Subject to the qualification described below regarding length of treatment and response to treatment, Aetna considers interferon alpha, pegylated interferon, interferon beta, and interferon gamma medically necessary for persons who meet the criteria for each drug specified below.

Interferon alpha

Aetna considers interferon alpha medically necessary for the following indications:

1. AIDS-associated Kaposi's sarcoma;
2. Hairy cell leukemia;
3. Condylomata acuminata (genital warts) (intralesional only);
4. Hepatitis C (non-A, non-B hepatitis), in persons with compensated liver disease (laboratory parameters are all within the following ranges: bilirubin less than 2 mg/dL; albumin stable and within normal limits; INR less than 2; WBC greater than 3000/mm3; platelets greater than 70,000/mm3; no history of hepatic encephalopathy, variceal bleeding, ascites, or other clinical signs of decompensation; serum creatinine normal or near normal) (the safety and efficacy have not been established for treatment of persons with decompensated liver disease or for immune suppressed transplant recipients). Continued treatment with interferon alpha is considered not medically necessary for persons with HCV genotypes 1 and 4 through 6 who have failed to attain an early virologic response after 12 weeks of treatment (where early virologic response is indicated by achievement of at least a 100-fold (2 log10) decrease in serum HCV from pretreatment baseline). Up to a maximum of 24 weeks of interferon alpha is considered medically necessary for persons with HCV genotypes 2, 3, and 7 through 10; and up to a maximum of 48 weeks of interferon alpha is considered medically necessary for persons with HCV genotypes 1 and 4 through 6. A course of standard interferon alpha in persons with hepatitis C who have failed to respond or relapsed after an adequate course of pegylated interferon alpha is considered experimental and investigational because of a lack of evidence on the effectiveness of standard interferon in these persons. Note: Upon medical review, extended treatment with interferon alpha beyond these limits may be considered medially necessary for persons with cryoglobulinemia and for liver transplant recipients with recurrent hepatitis C infection.

5. Persons with chronic hepatitis B who meet all of the following criteria:

   1. Serum aminotransferase (AST) greater than double the upper limit of normal range (AST normal range 0-35 u/l); and

   2. Member has compensated liver disease (laboratory parameters are all within the following range: bilirubin less than 2mg/dL; albumin stable and within normal limits; PT less than 3 seconds prolonged or INR less than 2; WBC greater than 3000/mm3; platelets greater than 70,000/mm3; no history of hepatic encephalopathy, variceal bleeding, ascites, or other clinical signs of decompensation; serum creatinine normal or near normal).

   A course of standard interferon alpha in persons with hepatitis B who have failed an adequate course of pegylated interferon alpha is considered experimental and investigational because of a lack of evidence on the effectiveness of standard interferon in these persons.

   (The use of interferon alpha is considered contraindicated in the following persons with hepatitis B: those who are HIV positive; hepatitis B surface antigen (HBs Ag) positive persons undergoing liver transplantation; and those with a history of or currently active autoimmune hepatitis);

6. Malignant melanoma;
7. Renal cell carcinoma;
8. Life-threatening hemangioma of infancy (intralesional) when member is intolerant of, or the hemangioma is resistant to, corticosteroid therapy;
9. Carcinoid syndrome;
10. Chronic myelogenous leukemia (not in accelerated phase);
11. Essential thrombocythemia;
12. Low-grade non-Hodgkin's lymphoma (stage III/IV) (interferon alpha is used for treatment of non-Hodgkin's lymphomas, especially follicular small cleaved cell lymphoma (nodular poorly differentiated types));
13. Respiratory papillomatosis;

14. Persons with polycythemia vera who meet all of the following criteria:

    1. Phlebotomy is not effective, not tolerated, or contraindicated; and

    2. Oral therapy with hydroxyurea or other myelosuppressive agent is not effective, not tolerated, or is contraindicated.

    Note: Failure of phlebotomy and/or myelosuppressive agents may be defined as any of the following:

    • Lack of hematological control (e.g., hematocrit greater than 45 or platelet count greater than 600 x 109/L);
    • Phlebotomy required more often than once every two months;
    • Occurrence of thrombotic or hemorrhagic complications;
    • Occurrence of intractable symptoms (e.g., headaches, pruritis); or

    • Occurrence of symptoms related to hepatosplenomegaly.

15. Cutaneous T-cell lymphoma (including mycosis fungoides);
16. Multiple myeloma;
17. Ovarian carcinoma, in persons who cannot tolerate, or whose tumor is resistant to, standard first-line therapy;
18. Colorectal carcinoma, when used in conjunction with 5-FU;
19. Pancreatic islet cell carcinoma;
20. Cervical carcinoma, in persons who cannot tolerate, or whose tumor is resistant to, standard first-line therapy;
21. Superficial bladder cancer (carcinoma in situ of the bladder);
22. Basal cell carcinoma, when surgical intervention is contraindicated (interferon therapy in basal cell carcinoma is only considered medically necessary only for those persons in which surgical intervention is contraindicated; surgical intervention is considered first-line therapy for basal cell carcinoma, and has been shown to have a 95% treatment success rate);
23. Malignant mesothelioma in persons who have relapsed following surgery and failed treatment with or cannot tolerate first-line chemotherapy;
24. Vulvar vestibulitis;
25. Kasabach-Merritt syndrome;
26. Waldenstrom's macroglobulinemia;
27. Ocular herpes simplex (interferon alpha eye drops);
28. Hepatocellular carcinoma, for persons with hepatitis C and completely resected tumors, or
29. Desmoid tumors, for unresctable disease or gross residual disease following surgery.

