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Right First Time – Therapeutic Strategy for Chronic Hepatitis B
Headline Hepatitis B Virus News on Figure 1: Natural History of Hepatitis B
Third-generation Agents
Entecavir – Six-year Resistance
Acute infection
Helena Brett-Smith presented results from a study examining resistance
to entecavir over a six-year period. This study included two cohorts:
Resolved infection
Chronic infection
treatment-naïve and lamivudine-refractory patients. HBV genotype was 5% neonates
assessed at baseline and if HBV DNA levels rose above 300 copies/ml
90% adults
(50IU/ml) at any of the annual time-points or if virological breakthrough
Immune
Chronic hepatitis
occurred (≥1 log increase from nadir in serum HBV DNA). For the 663
tolerance
Wild-type virus HBeAg+ Inactive carrier
Pre-core mutant HBeAg-
NUC-naïve patients (both HBeAg-positive and -negative), the cumulative
probability of developing entecavir resistance during the six-year period
Reactivation
was 1.2%. Resistance developed during the first three years, with no Cirrhosis
30–50 years
new cases thereafter.* Furthermore, 94% of patients maintained HBV
DNA levels <300 copies/ml. A total of 99 patients completed six years of
treatment; however, 89% of those discontinuing had HBV DNA levels
Hepatocellular carcinoma
of <300 copies/ml at the last treatment visit. Brett-Smith commented 16
Adapted from Seeger et al., 2007.
that the main limitations of the study concerned the use of a higher
dose of entecavir during years two to six (1mg compared with 0.5mg)
Figure 2: Interplay Between Immune Response and
and the high number of patient withdrawals from the study due to Hepatitis B Virus Replication
protocol-defined criteria for response and non-response to the study
drug.
†
These were similar to the limitations of a previous study in which
no evidence of resistance to tenofovir was shown. However, the addition
HBsAg+
of emtricitabine to the treatment regimen was permitted, which may
Immunotolerant phase Immunoactive phase Inactive carrier phase Reactivation
have confounded the results.
8–10
In a another study, variable resistance
HBeAg + HBeAg-/anti-HBe+
rates depending on HBeAg status were demonstrated: treatment
with telbivudine for two years resulted in a 25% rate of resistance for
HBeAg-positive patients and an 11% rate for HBeAg-negative
HBV-DNA
patients.
11,12
In a further but similar study, resistance to adefovir gradually
increased to 29% over a five-year period in HBeAg-negative patients.
13
In
conclusion, in naïve patients, entecavir has high potency and a high
genetic barrier. Resistance is rare over a six-year treatment period, with
a recorded rate of 1.2%.
ALT
Tenofovir – Two-year Safety and Efficacy
Minimal CH Moderate to severe CH Remission Moderate to severe CH
Maria Buti (Spain) introduced a two-year study of the safety and efficacy
of tenofovir, a potent antiviral agent. This study was a sub-analysis of an
Cirrhosis Inactive cirrhosis Cirrhosis
efficacy study comparing patients with cirrhosis versus those without
cirrhosis. A total of 641 non-cirrhotic and cirrhotic patients, HBeAg-
2 3
Adapted from Fattovich, 2003 and Fattovich, 2003.
positive and -negative, were enrolled and randomised 1:2 to receive
adefovir 10mg daily or tenofovir 300mg daily, respectively.
14,15
After 48 inflammation to cirrhosis and finally HCC is typical, the development of
weeks all patients were moved to the open-label extension to receive HCC directly can occur in a small proportion of patients, particularly
tenofovir 300mg daily. Tenofovir maintained HBV suppression to <400 those with immune tolerance or during the inactive carrier phase of
copies/ml in 78% of HBeAg-positive patients and 91% of HBeAg- infection. The relationship between the immune system response, the
negative patients after a two-year treatment period. During the stage of HBV infection and HBV DNA level is shown in Figure 2. These
extension study, patients with HBV DNA >400 copies/ml had the option stages are not necessarily sequential, and HBV DNA can persist in the
to add emtricitabine to the tenofovir. Tenofovir was well tolerated in liver and other organs even in the absence of HBsAg. Professor Zoulim
patients both with and without cirrhosis. None developed recapped the goal of therapy (see ‘EASL Clinical Practice Guidelines’,
decompensated liver disease or evidence of impaired hepatic function. p.28), explaining that because covalently closed circular DNA (cccDNA)
No patients with cirrhosis died, although one developed HCC. No HBV is very stable and persistent, chronic HBV infection may never be
resistant mutations arose over 96 weeks of tenofovir monotherapy, entirely eradicated. The practical end-point of the clinical practice
although ‘at risk’ patients were switched to combination therapy. guidelines is therefore to reduce HBV DNA levels, ideally below the
Overall, tenofovir for 96 weeks showed potent viral suppression and lower limit of realtime polymerase chain reaction (PCR) assays
good tolerability and was not compromised by presence of cirrhosis. (10–15IU/ml), which will lead to biochemical remission and histological
improvement and prevent complications. Sustained reduction in viral
Discussion of Therapeutic End-points load will also reduce the emergence of resistance to therapy and
The end-points of the new clinical practice guidelines were discussed by improve the chances of achieving HBeAg seroconversion and HBsAg
Fabien Zoulim (France). While progression from chronic hepatic loss. Sustained HBsAg loss with or without anti-HBs seroconversion is
*Two studies not cited at the meeting evaluated the efficacy and resistance of entecavir and demonstrated no resistance for up to 18 months of treatment.
†
Direct comparison of entecavir with other antiviral agents is difficult due to differences in study design, patient population, etc.
EUROPEAN GASTROENTEROLOGY & HEPATOLOGY REVIEW 27
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