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 Table of Contents    
Year : 2009  |  Volume : 6  |  Issue : 1  |  Page : 116-130
Management of HBV-related cirrhosis: Role of nucleoside analogs

Department of Gastroenterology, Stanley Medical College Hospital, Chennai, India

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Date of Web Publication19-Feb-2011


In the management of HBV related cirrhosis of the liver, viral suppression with safe and effective antiviral agents is essential. Besides, antiviral therapy for long term use in cirrhotics should be safe and affordable with low risk of drug resistance. Treatment of compensated HBV cirrhosis can diminish the risk of hepatic decompensation and progression to hepatocellular carcinoma [HCC]. Regression of fibrosis and reversal of cirrhosis have also been reported with antiviral therapy. Further, in decompensated cirrhosis, although liver transplantation is considered as the definitive therapy, inhibition of viral replication before transplantation can delay the need for liver transplant and also prevent HBV recurrence in the post-transplantation period. These patients while on antiviral therapy need close monitoring for viral resistance and adverse events, besides continued surveillance for HCC. This article reviews the literature on the role of nucleoside analogues in the management of HBV related chronic liver disease.

Keywords: Cirrhosis, HBV, Hepatitis B virus, hepatocellular carcinoma, nucleoside and nucleotide analogues

How to cite this article:
Mohan P, Jayanthi V. Management of HBV-related cirrhosis: Role of nucleoside analogs. Hep B Annual 2009;6:116-30

How to cite this URL:
Mohan P, Jayanthi V. Management of HBV-related cirrhosis: Role of nucleoside analogs. Hep B Annual [serial online] 2009 [cited 2024 Feb 21];6:116-30. Available from: https://www.hepatitisbannual.org/text.asp?2009/6/1/116/76909

   Introduction Top

Individuals infected with hepatitis B virus (HBV) infection are at an increased risk of developing chronic hepatitis, liver cirrhosis, hepatic decompensation, and hepatocellular carcinoma (HCC). [1] World over, approximately, 350 million people are infected with HBV and the number of deaths due to HBV infection is approximately 1 million per year. [2]

The introduction of oral nucleoside/tide antiviral agents has revolutionized the management of HBV-related cirrhosis. Today, it is the recommended treatment for HBV-related chronic liver disease. These drugs through an effective inhibition of viral replication, can suppress spontaneous clinical and subclinical flares of activity. The drugs are capable of stabilizing the liver function and can also improve survival by preventing hepatic decompensation and progression to HCC. [3],[4] Although interferon is recommended for compensated cirrhosis, it is relatively contraindicated in decompensated cirrhosis; severe sepsis may set in with worsening of liver failure. [5],[6]

   Natural History Top

A majority of patients with acute hepatitis B infection clear the virus spontaneously, whereas 10% can progress to chronic hepatitis. Chronic infection also occurs with perinatal transmission. [7],[8],9[],[10],[11] Low baseline HBV replication is associated with slow progression of chronic hepatitis to advanced fibrosis, clinically significant chronic liver disease, or HCC and manifests in the fourth or fifth decade of life. [12],[13] The annual incidence of progression of chronic HBV infection to cirrhosis is 2.1% and cirrhosis to HCC is 3%-6%. [14],[15],[16] HBV carriers have a 100-fold relative risk of developing HCC. [1]

Diagnosis is often missed in the slow progressive groups of patients as the majority is asymptomatic. Rapid progression to decompensation and HCC occurs in 20% of patients over a period of 5 years, especially when the patient is older, with persistent elevations of alanine aminotransferase (ALT) levels, [17] the individual is HBeAg positive and has elevated HBV DNA levels. [7],[8],[9],[10],[18],[19],[20]

Host, viral, and environmental factors associated with progression of HBV-related liver disease

