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Genvoya TAF Regimen Works Well with Improved Bone and Kidney Safety at 96 Weeks

The Genvoya single-tablet regimen containing tenofovir alafenamide (TAF) suppressed HIV as well as a similar coformulation containing the older tenofovir disoproxil fumarate (TDF), but demonstrated better bone and kidney tolerability after 2 years of treatment, according to a report in the May 1 edition of the Journal of Acquired Immune Deficiency Syndromes.

Gilead Sciences' TAF is a new pro-drug that delivers the active agent (tenofovir diphosphate) to HIV-infected cells more efficiently than the current TDF formulation (Viread, also in Truvada, Atripla, Complera, and Stribild). TDF is considered generally safe and well-tolerated, but it can cause bone loss soon after starting therapy and can lead to kidney problems in susceptible people. TAF produces high intracellular drug levels with a smaller dose than TDF, which means lower concentrations in the blood and less drug exposure for the kidneys, bones, and other organs and tissues.

David Wohl from the University of North Carolina at Chapel Hill and colleagues conducted a pair of Phase 3 studies doing a head-to-headcomparison of first-line HIV treatment using a TAF-based versus a TDF-based single-tablet regimen (GS-US-292-0104/NCT01780506and GS-US-292-0111/NCT01797445).

Together, these international clinical trialsenrolled 1733 previously untreated participants. About 85% were men and the median age was 34 years. The median baseline CD4 T-cell count was approximately 400 cells/mm³ and nearly a quarter had high viral load (>100,000 copies/mL). At baseline they had near-normal kidney function with an estimated glomerular filtration rate -- an indicator of creatinine clearance -- of at least 50 mL/min (median 116 mL/min).

Participants were randomly assigned to receive a once-daily single-tablet regimen containing 150 mg elvitegravir, 150 mg of the booster cobicistat, and 200 mg emtricitabine, with either 10 mg TAF (Stribild coformulation) or 300 mg TDF (Genvoya coformulation).

Results

• As described at the 2015 Conference on Retroviruses and Opportunistic Infections, at 48 weeks both coformulations demonstrated similar high efficacy: 92% taking Genvoya and 90% taking Stribildhad viral load <50 copies/mL.
• At 96 weeks viral suppression rates remained high with both regimens: 87% with Genvoya and 85% with Stribild.
• 10 participants (1.2%) in the Genvoya arm and 8 (0.9%) in the Stribild arm experienced virological failure with detectable drug resistance mutations at 96 weeks.
• 3 participants in each arm had newly detected antiretroviral resistance between week 48 and week 96.
• Treatment was generally safe and well-tolerated, with similar rates of overall adverse events (42% for Genvoya vs 46% for Stribild), serious adverse events (11% vs 10%), and discontinuations due to adverse events (1.2% vs 2.3%).
• The most common adverse events in both arms were nausea, diarrhea, and headache.
• Genvoya recipients had smaller declines in bone mineral density at the spine and hip than those taking Stribild at week 48, with the difference increasing by week 96.
• Hip bone density declined initially and then stabilized in the Genvoya group, while continuing to fall in the Stribild group.
• Spine bone density declined initially, stabilized, and trended toward improvement in the Genvoya group, while declining then stabilizing in the Stribild group.
• 3 men in the Stribild arm, but none in the Genvoya arm, discontinued therapy due to a >5% decrease in bone mineral density between week 48 and week 96.
• Bone fractures were rare in both treatment arms (0.3% vs 1.0%) and were due to trauma rather than fragility.
• The Genvoya group had more favorable changes in proteinuria, proximal tubular proteinuria, and albuminuria (protein and albumin in the urine, indicators of impaired kidney function).
• The median change in estimated creatinine clearance from baseline to week 96 was significantly smaller with Genvoya than with Stribild (-2.0 vs -7.5 mL/min), and half as many Stribild recipients had a >25% decrease (15% vs 30%).
• No Genvoya recipients discontinued treatment due to renal adverse events, while 6 Stribild recipients stopped therapy for this reason (4 before week 48 and 2 between week 48 and week 96).
• There were no cases of proximal renal tubulopathy in the Genvoya arm compared with 2 in the Stribild arm.
• Genvoya recipients had higher total, LDL, and HDL cholesterol levels, indicating that the cholesterol-lowering effect of tenofovir was not as strong as it was in the Stribild arm.
• However, there were no significant differences in cardiovascular events or initiation of lipid-modifying medications (3.8% for Genvoya vs 4.4% for Stribild).

"These longer-term data support [elvitegravir/cobicistat/emtricitabine/TAF] as a safe, well-tolerated, and durable regimen for initial HIV-1 treatment," the study authors concluded.

"Together, these longer-term safety data support the hypothesis that circulating levels of tenofovir are responsible for the bone and renal toxicity of TDF and that the markedly reduced tenofovir level delivered by TAF minimizes such exposure and is protective against renal and bone effects," they added in their discussion.

5/3/16

Reference

D Wohl, S Oka, N Clumeck, et al. Brief Report: A Randomized, Double-Blind Comparison of Tenofovir Alafenamide Versus Tenofovir Disoproxil Fumarate, Each Coformulated With Elvitegravir, Cobicistat, and Emtricitabine for Initial HIV-1 Treatment: Week 96 Results. Journal of Acquired Immune Deficiency Syndromes72(1):58-64. May 1, 2016.