Background: Vaginal products for HIV prevention that can be used on-demand before or after sex may be a preferable option for women with low frequency or unplanned sexual activity or who prefer not to use daily pre-exposure prophylaxis (PrEP). We performed dose ranging pharmacokinetics (PK) and efficacy studies of a vaginally applied insert containing tenofovir alafenamide fumarate (TAF) and elvitegravir (EVG) in macaques under PrEP or post-exposure prophylaxis (PEP) modalities.Methods: PK studies were performed in 3 groups of pigtailed macaques receiving inserts with different fixed-dose combinations of TAF and EVG (10/8, 20/16 and 40/24 mg). PrEP and PEP efficacy of a selected insert was investigated in a repeat exposure vaginal SHIV transmission model. Inserts were administered 4h before (n=6) or after (n=6) repeated weekly SHIV exposures. Infection outcome was compared with macaques receiving placebo inserts (n=12).Findings: Dose ranging studies showed rapid and sustained high drug concentrations in vaginal fluids and tissues across insert formulations with minimal dose proportionality. TAF/EVG (20/16mg) inserts were selected for efficacy evaluation. Five of the 6 animals receiving these inserts 4h before and 6/6 animals receiving inserts 4h after SHIV exposure were protected after 13 challenges (p=0.0088 and 0.0077 compared to placebo, respectively). The calculated PrEP and PEP efficacy was 91.0% (95%CI=32.2%-98.8%) and 100% (95%CI=undefined), respectively.Interpretation: Inserts containing TAF/EVG provided high protection against vaginal SHIV infection when administered within a 4h window before or after SHIV exposure. Our results support the clinical development of TAF/EVG inserts for on-demand PrEP and PEP in women.Funding Information: Funded by CDC intramural funds, an interagency agreement between CDC and USAID (USAID/CDC IAA AID-GH-T-15-00002), and by the U.S. President’s Emergency Plan for AIDS Relief (PEPFAR) through the U.S. Agency for International Development (USAID) under a Cooperative Agreement (AID-OAA-A-14-00010) with CONRAD/Eastern Virginia Medical School. Declaration of Interests: P J.G.G-L and W.H. are named in US. Government (USG) patents on “Inhibition of HIV infection through chemoprophylaxis” and in US. Government patent applications on “HIV postexposure prophylaxis” and “HIV pre-exposure prophylaxis”. M.M.P, O.N.S., V.A., T.J.M, J.L.S., G.F.D. and M.R.C. are named in patent applications on “Pharmaceutical compositions and methods of making on demand solid dosage formulations,” inventions that were developed under USAID-funded cooperative agreements. The findings and conclusions of this manuscript are those of the authors and do not necessarily represent the official views of CDC, USAID, PEPFAR, EVMS, or the USG.Ethics Approval Statement: All animal procedures were approved by the Centers for Disease Control and Prevention (CDC) Institutional Animal Care and Use Committee (IACUC). Sexually mature female pigtailed macaques (Macaca nemestrina) were utilized for this study. Macaques were cared for by CDC veterinarians in compliance with the Guide for the Care and Use of Laboratory Animals 8th Ed.
Abstract Objectives We conducted a detailed pharmacokinetic assessment in macaques treated with vaginal gels formulated with HIV integrase strand transfer inhibitors (INSTIs) to better understand drug distribution and identify INSTI concentrations associated with previously demonstrated in vivo protection against vaginal simian HIV challenge. Methods Six macaques received vaginal gel containing 1% raltegravir (30 mg) once-weekly over 6 weeks. Following a washout period, five macaques received once-weekly gel containing 0.23% L-870,812 (7 mg). Drug concentrations were measured in plasma, mucosal fluids and vaginal tissues at baseline and 2, 5 and 24 h post-dosing. Results The median maximum concentration (Cmax) for raltegravir and L-870,812 in plasma was below the limit of quantification and 41.1 ng/mL, respectively. The Cmax in vaginal fluids (1441 and 1250 μg/mL) and tissues (266.7 and 368.4 μg/g) was achieved 2–5 h after dosing, respectively. A similar half-life was observed for raltegravir and L-870,812 in vaginal fluids (8–10 h) and remained 3–4 orders of magnitude above the protein-adjusted IC95 (0.016 and 0.106 μg/mL, respectively) at 24 h. Drug concentrations in vaginal fluids correlated well with those in vaginal tissues (Pearson r ≥ 0.788). Both drugs were consistently detected in rectal fluids 2 h after vaginal dosing, albeit at much lower levels (31–92-fold) than those in vaginal fluids. Conclusions To the best of our knowledge, this study provides the first data on INSTI levels in vaginal tissues associated with in vivo protection and demonstrates rectal drug distribution of INSTIs after vaginal dosing. These findings may inform dose selection for topical products with INSTIs for HIV prevention.
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.
Abstract Background FTY 720 is an immunomodulatory agent that reduces lymphocytes in peripheral tissues and circulation. Such agents may be effective as vaginal microbicides for HIV prevention. Systemic or vaginal application of FTY 720 may reduce lymphocyte concentrations in genital tissues, reducing HIV target cell numbers. Methods Five female pigtail macaques received topical vaginal gel FTY 720 (n = 2), intravenous ( IV ) FTY 720 (n = 2), or placebo gel (n = 1) in this pilot study. Circulating and mucosal lymphocytes and genital mucosa, cytokines, and tissue histology were analyzed to document topical and IV FTY 720 effects. Results Topical and IV FTY 720 appeared to decrease the levels of cervicovaginal IL ‐8, IL ‐1ra, and genital inflammatory cells. Small sample size precluded statistical analysis. Topical administration had no overt adverse effects. Conclusions This study introduces FTY 720 as an immunomodulatory agent for the vaginal mucosa, compares topical effects to those of IV administration, and provides the basis for future studies involving FTY 720 for HIV prevention.
Objective: The opioid epidemic has increased parentally acquired HIV infection. To inform the development of a long-acting prevention strategy, we evaluated the protective efficacy of broadly neutralizing antibodies (bNAbs) against intravenous simian-human immunodeficiency virus (SHIV) infection in macaques. Design: Five cynomolgus macaques were injected once subcutaneously with 10-1074 and 3BNC117 (10 mg each kg −1 ) and were repeatedly challenged intravenously once weekly with SHIV AD8-EO (130 TCID 50 ), until infection was confirmed via plasma viral load assay. Two control macaques, which received no antibody, were challenged identically. Methods: Plasma viremia was monitored via RT-qPCR assay. bNAb concentrations were determined longitudinally in plasma samples via TZM-bl neutralization assays using virions pseudotyped with 10-1074-sensitive (X2088_c9) or 3BNC117-sensitive (Q769.d22) HIV envelope proteins. Results: Passively immunized macaques were protected against a median of five weekly intravenous SHIV challenges, as compared to untreated controls, which were infected following a single challenge. Of the two bNAbs, 10-1074 exhibited relatively longer persistence in vivo . The median plasma level of 10-1074 at SHIV breakthrough was 1.1 μg ml −1 (range: 0.6–1.6 μg ml −1 ), whereas 3BNC117 was undetectable. Probit modeling estimated that 6.6 μg ml −1 of 10-1074 in plasma corresponded to a 99% reduction in per-challenge infection probability, as compared to controls. Conclusions: Significant protection against repeated intravenous SHIV challenges was observed following administration of 10-1074 and 3BNC117 and was due primarily to 10-1074. Our findings extend preclinical studies of bNAb-mediated protection against mucosal SHIV acquisition and support the possibility that intermittent subcutaneous injections of 10-1074 could serve as long-acting preexposure prophylaxis for persons who inject drugs.
