Nichole Klatt

Nichole Klatt, assistant professor of pharmaceutics and pathobiology at the UW, researched how the bacterium Gardnerella breaks down the gel form of tenofovir.

In the lab of Nichole Klatt, assistant professor of pharmaceutics and pathobiology at the UW, postdoctoral fellow Alex Zevin and graduate student Ryan Cheu discovered why the well-known bacterium Gardnerella is able to break down the experimental gel version of the preventative HIV drug tenofovir. This renders it useless, which may explain some of the issues with its efficacy during clinical trials.

The gel version of tenofovir is intended to be inserted into the vaginal canal within 12 hours of having sex (before or after) to reduce the risk of HIV infection. Other versions of tenofovir, in tablet form, are widely used to treat HIV currently, though it remains incurable.

The discovery that Gardnerella may be reducing the efficacy of tenofovir was published in May, but the background of tenofovir gel is rather complex. 

The gel underwent a large study in sub-saharan Africa. Most of the scientific community references this trial as a disappointment. Many had predicted that the gel was going to be a breakthrough, but when its low efficacy results were relayed at the 2015 Conference on Retroviruses and Opportunistic Infections in Seattle, that hope flickered out.

The realization that Gardnerella might be impacting the efficacy of tenofovir gel stemmed from a partnering lab’s clinical trials with Adam Burgener, assistant professor at the University of Manitoba and the Public Health Agency of Canada. There, Burgener and his team found that women with Gardnerella-dominant vaginal bacteria were less protected when using tenofovir than women with Lactobacillus-dominant vaginal bacteria. Klatt’s lab has determined why efficacy on the tenofovir gel was reduced: the enzymes in Gardnerella. 

These new findings imply the tenofovir gel failed in the study due to the presence of the bacterium, not because women in the clinical trial failed to use it properly, which was the original suspicion.

“Science isn’t a one shot thing,” Klatt said. “We had to really do a lot of experiments to make sure we were right, so [it was] several months of running these experiments.”

The vaginal microbiomes of women vary worldwide. While Gardnerella dominance is less common in the United States, it’s actually much more typical in sub-saharan Africa, which is where the tenofovir gel trials took place.

Efficacy results change under different variables like location and biological make-up, according to Cheu. This creates “huge disparities” between claims to efficacy put forth by drug companies.

“But, in general, women’s health is just understudied,” Klatt said. “It’s a general problem in the field. We just haven’t studied it well enough as a scientific community.”

While Gardnerella is a serious nuisance to the gel version of tenofovir, it is a normal part of the vaginal microbiome in many women, which complicates how it might be treated, according to Klatt. 

Many Gardnerella-dominant women experience no symptoms, but they may have a condition known as bacterial vaginosis, which can be diagnosed by a doctor using a pH test. Antibiotics could then be given to treat Gardnerella’s associated infection of bacterial vaginosis, but Klatt suspects it will take more than just antibiotics.

“It’s not as simple as it seems because the antibiotics used to get rid of Gardnerella work about 60 percent of the time,” Klatt said. “It’s a good concept in theory, and it will take a lot more work.”

Klatt also noted that in Africa, where Gardnerella is a much more frequent bacterium for women, and has the highest rates of HIV infection, a woman can have the Gardnerella bacteria but not suffer from bacterial vaginosis. The two don’t always correlate.

“We have a whole laundry list of things we’re looking at now,” Klatt said. 

The Klatt lab will investigate whether Gardnerella is able to break down other drugs in a similar way. They’re also checking if other bacteria break down any other prophylactic drugs. 

Cheu said discoveries and projects like this one are why he got into the pharmaceutical field. He explained that sometimes issues around drug testing can be systemic because scientists assume only certain microbiomes are relevant. They try to put it in “a box,” according to Cheu.

“The hope is that as more and more of these studies come out … microbiomes will be looked at more for explaining the lack of efficacy,” Cheu said.

 

Reach reporter Kelsey Hamlin at science@dailyuw.com. Twitter: @ItsKelseyHamlin

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