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