Epidemiology and natural history of hepatitis B infection
Hepatitis B is a major global health problem, with approximately 350 million chronically infected individuals worldwide.1
In recent years, the geographic epidemiology of hepatitis B virus infection has changed, likely due to increased migration from highly endemic areas.2,3
Therefore, even countries with a low prevalence of the disease are experiencing the burden of hepatitis B virus.4
HBV disease burden in the United States
In 2003, there were an estimated 1.25 million persons in the United States with chronic hepatitis B virus infection.6
From 1990 to 2005, the estimated incidence of new HBV infections declined from approximately 232,000 to about 51,000 infections.7
The prevalence of chronic infections in those who have immigrated to the United States from Central and Southeast Asia, the Middle East, and Africa reflects the prevalence of HBV infections in their respective countries and regions.
7
HBV genotypes
To date, 8 hepatitis B virus genotypes have been identified (A, B, C, D, E, F, G, and H). There is a significant correlation between genotype and country of birth.9
Patients with chronic hepatitis B virus infection are at increased risk of developing cirrhosis, hepatic decompensation, and hepatocellular carcinoma, and, globally, more than 1 million people die each year of the infection.11
HCC=hepatocellular carcinoma.
Goals of hepatitis B treatment
In contrast to chronic hepatitis C infection, complete viral eradication is not a realistic goal of treatment in hepatitis B infection.
10
Rather, the primary goal of therapy in chronic hepatitis B is to suppress viral replication and to prevent progression of liver disease to cirrhosis, which may result in liver failure or hepatocellular carcinoma, leading, in turn, to death or transplantation.10
OLT=orthotopic liver transplantation.
Treatment strategies
The goals of treatment are to provide:
- A durable virologic response as a result of a finite course of therapy10
- A low likelihood of drug resistance10
- A chance for HBsAg antigen loss and HBsAg seroconversion10
The significance of HBsAg seroconversion (loss of HBsAg and appearance of HBsAb)
HBsAg seroconversion is considered an important goal of therapy, since it represents an identical state to that achieved in patients who effectively control HBV following acute infection, and therefore, HBsAg seroconversion constitutes the closest outcome to a “cure” in chronic HBV.14,15
Treatment guidelines
According to current treatment guidelines, several factors should be taken into consideration when deciding on the most appropriate treatment, including the needs of the individual patient and the duration of therapy.
The following clinical algorithm by Keeffe et al describes the treatment options for patients with chronic HBV based on HBeAg, HBV DNA, and ALT status10:
Treatment options for patients with compensated and decompensated cirrhosis, regardless of HBeAg status, are depicted below.10
PEGASYS is contraindicated in patients with hepatic decompensation (Child-Pugh score >6 [class B and C]) in cirrhotic patients before or during treatment.
PEGASYS dual mode of action
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.15
By contrast, nucleoside and nucleotide analogs have a single mode of action and are purely antiviral in activity.16
As a result of extensive studies (Cooksley, Lau, Marcellin) including more than 1500 patients in multiple countries, PEGASYS is the first and only pegylated interferon approved for the treatment of patients with chronic HBV.17-20
PEGASYS indication in chronic HBV infection
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.
PEGASYS for HBeAg-positive chronic HBV
In the HBeAg-positive study, 87% of the patients were of Asian descent. The study design is as follows18:
Treatment outcomes with PEGASYS for HBeAg-positive chronic HBV
Conclusions regarding comparative efficacy of PEGASYS and lamivudine treatment based on 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 posttreatment (week 72), patients who had been treated with 48 weeks of PEGASYS monotherapy achieved higher rates of HBeAg seroconversion than those treated with the same duration of PEGASYS and lamivudine or lamivudine monotherapy (32% vs 27% vs 19%, respectively).18
Hepatitis B virus DNA suppression
Although the combination of PEGASYS and lamivudine resulted in a greater degree of viral load reduction on treatment, it appeared to offer no advantages over treatment with PEGASYS alone in terms of HBeAg seroconversion.18
HBsAg seroconversion
In the treatment of chronic HBV, HBsAg seroconversion is considered to be the ultimate goal of therapy, as it is associated with positive long-term clinical outcomes.12,13,21
HBsAg seroconversion in HBeAg-positive chronic HBV patients
- The rate of sustained HBsAg seroconversion 24 weeks after the end of treatment (week 72) was significantly higher in the PEGASYS-containing arms (3% in both arms) than in the lamivudine arm (0%; P=0.004)21
- Sustained HBsAg seroconversion occurred exclusively in patients who achieved a sustained HBeAg response at week 7221
- The rate of HBsAg seroconversion among HBeAg responders was 10% for PEGASYS-treated patients compared with 0% for those treated with lamivudine21
PEGASYS for HBeAg-negative chronic HBV
Over 60% of patients studied in a large-scale trial of a “difficult-to-treat” form of chronic HBV were of Asian descent.19
The key findings of this study were published by Marcellin and colleagues (N Engl J Med, 2004).19
ALT normalization
Conclusions regarding comparative efficacy of PEGASYS and lamivudine treatment based on 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.
