Project Gel a Randomized Rectal Microbicide Safety and Acceptability Study in Young Men and Transgender Women.
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ABSTRACT: The purpose of Project Gel was to determine the safety and acceptability of rectal microbicides in young men who have sex with men (MSM) and transgender women (TGW) at risk of HIV infection.MSM and TGW aged 18-30 years were enrolled at three sites; Pittsburgh, PA; Boston, MA; and San Juan, PR. Stage 1A was a cross-sectional assessment of sexual health and behavior in MSM and TGW. A subset of participants from Stage 1A were then enrolled in Stage 1B, a 12-week evaluation of the safety and acceptability of a placebo rectal gel. This was followed by the final phase of the study (Stage 2) in which a subset of participants from Stage 1B were enrolled into a Phase 1 rectal safety and acceptability evaluation of tenofovir (TFV) 1% gel.248 participants were enrolled into Stage 1A. Participants' average age was 23.3 years. The most common sexually transmitted infection (STIs) at baseline were Herpes simplex (HSV)-2 (16.1% by serology) and rectal Chlamydia trachomatis (CT) (10.1% by NAAT). 134 participants were enrolled into Stage 1B. During the 12 week period of follow-up 2 HIV, 5 rectal CT, and 5 rectal Neisseria gonorrhea infections were detected. The majority of adverse events (AEs) were infections (N = 56) or gastrointestinal (N = 46) and were mild (69.6%) or moderate (28.0%). Of the participants who completed Stage 1B, 24 were enrolled into Stage 2 and randomized (1:1) to receive TFV or placebo gel. All participants completed Stage 2. The majority of AEs were gastrointestinal (N = 10) and of mild (87.2%) or moderate (10.3%) severity.In this study we were able to enroll a sexually active population of young MSM and TGW who were willing to use rectal microbicides. TFV gel was safe and acceptable and should be further developed as an alternative HIV prevention intervention for this population.ClinicalTrials.gov NCT01283360.
<h4>Objectives</h4>The purpose of Project Gel was to determine the safety and acceptability of rectal microbicides in young men who have sex with men (MSM) and transgender women (TGW) at risk of HIV infection.<h4>Methods</h4>MSM and TGW aged 18-30 years were enrolled at three sites; Pittsburgh, PA; Boston, MA; and San Juan, PR. Stage 1A was a cross-sectional assessment of sexual health and behavior in MSM and TGW. A subset of participants from Stage 1A were then enrolled in Stage 1B, a 12-week e ...[more]
Project description:Trials to assess microbicide safety require strict adherence to prescribed regimens. If adherence is suboptimal, safety cannot be adequately assessed. MTN-017 was a phase 2, randomized sequence, open-label, expanded safety and acceptability crossover study comparing 1) daily oral emtricitabine/tenofovir disoproxil fumarate (FTC/TDF), 2) daily use of reduced-glycerin 1% tenofovir (RG-TFV) gel applied rectally, and 3) RG-TFV gel applied before and after receptive anal intercourse (RAI)-if participants had no RAI in a week, they were asked to use two doses of gel within 24 hours. Product use was assessed by mixed methods including unused product return count, text messaging reports, and qualitative plasma TFV pharmacokinetic (PK) results. Convergence interviews engaged participants in determining the most accurate number of doses used based on product count and text messaging reports. Client-centered adherence counseling was also used. Participants (N = 187) were men who have sex with men and transgender women enrolled in the United States (42%), Thailand (29%), Peru (19%) and South Africa (10%). Mean age was 31.4 years (range 18-64 years). Based on convergence interviews, over an 8-week period, 94% of participants had ?80% adherence to daily tablet, 41% having perfect adherence; 83% had ?80% adherence to daily gel, 29% having perfect adherence; and 93% had ?80% adherence to twice-weekly use during the RAI-associated gel regimen, 75% having perfect adherence and 77% having ?80% adherence to gel use before and after RAI. Only 4.4% of all daily product PK results were undetectable and unexpected (TFV concentrations <0.31 ng/mL) given self-reported product use near sampling date. The mixed methods adherence measurement indicated high adherence to product use in all three regimens. Adherence to RAI-associated rectal gel use was as high as adherence to daily oral PrEP. A rectal microbicide gel, if efficacious, could be an alternative for individuals uninterested in daily oral PrEP.
