A co-formulation of tenofovir alafenamide (TAF) plus emtricitabine, used with a third antiretroviral drug, maintained viral suppression as well as tenofovir disoproxil fumarate (TDF) plus emtricitabine in older individuals, and was associated with improvements in kidney function and bone density, which may be of greater concern for this group, according to a presentation at IDWeek 2016 in New Orleans.
Gilead Sciences’ tenofovir disoproxil fumarate (brand name Viread) and a co-formulation of TDF and emtricitabine (Truvada) are among the most widely used antiretrovirals. These drugs are also part of the Atripla, Eviplera and Stribild single-tablet regimens. TDF is generally safe and well tolerated, but it can cause modest bone loss and kidney problems in susceptible individuals.
TAF (part of the Descovy, Genvoya and Odefsey combination pills, but not sold separately) is a pro-drug formulation that delivers the active drug to HIV-infected cells more efficiently than TDF. TAF produces adequate intracellular drug levels with smaller doses, which means lower concentrations in the blood and less drug exposure for the kidneys, bones and other organs and tissues.
The study led by Dr Eric S Daar, at the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Centre, Torrance, California, compared the TAF/emtricitabine and TDF/emtricitabine co-formulations when used in triple antiretroviral therapy regimens with various third drugs.
This study included 663 people initially taking TDF/emtricitabine plus a third drug, but not using a single-tablet regimen. At enrollment they had undetectable viral load (< 50 copies/ml) and near-normal kidney function (estimated GFR > 50 ml/min).
Participants were randomly assigned to either stay on TDF/emtricitabine or switch to TAF/emtricitabine as an NRTI backbone, 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 10mg if taken with boosted protease inhibitors or 25mg with unboosted third agents; the TDF dose was always 300mg.
The overall results showed that the regimens worked equally well, with 94% in the TAF/emtricitabine group and 93% in the TDF/emtricitabine group having undetectable viral load at 48 weeks. Kidney function and bone mineral density improved in people who switched to TAF/emtricitabine.
At IDWeek, Daar presented findings from a subgroup analysis of older participants in the study – age 50 or over – a group that is at increased risk for kidney and bone problems as they age, and therefore may benefit most from using TAF rather than TDF.
This analysis included 150 people randomised to TAF/emtricitabine and 144 assigned to TDF/emtricitabine. Nearly 90% were men, more than 80% were white and the median age was approximately 55 years (range 50-79). The median baseline CD4 count was approximately 660 cells/mm3 in the TAF/emtricitabine arm and 590 cells/mm3 in the TDF/emtricitabine arm. The median eGFR was about 91 ml/min, just over 40% had hypertension and 7% had diabetes – known risk factors for kidney disease.
Mirroring the overall results, viral suppression rates at 48 weeks were high in both groups: 96% in the TAF/emtricitabine arm and 94% in the TDF/emtricitabine arm. Only 1% experienced virological failure and 4% in both arms were missing 48-week data.
Both regimens were generally safe and well tolerated, but kidney and bone outcomes favoured TAF/emtricitabine. In both arms, 10% of participants experienced drug-related adverse events and 4% had serious adverse events; 3% in the TAF/emtricitabine arm and 1% in the TDF/emtricitabine arm discontinued treatment due to adverse events, none of which were kidney- or bone-related.
People who switched to the TAF/emtricitabine arm saw a median eGFR increase of +8.8 ml/min compared to +2.5 ml/min in the TDF/emtricitabine arm, a significant difference. Urine biomarkers improved in the TAF/emtricitabine arm while worsening in the TDF/emtricitabine arm: protein-to-creatinine ratio (-15% vs +10%), albumin-to-creatinine ratio (-2% vs +16%), retinol blinding protein-to-creatinine ratio (-17% vs +23%) and beta-2-microglobulin-to-creatinine ratio (-42% vs +26%).
Spine bone mineral density rose by a mean +1.9% in the TAF/emtricitabine arm, while falling by -0.2% in the TDF/emtricitabine arm. The corresponding changes in hip bone density were +1.0% and -0.3%, respectively.
Blood lipid levels increased slightly in the TAF/emtricitabine group, but the total cholesterol-to-HDL ratio stayed about the same. This occurs because tenofovir reduces lipid levels and this effect is diminished with TAF compared to TDF.
In people age 50 and older, “Efficacy and safety [of TAF/emtricitabine], including renal and bone safety profile, [were] consistent with overall study population and those
TAF/emtricitabine “is an important backbone for older patients living with HIV,” they concluded. “This is of particular importance as the population living with HIV ages and experiences more renal and bone-related comorbidities.”
Speaking from the audience, Joseph Eron of the University of North Carolina noted that age 50 or 55 is really not that old, and it would be useful to look at continuous trends extending to older ages when kidney problems and bone loss become more common.
Background: As the HIV-infected population ages and has increasing prevalence of co-morbidities, efficacy and safety of antiretrovirals in older participants is of heightened importance. Tenofovir alafenamide (TAF) has a potential to benefit older individuals, as it has previously demonstrated an improved renal and bone safety profile compared to tenofovir disoproxil fumarate (TDF).
Methods: We conducted a 48-week subgroup analysis in those ≥ 50 years old for efficacy (pre-specified) and safety (post-hoc) from a randomized, double blind, active-controlled study in virologically suppressed HIV-infected participants who switched to emtricitabine/TAF (FTC/TAF) from FTC/TDF vs continuing FTC/TDF while remaining on their original third agent.
Results: Of 663 treated, 294 were ≥ 50 years (FTC/TAF n=150, FTC/TDF n=144). Baseline viral load, CD4 counts, renal laboratory parameters, and bone mineral density (BMD) were similar between the two arms within those ≥ and < 50 years. For participants ≥ 50 years, virologic success by FDA snapshot algorithm at Week 48 was FTC/TAF 96.0% vs. FTC/TDF 94.4%; for those < 50 years, it was 92.9% vs 91.9%. Few participants discontinued study drug due to adverse events in either subgroups (≥ 50 years, FTC/TAF 3.3% vs. FTC/TDF 1.4%; < 50 years, 1.1% vs. 0.5%). The assessment of renal and bone safety using estimated glomerular filtration rate (eGFR), renal biomarkers, and BMD had significant differences between the two arms that consistently favored FTC/TAF over FTC/TDF (Table 1). No cases of Fanconi syndrome or proximal renal tubulopathy were reported in the overall population.
Conclusion: Participants ≥ 50 years receiving 48 weeks of FTC/TAF had comparable efficacy and improved bone and renal safety compared to those remaining on FTC/TDF. These findings demonstrate improved safety with TAF relative to TDF in older individuals. This is of particular importance as the population living with HIV ages and experiences more renal and bone-related comorbidities.
Eric S Daar, Joel Gallant, Gordon Crofoot, Kenneth Lichtenstein, Anthony Lamarca, Peter Shalit, Christopher Lucasti, Daniel Coulston, Craig Dietz, Mingjin Yan, Sandra Friborg, Martin Rhee