Intermittent Prophylaxis with Oral Truvada Protects Macaques from Rectal SHIV Infection

Abstract

HIV continues to spread globally, mainly through sexual contact. Despite advances in treatment and care, preventing transmission with vaccines or microbicides has proven difficult. A promising strategy to avoid transmission is prophylactic treatment with antiretroviral drugs before exposure to HIV. Clinical trials evaluating the efficacy of daily treatment with the reverse transcriptase inhibitors tenofovir disoproxil fumarate (TDF) or Truvada (TDF plus emtricitabine) are under way. We hypothesized that intermittent prophylactic treatment with long-acting antiviral drugs would be as effective as daily dosing in blocking the earliest stages of viral replication and preventing mucosal transmission. We tested this hypothesis by intermittently giving prophylactic Truvada to macaque monkeys and then exposing them rectally to simian-human immunodeficiency virus (SHIV) once a week for 14 weeks. A simple regimen with an oral dose of Truvada given 1, 3, or 7 days before exposure followed by a second dose 2 hours after exposure was as protective as daily drug administration, possibly because of the long intracellular persistence of the drugs. In addition, a two-dose regimen initiated 2 hours before or after virus exposure was effective, and full protection was obtained by doubling the Truvada concentration in both doses. We saw no protection if the first dose was delayed until 24 hours after exposure, underscoring the importance of blocking initial replication in the mucosa. Our results show that intermittent prophylactic treatment with an antiviral drug can be highly effective in preventing SHIV infection, with a wide window of protection. They strengthen the possibility of developing feasible, cost-effective strategies to prevent HIV transmission in humans.

HIV, transmitted drug resistance, and the paradox of preexposure prophylaxis

“…However, macaques exposed to an SIV isolate carrying the TDF resistance mutation (K65R) were not protected by TDF, which suggests PrEP may be less effective against ARV-resistant viruses (19). Substantial reductions in viremia and blunted acute viremias (up to 2log 10 reduction) have been observed in a patient failing Truvada and in macaques failing PrEP with FTC, Truvada, or a CCR5 inhibitor (17,18,(20)(21)(22). These results suggest that even when PrEP does not prevent infection it may, by reducing viral load and/or reducing CD4 + T-cell depletion, help preserve immune function that could attenuate the course of HIV infection (21).…”

Les moyens de prévention de l’infection à VIH à base d’antirétroviraux

“…Des essais, dont un en France (essai ANRS IPERGAY), évaluent actuellement l'efficacité d'une PrEP orale intermittente consistant à prendre des comprimés, non pas en continu, mais avant et après l'exposition au risque VIH. Des études chez l'animal ont déjà validé la preuve de concept de cette posologie [47]. L'intermittence pourrait augmenter l'adhésion des personnes à cette stratégie, améliorer la tolérance et également réduire les coûts qu'entraînerait une prise de la PrEP en continu.…”

HIV Prevention by Oral Preexposure Prophylaxis

“…However, the high drug doses and subcutaneous drug delivery might have overestimated efficacy in both studies. More recent work using human equivalent doses of Truvada showed that macaques can be protected from rectal SHIV infection by several PrEP modalities, including a single oral dose given 1 -7 d before exposure, followed by a second dose 2 h after exposure (Garcia-Lerma et al 2010). Exposure-driven prophylactic modalities initiated around the time of exposure also maintained protection.…”