Description of the condition
Chronic hepatitis B virus (HBV) infection is a serious health problem because of its worldwide distribution and its potential adverse sequelae, including cirrhosis, hepatocellular carcinoma, and death (Lavanchy 2004). It is estimated that each year, worldwide, more than 200,000 people, chronic carriers of HBV, die of liver cirrhosis, and more than 300,000 people, chronic carriers of HBV, die of hepatocellular carcinoma (Perz 2006). Since HBV replication, defined as the presence of hepatitis B e antigen (HBeAg) or HBV deoxyribonucleic acid (DNA) more than 2000 international units (IU)/mL in the blood, or both, may persist after the development of cirrhosis, liver disease may continue to progress, and hepatic decompensation or hepatocellular carcinoma may occur (Chen 2007). Hepatic decompensation usually presents with at least one episode of ascites, jaundice, hepatic encephalopathy, or variceal bleeding (De Jongh 1992).
An estimated 15% to 40% of untreated patients with chronic HBV infection may develop cirrhosis, liver failure, hepatocellular carcinoma, or a combination of these (Lavanchy 2004). The aim of anti-viral therapy in these patients is to prevent the development of cirrhosis and its associated complications, in an effort to improve patient survival and quality of life (Belongia 2008). However, patients with decompensated HBV cirrhosis at initial presentation have a poor short-term prognosis with an estimated five-year survival of only 14% (De Jongh 1992). Although liver transplantation is an effective treatment option for decompensated HBV cirrhosis, the ongoing shortage of donor organs and limited availability of this resource worldwide precludes the majority of HBV patients in endemic areas from undergoing transplantation (Liaw 2008).
Seven drugs are currently approved for the management of chronic HBV infection: standard interferon, lamivudine, adefovir, entecavir, pegylated interferon-alpha (peginterferon-alpha), telbivudine, and tenofovir (Lok 2009). Interferons enhance host immunity against HBV-infected hepatocytes but have a number of dose-dependent adverse effects including neuropsychiatric toxicity and myelotoxicity, which preclude their safe use in patients with advanced HBV (Lok 2009). Interferon was not only poorly tolerated in patients with decompensated HBV cirrhosis but also associated with disease flares and worsening liver disease status (Perrillo 1995). In contrast, oral anti-viral agents have a generally favourable adverse effect profile and are well tolerated in patients with compensated as well as decompensated HBV (Liaw 2004). In addition, these agents can directly and rapidly inhibit HBV replication and lead to improvement in hepatic necro-inflammation, serum alanine aminotransferase levels, and global liver function even in patients with advanced disease (Liaw 2004). All of these antivirals are competitive inhibitors of the HBV DNA polymerase via competition with the incorporation of the natural endogenous intracellular nucleotides in nascent HBV DNA and cause DNA chain termination. Furthermore, all of these nucleoside analogues have activities conferring biochemical, virological, and serological improvement in patients with chronic hepatitis B (Lok 2009; EASL 2012; Liaw 2012). Nucleoside analogues can also retard the progression of fibrosis and reverse fibrosis and cirrhosis (Dienstag 2003; Hadziyannis 2006; Chang 2010). Long-term therapy may also prevent hepatic decompensation in patients with advanced fibrosis and cirrhosis (Liaw 2004). The generally favourable adverse effect profiles of lamivudine, adefovir, entecavir, telbivudine, and tenofovir, coupled with the low rates of anti-viral drug resistance with newer agents such as entecavir, which had the lowest rate of drug resistance in treatment-naive patients with HBeAg-positive chronic hepatitis B, make them attractive for use beyond one year. However, infrequent but serious adverse events such as myopathy, neuropathy, and pancreatitis as well as reversible renal impairment have been reported during post-marketing surveillance (Keeffe 2006; Lok 2007).
The Child-Turcotte-Pugh (CTP) score and model for end-stage liver disease (MELD) score are the two liver-specific scoring systems that have been used to assess disease severity in patients with cirrhosis. The CTP score was originally developed to predict post-operative mortality in bleeding patients with alcoholic liver cirrhosis undergoing portal-systemic shunt surgery (Pugh 1973). Although it predicts one-year survival and post-surgical risks of complications, it does not predict short-term mortality (Schuppan 2008). The MELD score was initially developed to predict short-term mortality in patients undergoing transjugular intrahepatic portosystemic shunting (Malinchoc 2000). It was later used to predict three-month mortality in patients with cirrhosis, irrespective of cause, and has been adopted to prioritise organ allocation for liver transplantation in the United States since 2002 (Kamath 2001; Wiesner 2003). A major feature of the MELD scoring system is the inclusion of renal function in the model. Renal dysfunction commonly occurs during the course of disease progression in cirrhosis and has been shown to have a detrimental prognostic impact on survival (Fernandez 2001).
Description of the intervention
Oral antiviral agents for treatment of HBV, such as lamivudine, adefovir, entecavir, telbivudine, and tenofovir, are chemically modified analogues of naturally occurring nucleosides or nucleotides that pharmacologically inhibit the polymerase activity of HBV, leading to reduced viral replication and decreases in serum HBV DNA levels.
How the intervention might work
Antiviral agents could improve a patient's quality of life and decrease the progression to liver cirrhosis and chances of developing hepatocellular carcinoma as well as the risk of death.
Why it is important to do this review
Although antiviral agents seem to be beneficial for patients with HBV-related cirrhosis, these drugs have a warning because of their potential for inhibition of human DNA polymerase gamma involved in mitochondrial DNA replication. A reduction in intracellular mitochondrial DNA levels can lead to varying clinical manifestations of mitochondrial toxicity in long-term treatment. So, there is no clear safety profile of the nucleoside analogues when given alone or in combination for prolonged periods of time. This review aims to provide evidence of the beneficial and harmful effects of treatment with antiviral agents in patients with HBV-related liver cirrhosis.
There are currently two Cochrane systematic review protocols that concentrate on chronic hepatitis B. Whitfield 2010 is evaluating the beneficial and harmful effects of levamisole for patients with chronic hepatitis B while Zhao 2010 is evaluating the effects of telbivudine for chronic hepatitis B.
To date, no systematic review has been conducted on the benefits and harms of antiviral agents for liver cirrhosis related to hepatitis B and their effect on progression of cirrhosis and developing of hepatocellular carcinoma.