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.

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.