CurrentAetnaPolicy 0404

Interferons

Aetna clinical policy describing medical necessity, precertification, indications, continuation criteria, prescriber specialty requirements, and dosing/administration for various interferon products for Aetna members and participating providers.

Policy Summary

PayerAetna

PolicyInterferons

Policy CodePolicy 0404

Change TypeNo material changes noted

Effective Date04/04/2000

Next Review Date10/24/2024

Key ActionPrecertification required for interferon beta-1a (Avonex); call or fax and submit Statement of Medical Necessity.

SourceLink

POLICY UPDATE CHANGES

No material clinical or coverage changes in this revision.

0404Policy number 0404

12/15/2023Last review date

04/04/2000Effective date

RequiredAvonex precertification

2Actimmune FDA indications

Coverage Criteria and Medical Necessity

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inv-01: Initial Approval - Intron A

Interferon alfa-2b (Intron A) - Criteria for Initial Approval

Indications: Malignant melanoma; OR Adult T-cell leukemia/lymphoma (when used in combination with zidovudine); OR Hairy cell leukemia; OR Clinically aggressive follicular lymphoma; OR Renal cell carcinoma (when used in combination with bevacizumab); OR Condylomata acuminata; OR AIDS-related Kaposi sarcoma; OR Chronic myeloid leukemia (CML); OR Chronic hepatitis C virus infection; OR Chronic hepatitis B (including hepatitis D co-infection); OR Ocular surface neoplasia (conjunctival and corneal neoplasm)

Aetna considers all other indications experimental and investigational.

inv-02: Continuation Therapy - Intron A

Continuation of Therapy - Intron A and indication-specific continuation rules

Chronic Hepatitis C continuation: Continuation up to a total of 96 weeks when the member is receiving clinical benefit and there is no evidence of unacceptable toxicity while on the current regimen.<=96 weeks total

Extend to 72-96 weeks if ALT normalized at 16 weeks per dosing guidance.

Chronic Hepatitis B continuation: Continuation up to a total of 24 weeks when the member is receiving clinical benefit and there is no evidence of unacceptable toxicity while on the current regimen.<=24 weeks total

Hairy Cell Leukemia continuation: Continuation up to a total of 6 months when the member is receiving clinical benefit and there is no evidence of unacceptable toxicity while on the current regimen.<=6 months

Dose: 2 million IU/m2 IM or SC three times weekly per dosing guidance.

All other indications continuation: Continuation medically necessary when there is evidence of clinical benefit and no unacceptable toxicity or disease progression while on the current regimen.

Applies to indications listed in initial approval other than HCV, HBV, and hairy cell leukemia.

inv-03: Initial and Continuation - Alferon N

Interferon alfa-n3 (Alferon N)

Initial Approval: Intralesional treatment of refractory or recurring external condylomata acuminata (venereal/genital warts)

All other indications are considered experimental and investigational.

Continuation medically necessary when the member is receiving clinical benefit or there is no evidence of unacceptable toxicity.

inv-04: Initial and Continuation - Avonex

Interferon beta-1a (Avonex)

Initial Approval: Relapsing forms of multiple sclerosis (including relapsing-remitting and secondary progressive disease with relapses) OR Clinically isolated syndrome (CIS)

Must be prescribed by or in consultation with a neurologist; all other indications experimental and investigational.

Continuation medically necessary for members experiencing disease stability or improvement while receiving Avonex.

Do not use concomitantly with other disease-modifying MS agents.

inv-05: Initial and Continuation - Actimmune

Interferon gamma-1b (Actimmune)

Initial Approval: Chronic granulomatous disease to reduce frequency and severity of infections; OR Mycosis fungoides/Sezary syndrome; OR Severe malignant osteopetrosis to delay progression

Prescriber must be specialist appropriate to the indication (e.g., immunologist, endocrinologist, hematologist/oncologist).

Continuation medically necessary when the member is experiencing benefit from therapy as evidenced by disease stability or improvement.

Recommended baseline and periodic monitoring (hematologic, renal, hepatic) per product guidance.

inv-06: Initial and Continuation - Pegasys

Peginterferon alfa-2a (Pegasys)

Initial Approval: Adult T-cell leukemia/lymphoma; OR Chronic hepatitis B (including HDV co-infection) for treatment up to 48 weeks; OR Chronic hepatitis C; OR Chronic myeloid leukemia in pregnancy; OR Erdheim-Chester disease; OR Hairy cell leukemia; OR Mycosis fungoides/Sezary syndrome; OR Myeloproliferative neoplasms (including essential thrombocythemia, polycythemia vera, symptomatic lower-risk myelofibrosis); OR Primary cutaneous CD30+ T-cell lymphoproliferative disorders; OR Systemic mastocytosis<=48 weeks for HBV

All other indications are experimental and investigational.

Continuation for chronic HCV and chronic HBV requires meeting all initial selection criteria; continuation for myeloproliferative neoplasms and systemic mastocytosis requires evidence of benefit (symptom or marker improvement); other indications require no unacceptable toxicity or disease progression.

inv-07: Initial and Continuation - Besremi

Ropeginterferon alfa-2b (Besremi)

Initial Approval: Treatment of polycythemia vera (adult patients)

All other indications experimental and investigational.

Continuation medically necessary if the member is experiencing benefit as evidenced by improvement in symptoms and/or disease markers (e.g., hematologic response, spleen size stabilization)

Follow product contraindications and monitoring guidance.

inv-08: Dosing/Administration (informational)

Dosing regimens presented for specific products and indications (informational). Coverage contingent on meeting selection criteria elsewhere in this policy.

Intron A - malignant melanoma dosing: Induction: 20 million IU/m2 IV over 20 minutes, 5 consecutive days per week for 4 weeks; Maintenance: 10 million IU/m2 subcutaneously 3 times/week for 48 weeks.

Source: product dosing guidance (Intron A).

Intron A - follicular lymphoma dosing: 5 million IU subcutaneously 3 times/week for up to 18 months in conjunction with and following completion of anthracycline-containing chemotherapy.

Source: dosing guidance for follicular lymphoma.

Intron A - condylomata acuminata dosing: 1 million IU per lesion (maximum 5 lesions per course), injected three times weekly on alternate days for 3 weeks; additional course may be administered at 12 to 16 weeks.

Source: dosing guidance for condylomata acuminata.

inv-09: Experimental and Investigational

Aetna-designated experimental and investigational uses of interferons (non-exhaustive).

COVID-19: Interferon therapy is considered experimental and investigational for treatment of COVID-19.

Intron A - other experimental uses: Interferon alfa-2b (Intron A) is experimental/investigational for numerous indications not listed in the initial approval section (examples listed in policy).

See policy experimental/investigational list for specific conditions.

Avonex experimental uses: Interferon beta-1a (Avonex) in combination with other disease-modifying MS treatments (excluding Ampyra and Nuedexta) and testing for neutralizing antibodies are experimental/investigational.

