Dataset Information

A Novel Microbicide/Contraceptive Intravaginal Ring Protects Macaque Genital Mucosa against SHIV-RT Infection Ex Vivo.

ABSTRACT: Women need multipurpose prevention products (MPTs) that protect against sexually transmitted infections (STIs) and provide contraception. The Population Council has developed a prototype intravaginal ring (IVR) releasing the non-nucleoside reverse transcriptase inhibitor (NNRTI) MIV-150 (M), zinc acetate (ZA), carrageenan (CG) and levonorgestrel (LNG) (MZCL IVR) to protect against HIV, HSV-2, HPV and unintended pregnancy. Our objective was to evaluate the anti-SHIV-RT activity of MZCL IVR in genital mucosa. First, macaque vaginal tissues were challenged with SHIV-RT in the presence of (i) MIV-150 ± LNG or (ii) vaginal fluids (VF); available from studies completed earlier) collected at various time points post insertion of MZCL and MZC IVRs. Then, (iii) MZCL IVRs (vs. LNG IVRs) were inserted in non-Depo Provera-treated macaques for 24h and VF, genital biopsies, and blood were collected and tissues were challenged with SHIV-RT. Infection was monitored with one step SIV gag qRT-PCR or p27 ELISA. MIV-150 (LCMS/MS, RIA), LNG (RIA) and CG (ELISA) were measured in different compartments. Log-normal generalized mixed linear models were used for analysis. LNG did not affect the anti-SHIV-RT activity of MIV-150 in vitro. MIV-150 in VF from MZC/MZCL IVR-treated macaques inhibited SHIV-RT in vaginal mucosa in a dose-dependent manner (p<0.05). MIV-150 in vaginal tissue from MZCL IVR-treated animals inhibited ex vivo infection relative to baseline (96%; p<0.0001) and post LNG IVR group (90%, p<0.001). No MIV-150 dose-dependent protection was observed, likely because of high MIV-150 concentrations in all vaginal tissue samples. In cervical tissue, MIV-150 inhibited infection vs. baseline (99%; p<0.05). No cervical tissue was available for MIV-150 measurement. Exposure to LNG IVR did not change tissue infection level. These observations support further development of MZCL IVR as a multipurpose prevention technology to improve women's sexual and reproductive health.

SUBMITTER: Villegas G

PROVIDER: S-EPMC4948912 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:BACKGROUND:HIV antiretroviral-based intravaginal rings with and without co-formulated contraception hold promise for increasing HIV prevention options for women. Acceptance of and ability to correctly and consistently use this technology may create challenges for future ring-based microbicide trials in settings where this technology has not been introduced. We examined baseline factors associated with enrolling in a contraceptive intravaginal ring study in Kisumu, Kenya and describe notional acceptability (willingness to switch to a contraceptive ring based solely on information received about it). METHODS:Demographic, psychosocial, and behavioral eligibility screening of women 18-34 years was undertaken. Testing for pregnancy, HIV, and other sexually transmitted infections (STIs) was also conducted. We compared enrollment status across groups of categorical predictors using prevalence ratios (PR) and 95% confidence interval (CI) estimates obtained from a log-binomial regression model. RESULTS:Out of 692 women pre-screened April to November 2014, 463 completed screening, and 302 women were enrolled. Approximately 97% of pre-screened women were willing to switch from their current contraceptive method to use the intravaginal ring exclusively for the 6-month intervention period. Pregnancy, HIV, and STI prevalence were 1.7%, 14.5%, and 70.4% respectively for the 463 women screened. Women 18-24 (PR=1.47, CI 1.15-1.88) were more likely to be enrolled than those 30-34 years of age, as were married/cohabitating women (PR=1.62, CI 1.22-2.16) compared to those separated, divorced, or widowed. In adjusted analyses, sexual debut at less than 17 years of age, one lifetime sexual partner, abnormal vaginal bleeding in the past 12 months, condomless vaginal or anal sex in the past 3 months, and not having a sexual partner of unknown HIV status in the past 3 months were predictive of enrollment. CONCLUSION:High notional acceptability suggests feasibility for contraceptive intravaginal ring use. Factors associated with ring use initiation and 6-month use will need to be assessed.

Project description:Globally, women bear an uneven burden for sexual HIV acquisition. Results from two clinical trials evaluating intravaginal rings (IVRs) delivering the antiretroviral agent dapivirine have shown that protection from HIV infection can be achieved with this modality, but high adherence is essential. Multipurpose prevention technologies (MPTs) can potentially increase product adherence by offering protection against multiple vaginally transmitted infections and unintended pregnancy. Here we describe a coitally independent, long-acting pod-IVR MPT that could potentially prevent HIV and HSV infection as well as unintended pregnancy. The pharmacokinetics of MPT pod-IVRs delivering tenofovir alafenamide hemifumarate (TAF2) to prevent HIV, acyclovir (ACV) to prevent HSV, and etonogestrel (ENG) in combination with ethinyl estradiol (EE), FDA-approved hormonal contraceptives, were evaluated in pigtailed macaques (N = 6) over 35 days. Pod IVRs were exchanged at 14 days with the only modification being lower ENG release rates in the second IVR. Plasma progesterone was monitored weekly to determine the effect of ENG/EE on menstrual cycle. The mean in vivo release rates (mg d-1) for the two formulations over 30 days ranged as follows: TAF2 0.35-0.40; ACV 0.56-0.70; EE 0.03-0.08; ENG (high releasing) 0.63; and ENG (low releasing) 0.05. Mean peak progesterone levels were 4.4 ± 1.8 ng mL-1 prior to IVR insertion and 0.075 ± 0.064 ng mL-1 for 5 weeks after insertion, suggesting that systemic EE/ENG levels were sufficient to suppress menstruation. The TAF2 and ACV release rates and resulting vaginal tissue drug concentrations (medians: TFV, 2.4 ng mg-1; ACV, 0.2 ng mg-1) may be sufficient to protect against HIV and HSV infection, respectively. This proof of principle study demonstrates that MPT-pod IVRs could serve as a potent biomedical prevention tool to protect women's sexual and reproductive health and may increase adherence to HIV PrEP even among younger high-risk populations.

Dataset Information

A Novel Microbicide/Contraceptive Intravaginal Ring Protects Macaque Genital Mucosa against SHIV-RT Infection Ex Vivo.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets