Barbara Friedland

Efficacy of Carraguard for prevention of HIV infection in women in South Africa: a randomised, double-blind, placebo-controlled trial

BACKGROUND Female-initiated HIV-prevention options, such as microbicides, are urgently needed. We assessed Carraguard, a carrageenan-based compound developed by the Population Council, for its efficacy and long-term safety in prevention of HIV infection in women. METHODS We undertook a randomised, placebo-controlled, double-blind trial in three South African sites in sexually-active, HIV-negative women, aged 16 years and older. 6202 participants, who were randomly assigned by a block randomisation scheme to Carraguard (n=3103) or placebo (methylcellulose [n=3099]), were instructed to use one applicator of gel plus a condom during each vaginal sex act. Participants were followed up for up to 2 years. Visits every 3 months included testing for HIV presence and pregnancy, pelvic examinations, risk reduction counselling, and treatment for curable sexually transmitted infections and symptomatic vaginal infections. The primary outcome was time to HIV seroconversion. Analysis was in the efficacy population (a subset of the intention-to-treat population, excluding participants for whom efficacy could not be assessed). This study is registered with ClinicalTrials.gov, number NCT00213083. FINDINGS For the primary outcome (time to HIV seroconversion) we analysed 3011 women in the Carraguard group and 2994 in the placebo group. HIV incidence was 3.3 per 100 woman-years (95% CI 2.8-3.9) in the Carraguard group (134 events) and 3.8 per 100 woman-years (95% CI 3.2-4.4) in the placebo group (151 events), with no significant difference in the distribution of time to seroconversion (p=0.30). The covariate-adjusted hazard ratio was 0.87 (95% CI 0.69-1.09). Rates of self-reported gel use (96.2% Carraguard, 95.9% placebo) and condom use (64.1% in both groups) at last sex acts were similar in both groups. On the basis of applicator testing, however, gel was estimated to have been used in only 42.1% of sex acts, on average (41.1% Carraguard, 43.1% placebo). 1420 (23%) women in the intention-to-treat population had adverse events (713 Carraguard, 707 placebo), and 95 (2%) women had adverse events that were related to gel use (48 Carraguard, 47 placebo). Serious adverse events occurred in 72 (2%) women in the Carraguard group and 78 (3%) in the placebo group, only one of which was considered possibly related to gel use (placebo group). INTERPRETATION This study did not show Carraguards efficacy in prevention of vaginal transmission of HIV. No safety concerns were recorded.

Hormonal Contraception and the Risk of HIV Acquisition: An Individual Participant Data Meta-analysis:

In a meta-analysis of individual participant data, Charles Morrison and colleagues explore the association between hormonal contraception use and risk of HIV infection in sub-Saharan Africa.

Safety and acceptability of the candidate microbicide Carraguard in Thai Women: findings from a Phase II Clinical Trial

Objective:To determine the safety and acceptability of vaginal application of Carraguard, a carrageenan-derived candidate microbicide gel. Design:A randomized, placebo-controlled, triple-blinded clinical trial was conducted in Chiang Rai, northern Thailand. Methods:Women were asked to insert one applicator of study gel vaginally at least three times per week (with or without sex) and to use gel with condoms every time they had sex. Safety was assessed by visual inspection of the vagina and cervix, changes in vaginal flora and self-reported symptoms at day 14, month 1 and then monthly for up to 1 year. Acceptability was assessed through reported use of the gel, return of used and unused applicators, and quarterly interviews. Results:One hundred sixty-five women were randomized: 83 to Carraguard and 82 to the placebo (methylcellulose gel) group. Study gel use was similarly high in both groups throughout the trial with an average of four applicators per week. Carraguard use was not associated with abnormal genital clinical findings, abnormal vaginal flora, Pap smear abnormalities or other abnormal clinical signs or symptoms. Adverse events were mostly mild, not attributed to gel use, and similarly distributed between groups. Participants in both groups reported high acceptability. Conclusions:Carraguard can safely be used an average of four times per week with or without sex and is acceptable to Thai women. A Phase III efficacy trial of Carraguard is warranted and is currently ongoing in South Africa.

