Chronic hepatitis B is one of the leading causes of hepatocellular. Surrogate End Points and Long-Term Outcome in Patients With Chronic Hepatitis B

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1 CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2009;7: Surrogate End Points and Long-Term Outcome in Patients With Chronic Hepatitis B VINCENT WAI SUN WONG,*, GRACE LAI HUNG WONG,*, ANGEL MEI LING CHIM,*, PAUL CHEUNG LUNG CHOI, ANTHONY WING HUNG CHAN, STEVEN WOON CHOY TSANG, ALEX YUI HUI,*, HOI YUN CHAN,*, JOSEPH JAO YIU SUNG,*, and HENRY LIK YUEN CHAN*, *Department of Medicine and Therapeutics, Institute of Digestive Disease, and Department of Anatomical and Cellular Pathology, the Chinese University of Hong Kong; and Department of Medicine, Tseung Kwan O Hospital, Hong Kong See related article, DunnCetal, on page 1289 in Gastroenterology. BACKGROUND & AIMS: It is unclear whether surrogate end points reported in clinical trials correlate with long-term outcome of patients with chronic hepatitis B. METHODS: Patients with chronic hepatitis B who participated in any of 4 randomized controlled trials were followed prospectively for liver-related events (hepatocellular carcinoma, ascites, spontaneous bacterial peritonitis, variceal bleeding, liver transplantation, and death). Biochemical (normal ALT levels), virologic (levels of hepatitis B virus DNA below 10,000 copies/ml), and histologic (reduction of necroinflammation grading by 2 points or more with no increase in fibrosis staging) s were evaluated at the end of each trial. RESULTS: One hundred ninety-five patients with adequate pretreatment and post-treatment liver biopsies (15 mm long and 6 portal tracts) were followed for 86 months (interquartile range, 77 98). Liver-related events occurred in 12 patients (6%). The risk of liver-related events was lower in patients with biochemical (hazard ratio, 0.21; 95% confidence interval, ) and histologic (hazard ratio, 0.095; 95% confidence interval, ) s. Only 1 patient with a histologic and 1 patient with an ALT level below Prati s cutoffs (30 IU/L in men and 19 IU/L in women) developed liver-related events. Fifteen of 25 patients (60%) with cirrhosis at baseline had regression of cirrhosis, and none of these patients died or developed liver-related events. In contrast, 3 of these patients still developed liver-related events, despite an initial virologic, and 2 had virologic breakthrough. CONCLUSIONS: Biochemical and histologic s, particularly regression of cirrhosis, in patients with chronic hepatitis B are associated with decreased liver-related complications. Chronic hepatitis B is one of the leading causes of hepatocellular carcinoma (HCC) and cirrhosis. 1 It is estimated that more than 350 million people suffer from chronic hepatitis B worldwide. Up to 25% of chronic hepatitis B patients will develop HCC. Interferon (or peginterferon) and oral nucleos(t)ide analogs are standard treatments of chronic hepatitis B. These drugs can normalize serum ALT level, reduce the viral load, promote HBeAg seroconversion, and improve histologic necroinflammation and fibrosis. In patients with severe liver fibrosis or early cirrhosis, lamivudine might also reduce the incidence of liver decompensation and HCC. 2 Although lamivudine and interferon also appear to reduce the incidence of HCC in patients without cirrhosis at baseline, the data are largely from retrospective and case-control studies. 3 Because cirrhotic complications and HCC take a long time to develop, it is difficult to conduct clinical trials with them as primary end points, especially in noncirrhotic patients among whom the incidence of liver-related complications is even lower. In most clinical trials, surrogate end points are used to reflect the efficacy of antiviral therapy. The commonly used surrogate end points include biochemical (normalization of serum ALT), virologic (suppression of HBV DNA and HBeAg seroconversion), and histologic. 4 8 In the recent National Institutes of Health Consensus Development Conference, whether these surrogate end points can reflect clinical outcome was questioned. 