Improving on the results of CAPRISA 004: what’s genital tract inflammation got to do with it?

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Dr. Quarraisha Karim presents alongside her husband Salim on further data derived from the CAPRISA study at the 19th Conference on Retroviruses and Opportunistic Infections Monday in Seattle.

Investigators hinted at a way to improve upon the HIV prevention results achieved in the CAPRISA 004 one percent tenofovir vaginal microbicide study, which found a 39 percent protective benefit for women using the pre- and post- coital gel. Lead CAPRISA investigators Drs. Salim and Quarraisha Abdool Karim broached the subject during a thoughtful plenary presentation Monday night at the 19th Conference on Retroviruses and Opportunistic Infections (CROI) in Seattle that highlighted the various accomplishments of the CAPRISA project in HIV prevention and treatment innovation.

The pair did a lot of early epidemiological work in Africa, and noticed the disproportionate burden of HIV on young women emerging, as compared to men, eventually resulting in exponential growth and rapid spread of the disease.  In Kwazulu-Natal, for example, HIV prevalence exceeded 40 percent among women of child-bearing age.

Quarraisha showed data on HIV prevalence in Vulindlela schools by age and gender (grades nine and 10). Boys had HIV prevalence rates of about one percent in all age groups – from boys less than age 14 up to age 20. Girls in these same classrooms, however, showed a very different picture. Girls age 14 already had a 2.2 percent HIV prevalence, which increased to 3.6 percent by age 16, and again increased to 16 percent in the 18 to 19 age group. Prevention in this age group is crucial, Quarraisha said.

Quarraisha discussed the inability of many women in sub-Saharan Africa to negotiate use of male or female condoms, and the urgent need for new prevention methods for women beyond the “ABC’s” — abstinence, behavior change, and condoms.

What followed was a focus on microbicides – and it was a long road, Quarraisha said. Despite multiple disappointing microbicide trials, in 2003 they developed the CAPRISA 004 trial to assess the safety and effectiveness of one percent tenofovir vaginal gel. They developed the “BAT” – 24 (“B”efore, “A”fter, not more than “T”wice a day) coitally related gel use dosing method after consultation with women who shared that many of their partners were migrant workers that they did not see on a regular basis. The need for protection was rare and sporadic. The CAPRISA 004 trial served as proof of concept for the one percent tenofovir vaginal gel – it reduced HSV-2 transmission by 51 percent, HIV transmission by 39 percent, and was found to be safe.

But, Salim said, we needed to understand why we only saw 39 percent protection – and not a better result. What insight could we gain by going back into the lab? Salim presented three important lessons they found by investigating further.

First, adherence is critical – there is no point in promoting a particular product if they do not adhere to it. Those who used the gel before and after more than 80 percent of sex acts saw a protective benefit of 54 percent; whereas those who used it less than 50 percent of the time saw a drop in efficacy to 28 percent. This opens the door to research how we might enhance woman’s ability to adhere, Salim said.

Second, high levels of the drug are needed to achieve protection. High vaginal concentrations were needed at exposure. That tells us that adherence is important to ensure you have high level of the drug available at the time of exposure, Salim said, adding that in order to achieve that with oral formulations you have to get very high levels of adherence.

Third, Salim emphasized the importance of genital tract inflammation (GTI), which increases HIV risk and undermines tenofovir gel effectiveness. In those women in the CAPRISA 004 trial with no detectible tenofovir in the vagina, seven of the 17 who HIV seroconverted had evidence of genital inflammation. They have a fourteen times higher risk of acquiring HIV than a woman without GTI, Karim said.  Four of the six women who acquired HIV with tenofovir exposure had GTI, he added, versus zero of the 24 who remained negative, showing the ability of GTI to undermine the microbicide’s effectiveness.

Salim mentioned the need to investigate possible anti-inflammatory use in the vagina, perhaps co-formulated with a microbicide gel, which they are discussing now. The World Health Organization has started working on guidelines for tenofovir gel use in women, he added, and they hope to get the product out for general use in the next three to four years.

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