Actimmune experimental uses: Interferon gamma-1b (Actimmune) is experimental/investigational for listed conditions (e.g., idiopathic pulmonary fibrosis, various neoplasms) outside approved indications.

inv-10: Product-specific covered indications and selection

Product-specific covered indications and selection — general requirement

General requirement: Product is used for an FDA-approved indication or a compendial use listed in the policy and appropriate ICD-10/HCPCS codes are submitted to support the requested therapy.

See product-specific sections for listed indications; all other uses considered experimental/investigational.

inv-11: Consensus interferon (Infergen) retreatment criteria for chronic hepatitis C nonresponders

Consensus interferon (Infergen) retreatment criteria for chronic hepatitis C nonresponders

Retreatment population: Member is a prior non-responder to pegylated interferon plus ribavirin defined as <2 log decline in viral load during ≥12 weeks of prior therapy with ≥80% adherence OR detectable viral load at end-of-treatment after ≥24 weeks of prior therapy.

Majority of trial subjects were genotype 1; consensus interferon discontinued commercially in 2013.

Dosing options studied: Consensus interferon dosing studied included 9 mcg or 15 mcg regimens plus ribavirin (combination daily or thrice-weekly schedules) with treatment durations up to 48 weeks.

Sustained virologic response rates were low in genotype 1 nonresponders.

Stopping rule: Discontinue therapy if failure to achieve at least a 2-log10 reduction in HCV RNA at 12 weeks or if HCV RNA remains detectable at week 24, as sustained response is highly unlikely.<2 log drop at 12 weeks or detectable at week 24

inv-12: Intron A — follicular Non-Hodgkin’s Lymphoma (initial therapy)

Intron A — follicular Non-Hodgkin’s Lymphoma (initial therapy)

Indication and context: Intron A (interferon alfa-2b) is indicated for initial treatment of clinically aggressive follicular Non-Hodgkin’s lymphoma in conjunction with anthracycline-containing combination chemotherapy in patients 18 years of age or older.age >= 18

Efficacy not demonstrated in low-grade, low-tumor burden follicular NHL; large tumor burden criteria must be documented.

Large tumor burden definition (documentation): Large tumor burden defined by any one of: nodal or extranodal tumor mass diameter >7 cm; involvement of ≥3 nodal sites each >3 cm; systemic symptoms; splenomegaly; serous effusion; orbital or epidural involvement; ureteral compression; OR leukemia.

Documentation of tumor burden required to support use with CHVP per trial criteria.

inv-13: NETs — interferon alfa-2b vs bevacizumab

NETs — interferon alfa-2b vs bevacizumab (evidence summary relevant to therapeutic selection)

SWOG S0518 findings: In advanced NETs treated with octreotide LAR, addition of bevacizumab versus interferon alfa-2b produced no significant difference in centrally assessed progression-free survival (median 16.6 vs 15.4 months); time to treatment failure favored bevacizumab and confirmed response rates were higher with bevacizumab.

Trial enrolled 427 patients; differing adverse-event profiles may inform agent selection rather than superiority of IFN.

inv-14: NMIBC — BCG with or without interferon

NMIBC — BCG with or without interferon (evidence summary)

Cochrane review conclusion: Cochrane review of 5 randomized trials (1,231 participants) found no clear differences in recurrence or progression between intravesical BCG plus IFN-α and BCG alone; evidence quality rated low to very low.

Alternating regimens produced mixed results; additional high-quality trials required.

inv-15: Besremi (ropeginterferon alfa-2b) coverage

Besremi (ropeginterferon alfa-2b) coverage for polycythemia vera

Besremi covered criteria: 1) Adult patient with a diagnosis of polycythemia vera; AND 2) Indication aligns with FDA approval for polycythemia vera; AND 3) No contraindications present (e.g., history of severe psychiatric disorder, hepatic impairment Child-Pugh B/C, active untreated autoimmune disease, hypersensitivity, or transplant recipient); AND 4) Prescriber has considered alternative therapies and will monitor for known interferon-related toxicities.

Maximum dose per product labeling: up to 500 mcg; monitor for neuropsychiatric and hematologic adverse events.

inv-16: Peginterferon alfa-2a for chronic hepatitis B

Peginterferon alfa-2a for chronic hepatitis B — coverage criteria

Peginterferon alfa-2a HBV criteria: 1) Adult with chronic hepatitis B and compensated liver disease; AND 2) Evidence of HBV replication meeting trial thresholds (HBeAg-positive: >500,000 copies/ml OR HBeAg-negative: >100,000 copies/ml); AND 3) ALT between 1 and 10 times the upper limit of normal; AND 4) Liver biopsy compatible with chronic hepatitis; AND 5) No hepatic decompensation or listed contraindications.

Treatment limited to 48 weeks; treatment beyond 48 weeks considered experimental/investigational.

inv-17: Peginterferon alfa-2b (HCV) coverage stance

Peginterferon alfa-2b (PegIntron/Sylatron) — coverage stance and considerations

Peginterferon alfa-2b considerations: PegIntron/Sylatron were historically used for chronic HCV in genotype-specific regimens often combined with ribavirin; many formulations have been discontinued or have limited availability, and current HCV guidelines no longer recommend pegylated interferon regimens where DAAs are available.

When used, authorization should document rationale, genotype, prior therapies, and availability of DAAs.

inv-18: Coverage considerations and clinical criteria

Coverage considerations and clinical decision points derived from evidence and guideline excerpts

HCV genotype 1 or 4 stopping/continuation rule: For patients with HCV genotype 1 or 4 receiving pegylated interferon-based therapy, assess HCV RNA at 12 weeks: if undetectable or ≥2 log10 reduction (EVR), continue therapy to 48 weeks; if not, discontinue therapy because likelihood of response is extremely low.HCV RNA decrease >=2 log10 or undetectable at week 12

NICE guidance: <1% of baseline at 12 weeks required to continue.

Extended duration for slow responders: Consider extending therapy to 72 weeks for genotype 1 patients who achieve delayed clearance between weeks 12 and 24, recognizing benefit is variable and patient selection is important.Clearance between weeks 12 and 24

Evidence supports extension in select slow responders (AASLD).

Genotypes 2 and 3 standard duration:

inv-19: Interferon use in Hypereosinophilic Syndrome (HES)

Interferon use in Hypereosinophilic Syndrome (HES)

HES second-line: Conventional or pegylated interferon alfa may be considered as second-line therapy when mepolizumab is unavailable or the patient is ineligible, or when glucocorticoids fail or cause unacceptable toxicity.

Use requires documentation of prior therapy attempts and rationale per UpToDate guidance.

inv-20: Interferon use in Idiopathic Sudden Sensorineural Hearing Loss (ISSHL)

Interferon use in Idiopathic Sudden Sensorineural Hearing Loss (ISSHL) — limited evidence

ISSHL: Interferon-alpha has been used in small studies for severe ISSHL with some reports of recovery, but guideline reviews note insufficient evidence to recommend routine use.