9,10 To address this important clinical question, we evaluated the long-term clinical outcomes of chronic hepatitis B with and without biochemical, virologic, and histologic among patients who have participated in 4 of our previous clinical trials. Patients and Methods Patients This was a prospective cohort study. Chronic hepatitis B patients enrolled in 4 randomized controlled trials between 1998 and 2004 at Prince of Wales Hospital, Hong Kong, were prospectively followed after the end of study treatment. 2,11 13 The study design and timing of liver biopsies are shown in Figure 1. At study entry, all patients had positive hepatitis B surface antigen for at least 6 months and detectable HBV DNA. Patients with evidence of HCC at baseline, serum ALT level more than 10 times the upper limit of normal, hepatic decompensation, autoimmune hepatitis, coinfection with hepatitis C or D viruses or human immunodeficiency virus, other serious concurrent illness (eg, alcoholism, uncontrolled diabetes, or cancer), and abnormal serum creatinine were excluded. In this study, we included only patients with satisfactory liver biopsy specimens ( 15 mm in length and containing 6 portal tracts) both before and after study treatment. All patients provided informed written consent. Abbreviations used in this paper: anti-hbe, antibody against hepatitis B e antigen; CI, confidence interval; HCC, hepatocellular carcinoma; HR, hazard ratio by the AGA Institute /09/$36.00 doi: /j.cgh

2 1114 WONG ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 7, No. 10 After the end of the clinical trials, the patients were prospectively followed up in the outpatient clinic every 3 6 months as clinically indicated. According to our local reimbursement system, antiviral drugs were mostly paid by patients. Therefore, the choice of antiviral drugs after the clinical trials was a joint decision between the doctors and patients. During each followup, liver function tests, serum alpha-fetoprotein, HBeAg, and antibody against hepatitis B e antigen (anti-hbe) were checked. HBV DNA was checked every 6 months in patients who continued to receive antiviral therapy. Hepatitis B surface antigen was checked yearly. Ultrasound scan of the abdomen was performed every 1 2 years for surveillance of HCC or more frequently if alpha-fetoprotein increased by more than 20 g/l. Surrogate End Points Biochemical, virologic, and histologic end points in the clinical trials were correlated with long-term clinical outcome. Owing to the timing of follow-up liver biopsy per protocol, end points were assessed on the day of the last dose of study drugs in 3 studies 2,11,12 and assessed at 24 weeks after treatment cessation in 1 study. 13 Biochemical was defined as serum ALT below the upper limit of normal (58 IU/L). Because recent data suggested that the upper limit of normal of ALT should be lowered, we also analyzed the data by using the alternative criteria proposed by Prati et al 14 ( 30 IU/L in men and 19 IU/L in women). Virologic was defined as a reduction of HBV DNA to less than 10,000 copies/ml. We also analyzed our data by using undetectable HBV DNA by polymerase chain reaction. In patients with positive HBeAg, we examined the effect of HBeAg loss (HBeAg became negative, with or without anti-hbe) and HBeAg seroconversion (HBeAg became negative, and anti-hbe became positive). HBeAg and anti-hbe were measured by enzyme-linked immunosorbent assay (Sanofi Diagnostics, Pasteru, France). HBV DNA was measured by TaqMan real-time polymerase chain reaction with Eurohep standard to set the standard curve as described previously. 15 The range of HBV DNA detection was from 10 2 to 10 9 copies/ml. Liver biopsies were evaluated by 2 pathologists who were blinded to the treatment assignment (P.C.L.C., A.W.H.C.). Ishak scoring system was used to score the histologic activity index (0 18) and liver fibrosis (0 6). 16 As in most previously reported pivotal clinical trials, histologic was defined as a decrease in the necroinflammation grade by 2 points or more, with no deterioration in fibrosis stage by 1 or more in the post-treatment liver biopsies. 4,6 8 Cirrhosis was defined as Ishak stage 5 or 6. Regression of cirrhosis was defined as a decrease in the Ishak stage of 2 points or more among patients with cirrhosis at baseline. 17 Figure 1. Study design and timing of liver biopsies of the 4 clinical trials. Clinical Outcome The clinical outcome was a composite end point of liver-related complications (ascites, spontaneous bacterial peritonitis, variceal bleeding, HCC, liver transplantation) and death from liver-related causes. For patients with more than 1 liverrelated complication, only the first event was analyzed. Ascites was defined as free peritoneal fluid identified by ultrasound or computed tomography scans, or as clinically evident ascites confirmed by paracentesis. Spontaneous bacterial peritonitis was defined as an ascitic fluid polymorph count of 250/mm 3 or above with or without positive bacterial culture. Variceal bleed-

