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MEDICAL POLICY
POLICY TITLE
INTERFERON ALPHA THERAPY (INTERFERON ALFA-2A,
INTERFERON ALFA-2B, INTERFERON ALFA-N3 AND INTERFERON
ALFACON-1)
POLICY NUMBER
MP-2.116
Original Issue Date (Created):
July 10, 2002
Most Recent Review Date (Revised):
July 22, 2014
Effective Date:
October 1, 2014
POLICY
RATIONALE
DISCLAIMER
POLICY HISTORY
I.
PRODUCT VARIATIONS
DEFINITIONS
CODING INFORMATION
DESCRIPTION/BACKGROUND
BENEFIT VARIATIONS
REFERENCES
POLICY
The use of recombinant or natural interferon alpha may be considered medically necessary
in off-label use for the following indications:










Bladder carcinoma
Malignant carcinoid tumor and carcinoid syndrome
Cervical cancer
Malignant islet-cell tumors
Multiple myeloma
Mycosis fungoides
Non-Hodgkin's lymphoma (other than follicular lymphoma)
Papillomatosis of the larynx
Myeloproliferative disorders (i.e., essential thrombocytopenia and polycythemia vera)
when other treatments fail
Renal cell cancer.
The use of recombinant or natural interferon alpha may be considered medically necessary
for the following labeled indications:
 Philadelphia chromosome-positive chronic myelogenous leukemia (chronic phase)
 AIDS-related Kaposi's sarcoma
 Follicular lymphoma
 Hairy cell leukemia
 Condyloma acuminata
 Malignant melanoma
 Chronic hepatitis B
 Hepatitis C, initial treatment or salvage treatment for relapsed hepatitis C (Interferon
alfa or peginterferon alone or in combination with ribavirin).
Page 1
MEDICAL POLICY
POLICY TITLE
INTERFERON ALPHA THERAPY (INTERFERON ALFA-2A,
INTERFERON ALFA-2B, INTERFERON ALFA-N3 AND INTERFERON
ALFACON-1)
POLICY NUMBER
MP-2.116
Genotyping of hepatitis C virus may be considered medically necessary as a technique to
determine duration of interferon therapy.
Recombinant and natural interferons are considered investigational for the treatment of
any off-label solid tumor indications including, but not limited to, the following:
 Brain tumors, malignant
 Breast cancer
 Cancer or precancers of oral cavity
 Colorectal cancer
 Cutaneous squamous cell cancer (including actinic keratoses, basal cell carcinomas)
 Head and neck cancers, recurrent or metastatic

Lung Cancer, non-small cell

Medullary thyroid carcinoma

Merkel cell carcinoma

Metastatic apudomas

Neuroendocrine tumors (except malignant carcinoid tumors)

Osteosarcoma

Ovarian cancer

Pancreatic cancer (except malignant islet-cell tumors)

Recurrent respiratory papillomatosis (except papillomatosis of larynx)

Teratoma, testicular, mature-growing.
Recombinant or natural interferon alfa is considered investigational for the treatment of
any off-label clinical condition other than those specified in the policy as there is
insufficient evidence to support a conclusion concerning the health outcomes or benefits
associated with the use of interferon for these indications.
Cross-references
MP-2.103 Off-Label Use of Prescription Drugs and Medical Devices
Page 2
MEDICAL POLICY
POLICY TITLE
INTERFERON ALPHA THERAPY (INTERFERON ALFA-2A,
INTERFERON ALFA-2B, INTERFERON ALFA-N3 AND INTERFERON
ALFACON-1)
POLICY NUMBER
MP-2.116
II. PRODUCT VARIATIONS
Top
[N] = No product variation, policy applies as stated
[Y] = Standard product coverage varies from application of this policy, see below
[N] PPO
[N] SpecialCare
[N] HMO
[N] POS
[N] CHIP
[N] Indemnity
[Y] SeniorBlue HMO*
[Y] FEP PPO**
[Y] SeniorBlue PPO*
*“FDA approved drugs used for indications other than what is indicated on the official
label may be covered under Medicare if determined that the use is medically accepted,
taking into consideration the major drug compendia, authoritative medical literature
and/or accepted standards of medical practice.” Refer to Medicare Benefit Policy Manual
(100-2, Chapter 15, Section 50.4.2- Unlabeled Use of Drug).”
http://www.cms.gov/manuals/Downloads/bp102c15.pdf
*“Off-label use of FDA approved drugs and biologicals used in an anti-cancer
chemotherapeutic regimen for medically accepted indications may be covered under
Medicare if the indications are supported in either one or more Medicare recognized
compendia or in peer-reviewed literature. Refer to Medicare Benefit Policy Manual
(100-2, Chapter 15, Section 50.4.5- Off-Label Use of Drugs and Biologicals in an AntiCancer Chemotherapeutic Regimen) for the compendia list.”
http://www.cms.gov/manuals/Downloads/bp102c15.pdf
** Refer to FEP Medical Policy Manual for the following policies:
5.03.01
Hepatitis B Interon A Monotherapy
5.03.02
Hepatitis B Pegasys
5.03.03
Hepatitis C Infergen Motherapy
5.03.04
Hepatitis C Infergen with Ribavirin
5.03.05
Hepatitis C Intron A Monotherapy
5.03.06
Hepatitis C Intron A with Ribavirin
5.03.07
Hepatitis C Pegasys
Page 3
MEDICAL POLICY
POLICY TITLE
INTERFERON ALPHA THERAPY (INTERFERON ALFA-2A,
INTERFERON ALFA-2B, INTERFERON ALFA-N3 AND INTERFERON
ALFACON-1)
POLICY NUMBER
MP-2.116
5.03.08
Hepatitis C Pegasys Ribavirin
5.03.09
Hepatitis C Pegasys Ribavirin Incivek
5.03.10
Hepatitis C Pegasys Ribarvin Victrelis
5.03.11
Hepatitis C Pegintron
5.03.12
Hepatitis C Pegintron Ribavirin
5.03.13
Hepatitis C Pegintron Ribavirin Incivek
5.03.14
Hepatitis C Pegintron Ribavirin Victrelis
5.04.02
Alferon
5.04.01
Actimmune
5.04.07
Intron A
5.04.11
Sylatron
The FEP Medical Policy manual can be found at: www.fepblue.org
III. DESCRIPTION/BACKGROUND
Top
Interferon comprises approximately twenty (20) naturally occurring proteins. Three classes
of interferons have been identified: alpha, beta, and gamma. Each class is chemically
unique, is synthesized and released primarily by different sets of cells, and has a specific
function. The body normally produces these substances; however, they are also made in
the laboratory with recombinant DNA technology.
