Early response to lamivudine therapy in ... - Wiley Online Library

Liver International ISSN 1478-3223

CLINICAL STUDIES

Early response to lamivudine therapy in clinically non-cirrhotic chronic hepatitis B patients with decompensation Chia-Yen Dai1,2,3, Ming-Lung Yu1,2, Ming-Yen Hsieh1, LI-Po Lee1, Nai-Jen Hou1,3, Jee-Fu Huang1,3, Shinn-Cherng Chen1,2, Zu-Yau Lin1,2, Ming-Yuh Hsieh1,2, Liang-Yen Wang1,2, Jun-Fa Tsai1,2, Wen-Yu Chang1,2 and Wan-Long Chuang1,4 1 Department of Internal Medicine, Division of Hepatobiliary, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan 2 College of Medicine, Faculty of Internal Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan 3 Department of Internal Medicine, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung, Taiwan 4 Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

Keywords chronic hepatitis B – decompensation – Index – lamivudine – MELD

Correspondence Wan-Long Chuang, MD, PhD, Department of Internal Medicine, Hepatobiliary Division, Kaohsiung Medical University Hospital, No. 100, Tz-You 1st Rd, Kaohsiung 807, Taiwan Tel: 1886 7 3121101 ext., 7475 Fax: 1886 7 3234553 e-mail: [email protected], [email protected] Received 5 March 2007 accepted 11 June 2007 DOI:10.1111/j.1478-3231.2007.01565.x

Abstract This study aimed to elucidate the rate and predictors of early (6 months) therapeutic responses to lamivudine, the rate of early mortality and the use of the model for endstage liver disease (MELD) and Index in predicting the survival in patients with a clinical diagnosis of non-cirrhotic chronic hepatitis B with decompensation. Ninetyeight patients with lamivudine therapy were enrolled and MELD and Index scores were calculated. Surviving patients were treated with lamivudine for more than 6 months. Four (4.1%) of the 98 patients died after initiation of lamivudine therapy. After a 6-month lamivudine therapy, 80 (85.1%) patients and 71 (75.5%) patients had normal alanine aminotransferase (ALT) values and negative hepatitis B virus (HBV) DNA (o 200 copies/mL), respectively, and hepatitis B e antigen (HBeAg)-negative patients had a significantly higher rate of negative HBV DNA than HBeAg-positive patients (P = 0.002). The rates of HBeAg seroconversion and negative HBV DNA were 28.8 and 63.5%, respectively, and patients with HBeAg seroconversion had a significantly higher rate of negative HBV DNA (P = 0.004). By multivariate analyses, older age, HBV nongenotype B infection, negative HBeAg and higher ALT levels were factors associated with negative HBV DNA, and a higher ALT level was associated with HBeAg seroconversion at month 6 after lamivudine therapy. MELD score and Index score were significantly associated with death and areas under the receiver operating characteristic curve for predicting survival were 0.936 and 0.907 respectively. We concluded that after 6-month lamivudine therapy, the patients who survived achieved favourable biochemical, virological responses and rate of HBeAg seroconversion. Both MELD and Index scoring systems are good models to predict the 6-month survival.

Hepatitis B virus (HBV) infection is a major clinical problem, with a worldwide distribution, and chronic hepatitis B (CHB) with severe exacerbation and subsequent decompensation has adverse clinical outcome and results in limited survival (1, 2). More than 1 million deaths occur per year because of CHB-related liver failure and hepatocellular carcinoma (HCC) (3, 4) and the mortality of patients undergoing medical therapy remains high. Lamivudine has been reported to markedly suppress HBV replication, lead to improvement in liver function and fibrosis in histopathology and effectively reduce the risk of significant liver complications for CHB patients and cirrhosis or advanced fibrosis (5–7).