AAO-HNSF guideline advises against routine prescribing of interferon for ISSHL due to insufficient evidence.

inv-21: Interferon use in Fibrolamellar HCC

Interferon use in Fibrolamellar Hepatocellular Carcinoma (FLC) — case reports and small series

FLC systemic therapy: Case reports and small series report objective responses with regimens including interferon-alpha often combined with 5-FU or platinum-based agents; randomized evidence is lacking and interferon use remains investigational in FLC.

Document prior therapies and rationale when requesting interferon for FLC.

inv-22: Interferon-gamma for Chronic Granulomatous Disease

Interferon-gamma for Chronic Granulomatous Disease (CGD)

CGD_IFN-gamma: Subcutaneous IFN-gamma added to antimicrobial prophylaxis is associated with reduced serious infections (meta-analysis RR 0.56; 95% CI: 0.35-0.90); use is supported but evidence base is limited.

Prescriber specialty and monitoring appropriate to indication recommended.

inv-23: Interferon therapy for COVID-19

Interferon therapy for COVID-19 — evidence summary and policy stance

COVID-19 general: Systematic reviews and large trials report heterogeneous results for interferon regimens in COVID-19: some small or early studies suggested benefit for discharge or reduced ICU admission, while larger RCTs (including WHO Solidarity) do not show mortality benefit; overall evidence is insufficient to recommend routine interferon use for hospitalized COVID-19 patients.

Aetna considers interferon therapy for COVID-19 experimental and investigational.

Outpatient pegylated IFN-lambda: A randomized adaptive platform trial showed a single 180 μg subcutaneous dose of pegylated IFN-lambda reduced a composite of hospitalization/ED observation in predominantly vaccinated outpatients (2.7% vs 5.6%); this is emerging evidence and indication-specific authorization should require trial details and timing relative to symptom onset.

Consideration for authorization should document indication and timing per trial criteria.

inv-24: Evidence summaries by indication

Evidence summaries by indication (selection of notable findings)

COVID-19 inpatient/outpatient summaries: IFN-α/β trials in hospitalized patients show mixed results with no clear mortality benefit but some increased discharge rates; outpatient single-dose pegylated IFN-lambda showed reduced composite hospitalization/ED events in a randomized trial.

Heterogeneous study designs and populations limit generalizability.

Plexiform neurofibromas: Phase I data of pegylated interferon-α-2b demonstrated clinical/radiographic improvement in some pediatric patients at RP2D 1 μg/kg/week; further study needed.

Pulmonary TB adjunct IFN-gamma: Systematic review/meta-analysis suggests aerosolized IFN-gamma may improve sputum conversion and radiographic outcomes; trial quality limited (rated C).

Pancreatic cancer adjuvant IFN: Early-phase and feasibility studies report immunologic activation and possible survival signals, but randomized data remain inconclusive and interferon is not a guideline-recommended adjuvant option.

inv-25: Evidence summaries by indication

Additional evidence summaries and situational context (informational)

Sjogren's dry eye: Systematic review found insufficient rigorous trials to recommend interferon-alpha for Sjogren's-associated dry eye; standard treatments preferred.

Cutaneous SCC and OSSN: Intralesional or subconjunctival interferon formulations have reported activity in small series/pilot studies for non-melanoma skin cancers and ocular surface squamous neoplasia, but randomized evidence is limited.

Use may be considered in selected local/unresectable scenarios with appropriate documentation.

Systemic mastocytosis: Interferon-alpha has been used for slowly progressive symptomatic systemic mastocytosis not candidates for other therapies; often combined with prednisone in case series.

VSV-IFNβ preclinical evidence: Preclinical studies of vesicular stomatitis virus encoding IFN-beta show mostly positive outcomes in animal models but remain translational and investigational for cancer therapy.

Aetna considers interferon products medically necessary only for the specific indications listed in each agent’s "Criteria for Initial Approval" section. All other indications not explicitly listed are considered experimental and investigational and are not eligible for coverage under this Clinical Policy Bulletin.

The ICD-10 codes presented in the coding section of this policy represent diagnoses that, when supported by the policy’s clinical selection criteria, are indicative of covered use for the interferon product requested. Submit the appropriate covered ICD-10 diagnosis code(s) listed in the CPB to support medical necessity when requesting authorization.

The policy lists specific ICD-10 codes and diagnostic categories that are explicitly identified as not covered for the indications in this CPB. Claims submitted with those ICD-10 codes for the listed indications (examples include certain herpesviral infections, varicella/zoster codes, some malignant bone neoplasms, viral wart codes, progressive multifocal leukoencephalopathy, and COVID-19 among others) may be denied as not covered for the requested interferon therapy.

Although Intron A (interferon alfa-2b) is an option for initial treatment of clinically aggressive follicular Non-Hodgkin’s Lymphoma in conjunction with anthracycline-containing chemotherapy in adults, efficacy of Intron A in patients with low-grade, low–tumor burden follicular NHL has not been demonstrated and such presentations are not supported by the evidence cited.

Interferon gamma-1b (Actimmune) was evaluated for idiopathic pulmonary fibrosis (IPF) but large randomized trials and the subsequent development program did not demonstrate a survival or progression-free survival benefit; development for IPF was discontinued. Therefore, Actimmune is not supported for treatment of IPF based on lack of demonstrated benefit in the trials cited.

Product labeling for Besremi (ropeginterferon alfa-2b) includes several contraindications and warnings. Exclusions include hepatic impairment (Child-Pugh B or C), history or presence of severe psychiatric disorders (e.g., severe depression or suicidal ideation), hypersensitivity to interferons or product components, active serious/untreated autoimmune disease, and immunosuppressed transplant recipients. These contraindications should be considered when assessing medical necessity.

Current AASLD/IDSA guidance and the policy narrative emphasize that where direct-acting antiviral (DAA) regimens for hepatitis C are available, these agents are preferred over interferon-based therapy. DAA regimens are generally recommended over interferon; interferon-based regimens are reserved for situations where DAAs are inaccessible or not an option and requests should include justification if interferon is requested in lieu of DAAs.

The AAO‑HNSF guideline on sudden hearing loss concludes that evidence is insufficient to support routine prescribing of antivirals, vasodilators, interferon or other complementary therapies for idiopathic sudden sensorineural hearing loss. Accordingly, routine interferon use for ISSHL is not recommended based on guideline guidance and limited evidence.

A systematic review of therapies for Sjogren’s syndrome–associated dry eye identified a paucity of rigorous clinical trials and specifically discussed interferon‑alpha without recommending it as a therapeutic option. Therefore, interferon‑alpha is not recommended for Sjogren’s dry eye based on the limited and low-quality evidence available.

The CPB includes evidence summaries and discussion sections where some interventions and study results are described; however, in several narrative segments there are no explicit exclusion lists or formal 'not covered' statements provided. These portions are informational and do not by themselves constitute a coverage rule.

