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The Lancet

Volume 372, Issue 9654, 6–12 December 2008, Pages 1977-1987
The Lancet

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

https://doi.org/10.1016/S0140-6736(08)61842-5Get rights and content

Summary

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 Carraguard's efficacy in prevention of vaginal transmission of HIV. No safety concerns were recorded.

Funding

US Agency for International Development, Bill & Melinda Gates Foundation.

Introduction

About 33·2 million people worldwide are living with HIV, of whom 68% are residing in sub-Saharan Africa.1 Women and girls are disproportionately affected, accounting for 61% of HIV-infected individuals in sub-Saharan Africa.1 In South Africa—the country with the greatest number of people living with HIV globally—yearly HIV incidence is highest in women aged 20–29 years (5·6%), which is a rate that is six times higher than that for men of the same age (0·9%). Furthermore, in 15–24-year-olds, 90% of new HIV infections occur in girls and women.2 Existing strategies for risk reduction—abstinence, mutual monogamy, and condom use—are not feasible for many women, and male circumcision, which has a protective effect in men, does not reduce risk in women.3 Vaginal microbicides, which are formulated as gels, films, creams, or rings, are being developed as female-initiated HIV-prevention options that could reduce male-to-female transmission of HIV, and possibly other sexually transmitted infections (STIs).

Previous effectiveness trials of candidate microbicides have been unsuccessful. In 2002, a study of Col-1492, a spermicide containing nonoxynol-9, reported that frequent use was associated with an increased risk of HIV infection.4 Furthermore, two effectiveness trials of the microbicide candidate Savvy (C31G)5, 6 were stopped early because of insufficient rate of HIV infection and a low likelihood of showing a protective effect. Additionally, a trial of the candidate UsherCell (cellulose sulphate) was terminated because of a trend towards increased risk of HIV infection in the active product group.7

The candidate microbicide Carraguard (PC-515), developed by the Population Council, is a non-contraceptive, odourless, colourless gel made from a specific type of carrageenan (product number PDR98-15, FMC, Philadelphia, PA, USA), which is derived from seaweed. PDR98-15 prevents in vitro the mucosal transmission of HIV-1 at concentrations 100–1000 times lower than those associated with substantial cellular toxic effects,8, 9, 10 both in the presence and absence of semen.11 Although the mechanism of action is unknown, the negatively charged PDR98-15 probably works by binding to the positively charged regions of the viral envelope of free-virus cells and acting as a barrier between infected and non-infected cells. Additional non-clinical studies showed that PDR98-15 might also protect against HIV-2 and other STIs, including herpes simplex virus type 2,12 Neisseria gonorrhoeae,13 and human papillomavirus.14 Carraguard is also effective in blocking transmission of the recombinant simian/human immunodeficiency virus in rhesus macaques.15

Non-clinical and clinical studies have confirmed the safety of carrageenan formulations for vaginal use. In-vitro toxicological studies have reported that PDR98-15 does not have a proliferative effect on cervical cells or a negative effect on lactobacillus acidophilus.16, 17 In-vivo animal studies (in mice, rats, and rabbits) have shown that Carraguard does not cause vaginal14 or rectal18 irritation, or toxic effects or reproductive toxic effects, when given before mating through organogenesis. In phase I and II clinical studies, carrageenan formulations caused no observable irritation to the lower reproductive tract19, 20 and were not associated with vaginal flora changes when used for up to 1 year.21, 22, 23 Further clinical research showed that direct application to the penis was not associated with any irritation and that vaginal shedding of virus in HIV-positive women did not increase with gel use.14, 24 In an expanded safety study of Carraguard, investigators recorded 16 HIV seroconversions (eight in the Carraguard group and eight in the placebo group; rate ratio 1·04 [95% CI 0·34–3·17]), but the study was not powered to assess efficacy.14

On the basis of these data and the urgent need for a vaginal microbicide, we undertook a phase III trial of Carraguard to assess its efficacy in prevention of HIV seroconversion in women and to establish its long-term safety.

Section snippets

Study design and population

Between March 17, 2004, and March 31, 2007, we undertook a randomised, placebo-controlled, double-blind trial in collaboration with three South African research institutions: the Medical Research Council (MRC) of South Africa; the University of Limpopo, Medunsa Campus (Medunsa); and the University of Cape Town (UCT) at sites in Isipingo (KwaZulu-Natal), Soshanguve (Gauteng), and Gugulethu (Western Cape), respectively. Eligible volunteers were sexually-active, HIV-negative women, aged 16 years

Results

Figure 1 shows the trial profile. 9564 women were screened and 6202 were enrolled into the trial and randomly assigned. HIV-positive status was the primary reason for exclusion, with an overall prevalence of 28% (n=2614) in the screened population with varying rates by site (43% [n=1197/2813] MRC, 25% [868/3520] Medunsa, 18% [549/3027] UCT). Participant disposition was similar in the two groups: 69% of women (n=2133) in the Carraguard group and 68% (n=2111) in the placebo group completed the

Discussion

This trial was unable to show that Carraguard reduces the risk of male-to-female transmission of HIV. Although we recorded fewer HIV infections in the Carraguard group than in the placebo group, the difference was not significant. Furthermore, the 95% CI for the hazard ratio excludes the possibility that Carraguard is 33% effective (the target level of the trial). In view of this result, and despite promising evidence of efficacy from non-clinical data, Carraguard is unlikely to have a

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