Project description:OBJECTIVES:To measure potential acceptability of rectal microbicides and to explore factors likely to affect their acceptability among men who have sex with men (MSM). METHODS:Cross-sectional and retrospective surveys were conducted in this study. A questionnaire and a scale were used to measure the acceptability score for physical and functional characteristics of hypothetical rectal microbicides. We also evaluated the involvement of other factors such as sexual behaviors, social context, etc. RESULTS:MSMs we interviewed showed a high acceptability to rectal microbicides, indicated by the mean acceptability score of 2.92 (SD, 0.54, scale of 1-4). The results also suggested that microbicides were preferred in a cream form that can moisten and lubricate the rectum, prevent HIV infection and go unnoticed by their partners. Multivariate analysis showed that the microbicides acceptability varied significantly by education level (? = 0.135; P = 0.028), having casual partners (? = 0.174; P = 0.007), frequency of lubricant use (? = 0.134; P = 0.031), history of HIV test (? = 0.129; P = 0.036), willingness to use lubricant (? = 0.126; P = 0.045), locus of control by partners regarding STI infection (? = 0.168; P = 0.009). CONCLUSIONS:A positive response to rectal microbicides among MSMs was found in our study, suggesting that rectal microbicides might have a potential market in MSMs and they might play an important role in HIV/STIs prevention as a supplement. Further studies may be considered to combine the acceptability study with clinical research together to understand the true feelings of MSMs when they use the products.
Project description:BACKGROUND:Few studies of microbicide acceptability among HIV-infected women have been done. We assessed Carraguard® vaginal gel acceptability among participants in a randomized, controlled, crossover safety trial in HIV-infected women in Thailand. METHODOLOGY/PRINCIPAL FINDINGS:Participants used each of 3 treatments (Carraguard gel, methylcellulose placebo gel, and no product) for 7 days, were randomized to one of six treatment sequences, and were blinded to the type of gel they received in the two gel-use periods. After both gel-use periods, acceptability was assessed by face-to-face interview. Responses were compared to those of women participating in two previous Carraguard safety studies at the same study site. Sixty women enrolled with a median age of 34 years; 25% were sexually active. Self-reported adherence (98%) and overall satisfaction rating of the gels (87% liked "somewhat" or "very much") were high, and most (77%) considered the volume of gel "just right." For most characteristics, crossover trial participants evaluated the gels more favorably than women in the other two trials, but there were few differences in the desired characteristics of a hypothetical microbicide. Almost half (48%) of crossover trial participants noticed a difference between Carraguard and placebo gels; 33% preferred Carraguard while 12% preferred placebo (p?=?0.01). CONCLUSIONS/SIGNIFICANCE:Daily Carraguard vaginal gel use was highly acceptable in this population of HIV-infected women, who assessed the gels more positively than women in two other trials at the site. This may be attributable to higher perceived need for protection among HIV-infected women, as well as to study design differences. This trial was registered in the U.S. National Institutes of Health clinical trials registry under registration number NCT00213044.
