Dataset Information

Impact of the griffithsin anti-HIV microbicide and placebo gels on the rectal mucosal proteome and microbiome in non-human primates.

ABSTRACT: Topical microbicides are being explored as an HIV prevention method for individuals who practice receptive anal intercourse. In vivo studies of these microbicides are critical to confirm safety. Here, we evaluated the impact of a rectal microbicide containing the antiviral lectin, Griffithsin (GRFT), on the rectal mucosal proteome and microbiome. Using a randomized, crossover placebo-controlled design, six rhesus macaques received applications of hydroxyethylcellulose (HEC)- or carbopol-formulated 0.1% GRFT gels. Rectal mucosal samples were then evaluated by label-free tandem MS/MS and 16?S rRNA gene amplicon sequencing, for proteomics and microbiome analyses, respectively. Compared to placebo, GRFT gels were not associated with any significant changes to protein levels at any time point (FDR < 5%), but increased abundances of two common and beneficial microbial taxa after 24?hours were observed in HEC-GRFT gel (p?

SUBMITTER: Girard L

PROVIDER: S-EPMC5966460 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Impact of the griffithsin anti-HIV microbicide and placebo gels on the rectal mucosal proteome and microbiome in non-human primates.

Girard Lauren L Birse Kenzie K Holm Johanna B JB Gajer Pawel P Humphrys Mike S MS Garber David D Guenthner Patricia P Noël-Romas Laura L Abou Max M McCorrister Stuart S Westmacott Garrett G Wang Lin L Rohan Lisa C LC Matoba Nobuyuki N McNicholl Janet J Palmer Kenneth E KE Ravel Jacques J Burgener Adam D AD

Scientific reports 20180523 1

Topical microbicides are being explored as an HIV prevention method for individuals who practice receptive anal intercourse. In vivo studies of these microbicides are critical to confirm safety. Here, we evaluated the impact of a rectal microbicide containing the antiviral lectin, Griffithsin (GRFT), on the rectal mucosal proteome and microbiome. Using a randomized, crossover placebo-controlled design, six rhesus macaques received applications of hydroxyethylcellulose (HEC)- or carbopol-formulat ...[more]

PMID: 29795295

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Project description:Gels are one of the soft material platforms being evaluated to deliver topically acting anti-HIV drugs (microbicides) to the vaginal environment. For each drug, its loaded concentration, gel properties and applied volume, and frequency of dosing can be designed to optimize PK and, thence, PD. These factors also impact user sensory perceptions and acceptability. Deterministic compartmental modeling of vaginal deployment and drug delivery achieved by test gels can help delineate how multiple parameters characterizing drug, vehicle, vaginal environment, and dosing govern details of PK and PD and also gel leakage from the canal. Such microbicide delivery is a transport process combining convection, e.g., from gel spreading along the vaginal canal, with drug diffusion in multiple compartments, including gel, mucosal epithelium, and stroma. The present work builds upon prior models of gel coating flows and drug diffusion (without convection) in the vaginal environment. It combines and extends these initial approaches in several key ways, including: (1) linking convective drug transport due to gel spreading with drug diffusion and (2) accounting for natural variations in dimensions of the canal and the site of gel placement therein. Results are obtained for a leading microbicide drug, tenofovir, delivered by three prototype microbicide gels, with a range of rheological properties. The model includes phosphorylation of tenofovir to tenofovir diphosphate (which manifests reverse transcriptase activity in host cells), the stromal concentration distributions of which are related to reference prophylactic values against HIV. This yields a computed summary measure related to gel protection ("percent protected"). Analyses illustrate tradeoffs amongst gel properties, drug loading, volume and site of placement, and vaginal dimensions, in the time and space history of gel distribution and tenofovir transport to sites of its anti-HIV action and concentrations and potential prophylactic actions of tenofovir diphosphate therein.