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Because the prognosis is especially grave for patients with CHB-related decompensated liver cirrhosis, lamivudine treatment has been suggested in patients with advanced cirrhosis, impending or obvious features of hepatic decompensation with significant improvement of liver function (7–10). Some clinical factors have been reported as predictors for responses, such as hepatitis B e antigen (HBeAg) seroconversion and sustained suppression of HBV DNA, in lamivudine-treated CHB patients (11, 12). For patients a waiting orthotopic liver transplantation (OLT), the exact timing for surgical intervention has a critical impact on mortality and morbidity (13). It is important to establish a good model to estimate the

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prognosis of severe hepatitis and assess the severity of disease in order to select a reasonable and effective therapy on the basis of clinical parameters. A scoring system, model for end-stage liver disease (MELD) score, has become the prevailing criterion for donor liver allocation (14, 15) and has been confirmed to be correlated with residual liver function and predicting outcome in patients with decompensated cirrhosis with a high accuracy (16). The MELD score is a reliable measure of short-term mortality risk to predict 3-month mortality in a broad variety of liver transplantation candidates (14). Another scoring system called Index has been created and designed to predict 6-month mortality for patients with decompensated liver cirrhosis receiving lamivudine (17). Both scores have been used to predict the mortality of end-stage liver disease and cirrhosis. However, whether these scores are able to predict early mortality in non-cirrhotic patients with decompensated exacerbation receiving lamivudine is not well established. In the present study, we aimed to evaluate the biochemical and virological responses to early (6 months) lamivudine therapy and their predictors and the early mortality in the clinically non-cirrhotic patients with HBV-related decompensation in Taiwan. The usefulness of the MELD and Index score in predicting the 6-month survival of patients treated with lamivudine was also evaluated. Patients and methods Patients Ninety-eight consecutive CHB patients with decompensation from May 2000 to March 2006 were enrolled retrospectively in this study. These included 80 males and 18 females, aged between 18 and 85 years (mean 40.1 14.5 years). All patients were treatment-naı¨ve, seropositive for hepatitis B surface antigen (HBsAg) for more than 6 months and without a concurrent hepatitis C, D or human immunodeficiency virus infection and with one of the following laboratory data: either serum total bilirubin level Z3 mg/dL and/or prolonged prothrombin time (PT) Z3 s. Patients with autoimmune hepatitis, alcohol abuse (Z80 g ethanol/day), with evidence of HCC before lamivudine therapy and HCC diagnosed within 6 months after initiation of therapy were not enrolled. Patients with evidence of liver cirrhosis diagnosed by imaging features that suggested cirrhosis, along with the presence of thrombocytopaenia, oesophageal varices, ascites or encephalopathy (18) were also excluded. All patients received lamivudine therapy orally, administered daily as a single 100 mg tablet. Liver International (2007) c 2007 Blackwell Munksgaard 2007 The Authors. Journal compilation

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Lamivudine for non-LC decompensated CHB

Those who survived were all treated with lamivudine for at least 6 months for evaluation of survival in this study. All patients had given their informed consent. Laboratory tests Hepatitis B surface antigen, HBeAg, antibody to HBeAg (anti-HBe) and anti-delta were analysed by radioimmunoassay (General Biological Cooperation, Sinchu, Taiwan). Anti-hepatitis C virus was detected using a third-generation, commercially available enzyme-linked immunosorbent assay kit (Abbott, North Chicago, IL, USA). Pretreatment serum HBV DNA was determined using a branched-chain amplification (bDNA) assay (Quantiplex HBV DNA; Chiron Corporation, Emeryville, CA, USA) with a lower limit of detection: 7 105 genome equivalents/mL for calculating the Index scores. After lamivudine therapy for 6 months, HBV DNA was measured by a standardized automated quantitative polymerase chain reaction (PCR) assay (Cobas Amplicor HBV Monitor; Roche Diagnostics, Pleasanton, CA, USA; detection limit 200 copies/mL) (19). The identification of HBV genotypes was performed by PCR restriction fragment length polymorphism of the surface gene of HBV, as described previously by Mizokami et al. (20). Model for end-stage liver disease score and Index The MELD score and Fontana’s Index were calculated according to the laboratory data and the formulas: score of MELD = 3.78 loge[total bilirubin (mg/dL)] 111.2 loge International normalized ratio (INR) 19.57 loge[creatinine (mg/dL)]16.43 (constant for liver disease aetiology: 0 if cholestatic or alcoholic, 1 otherwise) (21); Index score = 0.5 bilirubin (mg/ dL)11.7 creatinine (mg/dL)11.8 HBV DNA (0 or 1) (17). Statistical methods Frequency was compared between groups using the w2 test with Yate’s correction or Fisher’s exact test. Group means were compared using Student’s t-test or Mann–Whitney U-test. The optimal cut-off values of MELD and Index to discriminate between patients who survived and those who died with the best sensitivity and specificity were calculated by receiver operating characteristic (ROC). Using the selected cutoffs of MELD and Index scores, corresponding sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy were obtained. The concordance (c)-statistic, which was equivalent to the area under ROC curve, was measured