3 October 2009 SURROGATE END POINTS IN HEPATITIS B 1115 Table 1. Baseline Characteristics of Chronic Hepatitis B Patients in the Long-Term Follow-up Program Characteristics All (N 195) With liver-related events (N 12) Without liver-related events (N 183) P value Age (y) 38 (30 45) 53 (47 57) 38 (28 44).001 Male gender, n (%) 144 (74) 11 (92) 133 (73).19 Study drugs, n (%) Peginterferon lamivudine 71 (36) 1 (8) 70 (38).059 Lamivudine 104 (53) 6 (50) 98 (54).81 Placebo 20 (10) 5 (42) 15 (8).001 Baseline ALT (IU/L) 119 (85 196) 112 (59 186) 119 (86 198).35 Bilirubin ( mol/l) 10 (7 14) 10 (8 14) 10 (7 14).69 Albumin (g/l) 40 (37 42) 38 (38 39) 40 (37 42).043 Platelet count ( 10 9 /L) 185 ( ) 156 (83 187) 187 ( ).009 International normalized ratio 1.08 ( ) 1.15 ( ) 1.08 ( ).001 HBeAg positive, n (%) 144 (74) 6 (50) 138 (75).052 Anti-HBe positive, n (%) 50 (26) 5 (42) 45 (25).19 Baseline HBV DNA (copies/ml) ( to ( to ( to ) ) ) Baseline histologic activity index 5 (3 7) 5 (3 7) 5 (2 7).84 Post-treatment histologic activity index 2 (1 5) 7 (4 7) 2 (1 4).001 Change in histologic activity index 2 ( 5 to0) 1( 1 to3) 2 ( 5 to 0).012 Baseline fibrosis stage 1 (1 2) 3 (2 5) 1 (1 2).001 Post-treatment fibrosis stage 1 (1 2) 5 (2 6) 1 (1 2).001 Cirrhosis at baseline, n (%) 25 (13) 3 (25) 22 (12).19 Regression of cirrhosis, n (%) a 15 (60) 0 15 (68).052 Open-labeled treatment after drug trial, n(%) Peginterferon 13 (7) 0 13 (7) 1.0 Lamivudine 38 (19) 2 (17) 36 (20) 1.0 Adefovir dipivoxil 27 (14) 3 (25) 24 (13).22 Entecavir 23 (12) 3 (25) 20 (11).16 Telbivudine 2 (1) 0 2 (1) 1.0 Follow-up (mo) 86 (77 98) 95 (71 110) 86 (78 98).54 a Only patients with cirrhosis at baseline were analyzed. ing was defined as hematemesis and/or melena, with esophageal or gastric varices identified during upper gastrointestinal endoscopy and no other lesion that might explain the bleeding episode. Computed tomography, hepatic angiogram, and/or liver biopsy was performed to confirm the diagnosis of HCC. Statistics All analyses were performed by using the Statistical Package for Social Sciences (version 16.0; SPSS Inc, Chicago, IL). Continuous variables were presented as median (interquartile range) and compared by using Mann Whitney U test. Categorical variables were compared by using 2 test or Fisher exact test as appropriate. All clinical outcomes were censored in September Total duration of follow-up was calculated from the date of the dose of study medication until the last consultation, death, or liver transplantation. The time to liverrelated complications or to the last follow-up was plotted according to groups by Kaplan Meier estimates and compared by using the log-rank test. Cox proportional hazard model was used to adjust for the presence of cirrhosis before treatment and open-labeled treatment after the end of drug trials. A two-sided P value of less than.05 was considered statistically significant. Results Two hundred forty-six patients participated in the 4 clinical trials. After excluding 5 patients with early withdrawal, 34 patients who refused follow-up liver biopsies, and 12 patients with unsatisfactory liver biopsy specimens, 195 patients were included in the long-term follow-up study (Figure 1). Seventy-one (36%) patients received peginterferon-alfa plus lamivudine, 104 (53%) patients received lamivudine monotherapy, and 20 (10%) patients received placebo (Table 1). The interval between the baseline and end-of-trial assessment was 24 months (interquartile range, months). After the completion of clinical trials, 13 (7%) patients used peginterferon-alfa, and 81 (41.5%) patients used oral nucleos(t)ide analogs for persistent hepatitis activity. At a median follow-up of 86 months (range, months), 