The effect of lamivudine therapy in hepatic decompensation during acute exacerbation of chronic hepatitis B

Journal of Hepatology 38 (2003) 322–327 www.elsevier.com/locate/jhep

The effect of lamivudine therapy in hepatic decompensation during acute exacerbation of chronic hepatitis B q Rong-Nan Chien †, Chia-Hsien Lin, Yun-Fan Liaw* Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University, 199, Tung Hwa North Road, Taipei, 105 Taiwan

Background/Aims: Severe acute exacerbation (AE) of chronic hepatitis B (CHB) can lead to hepatic decompensation and death. The aim of this study was to investigate the effect of lamivudine therapy in hepatic decompensation during such AEs. Methods: In a 10-month period, a total of 60 consecutive AE patients with jaundice and prolonged prothrombin time over 3 s were treated with lamivudine 150 mg daily. As a historical control, another 31 CHB patients with AE resulting in hepatic decompensation hospitalized in an immediate past 6-month period were enrolled for comparison. Results: Patients in both groups were comparable in clinical and biochemical features. After a median treatment period of 6 weeks (range 1–48 weeks), all of the 25 patients with pretherapy bilirubin level ,20 mg/dl in the treatment group survived, while five (25%) of 20 patients in the control group died (P ¼ 0.013; odds ratios, 2.667; 95% confidence interval, 1.787–3.979). However, the mortality rate was similar in patients with pretherapy bilirubin level $20 mg/dl in both groups. Conclusions: These results suggest that lamivudine may prevent fatality in CHB patients with hepatic decompensation if therapy starts early enough or before serum bilirubin level rise over 20 mg/dl, but helps little if serum level already rised over that level. q 2002 Published by Elsevier Science B.V. on behalf of the European Association for the Study of the Liver. Keywords: Acute exacerbation; Hepatic decompensation; Chronic hepatitis B; Bilirubin; Lamivudine

1. Introduction One of the characteristics of the natural course of chronic hepatitis B virus (HBV) infections is the fluctuation of serum aspartate (AST) and alanine aminotransferase (ALT). It is not uncommon to encounter episodes with abrupt AST and ALT elevation by two-fold to a level over five times the upper limit of normal (ULN), or over 300 U/l (if normal ,40 U/l) in patients with a baseline ALT level below 200 U/l [1–3]. Previous studies have labeled such

Received 3 April 2002; received in revised form 31 October 2002; accepted 26 November 2002 q The authors who have taken part in this study have not a relationship with the manufacturers of the drugs involved either in the past or present and did not receive funding from the manufacturers to carry out their research. * Corresponding author. Tel.: 1886-3-3281200, ext. 8120; fax: 1886-33282824. E-mail address: [email protected] (Y.-F. Liaw). † Current address: 222 Mai Chin Road, Keelung, Taiwan.

episodes ‘acute exacerbation’ (AE) as the results of the effort of the host to get rid of the replicating virus(es) via cytotoxic T lymphocyte mediated, class I human leucocyte antigen restricted immune reactions [4,5]. Some of the AEs may be so severe that hepatic decompensation may develop [6,7]. Since hepatic decompensation in this setting has a high mortality rate under standard supportive treatment, rescue measure(s) are needed. Lamivudine is a nucleoside analogue with rapid and potent inhibitory effects on HBV polymerase/reverse transcriptase activity [8]. Previous study has shown that patients with a pretherapy ALT level over five-fold the ULN have a hepatitis B e antigen (HBeAg) seroconversion rate of 64% after 1-year lamivudine therapy [9]. Furthermore, a pilot study using lamivudine in patients with AE of chronic hepatitis B (CHB) showed a 70% HBeAg seroconversion rate in a 6-month treatment period [10]. In addition, sporadic case reports have shown that lamivudine is safe and effective in fulminant hepatitis B [11], fibrosing cholestatic hepatitis [12], HBV

0168-8278/02/$20.00 q 2002 Published by Elsevier Science B.V. on behalf of the European Association for the Study of the Liver. doi:10.1016/S 0168 -82 78(02)00419-1

