***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: BACKGROUND Long-term effects of lamivudine treatment on chronic hepatitis B patients without advanced disease remain unknown . Our aim was to investigate the effects of long-term lamivudine treatment and lamivudine-resistant virus ( YMDD ) on the development of cirrhosis and hepatocellular carcinoma ( HCC ) in asymptomatic patients without advanced disease . METHODS One hundred and forty-two hepatitis B e antigen (HBeAg)-positive patients ( median age : 33.9 years ) on long-term lamivudine ( median treatment duration : 89.9 months ) and 124 HBeAg-positive controls ( median age : 33.4 years ) were prospect ively followed up . Patients were monitored for the development of cirrhosis and HCC , liver biochemistry , hepatitis B virus ( HBV ) DNA levels , HBeAg seroconversion and hepatitis flares . YMDD mutations ( YMDD-MT ) were determined annually . RESULTS Lamivudine-treated patients had a significantly lower cumulative rate of development of cirrhosis and /or HCC compared with controls ( P = 0.005 ) . YMDD-MT occurred in 76.3 % of patients after 8 years of lamivudine treatment . When compared with controls and patients with YMDD-MT , patients without YMDD-MT had the greatest reduction of HBV DNA and bilirubin levels , slowest decline of albumin level , highest rate of HBeAg seroconversion and lowest risk of hepatitis flare . Patients with YMDD-MT still had a lower risk for developing cirrhosis and /or HCC ( P = 0.024 ) and a greater HBV DNA reduction ( P = 0.001 ) in comparison with controls . Patients with YMDD-MT and controls had a similar chance of hepatitis flares and hepatic decompensation . CONCLUSIONS Long-term lamivudine treatment was associated with a reduced chance of developing cirrhosis and HCC in patients without advanced disease . Although YMDD-MT reduced the benefits from lamivudine therapy , the outcome of these patients was still better than untreated patients BACKGROUND The effectiveness of antiviral therapy in preventing disease progression in patients with chronic hepatitis B and advanced fibrosis or cirrhosis is unknown . METHODS Patients with chronic hepatitis B who had histologically confirmed cirrhosis or advanced fibrosis were r and omly assigned in a 2:1 ratio to receive lamivudine ( 100 mg per day ) or placebo for a maximum of five years . Of 651 patients , 436 were assigned to receive lamivudine and 215 to receive placebo .  The primary end point was time to disease progression , defined by hepatic decompensation , hepatocellular carcinoma , spontaneous bacterial peritonitis , bleeding gastroesophageal varices , or death related to liver disease . An independent data and safety monitoring board monitored the progress of the study and performed interim analyses of the data . RESULTS We r and omly assigned 651 patients ( 98 percent Asian and 85 percent male ) to receive lamivudine or placebo . The study was terminated after a median duration of treatment of 32.4 months ( range , 0 to 42 ) owing to a significant difference between treatment groups in the number of end points reached . End points were reached by 7.8 percent of the patients receiving lamivudine and 17.7 percent of those receiving placebo ( hazard ratio for disease progression , 0.45 ; P=0.001 ) . The Child-Pugh score increased in 3.4 percent of the patients receiving lamivudine and 8.8 percent of those receiving placebo ( hazard ratio , 0.45 ; P=0.02 ) , whereas hepatocellular carcinoma occurred in 3.9 percent of those in the lamivudine group and 7.4 percent of those in the placebo group ( hazard ratio , 0.49 ; P=0.047 ) . Genotypic resistance YMDD mutations developed in 49 percent of the patients treated with lamivudine , and the Child-Pugh score was more likely to increase in patients with these mutations than in the other patients treated with lamivudine ( 7 percent vs. < 1 percent ) . Overall , 12 percent of the patients in the lamivudine group and 18 percent of the patients in the placebo group reported serious adverse events . CONCLUSIONS Continuous treatment with lamivudine delays clinical progression in patients with chronic hepatitis B and advanced fibrosis or cirrhosis by significantly