12 (6%) patients developed liver-related events. One (1%) patient developed ascites and spontaneous bacterial peritonitis, and one (1%) patient developed variceal bleeding. Ten (5%) patients developed HCC, of whom 1 had liver transplantation and 3 died. Histologic Response The median length of liver biopsy specimens was 17 mm (15 22 mm). One hundred (51%) patients achieved histologic. Patients with histologic were less likely to develop liver-related events (hazard ratio [HR], 0.095; 95% confidence interval [CI], ; P.025) (Figure 2). The association remained significant after adjusting for the presence of cirrhosis before treatment (adjusted HR, 0.074; 95% CI, ; P.014) and post-study antiviral treatment (adjusted HR, 0.098; 95% CI, ; P.026). Only one (1%)

4 1116 WONG ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 7, No. 10 patient with histologic developed HCC, compared with 11 (12%) liver-related events in patients without histologic (Table 2). The patient who developed HCC despite histologic was a 55-year-old man with HBeAg-positive chronic hepatitis B who received peginterferon-alfa plus lamivudine (patient 1, Table 3). His pretreatment ALT was 183 IU/L, and HBV DNA was copies/ml. His pretreatment histologic activity index was 14 points, and fibrosis stage was 2. At post-treatment week 24, his ALT was 42 IU/L, and HBeAg seroconversion was achieved. HBV DNA was 13,800 copies/ml. Follow-up liver biopsy showed improved histologic activity index to 2 points and stage 1 fibrosis. At month 36, his ALT rose to 375 IU/L, and lamivudine was resumed. HCC was detected at month 41. He received surgical resection and had radiofrequency ablation for HCC recurrence at month 62. At the last follow-up at month 76, he was still in complete remission. Twenty-five (13%) patients had liver cirrhosis at baseline. Fifteen (60%) patients had regression of cirrhosis, and 10 (40%) patients had persistent cirrhosis on follow-up liver biopsies. Liver-related events occurred in 3 (30%) patients with persistent cirrhosis but none of those with regression of cirrhosis (HR, 0.006; 95% CI, 0 191; P.34). The 3 patients developed HCC at months. One patient received live-donor liver transplantation, and one received surgical resection for HCC, and both were in complete remission at the time of analysis. The last patient died of metastatic disease despite radiofrequency ablation. Histologic occurred in 7 (47%) patients with regression of cirrhosis and 3 (30%) patients with persistent cirrhosis (P.68). Biochemical occurred in 7 (47%) patients with regression of cirrhosis and 5 (50%) patients with persistent cirrhosis (P.87). Virologic occurred in 10 (67%) patients with regression of cirrhosis and 2 (20%) patients with persistent cirrhosis (P.041). Nine patients who did not have cirrhosis at baseline developed liver-related events. Their median baseline fibrosis stage was 2 (2 4). Four patients progressed to cirrhosis on follow-up liver biopsies. Figure 2. Kaplan Meier estimates of time to a liver-related event and death in patients with and without (A) histologic, (B) biochemical, and (C) virologic. Comparison was by log-rank test. Biochemical Response One hundred fifty-two (78%) patients achieved biochemical (ALT 58 IU/L), of whom 67 (34%) had ALT below Prati s cutoffs ( 30 IU/L in men and 19 IU/L in women) at the time of assessment. With the laboratory normal range to define biochemical, patients with biochemical were less likely to develop liver-related events and HCC (HR, 0.21; 95% CI, ; P.009) (Figure 2). The association remained significant after adjusting for the presence of cirrhosis at baseline (adjusted HR, 0.22; 95% CI, ; P 0.012) and post-study antiviral treatment (adjusted HR, 0.23; 95% CI, ; P.015). However, liver-related events still occurred in 5 (3%) patients with biochemical (Table 2). In contrast, 1 of 67 (2%) patients with ALT below Prati s cutoffs developed a liver-related event, compared with 11 of 128 (9%) patients with ALT above Prati s cutoffs (HR, 0.23; 95% CI, ; P.16). The patient with ALT below Prati s cutoffs was a 60-year-old man with HBeAg-positive chronic hepatitis B who received lamivudine (patient 6, Table 3). At the end of trial, his HBV DNA was undetectable and HBeAg turned negative, although anti-hbe remained negative.

