JAC Advance Access originally published online on March 1, 2007
Journal of Antimicrobial Chemotherapy 2007 59(4):807-809; doi:10.1093/jac/dkm026
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Correspondence |
Hepatitis B virus resistance to adefovir in a nucleotide naive patient with chronic hepatitis B virus infection
1 Department of Microbiology, St James's Hospital, James's Street, Dublin 8, Ireland 2 Department of Clinical Microbiology, University of Dublin, Trinity College, Dublin 2, Ireland 3 School of Biological Sciences, Dublin Institute of Technology, Kevin Street, Dublin 8, Ireland 4 Department of Hepatology, St James's Hospital, James's Street, Dublin 8, Ireland 5 National Virus Reference Laboratory, University College Dublin, Belfield, Dublin 4, Ireland
* Corresponding author. Tel: +353-1-4162966; Fax: +353-1-4738902; E-mail: bcrowley{at}stjames.ie
Keywords: lamivudine treatment , primary adefovir resistance , HBV
Antiviral therapy of chronic hepatitis B (CHB) remains a major clinical challenge. The new orally active nucleos(t)ide analogues, such as lamivudine, adefovir and entecavir, have been shown to be efficacious in controlling viral replication, decreasing inflammatory activity within the liver and preventing the progression of CHB infection to liver cirrhosis and hepatocellular carcinoma.1 However, due to the spontaneous error rate of the hepatitis B virus (HBV) polymerase gene and persistence of HBV in infected individuals, long-term antiviral treatment is needed in most individuals and therefore increases the risk of selecting drug-resistant mutants.
Drug resistance is associated with the development of polymerase gene mutations, followed by a rise in HBV viral load and a subsequent increase in alanine transaminase levels with exacerbation of liver disease. Genotypic resistance occurs in 
20% of individuals per year, but at a lower rate in those treated with adefovir (3% at year 2 and 29% at year 5 of treatment).2 The major lamivudine resistance mutations in HBV are located in the highly conserved reverse transcriptase (rt) domain of the polymerase gene, specifically in the tyrosine-methionine-aspartate-aspartate (YMDD) motif in the C domain, at position rtM204I/V. Additional compensatory mutations are selected downstream in the B domain at positions rtL180M and rtV173L, which augment drug resistance and enhance viral replication efficiency in vitro.3 Adefovir resistance is associated with mutations located in the B and D domains, at positions rtA181T/V and rtN236T, respectively.2 Adefovir is effective in suppressing lamivudine-resistant HBV and, therefore, is most commonly used in patients with lamivudine-resistant HBV infection.2 While acquired resistance to adefovir is important, primary resistance to this nucleotide analogue was reported recently.4 A variant of HBV was detected in three non-responders even before they commenced treatment with adefovir. The associated mutation rtI233V significantly increased resistance to adefovir in vitro. This variant occurs in 2% of individuals with CHB.4
In this report, molecular evidence is presented of the emergence of primary adefovir resistance in a patient on prolonged lamivudine treatment for chronic HBV infection.
A 40-year-old lady presented to St James's Hospital, Dublin, with hepatitis Be antigen (HBeAg)-positive chronic HBV infection in April 1999. A liver biopsy performed in July 1999 showed bridging fibrosis consistent with early cirrhosis. She was given interferon monotherapy 5 MU daily but this was stopped after 16 weeks because of severe side effects. She remained HBeAg-positive at the end of interferon treatment. No HBV DNA levels were determined before or after interferon treatment. In July 2000 she was started on lamivudine monotherapy (100 mg/day). She became HBeAg-negative in April 2003. HBV DNA was undetectable at this time by hybridization assay (Digene HCII) (limit of detection 1.4 x 105 IU/mL). She continued on lamivudine monotherapy and remained stable until July 2006 when alanine transaminase levels were noted to be raised at 46 IU/L (normal range < 35 IU/L). HBV DNA levels measured by realtime PCR were 5.2E + 02 IU/mL (HBV PCR kit, Artus, Hamburg, Germany) and 3.8E + 03 IU/mL (Cobas Ampliprep/Cobas Taqman HBV test, Roche Diagnostics, Mannheim, Germany) in July 2004 and June 2006, respectively. Resistance to lamivudine was suspected. Nucleic acid sequencing of the HBV polymerase gene from sera collected in 2004 and June 2006 was performed as described previously.5 Mutations associated with lamivudine resistance were detected at positions rtL180M and rtM204V in both samples, with the rtV173L mutation appearing in serum collected from 2006 (Table 1). The latter mutation did not appear to affect the replicative capacity of HBV since there was no biologically significant difference in HBV DNA levels in July 2004 and June 2006. Surprisingly, a mutation associated with adefovir resistance was identified at position rtA181V in both samples, although the patient has never been treated with adefovir. She has now started treatment with tenofovir (300 mg/day).
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Genotypic primary resistance to adefovir can occur without prior adefovir treatment. In this report, the patient received lamivudine monotherapy for several years and developed the rtA181V mutation which confers resistance to adefovir.2 This finding supports a previous report of the emergence of the rtA181T mutation in 4 of 23 patients on long-term lamivudine therapy. Similar to the current case, the amino acid substitution at position 181 appeared concomitantly with the appearance of YMDD motif mutations.6 The results suggest that amino acid substitutions at 181 of the HBV polymerase gene may confer resistance to the licensed nucleoside and nucleotide antiviral analogues, lamivudine and adefovir, respectively. Furthermore, while the rtI233V mutation has been shown to cause primary adefovir resistance,4 there was no evidence of the mutation in this case. The emergence of the rtA181V mutation in a patient with no prior adefovir treatment confirms the need to test for the presence of adefovir resistance mutations in patients who develop lamivudine resistance.
This report showed that development of primary adefovir resistance can be associated with long-term lamivudine monotherapy. Furthermore, HBV polymerase gene sequencing should become part of the treatment monitoring algorithm to improve treatment efficacy. The amino acid substitution at position 181 may be important in conferring cross-resistance to anti-HBV drugs and therefore should be investigated further.
Dr Brendan Crowley has received a financial contibution in the form of a research grant from Gilead Sciences, Foster City, CA, USA.
References
1 Liaw YF, Leung NW, Chang TT, et al. (2000) Effects of extended lamivudine therapy in Asian patients with chronic hepatitis B. Hepatitis Lamivudine Study Group. Gastroenterology 119:172–80.[CrossRef][Web of Science][Medline]
2 Locarnini S, Qi X, Arterburn S, et al. (2005) Incidence and predictors of emergence of HBV mutations associated with ADV resistance during 4 years of adefovir therapy for patients with chronic HBV. J Hepatol 42:Suppl 2, A36.
3
Delaney WE IV, Yang H, Westland CE, et al. (2003) The hepatitis B virus polymerase mutation rtV173L is selected during lamivudine therapy and enhances viral replication in vitro. J Virol 77:11833–41.
4
Schildgen O, Sirma H, Funk A, et al. (2006) Variant of hepatitis B virus with primary resistance to adefovir. N Engl J Med 354:1807–12.
5 Aye TT, Bartholomeusz A, Shaw T, et al. (1997) Hepatitis B virus polymerase mutations during antiviral therapy in a patient following liver transplantation. J Hepatol 26:1148–53.[CrossRef][Web of Science][Medline]
6 Yeh CT, Chien RN, Chu CM, et al. (2000) Clearance of the original hepatitis B virus YMDD-motif mutants with emergence of distinct lamivudine-resistant mutants during prolonged lamivudine therapy. Hepatology 31:1318–26.[CrossRef][Web of Science][Medline]
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