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Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. References

Background:

Exacerbation of chronic hepatitis B infection can lead to fulminant hepatic failure with a mortality of up to 90%.

Aim:

To evaluate the efficacy of lamivudine in the treatment of this subgroup of patients.

Methods:

Twenty-four patients with exacerbation of chronic hepatitis B infection and fulminant hepatic failure were treated with lamivudine, 100 mg daily. Hepatitis A, C, D and human immunodeficiency virus co-infections and hepatocellular carcinoma were excluded.

Results:

The median age was 53 years (range, 24–77 years) with a male predominance of 20:4. Seventeen patients were hepatitis B e antigen positive. Mean hepatitis B virus DNA was 2079 Meq/mL. Eight patients (33%) survived (group A). Thirteen patients died and three patients received liver transplantation (67%) (group B). Baseline laboratory results were comparable between the two groups, including serum albumin, bilirubin, alanine aminotransferase, prothrombin time and creatinine. Group B patients had significantly more comorbid illnesses at baseline and more complications, including sepsis and renal failure, compared with group A patients. Six out of eight survivors (75%) had full hepatitis B e antigen seroconversion, but this was not sustained in four patients.

Conclusions:

Lamivudine may be useful in treating patients with fulminant hepatic failure due to exacerbation of chronic hepatitis B. Hepatitis B e antigen seroconversion was less durable in this subgroup of patients and long-term therapy may be required.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. References

Chronic hepatitis B infection is a major global health problem with an estimated 400 million hepatitis B carriers world-wide.1 Spontaneous acute exacerbation of chronic hepatitis B infection is relatively common, with a cumulative probability of 15–37% after 4 years of follow-up.2 Positive hepatitis B e antigen (HBeAg), elevated transaminase levels at presentation and male gender are associated with more frequent development of acute exacerbation.2 Severe reactivation of chronic hepatitis B infection can lead to fulminant or subfulminant hepatic failure.3–5 The prognosis of patients with fulminant hepatic failure (excluding acetaminophen-induced liver failure) is extremely poor, with a mortality of 65–93%.6 Liver transplantation has been the only therapy available to salvage patients with fulminant liver failure,7–9 with a 5-year survival rate of around 61%.10

Lamivudine is a nucleoside analogue that has been shown to be highly effective in suppressing hepatitis B virus replication in compensated chronic hepatitis B infection with concomitant normalization of liver transaminases and improvement in histology.11, 12 There have been case reports of the use of lamivudine in the treatment of icteric hepatitis due to reactivation of chronic hepatitis B infection and decompensated chronic hepatitis B cirrhosis.13–18 These reports indicated a better response if lamivudine was instituted early. In this paper, we report the role and efficacy of lamivudine in patients with fulminant exacerbation of chronic hepatitis B.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. References

Between January 1996 and December 1999, 24 patients suffering from fulminant hepatic failure and severe reactivation of chronic hepatitis B infection were identified. Fulminant hepatic failure was defined as hepatic encephalopathy occurring within 8 weeks from the onset of jaundice.19 Other inclusion criteria included: (i) the presence of hepatitis B surface antigen in the serum for at least 6 months; (ii) evidence of active viral replication as documented by positive HBeAg or measurable hepatitis B virus DNA in the serum; and (iii) flare of hepatitis, defined as serum alanine aminotransferase more than five times the upper limit of normal.20 Super-infection or coinfection with hepatitis A, C, D and human immunodeficiency virus and hepatocellular carcinoma were exclusion criteria. All patients were treated with lamivudine, 100 mg daily.

Full clinical and laboratory assessments, including full blood counts, clotting profiles, electrolytes, liver biochemistry, virological tests and abdominal ultrasound examination, were performed at baseline. Lactulose, vitamin K, H2 antagonists and antibiotics (after full sepsis work-up) were administered when indicated. Patients were closely monitored in hospital for complications, including hepatic encephalopathy, sepsis, renal failure and gastrointestinal bleeding. Patients who had attained the King’s College criteria for liver transplantation were referred for this procedure.21 The survivors were followed up at weeks 1, 2, 4 and 8 after discharge and every 3 months thereafter. HBeAg, anti-HBe antibody, serum albumin, total bilirubin, alanine aminotransferase and prothrombin time were monitored during follow-up. Hepatitis B virus DNA levels were determined when HBeAg seroconversion occurred or at six-monthly intervals. Lamivudine was discontinued when full HBeAg seroconversion (HBeAg, anti-HBe antibody positive, normal alanine aminotransferase and undetectable hepatitis B virus DNA) was documented on two consecutive occasions at least 3 months apart.

