ASM Microbe 2016: Switching from Tenofovir DF to TAF Improves Bone and Kidney Safety

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People with HIV who switched from the older tenofovir disoproxil fumarate (TDF) formulation to tenofovir alafenamide (TAF) were more likely to maintain viral load suppression and showed improvements in bone density and kidney function biomarkers, according studies presented at the 2016 ASM Microbe conference last month in Boston.

Gilead Sciences' tenofovir disoproxil fumarate(brand name Viread and a component of the Truvada, Atripla, Complera, and Stribild coformulations) is one of the most widely used antiretroviral drugs and has been considered generally safe and well-tolerated, but it can cause bone loss soon after starting treatment and lead to kidney problems in susceptible individuals.

Tenofovir alafenamide is a new pro-drug that delivers the active agent, tenofovir diphosphate, more efficiently to cells. It produces adequate intracellular drug levels at a much lower dose, which means much lower concentrations in blood plasma and less drug exposure for the bones, kidneys, and other organs and tissues. The U.S. Food and Drug Administration recently approved TAF as a component of the Genvoya, Odefsey, and Descovy coformulations.

At ASM Microbe, Edwin DeJesus from the Orlando Immunology Center and colleagues presented a poster describing 96-week results from Gilead's study GS-US-292-0109, a Phase 3 trial in which patients with viral suppression on a TDF-containing regimen either stayed on the same treatment or switched to a TAF-containing regimen (NCT1815736).

The study included 1436 HV-positive people with undetectable viral load (<50 copies/mL) at baseline. About 90% were men, two-thirds were white, about 19% were black (a group at higher risk for kidney disease), the median age was about 41 years, and the median CD4 T-cell count was approximately 670 cells/mm3. They had to have near-normal kidney function at baseline, with an estimated glomerular filtration rate (eGFR) above 50 mL/min; the median was around 106 mL/min.

At study entry participants were taking Atripla (efavirenz/TDF/emtricitabine), Stribild (elvitegravir/cobicistat/TDF/emtricitabine), or boosted atazanavir (Reyataz) plus Truvada (TDF/emtricitabine). They were randomly assigned (2:1) to either remain on this regimen or switch to Genvoya (elvitegravir/cobicistat/TDF/emtricitabine).

At the International AIDS Society Conference last summer, researchers reported that at 48 weeks participants who switched from TDF-containing regimens to Genvoya were significantly more likely to maintain virological suppression and had significant improvements in spine and hip bone mineral density (BMD) and markers of kidney function.

Results

"Patients who switched to [Genvoya] from a TDF-based regimen were significantly more likely to maintain virologic success" and "had significant improvements in spine and hip BMD, had significant reductions in osteopenia/osteoporosis, and had significant improvements in proteinuria and other markers of renal function," the researchers concluded.

A related study by E. Turner Overton from the University of Alabama at Birmingham and colleagues looked in more detail at bone loss among people taking tenofovir. Their poster presented an analysis of changes in bone mineral density, parathyroid hormone (PTH, a hormone that regulates calcium and phosphate metabolism) levels, and serum bone turnover markers (P1NP and CTx) through week 48 in people who switched from TDF-containing regimens to Genvoya in the same trial.

In addition to the previously reported gains in spine and hip bone density, median PTH levels decreased following the switch to Genvoya, while levels in the TDF group decreased. Bone turnover biomarkers decreased significantly in the switch group.

"These data suggest switching from TDF to TAF may be associated with reduced risk of osteoporosis and fragility fracture over the long term, the researchers concluded -- an important consideration as people with HIV live longer and require lifelong antiretroviral treatment.

Finally, Gregory Huhn from the CORE Center in Chicago and colleagues analyzed renal outcomes among patients considered at high risk for chronic kidney disease (CKD) who switched from TDF to TAF in the same trial.

Most doctors advise that people with poor kidney function should not use TDF, and current TDF prescribing instructions include dose reductions for people with pre-existing kidney impairment. But it may be safer for people with kidney dysfunction to use TAF.

Huhn's team categorized participants into 2 groups according to high or low risk for chronic kidney disease. The high-risk group had 2 or more predisposing factors including female sex, black race, age 50 or older, a CD4 count <200 cells/mm3, abnormal blood lipids, high blood pressures, diabetes, use of NSAIDs, and clinical or subclinical renal adverse events at baseline; the low-risk group had 0 or 1 factors. 323 people who switched to TAF and 168 who remained on TDF regimens were deemed high risk.

Outcomes of interest included incident or new CKD, defined as eGFR <60 mL/min among people who started with >60, drug discontinuations due to kidney-related adverse events, and changes in renal biomarkers including urine protein and albumin, and retinol binding protein to creatinine and beta-2- macroglobulin to creatinine ratios.

Incident chronic kidney disease developed in 2% of TAF switchers and 3% of continuing TDF users considered high risk -- not a significant difference. Among people considered at low risk for CKD, 1% of TAF switchers and 2% who stayed on TDF developed CKD, which did reach statistical significance. In the high-risk category 2 TAF switchers and 2 TDF users discontinued due to renal adverse events, as did 3 low-risk TDF users but no low-risk TAF switchers. A single high-risk patient who remained on TDF developed Fanconi syndrome.

Urine protein and albumin decreased in the TAF switch arm while increasing in participants who stayed on TDF across all CKD risk categories. However, only high-risk patients had a substantial change -- about a 33% rise. Declines in tubular proteinuria among TAF switchers and increases among continuing TDF users were seen in high, medium, and low CKD risk groups.

Based on these findings, the researchers summarized, people with high risk for kidney disease who switched to Genvoya "experienced low incidence of CKD," had no discontinuations due to renal tubulopathy, and saw significant reductions in proteinuria and tubular proteinuria.

"These results demonstrate the durable efficacy and improved renal safety of [Genvoya] as a switch regimen for adults with underlying risk for CKD," they concluded.

7/10/16

References

E DeJesus, B Haas, S Segal-Maurer, et al. Superior Efficacy and Improved Renal and Bone Safety After Switching from a Tenofovir Disoproxil Fumarate (TDF) Regimen to a Tenofovir Alafenamide (TAF) Based Regimen Through 96 Weeks (W96) of Treatment. ASM Microbe. June 16-20, 2016. Abstract LB-087.

TE Overton, P Shalit, G Crofoot, et al. Switch from TDF Regimens to E/C/F/TAF Is Associated with Improved Bone Mineral Density, Decreased Serum PTH and Decreased Bone Turnover Biomarkers. ASM Microbe. June 16-20, 2016. Abstract 411/PW-027.

GHuhn, B Rijnders, M Thompson, et al. Switching from TDF to TAF in Patients with High Risk for CKD. ASM Microbe. June 16-20, 2016. Oral abstract session 371.