Abstract
With more than 7,000 new HIV infections daily worldwide, there is an urgent need for non-vaccine biomedical prevention (nBP) strategies that are safe, effective, and acceptable. Clinical trials have demonstrated that pre-exposure prophylaxis (PrEP) with antiretrovirals (ARVs) can be effective at preventing HIV infection. In contrast, other trials using the same ARVs failed to show consistent efficacy. Topical (vaginal and rectal) dosing is a promising regimen for HIV PrEP as it leads to low systematic drug exposure. A series of titration studies were carried out in bone marrow/liver/thymus (BLT) mice aimed at determining the adequate drug concentrations applied vaginally or rectally that offer protection against rectal or vaginal HIV challenge. The dose-response relationship of these agents was measured and showed that topical tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) can offer 100% protection against rectal or vaginal HIV challenges. From the challenge data, EC50 values of 4.6 μM for TDF and 0.6 μM for FTC for HIV vaginal administration and 6.1 μM TDF and 0.18 μM for FTC for rectal administration were obtained. These findings suggest that the BLT mouse model is highly suitable for studying the dose-response relationship in single and combination ARV studies of vaginal or rectal HIV exposure. Application of this sensitive HIV infection model to more complex binary and ternary ARV combinations, particularly where agents have different mechanisms of action, should allow selection of optimal ARV combinations to be advanced into pre-clinical and clinical development as nBP products.
Highlights
More than 7,000 new HIV infections occur daily [1], creating an urgent need to identify new strategies that prevent transmission of the virus
Applied tenofovir disoproxil fumarate (TDF) offered no protection against a vaginal HIV challenge at 8, 80 and 800 nM, 66.7% protection at 8,000 nM and 100% at 80,000 nM, while frequently in combination with emtricitabine (FTC) offered no protection at 1 and 10 nM, 33.3% protection at 100 nM and 100% at 1,000 and 10,000 nM
It is well established that pre-exposure prophylaxis (PrEP) with ARV drugs delivered orally [11,12,13,14,15,16] or topically [2,3,4,5,6,7,8,9,10, 17,18,19,20,21,22,23,24] can significantly reduce HIV infection in individuals who are adherent to the drug regimen
Summary
More than 7,000 new HIV infections occur daily [1], creating an urgent need to identify new strategies that prevent transmission of the virus. Multiple clinical trials based on tenofovir (TFV) dosing regimes, frequently in combination with emtricitabine (FTC), provided evidence that PrEP significantly reduced HIV infection in individuals [16,17,18,19,20,21,22,23,24]. Two additional trials with 1% tenofovir gel with pericoital (VOICE) [25] and daily (FACTS) [26] dosing regimens failed to provide efficacy against new sexual HIV infections
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