Research Works to Understand Drug Efficacy Sex Disparity in HIV Prevention

Pre-exposure prophylactic (PrEP) medications work to prevent human immunodeficiency virus (HIV) from establishing infection inside the body. PrEP drugs are shown to be highly effective in men, but much less so in women. Nichole (Nikki) Klatt, PhD, a professor and the director of the Division of Surgical Outcomes and Precision Medicine Research in the University of Minnesota Medical School’s Department of Surgery, is conducting research to try and determine why.

“It starts with how the body responds to disease. So much work is done on the blood, but a lot of host response comes from mucosal sites. We also have to consider the microbiome, which is all of the microorganisms — such as bacteria — that live throughout the body and contribute to our health. It’s such a complex issue and it's a challenge, which is fascinating to me. I’m particularly passionate about this because women’s health is severely understudied,” Dr. Klatt said.

Bacterial vaginosis (BV), a highly common syndrome among women that’s caused by an imbalance of bacteria, can lead to many unpleasant symptoms and negative outcomes. 

A recent study by Dr. Klatt’s lab demonstrated that vaginal microbial communities may also impact PrEP drug efficacy.

“There’s a huge disparity. Men that take PrEP have 80 to 90 percent protection against HIV, while women have negative 40 to 70 percent. It didn’t make any sense, so we wanted to understand the biology behind it,” Dr. Klatt said. 

Dr. Klatt and colleagues have also found that women with a normal, healthy vaginal microbiome have more PrEP drug efficacy than those with BV. In the most recent follow up study, Dr. Klatt’s lab used cervicovaginal lavage samples from women with and without BV to determine how the microbiome interacts with multiple drugs used for HIV prevention. 

“The vaginal microbiome affects everything. This isn’t just a small issue. It can cause increased STIs in women, increased chance of preterm birth and fertility problems. It causes extreme discomfort and affects more than 50 percent of women. There are massive consequences for having an imbalance in the vagina’s microbiome and yet there’s just not much research on it,” Dr. Klatt said.

For HIV to replicate, it must infect a specific type of white blood cell in the body's immune system. If bacteria metabolize a PrEP drug first, then the drug is unable to get into the necessary cells to provide that protection, essentially rendering it inactive. 

With wide-ranging implications behind it, the research is about more than just correlations and associations — it’s about finding the root mechanisms that lead to causality. “What we try to do is go from looking at a broad picture of a health problem, take that and identify what’s associated with that health problem, and then go into the lab and test ideas to find cause and effect. We’re not just making an association and ending there. We take it to the next level to try and understand why,” Dr. Klatt said. 

This research can inform clinical care by helping to personalize medicine. It’s imperative to understand if a specific drug is more effective for someone based on their individual circumstances. One PrEP drug might be given to someone else, but it could be less effective, completely ineffective or there could be better options available. Dr. Klatt’s research intends to provide the knowledge behind those future clinical decisions. 

“We’re working hard on using new systems biology approaches to discover what really causes the imbalance because we just don’t know why some women have BV and some women don’t. We need to figure out what works. There’s basically one therapy available right now, and it hardly works. We want to see how we can use biology to guide future clinical trials and drug targets,” Dr. Klatt said.

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Dr. Klatt (second from the right) and several members of her lab.

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