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reactivation during cytotoxic chemotherapy [13] and decompensated HBV cirrhosis [14]. These encouraging findings prompted us to conduct a trial in patients with hepatic decompensation during AE of CHB. 2. Patients and methods 2.1. Patients In a 10-month period, a consecutive series of 60 CHB patients with AE and hepatic decompensation were treated with lamivudine 150 mg daily (the dose available during the study period) as soon as the patients were hospitalized. All patients met one of the following criteria: (a) presence of hepatitis B surface antigen (HBsAg) and HBeAg in the serum for a minimum of 6 months; (b) seropositive for HBsAg but negative for IgM antiHBc in those without previous history of acute or chronic liver disease, or so called ‘previously unrecognized asymptomtic HBsAg carrier’ [15]. Patients with previous anti-viral therapy, concurrent hepatitis A virus (HAV), hepatitis C virus (HCV) or hepatitis delta virus (HDV) infection were excluded. Drugs and alcohol were also excluded as likely cause. ‘Acute exacerbation’ was defined as a phenomenon of abrupt elevation of ALT (n , 36 U/l) to more than 300 U/l in patients with chronic hepatitis whose original ALT levels were less than five times the ULN and whose bilirubin levels were within the normal limit, or twofold elevation of ALT to a level more than five times ULN [1–3]. Patients were considered as having hepatic decompensation if they had jaundice and prolongation of prothrombin time (PT) over 3 s and/or if they developed ascites and/or features of hepatic encephalopathy [6]. Liver cirrhosis was diagnosed histologically or by characteristic ultrasonography findings [16] at least twice 4– 6 months apart. As a historical control, another consecutive series of 31 CHB patients with AE resulting in hepatic decompensation hospitalized in an immediate past 6-month period were enrolled for comparison.

2.2. Evaluation During admission and follow-up visit, serial serum samples were assayed for PT, AST, ALT, bilirubin, albumin, a-fetoprotein (AFP) and markers of HBV replication. All biochemical tests were carried out in the clinical pathology laboratories of Chang Gung Memorial Hospital with routine automated techniques. Immunoglobulin M class anti-HAV (IgM antiHAV) and hepatitis B core antigen (IgM anti-HBc), HBsAg, antibody to HDV, HBeAg and anti-HBe, were assayed using commercially available radioimmunoassay kits (HAVABM, CORABM, Austria II, and anti-delta, Abbott Laboratories North Chicago, Il, HBeAg/anti-HBe test, Diasorin, Saluggia, Italy). Serum antibodies to HCV (anti-HCV) was assayed using a third generation enzyme immunoassay kit (AxSYM wHCV. Version 3.0 Abbott Lab). The first available stored serum specimen during admission in 22 control patients and three lamivudine treated patients was assayed for HBV DNA retrospectively. Serum HBV-DNA was quantified using a crosslinking chemical hybridization assay (XLnt TM, Naxcor, Menlo-Park, CA), which has been shown to be more sensitive and specific than branchedDNA signal amplication assay [17]. The sensitivity of this test is 1.8 pg/ml. HCV-RNA was qualitatively assayed using a combined reverse transcription-polymerase chain reaction (RT-PCR) (Amplicor HCV Monitor Test; Roche Diagnostic Inc., Indianapolis, Indiana). The detection threshold for the RT-PCR assay is100 copies/ml.

2.3. Statistical analysis Results are given as mean ^ standard deviation(SD) or median ranges as summarized in Table 1. Analysis was conducted using two-sample t test, Mann–Whitney test , the x 2 test and Fisher’s exact test where appropriate. All statistical testing was two tailed at the 5% level. Stepwise logistic regression was performed to determine if mortality is related to the following baseline variables: treatment, age, gender, pretherapy levels of ALT,

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HBV DNA, albumin, bilirubin, AFP, prolongation of PT, status of HBeAg, presence of liver cirrhosis, ascites, hepatic encephalopathy and Child–Pugh scores. Age, pretherapy levels of ALT, HBV DNA, albumin, bilirubin, AFP, prolongation of PT and Child–Pugh scores were fitted as continuous variables. The stepwise logistic regression model was used with generous P value for entry ðP ¼ 0:2Þ and exit ðP ¼ 0:25Þ criteria so that the study was controlled for characteristics with a marginal association. Statistical significance was tested by maximum likelihood function. Two patients with missing albumin value and one patient with missing AFP data were not included in the logistic regression analysis. The analysis results were presented in Table 2. The analysis software was Statistical Package for Social Science (SPSS Inc. Chicago, Illinois.) version 10.0.

