157 – Optimizing On-Demand Tenofovir Disoproxil Fumarate/Emtricitabine Dosing in Women for HIV Prevention

Background

Despite availability of long-acting products for HIV pre-exposure prophylaxis (PrEP), some women may prefer on-demand oral PrEP. Using an existing PK/PD model (Cottrell JID 2016), we previously predicted protective drug exposure would be sustained in the female genital tract (FGT) for 5 days after sex for >80% of the population using the 2-1-1 IPERGAY regimen (#2 tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) tablets pre-sex then #1 tablet 24 and 48 hours after), and >90% of the population regularly taking 4 tablets/week on Tuesday, Thursday, Saturday, and Sunday. Here, we sought to identify the optimal on-demand TDF/FTC regimen to achieve protective drug exposure in the FGT over 5-10 days post-sex.

Methods

TDF/FTC tissue PK/PD predictions were generated via the aforementioned published in vivo/in vitro model with the EC₉₀ derived from an in vitro synergy model of TDF/FTC’s active metabolites vs competing endogenous nucleotides. The proportions of 1000 predicted profiles achieving EC₉₀ in the FGT at 5, 7, and 10 days post-sex were calculated for all simulated dosing scenarios. These were extensions of the 2-1-1 regimen and included: 2-2-1, 2-2-2, 2-1-1-1, 2-2-1-1, 2-2-2-1, and 2-2-2-2. PK modeling/simulation was performed in NONMEM v7.2, and R was used for synergy modeling and data management/visualization. 

Results

Table 1 shows proportion achieving EC₉₀ in the FGT over time following sex. All regimens demonstrate >80% achievement of EC₉₀ at 5 days. A 2^nd double-dose increases the proportion achieving EC₉₀ at 7 days by 20-30% compared to the IPERGAY regimen. Extending to 4 days of dosing increases the proportion achieving EC₉₀ >80% at 7 days post-sex. No regimen sustained this high proportion achieving EC₉₀ for 10 days post sex. 

Conclusions

Our model suggests prevention of HIV acquisition via the FGT using on-demand TDF/FTC dosing with an initial double-dose is likely, with high (>80%) protection for 5 days after sex. Adding a 4^th day of dosing is required to achieve >80% protection for 7 days, with 2-2-2-2 at 95% and 2-1-1-1 at 84% protection. While limited data suggest 2-2-2-2 dosing is safe for short-term use, the 2-1-1-1 regimen may better balance safety, efficacy, and tolerability while maintaining effectiveness comparable to 4 daily doses/week reported by recent analyses of PrEP clinical trial data. The 2-2-2, 2-1-1-1, and 2-2-1-1 regimens could be considered in future clinical studies of on-demand PrEP in cisgender women. 

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