The Follow-up Study of Chronic Hepatitis B Patients With Liver Cirrhosis Receiving Anti-HBV Therapy
The Follow-up Study of Chronic Hepatitis B Patients With Liver Cirrhosis Receiving Anti-HBV Therapy
Hepatitis B virus (HBV) infection is a global health problem, especially in the endemic area
 like Taiwan, where there are more than 3 million chronic hepatitis B carriers. Patients with
 chronic HBV infection are at increased risk of developing cirrhosis, which may have
 disastrous complications, including hepatic decompensation, and hepatocellular carcinoma
 (HCC). The liver cirrhosis related complications accounts for the 8th leading cause of deaths
 in Taiwan; whereas, the HCC is the 2nd leading cause of deaths among all cancers. Therefore,
 it is prudent to develop strategies to prevent or halt the progression of liver cirrhosis.

 For HBV patients who have already had cirrhosis, the main treatment objective is to reduce
 their risk of complications. A large-scale multicenter clinical trial showed that viral
 suppression using lamivudine in patients with advanced fibrosis effectively decreases the
 risk of HCC and liver-related complications. This study highlights the importance to treat
 HBV-related cirrhosis patients; however, several issues remain to be addressed.

 The first issue is that this clinical trial only enrolled patients with positive HBeAg or
 HBV-DNA level >1.4 x105 IU/mL. However, the current recommended threshold for cirrhotic
 patients to start anti-viral treatment is 2000 IU/mL. Whether anti-HBV therapy benefits
 cirrhotic patients in this level is still unclear. Second, lamivudine was used in this
 clinical trial; however, the high resistant rate of lamivudine during treatment probably
 lowers its protective effect against HCC. Whether a more potent anti-HBV agent with extremely
 low resistance profile, entecavir, is more beneficial to HBV-related cirrhotic patients is
 also unclear.

 The Bureau of National Health Institute launched the reimbursement program for anti-HBV
 therapy since 2003 and extended this program to cirrhotic patients with HBV DNA level > 2000
 IU/mL for long-term use since Aug, 2010. Taking this advantage, we may explore the
 above-mentioned clinical questions more easily.

 To address these issues, we will first retrospectively collect a cohort of HBV-related
 cirrhosis patients. All the patients will be enrolled from the time before oral anti-HBV
 therapy is widely used. We will determine their baseline serum HBV-DNA levels using the
 stored sera and enrolled those with baseline HBV-DNA levels higher than 2000 IU/mL as our
 historical controls. Second, we will enroll a retrospective cohort of HBV-related cirrhotic
 patients from 2008 who had HBV-DNA levels higher than 2000 IU/mL and received indefinite
 therapy of entecavir. By comparing these two cohorts, we will be able to clarify whether
 indefinite viral suppression by entecavir is beneficial for the cirrhotic patients.

 With comprehensive analysis, we wish to document that re-setting the risk level of HBV DNA
 from 140,000 IU/mL to 2,000 IU/mL is more beneficial for HBV-related cirrhotic patients and
 long-term entecavir does lower the risk of HCC further. These lines of evidence will assist
 in delivering appropriate and more aggressive treatment for these high-risk patients.
Inclusion Criteria for treatment group:

 1. Age older than 20 years old.

 2. HBsAg (+) > 6 months

 3. Baseline serum HBV DNA ≧ 2000 IU/mL (10,000 copies/mL)

 4. Liver cirrhosis (Child A) before or at enrollment, diagnosed by 1). Liver
 biopsy（Metavir F4 or Ishak > F5） or 2). Ultrasonographic evidence of cirrhosis with
 signs of portal hypertension (splenomegaly or presence of esophageal or gastric
 varices)

 5. Receiving long-term anti-HBV therapy

 Inclusion Criteria for control group:

 1. Age older than 20 years old.

 2. HBsAg (+) > 6 months

 3. Baseline serum HBV DNA ≧ 2000 IU/mL (10,000 copies/mL)

 4. Liver cirrhosis (Child A) before or at enrollment, diagnosed by 1). Liver
 biopsy（Metavir F4 or Ishak > F5） or 2). Ultrasonographic evidence of cirrhosis with
 signs of portal hypertension (splenomegaly or presence of esophageal or gastric
 varices)

 5. without receiving treatment

 Exclusion Criteria:

 1. . Co-infection of HCV (anti-HCV (+)) or HIV

 2. . Alcoholism (alcohol consumption > 20 gm/day)

 3. . Serological evidence suggestive of autoimmune hepatitis, primary biliary cirrhosis,
 Wilson's disease and hemochromatosis

 4. . Liver decompensation (Child-Pugh classification of B or C)

 5. . Evidence of HCC at study entry

 6. . Pregnant women