AHFS Class:

• Interferons 8:18.20

Generic Name(s):

• Peginterferon Alfa

• Peginterferon Alfa-2a

Peginterferon alfa is an antiviral agent that contains interferon alfa (recombinant DNA origin) covalently bound to monomethoxy polyethylene glycol (PEG).20

Chronic Hepatitis B Virus Infection

Peginterferon alfa-2a is used in adults with hepatitis B e antigen (HBeAg)-positive or HBeAg-negative chronic hepatitis B virus (HBV) infection who have compensated liver disease and evidence of viral replication and liver inflammation.20,97 Peginterferon alfa-2a is also used for the treatment of HBeAg-positive chronic HBV infection in non-cirrhotic pediatric patients 3 years of age and older with evidence of viral replication and elevations in serum alanine aminotransferase (ALT).20

The efficacy and safety of peginterferon alfa-2a have not been established in patients with HBV coinfected with hepatitis C virus (HCV) or human immunodeficiency virus (HIV).20

Clinical Experience

Safety and efficacy of peginterferon alfa-2a for the treatment of chronic HBV infection in adults were assessed in 2 controlled clinical trials in patients with compensated liver disease and evidence of HBV replication (study 8 and study 9).20,138,139 Patients were randomized to receive 48 weeks of treatment with peginterferon alfa-2a monotherapy (180 mcg once weekly), peginterferon alfa-2a (180 mcg once weekly) in conjunction with oral lamivudine (100 mg once daily), or lamivudine monotherapy (100 mg once daily).20,138,139 At study entry, all patients had serum ALT concentrations between 1-10 times the upper limit of normal (ULN) and liver biopsy findings compatible with chronic hepatitis.20,138,139 Patients in study 8 were HBeAg-positive and had serum HBV levels exceeding 500,000 copies/mL;20,138 patients in study 9 were HBeAg-negative and had serum HBV levels exceeding 100,000 copies/mL.139

At 24 weeks after treatment was completed (week 72), data from study 8 indicated that HBeAg seroconversion occurred in 32% of patients treated with peginterferon alfa-2a monotherapy compared with 19% of patients treated with lamivudine monotherapy.20,138 An HBV DNA response (HBV levels <100,000 copies/mL for HBeAg-positive patients and <20,000 copies/mL for HBe-Ag-negative patients) and ALT normalization occurred in 32 and 41%, respectively, of patients treated with peginterferon alfa-2a compared with 22 and 28%, respectively, of those treated with lamivudine.20,138

Data from study 9 indicated that an HBV DNA response and ALT normalization occurred in 43 and 59%, respectively, of patients treated with peginterferon alfa-2a compared with 29 and 44%, respectively, of patients treated with lamivudine.20,139

In studies 8 and 9, histologic improvement was evident on liver biopsy in 41 and 48%, respectively, of patients treated with peginterferon alfa-2a and 40 and 41%, respectively, of patients treated with lamivudine.20,139 Conclusions regarding comparative efficacy based on results of these studies are limited by the different mechanisms of action of peginterferon alfa-2a and lamivudine; most treatment effects of lamivudine are unlikely to persist 24 weeks after therapy is withdrawn.20 Concomitant use of peginterferon alfa-2a and lamivudine did not result in any additional sustained response compared with peginterferon monotherapy.20,138,139

Safety and efficacy of peginterferon alfa-2a for the treatment of chronic HBV infection (HBeAg-positive in the immune-active phase) in pediatric patients were assessed in a clinical study (study 10) in previously untreated children 3 years of age and older.20 The study excluded patients with cirrhosis.20 Patients without advanced fibrosis were randomized 2:1 to peginterferon alfa-2a once weekly (dosing regimen based on body surface area) for 48 weeks or placebo; patients with advanced fibrosis were assigned to peginterferon alfa-2a treatment.20 All patients were followed up for 24 weeks post-treatment or post-principal observation period for those placebo patients switching to active treatment.20 Serological, virological, and biochemical responses after 48 weeks of peginterferon alfa-2a treatment or observation and 24 weeks follow-up for HBeAg seroconversion, HBV DNA <20,000 IU/mL, HBV DNA <2,000 IU/mL, ALT normalization, HBsAg seroconversion, and loss of HBsAg were 26, 34, 29, 52, 8, and 9% and 6, 4, 2, 12, 0, and 0% for patients receiving peginterferon alfa-2a and placebo, respectively.20 Patients with advanced fibrosis had similar responses compared to the randomized patients receiving peginterferon alfa-2a treatment.20

Clinical Perspective

The American Association for the Study of Liver Diseases (AASLD) has published guidelines for the management of chronic HBV infection.97 The guidelines strongly recommend antiviral therapy in adults with immune-active chronic HBV infection (HBeAg negative or HBeAg positive) to decrease the risk of liver-related complications.97 The drugs of choice for initial treatment of immune-active chronic HBV infection are peginterferon alfa, entecavir, tenofovir disoproxil fumarate (TDF), or tenofovir alafenamide (TAF); such treatments are preferred because they have demonstrated a lack of resistance with long-term use.97 Direct comparison studies have not shown any of these agents to be superior over another; choice of therapy should be individualized based on patient characteristics and comorbidities, previous treatments, tolerability, and cost.97 The treatment of chronic HBV infection is complex and rapidly evolving; consult the AASLD guidelines for the most updated information.97

Chronic Hepatitis C Virus Infection

Peginterferon alfa-2a is used in conjunction with other hepatitis C antiviral drugs for the treatment of chronic HCV infection in adults with compensated liver disease.20,120,121,342,420,421,422,423,426,427 Peginterferon alfa-2a is also used in combination with ribavirin in pediatric patients 5 years of age and older with chronic HCV infection and compensated liver disease.20 The manufacturer states that peginterferon alfa-2a monotherapy is only indicated for the treatment of patients with chronic HCV and compensated liver disease if there are contraindications or significant intolerance to other HCV antiviral drugs.20

Peginterferon alfa-2a alone or in combination with ribavirin without additional HCV antiviral drugsis not recommended for treatment of patients with chronic HCV infection who previously failed therapywith an interferon alfa.20 Peginterferon alfa-2a is also not recommended for treatment of patients with chronic HCV infection who have had solid organ transplantation.20

Peginterferon alfa has been used in conjunction with ribavirin for the treatment of chronic HCV infection; efficacy and safety of such therapy have been well-established in multiple clinical studies.119,120,121,420,421,422,423,427