Host factors predisposing to progression of HBV-related liver disease includes the following: age of acquisition of HBV infection, older age, concomitant alcohol consumption, smoking, [21] and advanced fibrosis on biopsy. Viral factors include active viral replication, genotype, co-infection with HCV, HDV, or HIV virus and the mutant variants. 13,[22],[23],[24],[25] HBV genotype C individuals in Asian countries often have more active liver disease, with a delayed HBeAg seroconversion, and a rapid progression to cirrhosis. [26],[27] These patients also have higher prevalence of basal core promoter mutants, which is associated with higher HBV viral load and increased rates of HCC. [28],[29],[30]

Aflatoxin has been reported as an environmental factor to be associated with an increased risk of cirrhosis or HCC. [31],[32]

   Perinatal Transmission, Chronic Hepatitis, and HCC Top

In 30%-50% of HCC associated with HBV, HCC occurs in a background of a normal liver or chronic hepatitis. [33] This often follows perinatal acquired infection.

Rationale for antiviral therapy in hepatitis B virus compensated and decompensated cirrhosis

In compensated cirrhosis, the goal of treatment is to prevent decompensation, reverse cirrhosis, and progression to HCC. With the use of nucleoside/tide analogs, one may succeed in achieving a sustained reduction in circulating HBV DNA and clearance of HBeAg with reduction in necro-inflammatory activity on liver biopsy. This can result in significant improvement in the clinical outcome and survival of the patient. [34],[35],[36]

In decompensated cirrhosis, patients would ultimately be listed for a liver transplant. The aim of treatment in these patients will be to maintain/improve the liver function, prevent progression to HCC, and finally to lower the HBV recurrence rates in posttransplant period. Low or undetectable levels of HBV DNA in pretransplant period are associated with a higher survival rate than those with high levels of viral replication.

   Treatment Recommendations Top

Interferon in compensated cirrhosis

Treatment is recommended for compensated cirrhosis irrespective of HBV DNA and ALT levels. A normal ALT level or low HBV DNA levels below 2000 IU/mL does not preclude the institution of drug therapy in these patients.

Interferon in HBeAg-positive compensated chronic liver disease

Interferon-α is considered safe in HBV-related liver disease, including those who are HBeAg positive with compensated cirrhosis. The response to treatment in cirrhosis is similar to those without cirrhosis. Less than 1% develop hepatic decompensaton. [35],[37],[38] Approximately, a third of the patients with HBeAg seroconversion with sustained loss of HBV DNA show reduction of necro-inflammatory activity and fibrosis. [37],[38],[39] Long-term follow-up of IFN-treated cirrhotic patients has shown a significantly reduced incidence of HCC. [18],[40]

Interferon in HBeAg-negative compensated chronic liver disease

The virologic and histologic response to IFN-α is suboptimal. [41],[42],[43] High rates of relapse after discontinuation of treatment has been reported. The reported overall sustained response is 20%-25%.

There are fewer studies on the role of PEG-IFN in the treatment of HBV-related cirrhosis. Buster et al[44] have shown PEG-IFN-α 2b to be safe and effective in patients with advanced fibrosis or cirrhosis.

Compared with interferon, which at times requires a 12- or 24-month therapy, orally administered antiviral drugs, such as lamivudine and adefovir dipivoxil are easier to administer with fewer adverse effects in HBeAg-negative patients.

   Role of Nucleoside Analogs Irrespective of HBeAg Status Top

Compensated cirrhosis

Long-term treatment with lamivudine can prevent disease progression and complications of compensated HBV infection but the benefit on survival is unclear. [45] A major drawback with lamuvidine is the development of resistance at the end of 1 year. This has been overcome by introducing a combination of lamuvidine and adefovir dipivoxil. Adding adefovir to lamuvidine [46],[47],[48] is a better option than switching over to adefovir, which has been associated with a higher risk of adefovir resistance. Long-term use of adefovir toward viral suppression may be effective in reversing fibrosis and even cirrhosis. [49],[50],[51] Nephrotoxicity is a major concern with adefovir when used for a long term.