Interferons attach to special receptors on the surface of cell membranes. They have a
variety of functions, including enhancing or inhibiting enzymes, decreasing cell
proliferation, or enhancing the activity of macrophages and T-lymphocytes. Interferons
may be used to treat conditions such as certain types of cancers, condyloma acuminata
(genital warts), respiratory papillomatosis, and hepatitis B and C (alone or in combination
with an antiviral agent, oral ribavirin [e.g. Rebetol®, Copegus®] for hepatitis C).
Genotyping of hepatitis C virus may be required as a technique to determine duration of
interferon therapy. Hepatitis C, a single-stranded RNA virus, is genetically complex with
several recognized genotypes. Genotypes 1, 2, and 3 are the most frequently encountered
genotypes worldwide, type 1a most frequently found in Northern Europe and North
Page 4
MEDICAL POLICY
POLICY TITLE
INTERFERON ALPHA THERAPY (INTERFERON ALFA-2A,
INTERFERON ALFA-2B, INTERFERON ALFA-N3 AND INTERFERON
ALFACON-1)
POLICY NUMBER
MP-2.116
America, genotype 1 has been associated with a poorer response to interferon and/or
ribavirin compared to other genotypes.
The U. S. Food and Drug Administration (FDA) has licensed 3 forms of alpha interferon:
(IFNα-2a, IFNα-2b, and IFNα-n3). Examples of alpha interferons include: interferon alfa2b (Intron®-A), interferon alfa-n3 (Alfernon®) and interferon alfacon-1 (Infergen®).
Another type of alpha interferon is pegylated interferon which is designed to have a longer
duration of action. Examples of pegylated interferon include peginterferon alfa-2a
(Pegasys®), and peginterferon alfa-2b (Peg-Intron™). Route of administration for
interferons varies by individual agent. Although most are administered by subcutaneous
injection, some alpha interferons may also be administered by intravenous, intramuscular
or intralesional injection. Dosage and duration of interferon treatment varies according to
agent, clinical condition and response.
Safety Information
The FDA has issued the following Black Box Warnings:
Interferon alfacon-1 (Infergen®)
 May cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune,
ischemic, and infectious disorders. Monitor closely and withdraw therapy with
persistently severe or worsening signs or symptoms of the above disorders.
 Use with Ribavirin: Ribavirin may cause birth defects and fetal death; avoid
pregnancy in female patients and female partners of male patients. Ribavirin causes
hemolytic anemia which may exacerbate cardiac disease. Ribavirin is a potential
carcinogen.
Peginterferon alfa-2a (Pegasys®)
 Alpha interferons, including Pegasys® may cause or aggravate fatal or life-threatening
neuropsychiatric, autoimmune, ischemic, and infectious disorders. Patients should be
monitored closely with periodic clinical and laboratory evaluations. Therapy should be
withdrawn in patients with persistently severe or worsening signs or symptoms of
these conditions. In many, but not all cases, these disorders resolve after stopping
Pegasys therapy.
 Use with Ribavirin. Ribavirin, including Copegus®, may cause birth defects and/or
death of the fetus. Extreme care must be taken to avoid pregnancy in female patients
and in female partners of male patients. Ribavirin causes hemolytic anemia. The anemia
associated with ribavirin therapy may result in a worsening of cardiac disease. Ribavirin
is genotoxic and mutagenic and should be considered a potential carcinogen.
Page 5
MEDICAL POLICY
POLICY TITLE
INTERFERON ALPHA THERAPY (INTERFERON ALFA-2A,
INTERFERON ALFA-2B, INTERFERON ALFA-N3 AND INTERFERON
ALFACON-1)
POLICY NUMBER
MP-2.116
Pegylated interferon alfa-2b (PegIntron ™)
 May cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune,
ischemic, and infectious disorders. Monitor closely and withdraw therapy with
persistently severe or worsening signs or symptoms of the above disorders. (5)
 Use with Ribavirin: Ribavirin may cause birth defects and fetal death; avoid
pregnancy in female patients and female partners of male patients. Ribavirin is a
potential carcinogen.
Interferon alfa-2b (Intron® A)
Alpha interferons, including Intron® A, cause or aggravate fatal or life-threatening
neuropsychiatric, autoimmune, ischemic, and infectious disorders. Patients should be
monitored closely with periodic clinical and laboratory evaluations. Patients with
persistently severe or worsening signs or symptoms of these conditions should be
withdrawn from therapy. In many but not all cases these disorders resolve after
stopping Intron A therapy.
IV. RATIONALE
The FDA approved label indications for pegylated interferon therapy include Hepatitis B
virus (HBV) infection, and Hepatitis C virus (HCV) infection with or without HIV coinfection. There are two FDA approved pegylated interferon agents, Pegasys and
PegIntron. This policy will not differentiate between the two peginterferon alfa agents
based on FDA indications. Treatment for oncology diagnoses will also be approved
although there are few studies evaluating peginterferon in oncology. Available studies
indicate similar efficacy between the pegylated and nonpegylated interferons for cancer
indications. However, some state statues require automatic approval of chemotherapeutic
agents for patients with cancerous or pre-cancerous conditions.
Hepatitis B Virus (HBV)
The diagnosis of HBV is based on the presence of serological markers in the blood,
which include Hepatitis B viral DNA (HBV DNA), hepatitis B surface antigen (HBsAG)
or hepatitis B ‘e’ antigen (HBeAg). The HBeAG is an indicator of viral replication, but
some variant forms of the virus do not express HBeAg. The policy allows peginterferon
therapy if there are serologic markers confirming HBV infection. Quantification of viral
load will not be required.
