Comparison of clinical outcome between patients continuing and discontinuing lamivudine therapy after biochemical breakthrough of YMDD mutants☆
Introduction
Hepatitis B virus (HBV) infection is a major health problem leading to around one million deaths annually worldwide [1]. A wide range of clinical manifestations has been established for chronic hepatitis B virus infection, from asymptomatic carriers to severe chronic liver disease, including those with cirrhosis and hepatocellular carcinoma [2], [3]. Lamivudine, an oral nucleoside analogue, inhibits HBV replication [4], [5]. It can markedly reduce serum HBV DNA levels and normalise alanine aminotransferase (ALT) levels associated with improvement in liver necroinflammatory activity [5]. However, the greatest drawback with lamivudine treatment is the emergence of drug-resistant HBV mutants, the mutation of the tyrosine–metheonine–aspartate–aspartate (YMDD) motif in the C domain of the HBV DNA polymerase gene [5], [6].
Genotypic resistant mutations have been detected in 14–32% of patients after 1 year of treatment [5], [6] increasing to 38, 49, and 66% after 2, 3, and 4 years of treatment, respectively, [7], [8], [9], [10]. Despite of having resistant to lamivudine, patients with YMDD mutants have significantly lower HBV DNA levels and ALT levels compared with baseline values [8] because of the decreased replication state of the mutants [11]. A follow-up study on continued lamivudine therapy after the emergence of YMDD mutation showed that acute exacerbation of hepatitis with or without hepatic decompensation may occur, although it is frequently followed by clinical recovery, HBeAg seroconversion, and YMDD mutant clearance [12]. Furthermore, fatal hepatic failure after the emergence of the YMDD mutants during lamivudine therapy has been reported [13].
For patients from whom YMDD mutants have emerged, the current practice of treatment is to continue lamivudine therapy in order to prevent the return of wild type virus [14]. According to the recommendations by Asian-Pacific consensus statement on the management of chronic hepatitis B, stopping lamivudine therapy with close monitoring may be an option in patients who develop YMDD mutants if adefovir dipivoxil is not available [15]. Thus, stopping or continuing lamivudine therapy when YMDD mutants emerge during lamivudine therapy is still a controversial issue. The aim of this study was to compare the differences of the incidence and clinical course of acute exacerbations after the emergence of YMDD mutants in patients discontinuing and continuing lamivudine therapy.
Section snippets
Patients
This investigation was a retrospective study. From January 2000 to August 2002, 67 chronic hepatitis B patients, who received lamivudine at Chang Gung Memorial Hospital in Kaoshiung, experienced a flare-up of ALT levels (abrupt increase of ALT greater than two folds) during lamivudine treatment. Serum specimens from these 67 patients were assayed for the detection of HBV DNA levels and HBV YMDD mutation. Lamivudine was given at a dose of 100 or 150 mg/d orally. All the patients had positive HBV
Results
YMDD mutant with biochemical breakthroughs occurred 6–31 months (median, 12 months) after the commencement of lamivudine therapy. Lamivudine retreated patients had a shorter period for biochemical breakthrough after the emergence of YMDD mutants than naı̈ve patients (10.2±3.7 vs. 13.9±5.7 months; P=0.035). Among the 51 patients, 30 (59%) had one single YMDD variant: 27 (53%) had rtM204I, 1 (2%) had rtM204V, and 2 (4%) had rtL180M. Twenty-one patients (41%) had rtL180M variants: 18 (35%) had
Discussion
Our data showed that 61 and 24% of patients experienced acute exacerbation and hepatic decompensation, respectively, after biochemical breakthrough. Liaw et al. [12] reported that 13 (40.6%) and 3 (10%) of 32 patients experienced acute exacerbation and hepatic decompensation, respectively, after the emergence of the YMDD mutants, and there were no fatal cases. In this study, 49% of patients had a liver cirrhosis background before treatment, thus the rate of hepatic decompensation and fatality
Acknowledgements
This study was support by grant CMRP 1001 and CMRP 767 from Chang Gung Memorial Hospital to CM Lee.
References (33)
- et al.
Lamivudine is effective in suppressing hepatitis B virus DNA in Chinese hepatitis B surface antigen carriers: a placebo-controlled trial
Hepatology
(1997) - et al.
Effects of extended lamivudine therapy in Asian patients with chronic hepatitis B. Asia Hepatitis Lamivudine Study Group
Gastroenterology
(2000) - et al.