Peginterferon alfa-2a (Pegasys) is described in the policy for HBV therapy with a recommended treatment duration of up to 48 weeks; treatment of chronic hepatitis B with peginterferon alfa-2a for more than 48 weeks is considered experimental and investigational and is not supported by the CPB.

The policy designates many uses of interferon alfa-2b (Intron A) outside the listed, agent-specific indications as experimental and investigational because effectiveness has not been established for those numerous additional indications.

The CPB identifies several clinical conditions and diagnostic categories for which interferon therapy is considered not supported or not established (for example certain degenerative nervous system diseases, idiopathic pulmonary fibrosis, COVID‑19 and a range of other listed conditions). Use of interferons for these non‑covered conditions is considered experimental/investigational for the indications listed.

Randomized trials and subsequent analyses failed to show consistent benefit for IFN‑gamma‑1b in idiopathic pulmonary fibrosis; large phase‑3 data and program decisions led to discontinuation of development for IPF. The evidence therefore does not support IFN‑gamma‑1b for IPF, and trials did not demonstrate improvement in progression‑free survival or overall survival in the larger studies cited.

Long-term maintenance or repeat pegylated interferon therapy has been evaluated in trials such as HALT‑C and other studies. Maintenance or repeat long-term (>1 year) pegylated interferon therapy has not been shown to provide clinical benefit and is not supported by the safety and efficacy data cited in this policy.

Several meta-analyses and systematic reviews of subcutaneous interferon‑beta in hospitalized COVID-19 populations report no consistent benefit on major endpoints such as 28‑day mortality; pooled analyses showed heterogenous results and overall do not support subcutaneous IFN‑β for improving survival in general hospitalized COVID‑19 patients.

A randomized trial of adjuvant interferon‑α2a plus 13‑cis‑retinoic acid in high‑risk cutaneous squamous cell carcinoma did not improve time to recurrence compared with observation. Thus the cited randomized data do not support this adjuvant regimen for recurrence prevention in that study population.

A systematic review of interventions for Sjogren’s syndrome–associated dry eye concluded that trial evidence is limited and interferon‑alpha was not recommended as a therapeutic option in the literature reviewed.

See the policy's coding section for the full list of CPT and HCPCS/CPT procedure codes referenced for interferon products and associated services; submit the appropriate codes when requesting authorization. (Refer to the CPB coding tables for the specific codes.)

Regimens and Dosing Considered Covered

Phase	Dose & Route	Schedule / Duration
Induction	20 million IU/m2 IV infusion over 20 minutes	5 consecutive days per week for 4 weeks
Maintenance	10 million IU/m2 subcutaneous injection	Three times weekly for 48 weeks

Agent / Setting	Dose & Route	Schedule / Duration
Interferon alfa-2b (Intron A) — follicular lymphoma (with anthracycline-containing chemotherapy)	5 million IU subcutaneously	Three times weekly for up to 18 months (in conjunction with and following completion of chemotherapy)

Regimen	Dose	Schedule / Duration
Interferon alfa-2b (retreatment contexts listed for HCV consensus interferon background) — follicular lymphoma schedule noted in Intron A labeling	5 million IU subcutaneously	Three times weekly for up to 18 months

Product	Starting Dose	Titration / Maximum
Ropeginterferon alfa-2b (Besremi) — polycythemia vera	Start 100 mcg SC every 2 weeks (50 mcg if receiving hydroxyurea)	Increase by 50 mcg every 2 weeks to a maximum of 500 mcg until hematologic parameters stabilized

Regimen / Context	Drugs Included	Response-Guided Monitoring
Historic HCV genotype 1 regimen (approved combination)	Boceprevir + peginterferon alfa + ribavirin	Duration determined by response-guided therapy using HCV-RNA at weeks 8, 12, and 24 per labeling

Agent / Use	Studied Doses	Notes on Duration / Stopping Rules
Consensus interferon (interferon alfacon-1) plus ribavirin — retreatment of HCV nonresponders	Monotherapy: 9 mcg 3x weekly (24 weeks) or 15 mcg 3x weekly (up to 48 weeks); Combination: 15 mcg daily with ribavirin (1,000–1,200 mg/day) up to 48 weeks	Persons failing to achieve ≥2 log drop at 12 weeks or undetectable HCV-RNA at week 24 unlikely to achieve SVR; discontinue per labeling

Trial Regimen	Intron A Dose	Schedule / Duration
CHVP chemotherapy regimen with adjunctive Intron A (follicular NHL trial)	Intron A 5 million IU subcutaneously	Three times weekly for 18 months (trial duration) alongside 12 CHVP cycles over 18 months

Combination	Dosing (Octreotide +...)	Schedule
Octreotide LAR with comparator therapies in NETs (SWOG S0518)	Octreotide LAR 20 mg q21d with either bevacizumab 15 mg/kg q21d or IFN-α-2b 5 million units	Octreotide every 21 days; bevacizumab q21d or IFN‑α‑2b three times weekly per arm

Product	Compendial Uses (examples)	Regimen Notes
Peginterferon alfa-2a (Pegasys)	Listed compendial uses include: Adult T-cell leukemia/lymphoma; CML; Erdheim-Chester disease; Hairy cell leukemia; Mycosis fungoides/Sezary syndrome; Myeloproliferative neoplasms; Primary cutaneous CD30+ disorders; Systemic mastocytosis	Standard Pegasys dosing for viral indications 180 mcg/week; oncology/compendial uses per cited sources and product labeling

Product	Indication (melanoma adjuvant)	Regimen / Note
Sylatron (peginterferon alfa-2b)	Adjuvant treatment of melanoma with microscopic or gross nodal involvement within 84 days of definitive resection	Use per FDA approval and product labeling; contraindicated in hepatic decompensation and certain psychiatric conditions

Study	Intervention	Result / Note
Chen et al (HCC post-resection RCT)	Adjuvant IFNα-2b for 53 weeks vs observation	No reduction in post-operative recurrence demonstrated; increased hematologic toxicity and treatment withdrawals observed

Tumor Type	Regimen	Evidence / Outcome
Fibrolamellar hepatocellular carcinoma (FLC)	5-FU combined with recombinant interferon alpha-2b (systemic, 21-day courses repeated monthly; thrice-weekly SC IFN-α-2b)	Small series reported objective responses (including CR and PR) in FLC patients; randomized evidence lacking

Setting	Regimen Components	Study Notes
Adjuvant / neoadjuvant pancreatic cancer (feasibility study)	Multimodality: continuous 5-FU, cisplatin, radiotherapy, plus subcutaneous recombinant IFN‑alpha administered 3 days weekly during radiotherapy	Small feasibility study (n=11) reported manageable toxicity and 4-year overall survival of 55%; further trials needed

Population	Agent & Dose	Schedule / RP2D
Pediatric/young adult patients with unresectable progressive plexiform neurofibromas	Pegylated interferon‑α‑2b administered weekly in dose-escalation cohorts	Recommended phase II dose (RP2D) identified at 1 μg/kg/week; continued for up to 2 years in trial