Project description:ObjectivesSuccessful control of the HIV/AIDS pandemic requires reduction of HIV-1 transmission at sexually-exposed mucosae. No prevention studies of the higher-risk rectal compartment exist. We report the first-in-field Phase 1 trial of a rectally-applied, vaginally-formulated microbicide gel with the RT-inhibitor UC781 measuring clinical and mucosal safety, acceptability and plasma drug levels. A first-in-Phase 1 assessment of preliminary pharmacodynamics was included by measuring changes in ex vivo HIV-1 suppression in rectal biopsy tissue after exposure to product in vivo.MethodsHIV-1 seronegative, sexually-abstinent men and women (N = 36) were randomized in a double-blind, placebo-controlled trial comparing UC781 gel at two concentrations (0.1%, 0.25%) with placebo gel (1∶1∶1). Baseline, single-dose exposure and a separate, 7-day at-home dosing were assessed. Safety and acceptability were primary endpoints. Changes in colorectal mucosal markers and UC781 plasma drug levels were secondary endpoints; ex vivo biopsy infectibility was an ancillary endpoint.ResultsAll 36 subjects enrolled completed the 7-14 week trial (100% retention) including 3 flexible sigmoidoscopies, each with 28 biopsies (14 at 10 cm; 14 at 30 cm). There were 81 Grade 1 adverse events (AEs) and 8 Grade 2; no Grade 3, 4 or procedure-related AEs were reported. Acceptability was high, including likelihood of future use. No changes in mucosal immunoinflammatory markers were identified. Plasma levels of UC781 were not detected. Ex vivo infection of biopsies using two titers of HIV-1(BaL) showed marked suppression of p24 in tissues exposed in vivo to 0.25% UC781; strong trends of suppression were seen with the lower 0.1% UC781 concentration.ConclusionsSingle and 7-day topical rectal exposure to both concentrations of UC781 were safe with no significant AEs, high acceptability, no detected plasma drug levels and no significant mucosal changes. Ex vivo biopsy infections demonstrated marked suppression of HIV infectibility, identifying a potential early biomarker of efficacy. (Registered at ClinicalTrials.gov; #NCT00408538).

Project description:BackgroundRectal microbicides, if proven effective, may aid in reducing human immunodeficiency virus (HIV) incidence; however, demonstration of efficacy and effectiveness is contingent on accurate measurement of product adherence. Delays in self-report, in particular, may affect the accuracy of behavioral data.ObjectiveThe aim of this study was to capitalize on mobile phone use by young men who have sex with men (YMSM), and examine the use of an interactive voice response system (IVRS) by YMSM aged 18-30 years enrolled in a multisite, 12-week microbicide safety and acceptability trial.MethodsYMSM (N=95) enrolled across 3 sites (Boston, Pittsburgh, and San Juan) were asked to report their use of an applicator applied placebo rectal gel product during receptive anal intercourse (RAI) using the IVRS. IVRS was available in Spanish and English. After the 12-week trial, we examined whether IVRS problems were associated with YMSM's sociodemographic characteristics (eg, age, race and ethnicity, and education), sexual behavior, or recruitment site. We used a multinomial logistic regression to compare YMSM who experienced no IVRS problems (n=40) with those who reported one IVRS problem (n=25) or two or more IVRS problems (n=30).ResultsWe recorded 1494 IVRS calls over 12 weeks. Over half of the participants (55/95; 58%) experienced challenges using the IVRS during the 12-week trial. YMSM reporting greater RAI occasions during the trial were more likely to experience one (odds ratio [OR]=1.08, 95% CI (1.02-1.14); P ≤.01) or more (OR=1.10, 95% CI (1.03-1.16); P ≤.001) IVRS challenges. Greater educational attainment was associated with multiple IVRS challenges (OR=7.08, 95% CI (1.6-31.6); P ≤.01). Participants in the Puerto Rico site were most likely to report multiple IVRS problems.ConclusionsAlthough IVRS was a useful data collection technology in our trial, several challenges experienced by English and Spanish speaking YMSM diminish its overall acceptability. We discuss strategies to optimize future development of IVRS data quality protocols based on lessons learned.

Dataset Information

Impact of the griffithsin anti-HIV microbicide and placebo gels on the rectal mucosal proteome and microbiome in non-human primates.

Publications

Impact of the griffithsin anti-HIV microbicide and placebo gels on the rectal mucosal proteome and microbiome in non-human primates.

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