An Intravaginal Ring That Releases the NNRTI MIV-150 Reduces SHIV Transmission in Macaques

Abstract

Microbicides may prevent HIV and sexually transmitted infections (STIs) in women; however, determining the optimal means of delivery of active pharmaceutical ingredients remains a major challenge. We previously demonstrated that a vaginal gel containing the non-nucleoside reverse transcriptase inhibitor MIV-150 partially protected macaques from SHIV-RT (simian/HIV reverse transcriptase) infection, and the addition of zinc acetate rendered the gel significantly protective. We test the activity of MIV-150 without the addition of zinc acetate when delivered from either ethylene vinyl acetate (EVA) or silicone intravaginal rings (IVRs). MIV-150 was successfully delivered, because it was detected in vaginal fluids and tissues by radioimmunoassay in pharmacokinetic studies. Moreover, EVA IVRs significantly protected macaques from SHIV-RT infection. Our results demonstrate that MIV-150–containing IVRs have the potential to prevent HIV infection and highlight the possible use of IVRs for delivering drugs that block HIV and other STIs.

MIV-150/Zinc Acetate Gel Inhibits Cell-Associated Simian-Human Immunodeficiency Virus Reverse Transcriptase Infection in a Macaque Vaginal Explant Model

“…The use of macaques was approved by the Animal Care and Use Committee of the TNPRC (OLAW assurance A4499-01), and the animal care complied with the regulations in the Animal Welfare Act (26) and the Guide for the Care and Use of Laboratory Animals (27). Anesthesia was administered prior to and during all procedures, and analgesics were provided afterwards as previously described (20,28). All biopsy procedures were performed by board-certified veterinarians (American College of Laboratory Animal Medicine).…”

MIV-150-Containing Intravaginal Rings Protect Macaque Vaginal Explants against SHIV-RT Infection

“…MIV-150 IVRs provided Ͼ80% protection against SHIV-RT in vivo in medroxyprogesterone (Depo-Provera [Depo])-treated animals when IVRs were inserted for 1 day (5 weeks post-Depo) or 14 days (3 weeks post-Depo) before challenge, but the protection was lost if the IVRs did not remain in place postchallenge (14). More MIV-150 was detected in the vaginal and ectocervical tissues, with the highest increase in vaginal tissue, when the IVRs were inserted for 14 days versus 1 day (5 weeks post-Depo) (14). The level of MIV-150 detected in VF 14 days after IVR insertion (5 weeks post-Depo) was ϳ100-fold higher than the 50% inhibitory concentration (IC 50 ) against SHIV-RT in TZM bl cells (14,15).…”

“…It was shown to safely deliver dapivirine over 7 days and provide tissue and VF drug concentrations in humans of Ͼ1,000-fold the 50% effective concentration (EC 50 ) against wild-type HIV in cell-based assays (12,13). The Population Council colleagues conducted proof-ofconcept pharmacokinetics (PK) and efficacy studies in macaques using NNRTI MIV-150 (100 mg) IVRs (14). MIV-150 IVRs provided Ͼ80% protection against SHIV-RT in vivo in medroxyprogesterone (Depo-Provera [Depo])-treated animals when IVRs were inserted for 1 day (5 weeks post-Depo) or 14 days (3 weeks post-Depo) before challenge, but the protection was lost if the IVRs did not remain in place postchallenge (14).…”

“…The Population Council colleagues conducted proof-ofconcept pharmacokinetics (PK) and efficacy studies in macaques using NNRTI MIV-150 (100 mg) IVRs (14). MIV-150 IVRs provided Ͼ80% protection against SHIV-RT in vivo in medroxyprogesterone (Depo-Provera [Depo])-treated animals when IVRs were inserted for 1 day (5 weeks post-Depo) or 14 days (3 weeks post-Depo) before challenge, but the protection was lost if the IVRs did not remain in place postchallenge (14). More MIV-150 was detected in the vaginal and ectocervical tissues, with the highest increase in vaginal tissue, when the IVRs were inserted for 14 days versus 1 day (5 weeks post-Depo) (14).…”

Low Frequency of Drug-Resistant Variants Selected by Long-Acting Rilpivirine in Macaques Infected with Simian Immunodeficiency Virus Containing HIV-1 Reverse Transcriptase

“…SIV is not susceptible to NNRTIs due to sequence differences within the RT coding region, but NNRTI sensitivity is established by swapping the SIV and HIV-1 RT coding regions (31,32). RT-SHIV macaque models have been used to study HIV-1 ART, drug resistance, PrEP, and persistence (30,(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48). In this study, we treated RT-SHIV-infected macaques with RPV LA and measured plasma viremia, drug concentrations, and drug-resistant isolates over 35 weeks.…”