3. Results The clinical features and laboratory data including gender, HBeAg status, levels of albumin, ALT, total bilirubin, PT, HBV DNA, AFP, ascites, hepatic encephalopathy, Child–Pugh scores, median follow-up period, and proportion of patients with cirrhosis were comparable between lamivudine treated patients and controls (Table 1), except that patients in the control group were younger than those in treated group with a marginal significance (39.9 ^ 13.2 vs. 44.9 ^ 12.2 years, P ¼ 0:041). The serum HBV DNA levels were undetectable upon admission in 28% of treated and 23% of control patients. Patients with undetectable serum HBV DNA levels presented with significantly higher bilirubin levels than those with detectable serum HBV DNA (27 ^ 10 mg/dl vs. 20 ^ 12 mg/dl in treated group and 24 ^ 7 mg/dl vs. 15 ^ 9 mg/dl in controls; P , 0:05, respectively). Otherwise the clinical features and mortality rate were similar between those with undetectable and detectable serum HBV DNA levels in both groups (5/11 or 45% vs. 18/49 or 37% in treated group and 0/3 or 0% vs. 10/28 or 36% in control group; P . 0:05). The median treatment period of lamivudine was 6 weeks (range; 1–48 weeks). No side effects was observed during lamivudine therapy in present study. The morbidity and mortality in hepatic decompensation during acute exacerbation of chronic hepatitis B are shown in Fig. 1. A total of 18 patients (30%) in the treated group and 11 patients (35%) in control group developed ascites upon admission and during the clinical course. The incidence was significantly higher in patients with initial bilirubin level $20 mg/dl in both groups. Hepatic encephalopathy occurred upon admission in one-tenth of the patients and increased to one-fourth of the patients in both groups during the clinical course. Notably, over 90% of them died thereafter. The incidence was significantly lower in patients with initial bilirubin level ,20 mg/dl in treated group, as compared with the counterpart in control group (0/ 25 vs. 5/20; P ¼ 0:013) and those with bilirubin level $20 mg/dl in treated group (0/25 vs. 17/35; P , 0:0001). One male patient in the treated group with initial bilirubin level of 38.5 mg/dl underwent liver transplantation after 1 month lamivudine treatment. Serial serum creatinine values were measured in 42 patients with initially rising bilirubin

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Table 1 Baseline clinical and laboratory data in patients with hepatic decompensation during acute exacerbation of chronic hepatitis B a Data

Lamivudine (N ¼ 60)

Control (N ¼ 31)

P value

Age (year, mean ^ SD) Male Previously unrecognized asymtomatic chronic HBsAg carrier HBeAg (1) Albumin (gm/dl) b ALT (IU/l) b Total bilirubin (mg/dl) b Less than 10 10–20 20–30 More than 30 Prothrombin time seconds prolonged b 3–5 More than 5 HBV DNA (pg/ml) b Less than 1.8 1.8–100 100–1000 More than 1000 Cirrhosis AFP (ng/ml) b . 100 Ascites Hepatic encephalopathy Child-Pugh scores b Follow-up (weeks) b

44.9 ^ 12.2 52 (87) 13 (22)

39.9 ^ 13.2 28 (90) 9 (29)

0.041 0.867 0.603

23 (38) 3.1 (2.2–4.9) 917 (92–2956) 22.0 (1.7–47.7) 12 (20) 13 (22) 19 (32) 16 (27) 9.7 (3.2–58.9)

15 (48) 3.5 (2.3–4.9) 997 (85–2851) 17.8 (2.4–36.7) 8 (26) 12 (39) 7 (23) 4 (13) 9.4 (3.1–43.6)

0.486 0.112 0.626 0.065 0.185

11 (18) 49 (82) 22 (0–21204) 17 (28) 18 (30) 9 (15) 16 (27) 19 (32) 125.5 (3–4660) 36 (60) 15 (25) 5 (8) 11 (6–13) 6 (1–48)