The 2009 American Association for the Study of Liver Disease (AASLD) guideline for
the treatment of HBV recommends initiation of treatment with any of the seven approved
antiviral medications, but peginterferon, tenofovir, or entecavir are preferred.
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MEDICAL POLICY
POLICY TITLE
INTERFERON ALPHA THERAPY (INTERFERON ALFA-2A,
INTERFERON ALFA-2B, INTERFERON ALFA-N3 AND INTERFERON
ALFACON-1)
POLICY NUMBER
MP-2.116
Advantages of peginterferon include a finite duration of treatment, a more durable
response, and lack of resistant mutants. The AASLD guideline for HBV recommends
duration of treatment with standard interferon for 16 weeks for HBeAg positive HBV and
48 weeks for peginterferon. The recommended treatment duration for HBeAg-negative
chronic hepatitis B is 48 weeks for both standard and peginterferon. The European
Association for the Study of the Liver (EASL) practice guideline (2009) also suggests
peginterferon for 48 weeks for both HBeAg positive HBV and HBeAg negative HBV.
To accommodate the 12 month treatment duration and allow for possible disruptions in
therapy, up to 18 months of peginterferon therapy will be allowed for a diagnosis of
HBV. Patients who fail to respond to interferon therapy may be retreated with
lamivudine or adefovir.
Hepatitis C Virus (HCV)
Patients who react positively to enzyme immunoassay for antibody to HCV or HCV
RNA, and have compensated liver disease are potential candidates for peginterferon
therapy. Antiviral therapy is not recommended routinely for patients who have
decompensated liver disease; history of severe, uncontrolled psychiatric disorder; or
severe hematologic cytopenia. This policy allows an initial six months of therapy if
detection of serologic markers confirms HCV infection. Although liver biopsy has been
regarded as the standard for defining liver disease status, it is not without risks including
pain, bleeding, or perforation of other organs. The procedure is subject to sampling error,
requires special expertise for interpreting the histopathology, adds cost to medical care,
and is anxiety-provoking for the patient. A liver biopsy may not be necessary in persons
infected with genotypes 2 or 3 HCV. This policy will not require that a biopsy be
performed.
Current treatment guidelines recommend a quantitative serum HCV RNA be performed
at the initiation of or shortly before treatment, and also at week 12 of therapy. Persons
who achieve a sustained virologic response (SVR) almost always have a dramatic earlier
reduction in the HCV RNA level defined often as a 2-log10 decrease or loss of HCV
RNA 12 weeks into therapy. In the absence of this type of response, the likelihood of an
SVR is 0-3%. Peginterferon therapy will be approved beyond the initial six months only
if a second serum HCV RNA level shows a 2-log10 decrease.
Duration of treatment is 12 continuous months for infection with HCV genotype 1, 4, 5,
or 6 if there is a response to therapy at 12 weeks, and six continuous months for genotype
2 and 3, which may be extended to 12 continuous months if there is evidence of cirrhosis,
high viral load, or delayed response (response at 24 weeks versus 12 weeks). There is
evidence that patients considered slow responders (positive HCV RNA after 12 weeks of
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MEDICAL POLICY
POLICY TITLE
INTERFERON ALPHA THERAPY (INTERFERON ALFA-2A,
INTERFERON ALFA-2B, INTERFERON ALFA-N3 AND INTERFERON
ALFACON-1)
POLICY NUMBER
MP-2.116
treatment but HCV RNA negative after 24 weeks) may benefit from a 72 week course of
therapy. To accommodate this extended length of therapy and to allow for possible
disruptions in therapy, this policy will allow for up to 24 months of therapy for a
diagnosis of HCV. Studies do not support the value of continuing therapy beyond 24
months for HCV.
The possibility of a shorter course of peginterferon therapy for patients infected with
genotype 2 or 3 HCV has been investigated in several clinical trials. In one, randomized,
open-label study (n=283), patients with HCV genotype 2 or 3 were treated with either 12
or 24 weeks of peginterferon alfa-2b. If a patient had a virologic response to treatment at
week 4, the patient was given treatment for 12 weeks. If no virological response was
seen at week 4, the patient was given treatment for 24 weeks. The shorter course of
therapy over 12 weeks was determined to be as effective as a 24-week course in patients
who have a response to treatment at 4 weeks. Another study of similar design (N=153)
including patients with HCV genotype 2 or 3 found that a course of 16 weeks is as
effective as a 24-week course in patients who have a response to treatment at 4 weeks.
However, a study by Shiffman et al. randomized 1,469 patients with HCV genotype 2 or
3 to receive 180 micrograms of peginterferon alfa-2a once weekly, plus 800 milligrams
of ribavirin daily, for either 16 weeks or 24 weeks; the study failed to demonstrate that
the 16-week regimen was noninferior to the 24-week regimen. The sustained virologic
response rate was significantly lower in patients treated for 16 weeks than in patients
treated for 24 weeks (62 percent versus 70 percent, p<0.001). Rate of relapse was
significantly greater in the 16-week group (31 percent versus 18 percent in the 24-week
group, p<0.001). Among patients with a rapid virologic response (no detectable HCV
RNA) at week 4, sustained virologic response rates were 79 percent in the 16-week group
and 85 percent in the 24-week group (p=0.02). In a phase III trial by Lagging et al. 382
patients infected with genotype 2 and 3 HCV were randomized to 12 or 24 weeks of
therapy with peginterferon alfa-2a and ribivirin. In this trial, 12 weeks of therapy was
inferior to 24 weeks in the intent-to-treat population (SRV rates: 59% versus 78%, p <
0.0001) and in the subgroups of patients infected with genotype 2 (56% versus 82%, p =
0.0006) or genotype 3 (58% versus 78%, p = 0.0015). Because of conflicting results in
these shorter course studies, this policy will not restrict the duration of therapy for
patients with HCV genotype 2 or 3 who demonstrate a rapid virologic response to a
shorter course.
