Discussion
PD, TAF, HSV-2
SEXUALLY TRANSMITTED INFECTION
We found that a single vaginal application of a TAF/EVG containing insert was safe, well tolerated and acceptable. There were no product related TEAEs. The insert rapidly delivered TAF, which converted into TFV, and EVG, yielding high concentrations in vaginal fluid by 4h after dosing (first time point evaluated) and leading to high tissue concentrations of EVG at 4 and 24h post dosing, followed by high TFV-DP, TFV active metabolite, concentrations 24-72h post dosing. Altogether these PK data were in agreement with the significant PD antiviral effect observed both in vaginal fluid and tissue.Data from several recent acceptability studies and discrete choice experiments using placebo products (The TAF/EVG insert is more discreet and convenient than the TFV vaginal gel, an extensively tested (As expected, the topical product resulted in low systemic absorption. Systemic TFV concentrations were consistent with past studies of peri-coital topical TFV vaginal gel (A single topical dose delivered high local mucosal concentrations of TAF, TFV and EVG for up to 72 hours post dosing. All but one participant had detectable vaginal concentrations of TFV and EVG for up to 7 days post dosing. TAF is a prodrug of TFV which rapidly partitions into tissues and in particular immune cells (As expected, we found significant positive linear correlations between vaginal fluid inhibition of HIV Similar to the vaginal fluid PK data, we found peak concentrations of the TFV prodrug, TAF, in tissue, at 4 hours post dosing. Concentrations of TFV, EVG and the active metabolite, TFV-DP, in vaginal tissue peaked at 24 hours post dosing. This study is limited by the fact that post dosing tissue PK samples were collected at 4 hours, 24 hours, 48 hours and 72 hours post dosing, so we cannot determine if these tissue concentrations peaked before or between 4 and 24 hours post dosing. However, data in non-human primates administered with the same insert vaginally show high levels of EVG and TAF/TFV in CV fluid and tissues two hours after insertion, the earliest time point studied (The benchmark of 1,000 fmol/mg for TFV-DP levels in tissue comes from a delayed efficacy study of TFV gel in macaques, demonstrating a drop in protection associated with TFV-DP mucosal levels below 1000 fmol/10Benchmark tissue concentrations have not been established for EVG in HIV-1 prevention, although its IC50 The likelihood of protection against mucosal HIV-1 acquisition is also supported by our clinical In addition, although not the primary outcomes of the trials, topical TFV gel reduced acquisition of genital HSV-2 compared to placebo in two previous Phase IIb trials (The strengths of this study include longitudinal follow up with systemic and local PK characterization and PD modeling in this first-in-woman study of a vaginal insert containing two potent anti-retrovirals (ARVs). Other ARVs are being developed as vaginal inserts for HIV-1 prevention (reviewed in (Product adherence was confirmed in all participants, since the dose was self-administered in the clinic. Although the sample size was based on feasibility and not statistical calculations, participants demonstrated high tissue and fluid PK concentrations, which correlated well with PD modeling endpoints. Because the sample size was consistent with a Phase I, first-in-human clinical trial, we could only obtain tissue for PK and PD sampling at only a few times post dosing. However, these times provide important initial PK profiles for post dosing intervals. We only tested a single dose, and so we will need to perform follow on safety, PK and PD studies to understand the performance of the product after multiple exposures. Our current PK data likely support a 72-hour span of protection, but we will need to confirm this hypothesis with additional PD modeling at the 72-hour mark.Acceptability data obtained for this low risk, Phase I study population may not be applicable to younger, at risk populations worldwide in different cultural contexts. While this study population was not the target end user, participants were interested in using the product outside of the trial if it protected from HIV and HSV, presumably due to the protection from HSV, which is the most common sexually transmitted infection world-wide. Phase I studies provide a good opportunity to detect major negative reactions to investigational products and discover certain product attributes that may need further refinement. We previously tested a vaginal insert containing tenofovir disoproxil fumarate and emtricitabine for HIV-1 prevention (CONRAD 117 (NCT01694407)) (In conclusion, these data support that a single, easy to use vaginal insert delivers high mucosal concentrations of TAF, TFV, TFV-DP, and EVG locally for an extended time (3+ days) after dosing. Clinical PK and PD surrogates, in addition to NHP studies, support efficacy against HIV-1, and possibly HSV-2, at the CV mucosal level. Additionally the inserts were safe and acceptable, and dissolved rapidly. An on-demand, event-driven product, delivering highly potent ARVs, throughout an extended window of time, will fill an important gap in the current HIV prevention options, especially for AGYWs.