GlaxoWellcome Research Development (UK) provided lamivudine on a compassionate basis. Hepatitis B surface antigen, immunoglobulin M anti-HBc antibody, immunoglobulin M anti-hepatitis A virus antibody and anti-hepatitis C virus antibody were measured using immunoenzymatic assays (Abbott Laboratories Ltd, Germany). HBeAg and anti-HBe antibody were measured by immunoenzymatic assays (Sanofi Diagnostics Pasteur, France). Human immunodeficiency virus antibody testing was also performed with an immunoenzymatic assay (Murex Biotech, UK). Serum hepatitis B virus DNA was measured by branched-chain DNA assay (Quantiplex, Chiron Corp., Emeryville, CA, USA). A two-tailed Mann–Whitney U-test and Fisher’s exact test were used to compare continuous and categorical data, respectively. Statistical significance was taken at P < 0.05. A survival curve was constructed using the Kaplan–Meier method.

The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki and was approved by the Clinical Research Ethics Committee of the Chinese University of Hong Kong. All patients or their relatives gave informed consent to participate in this study.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. References

The baseline characteristics of the 24 patients are given in Table 1. The median age of the whole cohort was 53 years (range, 24–77 years) with a male predominance (20:4). Five patients (21%) were immunoglobulin M anti-HBc antibody positive. Only two patients (patients 12 and 20) had no hepatitis B virus DNA measured, but both were HBeAg positive. Six patients (25%) had a history of alcohol consumption, but none drank more than 20 g per day. Patients 3 and 18 were taking prednisolone, 5 mg daily, but had received no recent dosage adjustment. Patients 13 and 21 were undergoing chemotherapy at the time of flare up of hepatitis, whereas patient 17 had finished chemotherapy 2 months previously. There was no history of recent introduction of other potentially hepatotoxic drugs, including herbal medicine.

Table 1.   Baseline characteristics, peak liver function tests and outcome in patients with fulminant liver failure due to hepatitis B virus reactivation Thumbnail image of

Jaundice (79%), dark urine (75%), malaise (58%), abdominal pain (36%), fever (23%), abdominal distension (21%), nausea and vomiting (9%) and confusion (9%) were the most common symptoms at presentation. All patients developed grade 1 hepatic encephalopathy within 3 weeks of jaundice. Lamivudine was started on day 1 to day 30 after admission (median, day 7). During hospitalization, complications developed in 18 patients; 10 patients (42%) had renal impairment, 10 (42%) had pneumonia, four (17%) had spontaneous bacterial peritonitis, two (8%) had urinary tract infection and one (4%) had gastrointestinal haemorrhage. Thirteen patients (54%) died. Three of the eight survivors and 13 of the 16 patients who died had attained the King’s College criteria for liver transplantation. Two patients had cadaveric liver transplantation and one patient had a living-related liver transplantation, and they were still alive at 14 months, 19 months and 12 months, respectively, following transplantation. The probability of transplant-free survival at 12 weeks was 33% (Figure 1). Of the eight survivors, seven were alive at their last visits at 27, 38, 50, 28, 35, 30 and 30 months. Patient 7 died of hepatocellular carcinoma 10 months after discharge from hospital.

image

Figure 1.  Transplant-free survival curve of patients with fulminant liver failure due to severe reactivation of chronic hepatitis B infection.

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Liver histology was available in eight patients. Three of the non-survivors had post-mortem examinations which confirmed the presence of massive hepatic necrosis (patients 13, 21 and 24) and cirrhosis (patients 21 and 24). The three explanted livers from patients 9, 10 and 11 also showed cirrhosis with severe cholestasis and submassive hepatic necrosis. Patient 5 had a liver biopsy more than 1 year after the initial episode of liver failure, and this showed mild chronic hepatitis with cirrhosis. Patient 17 had a liver biopsy confirming the presence of cirrhosis 1 year before her episode of liver failure, but declined a repeat biopsy.

Patients were classified into two groups: patients in group A survived without liver transplantation (eight patients) and patients in group B died of liver failure or received liver transplantation (16 patients). Group B patients had significantly more baseline comorbid illnesses compared with group A patients (Tables 1 and 2. Otherwise, there was no difference in the baseline liver biochemistry, renal function and viraemic status between the two groups (Table 2). Group B patients also had significantly more complications developing during hospitalization, including sepsis (such as pneumonia, urinary tract infection and spontaneous bacterial peritonitis; 14 vs. 2; P=0.005) and renal impairment (as indicated by serum creatinine above the upper limit of normal; 10 vs. 0; P=0.006), and greater impaired renal and liver biochemistry vs. group A patients (Table 3).

