CROI 2016: TAF/FTC Maintains Viral Suppression as Well as TDF with Less Bone and Kidney Toxicity

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A fixed-dose coformulation of tenofovir alafenamide (TAF) and emtricitabine (FTC), combined with a variety of third antiretroviral agents, maintained undetectable viral load in people who switched from similar regimens containing the older tenofovir disoproxil fumarate (TDF), according to a report presented at the Conference on Retroviruses and Opportunistic Infections (CROI 2016)this week in Boston. The study also showed improvement in kidney function biomarkers and bone density gains in the group taking TAF/FTC.

Gilead Sciences' tenofovir disoproxil fumarate (Viread) plus emtricitabine (Emtriva) is one of the most widely used nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) backbones used in antiretroviral therapy. These drugs make up the Truvada coformulation -- used for both HIV treatment and pre-exposure prophylaxis (PrEP) -- and are included in the single-tablet regimens Atripla, Complera, and Stribild. TDF is generally considered safe and well-tolerated, but it can cause modest bone loss and lead to kidney problems in susceptible individuals.

TAF is a new tenofovir pro-drug that delivers the active agent, tenofovir diphosphate, more efficiently to cells. TAF produces adequate intracellular drug levels with a 10-fold lower dose, which means about 90% lower drug concentrations in the blood plasma and less exposure for the kidneys, bones and other organs and tissues.

A single-tablet regimen containing TAF, FTC, elvitegravir, and the cobicistat booster (Genvoya) was recently approved in the U.S. and is under regulatory review in Europe. Studies presented last year showed that people who switched from a similar coformulation containing TDF (Stribild) to the TAF-containing combination maintained viral suppression and saw improvements in kidney function and bone density.

Gilead has also requested approval of a dual coformulation of TAF/FTC, which could be a successor to TDF/FTC or Truvada (to be marketed as Descovy). Joel Gallant from the Southwest Care Center in Santa Fe presented findings from a Phase 3 randomized clinical trial comparing TAF/FTC versus TDF/FTC when used in triple antiretroviral regimens with various third drugs (Study 311-1089; NCT02121795).

This analysis included 663 participants with undetectable HIV viral load (<50 copies/mL) at study entry. About 85% were men, 75% were white, 20% were black, the median age was 49 years, and the median baseline CD4 T-cell count was approximately 650 cells/mm3. At baseline they had near-normal kidney function with a median estimated GFR (eGFR) of at least 50 and median of 100 mL/min.

Study participants were randomly assigned to either switch to TAF/FTC or remain on TDF/FTC, both taken once-daily, while staying on the same third drug. Just under half were using boosted protease inhibitors while the rest were on unboosted third agents including NNRTIs and integrase inhibitors. The TAF dose was 10 mg if taken with boosted protease inhibitors or 25 mg with unboosted third agents; the TDF dose was 300 mg.

Participants were followed for 96 weeks and the primary endpoint was continued viral suppression (HIV RNA <50 copies/ml) at 48 weeks.

Results

Kidney Function

Bone Density

Lipid Levels

"[TAF/FTC] was non-inferior to [TDF/FTC] in maintaining virologic suppression in combination with a variety of third agents" and showed "significant improvements in multiple measures of renal and bone safety after switching from [TDF/FTC] to [TAF/FTC]," the researchers concluded. "These data support that [TAF/FTC] is an important NRTI backbone for antiretroviral treatment with safety benefits over [TDF/FTC]."

Gilead is developing 2 other TAF-containing single-tablet regimens, one with the NNRTI rilpivirine and the other with the HIV protease inhibitor darunavir. Stand-alone TAF is being studied as a treatment for hepatitis B. The company is also studying TAF in combination with GS-9883, an experimental integrase inhibitor that does not require boosting.

Given the kidney and bone benefits of TAF/FTC, some have suggested that it could potentially be a good alternative to Truvada for PrEP, but lower tenofovir levels in body tissues might be a concern. Data from animal and early human studies of TAF for HIV prevention are being presented this week at CROI. Investigators for these studies stress that TAF should not be used as PrEP until clinical trials are complete.

2/24/16

Reference

JE Gallant, E Daar, F Raffi, et al. Switching Tenofovir DF to Tenofovir Alafenamide in Virologically Suppressed Adults. Conference on Retroviruses and Opportunistic Infections. Boston, February 22-25, 2016. Abstract 29.