5 October 2009 SURROGATE END POINTS IN HEPATITIS B 1117 Table 2. Clinical Outcomes by Biochemical, Virologic, and Histologic Response a Outcome, n (%) Without biochemical (N 43) With biochemical (N 152) P value Without virologic (N 104) With virologic (N 91) P value Without histologic (N 95) With histologic (N 100) P value Liver-related events 7 (16) 5 (3) (9) 3 (3) (12) 1 (1).005 Ascites 0 1 (1) (1).29 1 (1) 0.31 Spontaneous bacterial 0 1 (1) (1).29 1 (1) 0.31 peritonitis Variceal bleeding 1 (2) (1) (1) 0.30 HCC 5 (12) 5 (3) (7) 3 (3).29 9 (10) 1 (1).016 Liver transplantation 1 (2) (1) (1) 0.32 Liver-related death 2 (5) 1 (1) (1) 2 (2).47 3 (3) a Comparison between patients with and without treatment was by log-rank test. Both pretreatment and post-treatment liver biopsies showed stage 6 fibrosis (cirrhosis). Eleven months after stopping lamivudine, he developed virologic relapse and HBeAg reversion. Despite resuming lamivudine treatment, he developed HCC at 92 months. At 105 months, he remained in complete remission after surgery resection. Virologic Response At the end of study intervention, 104 (53%) patients had HBV DNA less than 10,000 copies/ml, and 31 (16%) patients had undetectable HBV DNA. Among 144 patients with positive HBeAg at baseline, 71 (49%) had HBeAg loss, and 67 (47%) achieved HBeAg seroconversion. Patients with HBV DNA less than 10,000 copies/ml had similar rate of liver-related events to those with HBV DNA more than 10,000 copies/ml (HR, 0.57; 95% CI, ; P.35) (Figure 2). Similarly, two (7%) patients with undetectable HBV DNA and 10 (6%) patients with positive HBV DNA developed liver-related events (HR, 1.3; 95% CI, ; P.75). One patient with undetectable HBV DNA was a 57-year-old man who received lamivudine for HBeAg-negative chronic hepatitis B (patient 5, Table 3). At the end of clinical trial, the ALT was 57 IU/L, and HBV DNA became undetectable. Although histologic activity index decreased from 9 to 5 points, fibrosis stage rose from 4 to 6, indicating progression to cirrhosis. He was found to have multifocal HCC at 41 months. Despite systemic chemotherapy with Adriamycin, he died of progressive disease at 48 months. The other patient (patient 6) with undetectable HBV DNA had virologic relapse and was described above. Among HBeAg-positive patients, liver-related events occurred in 3 (4%) patients who achieved HBeAg loss and 3 (4%) patients who did not (HR, 0.99; 95% CI, ; P.99). Two (3%) patients who achieved HBeAg seroconversion and 4 (5%) patients who did not achieve HBeAg seroconversion developed liver-related events (HR, 0.62; 95% CI, ; P.58). Among 12 patients with liver-related events, 6 had lamivudine monotherapy. Only 1 patient had maintained virologic throughout the follow-up period (patient 5, Table 3). One patient had virologic relapse after stopping lamivudine (patient 6), and 4 patients had already had lamivudine resistance and virologic breakthrough during the clinical trial (HBV DNA, to copies/ml at the end of trial). Table 3. Clinical Features of 12 Patients With Liver-Related Events Patient no. Gender Age HBV DNA Fibrosis (y) Treatment ALT (IU/L) a HBeAg a (log copies/ml) a HAI a stage a Biochemical relapse b Virologic relapse b HBeAg reversion b Event Time to event (mo) 1 M 55 PEG-IFN 183/42 / 8.1/4.1 14/2 1/1 Y Y Y HCC 41 LMV 2 M 48 LMV 104/105 / 7.9/7.4 5/7 3/3 N/A N/A N/A Variceal 61 bleeding 3 M 43 LMV 62/85 / 7.1/7.1 2/8 5/5 N/A N/A N/A HCC 72 4 M 50 LMV 261/125 / 6.0/5.5 7/6 6/6 N/A N/A N/A HCC 78 5 M 57 LMV 147/52 / 6.2/UD 9/5 4/6 N N N/A HCC 41 6 M 60 LMV 119/18 / 5.9/UD 4/4 6/6 Y Y Y HCC 92 7 M 53 LMV 51/39 / 6.3/5.9 3/7 4/4 Y N/A Y HCC 89 8 M 53 Placebo 58/63 / 6.7/7.4 4/7 5/5 N/A N/A N/A HCC 78 9 F 46 Placebo 43/33 / 7.8/7.2 2/2 0/0 N N/A N/A HCC M 45 Placebo 187/285 / 6.6/6.6 5/7 6/6 N/A N/A N/A HCC M 56 Placebo 219/62 / 8.6/2.5 5/5 1/1 N/A Y N/A HCC M 57 Placebo 64/63 / 7.0/6.5 7/8 6/6 N/A N/A N/A Ascites 51 HAI, histologic activity index; LMV, lamivudine; N/A, not applicable; PEG-IFN, peginterferon; UD, undetectable. a Data separated by virgule represent baseline and end-of-trial values. b Biochemical relapse, virologic relapse, and HBeAg reversion refer to events after stopping study drugs.