Indication	Administration Route / Dose	Clinical Notes
Ocular surface squamous neoplasia (OSSN)	Subconjunctival/perilesional injections of pegylated IFNα2b (1 μg/kg) until tumor resolution	Pilot study (n=3) reported clinical resolution in all patients; mean time to resolution 47 days; recurrence in one patient successfully retreated
Cutaneous non-melanoma skin cancers (BCC/SCC)	Intralesional recombinant IFN‑alpha‑2b per historical series	Multiple case series show efficacy and good cosmetic outcomes; randomized trials limited and modality under-used

Coding and Billing

CPT/HCPCS codes referencedmixed

11900	Injection, intralesional; up to and including 7 lesions.
11901	Injection, intralesional; more than 7 lesions.
87520-87522	Infectious agent detection by nucleic acid; hepatitis C (direct probe, amplified probe, or quantification).
96401-96402	Chemotherapy administration, subcutaneous or intramuscular.
J9214	Injection, interferon, alfa-2B, recombinant, 1 million units.
J9035	Injection, bevacizumab, 10 mg.
S9559	Home injectable therapy; interferon, including administrative services, professional pharmacy services, care coordination, and all necessary supplies and equipment (drug and nursing visits coded separately), per diem.

ICD-10 codes covered when selection criteria metICD-10Covered

A63.0	Anogenital (venereal) warts [genital warts (intralesional only)].
B18.0-B18.1	Chronic viral hepatitis B.
B19.20-B19.21	Unspecified viral hepatitis C.
C43.0-C43.9	Malignant melanoma of skin [only Sylatron brand is considered medically necessary].
C46.0-C46.9	Kaposi's sarcoma [AIDS-associated].
C82.00-C82.99	Follicular lymphoma.
D45	Polycythemia vera.
D47.3	Essential (hemorrhagic) thrombocythemia.
Z22.51	Carrier of viral hepatitis B.

ICD-10 codes not covered for indications listedICD-10Not Covered

B00.1,B00.3,B00.50-B00.9	Herpesviral [herpes simplex] infections (not covered for CPB indications).
B01.0-B01.9	Varicella (chickenpox) (not covered).
B18.2	Chronic viral hepatitis C (listed as not covered in CPB).
B20	Human immunodeficiency virus [HIV] disease (listed as not covered in CPB).

Covered ICD-10 codes (examples from list)ICD-10Covered

C44.91	Basal cell carcinoma.
C79.32	Secondary malignant neoplasm of cerebral meninges [leptomeningeal metastases].
C90.00-C90.02	Multiple myeloma.
D18.00-D18.09	Hemangioma [intralesional] [life-threatening hemangioma of infancy when member is intolerant/resistant to corticosteroids].
G35	Multiple sclerosis.
U07.1	COVID-19.

HCPCS/J codes (covered or related)HCPCS

S0145	Injection, pegylated interferon alfa-2a, 180 mcg per ml.
S9559	Home injectable therapy; interferon, including administrative services, professional pharmacy services, care coordination, and all necessary supplies and equipment (drug and nursing visits coded separately), per diem.
J1595	Injection, glatiramer acetate, 20 mg [listed here as HCPCS related].
J1826	Injection, interferon beta-1a, 30 mcg.
J1830	Injection, interferon beta-1b, 0.25 mg.
J9215	Injection, interferon, alfa-N3, (human leukocyte derived), 250,000 IU.
J9216	Injection, interferon, gamma-1B, 3 million units.

Related CPT codes (laboratory)CPT

87520-87522

Infectious agent detection by nucleic acid; hepatitis C (direct probe technique, amplified probe technique, or quantification).

ICD-10 codes listed as NOT covered for indications in CPB (examples)ICD-10Not Covered

A81.2	Progressive multifocal leukoencephalopathy.
B07.0-B07.9	Viral warts.
C40.00-C41.9	Malignant neoplasm of bone and articular cartilage [osteosarcoma].
D21.0-D21.9	Other benign neoplasms of connective and other soft tissue.

Clinical references — no codes providedmixed

No codes listed

Duration for extension in HCV

HCV extension indicationIf patient tolerates therapy with normalization of ALT at 16 weeks, extend interferon alfa-2b to 72–96 weeks (18–24 months) at 3 million IU three times weekly.

Standard HCV dose for extension3 million IU subcutaneously three times per week during the extended period.

Criteria for extension benefitOnly patients with ALT normalization by week 16 considered for extension; those without ALT normalization or with persistently high HCV RNA after 16 weeks rarely benefit.

Maximum duration for peginterferon alfa-2a in HBV

Maximum recommended durationPeginterferon alfa-2a (Pegasys) treatment for chronic hepatitis B: up to 48 weeks total.

Beyond 48 weeksTreatment of chronic hepatitis B with peginterferon alfa-2a for more than 48 weeks is considered experimental and investigational.

Trial duration contextPhase III HBV trials used 48 weeks of therapy followed by 24 weeks off-treatment follow-up.

Ropeginterferon maximum dose

Maximum doseRopeginterferon alfa-2b (Besremi) maximum dose: 500 mcg.

Starting and titrationStart 100 mcg SC every 2 weeks (50 mcg if receiving hydroxyurea); increase by 50 mcg every 2 weeks until hematologic parameters stabilized.

Indication contextApproved for adults with polycythemia vera per prescribing information and PEGINVERA study dosing schema.

Virologic response stopping rule

12‑week virologic stopping ruleDiscontinue therapy if patient fails to achieve at least a 2‑log10 reduction in HCV RNA from baseline at 12 weeks.

24‑week virologic stopping ruleDiscontinue if HCV‑RNA remains detectable at week 24, as sustained response is unlikely.

RationalePatients not meeting these milestones have a very low likelihood of achieving sustained virologic response with continued interferon-based therapy.

HBV viral load thresholds used in trials

HBeAg‑positive trial thresholdHBeAg‑positive patients enrolled in HBV trials had serum HBV >500,000 copies/mL.

HBeAg‑negative trial thresholdHBeAg‑negative patients enrolled in HBV trials had serum HBV >100,000 copies/mL.

Trial inclusion contextThese viral load thresholds were required for enrollment in the phase III peginterferon alfa-2a HBV studies.

HBV DNA response definitions

HBeAg‑positive DNA responseHBV DNA response defined as less than 100,000 copies/mL for HBeAg‑positive patients.

HBeAg‑negative DNA responseHBV DNA response defined as less than 20,000 copies/mL for HBeAg‑negative patients.

Reported outcomesPeginterferon alfa-2a produced higher rates of DNA response and ALT normalization versus lamivudine in trials using these definitions.

EVR threshold

EVR definitionEarly virologic response (EVR) = undetectable HCV RNA or at least a 2‑log10 reduction in HCV RNA at 12 weeks.

Use of EVREVR at week 12 is used to determine continuation of interferon-based therapy for HCV genotypes with lower response rates.

Associated guidancePatients without EVR are unlikely to achieve sustained response and should be considered for discontinuation per labeling and guidelines.