Table 2.    Baseline characteristics of group A patients (survivors) and group B patients (non-survivors, including three orthotopic liver transplant patients) with fulminant liver failure due to reactivation of chronic hepatitis B infection Thumbnail image of
Table 3.   Complications and maximum laboratory values of group A patients (survivors) and group B patients (non- survivors, including three orthotopic liver transplant patients) Thumbnail image of

Full HBeAg seroconversion was documented in six out of eight (75%) patients (patients 1–5 and 8) during lamivudine treatment. They achieved HBeAg seroconversion at months 5, 21, 6, 4, 6 and 16, respectively. However, the HBeAg reverted back to positive in four patients (patients 2–5), with relapse of hepatitis at 3, 1, 3 and 7 months, respectively, after the cessation of therapy. Patient 4 developed liver failure during his relapse of hepatitis, with serum alanine aminotransferase, total bilirubin and prothrombin time peaking at 2000 IU/L, 348 μmol/L and 24.5 s, respectively. He fortunately responded to the reintroduction of lamivudine treatment (Figure 2). The other three patients responded to lamivudine treatment during their hepatitis relapse. A durable response was seen in patients 1 and 8, and lamivudine was discontinued after 9 months and 19 months of therapy, respectively. They remained well, with normal liver function, negative HBeAg, positive anti-HBe antibody and undetectable hepatitis B virus DNA, 24 and 4 months after cessation of lamivudine therapy, respectively. Patient 6 had an incomplete HBeAg seroconversion, with mild elevation of alanine aminotransferase (73–91 IU/L) after the HBeAg converted to anti-HBe antibody and the disappearance of hepatitis B virus DNA. Concomitant liver diseases, such as autoimmune hepatitis, Wilson’s disease, haemochromatosis and alpha-1-antitrypsin deficiency, were all excluded. Liver biopsy showed only minimal chronic hepatitis with mild fibrosis. He continued to take lamivudine.

image

Figure 2.  Clinical course of patient 4 showing severe reactivation of hepatitis after stopping lamivudine (Lam). ALT, alanine aminotransferase; HBV, hepatitis B virus; TB, total bilirubin.

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DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. References

The treatment of chronic hepatitis B has been revolutionized by the recent introduction of lamivudine, which is the first nucleoside analogue licensed for this condition by the Food and Drug Administration (USA). Studies have shown that lamivudine can produce a rapid reduction in hepatitis B virus DNA levels in both HBeAg positive and negative patients with compensated liver disease.10, 22 This is associated with the gradual normalization of serum alanine aminotransferase and a significant reduction in the histological activity index. In addition, lamivudine was shown to reduce significantly the Child–Pugh scores of some decompensated, end-stage cirrhotic patients awaiting liver transplantation. A few of these patients were de-listed from liver transplantation.16, 17

Data regarding the mortality rate and efficacy of lamivudine in the subgroup of patients with chronic hepatitis B infection with fulminant hepatitis B virus reactivation are lacking in the literature. Mortality rates of 0–60% have been reported in case series of cytotoxic drug-induced hepatitis B virus reactivation.23–26 In addition, one study of the spontaneous reactivation of chronic hepatitis B virus showed that two of 10 (20%) patients died.27 However, these studies included a small number of patients with varying degrees of liver dysfunction, ranging from mild icteric hepatitis to fulminant liver failure. In contrast, all of our patients had fulminant liver failure as indicated by the presence of hepatic encephalopathy. The mortality rate in this subgroup of patients without liver transplantation approached 90%.28 In our study, the overall mortality rate (including the three patients with liver transplantation) was 67%, suggesting that lamivudine may be effective in this subgroup of patients. However, direct comparison with historical controls is associated with potential pitfalls and biases. In the ideal situation, a double-blind, placebo-controlled, randomized trial would be the most appropriate way to address this issue. There were two reasons why we did not include a control group in our study. Firstly, fulminant hepatic failure is a rare complication of reactivation of chronic hepatitis B infection (even in areas of high endemicity), and therefore we would have encountered great difficulty in recruiting a sufficient number of patients to conduct a controlled trial. Secondly, many of these patients would have been considered for liver transplantation, and hence withholding lamivudine would have been unethical.