Co-infection with HCV and HIV

Because HCV infection tends to progress more rapidly in patients coinfected with HIV, the AASLD, US Centers for Disease Control and Prevention (CDC), National Institutes of Health (NIH), HIV Medicine Association of the Infectious Diseases Society of America (IDSA), and other experts state that all HIV-infected patients should be periodically screened for HCV and those coinfected with HCV should be offered treatment, provided there are no contraindications to such therapy.119,120,121,190,191,448 The risk of progression is even greater in patients with HCV/HIV coinfection who have low CD4 T lymphocyte cell counts.190 Although antiretroviral therapy appears to slow the rate of HCV disease progression in patients with HCV/HIV coinfection, several studies have demonstrated that the rate of disease progression continues to exceed that observed in patients without HIV.190 Initiation of antiretroviral therapy for patients with HCV/HIV coinfection should follow the recommendations for all persons with HIV infection, considering the need for concurrent HCV treatment with oral HCV direct-acting antiviral (DAA) regimens, the potential for drug-drug interactions, and the individual's HBV status.190

Peginterferon alfa has been previously used in multiple-drug regimens for the treatment of chronic HCV infection in patients coinfected with HIV.20,120,121,190,191,423 However, guidance no longer recommends the use of peginterferon-containing regimens to treat HCV infection, including in patients with HIV.190,448

Clinical Perspective

The Infectious Diseases Society of America (IDSA) and the American Association for the Study of Liver Diseases (AASLD) have published joint guidelines for the management of HCV infection.448 The guidelines strongly recommend universal treatment with DAA drugs in most patients with acute or chronic HCV infection.448 Although peginterferon alfa has been used in conjunction with ribavirin in drug regimens that include an HCV DAA, peginterferon alfa is no longer recommended in the 2023 AASLD guidelines as part of an initial treatment regimen for HCV infection due to inferior efficacy rates compared with other DAA regimens.448 The treatment of chronic HCV infection is complex and rapidly evolving; consult the AASLD and IDSA joint guidelines for the most updated information.448

Acute Hepatitis C Virus Infection

Peginterferon alfa has been used alone or in conjunction with oral ribavirin for the treatment of acute HCV infection† in an attempt to prevent progression to chronic HCV infection. 120,121,122,123,124,125,126,127,128,129,190

There is evidence that patients with acute HCV infection have higher treatment response rates than those with chronic HCV infection and that treatment of the acute infection can reduce the risk that the disease will evolve to chronic infection.119,120 Sustained virologic response rates of 62-90% or higher have been reported when peginterferon alfa or nonconjugated interferon alfa monotherapy or peginterferon alfa in conjunction with oral ribavirin was used for treatment of acute HCV infection.120,122,123,124,128,129 However, approximately 10-50% of patients with acute HCV infection have self-limited disease and spontaneous clearance of the virus without treatment; 120 the spontaneous resolution rate varies depending on whether the acute infection is asymptomatic or symptomatic, the route of HCV transmission, and age at which the infection was acquired.120

Patients with acute HCV infection should be treated upon initial diagnosis without awaiting spontaneous resolution.119 Mathematical modeling suggests that DAA treatment scale-up, especially among those at highest risk of transmission, can reduce HCV incidence and prevalence.119 Delay introduced by waiting for spontaneous clearance may be associated with loss to follow up.119

To date, there are insufficient data to support a particular regimen or treatment duration outside of a clinical trial.119 Because of their high efficacy and safety, the same regimens that are recommended for treating chronic HCV infection are recommended for acute HCV infection.119 Consultation with a specialist is advised to obtain the most up-to-date information regarding the treatment of acute HCV infection.119,121

Hepatitis E Virus Infection

Peginterferon alfa has been used alone or in conjunction with ribavirin for treatment of chronic hepatitis E virus (HEV) infection†.428,429,436,437

Chronic HEV infection has been reported almost exclusively among immunocompromised individuals, including solid organ transplant recipients, patients receiving cancer chemotherapy, and HIV-infected patients.428,429,436,437 Although optimal treatment of chronic HEV infection has not been identified, there is evidence that peginterferon alfa therapy is associated with a sustained virologic response in some solid organ transplant recipients.428,437

General

Pretreatment Screening

• Question patients regarding prior history of drug abuse.20
• Perform baseline ophthalmologic examination.20
• Screen all patients for HIV.20
• Perform standard hematological (i.e., complete blood count) and biochemical laboratory tests; evaluate liver and renal function.20
• Perform pregnancy testing for women of childbearing potential.20
• Perform electrocardiogram (ECG) in patients with preexisting cardiac abnormalities (when used in combination with ribavirin).20

Patient Monitoring

• Perform hematologic testing at 2 and 4 weeks and biochemical testing at 4 weeks.20 Additional testing should be performed periodically during therapy.20
• Closely monitor hepatic function and clinical status during therapy.20 Monitor renal function.20
• Monitor all patients for evidence of depression and other psychiatric symptoms.20
• Monitor patients closely for the development or aggravation of existing autoimmune, ischemic, and infectious disorders.20
• In patients with preexisting ophthalmologic disorders (e.g., diabetic or hypertensive retinopathy), perform periodic ophthalmologic examinations during therapy.20
• In women of childbearing potential, perform pregnancy testing monthly during combination therapy and for 6 months after discontinuing therapy.20

Administration

Peginterferon alfa-2a (Pegasys^®) is administered by subcutaneous injection once weekly.20

Subcutaneous injections of peginterferon alfa-2a should be made into the abdomen or thigh.20 Areas of the navel and waistline should be avoided.20 Injection sites should be rotated.20

Peginterferon alfa-2a may be self-administered if the clinician determines that the patient and/or their caregiver is competent to safely administer the drug after appropriate training and with medical follow-up as necessary.20 Patients and/or their caregivers who administer peginterferon alfa-2a in a home setting should be carefully instructed in the proper administration of the drug, including aseptic technique.20 They should be cautioned against reuse of syringes and needles and should be supplied with a puncture-resistant container for the proper, safe disposal of such equipment after use.20 In addition, they should be provided with instructions on the proper disposal of full disposal containers. 20

Vials and prefilled syringes containing peginterferon alfa-2a should be stored in a refrigerator at 2-8°C, protected from light, and should not be frozen or shaken.20 Vials and prefilled syringes should be allowed to reach room temperature and for condensation on the outside of the prefilled syringe to disappear before administration, but should not be kept out of a refrigerator for more than 24 hours.20

Vials and prefilled syringes containing peginterferon alfa-2a should be inspected visually for particulate matter and discoloration prior to administration.20 The solution should be clear and colorless to light yellow, and should not be used if discolored or cloudy or if particulates are present.20 Vials and prefilled syringes are for single-use only and any unused portions should be discarded.20

Dosage

Adult Dosage

Chronic HBV Infection

When peginterferon alfa-2a is used for treatment of chronic hepatitis B virus (HBV) infection in adults, the recommended dosage is 180 mcg once weekly by subcutaneous injection for 48 weeks.20,97

Chronic HCV Infection

When peginterferon alfa-2a is used in conjunction with other hepatitis C virus (HCV) antiviral agents for treatment of chronic HCV infection in adults without HIV coinfection, the usual dosage is 180 mcg once weekly by subcutaneous injection.20 Refer to the prescribing information for specific HCV antiviral drugs used in combination with peginterferon alfa-2a for information on stopping therapy based on treatment response; recommended treatment duration depends on HCV genotype (see Table 1).20