NICE 12-week viral load cutoff

NICE 12‑week cutoffNICE recommends continuing therapy for genotypes 1, 4, 5, 6 only if viral load at 12 weeks is <1% of baseline (approximately a ≥2‑log reduction); otherwise discontinue.

Genotype applicabilityGuidance applies to genotypes 1, 4, 5 and 6 (and mixed infections that include one of these genotypes).

Clinical impactThis threshold operationalizes early stopping to avoid ineffective prolonged interferon treatment in slow/nonresponders.

EDSS ambulation thresholds

EDSS 4.0Able to walk without aid or rest for 500 m; significant disability but self‑sufficient.

EDSS 5.5Disability severe enough to preclude full daily activities; able to walk without aid or rest for 100 m.

EDSS 6.0Requires a walking aid (cane, crutch, etc.) to walk about 100 m with or without resting.

Child-Pugh class numeric thresholds

Child‑Pugh Class ATotal score 5–6 = Class A (well‑compensated disease).

Child‑Pugh Class BTotal score 7–9 = Class B (significant functional compromise).

Child‑Pugh Class CTotal score 10–15 = Class C (decompensated disease).

Prior Authorization, Documentation & Provider Requirements

Prior Authorization

Prior Authorization Required

Prior authorization is required for interferon products in many situations. Precertification is specifically required for interferon beta-1a (Avonex) for applicable Aetna plan designs; call (866) 752-7021 or fax (888) 267-3277. Use the Aetna Statement of Medical Necessity (SMN) / Specialty Pharmacy precertification forms as applicable. Providers must submit clinical documentation supporting the requested indication, timing of administration, dose, frequency, route, and planned duration.

Prior authorization required for interferon products (including Avonex) where plan design requires precertification.
Precertification contact for Avonex: Phone (866) 752-7021; Fax (888) 267-3277; SMN forms via Aetna Specialty Pharmacy Precertification.
PA requests must include indication, timing (e.g., single-dose IFN‑lambda for COVID-19 or intended start date), and full treatment details (formulation, route, dose, frequency, duration).

Documentation Required

Match PA to FDA Indications & Contraindications

Coverage and PA determinations for interferon products should align with FDA-approved indications and contraindications for the specific interferon formulation. Consider FDA boxed warnings and contraindications such as autoimmune hepatitis, hepatic decompensation (Child‑Pugh B or C), pregnancy risks when used with ribavirin, severe psychiatric disorders, transplant recipients, and hypersensitivity.

PA should match FDA indications and contraindications for the specific interferon product requested.
Contraindications that may preclude coverage include hepatic decompensation, autoimmune hepatitis, pregnancy (with ribavirin), severe psychiatric illness, and transplant/immunosuppressed status.
Pegylated interferons carry boxed warnings regarding neuropsychiatric, autoimmune, ischemic, and infectious risks — document consideration of these risks in PA requests.

Prior Authorization

Pegylated Interferons for HCV — PA & Monitoring

Some interferon uses are conditional or have historical approval but are no longer guideline‑preferred. For hepatitis C, pegylated interferons (Pegasys, PegIntron) and stopping rules (nonresponse at 12 weeks — <2 log10 HCV RNA decline or detectable RNA depending on genotype) must be documented; however, current AASLD/IDSA guidance prefers direct-acting antivirals (DAAs) when available. Providers requesting pegylated interferon for HCV must document rationale (e.g., resource-limited setting, prior regimen failures) and baseline/interval virologic testing per labeling (baseline, week 4 for RVR when used, and week 12 EVR assessments).

Pegylated interferons for HCV: PA expected to document indication, prior HCV treatment history, and why DAAs are not being used when applicable.
Stopping rule: for genotypes 1 and 4, discontinue if EVR is not met at 12 weeks (less than 2 log10 drop or persistent HCV RNA).
Required virologic monitoring to support continuation: baseline HCV RNA and week 12 HCV RNA (and week 4 for RVR when relevant).

Prior Authorization

Prior Authorization Expectation for Intron A (Aggressive Follicular NHL)

Intron A (interferon alfa-2b) has FDA-approved and compendial uses (eg, follicular non-Hodgkin’s lymphoma). Prior authorization for Intron A in aggressive follicular NHL or other compendial oncology uses should include disease-specific documentation such as tumor burden criteria (eg, mass >7 cm, ≥3 nodal sites >3 cm, systemic B symptoms), prior therapies, and intent (initial therapy vs salvage).

Document FDA-approved indication or compendial rationale when requesting PA for Intron A (eg, follicular NHL).
For aggressive follicular NHL, include trial-defined large tumor burden criteria and systemic symptom documentation.
Submit prior treatment history and rationale for selecting Intron A versus alternatives.

Denial Risk

Experimental / Not Covered Indications & Actimmune (IPF)

Some interferon uses are considered experimental/investigational or not covered; requests for these indications may be denied. Examples include interferon therapy for COVID-19 (general IFN use) and certain neurodegenerative indications. Actimmune (interferon gamma‑1b) is not supported for idiopathic pulmonary fibrosis (IPF) due to lack of survival benefit in trials. Providers should avoid non-covered ICD‑10 codes when submitting PA requests to prevent administrative denial.

Interferon for COVID-19 is considered experimental/investigational — PA requests are unlikely to be approved.
Actimmune (interferon gamma-1b) not supported for IPF — trials showed lack of benefit and development was discontinued for this indication.
Do not submit PA requests using ICD‑10 codes listed as not covered (eg, U07.1 COVID-19) without supporting, guideline‑based rationale.

Billing Rule

Documentation & Coding Linkage

Documentation requirements: PA submissions should include diagnosis ICD‑10 codes that support the selection criteria, HCPCS/CPT codes where applicable (eg, J9214, J9215, S0145, S9559), prior treatment history, baseline labs and monitoring plans (CBC with diff, platelets, renal and hepatic function at baseline and every 3 months for interferon gamma-1b; HBV/HCV DNA levels and ALT ranges for peginterferon HBV use), and explicit treatment details (dose, frequency, route, duration). Insufficient documentation may lead to denial or delay.

Include covered ICD‑10 code(s) that match the requested indication and any applicable not‑covered list should not be used.
Include HCPCS/CPT codes supporting drug and administration (examples: J9214, J9215, S0145, S9559).
Required labs: baseline and periodic monitoring (eg, CBC with differential, platelets, renal/hepatic panels) and virologic monitoring for HCV/HBV per prescribing information.
For HBV peginterferon PA, document compensated liver disease, evidence of HBV replication, and ALT between the required ranges.

Note

Policy Scope, Missing Operational Criteria & Provider Responsibility

Operational notes and policy limits: this bulletin is a partial description of plan benefits and not a contract. Some sections include background only and do not state explicit PA codes, denial criteria, or step therapy algorithms; absence of a specified step therapy here does not imply none exist in member-specific benefit designs. Where no explicit authorization/denial criteria are stated in this section, apply general PA and documentation standards and consult the payer for plan-specific rules.