A higher proportion of patients achieved ALT normalization 24 weeks posttreatment (week 72) in the PEGASYS treatment arms than in the lamivudine treatment arm.19
Hepatitis B virus DNA suppression to <20,000 copies/mL
Twenty-four weeks posttreatment (week 72), hepatitis B virus DNA suppression to <20,000 copies/mL was achieved in 43%, 44%, and 29% of patients receiving PEGASYS, PEGASYS plus lamivudine, and lamivudine, respectively.22
HBV DNA suppression over time19
HBsAg seroconversion in HBeAg-negative chronic HBV patients with a combined response
- A significantly higher percentage of patients achieved sustained HBsAg seroconversion in the PEGASYS monotherapy arm (3%) compared with the lamivudine monotherapy arm (0%; P=0.03)21
- Sustained HBsAg seroconversion occurred almost exclusively in patients who achieved a combined response (ALT normalization and HBV DNA <20,000 copies/mL) at week 7219
- The rate of HBsAg seroconversion among patients who achieved a combined response was 10% for PEGASYS-treated patients compared with 0% for those treated with lamivudine only21
Thus, PEGASYS, with its dual immunomodulatory and antiviral mode of action, is able to achieve off-treatment sustained HBsAg seroconversion even in patients traditionally considered difficult to treat, such as Asian patients or those with HBeAg-negative chronic HBV.
Durability of response in HBeAg-negative chronic HBV19,23
Biochemical response over time
- Sustained biochemical response defined as23:
- Patient having normal ALT 6 months posttreatment and
- Elevated ALT was never documented at subsequent visits
- 44 patients (38%) treated with PEGASYS monotherapy fulfilled the criteria for a sustained biochemical response for up to 2 years posttreatment23
Virologic response over time
- Over one-quarter of patients maintained posttreatment HBV DNA levels below 104 copies/mL, a viral load that has been identified as being associated with a marked reduction in the risk of progressive liver disease and hepatocellular carcinoma23,24
- Virologic response rates remained stable from 9 months to 2 years posttreatment; patients who relapsed did so in the early months of follow-up23
Addition of lamivudine to PEGASYS did not provide an advantage in terms of sustained response23
Thus, a finite course of PEGASYS induced biochemical and virologic responses in approximately one-third of HBeAg-negative patients that were sustained for up to 2 years posttreatment, without the risk for drug resistance that is associated with long-term therapy.23
INDICATIONS
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.
Boxed WARNINGS and additional IMPORTANT SAFETY INFORMATION
Alpha interferons, including PEGASYS® (Peginterferon alfa-2a), may cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Patients should be monitored 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.
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.
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).
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.
WARNINGS
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, pulmonary hypertension, and sarcoidosis), colitis (ulcerative and hemorrhagic/ischemic colitis), pancreatitis, ophthalmologic disorders (decrease or loss of vision, retinopathy including macular edema and retinal thrombosis/hemorrhages, optic neuritis and papilledema), and peripheral neuropathy (in combination with telbivudine).
Adverse reactions reported during post-approval use of PEGASYS therapy, with and without ribavirin, include dehydration, hearing impairment, hearing loss, serious skin reactions, including erythema multiforme major, infections (bacterial, viral and fungal), and serous retinal detachment, and pure red cell aplasia.
MOST COMMON ADVERSE EVENTS
The most common adverse events reported for PEGASYS and COPEGUS combination therapy observed 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%).
WARNINGS SPECIFIC TO HEPATITIS C PATIENTS
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 alfa-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 alfa-based therapies and these events is difficult to establish.
WARNINGS SPECIFIC TO HEPATITIS B PATIENTS
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.
Please see full Prescribing Information, including Boxed WARNINGS for additional Important
Safety Information.
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