Background:
On-demand topical products for rectal use are desired by the community and could be an important tool for HIV prevention. A tenofovir alafenamide/elvitegravir (TAF/EVG) fast-dissolve insert has demonstrated protective efficacy in a NHP SHIV rectal challenge model. We evaluated the safety and pharmacokinetics (PK) of the TAF/EVG insert administered rectally at two dose levels.
Methods:
MTN-039 was a Phase 1, two-site, open-label, single arm, two-period study of rectal administration of one TAF/EVG insert (20/16 mg), followed by ≥7 day washout, then two TAF/EVG inserts. Inserts were administered in the clinic; blood, rectal fluid (RF), and rectal tissue (RT) were collected over 72 hours following administration (participants randomized to RT collection at 2h/48h or 24h/72h). EVG, TAF, and tenofovir (TFV) levels were measured in plasma, RF and RT homogenates; and TFV-DP in RT mononuclear cells. Ex vivo HIV infectivity of RT explants was done pre- and post-dosing as a pharmacodynamic (PD) measure.
Results:
Twenty-one participants without HIV (71% male) were enrolled and received study product (n=21 for 1 insert; n=19 for 2 inserts). TAF/EVG inserts were safe; 9 participants reported 17 adverse events (AEs); one mild AE (anal erythema) was related. Median peak plasma EVG, TAF and TFV concentrations (conc) for 1/2 inserts were 1.73/2.39, 29.5/41.9, and 2.64/4.42 ng/mL, respectively. EVG and TFV were detected in RF in all samples at 2h; median values for 1/2 inserts at 24h were EVG 2234/2597 ng/mL and TFV 2909/8277 ng/mL. EVG and TFV were detected in nearly all RT homogenates at 2h post-dose; EVG conc declined and were BLQ in 50%/30% for 1/2 inserts at 24 hours whereas TFV was measurable in the majority of samples for 72h. Median RT cell TFV-DP conc exceeded target levels for 72h. Compared to baseline, median cumulative log10 HIV p24 antigen was significantly reduced at all timepoints for both 1 and 2 inserts (p< 0.032 and p< 0.02, respectively), with median log10 declines with 2 inserts of -2.0, -1.8, -1.9, -1.7 at 2, 24, 48, and 72 h, respectively (Figure).
Conclusions:
Rectal administration of 1 or 2 TAF/EVG inserts was safe and achieved high RF and RT levels of EVG and TFV with low systemic drug exposure. RT cell TFV-DP concentrations were higher than observed at steady-state with oral TDF dosing, with demonstrable inhibition of HIV infection for up to 72h. These results indicate that the TAF/EVG insert has great potential as an on-demand rectal microbicide for HIV prevention.
Explant Challenge in Rectal Biopsy Supernatant: Median and inter-quartile range (boxplots) of the median log10 cumulative, weight-adjusted p24 levels from up to four rectal tissue explant supernatants per participant-timepoint.. The gray horizontal bars represent the inter-quartile range (dark gray) and overall range (light gray) of the weight-adjusted LLOQ of cumulative p24 concentrations. 