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to assess the ability of MELD and Index to predict the risk of death (22). A c-statistic 4 0.7 should be considered to be useful. Multivariate logistic regression analyses were performed to determine the adjusted odds ratio (OR) and 95% confidence interval (CI). All statistical tests were two tailed, and P values o 0.05 were considered to be significant. All procedures were performed using the SPSS for Windows version 12 (SPSS Inc., Chicago, IL, USA). Results

significantly higher bilirubin levels (P o 0.001), MELD score (P o 0.001), Index score (P o 0.001) and frequency of encephalopathy (P = 0.041) and significantly lower albumin levels than the patients who survived (P = 0.004). A higher mean age and INR for PT were noted in deceased than in survived patients; the differences, nevertheless, were not significant statistically (both P = 0.068). No difference was observed in other clinical and virological characteristics between two groups. In multivariate logistic regression analysis, the MELD score and Index score were significant factors associated with death, with their ORs and 95% CIs shown in Table 2.

Demographical and clinical features of patients During follow-up for more than 6 months (median length: 21 months, range, 6–75 months) in this study, four (4.1%) of the 98 clinically non-cirrhotic CHB patients with decompensation died on the fourth, seventh, eighth and 18th days after the initiation of lamivudine therapy (M group). All the four patient deaths were owing to complications of advanced HBVrelated liver failure. The other 94 patients were stabilized with suppressive antiviral therapy and survived more than 6 months (S group). The demographical and clinical features of the patients are shown in Table 1. Of 98 patients, 53 patients (54.1%) were positive for HBeAg and 81 patients (82.7%) had HBV genotype B infection. Comparison of S and M groups by univariate analysis showed that deceased patients had

Early response to lamivudine therapy The responses to lamivudine therapy for 6 months (M6) in 94 surviving patients [52 (55.3%) HBeAg positive] are shown in Figure 1. Eighty (85.1%) patients had normal ALT values [36 (85.7%) of 42 HBeAg-negative patients and 44 (84.6%) of 52 HBeAg-positive patients]. Seventy-one (75.5%) patients had negative HBV DNA (level o 200 copies/ mL). HBeAg-negative patients had a significantly higher rate of negative HBV DNA than HBeAgpositive patients (90.5 vs. 63.5%, P = 0.002). For 52 HBeAg-positive patients, 17 (32.7%) had negative HBeAg, and 15 of the 17 (88.2%) patients had positive anti-HBeAg [28.8% (15/52) of the overall rate of HBeAg seroconversion]. Thirty-three (63.5%) of the

Table 1. Demographic and clinical features of non-cirrhotic chronic hepatitis B patients with decompensation treated with lamivudine Age (years) Sex (male/female) Pretreatment ALT (U/L) Pretreatment albumin (g/dL) Pretreatment bilirubin (mg/dL) Pretreatment creatinine (mg/dL) Pretreatment INR for prothrombin time MELD score Index Ascites Encephalopathy Positive for HbeAg HBV genotype B C HBV DNA level Z7 105 copies/mL, n (%)

Total (n = 98)

S group (n = 94)

M group (n = 4)

P value

40.1 14.5 80/18 1203.0 1164.6 3.46 0.44 8.10 6.69 0.94 0.25 1.55 0.69 16.5 6.2 6.95 3.45 11 (11.2%) 1 (1.0%) 53 (54.1%)

39.5 14.5 76/18 1165.5 1167.3 3.48 0.44 7.50 5.91 0.94 0.25 1.48 0.55 15.9 5.5 6.63 3.01 10 (10.6%) 0 (0%) 52 (55.3%)

53.0 7.5 4/0 2080.6 725.7 3.10 0.14 21.93 9.81 0.95 0.21 3.29 1.30 29.7 8.1 14.38 5.08 1 (25.0%) 1 (25.0%) 1 (25.0%)

0.068 1.0 0.122 0.004 o 0.001 0.934 0.068 o 0.001 o 0.001 0.384 0.041 0.331

81 (82.7%) 17(17.3%) 77 (78.6%)

77 (95.1%) 17 (100%) 73 (77.7%)

4 (4.9%) 0 (0%) 4 (100%)

1.0 0.575

S group: patients survived 4 6 months. M group: patients survived o 6 months. P o 0.05: statistical significance (shown in bold). MELD score = 3.78 loge [Total bilirubin (mg/dL)]111.2 loge (INR)19.57 loge [creatinine (mg/dL)]16.43 (constant for liver disease aetiology). Index = 0.5 bilirubin (mg/dL)11.7 creatinine mg/dL11.8 HBV DNA (0 or 1). ALT, alanine aminotransferase; HBV, hepatitis B virus; INR, International normalized ratio; MELD, model for end-stage liver disease.

