Recent Patents on Anti-Infective Drug Discovery, 2006, 1, 85-94 85 1574-891X/06 $100.00+.00 © 2006 Bentham Science Publishers Ltd. Pegylated Interferons for the Treatment of Chronic Hepatitis B Chun-Jen Liu 1 and Jia-Horng Kao* ,1,2,3,4 1 Division of Gastroenterology, Department of Internal Medicine, 2 Graduate Institute of Clinical Medicine, 3 Hepatitis Research Center, and 4 Department of Medical Research, National Taiwan University Hospital and National Taiwan, University College of Medicine, Taipei, Taiwan Received: July 27, 2005; Accepted: August 17, 2005; Revised: August 30, 2005 Abstract: Five drugs are approved for the treatment of chronic hepatitis B: conventional interferon (IFN) alfa, lamivudine, adefovir dipivoxil, pegylated interferon (peginterferon) alfa-2a and entecavir. Conventional IFN monotherapy has a narrow range of efficacy, should be administered subcutaneously and is commonly associated with adverse effects. Lamivudine is cheaper and well tolerated, but the virological response may not be durable and prolonged lamivudine treatment is commonly associated with the emergence of drug-resistant mutants. Adefovir dipivoxil is potent but with nephrotoxicity at higher doses. Entecavir is active against both lamivudine- and adefovir dipivoxil-naïve and -resistant HBV, however, its long-term efficacy remains to be evaluated. Peginterferon alfa-2a has recently been shown to be superior to conventional IFN and lamivudine in the treatment of both HBeAg-positive and -negative chronic hepatitis B. By using peginterferon alfa-2a monotherapy, the overall virological and serological responses are around 30%-44%. However, peginterferon alfa-2a in combination with lamivudine does not improve the results at the end of follow-up. Adverse effects are usually tolerable and comparable with conventional IFN. Similar efficacy of peginterferon alfa-2b has also been demonstrated in HBeAg-positive chronic hepatitis B. These observations suggest an important and even a primary role of peginterferon alfa in the treatment of chronic HBV infection. Keywords: Chronic hepatitis, hepatitis B virus, treatment, pegylated interferon, interferon, lamivudine, adefovir, entecavir, genotype. INTRODUCTION Hepatitis B virus (HBV) infection causes a wide spect- rum of liver diseases, such as fulminant or acute hepatitis, chronic hepatitis, liver cirrhosis, and hepatocellular car- cinoma [1,2]. The number of individuals infected with this virus has been estimated to be as high as 350 millions and the annual mortality associated with persistent HBV infection is about 1.2 million worldwide [3]. Due to this problem, in addition to implement universal vaccination against primary HBV infection, effective treatment of chronic hepatitis B to prevent progression into end-stage liver diseases and hepatocellular carcinoma (HCC) is also needed. Currently, there are no effective antiviral agents to eradicate HBV in patients with chronic hepatitis B [4-6]. The short-term treatment goals are thus to permanently suppress HBV replication, reduce hepatitis activity, obtain hepatitis B e antigen (HBeAg) seroconversion, and improve fibrosis of the liver. Nowadays, 5 drugs have been approved for the treatment of chronic hepatitis B: conventional IFN (IFN) alfa, lamivudine (2',3'-dideoxy-3'-thiacytidine), adefovir dipivoxil (9-[2-(phosphonomethoxy)ethyl]adenine in the form of bis(pivaloyloxymethyl)ester), pegylated IFN (peginterferon) alfa-2a and recently entecavir (ETV; BMS- 200475) [4-21]. The IFN was first used to treat patients with chronic HBV infection more than 2 decades ago. IFN alfa *Address correspondence to this author at the Director, Hepatitis Research Center, National Taiwan University Hospital, 1 Chang-Te St., Taipei 100, Taiwan; Tel: 886-2-23123456; Ext: 7307; Fax: 886-2-23825962; E-mail: kjh@ha.mc.ntu.edu.tw was approved in the United States in 1992. Conventional IFN alfa monotherapy has a narrow range of efficacy [13- 15]. Because of the side effects associated with interferon and the inconvenience of frequent subcutaneous injections, lamivudine soon became a popular drug around the world. Lamivudine, approved in the United States in 1998, is cheaper, better tolerated, and has been shown to be effective in patients with both HBeAg-positive and -negative chronic hepatitis B [4-6]. However, virological response to lamivudine is not as durable as that occurred spontaneously or induced by IFN treatment. In addition, prolonged lamivudine treatment is commonly associated with the emergence of lamivudine-resistant tyrosine-methionine- aspartate-aspartate (YMDD) HBV mutants accompanied by the development of breakthrough hepatitis. Adefovir dipivoxil is potent and has been approved for the treatment of chronic hepatitis B in many countries, but is nephrotoxic at doses higher than 10 mg per day [7,9]. Entecavir, a carbocyclic deoxyguanosine analog, which is active against both lamivudine- and adefovir dipivoxil-naïve and resistant HBV, is the most potent anti-HBV agent ever discovered [22,23], however, its long-term efficacy remains to be evaluated. Peginterferon alfa-2a has recently been shown to be superior to both conventional IFN alfa and lamivudine [10,16,17]. Overall, satisfactory sustained serologic response (HBeAg seroconversion) and virological response could be achieved in around 32% and 32%-36%, respectively, of HBeAg-positive patients at 6 months after the end of peginterferon alfa-2a monotherapy [16,17]. Likewise, satisfactory sustained virological response was achieved using peginterferon alfa-2a alone in around 43% of HBeAg- negative patients [10], however, peginterferon alfa-2a in