A coformulation 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 last week at IDWeek 2106 in New Orleans.
Gilead Sciences’ tenofovir disoproxil fumarate(brand name Viread) and a coformulation of TDF and emtricitabine (Truvada) are among the most widely used antiretrovirals. These drugs are also part of the Atripla, Complera, 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.
Previous Phase 3 clinical trials have shown that a single-tablet regimen containing TAF, emtricitabine, and elvitegravir is as effective as a similar TDF regimen, but less toxic to the kidneys and bones, both for previously untreated people and those who switched from the TAF to the TDF combination.
The study described at IDWeek compared the TAF/emtricitabine and TDF/emtricitabine coformulations when used in triple antiretroviral therapy regimens with various third drugs (Study GS-US-311-1089; NCT02121795).
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 a 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 10 mg if taken with boosted protease inhibitors or 25 mg with unboosted third agents; the TDF dose was always 300 mg.
The overall results, presented at this years Conference on Retroviruses and Opportunistic Infections, 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 Eric Daar from UCLA Medical Center presented findings from a subgroup analysis of older participants in the study — age 50 or over — a group that is at incraesed 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 randomized 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 T-cell count was approximately 660 cells/mm3 in the TAF/emtricitabine am 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 favored TAF/emtricitabine.
- 10% of participants in both arms experienced drug-related adverse events and 4% in both arms 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 TAF/emtricitabine armsaw a median eGFR increase of +8.8 mL/min, compared to +2.5 mL/min in the TDF/emtricitabine arm, a significant difference.
- Urine biomarkersimproved in the TAF/emtricitabine armwhile 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/emtricitabinearm, while falling by -0.2% in the TDF/emtricitabinearm.
- The corresponding changes in hip bone density were +1.0% and -0.3%, respectively.
- Improvements in kidney function and bone density in older patients in the TAF/emtricitabine arm were similar to those seen in the overall study population.
- 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 patients age 50 and older, “Efficacy and safety [of TAF/emtricitabine], including renal and bone safety profile, [were] consistent with overall study population and those <50 years,” the researchers summarized.
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 from 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.
By Liz Highleyman
ES Daar, J Gallant, G Crofoot, et al. Efficacy and Safety of Tenofovir Alafenamide vs Tenofovir Disoproxil Fumarate in HIV-infected, Virologically Suppressed Older Adults: Subgroup Analysis of a Randomized, Double-blind Switch Study. IDWeek. New Orleans, October 26-30, 2016. Abstract 952.