Gilead Innovates on Tenofovir Disoproxil Fumarate With Tenofovir Alafenamide, Demonstrating Better Renal Outcomes

Gilead has refined the pharmacokinetics of tenofovir disoproxil fumarate (TDF), an anchor drug in several single-tablet medications for HIV-1, to create tenofovir alafenamide (TAF). Phase II results indicate superior renal outcomes and equivalent clinical outcomes with TAF versus TDF.

Gilead has refined the pharmacokinetics of tenofovir disoproxil fumarate (TDF), an anchor drug in several single-tablet medications for HIV-1, to create tenofovir alafenamide (TAF). Phase II results indicate superior renal outcomes and equivalent clinical outcomes with TAF versus TDF.

In a phase II trial, investigators Sax et al examined outcomes with 2 single-tablet regimens for HIV-1 treatment: Gilead’s prodrug of tenofovir, tenofovir alafenamide (TAF) versus traditional therapy with a combination containing tenofovir disoproxil fumarate (TDF).

Other medications in each single-tablet regimen included elvitegravir (an integrase inhibitor), cobicistat (an enzyme inhibitor that enhances the activity of eltegravir), and emtricitabine (a nucleoside reverse transcriptase inhibitor).1

Investigators randomized a total of 170 patients with HIV-1 and a CD4 cell count of 50 cells/microliter or greater in a 2:1 ratio to receive the TAF regimen (n = 112) or a regimen containing TDF (n = 58) and assessed HIV virologic suppression through virus levels over a 48-week study.1

Compared with the TDF-containing regimen, the TAF-containing regimen led to similar levels of virologic suppression at 2 end points (24 weeks and 48 weeks)1:

  • After 24 weeks of therapy, 86.6% of patients using the TAF regimen had an HIV copy count lower than 50 copies/mL, and 89.7% of patients using the TDF regimen had an HIV copy count lower than 50 copies/mL (P = .84 for this comparison, confirming noninferiority)
  • After 48 weeks of therapy, 88.4% of patients using the TAF regimen had an HIV copy count lower than 50 copies/mL, and 87.9% of patients using the TDF regimen had an HIV copy count lower than 50 copies/mL (P = .48 for this comparison, confirming noninferiority)

Mean improvements in CD4 cell count were comparable between groups, with patients receiving the TAF-based regimen experiencing a mean increase of 177 cells/microliter, and patients receiving the TDF-based regimen experiencing a mean increase of 204 cells/microliter over 48 weeks.1

In addition, over 48 weeks patients receiving the TAF-based regimen experienced significantly (P = .041) less deterioration of renal function, with a mean reduction of 5.5 mL/min in creatinine clearance versus a mean reduction of 10.1 mL/min in patients receiving the TDF-based regimen.1

Along with the smaller reduction in creatinine clearance, negative effects of renal disease (including tubular proteinuria and reductions in bone mineral density) were less common among patients receiving TAF-based regimens than patients receiving TDF-based regimens. These results indicate that TAF-based regimens translate not only to better renal outcomes than TDF-based regimens, but that these improved renal outcomes translate to real clinical end points including1:

  • Significantly less deterioration of hip (—0.62% with TAF versus –2.39% with TDF) and spine (–1.00% with TAF versus –3.37% with TDF) bone mineral density over 48 weeks (P <.001, all comparisons).

In terms of levels of total cholesterol (TC), low-density lipoprotein cholesterol, high-density lipoprotein (HDL), and the ratio of TC/HDL, levels were not substantially different between groups after 48 weeks of treatment.1

Adverse events were comparable between the 2 regimens, with the exception of nausea. A total of 21% of patients receiving the TAF-based regimen experienced nausea versus 12% of patients receiving the TDF-based regimen.1

These phase II results with a TAF-containing regimen indicate an advantage in terms of renal outcomes with use of TAF versus TDF. The effects of TDF on disrupting kidney function are well known.2 For instance, in 1000 HIV-infected patients, of whom 970 had available renal data, use of TDF with a protease inhibitor was a predictor of an increased risk of renal abnormalities.3

Gilead’s TAF-containing regimen may represent an improvement on TDF in terms of renal outcomes, with equivalent clinical outcomes in terms of CD4 cell counts and HIV viral load.

References:

  • Sax PE, Zolopa A, Brar I, et al. Tenofovir alafenamide vs. tenofovir disoproxil fumarate in single tablet regimens for initial HIV-1 therapy: a randomized phase 2 study. J Acquir Immune Defic Syndr.2014;67(1):52-58.
  • VIREAD (tenofovir disoproxil fumarate) tablets [package insert]. Foster City, CA: Gilead Sciences, Inc; 2013.
  • Bonjoch A, Juega J, Puig J, et al. High Prevalence of Signs of Renal Damage Despite Normal Renal Function in a Cohort of HIV-Infected Patients: Evaluation of Associated Factors. AIDS Patient Care STDS.2014.