COMPARISON OF ENTECAVIR AND TELBIVUDINE IN MANAGEMENT OF CHRONIC HEPATITIS B Shivaram Prasad Singh Department of Gastroenterology, S.C.B. Medical College, Cuttack – 753 007, India Correspondence: Dr. S. P. Singh, Department of Gastroenterology, S.C.B. Medical College, Cuttack - 753 007, India. E-mail: [email protected]

ABSTRACT The currently available options for the treatment of chronic hepatitis B virus (HBV) infection include standard and pegylated interferon alfa and four oral antiviral agents (lamivudine, adefovir, entecavir, and telbivudine). These treatment strategies are either therapies of Þnite duration which aim to achieve sustained offtherapy responses or long term treatments that aim to maintain on-therapy remission. Most agents designed to target hepatitis B are hindered by the development of resistance, poor tolerability or limited efÞcacy; therefore, new agents and treatment strategies are needed. Pegylated interferon alfa may offer higher sustained off-therapy responses after one year, but most patients do not respond. Oral antivirals are the only candidates for long term treatment of patients with chronic HBV infection. Viral suppression has favorable effects on outcome outcome and modiÞes the natural history of the disease. The oral nucleos(t)ide analogues are generally better tolerated than interferon. This article attempts to provide an overview of the data available on the two new drugs entecavir and telbivudine. Keywords: Chronic hepatitis B, drug resistance, entecavir, epidemiology, HBeAg, HBV DNA, hepatitis B virus, lamivudine, nucleoside analogue, seroconversion, telbivudine. 134

INTRODUCTION Chronic hepatitis B (CHB) is caused by persistent infection with hepatitis B virus (HBV). Chronic infection with HBV accounts for an enormous burden of disease worldwide, including up to half of all cases of cirrhosis, end-stage liver disease, and hepatocellular carcinoma.1 India belongs to the group of intermediate endemicity countries, with nearly three to four per cent of the population infected by the virus; besides, chronic hepatitis B constitutes more than 50% of the chronic hepatitis cases in the country.2 With the development of newer antiviral drugs, hepatitis B infection is now being considered a treatable disease and the use of nucleot(s) ide analogues is a milestone in the treatment of CHB. The FDA of the USA approved the use of lamivudine in adult patients in 1998, adefovir dipivoxil in 2002, and entecavir in March 2005;3 most recently, telbivudine. The efÞcacy of lamivudine, the Þrst nucleoside analogue used, is limited by the high rate of resistance. Adefovir has efÞcacy comparable to that of lamivudine but with low resistance rate. Entecavir has been particularly active in the control of hepatitis B virus replication and is associated with minimal resistance development, even during long treatment regimens.4 Telbivudine has demonstrated potent activity against HBV in phase III clinical studies, with good tolerance, lack of mitochondrial toxicity and no dose-limiting side effects.5 Telbivudine has not been compared directly with entecavir. However, in separate trials, both telbivudine and entecavir have shown greater antiviral effects than have adefovir and lamivudine.6 In this review we will look at the efÞcacy and safety of the two nucleot(s)ide analogues, entecavir and telbivudine. ENTECAVIR Entecavir, a new guanosine nucleoside analogue with speciÞc activity against HBV DNA polymerase, is the third agent in the nucleoside/nucleotide HBV polymerase inhibitor class. It has distinct advantages over lamivudine and adefovir dipivoxil: it has a three-step mechanism of action, is the most potent inhibitor of HBV DNA polymerase, is not associated with any major adverse effects and has a limited potential for resistance.7 Preclinical studies in Woodchucks demonstrated the antiviral activity of entecavir and its potential to reduce the incidence of hepatocellular carcinoma

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(HCC) and improve survival.8 In a randomized phase 2 trial in HBeAg-positive and HBeAgnegative patients who had not previously received a nucleoside analogue, entecavir at a dose of 0.5 mg once, daily, resulted in a signiÞcantly greater mean reduction in HBV DNA at 22 weeks than did lamivudine at a dose of 100 mg once daily (4.72 vs. 3.36 log copies per milliliter, P less than 0.001).9 In patients treated with entecavir 0.5 mg/day, 83.7% had an HBV-DNA level below the lower limit of detection of the Quantiplex branched DNA (bDNA) assay, compared with 57.5% treated with 100 mg/day lamivudine (P = 0.008).9 A randomized, dose-ranging, phase 2 study compared the efÞcacy and safety of entecavir with lamivudine in lamivudinerefractory patients. In HBeAg-positive and HBeAg-negative lamivudine-refractory patients, treatment with entecavir was well tolerated and resulted in signiÞcant reductions in HBV DNA levels and normalization of alanine aminotransferase levels.10 Entecavir has been compared to lamivudine in both HBeAg-positive and HBeAg-negative patients.11,12 HBEAG- POSITIVE PATIENTS In a double-blind, randomized phase 3 study of HBeAgpositive patients who had not previously received a nucleoside analogue, entecavir resulted in signiÞcantly higher rates of histologic, virologic, and biochemical improvement than did lamivudine, with a similar safety proÞle [Table 1].11 Histologic improvement after 48 weeks occurred in 226 of 314 patients in the entecavir group (72%) and 195 of 314 patients in the lamivudine group (62%, P is equal to 0.009). More patients in the entecavir group than in the lamivudine group had undetectable serum HBV DNA levels according to a polymerase-chain-reaction assay (67% vs. 36%, P less than 0.001) and normalization of alanine aminotransferase levels (68% vs. 60%, P is equal to 0.02). The mean reduction in serum HBV DNA from baseline to week 48 was greater with entecavir than with lamivudine (6.9 vs. 5.4 log [on a base-10 scale] copies per milliliter, P less than 0.001). HBeAg seroconversion occurred in 21% of entecavir-treated patients and 18% of those treated with lamivudine (P is equal to 0.33). No viral resistance

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Table 1: Virologic, biochemical and serologic endpoints at week 48 with entecavir vs. Lamivudine in HBeAg positive patients Endpoint

Entecavir Lamivudine P value (n=354) (n=355)

HBV DNA