ICAAC 2013: New Tenofovir Formulation Has Less Effect on Kidneys and Bones


Tenofovir alafenamide (TAF), a new formulation that reaches higher levels in cells but allows for lower dosing, was as effective as the current tenofovir disoproxil fumarate (TDF) formulation but had less impact on markers of kidney function and bone turnover, researchers reported at the 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2013) this week in Denver.

Tenofovir (Viread, also in the Truvada, Atripla, Complera, and Stribild coformulations) is among the most widely used antiretroviral drugs, as it is highly effective and generally regarded as safe and well-tolerated. However, it can cause kidney toxicity in susceptible individuals and is associated with bone loss that begins soon after starting treatment. The long-term consequences of these side effects are a growing concern in light of guidelines recommending earlier treatment and expanding use of Truvada for pre-exposure prophylaxis (PrEP).

Gilead Sciences' new TAF formulation produces 5-fold higher concentrations of active tenofovir diphosphate in the cells that harbor HIV, but drug levels in the blood remain much lower compared with TDF. This enables reduced dosing that is expected to have less detrimental effects on the kidneys and bones.

Paul Sax from Brigham and Women's Hospital in Boston presented late-breaking results from a Phase 2 study (GS-US-292-0102) comparing TAF at 10 mg versus TDF at 300 mg, both as part of a single-tablet regimen that also includes the integrase inhibitor elvitegravir, cobicistat (a pharmacoenhancer or "booster"), and emtricitabine. The TDF-containing coformulation is marketed as Stribild; the TAF version is not yet approved. Given the apparent advantages of TAF, advocates have asked Gilead to request approval for the single agent as well as the new coformulation.

This double-blind, placebo-controlled trial included 170 previously untreated people with HIV who were randomly assigned (2:1) to receive the TAF or TDF coformulations once-daily for 48 weeks.

Almost all participants were men, more than two-thirds were white, nearly one-third were black, and the median age was about 35 years. The median baseline CD4 T-cell count was about 390 cells/mm3 (though about 15% had less than 200 cells/mm3) and the median viral load was approximately 40,000 copies/mL. At study entry they had normal kidney function with a median estimated glomerular filtration rate (eGFR) of 115 mL/min. People with hepatitis B or C coinfection were excluded.


o   The TAF coformulation produced trough (minimum) and total (area under the curve) tenofovir plasma concentrations of 11 ng/mL and 326 ng*hr/mL, respectively, compared with 83 ng/mL and 3,795 ng*hr/mL with the TDF coformulation.

o   Overall plasma exposure was 91% lower with TAF.

o   Conversely, tenofovir diphosphate exposure in peripheral blood mononuclear cells was 5.3-fold higher with TAF than TDF

Treatment-naive patients taking the TAF coformulation had high levels of viral suppression over 48 weeks, comparable to those seen with Stribild, the researchers summarized. However, patients taking the TAF coformulation had a smaller decrease in eGFR and significantly smaller decreases in bone mineral density of the hip and spine.

Kidney biomarker changes have been attributed to cobicistat inhibiting renal tubule secretion, Sax noted. But it not clear why this effect is smaller with TAF than with TDF, since the dose of cobicistat in the coformulations is the same.

Sax added that Phase 3 studies are underway and researchers are making an "aggressive attempt" to enroll more women.



P Sax, I Brar, R Elion, et al. 48-week study of tenofovir alafenamide (TAF) versus tenofovir disoproxil fumarate (TDF), each in a single tablet regimen (STR) with elvitegravir, cobicistat, and emtricitabine [E/C/F/TAF vs. E/C/F/TDF] for initial HIV treatment. 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2013). Denver, September 10-13, 2013. Abstract H1464d.

Y Liu, K Kitrinos, D Babusis et al. Lack of tenofovir alafenamide (TAF) effect on primary osteoblasts in vitro at clinically relevant drug concentrations
. Abstract H-664. 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2013). Denver, September 10-13, 2013. Abstract H-664.

Other Source

Gilead Sciences. Gilead’s Tenofovir Alafenamide (TAF)-Based Single Tablet HIV Regimen Maintains High Viral Suppression Through 48 Weeks in Phase 2 Study. Press release. September 12, 2013.