We may have finally seen the arrival of tenofovir alafenamide (TAF) at CROI 2015. The new formulation of tenofovir has demonstrated all that can be demonstrated at 48 weeks, in the phase-3 randomized, double-blind, double-dummy clinical trials GS104 and GS111, which compared TAF to the older tenofovir (TDF, Viread) formulation.
Based on the 48-week snapshot analysis results, the combination of elvitegravir/cobicistat/emtricitabine/TAF (E/C/F/TAF) demonstrated non-inferior efficacy against the current formulation of elvitegravir/cobicistat/emtricitabine/tenofovir (Stribild), with 92% of participants achieving viral suppression (viral load < 50 copies/mL). The CD4 recovery at 48 weeks was significantly greater with E/C/F/TAF: +211 versus +181 cells (P = .024). The efficacy was similar in participants with a high baseline viral load or low (< 200 cells) CD4+ cell count. There was no difference in the selection of NRTI (nucleoside reverse transcriptase inhibitor) or integrase inhibitor resistance mutations among those subjects with virologic failure.
While TAF was non-inferior to TDF overall, differences were observed in renal, bone and lipid toxicity. Of note, the study included subjects with eGFR (estimated glomerular filtration rate, a signal of kidney function) ≥ 50 mL/min (eGFR ≥70 mL/min in the Stribild participants). The mean decline in eGFR was significantly lower in the TAF arm at 48 weeks: -6.6 ml/min vs. -11.2 ml/min (P < .001), despite having no clinical impact. All markers of kidney tubular function (urinary protein/creatinine ratio, albumin/creatinine ratio, retinol-binding protein and β2-microglobulin) showed significantly safer changes at 48 weeks (P < .001 for all).
Bone mineral density was also better preserved with TAF. Bone mineral density (as measured by DXA) had a decline of -1.30% and -0.66% in spine and hip in the TAF arm versus -2.36% and -2.95% in the TDF arm. The results of TAF appeared to be similar to other non-TDF strategies.
In terms of lipids, TAF showed a slightly worse lipid profile than TDF, with significantly higher increases in total-cholesterol, HDL-cholesterol and LDL-cholesterol. But the total/HDL ratio showed no differences, and TDF's advantage over TAF in triglycerides (P = .027) was very small, again without clinical significance. Therefore, lipids do not seem to be a big issue with TAF.
Finally, a single-arm switch study included 242 subjects with suppressed viremia and impaired baseline renal function (eGFR: 30-69 mL/min) who were switched to E/C/F/TAF. Of these, 65% were previously on TDF, and 44% on any boosted protease inhibitor. At 48 weeks, 92% maintained a viral load < 50 copies/mL.
A significant improvement was seen in retinol-binding protein and β2-microglobulin (surprisingly, starting in the first two weeks), and the percentage of subjects showing an improvement in proteinuria or albuminuria favored TAF.
Changes in bone mineral density were also significant, with +1.9% and 0.9% in spine and hip (P < .001 for both). Overall, good data for TAF, despite being impossible to show benefits in virological efficacy or clinical toxicity, something that was already expected with only 48 weeks of follow-up.
Which other studies presented at CROI 2015 will have lasting impact? Read more of Llibre and Young's top picks.
Josep M. Llibre, M.D., is in the HIV Unit of the "Lluita contra la SIDA" Foundation at University Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain. Llibre has received funding for research or payment for conferences or participation on advisory boards from Abbott, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Janssen-Cilag, Merck Sharp & Dohme, and ViiV Healthcare.
Benjamin Young, M.D., Ph.D., is senior vice president and chief medical officer of the International Association of Providers of AIDS Care based in Washington, D.C., and an adjunct professor at the Josef Korbel School of International Studies at the University of Denver. Young has received consulting or speaking fees from Bristol-Myers Squibb, Gilead Sciences, Merck & Co., and ViiV Healthcare. He has received research funding from Bristol-Myers Squibb Company, Gilead Sciences, Merck & Co., and ViiV Healthcare.