Aetna considers interferon alpha experimental and investigational for all other indications because it has not been shown to be effective for them:

1. Acute hepatitis B;
2. Age-related macular degeneration;
3. AIDS-related complex;
4. AIDS in combination with AZT;
5. Breast cancer;
6. Chickenpox;
7. Chronic delta hepatitis;
8. Cutaneous warts;
9. Cytomegalovirus (CMV);
10. Gardner syndrome;
11. Hepatitis D;
12. Hereditary hemorrhagic telangiectasia;
13. Herpes keratoconjunctivitis;
14. Keloids;
15. Multiple sclerosis
16. Peyronie's disease
17. Plexiform neurofibroma;
18. Prostate cancer;
19. Rhinoviruses;
20. Vaccinia; and
21. Varicella zoster virus (VZV).

Pegylated interferon alpha

1. Hepatitis C
   
   
   1. Aetna considers PEG-Intron (pegylated interferon alfa-2b) and Pegasys (pegylated interferon alfa-2a) medically necessary, either as monotherapy or in combination with ribavirin (Rebetol), for the treatment of chronic hepatitis C in persons with compensated liver disease (laboratory parameters are all within the following ranges: bilirubin less than 2 mg/dL; albumin stable and within normal limits; PT less than 3 seconds prolonged or INR less than 2; WBC greater than 3000/mm3; platelets greater than 70,000/mm3; no history of hepatic encephalopathy, variceal bleeding, ascites, or other clinical signs of decompensation; serum creatinine normal or near normal) (safety and efficacy have not been established for treatment of persons with decompensated liver disease) who are interferon naïve or who have relapsed or failed to respond to prior non-pegylated interferon therapy.
      
   2. Continued treatment with pegylated interferon alpha is considered not medically necessary for persons with HCV genotypes 1 and 4 who have failed to attain an early virologic response after 12 weeks of therapy. Early virologic response is indicated by achievement of at least a 100-fold (2 log10) decrease in serum HCV RNA from pretreatment baseline.
      
   3. For persons infected with HCV genotype 1 and genotypes 4 through 6 who have attained an early virologic response by 12 weeks of therapy, up to 48 weeks of treatment with pegylated interferons is considered medically necessary.
      
   4. For persons with other HCV genotypes (i.e., genotypes 2 and 3, and genotypes 7 through 10) up to 24 weeks of treatment with pegylated interferons is considered medically necessary. 
      
   5. Repeat or chronic maintenance treatment with pegylated interferon (PEG-Intron or Pegasys) is considered experimental and investigational for persons who have completed a therapeutic course of pegylated interferon and ribavirin.
      
   6. Up to 48 weeks of pegylated interferons is considered medically necessary for persons coinfected with HIV and HCV, regardless of HCV genotype, who have compensated liver disease, are on stable antiretroviral therapy, and (for HCV genotypes 1 and 4 through 6 only) have achieved an early virologic response after 12 weeks of therapy.
      
   7. Note: Upon medical review, extended treatment with pegylated interferon alpha beyond these limits may be considered medically necessary for persons with cryglobulinemia and for liver transplant recipients with recurrent hepatitis C infections.
      
      
2. Hepatitis B
   
   
   
   1. Peginterferon alfa-2a (Pegasys) is considered medically necessary for the treatment of adult persons with HBeAg positive or HBeAg negative chronic hepatitis B who have compensated liver disease (laboratory parameters are all within the following range: bilirubin less than 2mg/dL; albumin stable and within normal limits; PT less than 3 seconds prolonged or INR less than 2; WBC greater than 3000/mm3; platelets greater than 70,000/mm3; no history of hepatic encephalopathy, variceal bleeding, ascites, or other clinical signs of decompensation; serum creatinine concentrations less than 1.5 times upper limit of normal) and evidence of viral replication (HBV greater than 500,000 copies per ml for HBeAg positive and HBV greater than 100, 000 copies per ml for HBeAg negative) and liver inflammation (serum aminotransferase (AST) greater than the upper limit of normal range (AST normal range 0-35 u/l)), and who are interferon naïve or who have relapsed or failed to respond to prior non-pegylated interferon therapy.
      
   2. Treatment of chronic hepatitis B with peginterferon alfa-2a for more than 48 weeks is considered experimental and investigational.
      
   3. Repeat or chronic maintenance treatment with peginterferon alfa-2a is considered experimental and investigational for persons who have completed a therapeutic course of pegylated interferon and ribavirin.
      
   4. Note: Upon medical review, extended treatment with peginterferon alfa-2a beyond these limits may be considered medically necessary for liver transplant recipients with recurrent hepatitis B infections.

Aetna considers pegylated interferon alpha experimental and investigational for all other indications.

Note: Pegylated interferons are self-administered subcutaneously once weekly.

Consensus Interferon (Interferon alfacon-1)

1. Consensus interferon (Infergen interferon alfacon-1 is considered medically necessary for treatment of chronic hepatitis C in persons with compensated liver disease who meet medical necessity criteria for interferon alpha for hepatitis C (see section on interferon alpha above).
2. Use of consensus interferon for persons with hepatitis C who have failed to respond or relapsed after an adequate course of standard alpha interferon or pegylated interferons is considered experimental and investigational.  Although there is limited evidence regarding the use of consensus interferon in persons with hepatitis C who have relapsed or failed to respond to standard alpha interferon therapy, current guidelines indicate pegylated interferons as the treatment of choice for persons with hepatitis C, including those who relapsed or failed to respond to standard alpha interferon therapy. There is insufficient evidence in the peer-reviewed published medical literature comparing consensus interferon to pegylated interferons, and of the effectiveness of consensus interferon in persons with hepatitis C who have failed pegylated interferon therapy.
3. Repeat or chronic (more than 48 weeks) maintenance treatment with consensus interferon is considered experimental and investigational because there is insufficient evidence to show that repeat or prolonged therapy has a clinically significant impact on long term outcomes.
4. Consensus interferon is considered experimental and investigational for all other indications.  