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Table 2. Multivariate logistic regression analysis for factors associated with mortality, negative hepatitis B virus DNA and hepatitis B e antigen seroconversion in clinically non-cirrhotic chronic hepatitis B patients with decompensation treated with lamivudine

Factor Mortality (n = 98) MELD score Indexw

Comparison Per 1 score increase Per 1 score increase

95% Odds confidence ratio interval

P value

1.270 1.020–1.581

0.033

1.474 1.053–2.0964 0.024

Variables for multivariate analysis: MELD score, albumin level, encepha-

lopathy. wVariables for multivariate analysis: Index score, albumin level, encephalopathy. MELD, model for end-stage liver disease.

90 80

% patients

70 60 50 40 30 20 10 0 ALT normalization

Negative HBV DNA (level < 200 copies/mL)

Fig. 1. Responses to 6-month lamivudine therapy in 94 surviving patients with a clinical diagnosis of non-cirrhotic with chronic hepatitis B-related decompensation. Of the 52 hepatitis B e antigen (HBeAg)-positive patients, 15 (28.8%) patients achieved HBeAg seroconversion. The rates of negative hepatitis B virus (HBV) DNA were significantly different between HBeAgnegative and -positive patients, and between patients with and without HBeAg seroconversion. ALT, alanine aminotransferase.

52 patients had negative HBV DNA and patients achieving seroconversion had a significantly higher rate of negative HBV DNA than those who did not achieve seroconversion (93.3 vs. 51.4%, P = 0.004). Four (9.5%) of the 42 HBeAg-negative patients were positive for HBV DNA and all of them had normal ALT levels. Further analysis of factors associated with negative HBV DNA and HBeAg seroconversion was performed (Table 3). By univariate analyses, patients with negative HBV DNA at M6 were significantly older (P o 0.001), had a significantly higher frequency of negative HBeAg (P = 0.002) and had a lower frequency Liver International (2007) c 2007 Blackwell Munksgaard 2007 The Authors. Journal compilation

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of pretreatment HBV DNA Z105 copies/mL (P = 0.071) and a lower frequency of HBV genotype B infection (P = 0.062) than those with positive HBV DNA. Patients with HBeAg seroconversion had significantly higher ALT levels than those without HBeAg seroconversion at M6 (P = 0.040). Multivariate analyses showed that older age, HBV nongenotype B infection, negative HBeAg and higher ALT levels were factors associated with negative HBV DNA at M6 and higher ALT levels were independent factors associated with HBeAg seroconversion at M6, with their ORs and 95% CIs shown in Table 4. Predictors of survival In our study, the four deceased patients had MELD scores of 22.2, 23.5, 34.8 and 38.4, respectively, and Index scores of 7.5, 13.4, 18.0 and 18.4 respectively. ROC analysis software gave an output of the following results: the c-statistic for prediction of survival by the MELD score and Index score: 0.936 and 0.907; standard error: 0.038 and 0.069; P = 0.003 and 0.006; the optimal cut-off value: 22.2 and 8.29; corresponding sensitivity: 100 and 98.6%; specificity: 22.2 and 12.5%; PPV: 85.1 and 17.6%; NPV: 100 and 77.7%; and accuracy: 82.8 and 75.0% respectively. The comparison of scores between deceased and surviving patients according to the cut-off values is shown in Table 5. With cut-off values of 22.2 and 8.29 for the MELD and Index score, patients with MELD higher than 22.2 or Index score higher than 8.29 had a significantly higher rate of mortality than those who had lower scores than the cut-off values (22.4 vs. 0%, P = 0.001 and 12.5 vs. 1.4%, P = 0.044 respectively). Discussion Hepatic decompensation may result from CHB-related exacerbation with a poor prognosis, especially among patients with pre-existing liver cirrhosis with more than 50% mortality rate (23). For CHB-related decompensated cirrhosis, the promising therapeutic effects of lamivudine therapy have been demonstrated, with a total or partial reversal of signs of liver failure, rapid suppression of HBV replication and improvement of overall survival compared with historical controls (8, 24, 25). Even when treated with lamivudine, the mortality rate within 6 months after initiating therapy is, nevertheless, still high, with reports from 16 to 33% (24, 26). In the present study, with enrolment of 98 non-cirrhotic Taiwanese patients treated with lamivudine, we found, for the first time, a 4.1% mortality rate within 6 months after the start of therapy. It is noteworthy that all the four deaths

