Back HIV Prevention Pre-exposure (PrEP) HIVR4P 2014: Model Suggests More Frequent Truvada PrEP Needed for Vaginal vs Anal Sex

HIVR4P 2014: Model Suggests More Frequent Truvada PrEP Needed for Vaginal vs Anal Sex


Tenofovir reaches lower levels in vaginal and cervical tissue compared with rectal tissue, helping to explain why pre-exposure prophylaxis (PrEP) did not protect women as much as gay and bisexual men in clinical trials, and suggesting that women having vaginal sex may need to take PrEP more often than people having anal sex, researchers reported at the HIV Research for Prevention meeting this week in Cape Town.

Truvada (tenofovir + emtricitabine) was shown to be highly effective in the iPrEx trial of mostly men who have sex with men (MSM). Once-daily Truvada reduced the risk of HIV infection by 42% overall, rising to 92% among participants with blood drug levels indicating regular use. A mathematical model suggested that taking Truvada 4 times per week would provide 99% protection, and inan open-label extension of iPrEx, none of the men who took Truvada this often according to blood drug level measurements became infected.

The Partners PrEP and TDF2 trials,which looked at heterosexual couples in Africa, found that PrEP using Truvada or tenofovir alone reduced the risk of HIV acquisition by about 65% to 75%. But effectiveness was lower among African women in the Fem-PrEP and VOICEtrials. This has been largely attributed to poor adherence, but biological factors may also play a role, as tenofovir concentrations may not be as high in the female genital tract compared with rectal tissue.

Mackenzie Cottrell and Angela Kashuba from the University of North Carolina and colleagues used a mathematical model to predict how often people would need to take Truvada to achieve adequate protective drug levels.

This pharmacokinetic-pharmacodynamic model incorporated tissue concentrations of tenofovir diphosphate and emtricitabine triphosphate -- the active forms of the drugs -- and the ratios of these nucleoside/nucleotide analogs to endogenous or natural DNA nucleosides (dATP and dCTP) needed to inhibit HIV. Laboratory cultures of vaginal, cervical, and rectal cells were treated with tenofovir and emtricitabine for 24 hours before exposing them to HIV.

In addition, the researchers incorporated data from a Phase 1 clinical trial looking at the pharmacokinetics of tenofovir, emtricitabine, maraviroc (Selzentry), and raltegravir (Isentress) in women's vaginal, cervical, and rectal tissue. 48 women received a single dose of tenofovir or emtricitabine at 50%, 100%, or 200% of the licensed dose, and researchers measured drug concentrations in their vaginal, cervical, and rectal tissue over 48 hours.

The model predicted that after 7 days, a 200 mg dose of emtricitabine would produce ratios exceeding the 90% effective concentration (EC90) in vaginal tissue in >85% of the population, in cervical tissue in 50% of the population, and in rectal tissue in 75% of the population. A 300 mg dose of tenofovir produced ratios exceeding the EC90 for <50%, <50%, and 100% of the population in vaginal, cervical, and rectal tissue, respectively.

While 2 weekly doses of tenofovir/emtricitabine maintained drug levels above the EC90 in rectal tissue in 100% of the population, even with daily dosing only >75% and 50% of the population exceeded the EC90 in vaginal and cervical tissue.

"This model predicts available clinical trial data, whereby [tenofovir/emtricitabine] is [approximately] 70% effective in women with >adherence and >90% effective in MSM with [approximately] 30% adherence," the researchers concluded.

Importantly, this study looked at vaginal and cervical tissue versus rectal tissue, not women versus men. PrEP trials of heterosexual women have generally assumed that the women are mostly having vaginal sex, but of course many women have anal sex as well.

"It is easier to achieve the target ratio in rectal tissue than in cervical and vaginal tissues, according to the scientists, because the concentration of DNA molecules is lower and of tenofovir is higher in rectal tissue than in the female genital tract," according to a National Institute of Allergy and Infectious Diseases press release summarizing the study.

As this research is still at an early stage, both men and women who are prescribed Truvada for PrEP should take it daily as directed according to Centers for Disease Control and Prevention (CDC) guidelines, the release stresses.



ML Cottrell, KH Yang, HMA Prince, ADM Kashuba, et al. Predicting Effective Truvada PrEP Dosing Strategies With a Novel PK-PD Model Incorporating Tissue Active Metabolites and Endogenous Nucleotides (EN). HIV Research for Prevention (HIV R4P). Cape Town, South Africa, October 28-31, 2014. Abstract OA22.06 LB

Other Source

National Institute of Allergy and Infectious Diseases. Model by NIAID Grantees Explains Why HIV Prevention Dosing Differs by Sex. Press release. October 30, 2014.