Hormonal contraception and the risk of HIV acquisition among women in South Africa

Objectives:To evaluate the effect of hormonal contraception including combined oral contraceptives (COCs), and the injectable progestins depo-medroxyprogesterone acetate (DMPA) and norethisterone enanthate (Net-En) on the risk of HIV acquisition among women in South Africa. Design/methods:We analyzed data from 5567 women aged 16–49 years participating in the Carraguard Phase 3 Efficacy Trial. Participants were interviewed about contraceptive use and sexual behaviors and underwent pelvic examinations and HIV testing quarterly. We used marginal structural Cox regression models to estimate the effect of hormonal contraception exposure on HIV acquisition risk among women overall and among young women (16–24 years) in particular. Results:Two hundred and seventy participants became HIV-infected (3.7 per 100 woman-years); HIV incidence was 2.8, 4.6, 3.5 and 3.4 per 100 woman-years in the COC, DMPA, Net-En and nonhormonal contraceptive groups, respectively (P = 0.09). The adjusted hazard ratios (AHRs) were 0.84 [95% confidence interval (CI) 0.51–1.39], 1.28 (95% CI 0.92–1.78) and 0.92 (95% CI 0.64–1.32) among COC, DMPA and Net-En users, respectively, compared with the nonhormonal group controlling for covariates. Age modified the effect of hormonal contraception on HIV acquisition risk; among young women, the AHRs were 1.02 (95% CI 0.46–2.28) for COCs, 1.68 (95% CI 0.96–2.94) for DMPA and 1.36 (95% CI0.78–2.35) for Net-En users. Conclusions:In this study conducted among South African women, hormonal contraception did not significantly increase the risk of HIV acquisition. However, the effect estimate does not rule out a moderate increase in HIV risk associated with DMPA use found in some other recent studies.

Acceptability and feasibility of Micralax® applicators and of methyl cellulose gel placebo for large-scale clinical trials of vaginal microbicides

Objective(s)To evaluate the feasibility and acceptability of the Micralax® applicator and of methyl cellulose placebo gel for use in vaginal microbicide clinical trials. DesignA two-centre prospective study following women for 2 months. SettingTwo primary health care clinics in South Africa. Patients, participantsFemale volunteers (n = 28) 18 years or older who were HIV negative and had no clinically detectable genital tract abnormalities or reproductive tract infections. InterventionsParticipants used pre-filled Micralax® applicators to apply methyl cellulose gel every other day, as well as up to 1 h before to every episode of vaginal sex. Main outcome measure(s)Consistency in the weight of gel dispensed per application; side-effects attributed to applicator or gel use; and acceptability of the applicator and of the gel. ResultsOver a 2 month follow-up period the 22 women completing the study reported no adverse events related to gel or applicator use. The Micralax® applicator proved acceptable. The gel was not too messy and did not reduce sexual frequency or pleasure. On average, the applicator dispensed 4.7 ml per use (close to the 4 ml planned). ConclusionsThe Micralax® applicator performs well as a delivery system for potential vaginal microbicides; and methyl cellulose is an appropriate placebo for future microbicide trials.

A Randomized, Placebo-controlled Trial to Assess the Safety and Acceptability of Use of Carraguard Vaginal Gel by Heterosexual Couples in Thailand

Objectives: To determine the safety and acceptability of use of Carraguard, a carrageenan-derived candidate microbicide gel, during sexual intercourse in women and men. Study Design: We conducted a 6-month randomized, placebo-controlled trial among sexually active, couples at relatively lower risk for HIV infection in northern Thailand. Methods: Women inserted 1 applicator of study gel vaginally every time the couple had sex. Safety was assessed by symptom report and genital examination of both partners and by changes in vaginal flora. Acceptability was assessed by participant interview. Results: Overall, 55 couples were randomized, 28 to Carraguard use and 27 to the methyl-cellulose placebo gel group. Retention and study gel use were similarly high in both study groups; use of gel without condoms was reported in more than 95% of vaginal sex acts. The 2 study groups were similar in the proportions of women and men with symptoms or with genital findings without epithelial disruption, of men with findings with epithelial disruption, and of women with abnormal genital flora, whereas more women in the placebo group had findings with epithelial disruption. Women and men in both groups reported that the gel and applicator were acceptable. Conclusions: Carraguard can safely be used an average of 2 to 3 times per week during sex and is acceptable to Thai women and men.

Acceptability of Carraguard vaginal gel use among Thai couples.

