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Tenofovir Alafenamide (TAF) Still Noninferior to Current Tenofovir -- With Better Bone/Kidney Signals

August 13, 2015

Tenofovir alafenamide (TAF), a tenofovir prodrug, proved virologically noninferior to tenofovir disoproxil fumarate (TDF, Viread) in first-line coformulations with elvitegravir/cobicistat/emtricitabine (E/C/F/TAF and E/C/F/TDF) in two double-blind trials. Renal and bone safety signals favored E/C/F/TAF.

Because TAF is more stable in plasma than TDF, more intact TAF reaches target T cells, where it gets metabolized to active tenofovir-diphosphate. As a result, plasma tenofovir concentrations are 90% lower with TAF than TDF, and TAF should cause fewer side effects related to off-target tenofovir activity at sites such as bone and kidney.

Researchers in 16 countries conducted two identical phase-3, placebo-controlled trials comparing E/C/F/TAF with E/C/F/TDF in treatment-naive patients. Of the 1733 individuals who received study drugs, about 56% were white, 25% black and 15% women. Age averaged about 34 years. Everyone had creatinine clearance of 50 mL per minute or higher.

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After 48 weeks of treatment the U.S. Food and Drug Administration snapshot algorithm determined that 92% of participants randomized to E/C/F/TAF and 90% randomized to E/C/F/TDF had achieved a viral load below 50 copies/mL, a result establishing the virologic noninferiority of E/C/F/TAF to E/C/F/TDF in previously untreated patients. Virologic response did not differ by pretreatment viral load or CD4+ count, or by age, sex or race. Seven people randomized to E/C/F/TAF (0.8%) and five randomized to E/C/F/TDF (0.6%) had virologic failure with resistance.

Through 48 weeks, mean serum creatinine rose significantly less with E/C/F/TAF than with E/C/F/TDF (0.08 versus 0.12 mg/dL, P < .0001), and median change in proteinuria was significantly less in the TAF group (-3% versus +20%, P < .0001). Bone mineral density declined significantly less with TAF than TDF at the spine (mean -1.30% versus -2.86%, P < .0001) and hip (mean -0.66% versus -2.95%, P < .0001).

The researchers stress that their studies did not have the statistical power to compare clinical safety outcomes such as renal failure and fracture with TAF versus TDF. In an editorial on these studies, Christina Wyatt, M.D., and Jared Baeten, M.D., Ph.D. suggest TAF "might signal yet another evolution in [HIV] treatment -- i.e., toward regimens designed for lifelong use, achieving maximum adherence with minimum toxic effects." But they caution that only "[r]eal-world clinical experience will ascertain whether tenofovir alafenamide offers meaningful safety or cost benefits over currently approved treatment."

Mark Mascolini is a freelance writer focused on HIV infection.


Copyright © 2015 Remedy Health Media, LLC. All rights reserved.




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