6 1118 WONG ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 7, No. 10 Among 175 patients treated with lamivudine peginterferon, virologic breakthrough during lamivudine treatment occurred in 4 of 7 (57%) patients with liver-related events and 47 of 168 (28%) patients without liver-related events (P.20). Discussion In this prospective study with long-term follow-up, histologic at the end of treatment best protected against liver-related events. Liver-related events, including HCC and liver decompensation, were not observed in patients with regression of liver cirrhosis after treatment. Patients with normalization of ALT, particularly at a lower cutoff as proposed by Prati et al, 14 also had good prognosis. The main strength of this study was the inclusion of participants in clinical trials. The treatment and timing of end point assessment were well defined. The inclusion of these patients in prospective follow-up after the end of the clinical trials allowed accurate documentation of clinical outcomes. Compared with studies evaluating clinical outcomes after antiviral treatment, the current study used short-term surrogate end points, instead of on-treatment maintained, to predict long-term outcomes. Biochemical, virologic, and histologic end points were compared. Thus, this study allows evaluation of the meaning of surrogate end points that are commonly reported in drug trials. In our study, histologic end points correlated best with long-term prognosis. Only 1 patient achieving histologic developed liver-related events, compared with 11 patients who failed to achieve histologic. Among patients with cirrhosis at baseline, none of those with regression of cirrhosis developed liver-related events. Our finding is similar to that in chronic hepatitis C. In a study of 96 patients with hepatitis C related cirrhosis treated with peginterferon and ribavirin, the incidence of liver-related events was 0 in patients with regression of cirrhosis and 4 per 100 patient-years in patients without regression of cirrhosis. 17 In another retrospective study of 89 chronic hepatitis B patients treated with conventional interferon-alfa, liver complications (decompensation or HCC) were observed in 8 of 19 patients with increase in histologic activity index by 2 points and 3 of 70 patients without increase in histologic activity index. 25 Limited by the retrospective design, that study could not evaluate the value of biochemical and virologic in details. Besides, increase in histologic activity index is not a commonly used surrogate end point in treatment trials. Since the development of oral antiviral therapy, it has been observed that liver fibrosis, and to a certain extent cirrhosis, is a reversible process. 26 Our study further confirms that regression of cirrhosis can be translated into favorable clinical outcome not only in interferon-treated patients but also in those treated with oral nucleoside analogs. Although patients achieving biochemical have better prognosis, liver-related events still developed in 5 of 152 patients (3.3%) with biochemical. This can be explained by the development of liver-related events among patients with high-normal ALT level. The normal range of ALT is derived from the presumed normal population. However, because up to 30% of the general population have underlying nonalcoholic fatty liver disease, the older ALT cutoff values might be erroneously high. 27,28 In patients with chronic hepatitis B, the risk of liver fibrosis increases when ALT is higher than 0.5 times the upper limit of laboratory normal. 29 Among 3233 Chinese patients with chronic hepatitis B followed up for a median of 2 years, those with ALT times the upper limit of normal had increased risk of liver complications. 30 After excluding blood donors with abnormal body mass index, hyperglycemia, dyslipidemia, and medication use, Prati et al 14 found that the upper limit of normal of ALT should be lowered to 30 U/L in men and 19 U/L in women. Among 94,533 men and 47,522 women undergoing biennial health examination, subjects with ALT IU/L had 2.9-fold higher risk of dying from liver disease than those with ALT less than 20 IU/L. 31 In this study, only 1 patient with ALT below Prati s cutoffs developed a liver-related event. High HBV DNA has been implicated as a major factor associated with the development of HCC. 32,33 In our study, HBV DNA suppression, HBeAg loss, or HBeAg seroconversion at the end of drug trials were unable to predict clinical outcomes. The inferior performance of virologic end points suggests that these are just the first to antiviral therapy. Histologic and biochemical end points might reflect a reduction in liver injury more directly, which eventually translates into improved clinical outcome. Besides, the high rate of virologic relapse and breakthrough jeopardizes short-term virologic end points to predict clinical outcomes. It is noteworthy that all but one patient with liver-related events had virologic breakthrough as a result of lamivudine resistance or virologic relapse after cessation of treatment (Table 3). Although 2 patients with HBeAg seroconversion and 1 patient with HBeAg loss developed liverrelated events, all of them had HBeAg reversion and high HBV DNA before complications occurred. This suggests that virologic has to be maintained in the long run to prevent disease progression. The risk of lamivudine resistance is high. Virologic relapse is also common after cessation of treatment. 