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Table 3. Predictors for negative hepatitis B virus DNA and hepatitis B e antigen seroconversion 6 months after lamivudine therapy (M6) in non-cirrhotic chronic hepatitis B patients with decompensation HBV DNA at M6

Age (years) Sex (male/female) ALT (U/L) Albumin (g/dL) Bilirubin (mg/dL) Creatinine (mg/dL) INR for prothrombin time MELD score Index Ascites HBV DNA level Z105 copies/mL, n (%) HBV genotype B Positive for HbeAg

HBeAg seroconversion at M6

Negative (n = 71)

Positive (n = 23)

P value

Yes (n = 15)

No (n = 37)

P value

42.1 15.1 55/16 1264.2 1281.5 3.45 0.47 7.60 6.02 0.92 0.26 1.50 0.59 15.9 5.6 6.58 3.10 7 (9.9%) 52 (73.2%)

31.6 8.7 21/2 860.6 637.4 3.57 0.35 7.20 5.27 1.00 0.23 1.41 0.42 16.0 5.0 6.78 2.78 3 (13.0%) 21 (91.3%)

o 0.001 0.223 0.151 0.267 0.776 0.217 0.491 0.953 0.778 0.702 0.071

36.1 12.9 13/2 1530.3 1037.9 3.50 0.49 8.87 7.59 0.92 0.16 1.30 0.21 15.2 3.8 7.32 3.74 0 (0%) 14 (93.3%)

34.9 12.0 30/7 900.5 566.7 3.55 0.45 7.18 6.11 0.92 0.16 1.41 0.39 15.3 5.0 6.62 3.07 5 (13.5%) 31(83.8%)

0.762 1.0 0.040 0.760 0.403 0.961 0.327 0.981 0.486 0.305 0.658

55 (77.5%) 33 (46.5%)

22 (95.7%) 19 (82.6%)

0.062 0.002

13 (86.7%) –

30 (81.1%) –

1.0 –

P o 0.05: statistical significance (shown in bold). MELD score = 3.78 loge[total bilirubin (mg/dL)]111.2 loge(INR)19.57 loge[creatinine (mg/dL)]16.43(constant for liver disease aetiology). Index = 0.5 bilirubin (mg/dL)11.7 creatinine mg/dL11.8 HBV DNA (0 or 1). ALT, alanine aminotransferase; HBeAg, hepatitis B e antigen; HBV, hepatitis B virus; INR, International normalized ratio; MELD, model for end-stage liver disease.

Table 4. Multivariate logistic regression analysis for factors associated with negative hepatitis B virus DNA and hepatitis B e antigen seroconversion in clinically non-cirrhotic chronic hepatitis B patients with decompensation treated with lamivudine Factor

Comparison

Odds ratio

95% confidence interval

P value

Per 1 year increase B = 1, Non B = 0 Positive = 1, negative = 0 Per 1 U/L increase

1.080 0.075 0.236 1.001

1.023–1.145 0.008–0.727 0.067–0.976 1.000–1.002

0.006 0.025 0.046 0.004

Per 1 U/L increase

1.001

1.000–1.002

0.022

Negative HBV DNA at M6 (n = 94) Age HBV genotype HBeAg ALT HBeAg seroconversion at M6 (n = 52) ALT

M6: 6 months after initiation of lamivudine treatment. HBeAg, hepatitis B e antigen; HBV, hepatitis B virus.

occurred in the early period (within 18 days) after the start of lamivudine therapy among our patient group. Actually, most of the patients (75%, 3/4) died around the first week after therapy. Villeneuve et al. (25) have reported an interval of 2–19 weeks between death and the start of lamivudine therapy . In the report of Fontana et al. (17), 22% of the deaths of cirrhotic patients were still occurring after the first 6 months. Because cirrhotic patients have a worse liver function reserve than those who are non-cirrhotic and more frequently suffer from some severe complications such as ascites and oesophageal/gastric varies, cirrhotic patients may die later as a result of variceal bleeding or hepatic failure, even though hepatic injury decreased after lamivudine therapy. Our results showed that as long as non-cirrhotic patients with CHB-

