Severe acute exacerbation of chronic hepatitis B during pegylated interferon treatment and early intervention with corticosteroid
© Mao et al.; licensee BioMed Central Ltd. 2012
Received: 30 December 2011
Accepted: 24 July 2012
Published: 24 July 2012
Severe acute exacerbation or liver failure induced by standard interferon-α(IFN-α) therapy had been reported to occur in few patients with chronic hepatitis B. However, no report showed that pegylated interferon-α therapy was able to induce severe acute exacerbation of chronic hepatitis B. Here, we describe three patients with severe acute exacerbation of chronic hepatitis B during pegylated interferon-α2a (Pegasys) treatment. One patient progressed into acute-on-chronic liver failure (ACLF) at the second week of Pegasys treatment. Two patients progressed into acute-on-chronic pre-liver failure (pre-ACLF) at the second and eighth week of Pegasys treatment, respectively. Three patients recovered after early combined intervention with corticosteroid and lamivudine. Our data indicated that there was a risk of severe acute exacerbation among patients with chronic hepatitis B during receiving Pegasys treatment. Importantly, early combined intervention with corticosteroid and lamivudine should be introduced to prevent the disease progression and improve their prognosis once severe acute exacerbation was diagnosed.
It is estimated that over 350 million people worldwide are chronically infected with hepatitis B virus (HBV). Chronic hepatitis B is one of the most important causes of cirrhosis and hepatocellular carcinoma . Injected interferons (standard interferon-α and pegylated interferon-α) are approved to treat chronic hepatitis B in many countries, and have been confirmed to be effective in preventing the disease progression of chronic hepatitis B. Acute exacerbation of chronic hepatitis B is not uncommon during interferon-α(IFN-α) therapy because that IFN-αexerts a variety of immuno-modulatory effects . However, there were very few reports about severe acute exacerbation of chronic hepatitis B during IFN-α therapy [3, 4]. From January 2008 to December 2010, 254 patients with chronic hepatitis B received Pegylated interferon-α2a (Pegasys) therapy in our department. During Pegasys therapy, alanine aminotransferase (ALT) flare was observed in 25.2% (64/254) patients, including 9.4% (24/254) patients with serum ALT ≥ 420 IU/L (normal range 0–42 IU/L) and serum total bilirubin (T-Bil) ≤ 51.3 μmol/L (normal range 6–17.1 μmol/L), and 1.2% (3/254)patients with severe acute exacerbation (serum ALT ≥ 420 IU/L and T-Bil >51.3 μmol/L). In addition, severe acute exacerbation of chronic hepatitis B having a potential for progression to acute on chronic liver failure (ACLF) or acute on chronic pre-liver failure (pre-ACLF) with extremely high mortality, so it is highly important how to prevent the disease progression [5, 6]. Here, we introduced three patients with severe acute exacerbation of chronic hepatitis B during Pegasys treatment, including two patients with pre-ACLF and one patient with ACLF. Three patients were successfully treated with early intervention of corticosteroid and lamivudine.
Clinical characteristics at the baseline of Pegasys treatment
Course of disease (yr)
HBV DNA (Lc/ml
WBC x 10/L
Plt( x 10/L
Prothrombin activity (%)
Creatinine ( μmol/L)
T3 free (pmol/L)
T4 free (pmol/L)
Severe acute exacerbation of hepatitis B during pegasys treatment
Clinical characteristics at onset of severe acute exacerbation
Weeks of pegasys trreatment
HBV DNA (LC/ml)
Direct bilirubin (μmol/L)
Prothrombin activity (%)
Clinical course and treatment
Additionally, transfusion of magnesium isoglycyrrhizinate injection (200 mg/d) and reduced glutathione (1200 mg/d) were also given for 4 weeks among all three patients after being diagnosed to be ACLF or pre-ACLF.
The written informed consents were obtained from three patients before Pegasys and corticosteroid were administrated. Written informed consent was obtained from three patients for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal."
