A dual regimen of entecavir (Baraclude) plus tenofovir
(Viread) for 48 weeks led to virological response and was generally
well-tolerated among people with chronic hepatitis B who had experienced treatment failure with previous
nucleoside/nucleotide analogue treatment, according to a poster presented earlier this month at The Liver Meeting 2013, the 64th annual
meeting of the American Association for the Study of Liver Diseases (AASLD), in Washington, DC.
Chronic hepatitis B virus (HBV) infection
is treated with oral nucleoside/nucleotide analogues including lamivudine (Epivir), adefovir (Hepsera),
entecavir (Baraclude), telbivudine (Sebivo
or Tyzeka) and tenofovir (Viread). While these drugs can reduce
HBV viral load to an undetectable level while on therapy, they typically do not
lead to post-treatment sustained virological response or hepatitis B antigen
HBV can develop resistance mutations that
compromise long-term efficacy of treatment – especially of the oldest drug, lamivudine –
and limit future treatment options, but entecavir and tenofovir have a higher
barrier to resistance.
Maciej Jablkowski of the
Medical University of Lodz in Poland and colleagues conducted the ENTEBE study (AI463203) to evaluate the
safety and efficacy of entecavir plus tenofovir in people with chronic hepatitis B who had experienced treatment failure with previous nucleoside/nucleotide therapy.
This multicentre phase 3b trial enrolled 92
participants. Three-quarters were men, 76% were white and the median age was 43
years. A majority (62%) were hepatitis B 'e' antigen (HBeAg)-positive and 76%
had normal alanine aminotransferase (ALT) at baseline. People with
decompensated liver disease were excluded.
Most participants had previously been treated with
entecavir (53%) or lamivudine (22%) monotherapy; 12% had taken tenofovir and a
few had used adefovir (4%) or telbivudine (2%). About 5% had tried dual
combinations that included lamivudine or adefovir.
The patients had experienced prior treatment failure
as defined by European Association for the Study of the Liver (EASL)
guidelines. Nearly 10% had primary non-response (<1 log10 decline
in HBV DNA after 12 weeks of treatment), 57% had partial virological response
(decline of >1 log10 but still detectable at week 24 or 48) and
33% experienced viral breakthrough while on treatment (>1 log10
increase over the lowest level). At baseline, 52% had evidence of lamivudine
resistance, 25% had entecavir resistance and 7% had adefovir resistance. About
one-quarter had no resistance mutations and 16% had viral load too low for
All participants in this ongoing, open-label,
single-arm study were re-treated with 1mg entecavir plus 300mg tenofovir, both
once daily, for up to 96 weeks. After 96 weeks, study participants and investigators could
elect to pursue further treatment using commercially available hepatitis B drugs.
Those who discontinued study treatment at or before week 96 entered a
post-treatment follow-up phase of up to 24 weeks.
More than half of participants (54%) had HBV DNA
<50 IU/ml at week 12 of re-treatment, rising to 64% at week 24. The primary
analysis at week 48 found that 76% had viral load <50 IU/ml. Looking at the
lower limit of detection of 6 IU/ml, response rates were 13, 12 and 19%,
respectively, at these three time points.
Prior partial responders had the highest likelihood of
undetectable HBV viral load at week 48 (83%), followed by prior breakthroughs
(73%) and primary non-responders (56%). People who had previously taken
tenofovir were least likely to respond to re-treatment (55%) compared to those
previously taking entecavir (77%), lamivudine (85%) or adefovir (100%).
Five people who experienced virological failure on
re-treatment – all of whom had primary non-response to prior treatment – met
the criteria for resistance testing, but no treatment-emergent genotypic
resistance mutations were detected.
Serological response rates were much lower than
virological response. Only 5% of participants achieved HBeAg loss, 4% showed
HBeAg seroconversion, and none experienced hepatitis B surface antigen (HBsAg)
loss or seroconversion.
Entecavir/tenofovir combination therapy was
generally safe and well-tolerated. Only 3% of participants in the study experienced serious
adverse events, none of which were considered treatment-related, and just one
person discontinued therapy early for this reason. The most common side-effects were
gastrointestinal symptoms, fatigue and nausea. No serious kidney-related
adverse events were reported.
Based on these findings the
researchers concluded, "48 weeks of combination therapy with entecavir +
tenofovir is a highly effective second-line chronic hepatitis B therapy", regardless
of the type of prior nucleoside/nucleotide analogue treatment.