with risk factors for tenofovir toxicity who switched from tenofovir disoproxil
fumarate (TDF; Viread) to the new
tenofovir alafenamide (TAF; Vemlidy)
maintained hepatitis B virus (HBV) suppression and showed evidence of improved
kidney and bone safety, according to a report at the 2018 International
Liver Congress last month in Paris.
Nucleoside/nucleotide analogues like tenofovir suppress HBV replication during treatment, but they
usually do not lead to a cure, indicated by hepatitis B surface antigen (HBsAg)
clearance. Ongoing therapy is usually required and long-term safety is
TDF is one of the most effective antiviral drugs
for hepatitis B and is among the most widely used antiretrovirals for HIV. It
is generally considered safe and well tolerated, but it can cause bone loss and kidney problems in susceptible
A protein made in the liver, needed to maintain a balance of the fluids in the body. In a blood test, lower than normal levels of albumin and total protein may indicate liver damage or disease. If there is not enough albumin, fluid may accumulate in the abdomen (ascites).
levels of fat in the blood.
Phosphorus combined with oxygen in the blood forms a variety of phosphates, vital for energy
production, muscle and nerve function, and bone growth. Raised levels can
be a sign of conditions such as kidney disease and diabetes.
drug that is broken down into another active form inside the body.
Tenofovir alafenamide is a new
pro-drug formulation that produces high levels of the active drug in
hepatocytes and CD4 T-cells with smaller doses than TDF, which means lower levels
in the blood and less drug exposure for the kidneys and bones. Due to its good
efficacy and improved safety profile, the latest EASL and AASLD hepatitis B clinical
practice guidelines recommend TAF as a treatment option, especially for people
at higher risk for bone or kidney problems.
Edward Gane of Auckland Clinical Studies in
New Zealand presented findings from a pooled analysis of bone and
kidney safety in two head-to-head phase 3 studies comparing TAF and TDF, focusing
on the subgroup of participants with risk factors for kidney or bone toxicity.
Gilead Sciences' Study 108 enrolled 425
hepatitis B 'e' antigen (HBeAg)-negative participants and Study 110 enrolled
873 harder-to-treat HBeAg-positive people. A majority of participants in both
studies were men and 70-80% were Asian. The average ages were approximately
46 and 38 years, respectively. HBV genotype C was most common.
Participants in both studies were initially randomly
assigned to receive 25mg TAF or 300mg TDF once daily for 96 weeks, followed by
open-label TAF through 144 weeks. Part way through, the US Food and Drug
Administration required the study to extend its blinded period to 144 weeks and
the open-label extension to 384 weeks, or about 8 years.
Gane presented findings from an interim analysis of
540 participants who received 96 weeks of randomised treatment and 144 weeks of
open-label TAF. Of these, 183 people originally assigned to TAF and 101 people
who were originally assigned to TDF and switched to TAF – over half in both
groups – had at least one risk factor. About 60% had one risk factor, around 30%
had two and about 10% had three.
Risk factors included age over 60 years, osteoporosis
(serious bone loss) at the hip or spine, obesity (body mass index > 30)
and co-morbidities including high blood pressure, diabetes, cardiovascular
disease or hyperlipidaemia (elevated blood fat levels). Also included were
various measures of kidney function impairment, including having stage 2
chronic kidney disease with an estimated glomerular filtration rate (eGFR)
below 90 ml/min, albumin in the urine and low blood phosphate levels.
As reported at the 2016 International Liver Congress, TAF
suppressed HBV viral load as well as TDF at 48 weeks – with more than 90% of
HBeAg-negative and more than 60% of HBeAg-positive people having undetectable
HBV DNA – but with fewer detrimental effects on bone and kidney biomarkers. Results at 96 weeks were similar.
Combining the HBeAg-negative and positive participants,
people with > 1 TDF risk factors were more than 10 years older on
average than those with no risk factors (47 vs 34 years), were more likely
to be women (45% vs 28%) and were more likely to be HBeAg-negative (48% vs
26%). Median baseline HBV DNA levels and ALT liver enzyme levels were similar. In
the > 1 risk factors group, about half had a baseline eGFR below 90,
about 15% had spine osteoporosis and 2% had hip osteoporosis.
Looking only at the group with > 1 risk
factors, HBV suppression at 144 weeks was similar in people who switched from
TDF to TAF (84%) and those who stayed on TAF (89%). No resistance mutations
were seen in people with detectable viral load.
Treatment was generally safe and well tolerated. Among
those with > 1 risk factors, 10% of people who switched from TDF to
TAF and 4% of those who stayed on TAF had serious adverse events, but none were
considered treatment related. No one in any group stopped treatment due to
Bone mineral density at the hip and spine remained
stable in people originally randomised to TAF but declined in those who started
on TDF. After switching from TDF to TAF at 96 weeks, bone density rose again
and approached baseline levels by 144 weeks. Bone density patterns were similar
in people with no risk factors and those with > 1 risk factors.
Kidney function also remained stable in people who
were on TAF throughout the study. Among those assigned to tenofovir, eGFR
declined through week 96 but returned to near baseline levels after switching
to TAF. Again, kidney function patterns were similar in the no risk factors and
> 1 risk factors groups.
"A majority of patients on treatment at week 96
had at least one risk factor for TDF toxicity at baseline," the
researchers concluded. "Among chronic hepatitis B patients with TDF risk
factors, switching from TDF to TAF treatment is associated with maintenance of
viral suppression [and] improvement in bone and renal safety parameters."
Gane added that longer-term follow-up is needed to
determine the clinical significance – if any – of these biomarker changes.