The prevention of HIV and unintended pregnancies is a public health priority. Multi-purpose prevention technologies capable of long-acting HIV and pregnancy prevention are desirable for women. Here, we utilized a preclinical macaque model to evaluate the pharmacokinetics of biodegradable ε-polycaprolactone implants delivering the antiretroviral islatravir (ISL) and the contraceptive etonogestrel (ENG). Three implants were tested: ISL-62 mg, ISL-98 mg, and ENG-33 mg. Animals received one or two ISL-eluting implants, with doses of 42, 66, or 108 µg of ISL/day with or without an additional ENG-33 mg implant (31 µg/day). Drug release increased linearly with dose with median [range] plasma ISL levels of 1.3 [1.0–2.5], 1.9 [1.2–6.3] and 2.8 [2.3–11.6], respectively. The ISL-62 and 98 mg implants demonstrated stable drug release over three months with ISL-triphosphate (ISL-TP) concentr54ations in PBMCs above levels predicted to be efficacious for PrEP. Similarly, ENG implants demonstrated sustained drug release with median [range] plasma ENG levels of 495 [229–1110] pg/mL, which suppressed progesterone within two weeks and showed no evidence of altering ISL pharmacokinetics. Two of the six ISL-98 mg implants broke during the study and induced implant-site reactions, whereas no reactions were observed with intact implants. We show that ISL and ENG biodegradable implants are safe and yield sufficient drug levels to achieve prevention targets. The evaluation of optimized implants with increased mechanical robustness is underway for improved durability and vaginal efficacy in a SHIV challenge model.

Prevention of HIV infection and unintended pregnancies are public health priorities. In sub-Saharan Africa, where HIV prevalence is highest, depot medroxyprogesterone acetate (DMPA) is widely used as contraception. Therefore, understanding potential interactions between DMPA and antiretrovirals is critical. Here, we use a macaque model to investigate the effect of DMPA on the pharmacology of the antiretroviral tenofovir alafenamide (TAF). Female rhesus macaques received 30 mg of DMPA (n = 9) or were untreated (n = 9). Macaques received a human equivalent dose of TAF (1.5 mg/kg) orally by gavage. Tenofovir (TFV) and TFV-diphosphate (TFV-DP) were measured in blood, secretions, and tissues over 72 h. The median area under the curve (AUC_0–72h) values for TFV-DP in peripheral blood mononuclear cells were similar in DMPA-treated (6991 fmol*h/10⁶ cells) and untreated controls (5256 fmol*h/10⁶ cells) (P = 0.174). Rectal tissue TFV-DP concentrations from DMPA+ animals [median: 20.23 fmol/mg of tissue (range: 4.94–107.95)] were higher than the DMPA- group [median: below the limit of quantification (BLOQ-11.92)], (P = 0.019). TFV-DP was not detectable in vaginal tissue from either group. A high-dose DMPA treatment in macaques was associated with increased rectal TFV-DP levels, indicating a potential tissue-specific drug-drug interaction. The lack of detectable TFV-DP in the vaginal tissue warrants further investigation of PrEP efficacy with single-agent TAF products. DMPA did not affect systemic TAF metabolism, with similar PBMC TFV-DP in both groups, suggesting that DMPA use should not alter the antiviral activity of TAF.

Background: Pig‐tailed macaques (PTMs) are commonly used as preclinical models to assess antiretroviral drugs for HIV prevention research. Drug toxicities and disease pathologies are often preceded by changes in blood hematology. To better assess the safety profile of pharmaceuticals, we defined normal ranges of hematological values in PTMs using an Isolation Forest (iForest) algorithm.Methods: Eighteen female PTMs were evaluated. Blood was collected 1–24 times per animal for a total of 159 samples. Complete blood counts were performed, and iForest was used to analyze the hematology data to detect outliers.Results: Median, IQR, and ranges were calculated for 13 hematology parameters. From all samples, 22 outliers were detected. These outliers were excluded from the reference index.Conclusions: Using iForest, we defined a normal range for hematology parameters in female PTMs. This reference index can be a valuable tool for future studies evaluating drug toxicities in PTMs.

Background: Islatravir (ISL) is a first-in-class nucleoside reverse transcriptase translocation inhibitor with high potency and long half-life in peripheral blood mononuclear cells (PBMCs). However, treatment and prevention of HIV with oral ISL in humans has been associated with decreases in total lymphocytes, CD4 T-cells, and B-cells in a dose-dependent manner. We investigated in macaques the effects of oral ISL on lymphocytes, monocytes, granulocytes, and gene expression in PBMCs. Methods: Female pig-tailed macaques (n = 5) received an HIV pre-exposure prophylaxis dose of oral ISL adjusted allometrically once a week for 12 weeks. Complete blood counts and B- and T-cells were monitored prior to, during, and after ISL treatment, and changes in counts were evaluated by using a repeated measures model. Changes in gene expression were investigated in PBMCs during treatment and following treatment discontinuation. Results: ISL treatment was associated with declines in lymphocytes (11.9%, p = 0.0015) and monocytes (22.4%, p = 0.0003), but not granulocytes (0.3%, p = 0.9781). Total lymphocytes and monocytes returned to pre-treatment levels 6 weeks after treatment cessation (p = 0.8244 and p = 0.4620, respectively). Lymphocyte subpopulation analyses showed a significant decline in CD8 (−18.4%, p = 0.0364) and CD20 (−35.3%; p = 0.0002) cells but not CD4 cells (−7.4%; p = 0.3470). Gene set enrichment analysis showed negative enrichment (p_adj < 0.05) of gene pathways associated with immune regulation, cell proliferation, and inflammation. Conclusions: ISL treatment resulted in significant reductions in lymphocytes reproducing clinical toxicity. This effect was reversed after treatment cessation as observed in humans. Our results highlight the value of the macaque model to study immune alterations at the preclinical stage.