Discontinuance of treatment of HCV genotype 1 with peginterferon alfa-2a, in combination with ribavirin or alone, is recommended if HCV RNA levels have not decreased by at least a 2 log₁₀ reduction from baseline at week 12 or are still detectable after 24 weeks of treatment.20

Chronic HCV Infection with HIV Coinfection - Concomitant Antiviral Treatment

The recommended peginterferon alfa-2a dosage in adults with CHC and HIV coinfection is 180 mcg subcutaneously once weekly.20 If peginterferon alfa-2a is used in combination with other antiviral drugs, refer to the prescribing information of the other HCV antiviral drugs for the recommended dosage and duration of the entire treatment regimen (including peginterferon alfa-2a).20 If peginterferon alfa-2a and ribavirin are used without other HCV antiviral drugs, the recommended duration of therapy is 48 weeks (regardless of HCV genotype).20

Chronic HCV Infection Monotherapy

If peginterferon alfa-2a monotherapy is used for treatment of chronic HCV infection (i.e., if there are contraindications or significant intolerance to other HCV antiviral drugs), the usual dosage is 180 mcg once weekly by subcutaneous injection for 48 weeks.20

Acute HCV Infection

If peginterferon alfa-2a is used for the treatment of acute HCV infection†, some experts recommend a dosage of 180 mcg by subcutaneous injection once weekly for 24 weeks.120

Experts currently recommend treatment for acute HCV infection as described for chronic hepatitis C and that patients should be treated upon initial diagnosis without awaiting spontaneous resolution.119 Pangenotypic regimens are recommended if HCV genotyping is unavailable or if concern of exposure to more than 1 genotype exists.119 Using the same regimens to treat acute/recent HCV as for chronic HCV infection also simplifies management, as defining acute HCV may be clinically challenging.119

If treatment is initiated and a response is not obtained, some experts recommend that patients be retreated using the standard of care for chronic HCV infection.120

Pediatric Dosage

Chronic HBV Infection

When peginterferon alfa-2a is used for treatment of HBeAg-positive chronic HBV in non-cirrhotic pediatric patients ≥3 years of age with evidence of viral replication and elevations in serum ALT, the recommended dosage is 180 mcg/1.73 m² × body surface area (BSA) once weekly (maximum 180 mcg) by subcutaneous injection.20 The recommended treatment duration is 48 weeks.20 Maintain the recommended pediatric dosage through the entire duration of therapy in patients who turn 18 years of age during therapy.20

Chronic HCV Infection (Concomitant Peginterferon Alfa-2a and Oral Ribavirin)

When peginterferon alfa-2a is used in conjunction with oral ribavirin for treatment of chronic HCV infection and compensated liver disease in pediatric patients 5 years of age and older, the usual dosage is 180 mcg/1.73 m² × BSA once weekly (maximum 180 mcg) by subcutaneous injection.20

The recommended duration of treatment is 24 weeks for HCV genotype 2 or 3 and 48 weeks for other HCV genotypes.20

Maintain the recommended pediatric dosage (not the adult dosage) through the completion of therapy for patients who initiate treatment prior to their 18th birthday.20

Dosage Modification for Toxicity

Dosage of peginterferon alfa-2a should be adjusted in patients who develop adverse neuropsychiatric (i.e., depression) or hematologic effects, or other serious adverse effects or laboratory abnormalities.20

Depression

If mild depression occurs in an adult or pediatric patient receiving peginterferon alfa-2a, usual dosage of the drug can be continued, but the patient should be evaluated once weekly (by office visit and/or phone) during the initial 4—8 weeks.20 After 8 weeks of therapy, if the depression severity remains stable, continue weekly evaluations.20 If the depression severity worsens, consider psychiatric consultation and discontinue peginterferon alfa-2a or reduce dosage to 135 mcg in adults (135 mg/1.73 m² × BSA for pediatric patients) or 90 mcg once weekly for adults (90 mcg/1.73 m² × BSA for pediatric patients).20

If moderate depression develops, dosage of the drug should be reduced to 135 mcg in adults (135 mg/1.73 m² × BSA for pediatric patients) or 90 mcg in adults (90 mcg/1.73 m² × BSA for pediatric patients) once weekly and the patient evaluated once weekly (office visit at least every other week).20 After 8 weeks of therapy, if depression severity remains stable, consider psychiatric consultation and continue reduced dosing.20 If symptoms improve with the reduced dosage and remain stable for 4 weeks, resume normal visit schedule and the reduced dosage can be continued or dosage can be increased to the usual dosage.20 If depression severity worsens, obtain immediate psychiatric consultation and discontinue peginterferon alfa-2a permanently.20

If severe depression develops, peginterferon alfa-2a should be permanently discontinued and an immediate psychiatric consultation should be obtained; psychiatric therapy is necessary.20

Hematologic Effects

Dosage of peginterferon alfa-2a should be decreased to 135 mcg once weekly in adults with an absolute neutrophil count (ANC) of 500 to less than 750 cells/mm³.20 If ANC is less than 500 cells/mm³, peginterferon alfa-2a should be discontinued until ANC exceeds 1000 cells/mm³; the drug can then be resumed at a dosage of 90 mcg once weekly with monitoring of the ANC.20 Peginterferon alfa-2a dosage should be decreased to 90 mcg once weekly in adults with platelet counts of 25,000 to less than 50,000 cells/mm³, but should be discontinued in those with platelet counts less than 25,000 cells/mm³.20 The manufacturer's prescribing information should be consulted for more specific recommendations regarding dosage modification for hematologic effects.20

If a pediatric patient receiving peginterferon alfa-2a develops neutropenia (ANC less than 1000 cells/mm³) or decreased platelet counts (less than 50,000 cells/mm³), dosage modification or discontinuance of therapy may be recommended depending on the severity of the hematologic effect and the type of hepatitis being treated.20 The manufacturer's prescribing information should be consulted for more specific recommendations regarding dosage modification for hematologic effects.20

Special Populations

Hepatic Impairment

When peginterferon alfa-2a is used for treatment of chronic HBV infection in adults with elevated plasma ALT concentrations (greater than 5 times the upper limit of normal [ULN]), hepatic function should be monitored more frequently and consideration given to either reducing dosage to 135 mcg once weekly or temporarily discontinuing treatment.20 Treatment can be resumed after ALT flares subside.20 If ALT increases are persistent or severe (greater than 10 times the ULN), discontinuance of treatment should be considered.20 If ALT increases are progressive despite dosage reduction or are accompanied by increased bilirubin concentrations or evidence of hepatic decompensation, peginterferon alfa-2a therapy should be discontinued immediately.20

