A combination treatment of entecavir and early-phase corticosteroid in severe exacerbation of chronic hepatitis B

Abstract

Of patients with severe exacerbation of chronic hepatitis B accompanied by jaundice and coagulopathy, 20%-30% have a fatal outcome. In this report, we describe 2 cases of severe exacerbation of chronic hepatitis B with jaundice and coagulopathy who were successfully treated with a combination of entecavir and corticosteroid. In both cases, rapid reductions in serum hepatitis B virus (HBV)-DNA levels were observed, and corticosteroid was stopped after serum HBV-DNA levels became undetectable. Entecavir treatment was continued. Generally, entecavir treatment reduced serum HBV-DNA levels rapidly, although the improvement in liver function was delayed by a few weeks. During this time lag, liver cell injury continued and the disease progressed. Corticosteroid suppressed the excessive host immune response and was useful for stopping progressive deterioration. A combination of entecavir and early-phase corticosteroid may be a useful treatment in severe exacerbation of chronic hepatitis B.

Key Words: Acute exacerbation, Chronic hepatitis B, Corticosteroid, Entecavir, Hepatitis B virus, Hepatic coma

INTRODUCTION

An estimated 400 million people worldwide have chronic hepatitis B virus (HBV) infection, and more than 500 000 people die every year from complications of HBV-related chronic liver disease[1]. In patients chronically infected with HBV, acute exacerbations are clinically important because they can have severe or even fatal consequences[2]. An estimated 10%-30% of hepatitis B carriers experience acute exacerbation each year[3]. Hepatitis B e antigen (HBeAg) seroconversion and mortality occur in 2.7% and 0.7% of patients with acute exacerbation, respectively[4]. On the other hand, mortality occurs in 20%-30% of cases with severe exacerbation accompanied by jaundice and coagulopathy[56].

In the past decade, lamivudine (LMV) has revolutionized the treatment of chronic hepatitis B. Treatment with LMV significantly decreases the rate of hepatic decompensation and prevents the development of hepatocellular carcinoma[7]. On the other hand, LMV monotherapy confers no significant protection against rapid progression to hepatic failure in severe exacerbation of chronic hepatitis B, although LMV results in long-term benefits[5]. Furthermore, viral resistance, which is usually followed by a loss of clinical response, a rise in aminotransferase levels and worsening of hepatic histology, is related to mutations in the tyrosine-methionine-aspartate-aspartate (YMDD) motif which occurs in 70%-80% of patients treated continuously for 4-5 years[8]. Recently, the early introduction of high-dose corticosteroid was reported to improve the short-term prognosis of patients with severe exacerbation of chronic hepatitis B[9].

In this report, we describe 2 cases with severe exacerbation of chronic hepatitis B successfully treated with a combination of entecavir (ETV) and corticosteroid.

CASE REPORT

Case 1

A 33-year-old Japanese man was admitted to our hospital with general fatigue. He had been diagnosed as a carrier of HBV but had never received treatment. His family history included chronic hepatitis B in his late mother, who had died of severe exacerbation of the disease. On physical examination at admission, he was conscious and the bulbar conjunctiva was not icteric. Neither ascites nor pretibial edema was noted. Laboratory data on admission were as follows: bilirubin, 19 mg/L; aspartate aminotransferase, 698 IU/L; alanine aminotransferase, 756 IU/L; albumin, 33 g/L; and prothrombin activity, 47.7%. He was positive for both hepatitis B surface antigen (HBsAg) and HBeAg, and his serum HBV-DNA level measured by real-time quantitative polymerase chain reaction (TaqMan PCR, Roche Diagnostics) was 2.6 LGE/mL. He was diagnosed with severe exacerbation of chronic hepatitis B, and oral ETV treatment (0.5 mg/d) was initiated. On his fifth day of hospitalization, prednisolone (30 mg/d) was added. At 6 wk, his serum transaminase level was normal, after which the dose of prednisolone was tapered. At 12 wk, his serum HBV-DNA level was 3.3 LGE/mL and prednisolone was stopped. Since then, his transaminase level has remained normal (Figure 1).

Figure 1 Patient clinical course. ALT: Alanine aminotransferase; PT: Prothrombin activity; T. Bil: Total bilirubin; HBV DNA: Hepatitis B virus DNA. At 6 wk, his serum transaminase level was normalized. At 12 wk, his serum HBV-DNA level became 3.3 LGE/mL and prednisolone was stopped.

