Chronic hepatitis B is a major global health problem, with approximately 400 million chronically infected individuals worldwide.1 Patients with chronic hepatitis B virus infection are at increased risk of developing cirrhosis, hepatic decompensation, and hepatocellular carcinoma, which together account for more than 1 million deaths per year.2
In recent years, the geographic epidemiology of hepatitis B virus infection has changed due to increased migration from highly endemic areas.5,6 Therefore, even countries with a low prevalence of the disease, such as the United States, are experiencing the burden of hepatitis B virus.7
To date, eight hepatitis B virus genotypes have been identified (A, B, C, D, E, F, G, and H).11 There is a significant correlation between genotype and country of birth.
Treatment Objectives and Strategies
In contrast to chronic hepatitis C infection, complete viral eradication is not a realistic goal of treatment in hepatitis B infection. The primary objective of therapy for chronic hepatitis B is to stop viral replication and halt disease progression while improving liver histology. The goals of treatment are to provide:
- A durable virologic response as a result of a finite course of therapy
- A low likelihood of drug resistance
- A chance of HBsAg antigen loss and HBsAg seroconversion, which can be associated with the possibility of long-term benefits.
Treatment Guidelines
According to current treatment guidelines, several factors should be taken into consideration when deciding upon the most appropriate treatment. These factors include the needs of the individual patient and the duration of therapy.
The following algorithm describes the treatment options for patients with compensated and decompensated cirrhosis, regardless of HBeAg status.11 PEGASYS is contraindicated in patients with hepatic decompensation (Child-Pugh score greater than 6 [class B and C]) in cirrhotic patients before or during treatment.
PEGASYS has dual immunomodulatory and antiviral modes of action, allowing the immune system to continue to fight the hepatitis B virus even after cessation of therapy. As a result of extensive studies including more than 1,500 patients in 19 countries, PEGASYS is the first and only pegylated interferon approved for the treatment of patients with chronic hepatitis B.
HBeAg-positive Chronic Hepatitis B
In the HBeAg-positive study, 85% of the patients were of Asian decent. The study design is as follows:
Treatment Outcomes With PEGASYS
Conclusions regarding comparative efficacy of PEGASYS and lamivudine treatment based upon the end of follow-up results are limited by the different mechanisms of action of the two compounds. Most treatment effects of lamivudine are unlikely to persist 24 weeks after therapy is withdrawn.
HBeAg Seroconversion
At 24 weeks post-treatment (week 72), patients who had been treated with PEGASYS monotherapy achieved higher rates of HBeAg seroconversion than those treated with lamivudine monotherapy.
Hepatitis B Virus DNA Suppression
Despite more profound “on treatment” DNA suppression with lamivudine, rates of HBeAg seroconversion 24 weeks post-treatment were higher with PEGASYS monotherapy than with lamivudine monotherapy. This demonstrates that greater on-treatment viral suppression does not necessarily translate into increased rates of HBeAg seroconversion.
HBsAg seroconversion is an important secondary endpoint of hepatitis B therapy and a strong predictor of slowed disease progression.
HBeAg-negative Chronic Hepatitis B
Over 60% of patients studied in a large-scale study of a “difficult-to-treat” form of chronic hepatitis B were of Asian decent. The key findings were published in the New England Journal of Medicine in 2004 by Marcellin and colleagues.15
ALT Normalization
Conclusions regarding comparative efficacy of PEGASYS and lamivudine treatment based upon the end of follow-up results are limited by the different mechanisms of action of the two compounds. Most treatment effects of lamivudine are unlikely to persist 24 weeks after therapy is withdrawn.
At end of treatment, ALT normalization was achieved in 38%, 49%, and 73% of patients receiving PEGASYS, PEGASYS plus lamivudine, and lamivudine, respectively. A higher proportion of patients achieved ALT normalization 24 weeks post-treatment (week 72) in the PEGASYS treatment arms than in the lamivudine treatment group.