Patients who achieve undetectable HCV RNA during and at the end of therapy but
relapse are likely to respond and relapse again with subsequent treatment with the same
therapy. Longer duration of therapy with peginterferon or peginterferon plus ribavirin in
patients experiencing relapse is of unproven efficacy. Nonresponders to peginterferon
therapy have been considered for treatment with long-term maintenance therapy, which
Page 8
MEDICAL POLICY
POLICY TITLE
INTERFERON ALPHA THERAPY (INTERFERON ALFA-2A,
INTERFERON ALFA-2B, INTERFERON ALFA-N3 AND INTERFERON
ALFACON-1)
POLICY NUMBER
MP-2.116
may possibly slow the development of fibrosis and limit the progression of cirrhosis to
end-stage liver disease or hepatocellular carcinoma. There are currently several trials in
progress evaluating the long-term effect of low-dose peginterferon for patients with
chronic HCV and advanced fibrosis. One study, HALT-C (Hepatitis C Antiviral LongTerm Treatment against Cirrhosis), has been completed and published. In this
randomized, controlled trial (n=1050) of peginterferon alfa-2a, a low dose (90 mcg/week)
for 3.5 years was compared with no treatment in patients with chronic HCV and
advanced fibrosis who had not previously responded to therapy with peginterferon plus
ribavirin. The primary endpoint was progression of liver disease, as indicated by death,
hepatocellular carcinoma, hepatic decompensation, or for those with bridging fibrosis at
baseline, an increase in the Ishak fibrosis score of two or more points. After 3.5 years of
treatment, no significant differences were apparent between the groups in the rate of any
primary outcome (34.1% in the treatment group versus 33.8% in the control group
[Hazard Ratio 1.01; 95% CI, 0.81 to 1.27; p=0.90]). Fifty-three patients (5%) died, 31 in
the treatment group and 22 in the control group (p=0.18). There was a significant
difference in mortality between the treatment and control groups among patients with
noncirrhotic fibrosis (5% versus 1.9%, p=0.04), but not among patients with cirrhosis
(9.1% and 8.4%; p=0.93). The percentage of patients with at least one serious adverse
event was 38.6% in the treatment group and 31.8% in the control group (p=0.07). Dose
modifications for adverse events were frequent; by year 3.5, only 58.9% of patients who
were still in the study and had not had a clinical outcome were receiving the full 90 mcg
treatment dose of peginterferon. The AASLD 2009 treatment guidelines do not
recommend maintenance therapy for patients with bridging fibrosis or cirrhosis who have
failed a prior course of peginterferon and ribavirin.
Pegylated interferon therapy is not FDA approved for any other indication.
2009 Update Summary
A search of peer reviewed literature through November 2009 identified no new clinical
trial publications or any additional information that would change the coverage position
of this medical policy.
2012 Update
Peginterferon for the Treatment of Hepatitis C Virus
Patients who react positively to enzyme immunoassay for antibody to HCV or HCV
RNA and have compensated liver disease are potential candidates for peginterferon
therapy (Ghany et al.). Proper duration of treatment is 12 continuous months for
Page 9
MEDICAL POLICY
POLICY TITLE
INTERFERON ALPHA THERAPY (INTERFERON ALFA-2A,
INTERFERON ALFA-2B, INTERFERON ALFA-N3 AND INTERFERON
ALFACON-1)
POLICY NUMBER
MP-2.116
infection with HCV genotype 1, 4, 5, or 6 if there is a response to therapy at 12 weeks.
Duration is six continuous months for genotype 2 and 3, which may be extended to 12
continuous months if there is evidence of cirrhosis, high viral load, or delayed response
(response at 24 weeks versus 12 weeks) (NIH, 2002; Scottish Intercollegiate Guidelines
Network, 2006) There is evidence that patients considered slow responders (positive
HCV RNA after 12 weeks of treatment but HCV RNA negative after 24 weeks) may
benefit from a 72 week course of therapy. (Berg, et al.; Marcellin et al.)
Oral Agents Boceprevir and Telaprevir for the Treatment of Hepatitis C
The efficacy and safety of telaprevir was evaluated in three (ADVANCE,
ILLUMINATE, and REALIZE) phase 3 trials in adult patients with HCV (genotype 1).
The efficacy and safety of boceprevir was evaluated in two phase 3 clinical trials (HCV
SPRINT 2 and HCV RESPOND 2). For both drugs, only patients with genotype 1 were
treated – both treatment-naïve and patients who had failed a previous course of HCV
therapy.
Telaprevir, in combination with peginterferon and ribavirin, was given for 8-12 weeks
then followed by treatment with peginterferon and ribavirin. Treatment-naïve patients
were treated for a total treatment duration ranging from 24 weeks up to 48 weeks. In the
IILUMINATE trial, the viral cure rates found that there was no benefit to extending
telaprevir based therapy to 48 weeks for the majority of patients.
Both boceprevir trials included a four week lead-in phase of peginterferon plus ribavirin
(without boceprevir). Then boceprevir was added for the remainder of the study. For
treatment naïve patients, the four-week lead-in was followed by the triple combination of
boceprevir, peginterferon, ribavirin, and treatment duration was guided by on-treatment
response for either 28 weeks or 48 weeks. For treatment failure patients, the four-week
lead-in phase was followed by the triple combination of boceprevir, peginterferon,
ribavirin, and treatment duration was guided by on-treatment response for either 36
weeks or 48 weeks.
In phase 3 clinical studies for both drugs, sustained viral response (SVR) was
significantly higher with protease inhibitors in combination with peginterferon and
ribavirin than peginterferon plus ribavirin alone in both treatment naïve and in patients
who failed prior therapy (see table below).