Project description:Preexposure prophylaxis (PrEP) of HIV infection with tenofovir-containing regimens is effective, but plagued by poor adherence in some studies. Options for safe, effective, and acceptable PrEP products, especially for men and women at risk of HIV via receptive anal intercourse (RAI), are needed. We performed a randomized, partially blinded, first-in-human evaluation of four candidate rectal microbicide vehicles-aqueous gel, aqueous fluid, lipid gel, and lipid fluid-to select a prototype for further clinical development. Eight seronegative participants received three doses of each product with each dose separated by at least 2 weeks: one dose was given alone without simulated RAI in clinic, another dose was followed by simulated RAI in clinic, and another dose was self-administered at home in the context of RAI with a partner. Assessments included safety, acceptability, colon histology, ex vivo HIV infectivity of colon tissue explants, and colonic luminal distribution of vehicle and HIV surrogates. Adverse events were all mild and mainly sigmoidoscopy associated. There were minor differences in colon distribution of products and little effect of RAI. Vehicle distribution covered 95% (±7% standard deviation) of the distribution of an HIV surrogate in the colonic lumen. The lipid fluid vehicle increased HIV colon tissue infectability 5-fold [log10 p24 0.68 (95% confidence interval 0.08, 1.28)] and aqueous gel provided 6-fold protection [log10 p24 0.80 (95% confidence interval 0.20, 1.41)] compared to no product baseline. Colon permeability of lipid vehicles was more than 10-fold greater than aqueous vehicles. All products received similar acceptability ratings, though trends favored the gel products. Intensive simultaneous assessment of safety and toxicity, luminal and tissue distribution, ex vivo HIV infectivity, and product acceptability in relevant sexual contexts provided clear differentiation among candidate gels very early in product development. We selected the aqueous gel for further development as a rectal microbicide vehicle.
Project description:In MTN-007, a phase 1, randomized, double-blinded rectal microbicide trial, we used systems genomics/proteomics to determine the effect of tenofovir 1% gel, nonoxynol-9 2% gel, placebo gel or no treatment on rectal biopsies taken at baseline, after one application or after seven daily applications (15 subjects/arm). Experiments were repeated using primary vaginal epithelial cells from four healthy women.
Project description:In MTN-007, a phase 1, randomized, double-blinded rectal microbicide trial, we used systems genomics/proteomics to determine the effect of tenofovir 1% gel, nonoxynol-9 2% gel, placebo gel or no treatment on rectal biopsies taken at baseline, after one application or after seven daily applications (15 subjects/arm). Experiments were repeated using primary vaginal epithelial cells from four healthy women. 192 Arrays (8 donors per treatment group, 2 biopsy sites per donor (9cm and 15 cm), biopsies taken at baseline, after a single application, and after 7 daily applications)
Project description:Efforts to develop a range of HIV prevention products that can serve as behaviorally congruent viable alternatives to consistent condom use and oral pre-exposure prophylaxis (PrEP) remain crucial. MTN-035 was a randomized crossover trial seeking to evaluate the safety, acceptability, and adherence to three placebo modalities (insert, suppository, enema) prior to receptive anal intercourse (RAI). If participants had no RAI in a week, they were asked to use their assigned product without sex. We hypothesized that the modalities would be acceptable and safe for use prior to RAI, and that participants would report high adherence given their behavioral congruence with cleansing practices (e.g., douches and/or enemas) and their existing use to deliver medications (e.g., suppositories; fast-dissolving inserts) via the rectum. Participants (N = 217) were sexual and gender minorities enrolled in five different countries (Malawi, Peru, South Africa, Thailand, and the United States of America). Mean age was 24.9 years (range 18-35 years). 204 adverse events were reported by 98 participants (45.2%); 37 (18.1%) were deemed related to the study products. The proportion of participants reporting "high acceptability" was 72% (95%CI: 65% - 78%) for inserts, 66% (95%CI: 59% - 73%) for suppositories, and 73% (95%CI: 66% - 79%) for enemas. The proportion of participants reporting fully adherent per protocol (i.e., at least one use per week) was 75% (95%CI: 69% - 81%) for inserts, 74% (95%CI: 68% - 80%) for suppositories, and 83% (95%CI: 77% - 88%) for enemas. Participants fully adherent per RAI-act was similar among the three products: insert (n = 99; 58.9%), suppository (n = 101; 58.0%) and enema (n = 107; 58.8%). The efficacy and effectiveness of emerging HIV prevention drug depends on safe and acceptable delivery modalities that are easy to use consistently. Our findings demonstrate the safety and acceptability of, and adherence to, enemas, inserts, and suppositories as potential modalities through which to deliver a rectal microbicide.