In this study, only 33% survived without transplantation despite lamivudine treatment. Why was lamivudine ineffective in the majority of patients? Factors other than viral replication have a great impact on the prognosis. The livers of these patients had already undergone massive or submassive hepatic necrosis (as confirmed by histological examinations in six patients). Suppressing viral replication with lamivudine at this late stage was unlikely to be effective, as the main determinants for recovery are liver regeneration and the rapid cessation of ongoing necro-inflammation. Both factors are not directly dependent on hepatitis B virus, and both would take time to achieve. During this vulnerable period, these patients developed complications, including sepsis and renal failure, and many of the nonsurvivors died of multiorgan failure. Nine of the 16 patients (nonsurvivors and transplant recipients) had evidence of liver cirrhosis at the time of presentation. These patients may not be able to tolerate a severe flare up of hepatitis. There was a median delay of 7 days before starting lamivudine that could have affected the efficacy of this drug. The delay was unavoidable due to the compassionate use procedure.

Villeneuve et al., Yao and Bass and Kapoor et al. reported that lamivudine was efficacious in improving the Child–Pugh scores of patients with decompensated liver cirrhosis.16–18 However, there were several important differences between our patients and those reported in the above three studies. Firstly, all of our patients had a severe flare up of hepatitis (mean alanine aminotransferase, 1011 IU/L) compared with mild alanine aminotransferase elevation (means: 85 IU/L, 101 IU/L and 112 IU/L16–18) in the patients in the above studies. Secondly, our patients were either healthy chronic hepatitis B virus carriers or compensated cirrhotics just prior to their current hospital admission. In contrast, the whole cohort described by Villeneuve et al. and Yao and Bass had end-stage liver cirrhosis, and many had been listed for liver transplantation even before lamivudine therapy.

The mean baseline liver function tests and hepatitis B virus DNA levels were comparable between survivors (group A) and nonsurvivors (group B), suggesting that the two groups of patients had a flare up of hepatitis of similar severity. However, we found that nonsurvivors had significantly more comorbid illness, and tended to develop sepsis and renal failure during hospitalization. In addition, nonsurvivors had significantly higher peak serum urea, creatinine, total bilirubin and prothrombin time. Our findings concurred with published data from Taiwan showing that age, total bilirubin and prothrombin time were independent predictive factors for mortality in patients with fulminant hepatic failure.29 All patients who developed renal failure died. This was not at all surprising, as previous studies have shown nearly 100% mortality in fulminant liver failure complicated by renal impairment.30

Data from an Asian multicentre trial have suggested that high pre-treatment alanine aminotransferase levels can predict the development of HBeAg seroconversion. Sixty-four per cent of patients with pre-treatment alanine aminotransferase more than five times that of normal achieved HBeAg seroconversion.31 A study from the USA has suggested that lamivudine can be safely discontinued following the documentation of HBeAg loss or seroconversion.32 However, further data from Korea indicated that this HBeAg seroconversion might not be sustained.33 Six of eight (75%) survivors had full HBeAg seroconversion, but four patients (67%) had relapse of hepatitis and one (patient 4) had severe icteric hepatitis with hepatic decompensation after the cessation of lamivudine. Fortunately, all relapses responded to retreatment with lamivudine. Therefore, we caution the premature discontinuation of lamivudine. If the drug is to be stopped, patients should be monitored very closely for reactivation of hepatitis, and reintroduction may be required in these cases. We have not detected any clinical evidence of drug-resistant mutants during lamivudine treatment in our eight survivors so far, but we do expect the emergence of mutants as these patients continue to be treated.

We conclude that, when patients with chronic hepatitis B experience acute exacerbation, lamivudine treatment should be instituted early to prevent decompensation and fulminant liver failure. This is likely to reduce morbidity and mortality. Patients with baseline comorbid illness and those who develop sepsis, renal failure and marked liver function derangement during the course of disease are the most likely to die. Early treatment before the development of hepatic encephalopathy may be efficacious in abrogating the flare up of hepatitis, and may thus prevent the development of fulminant hepatic failure. We are currently adopting this approach. Despite the high HBeAg seroconversion rate among patients with active disease, this seroconversion was not durable on stopping treatment. The option of long-term lamivudine therapy is overshadowed by drug-resistant YMDD (tyrosine, methionie, aspartate, aspartate) variants. However, in patients with cirrhosis and/or a history of decompensation, there may be no other viable alternative at present. Combination with newer anti-virals may provide a more long-term solution.

References

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. References
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