 |
|
|
| |
Efficacy of Intermittent Prophylaxis with Tenofovir and Emtricitabine against Rectal SHIV Transmission in Macaques and Relationship to Systemic and Mucosal Drug Levels
|
| |
| |
Reported by Jules Levin
CROI 2010
Gerardo Garcia-Lerma*1, M-E Cong1, Q Zheng1, A Holder1, A Martin1, C-C Lin1, R Otten1, W Lee2, C-P Pau1, and W Heneine1
1CDC, Atlanta, GA, US and 2Gilead Sci, Foster City, CA, US
Background: Intermittent pre-exposure prophylaxis (iPrEP) with long-acting drugs is a promising HIV prevention strategy. We evaluated in macaques the efficacy of iPrEP dosing regimens with Truvada (FTC and TDF) or GS7340, a next-generation tenofovir (TFV) pro-drug that at low doses results in high TFV-diphosphate (TFV-DP) levels in peripheral blood mononuclear cells (PBMC). We also assessed drug pharmacokinetics and their relationship to efficacy.
Methods: Efficacy was evaluated by a repeat-challenge macaque model consisting of up to 14 weekly rectal SHIV exposures. Truvada was given orally to groups of 6 macaques according to the following schedule (times are relative to virus exposure): +2h/+26h, -2h/+24h, -22h/+2h, -3d/+2h, and -7d/+2h. Two additional groups of 6 animals received one dose of Truvada or GS7340 3 days prior to exposure without a post-exposure dose. Drug levels were evaluated at first dose in plasma, PBMC, rectal secretions, and tissues. The Cox proportional hazards model was used to estimate risks of infection in treated animals relative to 32 untreated controls.
Results: iPrEP modalities with Truvada containing both a pre- and a post-exposure dose or 2 post-exposure doses significantly reduced the risk of infection by 4.1-fold (+2h/+24h, P =0.03), 4-fold (-2h/+24h, P =0.02), 16.7-fold (-22h/+2h, P =0.006), 15.4-fold (-3d/+2h, P =0.008) and 9.3-fold (-7d/+2h, P =0.003).
The half-life of TFV-DP and FTC-TP in PBMC was 115 h and 24 h, respectively. FTC, but not TFV, was consistently detected in rectal secretions 2 to 5 h after dosing; concentrations of both FTC and TFV in secretions were highest at 24 hr (median = 743 and 1186 ng/mL, respectively). TFV-DP levels in rectal tissues were also high at 24 hr and remained high for 2 days to 7 days. Despite the long persistence of TFV-DP in PBMC and high TFV-DP levels in rectal tissues, a single - 3 day dose of Truvada was not effective (HR reduction = 0.5, P =0.16). A single -3d GS7340 dose was also ineffective (HR reduction = 0.5, P =0.24) despite the high TFV-DP levels seen at exposure (median = 773 fmol/106 PBMC). Median TFV-DP levels in PBMC after GS7340 dosing were 100-fold higher than after TDF dosing.
Conclusions: A single pre-exposure dose with Truvada or GS7340 was not sufficient to protect macaques despite the long persistence of TFV-DP. Combined with a post-exposure dose, iPrEP with Truvada was highly protective. The rapid FTC penetration in rectal tissues suggests that FTC plays an important role in the protection contributed by the post-exposure dose.
|
| |
|
|
|
|
|