When peginterferon alfa-2a is used for treatment of chronic HCV infection in adults with progressive ALT increases above baseline values, dosage should be reduced to 135 mcg once weekly and hepatic function monitored more frequently.20 Treatment can be resumed after ALT flares subside.20 If ALT increases are progressive despite dosage reduction or are accompanied by increased bilirubin concentrations or evidence of hepatic decompensation, peginterferon alfa-2a therapy should be discontinued immediately.20

In pediatric patients with chronic HBV infection, modify dosage to 135 mcg/1.73 m²x BSA if persistent or increasing elevations of ALT are more than or equal to 5, but less than 10 times the ULN.20 Monitor weekly ALT level to ensure it is stable or decreasing.20 If persistent ALT more than or equal to 10 times the ULN occurs, then discontinue treatment.20

In pediatric patients with chronic HCV infection, modify dosage to 135 mcg/1.73 m²x BSA if persistent or increasing elevations of ALT are more than or equal to 5, but less than 10 times the ULN.20 Monitor weekly, reduce dosage further if necessary, until stable or ALT level decreases.20 If persistent ALT more than or equal to 10 times the ULN occurs, then discontinue treatment.20

Renal Impairment

When peginterferon alfa-2a is used in adults, those with creatinine clearances of 30-50 mL/minute can receive the usual dosage of 180 mcg once weekly, but dosage should be reduced to 135 mcg once weekly in those with creatinine clearance less than 30 mL/minute, including those with end-stage renal disease requiring hemodialysis.20 If severe adverse reactions or laboratory abnormalities occur in adults, peginterferon alfa-2a dosage may be reduced to 90 mcg once weekly; if intolerance persists, the drug should be discontinued.20 Dosage recommendations for peginterferon alfa-2a in pediatric patients with renal impairment are not available.20

Geriatric Patients

Because geriatric patients are more likely to have decreased renal function, care should be taken in dose selection and it may be useful to monitor renal function.20

Contraindications

• Known hypersensitivity reactions (e.g., urticaria, angioedema, bronchoconstriction, anaphylaxis, Stevens-Johnson syndrome) to interferon alfas, including peginterferon alf-2a, or any ingredient in the formulation.20
• Autoimmune hepatitis.20
• Hepatic decompensation (Child-Pugh score >6, class B and C) in cirrhotic patients prior to treatment.20
• Hepatic decompensation (Child-Pugh score ≥6) in cirrhotic patients with chronic HCV infection who are coinfected with HIV prior to treatment.20
• Use in neonates and infants (this preparation contains benzyl alcohol).20
• When used in combination with other HCV antivirals, the contraindications applicable to those agents are applicable to combination therapy.20
• Concomitant use of ribavirin and peginterferon alfa-2a is contraindicated in women who are pregnant and men whose female partners are pregnant.20

Warnings/Precautions

Warnings

Risk of Serious Disorders

Interferon alfas, including peginterferon alfa-2a, may cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders.20 A boxed warning has been included about this risk in the prescribing information for the drug.20 Patients should be monitored closely with periodic clinical and laboratory evaluations and the drug discontinued in those with persistently severe or worsening signs or symptoms of these disorders.20 In many, but not all cases, these disorders resolve after peginterferon alfa-2a is discontinued.20

Other Warnings and Precautions

Pregnancy: Use with Ribavirin

Ribavirin may cause birth defects and/or death of the fetus.20 Female patients or female partners of male patients must avoid pregnancy while taking peginterferon alfa-2a and ribavirin.20 Do not initiate ribavirin therapy unless a confirmed negative pregnancy test has been obtained immediately prior to initiation of therapy.20 Women of childbearing potential and male partners of females of childbearing potential must use 2 forms of effective contraception during treatment and for at least 6 months after treatment has concluded.20 Routine monthly pregnancy tests must be performed during this time.20

Neuropsychiatric Effects

Life-threatening or fatal neuropsychiatric reactions (e.g., suicide, suicidal and homicidal ideation, depression, relapse of drug addiction, drug overdose) may occur in patients receiving peginterferon alfa-2a therapy.20 These reactions can occur in patients with and without a previous psychiatric illness.20 Neuropsychiatric adverse events observed with interferon alfas include aggressive behavior, psychoses, hallucinations, bipolar disorder, and mania.20

Peginterferon alfa-2a should be used with extreme caution in any patient with a history of depression.20 All patients receiving the drug should be monitored for evidence of depression and other psychiatric symptoms.20 Patients should be advised to report any sign or symptom of depression or suicidal ideation to their clinician.20 In severe cases, therapy should be immediately discontinued and psychiatric intervention instituted.20

Cardiovascular Disorders

Hypertension, supraventricular arrhythmia, chest pain, and myocardial infarction (MI) have been reported in patients receiving peginterferon alfa-2a therapy.20

Peginterferon alfa-2a should be used with caution in patients with preexisting cardiovascular disease.20

Because cardiac disease may be worsened by ribavirin-associated anemia, patients with a history of clinically important or unstable cardiac disease should not receive oral ribavirin in combination with peginterferon alfa-2a.20

Myelosuppression

Peginterferon alfa-2a suppresses bone marrow function and may cause severe cytopenias.20 Aplastic anemia has been reported rarely in patients receiving alfa interferons.20 Concomitant oral ribavirin may potentiate neutropenia and lymphopenia induced by alfa interferons, including peginterferon alfa-2a.20

Severe thrombocytopenia and neutropenia occur more frequently in patients coinfected with HIV than in those not coinfected with HIV; serious infections or bleeding may occur.20

Peginterferon alfa-2a and concomitant oral ribavirin should be used with caution in patients with baseline neutrophil counts less than 1500 cells/mm³, baseline platelet counts less than 90,000 cells/mm³, or baseline hemoglobin less than 10 g/dL.20

Complete blood counts (CBCs) should be performed prior to and routinely during peginterferon alfa-2a therapy.20 Dosage should be adjusted or the drug discontinued if necessary.20

Autoimmune Disease

Development or exacerbation of autoimmune disorders (e.g., thyroiditis, thrombotic or idiopathic thrombocytopenic purpura, rheumatoid arthritis, myositis, interstitial nephritis, hepatitis, systemic lupus erythematosus, psoriasis) has been reported in patients receiving alfa interferons.20

Peginterferon alfa-2a should be used with caution in patients with autoimmune disorders.20

Endocrine and Metabolic Effects

Peginterferon alfa-2a may cause or aggravate hypothyroidism or hyperthyroidism.20 Hyperglycemia, hypoglycemia, and diabetes mellitus have developed in patients receiving the drug.20

Patients with hypothyroidism, hyperthyroidism, or diabetes mellitus at baseline whose disease cannot be effectively treated with medication should not receive peginterferon alfa-2a.20 If these conditions develop during peginterferon alfa-2a therapy and cannot be controlled with pharmacologic therapy, discontinuance of peginterferon alfa-2a may be necessary.20