This Clinical Policy Bulletin provides a general, partial description of benefits and does not replace plan‑specific benefit verification.
No explicit PA code list or denials are specified in parts of this section — verify member benefits and any plan-level step therapy separately.
No step therapy algorithms are specified in this section. Treat requests per documented FDA/compendial criteria and payer-specific rules.

Line of Therapy Designations

inv-136: mixed

Aetna considers all other indications not listed above as experimental and investigational.

General exclusion: Interferon products requested for indications not explicitly listed in the product-specific 'Criteria for Initial Approval' sections are considered experimental and investigational.

See experimental/investigational lists for specific conditions.

inv-137: adjuvant

Adjuvant therapy designation (example: melanoma)

Adjuvant example: Adjuvant interferon alfa-2b dosing and use described for malignant melanoma (induction then maintenance phases); coverage contingent on meeting policy criteria.

Induction 20 million IU/m2 IV 5 days/week x4 weeks; maintenance 10 million IU/m2 SC 3x/week for 48 weeks.

inv-138: initial | adjunct

Initial or adjunct therapy designation (follicular NHL)

Initial/adjunct use: Intron A is indicated as adjunct to anthracycline-containing chemotherapy for initial treatment of clinically aggressive follicular NHL in adults with documented large tumor burden.age >=18; documented large tumor burden

inv-139: first-line

First-line therapy designation (example: Intron A added to CHVP)

First-line example: In randomized trials Intron A was administered with CHVP chemotherapy as initial therapy in clinically aggressive follicular NHL and prolonged progression-free survival compared to CHVP alone.

Documented trial regimens support initial/first-line use in this context.

inv-140: adjuvant

Adjuvant designation (melanoma adjuvant dosing cited)

Melanoma adjuvant: Adjuvant interferon alfa-2b regimen for malignant melanoma provided as an example of adjuvant use; coverage requires meeting policy selection criteria.

Induction and maintenance dosing per product labeling.

inv-141: salvage

Salvage therapy designation (contextual example)

Salvage example: Intralesional or systemic interferon regimens have been used as salvage or adjunctive options in selected refractory tumor types (e.g., non-melanoma skin cancer, OSSN) when standard local therapies are impractical.

Evidence largely from small series and pilot studies.

inv-142: adjuvant

Adjuvant context references (HCC adjuvant studies described)

HCC adjuvant context: Small randomized trials have evaluated prolonged interferon after HCC resection with mixed results; some HCV-related series suggested benefit while others (e.g., Chen et al) did not demonstrate reduced recurrence.

Use remains investigational for routine adjuvant HCC therapy.

inv-143: salvage

Salvage designation (fibrolamellar carcinoma context)

FLC salvage: Interferon-containing regimens have been used as salvage/systemic options in fibrolamellar HCC in case reports and small series; randomized evidence lacking and systemic standard treatments unestablished.

Document prior surgeries and systemic regimens when requesting therapy.

Biomarker and Diagnostic Requirements

EGFR — biomarker note

EGFR IHC mentionEGFR immunohistochemistry 2–3+ was reported in a single case report of fibrolamellar carcinoma; this is an isolated biomarker observation.

Evidence levelThis EGFR IHC finding derives from a case report and does not constitute a trial‑level biomarker requirement.

Clinical implicationEGFR expression suggested a potential rationale for EGFR‑directed therapy in the reported case but is not an established indication.

OAS1 haplotype — biomarker mention

OAS1 haplotypeAn OAS1 haplotype was identified as a potential biomarker associated with increased likelihood of response to pegylated IFN‑lambda in a COVID‑19 outpatient trial.

ContextAuthors noted that prevalence assessment of this haplotype is needed to evaluate its predictive utility.

Not a coverage requirementBiomarker mention is investigational in the context of IFN‑lambda outpatient COVID‑19 therapy and not an established selection criterion in the policy.

Biomarker note — miscellaneous

Miscellaneous biomarker mentionsEvidence summaries include limited biomarker observations (e.g., EGFR IHC, OAS1 haplotype) reported in case reports or subgroup analyses.

Evidence implicationThese biomarker notes are hypothesis‑generating and are not formal biomarker requirements for coverage in this policy.

RecommendationTreating clinicians may consider these findings for investigational use or study enrollment but should not rely on them for routine coverage decisions.

Definitions and Key Terms

Continuation of Therapy — definition

DefinitionContinuation of therapy: ongoing use is considered medically necessary when the member is receiving clinical benefit and there is no evidence of unacceptable toxicity or disease progression.

ApplicationApplies across interferon products when continuation criteria specific to an indication (e.g., HCV, HBV, hairy cell leukemia) are met.

DocumentationClinical benefit and absence of unacceptable toxicity should be documented to support continuation requests.

Prescriber Specialties — examples

Prescriber specialty exampleAvonex (interferon beta‑1a) must be prescribed by or in consultation with a neurologist.

General principleCertain interferon products require specialist prescribing or consultation appropriate to the indication (e.g., immunologist for Actimmune indications).

PA implicationPrior authorization reviews should confirm appropriate specialist involvement when required by product labeling or policy.

Ropeginterferon dosing (Besremi)

Besremi dosing summaryRopeginterferon alfa‑2b (Besremi) dosing for polycythemia vera: start 100 mcg SC every 2 weeks (50 mcg if on hydroxyurea), titrate by 50 mcg every 2 weeks to maximum 500 mcg.

Dose‑response notesPEGINVERA study used dose range up to 540 µg with responses observed across doses; maximum recommended in labeling is 500 mcg.

IndicationApproved for adults with polycythemia vera per prescribing information.

Interferon alfa-2b (Intron A) melanoma dosing

Intron A melanoma inductionInduction: 20 million IU/m2 IV over 20 minutes, 5 days/week for 4 weeks.

Intron A melanoma maintenanceMaintenance: 10 million IU/m2 subcutaneously 3 times/week for 48 weeks.

Treatment phase descriptionAdjuvant regimen delivered in induction and maintenance phases per product dosing guidance.

Type I and Type II interferons — distinction

Type I vs Type IIType I interferons (alfa and beta) bind the alfa/beta receptor; Type II interferon (gamma) binds a distinct receptor and has different immunologic effects.

Functional distinctionType I IFNs are antiviral and antiproliferative; IFN‑gamma (Type II) enhances macrophage oxidative metabolism and ADCC.

Clinical relevanceReceptor and functional differences underpin distinct indications and safety profiles across interferon products.

Consensus interferon — historic note

Consensus interferon statusConsensus interferon (interferon alfacon‑1; Infergen) was discontinued in September 2013 and is a non‑naturally occurring recombinant type I alfa interferon previously used for chronic hepatitis C.

Clinical roleIt was studied as retreatment for pegylated interferon/ribavirin nonresponders but is no longer commercially available.

ImplicationConsensus interferon dosing and stopping rules remain in historical labeling and trial reports but are not current standard therapy.