IFN-α is able to increase the expression of HLA-I antigens on hepatocytes, which attracts T lymphocytes, with subsequent cytolytic and noncytolytic viral inactivation . Acute exacerbation or ALT flare was usually observed among patients with chronic hepatitis B during IFN-αtreatment, and appeared to predict a successful outcome . However, patients with severe acute exacerbation tend to have a higher risk for progression to ACLF with extremely high mortality [5, 6]. Severe acute exacerbation or ACLF induced by standard interferon-α therapy had been reported to occur in few patients with chronic hepatitis B [3, 4]. Pegylated interferon-α has been used to treat chronic hepatitis B and C for more than five years. Liver failure induced by pegylated interferon-α therapy had been reported in chronic hepatitis C . But, no report showed that pegylated interferon-α therapy was able to induce severe acute exacerbation of chronic hepatitis B. Although severe acute exacerbation or ACLF during pegylated interferon-α is rarely occurred, but much attention should be paid by practicing physicians who take care of patients with chronic hepatitis B,because it is a life- threatening adverse effect. In the present cases, severe acute exacerbation of chronic hepatitis B occurred in two patients at the second week of Pegasys treatment, and in one patient at the eighth week of treatment.
Up to 30% of patients with chronic hepatitis B, included both HBeAg- positive and –negative patients, experience spontaneous reactivation of hepatitis every year. Severe acute exacerbation or ACLF may occur among a proportion of patients, and be associated with spontaneous HBe seroconversion. However, we think that severe acute exacerbation or ACLF occurred in three patients described here, is closely associated with Pegasys therapy, but is not a progressive course of underlying hepatitis activity, based on the following reasons. Firstly, case 1 did not spontaneously progress into severe acute exacerbation or ACLF during one month follow-up without antiviral treatment, but progressed into ACLF after two-weeks treatment with Pegasys. Secondly, HBe seroconversion in case 1 was observed after 64 weeks of LAM treatment or severe acute exacerbation being diagnosed, indicated that severe acute exacerbation in case 1 was not associated with spontaneous seroconversion of HBeAg. Thirdly, only mild ALT elevation and normal T-Bil levels were observed in case 2 at the onset and after three weeks of Pegasys treatment. Forthly, severe acute exacerbation was not observed in case 3 during twelve days follow-up from five days of pretreatment to the end of first week Pegasys treatment, but was observed after the five days of second week Pegasys treatment. Additionally, no superinfection by HAV, HCV, HDV, HEV, CMV, EBV and HIV was detected in three patients. Autoimmune hepatitis (AIH), alcoholism and drugs other than Pegasys were also excluded in three patients.
The mortality is very high once ACLF or pre-ACLF develop in patient with severe acute exacerbation of chronic hepatitis B. No evidence showed that antiviral therapy with nucleoside analog (NA) was able to improve short-term mortality in patients with ACLF or pre-ACLF associated HBV infection [5, 6]. Case 3 started to receive LAM therapy instead of Pegasys when he was diagnosed to be severe acute exacerbation at 13th day of Pegasys treatment. Interestingly, serum T-Bil was still rapidly increased after 4 days LAM treatment, indicated that short-term antiviral treatment alone was not able to prevent the disease progression once severe acute exacerbation was diagnosed.
However, corticosteroid can rapidly inhibit excessive immune response and inflammatory reaction, and have been confirmed to be effective in treating patients with pre-ACLF and the early stage of ACLF [6, 9]. Our data also showed that early intervention with corticosteroid and LAM was able to improve the liver function and prognosis of patients with ACLF and pre-ACLF. Our results also indicated that 5-days corticosteroid therapy was enough for rapid responders (the decline extent of serum T-Bil being ≥50% at 5 days), and a tapering-dose corticosteroid therapy was necessary for slow responders (<50%).
In summary, Pegasys therapy has a risk of inducing severe acute exacerbation including ACLF and pre-ACLF. Liver function should be tested once a week within 12 weeks of Pegasys therapy in order to find the risk of severe acute exacerbation as early as possible. Importantly, early combined intervention with corticosteroid and lamivudine should be introduced to prevent the disease progression and improve their prognosis once severe acute exacerbation was diagnosed.
Qing Mao collected the clinical data of one patient and drafted the manuscript, Hui-Yan Zhang collected the clinical data of one patient, Jian-Ping You collected the clinical data of one patient. Xu-Qing Zhang conceived of the study, participated in its design and performed the statistical analysis. All authors read and approved the final manuscript.
The authors thank our colleagues Jing Peng and Li Jiang for assistance in collection of clinical data.
This study was supported by Chinese National Natural Science Foundation grants 30872229.
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