Interferon beta

Aetna considers the use of interferon beta-1a (Avonex, Rebif) or interferon beta-1b (Betaseron) medically necessary for the treatment of relapsing/remitting multiple sclerosis in members who meet all of the conditions described below:

Member meets either of the following criteria for clinically definite or laboratory supported definite MS:

1. Clinically definite MS is defined as either:

   • Two attacks and clinical evidence of two separate lesions; or

   • Two attacks; clinical evidence of one lesion and para-clinical evidence of another, separate lesion

2. Laboratory-supported definite MS consists of demonstration of any of the following:

   • Two attacks; either clinical or para-clinical evidence of one lesion; and CSF OB/IgG*; or
   • One attack; clinical evidence of two separate lesions; and CSF OB/IgG*; or

   • One attack; clinical evidence of one lesion and para-clinical evidence of another separate lesion; and CSF OB/IgG*

   *CSF OB/IgG is defined as either:

   • IgG oligoclonal band (OB) in the CSF; or

   • Increased CNS synthesis of IgG (IgG is higher in CSF than in serum, and is increased in the CSF in the presence of a normal concentration of total protein).

   Limits: Oligoclonal bands must not be present in the member's serum and the serum IgG level must be normal.

Aetna considers interferon beta experimental and investigational for all other indications.

Aetna considers testing for neutralizing antibodies to interferon beta experimental and investigational (see CPB 264 - Multiple Sclerosis).

Notes: Because interferon beta is administered subcutaneously or intramuscularly, it is appropriate for administration by the member in the home setting.

The Biojector 2000 (Bioject, Inc.) is a needle-free injection system that uses CO2 as the power source and disposable needle-free syringes to deliver medication in a fraction of a second through a tiny orifice. Biojector 2000 is considered an acceptable alternative to conventional needle and syringes for members with exacerbating-remitting MS who cannot safely use needles for self-injection due to tremors and decreased coordination.

See also CPB 264 - Multiple Sclerosis.

Interferon gamma

Aetna considers interferon gamma medically necessary for the following indications:

1. Chronic granulomatous disease, to reduce the frequency and severity of infections; or
2. Severe, malignant osteopetrosis, to delay time to disease progression; or
3. Waldenstrom's macroglobulinemia; or
4. Chronic recalcitrant atopic dermatitis; or
5. Mycosis fungoides and Sezary syndrome.   

Aetna considers interferon gamma experimental and investigational for the treatment of idiopathic pulmonary fibrosis, malignant neoplasm of peritoneum and all other indications.

Interferons are biological response modifiers that are indicated in the treatment of numerous malignant and infectious disease conditions.

Interferon alpha products (Roferon; Intron-A; Alferon; Infergen) have been granted orphan-drug status by the FDA for several types of malignancies and viral infections and have unlabeled uses for several others. Although the efficacy of all alpha interferons (e.g., interferon alpha 2a, alpha 2b, alpha-n3, and alfacon-1) for various indications appear to be similar, differences in relative efficacy for a particular indication may exist. Interferon alpha should be used with caution in patients with preexisting psychiatric conditions or a history of severe psychiatric disorders. According to the product labeling, depression, confusion, and other alterations of mental status have been observed in some patients and suicidal ideation and attempted suicide have been observed rarely.

A Cochrane evidence review of treatments for herpes simplex eye disease (Wilhelmus, 2007) found that the combination of interferon-alpha eye drops and either trifluridine or acyclovir resulted in faster healing of dendritic keratitis than treatment with trifluridine or acyclovir alone; 90% of eyes healed within one week with combined interferon-antiviral therapy.

PEG-Intron, peginterferon alfa-2b powder for injection, either alone or in combination with ribavirin (Rebetol), is an alternative to standard interferon alfa plus ribavirin for treatment of chronic hepatitis C. PEG-Intron is a covalent conjugate of recombinant alfa interferon with monomethoxy polyethylene glycol (PEG). It offers an alternative to patients in whom combination therapy may be a contraindication or who are intolerant of this therapy. The drug is self-administered subcutaneously once weekly by patients and, therefore, is more convenient to use than the standard interferon alfa, which is injected three times weekly. Recently, studies of combination therapy with weekly PEG-Intron and daily ribavirin (Rebetol) reported that this combination was somewhat more effective than alpha interferon (Intron A) with Rebetol. Twenty-four weeks after treatment ended, 52% of patients who received the PEG-Intron combination had undetectable HCV virus levels in the blood compared to 46% for the Intron A combination. In patients with genotype 1 virus (a particularly difficult to treat variant of the HCV virus), the difference in sustained responses was 41% compared to 33%. Peg-Intron from Schering-Plough is the first pegylated interferon to have FDA approval in the United States.

Roche Pharmaceutical's Pegasys (pegylated interferon alfa-2a) has also been approved by the FDA for the treatment of adults with chronic hepatitis C who have compensated liver disease and have not previously been treated with interferon alpha. Patients in whom efficacy was demonstrated included patients with compensated cirrhosis. Pegasys was granted approval based on the results of three Phase III clinical trials that demonstrated it is an effective treatment for patients with chronic hepatitis C, including cirrhotic patients with compensated liver disease, versus treatment with Roferon-A (interferon alfa-2a). The sustained virological response rate in the patients treated with pegylated interferon alfa-2a was as high as 38% in the overall population versus 19% in the interferon alfa-2a group. The sustained virological response in patients with cirrhosis treated with pegylated interferon alfa-2a was as high as 30% versus 8% in the interferon alfa-2a group. Higher sustained virological response results were also found in patients with genotype 1, on pegylated interferon alfa-2a treatment (23%) versus interferon alfa-2a (6%), the most common type in the U.S. and most difficult to treat. Sustained virological response was defined as undetectable serum hepatitis C RNA levels post-treatment (on or after study week 68). Pegylated interferon alfa-2a is dosed at 180 µg as a subcutaneous injection once a week for a recommended duration of 48 weeks.

