Of the studies at CROI 2016 of new compounds with potential for development as PrEP, data on the new version of tenofovir -- called TAF -- were amongst the most awaited and the most difficult to interpret.
One of the reasons that many activists and doctors challenged Gilead's initial decision to only develop TAF as a component of complete single pill combinations, was that in addition to the needing for TAF for treatment, there was also the potential use for PrEP.
Somewhat reluctantly, the company conceded by developing TAF/FTC as a separate dual formulation. Although this was a later priority in the development programme, the dual formulation is now filed with the FDA and EMA. Based on early results at CROI, this insight for the potential of TAF as PrEP might proove important.
In the first presentation, Gerado Garcia-Lerma from the U.S. CDC in Atlanta reported results on the effectiveness of oral TAF and FTC following rectal exposure to simian HIV.
The animal dose of 1.5 mg/kg was selected to approximate to human drug levels using 25 mg TAF, based on a previous macaque study show similar levels of tenofovir diphosphate (TFV-DP) in cells (PBMCs) to previous animal studies with tenofovir DF but lower than expected exposure in rectal tissue.
TAF/FTC was dosed 24 hours before and two hours after weekly rectal exposure for 19 weeks, with six animals in the active arm and six receiving placebo.
All the control animals became infected within 1 to 10 exposures and seroconverted with high viral loads compared to none of the animals receiving TAF/FTC.
These results are very exciting, but came with a caution for a need for human efficacy studies before TAF is used for PrEP.
The second study, presented by Katy Garrett from the University of North Carolina, reported on levels of tenofovir and tenofovir diphosphate following a single oral 25 mg dose of TAF.
This study included eight HIV negative women, median age 27 years, who had drug levels measured in plasma, cervical fluid and vaginal and rectal tissue for 14 days after the single oral dose, with results compared to historical results in a similar tenofovir DF study.
In plasma and genital fluid, TFV concentrations peaked at 1 hour and were undetectable by day 7.
Levels of TFV-DP in PBMCs peaked at 12 hours in plasma, were still detectable at 10 days and were undetectable by day 14; however, TFV-DP level in the genital tract were variable and largely undetectable.
In rectal tissue, TFV levels peaked at 3 days and were detectable throughout, but TFV-DP also peaked at a 3 days but were undetectable by day 7.
When comparing these results to previous data with TDF, TAF resulted in the expected lower plasma and higher PBMC exposure. TAF levels in cervical fluid were 11-fold lower, with 58% undetectable (vs 23% with TDF). TFV exposure was 2-fold lower in genital tissue and TFV-DP was 1-fold lower (with 75% undetectable vs 25% with TDF).
In rectal tissue, instead of the expected increase compared to TDF, TFV levels were 10-fold lower, and TFV-DP were 13-fold lower (with 63% undetectable vs 0% with TDF).
The results from both studies need to be interpreted together before efficacy studies in humans. The high level of protection in the macaque study suggests that previous use of tissue concentrations as a surrogate marker for PrEP efficacy with TDF might not be appropriate for the mechanism of action with TAF.
Unless stated otherwise, all references are to the Programme and Abstracts of the Conference on Retroviruses and Opportunistic Infections, 22-25 February 2016, Boston, USA.
- Garcia-Lerma GJ et al. Chemoprophylaxis with oral FTC/TAF protects macaques from rectal SHIV infection . Oral abstract 107.
- Garrett KL et al. TFV and TFVdp in female mucosal tissues after a single dose of TAF. Oral late breaker abstract 102LB.