SVR Rates of the Addition of a Protease Inhibitor Compared to
Peginterferon/Ribavirin Therapy Alone (Incivek FDA Label, FDA—boceprevir
advisory committee)
Page 10
MEDICAL POLICY
POLICY TITLE
INTERFERON ALPHA THERAPY (INTERFERON ALFA-2A,
INTERFERON ALFA-2B, INTERFERON ALFA-N3 AND INTERFERON
ALFACON-1)
POLICY NUMBER
MP-2.116
Peginterferon /
ribavirin
Treatment naïve:
40-55% SVR
Treatment Experienced: 524% SVR
Telaprevir /
peginterferon /
ribavirin
Treatment naïve:
Boceprevir/
peginterferon /
ribavirin
Treatment naïve:
69-75% SVR
Treatment Experienced:
63-66% SVR
Treatment Experienced:
31-86% SVR
59-66% SVR
Clinical Guidelines
AASLD guidelines: Retreatment of Persons Who Failed to Respond to Previous Treatment for
Chronic Hepatitis C (Ghany et al.):



Retreatment with peginterferon and ribavirin in patients who did not achieve an SVR
after a prior full course of peginterferon and ribavirin is not recommended, even if a
different type of peginterferon is administered.
Retreatment with peginterferon and ribavirin can be considered for non-responders or
relapsers who have previously been treated with non-peginterferon with or without
ribavirin, or with peginterferon monotherapy, particularly if they have bridging fibrosis
or cirrhosis.
Maintenance therapy is not recommended for patients with bridging fibrosis or cirrhosis
who have failed a prior course of peginterferon and ribavirin.
The European Association for the Study of The Liver (EASL) clinical practice guidelines
recommends the following regarding the use of the direct acting antiviral agents:


Direct acting agents should only be used according to package labeling.
The following potential challenges of using HCV protease inhibitors in combination with
pegylated interferon alpha (PEG-INFa) and ribavirin should be considered:
1. Rapid emergence of resistance particularly in non-responder patients, nonadherent patients, and patients not able to tolerate optimal doses of PEG-INFa and
ribavirin.
2. More strict and frequent monitoring of HCV RNA.
3. Lower response rates to triple therapy in patients with advanced liver fibrosis.
4. Adherence to recommended stopping rules for the antiviral agent and/or the entire
treatment regimen.
5. Additional side effects associated with protease inhibitor therapy
Page 11
MEDICAL POLICY
POLICY TITLE
INTERFERON ALPHA THERAPY (INTERFERON ALFA-2A,
INTERFERON ALFA-2B, INTERFERON ALFA-N3 AND INTERFERON
ALFACON-1)
POLICY NUMBER
MP-2.116
V. DEFINITIONS
Top
GENOTYPE refers to the pair of genes present for a particular characteristic or protein.
OFF-LABEL DRUG USE The use of a prescription drug in the treatment of an illness or
injury for which it has not been specifically approved by the U.S. Food and Drug
Administration (FDA).
RNA is a nucleic acid, found mostly in the cytoplasm of cells (rather than the nucleus) that
is important in the synthesis of proteins.
VI. BENEFIT VARIATIONS
Top
The existence of this medical policy does not mean that this service is a covered benefit
under the member's contract. Benefit determinations should be based in all cases on the
applicable contract language. Medical policies do not constitute a description of benefits.
A member’s individual or group customer benefits govern which services are covered,
which are excluded, and which are subject to benefit limits and which require
preauthorization. Members and providers should consult the member’s benefit information
or contact Capital for benefit information.
VII. DISCLAIMER
Top
Capital’s medical policies are developed to assist in administering a member’s benefits, do not constitute
medical advice and are subject to change. Treating providers are solely responsible for medical advice and
treatment of members. Members should discuss any medical policy related to their coverage or condition
with their provider and consult their benefit information to determine if the service is covered. If there is a
discrepancy between this medical policy and a member’s benefit information, the benefit information will
govern. Capital considers the information contained in this medical policy to be proprietary and it may only
be disseminated as permitted by law.
VIII. CODING INFORMATION
Top
Note: This list of codes may not be all-inclusive, and codes are subject to change at any
time. The identification of a code in this section does not denote coverage as
coverage is determined by the terms of member benefit information. In addition, not
all covered services are eligible for separate reimbursement.
Page 12
MEDICAL POLICY
POLICY TITLE
INTERFERON ALPHA THERAPY (INTERFERON ALFA-2A,
INTERFERON ALFA-2B, INTERFERON ALFA-N3 AND INTERFERON
ALFACON-1)
POLICY NUMBER
MP-2.116
Covered when medically necessary:
HPCPS
Code
J9212
J9213
J9214
Description
S0145
S0148
INJECTION, INTERFERON ALFACON-1, RECOMBINANT, 1 MICROGRAM
INJECTION, INTERFERON, ALFA-2A, RECOMBINANT, 3 MILLION UNITS
INJECTION, INTERFERON, ALFA-2B, RECOMBINANT, 1 MILLION UNITS
INJECTION, INTERFERON, ALFA-N3, (HUMAN LEUKOCYTE DERIVED),
250,000 IU
