Marc Bourlière from
Hôpital Saint Joseph in Marseille and fellow investigators with the French
ANRS-HB06 PEGAN study conducted a randomised trial to evaluate the usefulness
of adding pegylated interferon for people with hepatitis B on suppressive
This phase 3 trial included 185 people with chronic hepatitis B at multiple centres in France. More than 80% were men, about 45% were
white, 35% were black, 15% were Asian and the mean age was about 48 years. All
were currently HBeAg-negative, but nearly 30% had previously been
HBeAg-positive when first diagnosed with hepatitis B. About a third had
advanced fibrosis or cirrhosis (stage F3-F4). Trial participants were stratified
according whether their HBsAg level at study entry was above or below 2.25 log10
Participants had been on stable nucleoside/nucleotide
therapy for at least one year with undetectable HBV DNA viral load (median 3.5
years, but ranging up to 19 years). A majority (nearly 60%) were using
tenofovir, 32% were using entecavir, 22% were using lamivudine and about 12%
were using adefovir; 40% had previously received interferon.
Participants in this open-label study were randomly
assigned to either stay on the same nucleoside/nucleotide analogues alone or to
continue these drugs and add 180mcg/week pegylated interferon alfa-2a for 48
weeks. Those with sustained HBsAg clearance for 24 weeks could stop treatment.
The primary endpoint was HBsAg loss at week 96, with continuing follow-up
through week 144.
At week 48, a total of seven people (8%) in the
add-on interferon group experienced HBsAg loss and four (4%) had HBs
seroconversion, compared with none in the nucleoside/nucleotide monotherapy
group – a statistically significant difference.
By week 96, the HBsAg loss rate in the interferon
group remained at 8% and two additional participants had HBs seroconversion (for a
total of 7%). The HBsAg loss rate in the nucleoside/nucleotide monotherapy
group had risen to 3% – no longer significantly different from the interferon
group – and one person (1%) had HBs seroconversion.
HBsAg levels fell to a greater extent in the add-on
interferon group compared to the monotherapy group (-0.89 vs -0.35 log10
IU/ml from week 0 to week 96). However, within the interferon group, participants could be divided into a good responder subgroup (HBsAg decline -3.74 log10
IU/ml) and a non-responder subgroup (-0.62 log10 IU/ml). HBsAg
decline usually occurred early, during the first 24 weeks of combination
treatment, but one person had a slow decline and did not achieve HBsAg loss
until week 96.
In a multivariate analysis, HBsAg loss was associated
with lower baseline HBsAg and using the full dose and duration of pegylated
interferon; duration of undetectable HBV DNA did not predict HBsAg loss.
Among people with baseline HBsAg <2 log10
IU/ml at baseline, 33% of people taking add-on interferon and 16% taking
nucleoside/nucleotide monotherapy achieved HBsAg loss. The corresponding rates
were 23% and 8% among people with a baseline HBsAg level <3 log10
IU/ml, and 4% and 0% among those with >3 log10 IU/ml.
Combination treatment with pegylated interferon was
generally safe, but side-effects were common. Twenty participants either stopped
interferon or had their dose reduced, mostly due to adverse events (an
additional five people refused to start interferon after randomisation). There
were about four times as many grade 3-4 adverse events in the interferon group
than in the monotherapy group, but this difference did not reach statistical
significance. People over age 50 and those with more symptoms were more likely
to discontinue treatment prematurely.
"Addition of [a] 48 weeks course of [pegylated
interferon alfa-2a] to [nucleoside/nucleotide] therapy in HBeAg-negative
chronic hepatitis B patients with undetectable HBV DNA for at least one year
results in higher rates of HBsAg loss and HBs seroconversion," the
researchers concluded. "Low baseline HBsAg level increase HBsAg loss and
However, they cautioned, "acceptability of [this]
regimen in patients treated with [nucleoside/nucleotide analogues] is poor and
discontinuation due to adverse events occurred in 20% of the patients."
For this reason, Bourlière
said, this combination should be offered to selected HBeAg-negative chronic
hepatitis B patients with better predicted response.
Bourlière noted that only half of the people with undetectable HBV DNA who were invited to join this study agreed
to do so, mostly due to the expected poor tolerability of pegylated interferon.