Study Sheds Light on Why Women Need More Truvada for HIV PrEP

Tenofovir and emtricitabine -- the drugs in the Truvada combination pill used for HIV pre-exposure prophylaxis (PrEP) -- reach higher levels in rectal compared with female genital tract tissue, and the rectum also contains fewer of the natural DNA building blocks that compete with the drugs, according to research published in the February 24 advance online edition of the Journal of Infectious Diseases.

Truvada PrEP is highly effective for preventing HIV in gay men who take it consistently. In the large iPrEx trial, once-daily Truvada reduced the risk of HIV infection by 42% overall compared to placebo, rising to 92% among participants with blood drug levels indicating regular use. In an open-label extension of iPrEx, none of the men or transgender women who took Truvada at least 4 times weekly became infected.

Randomized studies of PrEP for women -- including VOICE and FemPrEP -- have reported lower levels of protection. This is largely thought to be due to inadequate adherence, but biological factors may also play a role.

Mackenzie Cottrell and Angela Kashuba from the University of North Carolina at Chapel Hill and colleagues performed a pharmacokinetic-pharmacodynamic modeling study to estimate the number of doses of Truvada required for effective PrEP.

The researchers measured concentrations of tenofovir, emtricitabine, their active metabolites (tenofovir diphosphate and emtricitabine triphosphate) in colo-rectal and cervico-vaginal mucosal tissue samples from 47 health HIV-negative women.

They also measured levels of naturally occurring or endogenous nucleotides, the components used to build chains of DNA or RNA. As HIV's reverse transcriptase enzyme constructs chains of nucleotides to create new viral genetic material, nucleoside/nucleotide analogs such as tenofovir and emtricitabine act as defective building blocks, bringing construction of the chain to a halt.

The team found that tenofovir diphosphate levels were 10 times higher in colo-rectal tissue than in female genital tract tissue, while levels of endogenous nucleotides were 7 to 11 times lower.

This model predicted that, overall, at least 98% of the population would achieve protective mucosal tissue levels by the third daily dose of tenofovir disoproxil fumarate (TDF) plus emtricitabine -- the drugs in Truvada. However, they also estimated that while just 2 weekly doses (28% adherence) would be enough to protect colorectal tissue, a minimum adherence of 6 weekly doses (85%) would be needed to protect the female genital tract.

"This model is predictive of recent PrEP trial results where 2-3 doses/week was 75%-90% effective in men but ineffective in women," the study authors concluded. "These data provide a novel approach for future PrEP investigations that can optimize clinical trial dosing strategies."

Another study by David Glidden and colleagues with the iPrEx team,reported at last summer's International AIDS Society conference, also found that tenofovir reached one-tenth the level in cervical tissue as it did in rectal tissue when using Truvada for PrEP, and that it took longer to approach maximum levels. A study presented at the recent the Conference on Retroviruses and Opportunistic Infectionsfound that tenofovir diphosphate levels in rectal and female genital tract tissue was lower when using the new tenofovir alafenamide, or TAF.

The University of North Carolina study adds further information about how natural nucleotide levels may contribute to the effectiveness -- or lack thereof -- of Truvada PrEP for women.

Below is an edited excerpt from a University of North Carolina press release explaining the study and its findings in more detail.

Women Need More of the HIV Drug Truvada Than Men to Prevent Infection

Study first to explain why women need more frequent dosing of Truvada than men to protect against HIV

Chapel Hill, N.C. -- March 3, 2016 -- Women need daily doses of the antiviral medication Truvada to prevent HIV infection while men only need two doses per week due to the way the drug accumulates in different body tissues, according to a new study from pharmacy researchers at the University of North Carolina at Chapel Hill.

The study, published in the Journal of Infectious Diseases, represents an important paradigm shift for HIV prevention strategies and could have major implications for clinical trial designs, said Angela Kashuba, PharmD, senior author of the study and the John and Deborah McNeill Distinguished Professor at the UNC Eshelman School of Pharmacy.

"Our data highlight the fact that one dose does not fit all," Kashuba said. "In determining how best to use drugs to protect people from HIV, we need to understand where in their body they are at risk for being infected, along with the concentration of drug that is needed to protect that site from infection."

Previous clinical studies showed that Truvada, the only prophylactic drug approved by the Food and Drug Administration to help prevent the spread of HIV, was more effective at reducing infection rates in men than in women, despite similar rates of drug adherence. Kashuba and her team are the first to explain the mixed clinical trial results by showing that different tissues require more or less of the drug to combat the virus.

The team shows that vaginal, cervical, and rectal tissue all respond differently to Truvada. Twice as much of the drug is needed to prevent HIV infection in vaginal and cervical tissue than rectal tissue because fewer components of Truvada make it into those two tissue types. Also, there is more DNA material that the virus uses to reproduce present in vaginal and cervical tissues, thus requiring more of the drug to prevent infection.

"The more DNA material there is available for HIV to work with, the more medicine is needed to block the process," said Mackenzie Cottrell, MS, PharmD, a research assistant professor at the pharmacy school and lead author of the study. "In essence, we calculated the most effective drug-to-DNA ratio for each tissue type."

The UNC-Chapel Hill team used human cells in a test tube to measure how much DNA material was in the cells and how much Truvada was needed to prevent HIV infection in these cells. Then they gave healthy female volunteers Truvada and measured how much of the drug got into vaginal, cervical and rectal tissue, and how much DNA material was there. Using both the test tube and human data, Kashuba and her team created a mathematical model that predicts the drug-to-DNA ratios in vaginal, cervical and rectal tissues and calculates the amount of drug needed to prevent HIV from infecting human tissues.

"We are excited to be able to apply our research methods to explain the conundrum of mixed clinical trial results of Truvada prevention, and how men and women should best use HIV prevention therapy," Kashuba said. "Yet we would like to remind people who are taking pre-exposure prophylaxis that Truvada should be taken every day to reduce the risk of acquiring HIV infection. Patients should not change their medication regimen without first consulting their physicians."

Daily dosing of Truvada was approved in 2012 to help prevent the spread of HIV, and it is the only drug approved by the FDA that has been shown to reduce HIV infection rates.

3/30/16

Reference

ML Cottrell, KH Yang, HMA Prince, ADM Kashuba, et al. A Translational Pharmacology Approach to Predicting HIV Pre-Exposure Prophylaxis Outcomes in Men and Women Using Tenofovir Disoproxil Fumarate +/- Emtricitabine. Journal of Infectious Diseases. February 24, 2016 (online ahead of print).

Other Source

University of North Carolina. Women Need More of the HIV Drug Truvada Than Men to Prevent Infection. Press release. March 3, 2016.