Ocular Effects

Decrease or loss of vision, retinopathy including macular edema, retinal artery or vein thrombosis, retinal hemorrhages and cotton-wool spots, optic neuritis, papilledema, and serous retinal detachment are induced or aggravated by peginterferon alfa-2a and other interferon alfa preparations.20

Baseline ophthalmologic examination should be performed in all patients prior to initiation of peginterferon alfa-2a therapy.20 Patients with preexisting ophthalmologic disorders (e.g., diabetic or hypertensive retinopathy) should receive ophthalmologic examinations periodically during therapy.20

A prompt and complete eye examination should be performed in any patient who develops ocular symptoms.20

Peginterferon alfa-2a therapy should be discontinued in patients who develop new or worsening ophthalmologic disorders.20

Cerebrovascular Disorders

Ischemic and hemorrhagic cerebrovascular events have been reported in patients receiving alfa interferons, including peginterferon alfa-2a.20 Such events have occurred in patients with few or no reported risk factors for stroke, including patients younger than 45 years of age.20 Because these have been spontaneous reports, estimates of frequency and a causal relationship between alfa interferons and these events have not been established.20

Hepatic Failure and Hepatitis Exacerbations

Patients with chronic HCV infection and cirrhosis may be at risk of hepatic decompensation and death during interferon alfa (including peginterferon alfa-2a) therapy.20 Cirrhotic patients with HCV infection who are coinfected with HIV and are receiving highly active antiretroviral therapy (HAART) in conjunction with interferon alfa therapy (with or without oral ribavirin) appear to be at increased risk for development of hepatic decompensation compared with patients not receiving HAART.20 In reported cases, patients were receiving HAART that included HIV nucleoside reverse transcriptase inhibitors (abacavir, didanosine, lamivudine, zidovudine).20

Clinical status and hepatic function should be closely monitored during peginterferon alfa-2a therapy.20 Peginterferon alfa-2a and ribavirin should be immediately discontinued if hepatic decompensation (Child-Pugh score of 6 or greater) occurs.20

Patients with chronic hepatitis B virus (HBV) infection may experience HBV exacerbations (characterized by transient and potentially severe increases in serum ALT concentrations) during treatment.20 Transient acute exacerbations (flares) of HBV with ALT concentrations greater than 10 times the ULN have been reported in 12% of hepatitis B e antigen (HBeAg)-negative patients and 18% of HBeAg-positive patients during peginterferon alfa-2a treatment and in 7 and 12%, respectively, after treatment discontinuation.20 Marked transaminase flares during peginterferon alfa-2a treatment have been accompanied by other liver test abnormalities.20 If ALT flares occur, liver function should be monitored more frequently; a reduction in peginterferon alfa-2a dosage should be considered in patients experiencing transaminase flares.20 If ALT increases are progressive despite dosage reduction or are accompanied by increased bilirubin concentrations or evidence of hepatic decompensation, peginterferon alfa-2a should be immediately discontinued.20

Pulmonary Effects

Potentially severe and life-threatening dyspnea, pulmonary infiltrates, pneumonia, bronchiolitis obliterans, interstitial pneumonitis, pulmonary hypertension, and sarcoidosis may be induced or aggravated by peginterferon alfa-2a or other alfa interferon therapy.20

Peginterferon alfa-2a combination therapy should be discontinued in patients who develop pulmonary infiltrates or pulmonary function impairment.20 Recurrence of respiratory failure has occurred with interferon rechallenge, and patients should be closely monitored if peginterferon alfa-2a therapy is resumed.20

Infectious Complications

Serious and severe infections (bacterial, viral, fungal), some of which have resulted in death, have been observed in patients treated with alfa interferons, including peginterferon alfa-2a.20 While fever may be associated with the flu-like syndrome commonly reported during interferon therapy, other causes of high or persistent fever must be ruled out, particularly in patients with neutropenia.20

Appropriate anti-infective therapy should be initiated immediately and discontinuance of peginterferon alfa-2a considered in patients who develop severe infections.20

Colitis

Ulcerative and hemorrhagic/ischemic colitis, sometimes fatal, has been observed within 12 weeks of initiation of interferon alfa treatment.20

Peginterferon alfa-2a should be discontinued immediately in patients who develop signs and symptoms of colitis (e.g., abdominal pain, bloody diarrhea, fever).20 Colitis usually resolves within 1-3 weeks after the drug is discontinued.20

Pancreatitis

Pancreatitis, sometimes fatal, has occurred in patients receiving interferon alfa and ribavirin therapy.20

Peginterferon alfa-2a and ribavirin should be discontinued in patients with signs and symptoms suggestive of pancreatitis; the drugs should be permanently discontinued if a diagnosis of pancreatitis is established.20

Hypersensitivity

Serious acute hypersensitivity reactions (e.g., urticaria, angioedema, bronchoconstriction, anaphylaxis) have been observed during alfa interferon and ribavirin therapy.20 If such a reaction occurs, peginterferon alfa-2a and ribavirin therapy should be discontinued and appropriate medical therapy immediately provided.20

Serious skin reactions, including vesiculobullous eruptions, reactions in the spectrum of Stevens-Johnson syndrome (erythema multiforme major) with varying degrees of skin and mucosal involvement, and exfoliative dermatitis (erythroderma), have been reported in patients receiving interferon alfa-2a with and without ribavirin.20 Therapy must be discontinued if signs or symptoms of severe skin reactions occur.20

Immunogenicity

As with other interferon alfa therapies, neutralizing antibodies may develop in patients receiving peginterferon alfa-2a.20

In patients with chronic HBV infection receiving peginterferon alfa-2a, 29% of patients developed binding antibodies (13% of patients developed low-titer neutralizing antibodies).20

When antibody formation was assessed in patients with chronic HCV infection receiving peginterferon alfa-2a (with or without oral ribavirin), 9% of patients developed binding antibodies to peginterferon alfa-2a (3% of patients developed low-titer neutralizing antibodies).20

The clinical and pathologic importance of development of serum neutralizing antibodies is unknown.20 No apparent correlation of antibody development to clinical response or adverse events was observed.20 The percentage of individuals whose test results are considered positive for antibodies is highly dependent on the sensitivity and specificity of assays used.20 In addition, the observed incidence of antibody positivity in these assays may be influenced by several factors, including sample timing and handling, concomitant drug therapy, and underlying disease.20 For these reasons, comparison of the incidence of antibodies to different interferon or peginterferon preparations may be misleading.20

Organ Transplant Recipients

As with other alfa interferons, liver and renal graft rejections have been reported when peginterferon alfa-2a was used in organ transplant recipients.20

Safety and efficacy of peginterferon alfa-2a have not been established in patients with liver or other transplants.20

Specific Populations

Pregnancy

There are no adequate and well-controlled studies of peginterferon alfa-2a in pregnant women to inform a drug-associated risk.20 Based on animal reproduction studies, peginterferon alfa-2a can cause fetal harm and should be assumed to have abortifacient potential.20