reducing the incidence of hepatic decompensation and the risk of hepatocellular carcinoma BACKGROUND The long-term efficacy of lamivudine treatment for patients suffering from severe acute exacerbation of hepatitis B e antigen (HBeAg)-positive chronic hepatitis B is unknown . METHODS Consecutive patients with severe acute exacerbation of HBeAg-positive chronic hepatitis B were prospect ively recruited from 1999 to 2004 and treated with lamivudine . All patients had alanine aminotransferase ( ALT ) and serum bilirubin levels 10x and 3x above the upper limit of normal , respectively . HBeAg-positive patients without severe acute exacerbation served as controls . RESULTS Forty-five patients with severe acute exacerbation and 31 controls were treated with lamivudine  for a median of 2.8 ( range 1.0 - 7.1 ) years and 3.8 ( range 3.5 - 8.4 ) years , respectively . Compared with controls , patients with severe acute exacerbation had higher HBeAg seroconversion rates ( 78 % versus 52 % ; P=0.02 ) and lower risk of virological breakthrough . However , 33 % of patients with severe acute exacerbation still developed  lamivudine resistance and virological breakthrough by year 5 . HBV DNA levels at week 4 and prolonged baseline prothrombin time were independent factors associated with virological breakthrough . All patients with week 4 HBV DNA <3 log10 copies/ml had maintained virological response . Among 15 patients who stopped lamivudine after sustained HBeAg seroconversion for > or = 6 months , 11 ( 73 % ) had virological relapse at a median of 1.4 ( 0.2 - 3.9 ) years . ALT increased beyond 10x the upper limit of normal in six ( 38 % ) patients who stopped lamivudine and two ( 7 % ) patients on maintained lamivudine treatment ( P=0.02 ) . CONCLUSION Among patients with severe acute exacerbation of HBeAg-positive chronic hepatitis B treated with lamivudine , virological breakthrough and post-treatment relapse are common despite a high rate of HBeAg seroconversion . Severe hepatitis flare is also common particularly among patients developing virological relapse after discontinuation of lamivudine CONTEXT Serum hepatitis B virus ( HBV ) DNA level is a marker of viral replication and efficacy of antiviral treatment in individuals with chronic hepatitis B. OBJECTIVE To evaluate the relationship between serum HBV DNA level and risk of hepatocellular carcinoma . DESIGN , SETTING , AND PARTICIPANTS Prospect i ve cohort study of 3653 participants ( aged 30 - 65 years ) , who were seropositive for the hepatitis B surface antigen and seronegative for antibodies against the hepatitis C virus , recruited to a community-based cancer screening program in Taiwan between 1991 and 1992 . MAIN OUTCOME MEASURE Incidence of hepatocellular carcinoma during follow-up examination and by data linkage with the national cancer registry and the death certification systems . RESULTS There were 164 incident cases of hepatocellular carcinoma and 346 deaths during a mean follow-up of 11.4 years and 41,779 person-years of follow-up . The incidence of hepatocellular carcinoma increased with serum HBV DNA level at study entry in a dose-response relationship ranging from 108 per 100,000 person-years for an HBV DNA level of less than 300 copies/mL to 1152 per 100,000 person-years for an HBV DNA level of 1 million copies/mL or greater . The corresponding cumulative incidence rates of hepatocellular carcinoma were 1.3 % and 14.9 % , respectively . The biological gradient of hepatocellular carcinoma by serum HBV DNA levels remained significant ( P<.001 ) after adjustment for sex , age , cigarette smoking , alcohol consumption , serostatus for the hepatitis B e antigen ( HBeAg ) , serum alanine aminotransferase level , and liver cirrhosis at study entry . The dose-response relationship was most prominent for participants who were seronegative for HBeAg with normal serum alanine aminotransferase levels and no liver cirrhosis at study entry . Participants with persistent elevation of serum HBV DNA level during follow-up had the highest hepatocellular carcinoma risk . CONCLUSION Elevated serum HBV DNA level ( > or = 10,000 copies/mL ) is a strong risk predictor of hepatocellular carcinoma