“Today is the day we achieve proof of concept for microbicides,” said Professor Gita Ramjee, head of the HIV Research Unit of the South African Medical Research Council.
She was opening a session at the Eighteenth International AIDS Conference in Vienna, at which the researchers into a microbicide gel that prevented only four out of ten HIV infections were nonetheless given three standing ovations.
Ramjee was chairing the session in which the results of the CAPRISA trial of tenofovir gel showed that the microbicide prevented four out of ten HIV infections (39% efficacy), and prevented more than half of the infections in women who used the gel more than 80% of the time (54% efficacy).
Principal investigator Quarraisha Abdool Karim opened her presentation by noting that CAPRISA is the first proof that a prevention idea first mooted 20 years ago by epidemiologist Zena Stein, and first tested ten years ago in a trial of the spermicide nonoxynol-9, can be made to work. It is the first success out of 13 randomised controlled trials of the concept, two of which produced a negative result.
The main results of the trial were broken by the press yesterday (see aidsmap report: Tenofovir-based microbicide gel reduces risk of infection for women by 39%). Qarraisha Abdool Karim gave more details.
The CAPRISA study was conducted in two centres in Vulindlela, a rural area, and eThekwini, an urban one, in KwaZulu Natal, a province in which more than half of women aged 23 and 24 have HIV. Of the 889 women entering the trial, 845, half using 1% tenofovir gel and half using an inert placebo gel completed the trial, a retention rate of 95%. The women were instructed to insert an applicator full of gel up to 12 hours in advance of sex and another applicator up to 12 hours after sex. This ‘coitally-dependent’ use had been criticised when it was first included in the CAPRISA protocol, as many experts thought it would be difficult for the women to anticipate sex and that adherence might therefore be poor.
HIV infections double between the ages of 17 and 22 in young women in the area, and it was not surprising that 17 was when most of them started having sex. The average number of times the women had sex in a month was eight, on average they had had three or four sexual partners, and 29% said they always used condoms.
The results
There were 38 HIV infections in young women taking tenofovir and 60 in those on placebo, yielding annual incidence rates of 5.6% and 9.1% respectively and 39% efficacy (95% confidence interval, 6 to 61%, p=0.017).
This is the headline efficacy rate and includes the effect of less-than-perfect adherence. The efficacy of the gel, if it was used 100% of the time, would undoubtedly be higher. In women who used the gel on more than 80% of occasions, efficacy was 54%. However, even in women who used the gel less than half the time, 28% fewer infections occurred compared to the placebo group.
Young women with this technique will be able to take their health into their own hands. Aaron Motsoaledi, South African Minister of Health
By the end of the first year of the study there were only half as many infections in participants using tenofovir. But adherence rates fell as the study went along, and there was evidence that some women were infected because of ‘adherence fatigue’.
Adherence figures, derived from the collection of used applicators, showed that, in the first year, adherence amongst women who became infected was equal to or better in women using tenofovir than in women using the gel. However, in the subsequent 18 months of the 2.3 year study, adherence amongst those who, by the end of the study, had become infected fell increasingly behind those who stayed HIV-negative.
Sensitivity analyses were conducted to see whether the exclusion of certain participants for protocol violations had made any difference and the figures proved to be statistically robust.
Initial comments
Sheen McCormack of the UK Medical Research Council and principal investigator of the failed MDP 301 trial of the microbicide PRO2000 presented some of the background to CAPRISA. There had been 40 randomised controlled trials of 33 different prevention interventions in HIV, ranging from microfinance schemes to vaccines, but only six had had positive results: the three circumcision trials; an STI treatment trial whose positive result has never been reproducible; the unexpected and welcome, but weak, efficacy seen in the recent RV144 Thai vaccine trial; and now the first ever effective microbicide.
She said there was no chance that tenofovir as a microbicide could be licensed on the basis of CAPRISA as the lower bound of the 95% confidence interval was only 6%: in other words, there was a 1-in-20 chance that the true efficacy could be as low as this.
We are therefore entering a limbo period of two years before we get the results of the large VOICE trial, which will compare the efficacies of tenofovir gel, tenofovir pre-exposure prophylaxis (PrEP), and tenofovir/FTC PrEP. Even VOICE would not answer a number of research questions: would microbicides work for adolescents (CAPRISA volunteers were over 18)? Was it safe in pregnancy (pregnant women were dropped from the trial)? Was it safe in long-term use? And what about people who have frequent sex? One of the reasons most cited by volunteers for poor adherence was that the trial protocol stipulated gel application no more than once a day, but women often had sex more than once a day.
These and numerous other questions such as the use of other ARVs as microbicides, microbicides for anal sex, different formulations such as vaginal rings and so on were or would be answered by ongoing or planned studies, some of which were described at the 2010 International Microbicides Conference (see aidsmap reports: Microbicides: the quest for user-friendly formulations and Six existing drug classes now being tested as microbicides). But McCormack warned that the window for placebo-controlled trials might be closing soon and comparison trials would need larger groups.
Still, she said, CAPRISA gave a positive answer to the question of whether microbicides could ever work.
“Am I excited about CAPRISA? Yes!” she said. “But do I think it is ready to roll out? No.”
The South African Minister of Health, Aaron Motsoaledi, said that CAPRISA was “a step in the right direction. Women in their productive years bear the brunt of HIV more than any other group in the population but the methods we have so far – condoms, male circumcision – only work if the man is prepared to accept them. Young women with this technique will be able to take their health into their own hands.”
Pointing out that this was a study largely devised and entirely conducted in South Africa, he promised that his department “will do whatever we can to make sure our country, our continent and the world benefits from this exciting trial.”
Further information
Presentations and abstracts for this session are available on the official conference website.