34 This results in negation of the original beneficial effects. 2 To achieve maximal benefit, it is important to use drugs with high genetic barrier to resistance for extended duration so as to maintain the viral suppression. Two patients developed HCC despite undetectable HBV DNA. Nonetheless, both had cirrhosis at the end of treatment. This finding echoes the importance of the independent risks contributed by liver cirrhosis and viremia, and viral suppression alone is not enough to clear the risk of HCC in a cirrhotic patient. 35 Our study has a few limitations. First, the number of liverrelated events is small, precluding evaluation of independent factors associated with the events. However, the inclusion of patients with a wide spectrum of disease (from no fibrosis to compensated cirrhosis) provides important data on the longterm outcome of these patients. Second, as a result of our local reimbursement policy, patients might choose to stop treatment or purchase different drugs at the end of drug trials. The data were too heterogeneous for the analysis of the effect of maintenance therapy. The cessation of treatment in the majority of patients also does not allow us to evaluate their prognosis if antiviral therapy was continued. However, the surrogate end points chosen in this study are the ones commonly reported in drug trials. Our study serves to validate these surrogate end points for long-term outcomes regardless of subsequent intervention. Third, lamivudine has low genetic barrier to resistance. It is possible that short-term virologic is useful in predicting long-term outcome if a drug with lower risk of resistance is used. However, the patients participated in the

7 October 2009 SURROGATE END POINTS IN HEPATITIS B 1119 clinical trials before newer antiviral therapy was available. The follow-up duration of patients receiving newer drugs was too short to evaluate clinical outcomes. In conclusion, histologic, particularly regression of cirrhosis, in chronic hepatitis B is associated with decreased liver-related complications. The incidence of liver complications in patients with ALT below Prati s cutoffs after treatment is low. Our findings support the current definition of histologic in clinical trials and lowering the upper limit of normal of ALT. On the basis of our data, histologic end points have the highest outcome predictability, followed by ALT according to Prati s cutoffs, conventional biochemical end points, and virologic end points. References 1. Chan HL, Sung JJ. Hepatocellular carcinoma and hepatitis B virus. Semin Liver Dis 2006;26: 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: Sung JJ, Tsoi KK, Wong VW, et al. Meta-analysis: Treatment of hepatitis B infection reduces risk of hepatocellular carcinoma. Aliment Pharmacol Ther 2008;28: Lai CL, Chien RN, Leung NW, et al. A one-year trial of lamivudine for chronic hepatitis B: Asia Hepatitis Lamivudine Study Group. N Engl J Med 1998;339: Marcellin P, Chang TT, Lim SG, et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. N Engl J Med 2003;348: Lau GK, Piratvisuth T, Luo KX, et al. Peginterferon Alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B. N Engl J Med 2005;352: Chang TT, Gish RG, de Man R, et al. A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B. N Engl J Med 2006;354: Lai CL, Gane E, Liaw YF, et al. Telbivudine versus lamivudine in patients with chronic hepatitis B. N Engl J Med 2007;357: Sorrell MF, Belongia EA, Costa J, et al. National Institutes of Health Consensus Development Conference Statement: management of hepatitis B. Ann Intern Med 2009;: Shamliyan TA, Macdonald R, Shaukat A, et al. Antiviral therapy for adults with chronic hepatitis B: a systematic review for a National Institutes of Health Consensus Development Conference. Ann Intern Med 2009;: Chan HL, Wong VW, Chim AM, et al. Virological to different combination regimes of peginterferon alpha-2b and lamivudine in hepatitis B e antigen positive chronic hepatitis B. Antivir Ther 2007;12: Chan HL, Wang H, Niu J, et al. Two-year lamivudine treatment for hepatitis B e antigen-negative chronic hepatitis B: a double-blind, placebo-controlled trial. Antivir Ther 2007;12: Chan