Clinical trials of pegylated interferon alfa-2a have shown that patients with HCV genotypes 1 and 4 can determine at 12 weeks if they are unlikely to attain an early virological response with pegylated interferon alfa-2a.  According to an NIH Consensus Statement on Hepatitis C (1997; 2002), 12 weeks after beginning an initial course of therapy, patients who are unlikely to respond to that dosage and frequency can be identified by persistent elevation of serum ALT levels and presence of HCV RNA in the serum.  In this situation, therapy should be discontinued because the likelihood of future response is extremely low.  If HCV RNA is below the detection level of the assay or if there is at least a 2 log10 reduction in the HCV RNA titer from baseline, therapy should be continued for an additional 36 weeks.  Non-responders should be encouraged to participate in clinical trials directed toward this difficult-to-treat group.

According to guidelines from the National Institute for Health and Clinical Excellence (NICE, 2004), people infected with HCV of genotype 1, 4, 5 or 6, should initially be treated for 12 weeks. Only people showing, at 12 weeks, a reduction in viral load to less than 1% of its level at the start of treatment (at least a 2-log reduction) should continue treatment until 48 weeks. For people in whom viral load at 12 weeks exceeds 1% of its level at the start of treatment, treatment should be discontinued. These guidelines note that people infected with more than one genotype that includes one or more of genotypes 1, 4, 5, or 6 should be treated as for genotype 1 (NICE, 2004; see also.Hadziyannis, et al., 2004; NIH, 2002). These guidelines are based upon the observation that the SVRs for patients infected with HCV genotype 1 are much lower than those for genotypes 2 and 3, whereas SVRs for genotypes 4, 5 and 6 appear to be between those of the more  prevalent genotypes.

For persons with other HCV genotypes (i.e., genotypes 2 and 3, and 7 through 11), there is no proven benefit to extending therapy beyond 24 weeks (Hadziyannis, et al., 2004; NIH, 2002; NICE, 2004).

Infection with hepatitis C virus (HCV) genotype 6 is common in patients from parts of China and Southeast Asia.There is limited evidence regarding the appropriate duration of therapy for persons with genotype 6. Fung, et al. (2008) evaluated the effectiveness of pegylated interferon plus ribavirin for the treatment of chronic infection with hepatitis C virus (HCV) genotype 6 compared to genotype 1. Forty-two patients chronically infected with HCV were treated with pegylated interferon combined with oral ribavirin for 48 weeks. The investigators found no difference between genotypes 1 and 6 in the rates of early virological response (76% vs. 81%) and end-of-treatment response (71% vs. 81%). Patients infected with genotype 6 had a higher SVR than did patients infected with genotype 1 (86% vs. 52%). The overall adverse-effects profile was similar in both genotype groups. The investigators concluded that treatment with pegylated interferon and ribavirin for 48 weeks resulted in a significantly higher rate of SVR in patients infected with genotype 6 than in those infected with genotype 1. This suggests that the response of HCV genotype 6 to pegylated interferon is more similar to that for genotypes 2 and 3 than for genotypes 1 and 4. The investigators stated that further studies are required to determine whether lower dosages and 24 weeks of therapy may be sufficient for the treatment of genotype 6 infection.The findings of a higher SVR with interferon treatment in persons infected with genotype 6 versus genotype 1 was also found in an earlier study of standard interferon plus ribavirin (Yuen & Lai, 2006).

Nguyen, et al. (2004) reported on a retrospective study of 190 consecutive Asian-American patients who were diagnosed with HCV genotype 6 at a gastroenterology clinic in northern California between 2001 and 2004, 66 of whom were treatment-naïve and subsequently completed 24 weeks of interferon plus ribavirin or pegylated interferon plus ribavirin, or 48 weeks of pegylated interferon plus ribavirin therapy. The investigators found no statistical difference in SVR of 31 patients treated with 24 weeks of interferon plus ribavirin and in 23 patients treated with 24 weeks of pegylated interferon plus ribavirin (51.6% versus 39%,  p = 0.363). The SVR in 12 patients treated with 48 weeks of pegylated interferon plus ribavirin was significantly higher than that in those treated for only 24 weeks (75% versus 39%, p = 0.044). The investigators concluded that treatment-eligible patients with HCV genotype 6 should be treated with a full course of 48 weeks as tolerated. The investigators noted that larger prospective studies of patients with HCV genotype 6 are needed to confirm the optimal treatment duration with pegylated interferon plus ribavirin.

Data are scarce on patients infected with hepatitis C virus of genotype 5, due to the low prevalence of this genotype around the world. Antaki, et al. (2008) reported on a retrospective study of treatment outcomes of 26 HCV genotype 5 patients who had completed a course of therapy and a 6-month follow up. Treatment consisted of ribavirin plus standard or pegylated interferon. Patients were treated for 24 or 48 weeks. The investigators reported that an SVR was achieved in 54% (47% with standard interferon and 67% with pegylated interferon, p = 0.43). A trend towards better results was observed for younger patients, low viremia and mild fibrosis. The investigators reported that SVR was similar for treatment course of 24 or 48 weeks. The investigators concluded that treatment of HCV genotype 5 with combination therapy resulted in SVR in 54% of patients. The investigators stated that 24 weeks of treatment might be adequate, and that further research should evaluate the ideal duration of treatment.