independent of HBeAg , serum alanine aminotransferase level , and liver cirrhosis BACKGROUND & AIMS Data on the long-term safety of lamivudine are limited . The aim of this analysis was to determine the incidence of hepatitis flares , hepatic decompensation , and liver-disease-related ( LDR ) serious adverse events ( SAE ) during long-term lamivudine treatment . METHODS We review ed data on 998 patients with HBeAg-positive compensated chronic hepatitis B who received lamivudine for up to 6 years ( median , 4 years ) and 200 patients who received placebo for 1 year . RESULTS Hepatitis flares occurred in 10 % of the lamivudine-treated patients in year 1 and in 18%-21 % in years 2 - 5 . A temporal association between hepatitis flares and lamivudine-resistant mutations increased from 43 % in year 1 to > 80 % in year 3 . Ten hepatic decompensation events occurred in 8 ( < 1 % ) lamivudine-treated patients . Fifty-three ( 5 % ) lamivudine-treated patients experienced a total of 60 LDR SAEs . Four patients died , 2 from liver-related causes . The proportion of patients with a documented lamivudine-resistant mutation increased from 23 % in year 1 to 65 % in year 5 . During each year of the study , patients with lamivudine-resistant mutations experienced significantly more hepatitis flares than patients without lamivudine-resistant mutations ( P < 0.005 ) . The occurrence of hepatic decompensation ( 0%-2 % ) and LDR SAEs ( 1%-10 % ) among patients with lamivudine resistance remained stable during the first 4 years with mutations and increased afterward to 6 % ( P = 0.03 ) and 20 % ( P = 0.009 ) , respectively . CONCLUSIONS This study demonstrated that lamivudine treatment for up to 6 years has an excellent safety profile in patients with HBeAg-positive compensated liver disease , but patients with long-st and ing lamivudine-resistant mutations may experience worsening liver disease BACKGROUND / AIMS This study aim ed to evaluate the effect of interferon-alpha therapy on the long-term outcome of HBeAg-negative chronic hepatitis B. METHODS A cohort of 209 interferon-alpha treated and 195 untreated patients with histologically documented HBeAg-negative chronic hepatitis B were closely followed for a mean of 6 ( 1 - 13.5 ) years . Patients with decompensated liver disease and /or hepatocellular carcinoma at presentation were excluded . RESULTS Survival and complication ( liver decompensation and /or hepatocellular carcinoma ) -free survival were significantly worse in patients with compared to those without baseline cirrhosis and in patients older compared to those younger than 45 years ( P < 10(-4 ) ) . Sustained biochemical remission was achieved in 57 treated patients . Sustained responders had significantly better survival and complication-free survival than non-sustained responders ( P = 0.027 and P = 0.019 , respectively ) or than untreated patients ( P = 0.048 and P = 0.012 , respectively ) . Multivariate analysis showed that absence of baseline cirrhosis , younger age , and sustained biochemical remission were independently associated with an improved outcome . CONCLUSION In patients with HBeAg-negative chronic hepatitis B , sustained biochemical remission induced by interferon-alpha is associated with improved long-term outcome , even in the presence of cirrhosis and old age , both known factors associated with worse survival . Therefore , long-term biochemical remission appears to represent a satisfactory therapeutic target in this setting To assess whether extended treatment with interferon improves the outcome of hepatitis B e antigen (HBeAg)-negative chronic hepatitis B , 101 consecutive patients were treated with 6 MU of interferon alfa 2b 3 times weekly for 24 months . During the 68-month study , 30 patients ( 30 % ) had a sustained response 
    Output:
    
Chronic hepatitis B patients receiving medium-term nucleos(t)ide analogue therapy  had a significantly lower incidence of HCC compared to untreated patients but treatment does not completely eliminate the risk of HCC .
Among the treated patients , cirrhosis , HBeAg negative at baseline and failure to remain in virological remission were associated with an increased risk of HCC