HEPATOLOGY Lamivudine/pegylated interferon alfa-2b sequential combination therapy compared with lamivudine monotherapy in HBeAg-negative chronic hepatitis B Themistoklis Vassiliadis,* Konstantinos Tziomalos,* Kalliopi Patsiaoura, † Thomas Zagris,* Olga Giouleme,* Konstantinos Soufleris,* Nikolaos Grammatikos,* Konstantinos Theodoropoulos,* Alexandros Mpoumponaris,* Konstantina Dona,* Petros Zezos,* Nikolaos Nikolaidis, 1 * Eleni Orfanou-Koumerkeridou, ‡ Aikaterini Balaska* and Nikolaos Eugenidis* *2nd Propaedeutic Department of Internal Medicine and ‡ 4th Department of Internal Medicine, Aristotle University of Thessaloniki, Hippokration Hospital and † Department of Pathology, Hippokration Hospital, Thessaloniki, Greece Abstract Background and Aim: Monotherapy has been proven insufficient in achieving sustained control of chronic hepatitis B. We aimed to assess the efficacy of combined sequential administration of lamivudine and pegylated interferon alfa-2b in patients with hepatitis Be antigen (HBeAg)-negative chronic hepatitis B. Methods: Eighteen patients were given sequential combination treatment starting with 3 months of lamivudine monotherapy followed by 9 months of pegylated interferon alfa-2b (after a 3-month period of concomitant administration of the two drugs) and 24 patients received lamivudine monotherapy. Results: At the end of treatment, 88.9% of the patients who received sequential combi- nation treatment and 70.8% of those who received lamivudine monotherapy had hepatitis B virus (HBV) DNA levels below 400 copies/mL (P = not significant). At the end of treatment, 72.2% of the patients who received sequential combination treatment and 70.8% of those who received lamivudine monotherapy achieved alanine aminotransferase normal- ization (P = not significant). After 12 months of follow up, 33.3% of the patients who received sequential combination treatment and 16.7% of those who received lamivudine monotherapy had HBV-DNA levels below 400 copies/mL (P = 0.4). After 12 months of follow up, 72.2% of the patients who received sequential combination treatment and 25.0% of those who received lamivudine monotherapy had normal alanine aminotransferase levels (P < 0.01). Twenty-five percent of the patients in the lamivudine monotherapy group had virological breakthrough compared to none in the sequential combination treatment group (P = 0.06). Conclusions: Sequential combination treatment is able to improve sustained biochemical response rates and prevent the emergence of lamivudine-resistant mutants in patients with HBeAg-negative chronic hepatitis B. Key words combination treatment, HBeAg-negative chronic hepatitis B, lamivudine, lamivudine resistance, pegylated interferon alfa-2b, sequential treatment. Accepted for publication 22 May 2007. Correspondence Dr Konstantinos Tziomalos, 63, Solonos Street, Thessaloniki 54248, Greece. Email: ktziomalos@yahoo.com 1 Deceased. Introduction Chronic infection with hepatitis B virus (HBV) is a major global health problem, affecting more than 400 million people world- wide. 1 Approximately 15–40% of infected patients will develop cirrhosis, liver failure, or hepatocellular carcinoma. 2 HBV infec- tion accounts for 500 000–1.2 million deaths each year and is the 10th leading cause of death worldwide. 3,4 Hepatitis Be antigen (HBeAg)-negative/anti-HBe-positive chronic hepatitis B (CHB) appears to be the most common form of CHB in Southern Europe and Asia, where 30–80% of patients are HBeAg negative, whereas in Northern Europe and the USA 10–40% lack HBeAg. 5,6 Most patients with HBeAg-negative CHB harbor variants of HBV that contain mutations in the precore or core promoter regions of the HBV genome that abolish or downregulate the production of HBeAg. 5,6 HBeAg-negative CHB runs a discontinuous but relent- less course, punctuated by intermittent flares of viremia and cytolysis and has a poor prognosis. 5,7,8 Monotherapy with a single antiviral agent has been proven insufficient in achieving sustained control of CHB in the majority of patients. With conventional interferon (IFN) monotherapy, end- of-treatment response is achieved in approximately 50–70% of doi:10.1111/j.1440-1746.2007.05103.x 1582 Journal of Gastroenterology and Hepatology 22 (2007) 1582–1588 © 2007 The Authors Journal compilation © 2007 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd