovir diphosphate in this macaque model (22.6 fmol/10(6) cells) is comparable to that found in human studies for men who have sex with men (MSM).
- This macaque model effectively predicts the efficacy of oral tenofovir disoproxil fumarate/emtricitabine for HIV PrEP in humans.
- These findings support the use of intracellular tenofovir diphosphate levels as a biomarker for monitoring PrEP efficacy.
