with hepatitis B who switched from the old tenofovir disoproxil fumarate (TDF)
to the new tenofovir alafenamide (TAF) saw improvements in kidney function
biomarkers and recovery of bone loss, researchers reported at the International
Liver Congress last week in Amsterdam. The congress is the annual meeting of
the European Association for the Study of the Liver (EASL).
Due to its good efficacy and improved safety profile, updated
EASL hepatitis B clinical practice guidelines released at the conference now
recommend TAF as a new treatment option, especially for people at higher risk
for bone or kidney problems.
disoproxil fumarate (Viread) 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 individuals.
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 (tenofovir diphosphate) in hepatocytes and CD4 T-cells with smaller doses
than TDF, which means lower concentrations in the blood and less drug exposure
for the kidneys and bones.
In January, the European
marketing authorisation for stand-alone TAF – marketed as Vemlidy – for hepatitis B, following US Food and Drug Administration (FDA) approval in late
2016. Previously it was only available
in coformulations for HIV treatment.
Nucleoside/nucleotide analogues like tenofovir suppress hepatitis B virus (HBV) replication during
treatment, but they usually do not lead to a cure. Ongoing therapy is
generally required and long-term safety is important.
Henry Chan of the Chinese University of Hong Kong presented
a pooled analysis of bone and kidney safety in two long-running head-to-head studies
comparing TAF and TDF. This analysis focused on people who switched from TDF to
Gilead Sciences’ Study 108 enrolled 425 hepatitis B
‘e’ antigen (HBeAg)-negative participants and Study 110 enrolled 873 harder-to-treat
HBeAg-positive patients. In both studies a majority of participants were men.
The average age was around 46 years in Study 108 and 38 years in Study 110.
Approximately 70% and 80% of participants, respectively, were Asian, and HBV genotype
C was most common.
Initially participants in both studies were
randomly assigned to take 25mg TAF or 300mg TDF once daily for 96 weeks,
followed by open-label TAF through 144 weeks. Part way through, the FDA
required the study to extend its double-blind period to 144 weeks and the
open-label extension to 384 weeks. This offered the opportunity to do an unplanned analysis of a subset of participants who
completed 96 weeks of randomised treatment and started open-label TAF, without
joining the longer protocol.
At the Liver Congress, Maurizia
Brunetto of the University Hospital of Pisa presented full 96-week
safety and efficacy findings from Study 108, while Kosh Agarwal of King’s
College Hospital in London did so for Study 110.
Overall, the 96-week efficacy results did not differ much from the 48-week results presented at last year’s
In the HBeAg-negative study, 94% of TAF recipients and 93% of TDF
recipients had undetectable HBV DNA at 48 weeks. At 96 weeks the results were
similar, 90% and 91%, respectively. Hepatitis B surface antigen (HBsAg) levels
declined slightly in both treatment arms and only one patient on TAF
experienced HBsAg loss with seroconversion, generally considered a cure.
Significantly more people in the TAF arm had ALT normalisation according to
AASLD (American Association for the Study of Liver Disease) cut-offs (50% vs
In the HBeAg-positive study, response rates improved a bit with longer
follow-up. At 48 weeks, 64% of TAF recipients and 67% of TDF recipients had
undetectable HBV DNA, rising to 73% and 75%, respectively, at 96 weeks. Two
people achieved HBsAg loss and one experienced seroconversion. Again, ALT
normalisation was more likely in the TAF group (52% vs 42%, respectively).
In both studies, treatment remained generally safe and well tolerated.
Bone mineral density at the hip and spine remained stable in the TAF arm while
declining in the TDF arm. Kidney function, as indicated by estimated glomerular
filtration rate (eGFR), likewise remained stable in the TAF arm while falling
in the TDF arm.
Chan presented a preliminary pooled analysis of
the subset of patients who completed 96 weeks of randomised treatment plus 24
weeks of follow-up on open-label TAF (120 weeks total). Within this group, 361
people who were initially randomised to TAF stayed on that drug, while 180
people initially assigned to TDF switched to TAF. In the pooled group, 60% were
Viral load remained suppressed during the open-label
period: 88% of patients in both the ongoing TAF group and the TDF to TAF switch
group had undetectable HBV DNA at 120 weeks.
Other study findings showed improvements after
switching to TAF. Although more people assigned to TAF experienced ALT normalisation
during the randomised portion, ALT continued to fall over time. At 120 weeks,
63% of people in both the continued TAF group and the switch group achieved ALT
Looking at kidney function, during the randomised
portion creatinine clearance remained stable in the TAF arm but dropped in the
TDF arm. Among those who switched from TDF to TAF, it rose again. People with
moderate or worse kidney disease saw a significant improvement, from a median
of 76 to 81 ml/min. Two measures of proteinuria increased more in the TDF arm
during the randomised portion, but improved after switching to TAF.
Bone mineral density, especially at the hip, increased
among people who switched from TDF to TAF. Biomarkers of bone formation and
resorption were more favourable in the TAF arm during the randomised portion.
These biomarkers improved among people who switched from TDF to TAF, eventually
equalling levels seen in patients who were on TAF all along.
"A similar high rate of viral suppression (HBV
DNA < 29 IU/ml) was maintained through week 120 in chronic hepatitis B
patients who received TAF treatment and those that switched from TDF to TAF
treatment after 96 weeks," Chan and colleagues concluded. "Chronic
hepatitis B patients showed improvements in bone and renal safety profile 24
weeks after switching from TDF to TAF."
Chan said that
a phase 3 trial is now testing the safety and effectiveness of switching from
TDF to TAF, as the present study was not designed to do so. However, randomised
studies have seen favourable outcomes after people with HIV switched from TDF to TAF, including people
with HIV and HBV co-infection.
of waiting for patients to get renal disease or bone disease, we should be more
pre-emptive in trying to minimise these comorbidities," Agarwal said at
the hepatitis B guidelines presentation. "We are seeing changes in bone
turnover and renal markers that are not quite translating to clinical endpoints
yet, but we have the data on co-infection and we understand that the efficacy
[of TAF] is strong, so we should be thinking about the prevention of
comorbidities for what is still a long-term therapy for a majority of