Why do some women get HIV infection, even though they are using tenofovir gel for prophylaxis? A new study by scientists at the Centre for the AIDS Programme in Research in South Africa (CAPRISA) and Columbia University’s Mailman School of Public Health, shows that genital inflammation significantly reduces the effectiveness of tenofovir gel in preventing HIV infection in women. These findings indicate that both genital inflammation and adherence need to be addressed to improve the effectiveness of topical pre-exposure prophylaxis strategies for HIV prevention in women. The findings are published online in Nature Medicine.

The researchers measured small proteins, known as cytokines, in the vagina. Raised cytokines levels in the vagina indicate the presence of inflammatory immune responses, even in the absence of clinical symptoms.

HIV infection rates and cytokine levels as a marker of genital inflammation were studied in 774 women over 2.5 years. The researchers found that women with genital inflammation were at higher risk of subsequently contracting HIV compared to women without inflammation. The study further showed that tenofovir gel provided 57% protection against HIV acquisition in women who had no evidence of vaginal inflammation but provided no protection in women with genital inflammation, even if they used the gel consistently.

“This study gives us an important clue to enhance HIV prevention in women. It is not only adherence-related behaviors, but also biological processes in the vagina that need to be addressed to prevent HIV and enhance the effectiveness of topical PrEP,” said Salim Abdool Karim, PhD, director of CAPRISA and professor of epidemiology at the Mailman School of Public Health.

In the study, 9 pro-inflammatory cytokines were measured in specimens collected at over 2,139 clinic visits at a rural and urban clinic in KwaZulu-Natal, South Africa to define the levels of genital inflammation. In women who had no genital inflammation, women assigned to tenofovir gel had a HIV incidence rate of 2.3 per 100 person-years, compared to 5.4 per 100 person-years in women assigned to placebo gel. Conversely, in women with genital inflammation, the HIV incidence rate in those assigned to tenofovir gel was 6.8 per 100 person-years compared to 7.0 per 100 person-years in women assigned to placebo gel.

The study found that among women who used the gel most of the time (> 50% of sex acts), tenofovir gel was 75% protective in those women who had no genital inflammation as compared to no protection in women with evidence of genital inflammation.

In 2010, the CAPRISA 004 trial provided the first evidence that tenofovir can prevent sexual transmission of HIV. Tenofovir gel reduced HIV acquisition by 39% overall. Two subsequent studies found that tenofovir gel was not effective, most likely because most of the women in the trials did not use the gel consistently. A sub-group analysis of the FACTS001 and the MTN 003 trials showed that the gel was just over 50% effective in consistent users, highlighting the importance of high adherence. The new evidence emerging from this genital inflammation study indicates that there may be a biological basis for the differing results as well. The causes of genital inflammation are not well understood at present. Previous studies have shown that there are many possible causes of genital inflammation in women, including imbalances in the bacteria of the vaginal microbiome, sexually transmitted infections, and vaginal practices.

Commenting on the study, Dr. Jo-Ann Passmore, head of the CAPRISA mucosal immunology laboratory, a professor at the University of Cape Town, and principal investigator of this research said, “Genital inflammation, which is present in up to a third of women, makes it harder to protect women from HIV infection. The next step is to expand our results to assess how genital inflammation might affect the efficacy in HIV prevention trials of vaccines, passive immunization with antibodies, and antiretroviral PrEP administered through pills, rings, and implants.”