Extended lamivudine treatment in patients with chronic hepatitis B enhances hepatitis B e antigen seroconversion rates: results after 3 years of therapy
Hepatology
(2001) - et al.
Course of virologic breakthroughs under long-term lamivudine in HBeAg-negative precore mutant HBV liver disease
Hepatology
(2002) - et al.
Long-term therapy of chronic hepatitis B with lamivudine
Hepatology
(2000) - et al.
Lamivudine treatment in patients with severely decompensated cirrhosis due to replicating hepatitis B infection
J Hepatol
(2000) - et al.
Beneficial effects of lamivudine in hepatitis B virus-related decompensated cirrhosis
J Hepatol
(2000) - et al.
Adefovir dipivoxil therapy for lamivudine-resistant hepatitis B in pre- and post-liver transplantation patients
Hepatology
(2003) - et al.
Resistance surveillance in chronic hepatitis B patients treated with adefovir dipivoxil for up to 60 weeks
Hepatology
(2002) - et al.
Adefovir dipivoxil for the treatment of lamivudine-resistant hepatitis B mutants
Hepatolgy
(2000)
Successful orthotopic liver transplantation for lamivudine-associated YMDD mutant hepatitis B virus
Gastroenterology
Hepatitis B virus infection
N Engl J Med
From hepatitis to hepatoma: lessons from type B viral hepatitis
Science
Natural history of chronic hepatitis B virus infection: an immunopathological study
J Gastroenterol Hepatol
A one-year trial of lamivudine for chronic hepatitis B
N Engl J Med
Lamivudine as initial treatment for chronic hepatitis B in the United States
N Engl J Med
Cited by (39)
Comparison of the efficacy and safety of entecavir and tenofovir in nucleos(t)ide analogue-naive chronic hepatitis B patients with high viraemia: a retrospective cohort study
2017, Clinical Microbiology and InfectionCitation Excerpt :The VR was defined as HBV DNA <60 IU/mL for consistency of data interpretation. Mutations in the HBV DNA polymerase gene and HBV genotypes were assessed as described previously [15,16]. Categorical variables were analysed using a chi-square or Fisher exact test.
Entecavir vs. lamivudine in chronic hepatitis B patients with severe acute exacerbation and hepatic decompensation
2014, Journal of HepatologyCitation Excerpt :Serum HBV DNA levels were analyzed using the COBAS AmpliPrep-COBAS TaqMan HBV test (CAP-CTM; Roche Molecular Systems, Inc., Branchburg, NJ, USA), with a lower detection limit of 70 copies/ml. The sequences of pre-S, BCP and precore regions in sera were determined using nested polymerase chain reaction and direct sequencing, as described previously [28–30]. In BCP and precore regions, the variants of nucleotides 1753, 1762/1764, 1766/1768, 1896, and 1899 were analyzed in correlation with advanced liver diseases according to previous studies [30–32].
Evolution of full-length HBV sequences in chronic hepatitis B patients with sequential lamivudine and adefovir dipivoxil resistance
2010, Journal of HepatologyCitation Excerpt :Viral breakthrough associated with the selection of anti-viral-resistant HBV mutants is usually followed by biochemical breakthrough [19]. Acute exacerbation of hepatitis with or without hepatic decompensation may occur after the emergence of anti-viral-drug resistance [14,16,20,21]. However, most studies focused on the analysis of the A to D domain of the HBV DNA polymerase gene after detection of anti-viral-resistant HBV mutants and did not compare the entire genome.
Outcomes of Patients With Hepatitis B Who Developed Antiviral Resistance While on the Liver Transplant Waiting List
2007, Clinical Gastroenterology and HepatologyCitation Excerpt :Similarly, serum albumin and laboratory MELD at listing were independent predictors of survival without transplant. The finding that antiviral failure had no impact on survival of HBV patients on the OLT waiting list was unexpected because virologic breakthrough as a result of emergence of antiviral-resistant mutations had been reported to result in deaths from severe hepatitis flares.7–10,26 This might be explained in part by the inclusion of patients with low MELD scores; of the 53 patients with no documented HCC, 36 (68%) had MELD score <15 at listing.
- ☆
The authors of the study have declared that they did not receive funding neither do they have any relationship with the manufacturers of the drugs involved in the study.