Fabien Zoulim of Hospices Civils de Lyon in France and
colleagues conducted the phase 3b ENTEBE trial to evaluate the safety and
efficacy of entecavir plus tenofovir combination therapy for people with chronic hepatitis
B who experienced previous nucleoside/nucleotide treatment failure.
Developing resistance to one antiviral can confer cross-resistance
to similar drugs. But combining entecavir (a guanosine nucleoside analogue) and
tenofovir (an adenosine nucleotide analogue) may provide a single regimen that
works for all patients with prior nucleoside analogue failure, the researchers suggested
as background. These two drugs both have high barriers to resistance and
non-overlapping resistance profiles.
ENTEBE enrolled 144 previously treated participants in
Europe between May 2010 and September 2011, of whom 92 started treatment. Three-quarters
were men, most were white and the median age was 42 years. Two-thirds were
initially hepatitis B 'e' antigen (HBeAg)-positive and one-third
HBeAg-negative. A majority (54%) had HBV genotype D and 32% had genotype A. The
median alanine aminotransferase (ALT) level was 36.5 (near the upper limit of
normal) and they had compensated liver disease.
Participants had last taken nucleoside antivirals more
than seven days ago. Just over half had previously used entecavir, 22% had used
lamivudine, 12% had used tenofovir, 4% had used adefovir and the remainder had
used telbivudine (Sevibo or Tyzeka) or two-drug regimens. They had
experienced treatment failure, defined as HBV DNA >50 IU/ml, with
primary non-response (less than a 1-log decline; 10%), partial virological
response (57%) or viral breakthrough on therapy (33%). Among participants with
available viral sequencing data, 58% had at least one resistance mutation,
including 52% with lamivudine resistance, 26% with entecavir resistance and 7% with
adefovir resistance.
All participants received 1.0mg entecavir plus 300mg
tenofovir once daily. Treatment continued through week 96 and participants were
followed for a further 24 weeks off treatment.
A total of 89 people completed 48 weeks of treatment
(the primary analysis) and 86 people completed 96 weeks. At 48 weeks, 76% had
HBV viral load <50 IU/ml, rising to 85% by 96 weeks in an intent-to-treat
analysis.
Prior partial responders were most likely to respond
to entecavir plus lamivudine (90%), followed by those with prior viral
breakthrough (87%) and prior primary non-response (56%). Response rates were
88% for those who previously received entecavir monotherapy, 82% for those with
prior tenofovir monotherapy and 80% for those with prior lamivudine monotherapy.
The 14 people who did not have undetectable HBV
viral load at week 96 included six people with HBV DNA >50 IU/ml, six who
discontinued treatment before this time point and two with missing data. Among
six people who underwent resistance testing, no treatment-emergent resistance
mutations were observed through week 96.
Serological response rates were low, as is typically
seen with nucleoside/nucleotide therapy. At 96 weeks, 9% experienced HBeAg loss,
2% had HBeAg seroconversion, 2% had hepatitis B surface antigen (HBsAg) loss
and just 1% achieved HBsAg seroconversion (HBsAg loss and development of
protective anti-HBs antibodies).
Entecavir plus tenofovir was generally safe and
well-tolerated. There were no severe adverse events deemed related to study
drugs and only one person discontinued therapy due to an adverse event. The
most common treatment-related side-effects were fatigue and nausea. No one
experienced severe kidney or bone problems (potential side-effects of
tenofovir).
"Entecavir combined with [tenofovir] is a highly
effective and well tolerated option for rescue therapy, regardless of the type
of prior [nucleoside analogues] used," the researchers concluded. They
added that lower baseline HBV viral load – but not baseline resistance profile – was a predictor of virological response.