Comparison of clinical outcome between patients continuing and discontinuing lamivudine therapy after biochemical breakthrough of YMDD mutants q Chien-Hung Chen 1 , Chuan-Mo Lee 1, * , Sheng-Nan Lu 1 , Jing-Houng Wang 1 , Hung-Da Tung 1 , Chao-Hung Hung 1 , Wei-Jen Chen 2 , Chi-Sin Changchien 1 1 Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, 123 Ta Pei Road, Kaohsiung, Taiwan 2 Department of Pathology, Kaohsiung Chang Gung Memorial Hospital, 123 Ta Pei Road, Kaohsiung, Taiwan Background/Aims: The aim of this study was to compare the clinical outcome between patients continuing and discontinuing lamivudine therapy after the biochemical breakthrough of hepatitis B virus tyrosine – methionine – aspartate – aspartate (YMDD) mutant. Methods: YMDD mutants were detected in 51 chronic hepatitis B patients who experienced a flare-up of alanine aminotransferase (ALT) during lamivudine treatment. Twenty-seven of them discontinued lamivudine therapy (group A), and 24 continued therapy (group B) after biochemical breakthrough. The follow-up period was 12 months in both the groups. Results: There was no significant difference between groups A and B in the incidence and severity of ALT peaks and hepatic decompensation within the first 3 months after biochemical breakthrough. After the fourth month of biochemical breakthrough, however, group A experienced acute exacerbation more frequently [20/26 (77%) vs. 7/23 (30%); P 5 0.002] and higher ALT peaks than group B. The same result was found when the patients were divided into naı ¨ve and retreated or cirrhotic and non-cirrhotic groups. Hepatic decompensation at the onset of biochemical breakthrough was associated with higher mortality (OR 5 70, 95% CI 5 6.06 – 807.75). Conclusions: Patients who discontinued lamivudine therapy increased the frequency of flare-ups and higher ALT peaks than those who continued therapy after 4 months post-breakthrough. q 2004 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. Keywords: Tyrosine – methionine – aspartate – aspartate mutation; Lamivudine; Hepatitis B virus; Acute exacerbation; Hepatic decompensation; Adefovir 1. 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 necroinflam- matory 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, [7–10]. Despite of having resistant to lamivudine, patients with YMDD mutants have signifi- cantly lower HBV DNA levels and ALT levels compared Journal of Hepatology 41 (2004) 454–461 www.elsevier.com/locate/jhep 0168-8278/$30.00 q 2004 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.jhep.2004.04.032 Received 19 January 2004; received in revised form 12 April 2004; accepted 29 April 2004; available online 28 May 2004 q 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. * Corresponding author. Tel.: þ 886-7-7317123; fax: þ 886-7-7318762. E-mail address: chmolee@ms15.hinet.net (C.M. Lee).