Long-Term Efficacy of Entecavir for People with Hepatitis B

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Long-term entecavir (Baraclude) monotherapy leads to a virological response in a large majority of nucleoside/nucleotide analog-naive patients, even those who still have detectable HBV DNA at 48 weeks.

In the August 2011 issue of Hepatology, Roeland Zoutendijk and colleagues with the VIRGIL Surveillance Study Group described the results of an analysis investigating the efficacy of entecavir for 1 year or more in nucleoside/nucleoside analog-naive and -experienced patients with chronic hepatitis B virus (HBV) infection.

The researchers explored baseline factors associated with partial virological response to entecavir in previously untreated patients and whether achieving a partial response during early treatment compromised long-term entecavir success.

In Phase 3 trials of lamivudine (Epivir-HBV) vs entecavir, entecavir has shown superior biochemical, virological, and histological efficacy. Genotypic resistance to entecavir is rare even after 5 years of treatment. But entecavir’s efficacy is seriously compromised in patients for whom lamivudine is no longer effective and whose HBV has extensive entecavir resistance mutations.

Current European hepatitis B treatment guidelines suggest a change in regimen for h patients who still have detectable viral load at week 48 -- whatever their previous treatment. But as the authors of the present study point out, evidence to support this recommendation is scare and based on data from studies using weaker nucleoside/nucleotide analogs.

This cohort study within the European Network for Vigilance against Viral Resistance (VIRGIL) included all adults with chronic hepatitis B treated with entecavir monotherapy between 2003 and 2010 at 10 large European centers.

Eligibility criteria included having an HBV DNA viral load of at least 2000 IU/ mL when starting entecavir and having taken entecavir monotherapy for at least 3 months. People with coinfections (HIV, hepatitis C virus, hepatitis D virus) and those who had a liver transplant before starting entecavir were excluded from the study.

The analysis included 333 patients, although 20 (6%) were lost to follow-up. Of the 333 participants initially included, 75% were men, the median age was 43 years, and 43% were hepatitis B "e" antigen (HBeAg) positive; 48% were Caucasian, 28% were Asian, and the remaining 24% were classified as "other." HBV genotype was determined at start of entecavir therapy. The majority of the cohort had HBV genotype D (48%), followed by genotype A (21%), genotype C (14%), genotype B (9%), and other genotypes (7%).

Most participants (73%) were nucleoside/nucleotide analog-naive at baseline. Among the remainder, 22% had taken lamivudine previously, 11% had a history of lamivudine resistance, and 4% had lamivudine resistance at baseline. In addition, 15% of the cohort had taken adefovir (Hepsera) previously, 4% had a history of adefovir resistance, and 4% had adefovir resistance at baseline.

All participants took entecavir monotherapy for at least 3 months. They were seen every 3 months to test for alanine aminotransferase (ALT) levels, bilirubin, albumin, HBA DNA, HBeAg, and HBeAg antibodies.

Genotypic analysis was conducted at baseline for all nucleoside/nucleotide analog-experienced patients, in cases of virological breakthrough (an increase in HBV DNA > 1 log above nadir or lowest level at least twice following initial virological response), and in cases with HBV DNA > 200 IU/mL at the end of follow-up. For treatment-experienced patients, retrospective genotypic resistance was also assessed in stored serum samples obtained at the end of all previous nucleoside/nucleotide analog treatment regimens. If entecavir-resistant mutations were detected during follow-up, retrospective baseline genotypic analysis was performed for nucleoside/nucleotide analog-naive patients.

The primary outcome was virological response (HBV DNA < 80 IU/ml) during the on-treatment follow-up period. Secondary endpoints were HBeAg loss and seroconversion (in HBeAg positive participants), hepatitis B surface antigen (HBsAg) loss and seroconversion, emergence of entecavir-related mutations, and normalized ALT levels.

Results

The researchers wrote, “The current multicenter study showed that [entecavir] is effective up to 3 years in [nucleoside/nucleotide analog-naive] patients, irrespective of having a virological response at week 48."

"The vast majority of [nucleoside/nucleotide analog-naive] patients with a [partial virological response] achieved undetectable HBV DNA through prolonged therapy without treatment adaptation," they continued. "Genotypic resistance to [entecavir] was not detected in any of the patients with a [partial virological response] at week 48.”

The study showed that continuing entecavir treatment appears to be safe and effective for patients with detectable HBV DNA at week 48, especially those with a lower viral load at that time, 95% of whom went on to achieved full virological response.

The researchers concluded, "[I]n contrast to what is suggested in recently published European Association for the Study of the Liver guidelines on the management of chronic hepatitis B, adjustment of [entecavir] monotherapy in [nucleoside/nucleotide analog-naive] patients with a [partial virological response] at week 48 is not necessary.”

They added that data from studies investigating drugs (like lamivudine) with a low barrier to resistance cannot be translated to more potent drugs such as entecavir and tenofovir.

Investigator affiliations: Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands; Department of Hepatology and Gastroenterology, Imperial College London, London, United Kingdom; Department of Hepatology, Hotel Dieu Hospital Lyon, Lyon, France; Department of Hepatology and Gastroenterology, Queen Elizabeth Hospital, Birmingham, United Kingdom; Department of Gastroenterology, Hepatology, and Endocrinology, Medical School Hannover, Hannover, Germany; Liver Unit, IFI Institute, Asklepios Klinik St. Georg, Hamburg, Germany; Medizinische Klinik 1, Klinikum der Johann Wolfgang Goethe-Universitat, Frankfurt am Main, Germany; 8Department of Hepatology, Hospital Vall de Hebron, Barcelona, Spain; Clinic of Infectious Diseases, University of Foggia, Foggia, Italy; Klinik und Poliklinik fur Gastroenterologie und Rheumatologie, Leipzig, Germany; and Department for Internal Medicine, University Medical Center, Hamburg-Eppendorf, Germany.

Supported by the Foundation for Liver and Gastrointestinal Research Rotterdam, the European Network of Excellence for Vigilance against Viral Resistance, and a research grant from Bristol-Myers Squibb.

8/16/11

Reference

R Zoutendijk, JGP Reijnders, A Brown, et al for the VIRGIL Surveillance Study Group. Entecavir Treatment for Chronic Hepatitis B: Adaptation Is Not Needed for the Majority of Naive Patients with a Partial Virological Response. Hepatology 54(2):443-451 (abstract). August 2011.