Project description:The Centre for the AIDS Program of Research in South Africa (CAPRISA) 004 trial assessed the effectiveness and safety of a 1% vaginal gel formulation of tenofovir, a nucleotide reverse transcriptase inhibitor, for the prevention of HIV acquisition in women. A double-blind, randomized controlled trial was conducted comparing tenofovir gel (n = 445 women) with placebo gel (n = 444 women) in sexually active, HIV-uninfected 18- to 40-year-old women in urban and rural KwaZulu-Natal, South Africa. HIV serostatus, safety, sexual behavior, and gel and condom use were assessed at monthly follow-up visits for 30 months. HIV incidence in the tenofovir gel arm was 5.6 per 100 women-years (person time of study observation) (38 out of 680.6 women-years) compared with 9.1 per 100 women-years (60 out of 660.7 women-years) in the placebo gel arm (incidence rate ratio = 0.61; P = 0.017). In high adherers (gel adherence > 80%), HIV incidence was 54% lower (P = 0.025) in the tenofovir gel arm. In intermediate adherers (gel adherence 50 to 80%) and low adherers (gel adherence < 50%), the HIV incidence reduction was 38 and 28%, respectively. Tenofovir gel reduced HIV acquisition by an estimated 39% overall, and by 54% in women with high gel adherence. No increase in the overall adverse event rates was observed. There were no changes in viral load and no tenofovir resistance in HIV seroconverters. Tenofovir gel could potentially fill an important HIV prevention gap, especially for women unable to successfully negotiate mutual monogamy or condom use.
Project description:OBJECTIVESThe study was designed to assess the safety, adherence, acceptability, and effect on vaginal microflora of 3% SPL7013 Gel (VivaGel), a novel dendrimer topical microbicide that inhibits HIV, herpes simplex virus-2, and human papillomavirus in vitro and in animal models.DESIGNPhase 1, randomized, double-blind, placebo-controlled study on sexually active women.METHODSSixty-one sexually active women aged 18-24 years were recruited from three sites in the United States. Participants were randomized 1: 1: 1 to receive VivaGel, VivaGel placebo, or a hydroxyethylcellulose (HEC) placebo twice daily for 14 consecutive days. Safety endpoints included genitourinary and/or other adverse events. Changes in vaginal flora were determined from Gram-stained vaginal smears and quantitative vaginal culture.RESULTSNo serious adverse events or withdrawals due to adverse events were reported. Genitourinary symptoms were reported as follows: VivaGel (n = 17/22; 77.3%), VivaGel placebo (n = 14/21; 66.7%), and HEC (n = eight of 18; 44.4%; not significant, P = 0.1). The incidence of abnormal pelvic examination findings was similar across all gel arms of the study. Using pairwise comparison, women in the VivaGel arm had a significantly higher incidence of related genitourinary adverse events compared with women in the HEC gel arm (0.297 versus 0.111 per 100 person-years, respectively; P = 0.003). Exposure to VivaGel and VivaGel placebo resulted in minor shifts in the vaginal microflora, but there was no overall impact on incidence of bacterial vaginosis as assessed by Nugent score.CONCLUSIONVivaGel was generally well tolerated and comparable with the VivaGel placebo, although there was a higher incidence of low-grade related genital adverse events compared to the HEC placebo gel.
Project description:The last few years have seen important progress in demonstrating the efficacy of oral pre-exposure prophylaxis, vaginal microbicides, and treatment as prevention as effective strategies for reducing the risk of acquiring or transmitting HIV infection. There has also been significant progress in the development of rectal microbicides. Preclinical non-human primate studies have demonstrated that antiretroviral microbicides can provide significant protection from rectal challenge with SIV or SHIV. Recent Phase 1 rectal microbicide studies have characterized the safety, acceptability, compartmental pharmacokinetics (PK), and pharmacodynamics (PD) of both UC781 and tenofovir gels. The tenofovir gel formulation used in vaginal studies was not well tolerated in the rectum and newer rectal-specific formulations have been developed and evaluated in Phase 1 studies. The PK/PD data generated in these Phase 1 studies may reduce the risk of advancing ineffective candidate rectal microbicides into late stage development. Tenofovir gel is currently poised to move into Phase 2 evaluation and it is possible that a Phase 2B/3 effectiveness study with this product could be initiated in the next 2-3 years.
