investigational nucleotide analogue antivirals were shown to be active against
hepatitis B virus (HBV) with minimal potential for kidney and bone toxicity,
researchers reported at the International Liver Congress last week in
Amsterdam. Besifovir is in phase 3 clinical trials, while tenofovir exalidex is
in early development.
Nucleoside/nucleotide analogues for hepatitis B can suppress viral replication during treatment, but they
usually do not lead to a cure. Ongoing therapy is generally required, so
long-term safety and tolerability is a priority.
One of the most
widely used drugs in hepatitis B and HIV treatment, the nucleotide analogue tenofovir
disoproxil fumarate or TDF (Viread),
is generally considered safe, but it can cause bone
loss and kidney problems in some people.
- compensated cirrhosis
The earlier stage of
cirrhosis, during which the liver is damaged but still able to perform most of
its functions. See also ‘cirrhosis’ and ‘decompensated cirrhosis’.
drug that is broken down into another active form inside the body.
A newer pro-drug formulation,
tenofovir alafenamide or TAF (Vemlidy),
produces high levels of the active drug in hepatocytes and CD4 T-cells with
smaller doses, which gives a lower concentration in the blood and less exposure
for organs. Other research presented at the conference
showed that TAF works as well as TDF with less kidney toxicity and bone loss,
and people who switched from TDF to TAF showed improvements in kidney and bone markers.
Other companies are working
on related hepatitis B drug candidates that minimise kidney and bone toxicity.
Having more options allows clinicians to tailor therapy to individual patients,
and having competing drugs on the market can bring down the cost of treatment.
Sang Hoon Ahn of Yonsei
University in Seoul, South Korea, presented findings from a phase 3 trial of
besifovir, a guanosine nucleotide analogue pro-drug formerly known as LB80380 (LG Life Science) and ANA380
Besifovir has been in development for
more than a decade. Prior studies showed that it has potent activity against
HBV, including drug-resistant variants. It accumulates less in the kidneys than TDF or
adefovir (HepSera), so it is expected
to cause less renal toxicity. In a phase 2b study, besifovir suppressed HBV as
well as entecavir (Baraclude).
The only notable side-effect of besifovir was reduced
levels of carnitine, a compound that plays a role in cellular energy
production. In further trials, participants therefore received preventive carnitine
The phase 3 trial was a head-to-head comparison of 150mg
besifovir versus 300mg TDF taken for 48 weeks, followed by open-label besifovir
through week 192. All participants also received 660mg L-carnitine.
The study included 187
people with chronic hepatitis B, about 60% of whom were hepatitis B ‘e’
antigen-positive (HBeAg). About two-thirds were men and the mean age was
approximately 45 years. Almost all had HBV genotype A and about 20% had
compensated cirrhosis; people with decompensated liver disease were excluded.
No exclusion criteria related to kidney function were reported.
In an intent-to-treat
analysis at 48 weeks, 81% of participants taking besifovir and 85% of those
taking TDF achieved viral suppression with HBV DNA <400 copies/ml or <69
IU/ml; 64% and 69%, respectively, met a stricter cut-off of <116 copies/ml
or <20 IU/ml).
As expected, response was
better among HBeAg-negative patients, with 97% on besifovir and 100% on TDF having
HBV DNA <400 copies/ml. Among HBeAg-positive participants, the corresponding
response rates were 70% and 75%, respectively.
Five people (5%) in each
treatment arm experienced virological breakthrough, but none had drug
resistance mutations. Levels of HBV cccDNA in liver cells did not differ
between groups. One person in the TDF arm achieved hepatitis B surface antigen
About three-quarters of participants
in both treatment arms experienced ALT normalisation. Interestingly, HBeAg-positive
people were significantly more likely to see their ALT return to normal on TDF,
while among HBeAg-negative patients this was more likely on besifovir.
measures favoured besifovir. Among 29 people who underwent liver biopsy, those
taking besifovir were twice as likely as those on TDF to see a reduction of two
or more points in necro-inflammatory activity (78 vs 36%, respectively). The
proportion of people with the most severe fibrosis (stage 6 on the 6-point
Ishak scale) fell from 17 to 11% in the besifovir group, while rising from 9 to
18% in the TDF group.
Besifovir was generally
safe and well tolerated. One person taking besifovir had a serious adverse drug
reaction of muscle spasms, considered possibly related to treatment. One person
on besifovir stopped treatment due to liver cancer and one person on TDF did so
due to a rise in creatine
phosphokinase. About 7% of TDF recipients and 2%
on besifovir reported stomach pain, but no other events exceeded 5%.
Kidney and bone safety measures were
better with besifovir. Serum creatinine rose significantly less with besifovir
than with TDF. Estimated glomerular filtration rate (eGFR) declined more on
TDF, but the difference did not reach statistical significance. Bone mineral
density (BMD) T-scores decreased less in the besifovir group (-0.02 vs -0.10) –
a small but significant difference. The proportion of people with osteopenia or
osteoporosis did not change after 48 weeks on besifovir, but rose in the TDF
“In treatment-naive chronic hepatitis B patients,
48-week treatment of besifovir was non-inferior
to tenofovir in virologic response (HBV DNA <400 copies/ml),” the
researchers concluded. “It had a good
profile in BMD, nephrotoxicity, and histological response.”