HL, Leung NW, Hui AY, et al. A randomized, controlled trial of combination therapy for chronic hepatitis B: comparing pegylated interferon-alpha2b and lamivudine with lamivudine alone. Ann Intern Med 2005;142: Prati D, Taioli E, Zanella A, et al. Updated definitions of healthy ranges for serum alanine aminotransferase levels. Ann Intern Med 2002;137: Chan HL, Chui AK, Lau WY, et al. Factors associated with viral breakthrough in lamivudine monoprophylaxis of hepatitis B virus recurrence after liver transplantation. J Med Virol 2002;68: Ishak K, Baptista A, Bianchi L, et al. Histological grading and staging of chronic hepatitis. J Hepatol 1995;22: Mallet V, Gilgenkrantz H, Serpaggi J, et al. Brief communication: the relationship of regression of cirrhosis to outcome in chronic hepatitis C. Ann Intern Med 2008;149: Fattovich G, Giustina G, Realdi G, et al. Long-term outcome of hepatitis B e antigen-positive patients with compensated cirrhosis treated with interferon alfa: European Concerted Action on Viral Hepatitis (EUROHEP). Hepatology 1997;26: Ikeda K, Saitoh S, Suzuki Y, et al. Interferon decreases hepatocellular carcinogenesis in patients with cirrhosis caused by the hepatitis B virus: a pilot study. Cancer 1998;82: Papatheodoridis GV, Manesis E, Hadziyannis SJ. The long-term outcome of interferon-alpha treated and untreated patients with HBeAg-negative chronic hepatitis B. J Hepatol 2001;34: Lampertico P, Del Ninno E, Vigano M, et al. Long-term suppression of hepatitis B e antigen-negative chronic hepatitis B by 24-month interferon therapy. Hepatology 2003;37: van Zonneveld M, Honkoop P, Hansen BE, et al. Long-term follow-up of alpha-interferon treatment of patients with chronic hepatitis B. Hepatology 2004;39: Di Marco V, Marzano A, Lampertico P, et al. Clinical outcome of HBeAg-negative chronic hepatitis B in relation to virological to lamivudine. Hepatology 2004;40: Lin SM, Yu ML, Lee CM, et al. Interferon therapy in HBeAg positive chronic hepatitis reduces progression to cirrhosis and hepatocellular carcinoma. J Hepatol 2007;46: Hui CK, Leung N, Shek WH, et al. Changes in liver histology as a surrogate end point of antiviral therapy for chronic HBV can predict progression to liver complications. J Clin Gastroenterol 2008;42: Dienstag JL, Goldin RD, Heathcote EJ, et al. Histological outcome during long-term lamivudine therapy. Gastroenterology 2003; 124: Kim WR, Flamm SL, Di Bisceglie AM, et al. Serum activity of alanine aminotransferase (ALT) as an indicator of health and disease. Hepatology 2008;47: Wong VW, Wong GL, Tsang SW, et al. Metabolic and histological features of nonalcoholic fatty liver disease patients with different serum alanine aminotransferase levels. Aliment Pharmacol Ther 2009;29: Wong GL, Wong VW, Choi PC, et al. Evaluation of alanine transaminase and hepatitis B virus DNA to predict liver cirrhosis in hepatitis B e antigen-negative chronic hepatitis B using transient elastography. Am J Gastroenterol 2008;103: Yuen MF, Yuan HJ, Wong DK, et al. Prognostic determinants for chronic hepatitis B in Asians: therapeutic implications. Gut 2005;54: Kim HC, Nam CM, Jee SH, et al. Normal serum aminotransferase concentration and risk of mortality from liver diseases: prospective cohort study. BMJ 2004;328: Chen CJ, Yang HI, Su J, et al. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA 2006;295: Chan HL, Tse CH, Mo F, et al. High viral load and hepatitis B virus subgenotype ce are associated with increased risk of hepatocellular carcinoma. J Clin Oncol 2008;26: Wong VW, Wong GL, Tsang SW, et al. Long-term follow-up of lamivudine treatment in patients with severe acute exacerbation of hepatitis B e antigen (HBeAg)-positive chronic hepatitis B. Antivir Ther 2008;13: Chan HL. Revisiting the treatment recommendations for chronic hepatitis B. Hepatology 2009;49:700; author reply Reprint requests Address requests for reprints to: Prof Henry L. Y. Chan, Department of Medicine and Therapeutics, 9/F, Prince of Wales Hospital, 30-32

8 1120 WONG ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 7, No. 10 Ngan Shing Road, Shatin, Hong Kong. fax: (852) Conflicts of interest The authors disclose the following: Joseph Sung received consulting fees from the National Health Research Institutes of Taipei, the Hong Kong Police Force, Lippincott Williams & Wilkins, and the Hong Kong College of Physicians and paid lecture fees by AstraZeneca Hong Kong Limited, GSK Pharmaceuticals International, and the American Society for Gastrointestinal Endoscopy. Henry Chan is a member of the advisory board of Novartis Pharmaceutical, Schering-Plough Corporation, Bristol-Myers Squibb, and Pharmasset. The remaining authors disclose no conflicts. Funding This study is supported by the research fund of the Department of Medicine and Therapeutics, the Chinese University of Hong Kong.