10 (32) 21 (68) 58.6 (0–10120) 7 (23) 9 (29) 5 (16) 10 (32) 8 (26) 128 (6–1480) 16 (52) 11 (35) 2 (6) 9 (7–13) 8 (1–52)

0.218

a b

0.269

0.288 0.918

0.735 0.894 0.421 0.924 0.714 0.245

Data expressed as No.(%); NS, not significant. Data expressed as median (range).

level, 33 (79%) showed deterioration of renal function (median creatinine 3.7 mg%, range 2.1–8.7 mg%). The majority of them died thereafter. The dose of lamivudine was not adjusted because relatively higher dose was desirable in such grave condition. During the study, 38% of treated patients and 29% of the controls died. One third of the patients who died had underlying cirrhosis in both treated and control (35% vs. 22%;

P . 0:05). Of the patients with serum bilirubin ,20 mg/dl, all 25 lamivudine treated patients survived, while five (25%) of 20 untreated died (P ¼ 0:013; OR, 2.667; 95% CI, 1.787– 3.979) (Fig. 2). The difference in mortality was still significant if only patients with detectable serum HBV DNA were compared ðP ¼ 0:048Þ. But in patients with serum bilirubin level $20 mg/dl, there was no significant difference in mortality between lamivudine treated and untreated

Table 2 Stepwise logistic regression analysis on baseline variables and mortality a Baseline variables Treatment with lamivudine Yes ¼ 1 No ¼ 0 Total bilirubin (mg/dl) b Prolongation of PT (s) b Presence of ascites Yes ¼ 1 No ¼ 0 Child–Pugh scores Constant a b

Regression coefficent

Standard error

OR (CI)

P value

2 1.155

0.834

0.315 (0.061–1.617)

0.166

0.073 0.216

0.040 0.077

1.076 (0.995–1.164) 1.241 (1.067–1.443)

0.067 0.005

2 1.862

1.042

0.155 (0.020–1.198)

0.074

1.279 2 16.590

0.468 4.793

3.592 (1.434–8.996) 0.000

0.006 0.001

Abbreviations: OR(CI), odds ratio (9 5% confidence interval); PT, prothrombin time. The first value on admission.

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Fig. 1. The morbidity and mortality in hepatic decompensation during acute exacerbation of chronic hepatitis B. The incidence was significantly lower in patients with initial bilirubin level ,20 mg/dl in treated group, compared to control and those bilirubin level $20 mg/dl in treated patients. Data are means ^ SE. *P , 0.05; **, ***P , 0.0001. The vertical arrows indicate the proportion is 0% in each bars. Abbreviations: AS, ascites; FHF, fulminant hepatic failure; HE, hepatic encephalopathy.

patients. During a 4-month follow-up, there were significant improvement in both bilirubin level and prothrombin time in patients who survived. In addition, among patients who survived with available Child–Pugh assignment at both baseline and last study visit, 38 (78%) improved ($2 points) and 11 (22%) remained unchanged. There were neither ALT nor HBV DNA breakthrough developed through the whole clinical course. The relationship between mortality and dynamic changes of bilirubin levels during the clinical course are shown in Fig. 2. All patients with progressive rise of bilirubin levels

died, regardless of initial bilirubin level or lamivudine treatment (P # 0:001 in both initial bilirubin level ,20 and $20 mg/dl groups). None of the patients with initial bilirubin level ,20 mg/dl treated with laminudine showed persistently rising bilirubin levels and all survived. In contrast, four (20%) of the 20 counterparts in the control group showed progressive rise of bilirubin level and all four died (0/25 or 0% vs. 4/20 or 20%, P ¼ 0:033). In addition, 21 patients showed ‘rise and fall’ bilirubin levels. Among them, three (27%) of 11 patients with initial bilirubin level $20 mg/dl died. Of 41 patients demonstrated ‘fall’ bilirubin

Fig. 2. The relationship between mortality and dynamic changes of bilirubin level. None of the patients with initial bilirubin levels ,20 mg/dL treated with lamivudine showed persistently rising bilirubin levels and all survived. In contrast, four (20%) of the 20 counterparts in the control group showed progressive rise of bilirubin level and all died. Data are means ^ SE. *P ¼ 0.001; ** P ¼ 0.013. The vertical arrows indicate the proportion is 0% in each bars.