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related decompensation survive the few weeks after treatment with lamivudine, their liver decompensation seems to recover well and will remain stable at least the following 6 months. In a previous report, Chien et al. (27) reported that HBeAg seroconversion was achieved in 5–64% (vs. 2–14% with placebo) of patients with different ALT values at the end of 1-year therapy with lamivudine. Our patients with positive HBeAg and surviving 6 months after the start of lamivudine therapy achieved 28.8% of the seroconversion rate and patients with HBeAg seroconversion has a significantly higher rate (93.3%) of negative HBV DNA compared with those without HBeAg seroconversion (51.4%). Our data revealed favourable results of HBeAg seroconversion, normalization of ALT levels and viral suppression after

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Table 5. Comparison of model for end-stage liver disease and Index scores between clinically non-cirrhotic chronic hepatitis B-related decompensated patients who died or survived treated with lamivudine according to the cut-off values

MELD score 4 22.2 22.2 Index 4 8.29 8.29

S group (n = 94), n (%)

M group (n = 4), n (%)

14 (77.8) 80 (100)

4 (22.2) 0 (0)

21 (87.5) 73 (98.6)

3 (12.5) 1 (1.4)

P value 0.001

0.044

The optimal cut-off values with the best sensitivity and specificity were calculated by receiver operating characteristic (ROC). S group: patients survived 4 6 months. M group: patients survived o 6 months. MELD score = 3.78 loge[total bilirubin (mg/dL)]111.2 loge(INR)19.57 loge[creatinine (mg/dL)]16.43 (constant for liver disease aetiology). Index = 0.5 bilirubin (mg/dL)11.7 creatinine (mg/dL)11.8 HBV DNA (0 or 1). MELD, model for end-stage liver disease.

lamivudine therapy for 6 months in non-cirrhotic decompensated HBeAg-positive patients, although we did not include an untreated control group because it seemed unreasonable to perform such a study in patients with decompensated exacerbation. HBV genotype B was shown to be associated with a better response to thymosin alpha1 therapy (28), and Chien et al. (11) reported that younger HBV genotype B infection and age were factors related to sustained HBeAg response in lamivudine-treated CHB patients. Our results, similar to reports from Kao et al. (29) and Chan et al. (30), did not show the roles of the HBV genotype or age in the HBeAg seroconversion with 6-month lamivudine treatment and their association needs further long-term studies in non-cirrhotic patients with CHB-related decompensation. A higher ALT level is the only predictor for HBeAg seroconversion at M6 in this subgroup of patients, which supported the important role of a more vigorous immune clearance of HBV in facilitating HBeAg seroconversion with HBV DNA loss (7, 31). In a series of 32 patients with HBeAg-negative CHBrelated severe acute exacerbation, Chan et al. (32) reported a 94% of virological response at year 1 of lamivudine therapy. In our study, lamivudine therapy at month 6 yielded a significantly effective suppression of viral replication indicated by a high proportion of negative HBV DNA (90.5%), which is significantly higher than HBeAg-positive patients (63.5%). In all our 94 patients surviving 6 months after lamivudine therapy, the overall rates of negative HBV DNA (o 200 copies/mL) were 75.5%. We found that older Liver International (2007) c 2007 Blackwell Munksgaard 2007 The Authors. Journal compilation

