Pegylated Interferon Alfa in HBeAg-positive Chronic Hepatitis B

Background: Treatment with interferon-alfa has been shown to be effective in one-third of hepatitis B e antigen-positive chronic hepatitis B patients, but is clinically associated with relevant adverse events. Aim: To investigate the safety of peginterferon alfa-2b in 300 hepatitis B e antigen-positive patients with compensated liver disease. Methods: Patients were treated with peginterferon alfa-2b for 52 weeks combined with either lamivudine 100 mg/day or placebo. Peginterferon alfa-2b was administered for 100 μg once a week for 32 weeks; thereafter, the dose was reduced to 50 μg once a week. Adverse events and their effect on study medication were reported at monthly visits in a standardized way. Results: The most frequently reported side-effects were flu-like syndrome (68%), headache (40%), fatigue (39%), myalgia (29%) and local reaction at the injection site (29%). These symptoms typically occurred within the first month of therapy and subsided during the course of therapy. Neutropenia and thrombocytopenia induced by peginterferon alfa-2b increased the risk of infections and bleeding complications, but these complications were rare and mild.The frequency of all side-effects was not different between patients treated with peginterferon alfa-2b combined with lamivudine or placebo. In 69 (22%) patients the dose of peginterferon alfa-2b was reduced prematurely. Of these dose reductions, 36 (52%) were because of neutropenia. Therapy was discontinued in 28 (8%) patients. The most frequent reasons for early discontinuation were psychiatric side effects (depression, psychosis) and flu-like symptoms. Multivariate Cox regression analysis showed that low neutrophil count at baseline and cirrhosis were independent predictors of dose reduction or therapy discontinuation. Conclusion: We conclude that in patients with chronic hepatitis B and compensated liver disease prolonged peginterferon alfa-2b therapy is safe, and that pre-existent cirrhosis and neutropenia are the most important predictors of dose reduction or early treatment discontinuation. 18 C ha pt er 2 INTRODUCTION An estimated 400 million people are chronically infected with hepatitis B virus (HBV). Chronic hepatitis B (CHB) is the single most common cause of liver cirrhosis and hepatocellular carcinoma (HCC) worldwide1. Interferon-alpha (IFN) is effective in about one-third of the patients2. Reported HBeAg seroconversion rates range from 15 to 37%3– 5, depending on baseline characteristics such as alanine aminotransferase (ALT) levels and viral load. Response to IFN therapy was shown to result in sustained clearance of hepatitis B e antigen (HBeAg), HBV-DNA and normalization of aminotransferase levels6–8. Therapy with IFN is associated with considerable side-effects. Most frequently reported side-effects are flu-like syndrome, fatigue, headache and myalgia. Other clinically relevant side effects, such as depression, anorexia and insomnia, occur less frequently. Cases of suicide attempts during IFN therapy have been reported9–11. To improve response rates and possibly reduce the number of side effects, newer forms of IFN have been developed. ‘Pegylated’ forms of IFN (with a polyethylene glycolmoiety attached to it) have an improved pharmacokinetic profile with a prolonged half-life time9. Pegylated interferons have been reported to be safe and more effective than conventional IFN in patients with chronic hepatitis C12, 13. Until now, the safety data of these pegylated forms of IFN in the treatment of CHB are limited to the study of Cooksley et al.14, who investigated the safety of peginterferon alfa-2a in CHB patients. In this study, we assessed the safety of peginterferon alfa-2b (Peg-IFN α2b) alone or in combination with lamivudine in HBeAg-positive CHB. MATERIALS AND METHODS Patients In a randomized multicentre trial reported previously15, 307 HBeAg-positive CHB patients with compensated liver disease were treated with Peg-IFN α-2b in combination with either lamivudine or placebo. Inclusion criteria were hepatitis B surface antigen (HBsAg)-positivity for at least 6 months, age 3 16 years, ALT at least twice the upper limit of normal (ULN) and HBeAg positive on two occasions within 8 weeks prior to randomization. Patients were excluded if they had been treated with antiviral medication in the previous 6 months or any investigational drug within 30 days of entry in this protocol, were coinfected with hepatitis C, hepatitis D or human immunodeficiency virus (HIV), had alcoholic hepatitis or other causes of liver disease, had preexistent leucopenia or thrombocytopenia [white blood cell count (WBC) ≤ 3000/mm3, neutrophils ≤ 1800/mm3, platelets ≤ 100 000/mm3], had decompensated liver disease (prothombin time prolonged by > 3 seconds, serum albumin < 35 g/L, ascites, encephalopathy, history of variceal bleeding) or had hypothroidism or hyperthyroidism. Patients were also excluded in case of pregnancy, inadequate contraception, 19 The safety of Peginterferon 0 32 52 78 weeks Follow-up Peg-IFN 100 g Lamivudine Peg-IFN 50 g Follow-up Peg-IFN 100 g Placebo Peg-IFN 50 g The reported adverse events were also assessed in their relation to therapy by the treating physician and reported as unrelated, possibly related, probably related or related to therapy. Effect on study medication was scored as none, dose reduction or treatment discontinuation. Serious adverse events (SAE) were defined as events resulting in death, events that are lifethreatening, require or prolong in-patient hospitalization, as well as events which result in persistent or significant disability or incapacity, pregnancy, any congenital anomaly, cancer, or drug overdose. Hepatitis flares were defined as an increase in serum ALT to at least three times the baseline level. Psychiatric side effects included mood changes, irritability and depression. Autoimmune phenomena are not reported because they were not systematically investigated with, e.g. longitudinal assessment of auto-antibodies. Figure 1. Treatment Schedule any significant medical illness potentially interfering with the study or any contraindication specified for IFN. Ethics committees of the participating centres approved of the protocol and all patients provided written informed consent. Study design In this double-blinded trial, eligible patients were randomized to one of two treatment regimens (Figure 1). All patients received Peg-IFN α-2b for 52 weeks. Patients were treated with a 100 μg dose of Peg-IFN α-2b once a week until week 32, whereafter it was reduced to 50 μg once a week. In addition, patients received either placebo or 100 mg lamivudine orally. Patients were examined every 4 weeks during treatment and during the 6-month post-treatment follow-up. At visits, routine physical examination was performed and blood samples were obtained for haematological and biochemical screening [haemoglobin, WBC, neutrophils, platelets, ALT and aspartate aminotransferase (AST)]. All adverse events were reported by the treating physician on standard case-record forms and verified by the trialcoordinating centre. All participating investigators were instructed, received a protocol and were monitored every 3 months in order to ensure uniform scoring of side effects. Adverse events were graded according to the WHO recommendations for grading of acute and subacute toxicities16, and reported as mild, moderate, severe or life-threatening.