INJECTION, PEGYLATED INTERFERON ALFA-2A, 180 MCG PER ML
INJECTION, PEGYLATED INTERFERON ALFA-2B, 10 MCG
S9559
HIT INTERFERON W/CARE COORDINATION PER DIEM
J9215
ICD-9-CM
Diagnosis Description
Code*
042
HUMAN IMMUNODEFICIENCY VIRUS [HIV]
070.22
VIRAL HEPATITIS B WITH HEPATIC COMA, CHRONIC, WITHOUT MENTION OF HEPATITIS DELTA
070.23
VIRAL HEPATITIS B WITH HEPATIC COMA, CHRONIC, WITH HEPATITIS DELTA
070.32
VIRAL HEPATITIS B WITHOUT MENTION OF HEPATIC COMA, CHRONIC, WITHOUT MENTION OF HEPATITIS
DELTA
070.33
VIRAL HEPATITIS B WITHOUT MENTION OF HEPATIC COMA, CHRONIC, WITH HEPATITIS DELTA
070.41
ACUTE HEPATITIS C WITH HEPATIC COMA
070.44
CHRONIC HEPATITIS C WITH HEPATIC COMA
070.51
ACUTE HEPATITIS C WITHOUT MENTION OF HEPATIC COMA
070.54
CHRONIC HEPATITIS C WITHOUT MENTION OF HEPATIC COMA
070.70
UNSPECIFIED VIRAL HEPATITIS C WITHOUT HEPATIC COMA
070.71
UNSPECIFIED VIRAL HEPATITIS C WITH HEPATIC COMA
078.11
CONDYLOMA ACUMINATUM
157.4
MALIGNANT NEOPLASM OF ISLETS OF LANGERHANS
172.0-172.9
MALIGNANT MELANOMA
173.0
OTHER MALIGNANT NEOPLASM OF SKIN OF LIP
176.0
KAPOSI'S SARCOMA OF SKIN
180.0
MALIGNANT NEOPLASM OF ENDOCERVIX
188.0
MALIGNANT NEOPLASM OF TRIGONE OF URINARY BLADDER
189.0
MALIGNANT NEOPLASM OF KIDNEY, EXCEPT PELVIS
189.1
MALIGNANT NEOPLASM OF RENAL PELVIS
198.0
SECONDARY MALIGNANT NEOPLASM OF KIDNEY
198.1
SECONDARY MALIGNANT NEOPLASM OF OTHER URINARY ORGANS
198.82
SECONDARY MALIGNANT NEOPLASM OF GENITAL ORGANS
200.00
RETICULOSARCOMA, UNSPECIFIED SITE, EXTRANODAL AND SOLID ORGAN SITES
202.00
NODULAR LYMPHOMA, UNSPECIFIED SITE, EXTRANODAL AND SOLID ORGAN SITES
Page 13
MEDICAL POLICY
POLICY TITLE
INTERFERON ALPHA THERAPY (INTERFERON ALFA-2A,
INTERFERON ALFA-2B, INTERFERON ALFA-N3 AND INTERFERON
ALFACON-1)
POLICY NUMBER
MP-2.116
ICD-9-CM
Diagnosis Description
Code*
203.00
MULTIPLE MYELOMA, WITHOUT MENTION OF HAVING ACHIEVED REMISSION
203.01
MULTIPLE MYELOMA IN REMISSION
205.10
CHRONIC MYELOID LEUKEMIA, WITHOUT MENTION OF HAVING ACHIEVED REMISSION
205.11
CHRONIC MYELOID LEUKEMIA IN REMISSION
209.00
MALIGNANT CARCINOID TUMOR OF THE SMALL INTESTINE, UNSPECIFIED PORTION
209.10
MALIGNANT CARCINOID TUMOR OF THE LARGE INTESTINE, UNSPECIFIED PORTION
209.20
MALIGNANT CARCINOID TUMOR OF UNKNOWN PRIMARY SITE
212.1
BENIGN NEOPLASM OF LARYNX
233.1
CARCINOMA IN SITU OF CERVIX UTERI
233.7
CARCINOMA IN SITU OF BLADDER
233.9
CARCINOMA IN SITU OF OTHER AND UNSPECIFIED URINARY ORGANS
238.4
NEOPLASM OF UNCERTAIN BEHAVIOR OF POLYCYTHEMIA VERA
259.2
CARCINOID SYNDROME
287.30
PRIMARY THROMBOCYTOPENIA, UNSPECIFIED
289.0
POLYCYTHEMIA, SECONDARY
776.4
POLYCYTHEMIA NEONATORUM
*If applicable, please see Medicare LCD or NCD for additional covered diagnoses.
The following ICD-10 diagnosis codes will be effective October 1, 2015:
ICD-10CM
Diagnosis
Code*
B20
B18.1
B18.0
B18.1
B18.0
B17.11
B18.2
B17.10
B18.2
B19.20
B19.21
A63.0
C25.4
C43.0
D03.0
C44.0
C46.0
Description
Human immunodeficiency virus [HIV] disease
Chronic viral hepatitis B without delta-agent
Chronic viral hepatitis B with delta-agent
Chronic viral hepatitis B without delta-agent
Chronic viral hepatitis B with delta-agent
Acute hepatitis C with hepatic coma
Chronic viral hepatitis C
Acute hepatitis C without hepatic coma
Chronic viral hepatitis C
Unspecified viral hepatitis C without hepatic coma
Unspecified viral hepatitis C with hepatic coma
Anogenital (venereal) warts
Malignant neoplasm of endocrine pancreas
Malignant melanoma of lip
Melanoma in situ of lip
Malignant neoplasm of skin of lip
Kaposi's sarcoma of skin
Page 14
MEDICAL POLICY
POLICY TITLE
INTERFERON ALPHA THERAPY (INTERFERON ALFA-2A,
INTERFERON ALFA-2B, INTERFERON ALFA-N3 AND INTERFERON
ALFACON-1)
POLICY NUMBER
MP-2.116
C53.0
C67.0
C64.2
C64.1
C64.9
C65.2
C65.1
C65.9
C79.02
C79.01
C79.00
C79.11
C79.19
C79.10
C79.82
C83.39
C83.30
C82.69
C82.60
C82.09
C82.00
C82.19
C82.10
C82.29
C82.20
C82.39
C82.30
C82.49
C82.40
C82.99
C82.90
C82.89
C82.80
C90.00
C90.01
C92.10
C92.11
C7a.019
C7a.029
C7a.00
D14.1
Malignant neoplasm
Malignant neoplasm of trigone of bladder
Malignant neoplasm of left kidney, except renal pelvis
Malignant neoplasm of right kidney, except renal pelvis
Malignant neoplasm of unspecified kidney, except renal pelvis
Malignant neoplasm of left renal pelvis
Malignant neoplasm of right renal pelvis
Malignant neoplasm of unspecified renal pelvis
Secondary malignant neoplasm of left kidney and renal pelvis
Secondary malignant neoplasm of right kidney and renal pelvis
Secondary malignant neoplasm of unspecified kidney and renal pelvis
Secondary malignant neoplasm of bladder
Secondary malignant neoplasm of other urinary organs
Secondary malignant neoplasm of unspecified urinary organs
Secondary malignant neoplasm of genital organs
Diffuse large B-cell lymphoma, extranodal and solid organ sites
Diffuse large B-cell lymphoma, unspecified site
Cutaneous follicle center lymphoma, extranodal and solid organ sites
Cutaneous follicle center lymphoma, unspecified site
Follicular lymphoma grade I, extranodal and solid organ sites
Follicular lymphoma grade I, unspecified site