Peginterferon alfa-2a combination treatment with ribavirin is contraindicated in women who are pregnant and in the male partners of women who are pregnant as significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin.20

Lactation

It is not known whether peginterferon alfa-2a is distributed into human milk.20 The effects of peginterferon alfa-2a on the breastfed infant and the drug's effects on milk production also are not known.20 The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for peginterferon alfa-2a and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition.20

Females and Males of Reproductive Potential

Females of reproductive potential must undergo pregnancy testing before initiation of treatment with peginterferon alfa-2a alone or in combination with ribavirin or with other HCV drugs.20 Females of reproductive potential and female partners of male patients receiving peginterferon alfa-2a in combination with ribavirin must have a routine pregnancy test performed monthly during treatment and for at least 6 months following treatment.20

Peginterferon alfa-2a can cause disruption of the menstrual cycle based on its mechanism of action and studies in female monkeys.20 No female fertility study has been performed.20

Because of the abortifacient potential of peginterferon alfa-2a (without ribavirin), females of reproductive potential should be advised to use effective contraception during therapy.20 Female patients or female partners of male patients must avoid pregnancy while taking concomitant peginterferon alfa-2a and ribavirin.20 Women of childbearing potential and their male partners must use 2 forms of effective contraception during treatment and for at least 6 months after treatment has concluded.20

Pediatric Use

Efficacy and safety of peginterferon alfa-2a have been established for the treatment of chronic HCV infection in pediatric patients 5 to 17 years of age and for the treatment of chronic HBV infection in pediatric patients 3 to 17 years of age.20 Efficacy and safety of peginterferon alfa-2a in pediatric patients with chronic HCV infection younger than 5 years of age have not been established.20 Peginterferon alfa-2a has not been studied to date in pediatric patients with chronic HBV infection and liver cirrhosis and the efficacy and safety of the drug in pediatric patients younger than 3 years of age have not been established.20

Delays in weight and height increases compared with baseline have been reported in pediatric patients receiving peginterferon alfa-2a and oral ribavirin therapy for chronic HCV infection.20 Decreased weight and height for age z-scores as well as percentiles of the normative population have been reported.20 Data from pediatric patients receiving peginterferon alfa-2a and oral ribavirin indicate that at the end of treatment, 43% of patients experienced a weight percentile decrease of more than 15 percentiles and 25% experienced a height percentile decrease of more than 15 percentiles on their baseline height curves.20 At the end of 2-years follow-up after completion of treatment, most children had returned to baseline normative growth curve percentiles for weight and height but 16% of the patients were more than 15 percentiles below their baseline weight curve and 11% were more than 15 percentiles below their baseline height curve at 2 years posttreatment.20 The available longer-term data on patients who were followed up for 6 years post-treatment are too limited to determine the risk of reduced height in some patients.20

Delays in weight and height increases were also observed in chronic HBV pediatric patients during therapy with peginterferon alfa-2a lasting up to 48 weeks.20 After 48 weeks of treatment, 13% of pediatric patients were more than 15 percentiles below their baseline weight curve and 6% were more than 15 percentiles below their baseline height curve.20 At 24 weeks after the end of treatment, 11% of patients were more than 15 percentiles below their baseline weight curve and 12% were more than 15 percentiles below their baseline height curve.20 At 5 years post-treatment, the percentage of patients with decreases of more than 15 percentiles from their baseline curves was 29% for weight and 18% for height.20

The manufacturer states that peginterferon alfa-2a (Pegasys^®) is contraindicated in neonates and infants; each vial contains 10 mg and each prefilled syringe contains 5 mg of benzyl alcohol as a preservative.20 Although a causal relationship has not been established, administration of injections preserved with benzyl alcohol has been associated with toxicity (e.g., neurologic) in neonates and infants, which is sometimes fatal.21,22,23,24,25,26 Toxicity appears to have resulted from administration of large amounts (i.e., 100-400 mg/kg daily) of benzyl alcohol in these neonates.22,23,24,25,26 Although use of drugs preserved with benzyl alcohol should be avoided in neonates whenever possible, the American Academy of Pediatrics (AAP) states that the presence of small amounts of the preservative in a commercially available injection should not proscribe its use when indicated in neonates.21,22,23,24,25,26

Geriatric Use

The manufacturer states that younger patients generally have higher virologic response rates to peginterferon alfa-2a than older patients.20 Clinical studies of peginterferon alfa-2a did not include sufficient numbers of patients ≥65 years of age to determine whether they respond differently than younger adults.20

Peginterferon alfa-2a should be used with caution in geriatric patients.20 Adverse reactions related to alfa interferons, such as CNS, cardiac, and systemic (e.g., flu-like) effects, may be more severe in geriatric patients than in younger adults.20 Because geriatric patients are more likely to have decreased renal function and because patients with renal impairment may be at increased risk of drug-induced toxicity, dosage should be selected carefully and it may be useful to monitor renal function during therapy.20 The drug should be used with caution in geriatric patients with creatinine clearance ≤50 mL/minute, and the dosage should be reduced in patients with creatinine clearance <30 mL/minute.20

Hepatic Impairment

Patients with chronic HBV infection may be at risk for transient acute exacerbations (flares) of HBV infection during treatment.20

Patients with chronic HCV infection with cirrhosis may be at risk of hepatic decompensation and death.20 Clinical status and hepatic function should be closely monitored and peginterferon alfa-2a should be immediately discontinued if decompensation (Child-Pugh score of 6 or greater) occurs.20

If elevated plasma ALT concentrations occur, hepatic function should be monitored more frequently and dosage adjustments or discontinuance of peginterferon alfa-2a therapy may be necessary.20

Renal Impairment

Peginterferon alfa-2a should be used with caution and close clinical and laboratory monitoring (particularly for creatinine clearance and decreased hemoglobin) in patients with any degree of renal impairment.20

Dosage adjustments are required in patients with creatinine clearance less than 30 mL/minute.20 Data are not available regarding use of peginterferon alfa-2a in pediatric patients with renal impairment.20

Common Adverse Effects

The most common adverse reactions (incidence >40%) reported in adult patients receiving peginterferon alfa-2a are fatigue/asthenia, pyrexia, myalgia, and headache.20 The common adverse reactions observed in pediatric patients are similar to those reported in adults.20

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Studies using peginterferon alfa-2a (Pegasys^®) indicated potential pharmacokinetic interactions with drugs metabolized by cytochrome P-450 (CYP) isoenzyme 1A2 (e.g., theophylline), but did not identify pharmacokinetic interactions with representative drugs metabolized by CYP isoenzymes 2C9, 2C19, 2D6, or 3A4.20

Azathioprine

Pancytopenia (marked decreases in erythrocytes, neutrophils, and platelets) and bone marrow suppression have been reported in some patients receiving azathioprine concomitantly with peginterferon alfa-2a and oral ribavirin.20 These effects occurred within 3-7 weeks after initiation of concomitant therapy, reversed within 4-6 weeks after all 3 drugs were discontinued, and did not recur when either azathioprine or the regimen of peginterferon alfa-2a and oral ribavirin was reinitiated alone.20