Peginterferon alpha-2a (Pegasys) has also been approved by the FDA for treatment of hepatitis C in HIV coinfected persons, whose HIV disease is clinically stable (e.g., antiretroviral therapy not required or receiving stable antiretroviral therapy).  In studies submitted to the FDA, 868 HCV/HIV coinfected patients were randomized to receive peginterferon alpha-2a plus placebo, peginterferon alpha-2a plus ribavirin, or interferon alpha-2a plus ribavirin (Roche, 2005).  All subjects received 48 weeks of therapy, and sustained virologic response was assessed at 24-weeks of treatment free follow-up. All subjects included in the study had compensated liver disease, a CD4+ cell count greater than or equal to 200 cells/µL or CD4+ cell count greater than or equal to 100 cells/µL but less than 200 cells/µL and HIV-1 RNA less than 5000 copies/mL, and stable status of HIV.  Approximately 15% of patients in the study had cirrhosis.  Sustained virologic response was noted in 40% of subjects treated with peginterferon alpha-2a plus ribavirin, 20% of patients treated with peginterferon alpha-2a plus placebo (p < 0.0001), and 11% of subjects treated with interferon alpha-2a plus ribavirin (p < 0.0001). Of patients who did not demonstrate either either undetectable HCV RNA or at least a 2 log 10 reduceion from baseline in HCV RNA titer by 12 weeks of peginterferon alpha-2a and ribavirin combination therapy, 2% achieved a sustained virologic response.

There is inadequate evidence for the effectiveness of use of pegylated interferons as maintenance therapy.  According to the FDA-approved labeling for pegylated interferons, there are no safety and efficacy data on treatment with pegylated interferons for more than one year.

The NIH Consensus Conference on Hepatitis C (2002) stated: “Failure to respond to optimal therapy with pegylated interferon and ribavirin presents a significant problem, particularly in the presence of advanced fibrosis or cirrhosis.  Currently, several large-scale, multi-center U.S. trials are evaluating the role of maintenance therapy with pegylated interferon alone in preventing further progression of cirrhosis, clinical decompensation, or development of HCC.  Until the results of these studies are available, the role of long-term, continuous therapy with pegylated interferon (or ribavirin or both) for non-responders should be considered experimental.”

The impact of interferon (IFN)  treatment on the occurrence of complications related to HCV-related cirrhosis is controversial since the majority of studies are retrospective.  In a randomized controlled trial, Fartoux, et al. (2007) compared the effectiveness of prolonged IFN alpha-2a treatment versus non-treatment on complication-free survival in patients with compensated HCV cirrhosis.  A total of 102 patients (mean age of 60.5 +/- 9.5 years; male/female ratio, 0.82) with biopsy examination-proven HCV cirrhosis, Child-Pugh score A, who were hepato-cellular carcinoma (HCC) free, and had at least 1 risk factor of complications, were randomized to receive IFN or no therapy for 24 months.  During the follow-up evaluation, the complication rate was 24.5%: HCC occurred in 12 and decompensation unrelated to HCC occurred in 13 patients.  The number of HCC patients was similar in both groups. The probability of complication-free survival was not significantly different between treated and untreated patients (98% and 72.3% versus 90% and 70.7% at 12 and 24 months, respectively, p = 0.59). The median time until complication occurrence was 17.1 months in the treated group versus 13.6 months in the untreated group (p = 0.2).  The authors concluded that this randomized controlled trial showed that a 2-year course of IFN has little or no impact on complication-free survival in patients with high-risk compensated HCV cirrhosis.

A technology assessment of ribavirin and pegylated interferon in hepatitis C for the Wessex Institute for Health Research and Development (Shepherd, et al., 2004) noted that cryoglobulinemia and vasculiitis occurs in a minority of patients with hepatitis C, and these conditions are not likely to be the subject of clinical trials because of the relatively small number of patients affected.  The report noted, however, that clinicians point out that in some patients with vasculitis due to viral/antibody complexes the vasculitis can resolve after long-term treatment.  The report stated that appropriate treatment of such patients needs to be addressed.

HCV-related liver cirrhosis is the most common indication for liver transplantation in most transplant centers.  However, recurrence of hepatitis C-infection after liver transplant in HCV positive patients is almost universal (Neumann & Neuhaus, 2004). Severity of graft hepatitis increases during the long term follow-up and up to 30% of patients develop severe graft hepatitis and cirrhosis. This led to decreased patient and graft survival in HCV positive patients.  Prophylactic or therapeutic regimens which alter the course of disease in HCV positive patients are not established yet.  Anti-viral treatment with ribavarin in combination with pegylated interferon is being investigated to reduce the complications of HCV recurrence in the future (Triantos, et al., 2005). Treatment of recurrent hepatitis C virus after liver transplantation with either interferon or interferon and ribavirin has yielded only limited success (Shiffman, et al., 2003; Triantos, et al., 2005). Regardless of this, treatment is instituted.  Pegylated interferon is more effective than standard interferon for treatment of chronic hepatitis C virus infection in the nontransplantation setting when used either alone or with ribavirin. The effectiveness of peginterferon, both with and without ribavirin in the posttransplantation setting, is currently being explored.

