The microbicide Carraguard did not protect women against HIV infection in a major phase III study, the Population Council announced yesterday. Although safe, the product did not reduce the number of infections during the three year study compared with a gel containing placebo.
The study recruited 6,202 women at three sites in South Africa, and randomised women to receive either the active microbicide Carraguard or a gel containing placebo for vaginal use.
All women received condoms throughout the study, counselling on safer sex and risk reduction and treatment for curable sexually transmitted infections.
Women who tested HIV-positive during screening for the study, together with women who became infected during the study, received medical care funded by the Population Council, the trial’s sponsor. Twenty-seven per cent of women screened for the study tested HIV-positive.
There were 134 new infections in the Carraguard group (an incidence of 3.3 infections per 100 woman-years) and 151 new infections in a placebo group (an incidence of 3.7 per 100 woman-years). The difference between the two groups is not statistically significant.
There was no significant difference in the incidence of side-effects such as vaginal irritation between the Carraguard and placebo groups (around 2% in each arm), nor in loss to follow up and withdrawal rates.
Adherence raises concerns about real world use
Use of the microbicide was relatively low; the researchers calculated that only 41% of sex acts would have been covered by the microbicide, but it is unclear to what extent poor adherence compromised the efficacy of Carraguard.
In a statement issued today, South Africa's Treatment Action Campaign said: "The poor uptake is sobering news for the likely effectiveness of microbicides applied topically."
However, the findings on adherence need to be considered in context. Reinforcement of the importance of regular microbicide use took place only at quarterly study visits. There was no supportive ongoing education in the community, and researchers are still in the process of analysing the relationship between frequency of microbicide use and risk of seroconversion.
One critical component of this analysis will be data derived from a survey of returned gel applicators, an independent means of verifying adherence. When asked to self-report their use of the gel, 96% of women said they had used it before their last episode of sexual intercourse.
However, analysis of returned gel applicators showed that only 10% of women used the gel 100% of the time, 20% used it on around three-quarters of occasions, and 30% used it on less than one in four occasions.
Sexual behaviour and risk factors during the study
Despite the relatively low use of the microbicide, there were substantial reported changes in behaviour. Reported condom use increased from 33% at baseline to 64% during the trial, and the prevalence of most sexually transmitted infections fell during the study.
Women who had a sexually transmitted infection at baseline screening had a 1.7-fold increased risk of HIV infection compared with those who did not. Younger women (aged 16 to 24) were at increased risk of seroconversion, as were women at the Isipingo study site, in Limpopo province. Baseline coital frequency and baseline condom use were not associated with seroconversion risk.
Reactions
Carraguard is the first product developed as a microbicide to complete the final phase of product testing. It is manufactured from carrageenan, which is derived from seaweed.
“We are disappointed that this trial did not show Carraguard to be effective; nonetheless the completion of this trial is a milestone in HIV prevention research,” said Population Council president Peter Donaldson. “The trial has contributed significantly to the field’s body of knowledge regarding product development, trial design, and women’s and their partners’ willingness to use a vaginal gel consistently. The data from the trial will be used by the Population Council and others working on microbicides to improve future products and trials.”
Carraguard will continue to form the basis for future microbicide candidates, the Population Council said.
The Carraguard trial was funded by the US Agency for International Development (USAID) and the Bill & Melinda Gates Foundation. Jeff Spieler, senior science advisor in population and reproductive health at USAID, said, “We have always known that the path to developing a successful microbicide would be a long one. The Population Council has done groundbreaking work in completing this trial, even though we are terribly disappointed that the product was not shown to be effective. Now we all have to redouble our efforts to develop a microbicide that women can use to protect themselves.”
The Carraguard study results are the latest in a series of disappointments in the microbicide research field.
Two other major microbicide studies were halted altogether in 2007 after it was discovered that women who received the active product, UsherCell, or cellulose sulphate, were more likely to become infected in one study.
Last week it was concluded that a higher strength version of the microbicide PRO2000 should be dropped from a large phase III study because it was unlikely to show any significant impact on HIV incidence. A lower dose arm and another large randomised study of the same product continue.
A major international conference on microbicides takes place in Delhi, India from February 24-27th