Follicular lymphoma grade II, extranodal and solid organ sites
Follicular lymphoma grade II, unspecified site
Follicular lymphoma grade III, unspecified, extranodal and solid organ sites
Follicular lymphoma grade III, unspecified, unspecified site
Follicular lymphoma grade IIIa, extranodal and solid organ sites
Follicular lymphoma grade IIIa, unspecified site
Follicular lymphoma grade IIIb, extranodal and solid organ sites
Follicular lymphoma grade IIIb, unspecified site
Follicular lymphoma, unspecified, extranodal and solid organ sites
Follicular lymphoma, unspecified, unspecified site
Other types of follicular lymphoma, extranodal and solid organ sites
Other types of follicular lymphoma, unspecified site
Multiple myeloma not having achieved remission
Multiple myeloma in remission
Chronic myeloid leukemia, BCR/ABL-positive, not having achieved remission
Chronic myeloid leukemia, BCR/ABL-positive, in remission
Malignant carcinoid tumor of the small intestine, unspecified portion
Malignant carcinoid tumor of the large intestine, unspecified portion
Malignant carcinoid tumor of unspecified site
Benign neoplasm of larynx
Page 15
MEDICAL POLICY
POLICY TITLE
INTERFERON ALPHA THERAPY (INTERFERON ALFA-2A,
INTERFERON ALFA-2B, INTERFERON ALFA-N3 AND INTERFERON
ALFACON-1)
POLICY NUMBER
MP-2.116
D06.9
D06.0
D06.1
D06.7
D09.0
D09.19
D09.10
D45
E34.0
D47.3
D69.49
D75.1
P61.1
Carcinoma in situ of cervix, unspecified
Carcinoma in situ of endocervix
Carcinoma in situ of exocervix
Carcinoma in situ of other parts of cervix
Carcinoma in situ of bladder
Carcinoma in situ of other urinary organs
Carcinoma in situ of unspecified urinary organ
Polycythemia vera
Carcinoid syndrome
Essential (hemorrhagic) thrombocythemia
Other primary thrombocytopenia
Secondary polycythemia
Polycythemia neonatorum
*If applicable, please see Medicare LCD or NCD for additional covered diagnoses.
IX. REFERENCES
Top
Bacon, B, Regev, A, Ghalib, RH, et al. The DIRECT trial (daily-dose consensus interferon
and ribavirin: efficacy of combined therapy): treatment of non-responders to previous
pegylated interferon plus ribavirin: sustained virologic response data (abstract).
Hepatology 2007; 46 (Suppl):311A.
BCBSA TEC Assessments 1995: Interferon- Off-Label Oncology Indications - Lymphomas,
Leukemias, and Plasma-Cell Malignancies - Tab 16. Also Off-Label Oncology
Indications - Solid Tumor - Tab 17.
Berg, T., von Wagner, M., et al. Extended treatment duration for hepatic C virus type 1:
comparing 48 versus 72 weeks of peginterferon-alfa-2a plus ribavirin.
Gastroenterology 2006; 130(4):1357-1362.
Bisceglie A. Mechanism of action and efficacy of peginterferon for the treatment of chronic
hepatitis C virus infection. In: UpToDate Online Journal [serial online]. Waltham,
MA: UpToDate; updated January 9, 2014.[Website: www.uptodate.com. Accessed
June 16, 2014.
Borden EC, Sen GC, Uze G, et al.Interferons at age 50: past, current and future impact on
biomedicine.Nat Rev Drug Discov. 2007 Dec; 6(12):975-90.
Centers for Medicare and Medicaid Services (CMS) Medicare Benefit Policy Manual.
Publication 100-02. Chapter 15. Section 50.4.2. Unlabeled Use of Drug. Effective
10/01/03. [Website]: http://www.cms.gov/manuals/Downloads/bp102c15.pdf .
Accessed June 16, 2014.
Centers for Medicare and Medicaid Services (CMS) Medicare Benefit Policy Manual.
Publication 100-02. Chapter 15. Section 50.4.5. Off-Label Use of Anti-Cancer Drugs
Page 16
MEDICAL POLICY
POLICY TITLE
INTERFERON ALPHA THERAPY (INTERFERON ALFA-2A,
INTERFERON ALFA-2B, INTERFERON ALFA-N3 AND INTERFERON
ALFACON-1)
POLICY NUMBER
MP-2.116
and Biologicals. [Website]: http://www.cms.gov/manuals/Downloads/bp102c15.pdf .
Accessed June 16, 2014.
Centers for Medicare and Medicaid Services (CMS) Medicare Benefit Policy Manual.
Publication 100-02. Chapter 15. Sections 50, 50.4.1, 50.4.3. Drugs and Biologicals.
Effective 10/01/03. [Website]: http://www.cms.gov/manuals/Downloads/bp102c15.pdf .
Accessed June 16, 2014.
Chopra S.Mechanism of action and efficacy of standard interferon alfa for the treatment of
chronic hepatitis C virus infection. In: UpToDate Online Journal [serial online].
Waltham, MA: UpToDate; updated January 25, 2013. [Website]: www.uptodate.com.
Accessed June 16, 2014.
Friedman RM, Contente S.Treatment of hepatitis C infections with interferon: a historical
perspective.Hepat Res Treat. 2010;2010:323926.
Ghany MG, Strader DB, Thomas DL, Seeff LB. AASLD Practice Guidelines. Diagnosis,
management, and treatment of hepatitis C: an update. Hepatology 2009; 49(4); 133574.
Guilhot F, Roy L, Martineua G, Guilhot J, Millot F. Immunotherapy in chronic
myelogenous leukemia. Clinical Lymphoma & Myeloma 2007;7 Suppl 2:S64-70.
Ribavirin : drug information. In: UpToDate Online Journal [serial online]. Waltham, MA:
UpToDate;[Website]: www.uptodate.com . Accessed June 16, 2014.
Interferon alfacon-1(consensus interferon): drug information. In: UpToDate Online
Journal [serial online]. Waltham, MA: UpToDate;[Website]: www.uptodate.com .