Hepatitis B Virus DNA Suppression to <20,000 copies/mL
After a fixed 48-week course of PEGASYS, hepatitis B virus DNA suppression to <20,000 copies/mL was achieved in 81%, 92%, and 85% of patients receiving PEGASYS, PEGASYS plus lamivudine, and lamivudine, respectively. PEGASYS-containing regimens remained durable 24 weeks post-treatment (week 72).
HBsAg Response 24 Weeks Post-treatment (Week 72)
At 24 weeks post-treatment (week 72), patients who had been treated with PEGASYS monotherapy achieved higher rates of HBeAg seroconversion than those treated with lamivudine monotherapy.
IMPORTANT SAFETY INFORMATION
PEGASYS, alone or in combination with COPEGUS, is indicated for the treatment of adults with chronic hepatitis C virus infection who have compensated liver disease and have not been previously treated with interferon alpha. Patients in whom efficacy was demonstrated included patients with compensated liver disease and histological evidence of cirrhosis (Child-Pugh class A) and patients with HIV disease that is clinically stable (eg, antiretroviral therapy not required or receiving stable antiretroviral therapy). PEGASYS is indicated for the treatment of adult patients with HBeAg positive and HBeAg negative chronic hepatitis B who have compensated liver disease and evidence of viral replication and liver inflammation.
Alpha interferons, including PEGASYS® (Peginterferon alfa-2a), may cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Patients should bemonitored closely with periodic clinical and laboratory evaluations. Therapy should be withdrawn in patients with persistently severe or worsening signs or symptoms of these conditions. In many, but not all cases, these disorders resolve after stopping PEGASYS therapy (see CONTRAINDICATIONS, WARNINGS, PRECAUTIONS and ADVERSE REACTIONS in complete product information).
Use with Ribavirin. Ribavirin, including COPEGUS®, may cause birth defects and/or death of the fetus. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. Ribavirin causes hemolytic anemia. The anemia associated with ribavirin therapy may result in a worsening of cardiac disease. Ribavirin is genotoxic and mutagenic and should be considered a potential carcinogen (see CONTRAINDICATIONS, WARNINGS, PRECAUTIONS and ADVERSE REACTIONS in complete product information).
CONTRAINDICATIONS
PEGASYS is contraindicated in patients with hypersensitivity to PEGASYS or any of its components, autoimmune hepatitis, and hepatic decompensation (Child-Pugh score greater than 6; class B and C) in cirrhotic CHC monoinfected patients before or during treatment. PEGASYS is also contraindicated in hepatic decompensation with Child-Pugh score greater than or equal to 6 in cirrhotic CHC patients coinfected with HIV before or during treatment. PEGASYS is also contraindicated in neonates and infants because it contains benzyl alcohol. Benzyl alcohol is associated with an increased incidence of neurological and other complications in neonates and infants, which are sometimes fatal. PEGASYS and COPEGUS therapy is additionally contraindicated in patients with a hypersensitivity to COPEGUS or any of its components, in women who are pregnant, men whose female partners are pregnant, and patients with hemoglobinopathies (eg, thalassemia major, sickle-cell anemia).
Exacerbations of hepatitis during hepatitis B therapy are not uncommon and are characterized by transient and potentially severe increases in serum ALT. Patients experiencing ALT flares should receive more frequent monitoring of liver function. PEGASYS dose reduction should be considered in patients experiencing transaminase flares. If ALT increases are progressive despite reduction of PEGASYS dose or are accompanied by increased bilirubin or evidence of hepatic decompensation, PEGASYS should be immediately discontinued.