Decompensated cirrhosis

Patients with decompensated cirrhosis are difficult to treat and carry a poor prognosis. Antiviral therapy is mandatory. [19],[52] Most patients with decompensation are candidates for liver transplantation and the primary aim is to prevent reactivation following transplantation. Treatment is indicated even in patients with low HBV DNA levels. Ideally, the treatment should be initiated early when a significant clinical response can be predicted with control of viral replication. Reversal of early cirrhosis is also possible at this stage. The drugs are not as effective in advanced cirrhosis.

In mild decompensation, low doses of interferon with careful titration can result in the loss of HBV DNA and normalization of serum aminotransferase levels. Clinical improvement and recovery in liver function is noticeable in these cases. [5],[6],[53],[54] Acute flares of hepatitis in 50%-86% in Childs B or C cirrhosis prohibits the use of interferon in decompensated state. Spontaneous bacterial peritonitis, septicemia, and worsening of liver cell failure, are other drawbacks with interferon. [5],[6],[53],[55],[56]

As in compensated state, lamivudine, is well tolerated and is safe in HBeAg-positive and -negative patients with decompensated cirrhosis. [16],[57],[58] The drug suppresses HBV replication, normalizes ALT levels and reduces hepatic necro-inflammation and fibrosis. Reversal of cirrhosis has also been noted when the drug is introduced early in the course of illness. [59],[60] The results of clinical improvement or stabilization with lamuvidine is seen at the end of 6 months treatment. [61],[62] Overall, there is reduction in the rate of hepatic decompensation and progression to HCC. [3],[4],[62],[63],[64],[65],[66],[67] Posttransplant recurrence of HBV is also low. A major concern with lamuvidine apart from lamuvidine resistance is the hepatitis flares in cirrhosis, associated with breakthrough infection. The latter can worsen liver failure and even result in death. [58] The risk of HBV recurrence in posttransplant is likely to increase if pretransplant HBV DNA levels are high. [68],[69]

Adefovir is recommended in lamuvidine-resistant individuals as an add-on therapy to reduce the risk of flares and development of resistance to adefovir. [70],[71],[72] The combination has been associated with a 3-4 log reduction in serum HBV DNA levels during the course of treatment. [70] Schiff and colleagues reported a marked inhibition of viral replication, HBeAg loss in 48%, and HBeAg seroconversion in 23% of lamuvidine-resistant patients. [73] Blood urea and serum creatinine levels need to be closely monitored when on adefovir.

Results of the studies on the safety and efficacy of Entecavir in patients with decompensated cirrhosis are awaited. Tenofovir has been tried in decompensated cirrhosis is a few case reports. Significant clinical improvement has been reported in lamivudine- and adefovir-resistant cases. [74],[75] The role of telbivudine in decompensated cirrhosis is not clear.

The 3 drugs, Entecavir, telbivudine, and tenofovir have similar mechanisms of action with near identical safety profile. They are likely to be more effective and potent or at least as effective as lamivudine with lower or nearly no drug resistance and nephrotoxicity.

   Conclusion Top

Viral suppression with safe and effective antiviral agents is the cornerstone in the management of HBV cirrhosis. The ideal antiviral therapy for long-term use in HBV cirrhosis should be safe and affordable for long-term use and with a low risk of drug resistance. The treatment of compensated HBV cirrhosis can reduce the risk of hepatic decompensation and development of HCC. Regression of fibrosis and reversal of cirrhosis has been reported.

In patients with compensated cirrhosis and normal liver synthetic function, the outcome of antiviral therapy is similar in patients with and without cirrhosis. In decompensated cirrhosis, liver transplantation is considered as the definitive therapy. Inhibition of viral replication before transplantation can delay the need for liver transplant and also prevent HBV recurrence in the posttransplantation period.

Importantly, despite the use of an ideal antiviral agent in cirrhosis liver with close monitoring for viral resistance and adverse events, medical management of cirrhosis with continued surveillance for HCC is the most important aspect of management of patients with liver cirrhosis.

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Correspondence Address:
V Jayanthi
Department of Gastroenterology, Stanley Medical College Hospital, Chennai
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0972-9747.76909

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