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.