Preventing HIV Infection in Women

By Melanie Nicol

While the students are busy wrapping up their last week in Uganda, I thought I'd take this opportunity to talk more about my research. If I could describe my research in two words it would be "tissue pharmacology." I've already told you a bit about my project to understand drug penetration in the brain in the "Mushroom Meningitis of Uganda" post.. Now I'd like to aim a bit lower and talk about drug penetration in the genitals.

Global HIV statistics (UNAIDS and AMFAR)

My first research project as a graduate student was to develop a model using human vaginal tissue that could be used to evaluate drugs being considered for use in HIV prevention for women. Why focus on women? In the United States, women make up <25% of the people living with HIV. Globally, the statistics are quite different. The one that I always find the most sobering, HIV/AIDS is THE LEADING cause of death in women of reproductive age (ages 15-44). This statistic is largely driven by the epidemic in Sub-saharan Africa where young women are 2-3 times more likely to be infected than young men in the same age group.

Despite this, women are left with few effective options for prevention. Due to social structures and other barriers, women are seldom empowered to negotiate safe sex practices with their partners such as condom use. Pre-exposure prophylaxis, or PrEP, is the use of anti-HIV medications in people who are at high risk of getting HIV to protect themselves from infection. This is a similar concept to taking anti-malarial drugs prior to traveling to malaria-endemic countries. The approach has been shown to work for HIV as well although its far from optimized. A lot of questions remain. Which drugs should we use? How many drugs should we use? How long should they be used? Which populations should we target?

There is currently only one drug that's been shown to be effective as PrEP (although several more are still being studied). Truvada is a single pill that contains two different anti-HIV medications. Taking this drug once a day has been shown to be highly effective at preventing HIV acquisition. The World Health Organization as well as local governing agencies in many countries have endorsed the use of PrEP. However, not all studies of Truvada showed positive results. In fact, two of the major clinical trials done in African women found no reduction in infections in the group of women randomized to receive Truvada compared to those randomized to receive placebo. A lot of investigations have since tried to understand WHY these trials failed when others succeeded. The most obvious explanation is that adherence in these trials was low. Indeed, when random blood samples were tested, <30% of women had detectable concentrations of Truvada, suggesting most women were not taking the drug once daily as prescribed. Another explanation has emerged that is more complex-maybe the efficacy of this drug for HIV prevention is dependent on the site of exposure to HIV. Globally, the majority of HIV transmissions are through sexual transmission, heterosexual and homosexual.  But, not all mucosal surfaces are created equal. 

So, starting with that first project as a graduate student in 2009, I have spent the past (nearly 10) years researching how HIV drugs work in vaginal and cervical tissues. What I've learned: the female genital tract is a complex environment, and therefore interactions with drugs are equally complex. With 2nd year pharmacy student Joe Corbino, and UNC colleague Mackenzie Cottrell, we recently wrote a review on this topic that was just published this week.

Part of the MUJHU research team going through study supplies
(LtR) Betsy Kamira (study gynecologist), Esther Isingel 
(study coordinator), Samuel Kabwigu (study gynecologist), 
and Flavia Matovu (study site Principal Investigator)

In an effort to better understand this complex environment, specifically how this environment may affect the efficacy of PrEP medications, I am collaborating with Dr. Flavia Matovu of Makerere University and MUJHU Research. Dr. Matovu has an R01-funded research project where she is following a large number of women receiving Truvada (the drug used for PrEP). From this cohort, we recruited a small number (50) of subjects to provide additional sampling from the female genital tract. These samples (including biopsies and swabs) will be used to describe drug concentrations, characterize the vaginal microbiome, examine inflammatory status, and lastly test how these three things are related to each other. Additional patient factors, such as use of hormonal contraceptives, will also be looked at to see if this alters drug concentrations in genital tissue. This is an important consideration as women of reproductive age are one of the critical populations where HIV prevention options are sorely needed.

MUJHU Tower

Between November 2017 and April 2018, the MUJHU research team completed screening, enrollment, and sampling in all 50 women. (To give some perspective, I have an identical study here in Minnesota. We have been recruiting for a year now and 15 women have completed, highlighting the difference in the epidemic between Minnesota and Uganda.) The past few weeks, the local research team has been working to organize samples and prepare them for shipment. We've also been going through the data collected (quality control check) to ensure things haven't been missed. Soon the samples will be analyzed and we'll be able to start addressing our research questions. Very excited to see what we find!