If pancytopenia develops, all 3 drugs (azathioprine, peginterferon alfa-2a, ribavirin) should be discontinued and peginterferon alfa-2a and oral ribavirin therapy should not be restarted with concomitant azathioprine.20

Antiretroviral Agents

HIV Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

Cases of hepatic decompensation, including some fatalities, have been reported in cirrhotic patients with chronic hepatitis C virus (HCV) infection who were coinfected with HIV and receiving nucleoside reverse transcriptase inhibitor (NRTI) antiretroviral agents and peginterferon alfa-2a and oral ribavirin concomitantly.20 Patients receiving peginterferon alfa-2a and ribavirin in combination with other HCV antiviral drugs and NRTIs should be monitored closely for treatment-associated toxicities.20 If worsening toxicities are observed, consideration should be given to discontinuing or reducing the dosage of peginterferon alfa-2a and/or ribavirin; if hepatic decompensation occurs (Child-Pugh score of 6 or greater), HCV treatment should be discontinued immediately.20

Methadone

Concomitant use of methadone and peginterferon alfa-2a may increase methadone concentrations.20 Although the clinical importance is unknown, patients receiving the drugs concomitantly should be monitored for signs and symptoms of methadone toxicity.20

Ribavirin

Ribavirin may potentiate the hematologic effects (anemia, neutropenia, lymphopenia) induced by peginterferon alfa-2a.8,20

Theophylline

Concomitant use of theophylline and peginterferon alfa-2a increased AUC of theophylline by 25% because of inhibition of CYP1A2.20 Serum theophylline concentrations should be monitored and appropriate dosage adjustments considered for patients receiving these drugs concurrently.20

Description

Peginterferon alfa-2a is a covalent conjugate of recombinant alfa-2a interferon with a single branched bis-monomethoxy polyethylene glycol (PEG) chain.20 The drug induces the innate antiviral immune response by binding to the human type 1 interferon receptor leading to receptor dimerization and activating multiple intracellular signal transduction pathways initially mediated by the JAK/STAT pathway.20 Peginterferon alfa-2a is expected to have pleiotropic biological effects in the body.20

Peak serum concentrations occur 72-96 hours following subcutaneous administration of peginterferon alfa-2a.20 In adults receiving doses of 90-270 mcg, there is a nonlinear, dose-related increase in peak serum concentrations and AUC.20 Steady-state concentrations are attained within 5-8 weeks with once-weekly dosing.20 A s a result of conjugation with PEG, the clearance of peginterferon alfa-2a is 100 times lower and the mean half-life is 32 times greater (160 hours) than that reported for interferon alfa-2a and consequently, the peginterferon preparation can be administered once weekly.20

For children 2-8 years of age with HCV infection, the time to reach steady-state concentrations is approximately 12 weeks.20 In adults >62 years of age, peak serum concentrations are similar to those in younger adults, but AUC values are increased compared with those <62 years of age receiving 180 mcg of peginterferon alfa-2a.20

Advice to Patients

• Advise patients to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).20
• Patients receiving peginterferon alfa-2a alone or in combination with an approved HCV antiviral drug should be directed in its appropriate use, informed of the benefits and risks associated with treatment, and referred to FDA-approved patient labeling.20
• Inform patients that ribavirin must not be used by women who are pregnant or by men whose female partners are pregnant.20 Ribavirin therapy should not be initiated until a report of a negative pregnancy test has been obtained immediately before starting therapy.20 Advise female patients of childbearing potential and male patients with female partners of childbearing potential of the fetal risks and instruct these patients to use 2 forms of effective contraception during ribavirin therapy and for 6 months after treatment discontinuation.20 Routine monthly pregnancy tests must be performed during this time.20
• Advise patients to notify their healthcare provider immediately in the event of a pregnancy.20 To monitor maternal and fetal outcomes of pregnant women exposed to ribavirin, the Ribavirin Pregnancy Registry has been established.20 Patients should be encouraged to register by calling 1-800-593-2214.20
• Inform patients that flu-like symptoms (e.g., tiredness, weakness, fever, chills, muscle aches, joint pain, headache) are very common with therapy.20 Also inform patients that some of these symptoms may be decreased by injecting peginterferon alfa-2a in the evening.20 Inform patients which over-the-counter (OTC) medicines can be taken to help prevent or decrease symptoms.20
• Advise patients that laboratory evaluations are required before starting therapy and periodically thereafter.20 Instruct patients to remain well hydrated, especially during the initial stages of treatment.20
• Question patients about prior history of drug abuse before initiating peginterferon alfa-2a as relapse of drug addiction and drug overdoses have been reported in patients treated with interferons.20
• Inform patients that it is not known if therapy with peginterferon alfa-2a will prevent transmission of hepatitis B infection to others or prevent cirrhosis, liver failure, or liver cancer that might result from hepatitis B virus infection.20
• Inform patients that the effect of treatment of hepatitis C infection on transmission is not known, and that appropriate precautions to prevent transmission of the hepatitis C virus during treatment or in the event of treatment failure should be taken.20
• Caution patients who develop dizziness, confusion, somnolence, and fatigue to avoid driving or operating machinery.20
• Advise patients to avoid drinking alcohol to reduce the chance of further injury to the liver.20
• Advise patients not to switch to another brand of interferon without consulting their healthcare provider.20
• Advise patients to take their prescribed dose on the same day and at approximately the same time each week.20 Advise patients that if they miss a dose, but remember within 2 days, to take their missed dose as soon as they remember and then to take their next dose on the day they normally do.20 If they remember when more than 2 days have passed, advise patients to consult their healthcare provider.20 Patients should also be advised to consult their healthcare provider if the full dose is not received (e.g., leakage around the injection site).20
• Instruct patients on preparation and administration of peginterferon alfa-2a, including aseptic technique.20 Appropriate training for preparation using the vial and prefilled syringe must be given by a healthcare provider.20
• Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.20
• Inform patients of other important precautionary information.20

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Only references cited for selected revisions after 1984 are available electronically.

8. Glue P, Rouzier-Panis R, Raffanel C et al for the Hepatitis C Intervention Therapy Group. A dose-ranging study of pegylated interferon alfa-2b and ribavirin in chronic hepatitis C. Hepatology . 2000; 32:647-53. [PubMed 10960463]

20. zr pharma& GmbH. Pegasys^® (peginterferon alfa-2a) injection for subcutaneous use prescribing information. South San Francisco, CA; 2023 Dec.