Alferon N — formulation and indication

Alferon N descriptionAlferon N (interferon alfa‑n3) is a natural human leukocyte–derived interferon alfa formulation indicated for intralesional treatment of refractory external condylomata acuminata in adults.

MechanismActs similarly to native interferon alfa with antiviral and antiproliferative effects via IFN receptor activation.

Indication limitationAll other indications for Alferon N are considered experimental and investigational per policy.

Intron A — indications summary

Intron A approved indicationsInterferon alfa‑2b (Intron A) has multiple FDA‑approved indications including malignant melanoma, hairy cell leukemia, and follicular NHL (with chemotherapy).

Intron A roleUsed across malignant and infectious disease indications with specific dosing per indication.

DocumentationCoverage contingent on meeting indication‑specific selection criteria and documented benefit for continuation.

Avonex — indication and prescriber requirement

Avonex indicationAvonex (interferon beta‑1a) is indicated for relapsing forms of multiple sclerosis, including clinically isolated syndrome.

Prescribing requirementMust be prescribed by or in consultation with a neurologist per policy.

Therapy continuationContinuation medically necessary for members experiencing disease stability or improvement on Avonex.

Actimmune — indications and context

Actimmune indicationsActimmune (interferon gamma‑1b) indicated to reduce serious infections in chronic granulomatous disease (CGD) and to delay progression in severe malignant osteopetrosis.

Role in CGDUsed as adjunct to antimicrobial prophylaxis; evidence includes a single trial and follow‑up studies summarized in meta‑analysis.

MonitoringBaseline and periodic hematologic, renal and hepatic monitoring recommended during therapy.

Background, Evidence and Literature Summaries

Interferons are a family of endogenous cytokines with antiviral, antiproliferative and immunomodulatory effects. The CPB covers multiple interferon products — including interferon alfa-2b (Intron A), interferon alfa‑n3 (Alferon N), interferon beta‑1a (Avonex), interferon gamma‑1b (Actimmune), peginterferon alfa‑2a (Pegasys) and ropeginterferon alfa‑2b (Besremi) — each with distinct labeled indications, prescriber specialty considerations, continuation rules, and agent‑specific contraindications as summarized in the policy.

Randomized controlled trials and observational studies of interferons for COVID‑19 report heterogeneous results. Smaller RCTs and some meta-analyses suggested potential benefits for certain outcomes with early or specific formulations, while larger trials (including WHO Solidarity and pooled meta-analyses) did not demonstrate consistent mortality benefit; evidence is therefore conflicting and overall not sufficient to support routine interferon therapy for hospitalized COVID‑19 patients.

The policy contains study‑level summaries across indications (for example: phase I data for pegylated interferon‑α‑2b in plexiform neurofibromas, systematic reviews of IFN‑γ as adjunctive therapy in pulmonary tuberculosis, and small pilot studies of intralesional or subconjunctival interferon for ocular surface neoplasia). These summaries provide clinical context but are not prescriptive coverage rules.

Evidence summaries by indication highlight situational coverage considerations — for example, Intron A has an established role in clinically aggressive follicular NHL when used with chemotherapy, pegylated interferons have defined roles in hepatitis B and C within historic or resource‑limited contexts, and maintenance peginterferon strategies were not beneficial in HALT‑C. Readers should consult the CPB criteria sections for formal coverage determinations derived from these evidence summaries.

Trial evidence and product labeling indicate that extended peginterferon therapy beyond one year lacks sufficient safety and efficacy data; the policy notes absence of robust data to support routine long‑term pegylated interferon maintenance and highlights the HALT‑C findings that maintenance therapy did not reduce disease progression and increased adverse events.

Meta-analyses of IFN‑β in COVID‑19 varied in included trials and methods; several pooled analyses concluded that subcutaneous IFN‑β did not improve 28‑day mortality or other major endpoints in hospitalized patients, underscoring that the available evidence does not support routine use of subcutaneous IFN‑β to reduce mortality in this population.

A randomized trial examining adjuvant interferon‑α2a plus 13‑cis‑retinoic acid for high‑risk cutaneous squamous cell carcinoma did not show improvement in time to recurrence versus observation, and the policy cites this trial when summarizing adjuvant interferon evidence for cutaneous SCC.

A systematic review of therapies for Sjogren’s syndrome–associated dry eye identified limited trial evidence; the review discussed interferon‑alpha but did not recommend it as a therapeutic option, and the CPB cites this conclusion in its background evidence summary.

Policy Revision History

04/04/2000Effective date

Policy became effective.

12/15/2023Last review

Policy underwent last documented review on this date.

10/24/2024Next scheduled reviewLatest

Next scheduled policy review date.

No step therapy requirements are provided in the references section of the CPB; consult the policy's prior authorization and step therapy sections for any plan‑specific utilization management requirements.

Policy Summary

PayerAetna

PolicyInterferons

Policy CodePolicy 0404

Change TypeNo material changes noted

Effective Date04/04/2000

Next Review Date10/24/2024

Key ActionPrecertification required for interferon beta-1a (Avonex); call or fax and submit Statement of Medical Necessity.

SourceLink

On This Page

Intron A - AIDS-related Kaposi's sarcoma dosing: 30 million IU/m2 administered SC or IM three times weekly until progression or maximal response (after 16 weeks).

Source: dosing guidance for Kaposi sarcoma.

Avonex dosing: Interferon beta-1a (Avonex): 30 micrograms IM once weekly.

Source: Avonex prescribing information.

Pegasys dosing: Peginterferon alfa-2a (Pegasys): 180 mcg subcutaneously once weekly for adults; duration varies by indication (e.g., 48 weeks for CHB; genotype- and regimen-dependent for HCV).

See full prescribing information for indication-specific durations.

PegIntron dosing: Peginterferon alfa-2b (PegIntron) adult dose: 1.5 mcg/kg/week; pediatric dosing and genotype-specific durations per prescribing information.

Note: multiple PegIntron presentations have been discontinued or are of limited availability.

Besremi dosing for polycythemia vera: Start 100 mcg SC every 2 weeks (50 mcg if receiving hydroxyurea); increase by 50 mcg every 2 weeks to a maximum of 500 mcg until hematologic parameters are stabilized.max 500 mcg

Source: Besremi prescribing information.

Pegasys experimental uses: Peginterferon alfa-2a (Pegasys) is experimental/investigational for listed conditions (e.g., desmoid tumor, plexiform neurofibroma, warts) outside approved/compendial indications.

Per product labeling and trial guidance.

For genotypes 2 and 3 there is no proven benefit to extending therapy beyond 24 weeks; standard durations apply.

Nonresponders and maintenance therapy: Maintenance or long-term low-dose pegylated interferon therapy for initial nonresponders is not supported by trial data (e.g., HALT-C) and is not recommended.

Post-transplant recurrent HCV: Treatment of recurrent HCV after liver transplantation with interferon-based regimens has limited efficacy and greater adverse events; use with caution and case-by-case consideration.