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levels, only one (3%) in the control died. There is no statistical difference between treated patients and controls. Stepwise logistic regression analysis disclosed both prolongation of PT and baseline Child–Pugh scores were a significant predictor of mortality (P ¼ 0:005 and P ¼ 0:006, respectively), while baseline total bilirubin level and presence of ascites showed a marginal effect to predict mortality (P ¼ 0:067 and 0.074, respectively) (Table 2).

4. Discussion Previous studies have shown that 2.4% of AE in chronic hepatitis and 13.8% of AE in liver cirrhosis may develop hepatic decompensation [6,7], and the mortality rate in such patients was reported to be very high [18,19]. The overall mortality rate in the present series of untreated AE patients with decompensation was ,40%, which is much lower than a rate of 63–81% in previous reports [18,19]. Since virus superinfection, especially HCV and HDV, in previously unrecognized chronic HBsAg carrier or chronic hepatitis B is the major etiology of fulminant viral hepatitis and subacute hepatic failure in Taiwan [20,21], the exclusion of HCV or HDV superinfected patients may be responsible for the relatively lower mortality in the present study. Previous studies in Taiwan have shown that male patients with chronic hepatitis B were 1.45 times more likely to have abnormal ALT levels than women [22], and 85–90% of episodes of acute exacerbation occurred in male [1]. Present study is in consistent with previous observation. In addition, in severe exacerbation, such as bridging hepatic necrosis or those with AFP greater than 100 ng/ml, is more likely to be followed by HBeAg seroconversion [23]. Furthermore, in acute exacerbation, serum HBV-DNA usually increase to its peak level before the peak of ALT, and decrease precipitously thereafter [24]. Hence, it is conceivable that 60% of patients in present study in both groups have negativity of HBeAg and one-fourth of patients have undetectable serum HBV DNA. The results of the present study have shown that lamivudine may prevent fatality of AE patients with hepatic decompensation if therapy starts early enough, that is before serum bilirubin level rises over 20 mg/dl (0% vs. 25%, P ¼ 0:013; OR, 2.667; CI, 1.787–3.979). However, the case number in the present study is limited. This warrant further investigation in larger trials. Actually, we have since treated 71 patients with hepatic decompensation during AE of chronic hepatitis B with lamivudine 100 mg orally per day in the following one and half a year, including 46 (66%) patients with initial bilirubin level ,20 mg/dl, and found three (6.5%) patients died thereafter (Chien and Liaw, unpublished data). Put these data together with the treated patients in the present study, there were three (4.2%) out of 71 patients in the treated group died, compared to five (25%) of 20 patients in control group. The statistical analysis was still significant ðP ¼ 0:012Þ. One may argue that the present

study used a historical control instead of a randomized controlled group. Since patients with an ALT level .5XULN may be developing hepatic decompensation and lamivudine has a very rapid action and is highly effective in this group of patients [9,10,25], it seems not ethical to conduct a randomized controlled study in AE patients with or without hepatic decompensation. Of note is that progressive rise of bilirubin level is a grave prognosis sign as all 29 such patients, with or without lamivudine therapy, died. More importantly, none patients having lamivudine therapy before their bilirubin level was over 20 mg/ml showed progressive rise of serum bilirubin level and all survived. Even those having lamivudine therapy after their bilirubin level rised over 20 mg/ml, all seven patients with declining bilirubin and five of eight patients with bilirubin rise/ fall pattern survived. In conclusion, the results of the present study suggest that lamivudine therapy may prevent fatality of AE patients with hepatic decompensation if therapy starts before serum bilirubin level rise over 20 mg/dl, but fail to improve prognosis if therapy starts when serum level has already rised over that level. We therefore recommend to start lamivudine therapy as soon as a deteriorating AE is recognized to prevent hepatic decompensation in time or to reduce the fatality.

Acknowledgements The authors thank the critical review of biostatistics of assistant Professor M.C. Chen, excellent technical assistance of C.Y. Chen and the secretarial assistance of S.C. Chen and S.L. Chen. This study was supported by a grant from Chang Gung Research Fund (CMRP 800) and the Prosperous Foundation, Taipei, Taiwan.

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