Triantos, et al. (2005) reported on the results of a systematic evidence review of antiviral therapy for HCV in liver transplant recipients. The authors concluded that antiviral therapy for recurrent HCV infection and disease after liver transplantation has only been evaluated in 16 randomized studies (534 patients) and thus robust data to evaluate efficacy is scanty.  However it is clear from both randomized and the 74 nonrandomized (2061 patients) that treatment is far less effective and with more side effects than for chronic HCV hepatitis pretransplant.  Moreover the data concerning combinations of either interferon or pegylated interferon with ribavirin mainly reflect on treatment virologic response (OTVR) (maximum 36%) or end of treatment virologic response (ETVR) (maximum 32%) with very little data on sustained virologic response (SVR).  Thus, the authors concluded, currently there is no easily applicable, nor reasonably effective, antiviral therapy for HCV recurrence after liver transplantation, considering the frequency of side effects and need to reduce doses or to discontinue therapy.  The most applicable strategy is to treat established disease with pegylated interferon and ribavirin but only future results of ongoing randomized studies will define the cost effectiveness and applicability of this regimen.  The authors noted that the number of patients who have already failed antiviral therapy pretransplant may well further limit the likelihood of sustained viral clearance.  Most importantly data on stopping the progression of fibrosis or slowing it down significantly, are not available and unfortunately initial results are not promising.

Consensus guidelines from the from the International Liver Transplantation Society Expert Panel on Liver Transplantation and HCV (Wiesner, et al., 2003) state that “[a]lthough no firm recommendations can be made based on data, there are enough anecdotal and single center reports that suggest that a patient with recurrent HCV disease who has grade II fibrosis or higher should be given a trial of combination therapy with interferon.”  Regarding maintenance therapy in liver transplant recipients with recurrent HCV diseases, the Expert panel agreed that there were no data to recommend maintenance therapy as an approach.  Regarding the role of preemptive therapy in liver transplant recipients prior to HCV recurrence, the Expert panel stated that preemptive therapy should be considered in patients who undergo retransplantation for rapidly progressive recurrent hepatitis C and HCV-negative transplant recipients who receive organs from HCV-positive donors because of great clinical need.  The Expert panel noted, however, that “demonstration of efficacy is lacking at this time.”

The safety and effectiveness of peginterferon alpha-2a (Pegasys) for the treatment of chronic hepatitis B was assessed in two Phase III controlled clinical trials in HBeAg positive and HBeAg negative patients with hepatitis B.  In each study, patients were randomized to peginterferon alpha-2a 180 µg subcutanelusly once weekly, lamivudine 100 mg once daily, or both peginterferon alpha-2a plus lamivudine.  All patients received 48 weeks of their assigned therapy followed by 24 weeks of treatment-free follow-up.  These two clinical trials demonstrated that 24 weeks after a defined 48 week period of therapy, more patients achieved a sustained response with peginterferon alpha-2a than with lamivudine (Epivir).  These studies demonstrated that the addition of lamivudine to peginterferon alpha-2a did not improve response rates over peginterferon alpha-2a alone.

All patients included in these studies of peginterferon alpha-2a for chronic hepatitis B virus (HBV) infection were adults with compensated liver disease and evidence of HBV replication (serum HBV > 500,000 copies/mL for the study of HBeAg positive patients and serum HBV > 100,000 copies/mL for the study of HBeAg negative patients). All patients had serum alanine aminiotransferase (ALT) between 1 and 10 times the upper limit of normal and liver biopsy findings compatible with the diagnosis of chronic hepatitis.

In a study of HBeAg positive patients with chronic HBV infection, 32% of 271 patients treated with peginterferon alpha-2a seroconverted by the end of follow-up versus 19%seroconversion among 272 patients treated with lamivudine.  Subjects treated with peginterferon alpha-2a had a higher rate of DNA response (defined as < 100,000 copies per mL) (32%) by the end of follow-up than subjects treated with lamivudine (22%).  In a study of HBeAg negative patients with chronic HBV infection, 43% of 177 patients treated with peginterferon alpha-2a exhibited a HBV DNA response (defined as < 20.000 copies per mL) by the end of follow-up versus 29% of 181 patients treated with lamivudine.  Subjects treated with peginterferon alpha-2a had a higher rate of ALT normalization (59%) by the end of follow-up than subjects treated with lamivudine (44%). Conclusions regarding comparative efficacy of peginterferon alpha-2a and lamivudine treatment based upon the end of follow-up results are limited by the different mechanisms of action of the two compounds.  Most treatment effects of lamivudine are unlikely to persist 24 weeks after therapy is withdrawn.

The effectiveness of repeat or maintenance pegylated interferon treatment of chronic HBV infection is unknown.  According to guidelines from the American Gastroenterological Association (Dienstag and McHutchison, 2006), re-treatment is indicated for persons who have relapsed (with relapse defined as where HCV RNA is undetectable during and at the end of therapy but re-appears after completion of therapy) after having completed a course of less-effective therapy.  For example, it may be appropriate to re-treat a person with pegylated interferon plus ribavirin who have relapsed after a course of standard interferon plus ribavirin.  However, relapsers are likely to experience a response only to subsequently relapse again with a subsequent course of the same therapy (e.g., re-treatment of a person with pegylated interferon plus ribavirin who had relapsed following previous treatment with this same regimen).

The efficacy of interferon beta-1a (Avonex) and interferon beta-1b (Betaseron) appear similar for reducing the frequency and severity of exacerbations in relapsing, remitting multiple sclerosis (MS).  A randomized clinical study comparing Avonex to Rebif in 677 patients with primary relapsing/remitting MS found a statistically significant difference in favor of Rebif in the proportion of patients who were relapse free at 24 weeks. The investigators found that 75% of patients treated with Rebif were relapse-free, compared to 63% of patients treated with Avonex. However, the design of the study did not support any conclusion regarding effects on accumulation of disability.

However, the effectiveness of interferon beta in slowing disease progression and lessening accumulation of disability in secondary progressive MS is still being studied. Furthermore, the FDA has not approved interferon beta for the additional indication of chronic progressive MS.

The Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology (Goodinc, et al., 2007) evaluated the clinical and radiological impact of developing neutralizing antibodies (NAbs) to interferon beta (IFN-beta) while on this therapy for MS.  On the basis of Class II and III evidence, it is concluded that treatment of patients with MS with IFN-beta is associated with the production of NAbs (Level A).  NAbs in the serum are probably associated with a reduction in the radiographical and clinical effectiveness of IFN-beta treatment (Level B).  In addition, the rate of NAb production is probably less with IFN-beta-1a treatment than with IFN-beta-1b treatment, although the magnitude and persistence of this difference is difficult to determine (Level B).  Finally, it is probable that there is a difference in sero-prevalence due to variability in the dose of IFN-beta injected or in the frequency or route of its administration (Level B). Regardless of the explanation, it seems clear that IFN-beta-1a (as it is currently formulated for IM injection) is less immunogenic than the current IFN-beta preparations (either IFN-beta-1a or IFN-beta-1b) given multiple times per week subcutaneously (Level A). However, because NAbs disappear in some patients even with continued IFN-beta treatment (especially in patients with low titers), the persistence of this difference is difficult to determine (Level B). Although the finding of sustained high-titer NAbs (greater than 100 to 200 NU/ml) is associated with a reduction in the therapeutic effects of IFN-beta on radiographical and clinical measures of MS disease activity, there is insufficient information on the utilization of NAb testing to provide specific recommendations regarding when to test, which test to use, how many tests are necessary, or which cutoff titer to apply.

Currently, the only FDA-approved indications for interferon gamma (Actimmune) is for treatment of chronic granulomatous disease, and for delaying time to disease progression in patients with severe, malignant osteopetrosis. Interferon gamma has also been shown to be effective for the treatment of atopic dermatitis and Waldenstrom's macroglobulinemia.

Idiopathic pulmonary fibrosis (IPF) is a condition that has a poor prognosis, with a median survival of 4-5 years.  Preliminary data from a phase III trial of interferon (IFN) gamma-1b injection for the treatment of IPF failed to show a significant difference between IFN gamma-1b-treated patients and control group patients in progression free survival time, the primary endpoint of the study.  The double-blind, placebo-controlled trial at 58 U.S. and European centers randomized 300 patients to receive either placebo or 200 mcg of IFN gamma-1b injected subcutaneously 3 times a week.  However, there was non-significant 10% difference in progression-free survival time in favor of IFN gamma-1b treated patients, where progression free survival time is defined as either a decrease in forced vital capacity of > 10%, or an increase in A-a gradient of 5 mmHg, or death. There was also a positive trend in increased survival in IFN gamma-1b treated patients versus the control group; this survival benefit was statistically significant in IFN gamma-1b-treated patients with mild to moderate disease. The overall mortality in the IFN gamma-1b-treated patients was 9.9% versus 16.7% in the control population.  Of the 254 patients with mild to moderate disease, mortality was 4.8% in the IFN gamma-1b-treated patients and 16.4% in the control group. Trends were also observed later in the course of the study in favor of IFN gamma-1b in terms of improved breathing and reduced need for supplemental oxygen.  All remaining phase III trial patients in the active and control groups are being transitioned into an open-label clinical trial in which all patients receive IFN gamma-1b to track longer-term outcomes with IFN gamma-1b for a minimum of one year.

In a randomized prospective multi-center clinical trial, Antoniou, et al. (2006) examined the clinical effects of IFNgamma-1b administered subcutaneously thrice weekly versus colchicine for 2 years.  This study had no pre-specified end-points.  Fifty consecutive IPF patients were randomized.  Patients with mild-to-moderate IPF were eligible for the study if they had histologically proven IPF, or, in the absence of surgical biopsy, fulfilled the European Respiratory Society/American Thoracic Society criteria. In the intent-to-treat population, 5 out of 32 (15.6%) IFN gamma-1b patients and 7 out of 18 (38.8%) colchicine patients died after a median follow-up period of 25 months.  Patients treated with IFN gamma-1b showed a better outcome after 2 years of therapy, and fewer symptoms, as assessed using the St George's Respiratory Questionnaire, after 12 months of therapy. Also, the IFN gamma-1b group exhibited a higher forced vital capacity (percentage of the predicted value) after 24 months of treatment. No significant differences were detected in resting arterial oxygen tension, total lung capacity (% pred), transfer factor of the lung for carbon monoxide (% pred) and high-resolution computed tomographic scoring between the two treatment groups. These data suggest that long-term treatment with IFN gamma-1b may improve survival and outcome in patients with mild-to-moderate IPF.  The authors stated that further studies are needed to verify these results.  Additionally, the effect of IFN gamma-1b on progressive cases needs  to be evaluated.

Walter, et al. (2006) noted that the clinical course of IPF is variable; however, the long-term survival in IPF is poor.  Prednisone has been the mainstay of therapy since its release for clinical use in 1948.  Recently, prednisone combined with azathioprine or cyclophosphamide has been used.  A number of other drug combinations have been tried with prednisone (e.g., methotrexate, colchicine, penicillamine, or cyclosporine) but have failed or are not well-tolerated by the patient.  Few high quality, prospective, controlled clinical trials have been performed.  Thus, there is no good evidence to support the routine use of any specific therapy in the management of IPF. Additional large clinical trials are needed to confirm the potential usefulness of the newer agents (e.g., IFN gamma-1b, pirfenidone, N-acetylcysteine, coumadin, bosentan, or etanercept).