Objectives:To evaluate the acceptability of candidate microbicide Carraguard among couples participating in a safety trial. Study design:A 6-month randomized, placebo-controlled trial was conducted in sexually active, low-risk couples in Thailand. Methods:Couples who were monogamous, HIV uninfected, and not regular condom users were enrolled. Acceptability data were collected through structured questionnaires at repeated intervals. At the closing study visit, participants were asked questions about hypothetical product characteristics and future use. Compliance with gel use was assessed by questionnaires, coital diaries, and tracking of used and unused applicators. Results:Among 55 enrolled couples, follow up and adherence with gel use were high and sustained, with 80% of women using gel in over 95% of vaginal sex acts. Because acceptability results from Carraguard and placebo arms were similar, they were combined for this analysis. Overall, 92% of women and 83% of men liked the gel somewhat or very much; 66% of women and 72% of men reported increased sexual pleasure with gel use; and 55% of women and 62% of men reported increased frequency of intercourse. Only 15% of women but 43% of men thought that gel could be used without the man knowing. Although men and women had similar views overall, concordance within couples was low, with no kappa coefficients above 0.31. Conclusion:Carraguard gel use was acceptable to low-risk couples in northern Thailand. Reported associations between gel use and increased sexual pleasure and frequency suggest a potential to market microbicide products for both disease prevention and enhancement of pleasure.

Carraguard Vaginal Gel Safety in HIV-Positive Women and Men in South Africa

Objective:To assess the safety of the candidate microbicide Carraguard gel in HIV-positive women and men. Design:A randomized, placebo-controlled, triple-blinded clinical trial of Carraguard gel when applied vaginally once per day for 14 intermenstrual days by sexually abstinent and sexually active HIV-positive women; and when applied directly to the penis once per day for 7 days by sexually abstinent HIV-positive men. Methods:In each cohort (n = 20 per cohort), participants were randomized to Carraguard, methylcellulose placebo, or no product (1:1:1). In addition to traditional microbicide trial safety endpoints, the effects of microbicide use on vaginal shedding of HIV-1 RNA and markers of genital inflammation, epithelial sloughing, and microhemorrhage were also explored. Results:Gel compliance was high in both gel-use groups in the 3 cohorts. Carraguard use was not associated with abnormal genital findings, other abnormal clinical findings, markers of genital inflammation, epithelial sloughing or microhemorrhage, or self-reported symptoms in women and men, or with abnormal vaginal flora or genital shedding of HIV-1 RNA in women. Adverse events were mostly mild, not attributed to gel use, and similarly distributed between groups. Conclusions:Once-daily use of Carraguard for 7 to 14 days appeared to be safe in HIV-positive women and men.

Acceptability of Carraguard, a candidate microbicide and methyl cellulose placebo vaginal gels among HIV-positive women and men in Durban, South Africa

Background and MethodsWhen on the market, microbicides are likely to be used by individuals who do not know their HIV status. Hence, assessment of safety and acceptability among HIV positive men and women is important. Acceptability of Carraguard, the Population Councils lead microbicide candidate was assessed in a Phase I safety study among healthy HIV-positive sexually abstinent women and men, and sexually active women (20 per group), in Durban, South Africa. Participants were randomized to use Carraguard gel, placebo gel, or no product. All women in the gel arms applied 4 ml gel vaginally every evening for 14 intermenstrual days (women in the sexually active group inserted gel within 1 hour prior to sex on days when sex occurred), and sexually abstinent men applied gel directly to the penis every evening for 7 days. Acceptability was assessed by face-to-face structured questionnaires and semi-structured in-depth interviews with all participants. Gel use questions were applicable to participants in the gel arms only (13 sexually abstinent women, 14 sexually active women, and 13 abstinent men).ResultsOverall, 93% of the women liked the study gel (Carraguard or placebo) very much, 4% disliked it somewhat, and 4% were neutral. 15% of men and women disliked the gels color, smell, or packaging. Most women and men reported never experiencing pain or irritation during or after gel application. Although over two thirds of the women preferred some lubrication during sex, some of the women felt that the gel was frequently too wet. Twenty-one percent of women and 42% of men said they felt covert use of a microbicide would be acceptable. Over 60% of women and men would prefer to use a microbicide alone instead of using it with a condom.ConclusionAcceptability of Carraguard among HIV-positive women and men in Durban was good. The wetness experienced by the women may be attributed to the delivery of gel volume. The applicator was designed to deliver 4 mls whereas in fact between 4 ml to 5 mls were actually dispensed. Condom migration in the event of a partially effective product is of concern.

Engaging male partners in women's microbicide use: evidence from clinical trials and implications for future research and microbicide introduction

Constructively engaging male partners in women‐centred health programs such as family planning and prevention of mother‐to‐child HIV transmission has resulted in both improved health outcomes and stronger relationships. Concerted efforts to engage men in microbicide use could make it easier for women to access and use microbicides in the future. This paper synthesizes findings from studies that investigated mens role in their partners’ microbicide use during clinical trials to inform recommendations for male engagement in womens microbicide use.