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age, HBV nongenotype B infection, negative HBeAg and higher ALT levels were predictors for negative HBV DNA at M6. In previous studies, HBV genotype B infection has been reported to be associated with a long-term cumulative HBeAg seroconversion rate in CHB patients in nature course (33), and no differences in the median reduction of HBV DNA levels and longtern virological response between lamivudine-treated patients with HBV genotypes B and C at weeks 24 and 52 (34, 35). Whether the favourable virological results of 6-month lamivudine therapy in Taiwanese patients without HBV genotype B infection were specific to the patient groups of non-cirrhotic CHB-related decompensation needs further long-term study. For patients with decompensation, the MELD score has been shown to be suitable for use as a reliable measure to predicting 3-, 6- and 12-month mortality (14, 16, 36). Botta et al. (16) used an MELD score of 14 as the cut-off value to discriminate between deceased and surviving cirrhotic patients within 6 months with HBV-related decompensation. Fontana et al. (17) have created an Index score designed to predict 6-month mortality (95% probability of death with an Index score higher than 8) for patients with decompensated liver cirrhosis receiving lamivudine. We further found that both the MELD scores and Index score also seemed to discriminate successfully between surviving and deceased patients who were clinically non-cirrhotic. The higher cut-off values of an MELD score of 22.2 and an Index score of 8.29 to predict mortality accurately seemed to be optimal, which indicated that they had a better liver function reserve and might recover more easily, even though the major limitation of our ROC analysis in the present study was the small number of deaths. In summary, after 6-month lamivudine therapy for clinically non-cirrhotic patients with CHB-related decompensation, the surviving patients achieved favourable biochemical and virological responses, and rate of HBeAg seroconversion and age, HBV genotype, pretreatment HBeAg status and ALT levels were predictors for negative HBV DNA and ALT levels were predictors for HBeAg seroconversion. With 4.1% of the mortality rate, both the MELD and Index scoring systems, derived from clinical parameters in the initial presentation, were good models to predict 6-month survival with lamivudine therapy. References 1. Lee WM. Hepatitis B virus infection. N Engl J Med 1997; 337: 1733–45. 2. Sheen IS, Liaw YF, Tai DI, et al. Hepatic decompensation associated with hepatitis B e antigen clearance in chronic type B hepatitis. Gastroenterology 1985; 89: 732–5.

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3. Mast EE, Alter MJ, Margolils HS. Strategies to prevent and control hepatitis B and C virus infections: a global perspective. Vaccine 1999; 17: 1730–3. 4. McQuillan GM, Coleman PJ, Kruszon-Moran D, et al. Prevalence of hepatitis B virus infection in the United States: the National Health and Nutrition examination surveys, 1976 through 1994. Am J Public Health 1999; 89: 14–8. 5. Lai C, Chien R, Leung NWY, et al. A one year trial of lamivudine for chronic hepatitis B. N Engl J Med 1998; 339: 61–8. 6. Dienstag JL, Goldin RD, Heathcote EJ, et al. Histological outcome during long-term lamivudine therapy. Gastroenterology 2003; 124: 105–17. 7. Liaw YF, Sung JJ, Chow WC, et al. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med 2004; 351: 1521–31. 8. Yao FY, Bass NM. Lamivudine treatment in patients with severely decompensated cirrhosis due to replicating hepatitis B infection. J Hepatol 2000; 33: 301–7. 9. Lok AS, McMahon B. AASLD practice guidelines. chronic hepatitis B: update of recommendation. Hepatology 2004; 39: 857–61. 10. Liaw YF, Leung N, Guan R, et al. Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2005 update. Liver Int 2005; 25: 472–89. 11. Chien RN, Yeh CT, Tsai SL, Chu CM, Liaw YF. Determinants for sustained HBeAg response to lamivudine therapy. Hepatology 2003; 38: 1267–73. 12. Liaw YF, Leung NW, Chang TT, et al. Effects of extended lamivudine therapy in Asian patients with chronic hepatitis B. Asia Hepatitis Lamivudine Study Group. Gastroenterology 2000; 119: 172–80. 13. Carithers JL Jr. Liver transplantation. American Association for the study of liver diseases. Liver Transpl 2000; 6: 122–35. 14. Kamath PS, Wiesner RH, Malinchoc M, et al. A model to predict survival in patients with end stage liver disease. Hepatology 2001; 33: 464–70. 15. Freeman RB Jr, Wiesner RH, Roberts JP, et al. Improving liver allocation: MELD and PELD. Am J Transplant 2004; 4: 114–31. 16. Botta F, Giannini E, Romagnoli P, et al. MELD scoring system is useful for predicting prognosis in patients with liver cirrhosis and is correlated with residual liver function: a European study. Gut 2003; 52: 134–9. 17. Fontana RJ, Hann HW, Perrillo RP, et al. Determinants of early mortality in patients with decompensated chronic hepatitis B treated with antiviral therapy. Gastroenterology 2002; 123: 719–27. 18. Liaw YF, Tai DI, Chu CM, et al. The development of cirrhosis in patients with chronic type B hepatitis: a prospective study. Hepatology 1988; 8: 493–6. 19. Dai CY, Yu ML, Chen SC, et al. Clinical evaluation of the COBAS Amplicor HBV monitor test for measuring serum HBV DNA and comparison with the quantiplex branched DNA signal amplification assay in Taiwan. J Clin Pathol 2004; 57: 141–5.

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