Switching from tenofovir DF to TAF improves bone and kidney safety

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 to 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 co-formulations) 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.

TAF 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 lower concentrations in blood plasma and less drug exposure for the bones, kidneys and other organs and tissues. TAF is a component of the Genvoya, Odefsey, and Descovy co-formulations, recently approved for use in the European Union and in the US.



Relating to the kidneys.


Fat or fat-like substances found in the blood and body tissues. Lipids serve as building blocks for cells and as a source of energy for the body. Cholesterol and triglycerides are types of lipids.


Breakdown product of creatine phosphate in muscle, usually produced at a fairly constant rate by the body (depending on muscle mass). As a blood test, it is an important indicator of the health of the kidneys because it is an easily measured by-product of muscle metabolism that is excreted unchanged by the kidneys.

bone mineral density (BMD)

The higher your bone mineral content, the denser your bones are. And the denser your bones, the stronger they are and the less likely they are to break. A bone density test uses X-rays to measure how many grams of calcium and other bone minerals are packed into a segment of bone. The bones that are most commonly tested are in the spine, hip and sometimes the forearm. 


A substance which forms the structure of most cells and enzymes.

Edwin DeJesus of 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 people with viral suppression on a TDF-containing regimen either stayed on the same treatment or switched to a TAF-containing regimen.

The study included 1436 people with HIV who had an 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 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.

Dr DeJesus reported that, at 96 weeks, both regimens remained highly effective, but Genvoya had a statistically significant edge: 93% people who switched to the TAF regimen had an undetectable viral load compared to 89% of those who stayed on their TDF regimen; results were similar regardless of which TDF regimen they switched from. Just 2% of participants in both groups experienced virological failure, but people in the TDF arm were more likely to be missing viral load data (5% vs 9%).

All regimens were generally safe and well-tolerated, but again Genvoya had an advantage: 0.9% in the TAF group stopped treatment due to adverse events compared to 2.5% in the TDF group.

Spine bone density increased by 2.0% in the TAF switchers and fell by -0.3% in the continued TDF group; hip bone density rose by 2.1% and fell by -0.6%, respectively.

At 96 weeks, people who switched to TAF saw significant reductions in osteoporosis (brittle bones) or osteopenia (less severe bone density declines).

People who switched to TAF experienced significant improvements in kidney function markers (serum creatinine, phosphate and uric acid excretion, protein and albumin in the urine), while those who stayed on TDF regimens worsened.

There were two kidney-related adverse events leading to discontinuation in the TAF group (acute kidney injury and tubule-interstitial nephritis) and five in the TDF group (chronic kidney disease, Fanconi syndrome, renal colic and two cases of elevated blood creatinine).

However, the TAF group had worse blood lipid results. Tenofovir is known to reduce lipid levels, and the lower TAF concentration had a smaller effect than TDF.

Fasting lipids levels were higher in the TAF group than in the TDF group, and 8% vs 5% started lipid-lowering medications.

"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 of 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) 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 life-long antiretroviral treatment.

Finally, Gregory Huhn of the CORE Center in Chicago and colleagues analysed renal outcomes among people 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 categorised participants into two groups according to high or low risk for CKD. The high-risk group had two or more predisposing factors including female sex, black race, age 50 or older, a CD4 count < 200 cells/mm3, abnormal blood lipids, high blood pressure, diabetes, use of NSAIDs (nonsteroidal anti-inflammatory drugs), and clinical or subclinical renal adverse events at baseline; the low-risk group had zero or one factor. A total of 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 CKD 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 two TAF switchers and two TDF users discontinued due to renal adverse events, as did three 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 participants 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 summarised, 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.


DeJesus E 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. ASM Microbe, abstract LB-087, 2016. View abstract.

Overton TE 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, abstract 411/PW-027, 2016. View abstract.

Huhn G et al. Switching from TDF to TAF in patients with high risk for CKD. ASM Microbe, session 371, 2016. View abstract.