Accessed June 16, 2014.
Interferon alfa-n3 : drug information. In: UpToDate Online Journal [serial online].
Waltham, MA: UpToDate;[Website]: www.uptodate.com . Accessed June 16, 2014.
Lopez-Alcorocho JM, Rodriguez-Inigo E, Castillo I, Castellanos ME, Pardo M, Bartolome
J, Quiroga JA, Carreno V. The role of genomic and antigenomic HCV-RNA strands as
predictive factors of response to pegylated interferon plus ribavirin therapy. Aliment
Pharmacol Ther. 2007 May 15; 25(10):1193-201.
Maylin, S, Martinot-Peignoux, M, Moucari, R, et al. Eradication of hepatitis C virus in
patients successfully treated for chronic hepatitis C. Gastroenterology 2008; 135:821.
National Cancer Institute U.S. National Institutes of Health Gastrointestinal Carcinoid
Tumors (PDQ®): Treatment. 2/28/14.Website]:
http://www.cancer.gov/cancertopics/pdq/treatment/gastrointestinalcarcinoid/HealthPr
ofessional Accessed June 16, 2014.
National Comprehensive Cancer Network (NCCN). Clinical Practice Guideline: Bladder
Cancer v.2.2014. [Website]:
http://www.nccn.org/professionals/physician_gls/PDF/bladder.pdf. Accessed June 16,
2014.
Page 17
MEDICAL POLICY
POLICY TITLE
INTERFERON ALPHA THERAPY (INTERFERON ALFA-2A,
INTERFERON ALFA-2B, INTERFERON ALFA-N3 AND INTERFERON
ALFACON-1)
POLICY NUMBER
MP-2.116
.National Comprehensive Cancer Network (NCCN). Clinical Practice Guideline: Chronic
Myelogenous Leukemia. V.2.2014. [Website]:
http://www.nccn.org/professionals/physician_gls/PDF/cml.pdf . Accessed June 16,
2014.
National Comprehensive Cancer Network (NCCN). Clinical Practice Guideline: Kidney
Cancer v.3.2014. [Website]:
http://www.nccn.org/professionals/physician_gls/PDF/kidney.pdf . Accessed June 16,
2014.
National Comprehensive Cancer Network (NCCN). Clinical Practice Guideline:
Melanoma. V.4.2014..[Website]:
http://www.nccn.org/professionals/physician_gls/PDF/melanoma.pdf . Accessed June
16, 2014.
National Comprehensive Cancer Network (NCCN). Clinical Practice Guideline: Multiple
Myeloma v.2.2014.. [Website]:
http://www.nccn.org/professionals/physician_gls/PDF/myeloma.pdf.Accessed March 1,
2011. June 16, 2014.
National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in
Oncology-, Neuroendocrine Tumors. v. 2.2014. National Comprehensive Cancer
Network. [Website]:
http://www.nccn.org/professionals/physician_gls/PDF/neuroendocrine.pdf Accessed
June 16, 2014.
National Comprehensive Cancer Network (NCCN). Clinical Practice Guideline: NonHodgkin’s Lymphomas. V. 2.2014. [Website]:
http://www.nccn.org/professionals/physician_gls/PDF/nhl.pdf . June 16, 2014.
Pegylated interferon (peginterferon) alfa-2a: drug information. In: UpToDate Online
Journal [serial online]. Waltham, MA: UpToDate; [Website]: www.uptodate.com .
Accessed June 16, 2014.
Pegylated interferon (peginterferon) alfa-2b: drug information. In: UpToDate Online
Journal [serial online]. Waltham, MA: UpToDate; [Website]: www.uptodate.com .
Accessed June 16, 2014
Rigopoulou EI, Abbott WG, Williams R, Naoumov NV. Direct evidence for
immunomodulatory properties of ribavirin on T-cell reactivity to hepatitis C virus.
Antiviral Res. 2007 Jul; 75(1):36-42.
Simin M, Brok J, Stimac D, Gluud C, Gluud LL. Cochrane systematic review: pegylated
interferon plus ribavirin vs. interferon plus ribavirin for chronic hepatitis C.
Alimentary Pharmacology and Therapeutics 2007;25(10):1153-62.
Taber’s Cyclopedic Medical Dictionary, 20th edition.
Page 18
MEDICAL POLICY
POLICY TITLE
INTERFERON ALPHA THERAPY (INTERFERON ALFA-2A,
INTERFERON ALFA-2B, INTERFERON ALFA-N3 AND INTERFERON
ALFACON-1)
POLICY NUMBER
MP-2.116
Yu JW, Wang GQ, Sun LJ, Li XG, Li SC. Predictive value of rapid virological response and
early virological response on sustained virological response in HCV patients treated
with pegylated interferon alpha-2a and ribavirin. J Gastroenterol Hepatol. 2007 Jun;
22(6):832-6.
Weigand K, Stremmel W, Encke J. Treatment of hepatitis C virus infection. World J
Gastroenterol. 2007 Apr 7; 13(13):1897-905.
X. POLICY HISTORY
MP 2.116
Top
CAC 1/28/03
CAC 1/25/05
CAC 1/31/06
CAC 2/28/06
CAC 1/30/07
CAC 1/29/08 Consensus
J12 MAC 12/12/08
CAC 3/31/09
CAC 3/30/10 Consensus
CAC 4/26/11 Consensus
CAC 6/26/12 Consensus review; no changes, references updated. FEP
variation revised.
7/18/13 Admin coding review complete--rsb
CAC 9/24/13 Consensus review. No changes to policy statements.
References updated. FEP variation updated.
1/14/2014 Admin diag code range 172.0-172.9 added. No change to
effective date or current configuration.
CAC 7/22/14 Consensus review. References updated. No changes to the
policy statements. Rationale added.
TOP
Health care benefit programs issued or administered by Capital BlueCross and/or its subsidiaries, Capital Advantage Insurance
Company®, Capital Advantage Assurance Company® and Keystone Health Plan® Central. Independent licensees of the
BlueCross BlueShield Association. Communications issued by Capital BlueCross in its capacity as administrator of programs
and provider relations for all companies.
Page 19