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Resistance at a Cost
A study evaluated the ability of entecavir-resistant mutants to restore with an rtS202G mutation resulting in entecavir resistance, precore or
replication capacity and fitness. Replication-competent HBV strains basal core promoter mutations only partially restored replication. For
were generated with lamivudine resistance (rtM204V/rtL180M or those with lamivudine-only resistance, mutations in precore and
rtM204I) and entecavir resistance (rtS202G, rtS202I or rtT184G), then basal core promoter locations can fully restore fitness. For the
transfected into human hepatoma cells. Measurements of the entecavir mutations rtS202I or rtT184G, precore or basal core
replication rate using Northern blot, progeny DNA, quantitative promoter mutations had no significant effect on replication. In
polymerase chain recation (qPCR) and hepatitis B virus (HBV) protein conclusion, the presence of entecavir resistance impairs the
assays revealed that entecavir resistance significantly reduced the replicative capacity of HBV which cannot be fully restored by
viral replication capacity compared with wild-type HBV. For patients mutations in precore or basal core promoter.
Professor Locarnini reiterated that the EASL clinical practice guidelines in 28 patients emtricitabine was added to their regimen.
advocate the use of a potent drug with a high genetic barrier entecavir-treated patients achieved a minimum of 90% response rate,
to resistance as first-line therapy. HBV DNA monitoring is critical to which continued to improve over two years.
determine treatment failure and resistance should be identified before
viral breakthrough. Viral load suppression over the long term can “Viral suppression is readily achievable, but immune control represented
potentially lead to self-healing of the liver and reversal of fibrosis. by HBsAg seroconversion is still rare,” said Janssen. For HBeAg-positive
patients treated with telbivudine, adefovir or lamivudine for one year, the
Long-term Efficacy – From Clinical Trial to rate of HBsAg loss is negligible. The newer agents fare better: entecavir
Clinical Practice and tenofovir average 2 and 3% HBsAg loss, respectively.
After two years
Harry Janssen (The Netherlands) discussed the long-term efficacy of of treatment, loss of HBsAg increases to 5 and 6%, respectively.
the NUCs in clinical trials and in clinical practice.
Long-term Longer-term data for up to five years are available for adefovir and
clinical trial data from treatment-naïve chronic hepatitis B patients entecavir. HBV DNA suppression (<1,000 copies/ml) in HBeAg-positive
were first evaluated. patients treated with adefovir was approximately one-third after three
years. In HBeAg-negative patients it peaked at two years at 80%
Addressing specifically viral suppression in HBeAg-positive patients, before dropping to 67% by the fifth year.
The response rate (<30
Janssen presented a collation of the currently available data from three copies/ml) in HBeAg-positive patients treated with entecavir reached
pairs of studies (not actual head-to-head studies), each after 96 weeks 94% over five years.
The first-year response rate for HBeAg-negative
of treatment lamivudine versus telbivudine,
adefovir versus patients was 94%, but treatment cessation for 60 days resulted in a
and lamivudine versus entecavir.
Approximately 55–60% fall to 4%.* Reinstating treatment reproduced the same response
of patients achieved undetectable HBV DNA levels with telbivudine rate, however, which was maintained from week 48 to three years.
treatment compared with around 40% of those treated with lamivudine.
By comparison, adefovir, a slow-acting drug, resulted in 13% of patients Clinical Practice Data
with undetectable DNA after one year compared with 76% of those Investigator studies use real-life cohorts to analyse the effect of licensed
treated with tenofovir. In the second year in the latter study, the adefovir products. Janssen highlighted data from a recent study of 182 naïve
group was switched to tenofovir treatment, while emtricitabine was patients, mostly HBeAg-negative (82%), treated with entecavir. Overall,
added to tenofovir in 28 patients in the second group. A total of 78% of 89% of patients achieved undetectable HBV DNA (<12IU/ml) after one
patients in both groups achieved undetectable HBV DNA levels. year. Furthermore, there was a clear negative correlation between
When lamivudine was compared with entecavir, only 40% of patients baseline viral load and response at one year: 98% of patients with <5
treated with lamivudine achieved undetectable HBV DNA in both years, log
HBV DNA achieved undetectable levels, compared with only 75%
compared with 67% of those treated with entecavir in year one, rising to of patients with DNA >8log
(for an update see ‘Entecavir in Clinical
80% for year two. Practice’, p.35).
Nevertheless, all cohorts showed an increasing
response over time. Janssen also presented data from the ViRgil
However, HBeAg-negative patients are becoming more common, (vigilance against viral resistance) consortium, which investigated the
particularly in southern Europe (Mediterranean region). HBeAg- 12-month cumulative probability of virological response to entecavir in
negative patients tend to have a lower baseline HBV DNA and are 161 patients, 43% of whom were HBeAg-positive. After one year, 81% of
therefore more likely to show a positive response to antiviral treatment-naïve patients achieved a response (<80IU/ml) compared
treatment. Data were presented from the same three pairs of drugs for with 55% of previously treated individuals (see ‘ViRgil Data – Real-life
these patients. After one year of lamivudine treatment, the response Study’, p.36).
rate was 71%, but fell to 57% at year two.
By comparison, more than
80% of patients on telbivudine maintained a response over two years.
For adefovir, the one-year response rate was 63%, increasing to 89% in Janssen outlined the tolerability profile of NUCs, highlighting ALT flares
year two after therapy was switched to tenofovir.
More than 90% of as a concern. Differences between NUCs are minimal and
patients on tenofovir maintained a response over two years, although discontinuation rates are fairly low.
There have been no specific
*Treatment cessation was as per protocol; protocol-defined responders were followed up off-treatment for 24 weeks to assess sustainability of response.
34 EUROPEAN GASTROENTEROLOGY & HEPATOLOGY REVIEW
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