People with chronic
hepatitis B virus (HBV) infection are more likely to experience favourable
treatment response, as indicated by hepatitis B surface antigen (HBsAg) loss,
if they add pegylated interferon to tenofovir – although even then the cure
rate falls short of 10%, researchers reported at the American Association for the Study of Liver
Diseases (AASLD) Liver Meeting in Boston in November.
using nucleoside/nucleotide analogues like tenofovir (Viread) or entecavir (Baraclude)
is the mainstay of hepatitis B treatment. While antivirals are effective at
suppressing HBV viral load over the long term, they rarely lead to a cure,
indicated by the loss of hepatitis B surface antigen and seroconversion, or
development of anti-HBs antibodies. Several studies have looked at combining
antivirals with pegylated interferon – which stimulates the body's natural
immune responses against HBV – but results have been inconsistent.
Hepatitis B is
difficult to cure because bits of HBV DNA can integrate into the genome of
liver cells (although HBV does not insert a full set of viral genetic
instructions into latent cells, as HIV does). Interferon is better known as the
standard treatment for hepatitis C before the arrival of highly effective
direct-acting antivirals. Since HCV does not integrate its genetic material
into host cells, it is now possible to cure hepatitis C with a
combination of potent oral antivirals taken for as little as eight weeks
without interferon, which often causes difficult side-effects.
Jeorg Peterson from the University
of Hamburg, on behalf of an international team of collaborators, presented findings from a study of tenofovir plus
pegylated interferon alfa-2a (Pegasys or PegIntron) for chronic
hepatitis B, with the primary endpoint being HBsAg loss with a finite course of
treatment. Unlike most previous research, this large trial was adequately
powered to compare outcomes that occur in only a small proportion of people.
This open-label study enrolled a total of 740
people with chronic hepatitis B. Sixty per cent were hepatitis B 'e' antigen (HBeAg)-positive – which is somewhat easier to treat – while the rest were HBeAg-negative.
About two-thirds were men, three-quarters were Asian and the mean age was
approximately 37 years. The HBV genotype distribution reflected a largely Asian
population, with most having genotype C (43%), B (28%) or D (21%). The mean
baseline HBV DNA level was approximately 7.0 log10 IU/ml and the
mean HBsAg level was about 3.9 log10 IU/ml. People with advanced bridging
fibrosis or cirrhosis were excluded.
Participants were randomly assigned to
received one of the following regimens:
- Tenofovir + pegylated
interferon for 48 weeks.
- Tenofovir + pegylated
interferon for 16 weeks, continuing on tenofovir alone through week 48.
- Tenofovir monotherapy for
120 weeks (continuous therapy).
- Pegylated interferon
monotherapy for 48 weeks.
Petersen reported results after 72 weeks of
follow-up; participants in the study will continue to be followed through 120 weeks. People in
the study arms that stopped treatment at week 48 could restart tenofovir after
completing their assigned therapy if they met certain safety criteria.
At the end of treatment, HBsAg levels declined
most in the 48-week tenofovir plus pegylated interferon arm (-1.1 log10),
followed by interferon monotherapy (-0.8.1 log10), the 16-week
tenofovir combination regimen (-0.5 log10) and tenofovir monotherapy
At 48 weeks, 7.3% of participants taking the
48-week tenofovir plus pegylated interferon regimen showed HBsAg loss. Response
rates were substantially lower in the 16-week tenofovir combination arm and
interferon monotherapy arm (both 2.8%). No one taking tenofovir alone experienced
HBsAg loss, even though they were the only ones who remained on continuous
By 72 weeks, the rate of HBsAg loss rose to
9.0% in the 48-week tenofovir plus pegylated interferon group, while remaining
the same in the other three arms. A total of seven people experienced HBsAg
seroreversion, or reappearance after loss (four in the 48-week combination arm
and three in the 16-week combination arm).
HBeAg-positive participants were somewhat
more likely than HBeAg-negative people to achieve HBsAg loss at week 72 (11 vs
6 people). In both populations, HBsAg loss occurred most often in the 48-week
tenofovir plus pegylated interferon arm and not at all in the tenofovir
monotherapy arm. Some people with HBV genotypes A, B, C and D achieved HBsAg
loss, but the numbers were too small for meaningful comparisons.
Looking at HBsAg seroconversion, rates were
5.7% at 48 weeks at 8.0% at 72 weeks in the 48-week tenofovir plus pegylated
interferon arm, 0.6% at both time points in the 16-week combination arm, 2.3%
and 2.9% in the interferon monotherapy arm and again 0.0% in the tenofovir
Looking at the secondary endpoint of HBeAg
loss, the 48-week tenofovir plus pegylated interferon arm again performed best,
with rates of 25.9% at 48 weeks and 29.6% at 72 weeks. Rates in the other arms
were 20.0% and 24.8% with the 16-week combination regimen, 13.2% and 25.5% in the
interferon monotherapy arm, and 8.3% and 12.8% in the tenofovir monotherapy
arm. HBeAg seroconversion followed a similar pattern.
Finally, turning to viral load, a majority of
people in all the tenofovir-containing arms had undetectable HBV DNA at 48 weeks
(68.8% with the 48-week combination, 71.2% with the 16-week combination and
60.5% with tenofovir monotherapy). Viral rebound usually occurred after
stopping treatment, and the continuous tenofovir monotherapy group was the only
one with a good viral suppression rate at week 72 (71.9% compared with 7.0% and
3.3% in the tenofovir combination arms). Only 21.1% of people who took
pegylated interferon alone achieved undetectable HBV DNA at week 48, falling to
3.2% at week 72.
All treatment regimens were generally safe
and well-tolerated. More than half of people in the arms that stopped treatment
at week 48 ended up restarting tenofovir monotherapy, mostly due to resurgent
viral load or liver 'flares'. Early treatment discontinuation rates were
similar across arms (26 to 32%). Serious adverse events were reported by 10 to 11%
of people in the interferon-containing arms and 7% in the tenofovir monotherapy
"Combination therapy with [tenofovir] plus
[pegylated interferon] for 48 weeks led to higher rates of HBsAg loss compared
with either monotherapy in chronic hepatitis B patients without
cirrhosis," the researchers concluded. They suggested that
"consolidation therapy" after HBsAg loss may be important for
While outcomes were clearly better with extended tenofovir plus
pegylated interferon compared with either taken alone, the desired response of
HBsAg loss remained unlikely.
"At the end of
the day, is 7.3% that good – is it worth the effort?" asked AASLD president
Adrian di Bisceglie, who chose this as one of a
dozen Liver Meeting presentations highlighted at his opening press conference.
"The answer is it may be, but
the real answer is we need new treatments for hepatitis B."
Di Bisceglie also noted
that people with hepatitis B "on average seen to tolerate pegylated
interferon better" than those with hepatitis C, though we don't understand