21. American Academy of Pediatrics Committee on Fetus and Newborn and Committee on Drugs. Benzyl alcohol: toxic agent in neonatal units. Pediatrics . 1983; 72:356-8. (IDIS 175725)

22. Anon. Benzyl alcohol may be toxic to newborns. FDA Drug Bull . 1982; 12(2):10-11.

23. Centers for Disease Control. Neonatal deaths associated with use of benzyl alcohol. MMWR . 1982; 31:290-1.

24. Gershanik J, Boecler B, Ensley H et al. The gasping syndrome and benzyl alcohol poisoning. N Engl J Med . 1982; 307:1384-8.

25. Menon PA, Thach BT, Smith CH et al. Benzyl alcohol toxicity in a neonatal intensive care unit: incidence, symptomatology, and mortality. Am J Perinatol . 1984; 1:288-92.

26. Anderson CW, Ng KJ, Andresen B et al. Benzyl alcohol poisoning in a premature newborn infant. Am J Obstet Gynecol . 1984; 148:344-6.

97. Terrault NA, Lok ASF, McMahon BJ et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology . 2018 Apr; 67(4):1560-1599. doi: 10.1002/hep.29800. PMID: 29405329; PMCID: PMC5975958. [Web]

119. American Association for the Study of Liver Diseases (AASLD). Recommendations for testing, managing, and treating hepatitis C. From the AASLD website. Accessed 2024 May 29. [Web]

120. European Association for the Study of the Liver. EASL Clinical Practice Guidelines: management of hepatitis C virus infection. J Hepatol . 2011; 55:245-64. [PubMed 21371579]

121. Yee HS, Chang MF, Pocha C et al. Update on the management and treatment of hepatitis C virus infection: recommendations from the Department of Veterans Affairs Hepatitis C Resource Center Program and the National Hepatitis C Program Office. Am J Gastroenterol . 2012; 107:669-89. [PubMed 22525303]

122. Liu CH, Liang CC, Liu CJ et al. Pegylated interferon alfa-2a monotherapy for hemodialysis patients with acute hepatitis C. Clin Infect Dis . 2010; 51:541-9. [PubMed 20645865]

123. Wiegand J, Deterding K, Cornberg M et al. Treatment of acute hepatitis C: the success of monotherapy with (pegylated) interferon alpha. J Antimicrob Chemother . 2008; 62:860-5. [PubMed 18776191]

124. De Rosa FG, Mollaretti O, Audagnotto S et al. Efficacy of early pegylated interferon alpha-2b monotherapy for acute hepatitis C in HIV-infected patients. Clin Infect Dis . 2009; 48:1636-7. [PubMed 19416030]

125. Arends JE, van Assen S, Stek CJ et al. Pegylated interferon-α monotherapy leads to low response rates in HIV-infected patients with acute hepatitis C. Antivir Ther . 2011; 16:979-88. [PubMed 22024513]

126. van den Berk GE, Arends JE. Sustained viral response after only 6 weeks of peginterferon and ribavirin treatment for acute hepatitis C in a HIV-1-infected patient. AIDS . 2011; 25:1553-4. [PubMed 21747237]

127. Loomba R, Rivera MM, McBurney R et al. The natural history of acute hepatitis C: clinical presentation, laboratory findings and treatment outcomes. Aliment Pharmacol Ther . 2011; 33:559-65. [PubMed 21198704]

128. Piroth L, Larsen C, Binquet C et al. Treatment of acute hepatitis C in human immunodeficiency virus-infected patients: the HEPAIG study. Hepatology . 2010; 52:1915-21. [PubMed 21064156]

129. Vogel M, Dominguez S, Bhagani S et al. Treatment of acute HCV infection in HIV-positive patients: experience from a multicentre European cohort. Antivir Ther . 2010; 15:267-79. [PubMed 20386082]

138. Lau GK, Piratvisuth T, Luo KX et al. Peginterferon alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B. N Engl J Med . 2005; 352:2682-95. [PubMed 15987917]

139. Marcellin P, Lau GK, Bonino F et al. Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B. N Engl J Med . 2004; 351:1206-17. [PubMed 15371578]

190. Panel on Opportunistic Infections in HIV-infected Adults and Adolescents. Guidelines for prevention and treatment of opportunistic infections in adults and adolescents with HIV: recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America (May 2, 2024). Updates may be available at HIV.gov website. [Web]

191. Panel on Opportunistic Infection in HIV-exposed and HIV-infected children, US Department of Health and Human Services (HHS). Guidelines for the prevention and treatment of opportunistic infections in HIV-exposed and HIV-infected children: recommendations from the National Institutes of Health, Centers for Disease Control and Prevention, the HIV Medicine Association of the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the American Academy of Pediatrics (Sep 14, 2023). Updates may be available at HIV.gov website. [Web]

342. Manns MP, McHutchison JG, Gordon SC et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet . 2001; 358:958-65. [PubMed 11583749]

420. McHutchison JG, Lawitz EJ, Shiffman ML et al. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med . 2009; 361:580-93. [PubMed 19625712]

421. Hadziyannis SJ, Sette H, Morgan TR et al. Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med . 2004; 140:346-55. [PubMed 14996676]

422. Fried MW, Shiffman ML, Reddy KR et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med . 2002; 347:975-82. [PubMed 12324553]

423. Torriani FJ, Rodriguez-Torres M, Rockstroh JK et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients. N Engl J Med . 2004; 351:438-50. [PubMed 15282351]

426. Wirth S, Ribes-Koninckx C, Calzado MA et al. High sustained virologic response rates in children with chronic hepatitis C receiving peginterferon alfa-2b plus ribavirin. J Hepatol . 2010; 52:501-7. [PubMed 20189674]

427. Schwarz KB, Gonzalez-Peralta RP, Murray KF et al. The combination of ribavirin and peginterferon is superior to peginterferon and placebo for children and adolescents with chronic hepatitis C. Gastroenterology . 2011; 140:450-458.e1. [PubMed 21036173]

428. Haagsma EB, Riezebos-Brilman A, van den Berg AP et al. Treatment of chronic hepatitis E in liver transplant recipients with pegylated interferon alpha-2b. Liver Transpl . 2010; 16:474-7. [PubMed 20373458]

429. Kamar N, Abravanel F, Garrouste C et al. Three-month pegylated interferon-alpha-2a therapy for chronic hepatitis E virus infection in a haemodialysis patient. Nephrol Dial Transplant . 2010; 25:2792-5. [PubMed 20494897]

436. Hoofnagle JH, Nelson KE, Purcell RH. Hepatitis E. N Engl J Med . 2012; 367:1237-44. [PubMed 23013075]

437. Kamar N, Rostaing L, Abravanel F et al. Pegylated interferon-alpha for treating chronic hepatitis E virus infection after liver transplantation. Clin Infect Dis . 2010; 50:e30-3. [PubMed 20113176]

448. AASLD. Hepatitis C Guidance 2023 Update: American Association for the Study of Liver Diseases- Infectious Diseases Societyof America Recommendations for Testing, Managing,and Treating Hepatitis C Virus Infection. Clinical Infectious Diseases. 2023; 1-18.