Case 2

A 44-year-old Japanese woman was admitted to our hospital with general fatigue and anorexia. She had been diagnosed as a carrier of HBV but had never received treatment. Her family history included a father who was a carrier of HBV. On physical examination at admission, she was conscious and her bulbar conjunctiva was icteric. Neither ascites nor pretibial edema was noted. Laboratory data on admission were as follows: bilirubin, 96 mg/L; aspartate aminotransferase,

1389 IU/L; alanine aminotransferase, 573 IU/L; albumin, 31 g/L; and prothrombin activity, 22.7%. She was positive for both HBsAg and HBeAg, and her serum HBV-DNA level measured by transcription-mediated amplification assay (Roche Diagnostics) was 5.3 LGE/mL. She was diagnosed with severe exacerbation of chronic hepatitis B. A combination treatment of oral ETV (0.5 mg/d) and intravenous methylprednisolone (250 mg/d) was immediately started. One her sixth day of hospitalization, intravenous methylprednisolone was changed to oral prednisolone (50 mg/d). At 8 wk, her serum transaminase level was normal and her serum bilirubin levels and prothrombin activity were improved to 68.8% and 29 mg/L, respectively. Subsequently, the dose of prednisolone was tapered. At 15 wk, her serum HBV-DNA level became undetectable and prednisolone was stopped. One year later, her ETV treatment has continued, and her serum HBV-DNA level has continued to be undetectable (Figure 2).

Figure 2 Patient clinical course. ALT: Alanine aminotransferase; PT: Prothrombin activity; T. Bil: Total bilirubin; HBV DNA: Hepatitis B virus DNA. At 8 wk, her serum transaminase level was normalized. At 15 wk, her serum HBV-DNA level became undetectable and the prednisolone was stopped.

DISCUSSION

ETV suppresses HBV replication significantly better than LMV. The mean reduction in serum HBV-DNA levels from baseline to week 48 is reported to be 6.9 log in HBeAg-positive patients and 5.0 log in HBeAg-negative patients[1011]. Furthermore, ETV shows a lower frequency of virologic rebound (2% in the first year of drug administration) compared with LMV. Thus, ETV is considered a first-choice therapy for patients with chronic hepatitis B not previously treated with a nucleoside analogue. However, for patients with severe exacerbation of chronic hepatitis B, treatment during the first 2 wk determines their prognosis[9]. The liver cell injury caused by HBV infection is mediated mainly by the response of CD8+ cytotoxic T lymphocytes to small epitopes of HBV proteins, especially the hepatitis B core antigen, present on the surface of liver cells[12]. ETV treatment reduces serum HBV-DNA levels rapidly, although the improvement in liver function is delayed by a few weeks. During this time lag, liver cell injury continues and the disease progresses. Corticosteroid suppresses the excessive host immune response and is useful for stopping progressive deterioration. On the other hand, patients not treated with any antiviral drugs show a subsequent rebound increase in serum transaminase levels 4 to 10 wk after withdrawal of corticosteroid[13]. Thus, we consider that a combination of ETV and early-phase corticosteroid may be reasonable for improving prognosis in severe exacerbation of chronic hepatitis B.

Corticosteroid has been reported to directly stimulate HBV replication through specific glucocorticoid receptors in the HBV genome in cultured human hepatoma cells[14]. Clinically, immunosuppressive treatment has been indicated to have a potentiating effect on HBV replication in patients with chronic active hepatitis B[15]. Furthermore, corticosteroid has been reported to delay the normalization of serum transaminase levels[16]. However, in this study, both our patients showed rapid reductions in serum HBV-DNA levels despite corticosteroid treatment. We consider that this may be attributable to the antiviral effect of ETV, which may be strong enough to overcome HBV replication activated by corticosteroid treatment.

In this study, 0.5 mg/kg or more of prednisolone was administered daily. When the patient showed a trend toward remission in serum transaminase levels, the dose of prednisolone was tapered. After serum HBV-DNA level became undetectable, prednisolone was stopped. In Japan, ETV is administered at a dose of 0.5 mg daily in order to treat chronic HBV infection in accordance with Japanese national health insurance rules. However, further study is required in order to confirm adequate doses of prednisolone and ETV in severe exacerbation of chronic hepatitis B.

In conclusion, the combination treatment of ETV and corticosteroid may improve the prognosis in severe exacerbation of chronic hepatitis B. However, this is a case report; prospective studies of large study populations are needed in order to confirm the effectiveness of this combination treatment.