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Switching from tenofovir DF to TAF improves bone and kidney safety
Liz Highleyman, 2016-07-11 09:50:00
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
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 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
coformulations, recently approved for use in the European Union and in the US.
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
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
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 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
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
"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
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 categorised participants into two groups
according to high or low risk for chronic kidney disease. 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 pressures, diabetes, use of NSAIDs, and clinical or subclinical renal
adverse events at baseline; the low-risk group had zero or one factors. 323
people who switched to TAF and 168 who remained on TDF regimens were deemed
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 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
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 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
"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.