AVOIDING PREGNANCY
COPEGUS THERAPY SHOULD NOT BE STARTED UNLESS A REPORT OF A NEGATIVE PREGNANCY TEST HAS BEEN OBTAINED IMMEDIATELY PRIOR TO INITIATION OF THERAPY. Women of childbearing potential and men must use two forms of effective contraception during treatment and during the 6 months after treatment has concluded. Routine monthly pregnancy tests must be performed during this time. If pregnancy should occur during treatment or during 6 months post-therapy, the patient must be advised of the significant teratogenic risk of COPEGUS therapy to the fetus. Healthcare providers and patients are strongly encouraged to immediately report any pregnancy in a patient or partner of a patient during treatment or during 6 months after treatment cessation to the Ribavirin Pregnancy Registry at 1-800-593-2214.
ADDITIONAL SAFETY CONCERNS
Chronic hepatitis C (CHC) patients with cirrhosis may be at risk of hepatic decompensation and death when treated with alpha interferons, including PEGASYS. Cirrhotic CHC patients coinfected with HIV receiving highly active antiretroviral therapy (HAART) and interferon alfa-2a with or without ribavirin appear to be at increased risk for the development of hepatic decompensation compared to patients not receiving HAART. During treatment, patients’ clinical status and hepatic function should be closely monitored, and PEGASYS treatment should be immediately discontinued if decompensation (Child-Pugh score ≥6) is observed. Ischemic and hemorrhagic cerebrovascular events have been observed in patients treated with interferon alpha-based therapies, including PEGASYS. Events occurred in patients with few or no reported risk factors for stroke, including patients less than 45 years of age. Because these are spontaneous reports, estimates of frequency cannot be made and a causal relationship between interferon alpha-based therapies and these events is difficult to establish.
INCIDENCE OF ADVERSE EVENTS
The most common adverse events reported for PEGASYS and COPEGUS combination therapyobserved in clinical trials were fatigue/asthenia (65%), headache (43%), pyrexia (41%), myalgia (40%), irritability/anxiety/nervousness (33%), insomnia (30%), alopecia (28%), neutropenia (27%), nausea/vomiting (25%), rigors (25%), anorexia (24%), injection-site reaction (23%), arthralgia (22%), depression (20%), pruritus (19%) and dermatitis (16%). The adverse event profile of coinfected patients treated with PEGASYS and COPEGUS was generally similar to that shown for monoinfected patients. Events occurring more frequently in coinfected patients were neutropenia (40%), anemia (14%), thrombocytopenia (8%), weight decrease (16%) and mood alteration (9%). In clinical trials of 48-week treatment duration, the adverse event profile of PEGASYS in chronic hepatitis B was similar to that seen in chronic hepatitis C PEGASYS monotherapy use, except for exacerbations of hepatitis. The most common adverse events reported for PEGASYS, observed in clinical studies, were pyrexia (54%), headache (27%), myalgia (26%), fatigue (24%), alopecia (18%) and anorexia (16%).
Serious adverse events in hepatitis B and hepatitis C trials included neuropsychiatric disorders(homicidal ideation, suicidal ideation, suicide attempt, suicide, psychotic disorder and hallucinations), serious and severe bacterial infections (sepsis), bone marrow toxicity (cytopenia and rarely, aplastic anemia), cardiovascular disorders (hypertension, supraventricular arrhythmias and myocardial infarction), hypersensitivity (including anaphylaxis), endocrine disorders (including thyroid disorders and diabetes mellitus), autoimmune disorders (including idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura, psoriasis, lupus, rheumatoid arthritis and interstitial nephritis), pulmonary disorders (dyspnea, pneumonia, bronchiolitis obliterans, interstitial pneumonitis and sarcoidosis), colitis (ulcerative and hemorrhagic/ischemic colitis), pancreatitis, and ophthalmologic disorders (decrease or loss of vision, retinopathy including macular edema and retinal thrombosis/hemorrhages, optic neuritis and papilledema). Adverse reactions reported during post-approval use of PEGASYS therapy, with and without ribavirin, include hearing impairment, hearing loss, serious skin reactions, including erythema multiforme major, and infections (bacterial, viral and fungal).
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