It should be noted that in March 2007, InterMune abandoned efforts to develop Actimmune (IFN gamma-1b) as a treatment for IPF because results from a late-stage clinical trial showed the drug did not prolong lives. The Phase 3 INSPIRE clinical trial evaluating Actimmune (IFN gamma-1b) in IPF patients with with mild to moderate impairment in lung function was discontinued based upon the recommendation of the study’s independent data monitoring committee (DMC).  In a planned interim analysis that included a total of 115 deaths, the DMC found the overall survival result crossed a pre-defined stopping boundary for lack of benefit of Actimmune relative to placebo. Among the 826 randomized patients, there was not a statistically significant difference between treatment groups in overall mortality (14.5% in the Actimmune group as compared to 12.7% in the placebo group).  Based on a preliminary review of the interim safety data, the adverse events associated with Actimmune appear generally consistent with prior clinical experience, including constitutional symptoms, neutropenia and possibly pneumonia.

Guidelines from the National Comprehensive Cancer Network (2008) recommend the use of interferon gamma-1b in selected persons with mycosis fungoides (MF) and Sezary syndrome (SS). NCCN guidelines recommend use of IFN gamma-1b as primary treatment as systemic biologic therapy in patients with stage IA to IIA MF and SS with blood involvement, and stage IIB to IV MF and SS. NCCN guidelines recommend use of IFN gamma-1b a single agent or in combination therapy as indicated below:

• single agent for stage IA to IIA and stage III MF with blood involvement
• single agent or in combination with radiation therapy for stage IIB MF limited-extent tumor disease
• single agent or in combination with systemic retinoids, phototherapy, or photopheresis (with or without systemic retinoids) stage IA to IIB with large cell transformed MF, stage IIB MF (generalized tumor disease or limited-extent tumor disease with blood involvement) or SS
• single agent or in combination with skin-directed therapies (corticosteroids, carmustine, mechlorethamine hydrochloride, phototherapy, or total skin electron beam therapy) for stage III MF with no blood involvement

According to NCCN (2008) guidelines, interferon gamma-1B may be used as adjuvant systemic biologic therapy after total skin electron beam therapy for stage IIB MF generalized tumor disease or limited tumor disease with blood involvement or large cell transformation or after chemotherapy for stage IV MF with bulky lymph nodes or visceral disease.  NCCN guidelines also indicate interferon gamma-1B as systemic biologic therapy for patients with refractory or progressive MF, as a single agent or in combination with systemic retinoids, phototherapy, or photopheresis (with or without systemic retinoids).

Consensus interferon (interferon alfacon-1; Infergen) is a non-naturally occurring recombinant type 1 alpha interferon.  It has been approved by the U.S. Food and Drug Administration (FDA) for use in the treatment of chronic hepatitis C in person 18 years of age or older with compensated liver disease who have anti-hepatitic C virus serum antibodies and/or the presence of hepatitis C virus RNA.  Although there are studies comparing standard alpha interferon to consensus interferon, and limited evidence regarding the use of consensus interferon in persons with hepatitis C who fail to respond to standard alpha interferon therapy, current guidelines indicate pegylated interferons as the treatment of choice for persons with hepatitis C, including those who fail to respond to standard alpha interferon therapy.  There are insufficient published studies comparing consensus interferon to pegylated interferons, and insufficient evidence of the effectiveness of consensus interferon in persons with hepatitis C who have failed pegylated interferon therapy.  An ongoing open-label multicenter controlled clinical trial is currently evaluating the effectiveness of consensus interferon plus ribavirin in persons with hepatitis C who were non-responsive to previous pegylated interferon and ribavirin.  This study, the DIRECT (Daily-Dose Consensus Interferon and Ribavrin: Efficacy of Combined Therapy) trial is evaluating the comparative effectiveness of ribavirin plus two different doses of consensus interferon versus no treatment in subjects with hepatitis C who were nonresponsive to at least 12 weeks of pegylated interferon and ribavirin therapy (Bacon, et al., 2006).

Recurrence is common following hepatic resection for HCC. Interferon possesses anti-angiogenic, anti-proliferative, anti-viral, and immunomodulatoryeffects; and may be an effective form of adjuvant therapy.  Small randomized controlled clinical trials suggest a benefit from prolonged interferon therapy following resection of hepatocellular carcinoma in persons with hepatitis C (Shiratori, et al., 2003; Nishiguchi, et al., 2005; Mazzaferro, et al., 2006). Guidelines from the National Comprehensive Cancer Network (2008) recommend use of interferon in hepatocellular carcinoma for treatment of selected low-risk hepatitis C patients with completely resected tumors and good performance status. 

Interferon is also being evaluated for use following resection of hepatocellular carcinoma in persons with hepatitis B. Lo, et al. (2007) performed a randomized controlled trial of adjuvant interferon therapy in patients with predominantly hepatitis B-related HCC to examine if the prognosis after hepatic resection could be improved. Patients with no residual disease after hepatic resection for HCC were randomly assigned with stratification by pathologic tumour-node-metastasis (pTNM) stage to receive no treatment (control group), interferon alpha-2b 10 MIU/m (IFN-I group) or 30 MIU/m (IFN-II group) thrice-weekly for 16 weeks. Enrollment to the IFN-II group was terminated because adverse effects resulted in treatment discontinuation in the first 6 patients.  A total of 40 patients each had been enrolled into the control group and IFN-I group. The baseline clinical, laboratory, and tumor characteristics of both groups were comparable. The 1- and 5-year survival rates were 85% and 61%, respectively, for the control group and 97% and 79%, respectively, for the IFN-I group (p = 0.137).  After adjusting for the confounding prognostic factors in a Cox model, the relative risk of death for interferon treatment was 0.42 (95% CI, 0.17 - 1.05; p = 0.063).  Exploratory subset analysis showed that adjuvant interferon had no survival benefit for pTNM stage I/II tumor (5-year survival 90% in both groups; p = 0.917) but prevented early recurrence and improved the 5-year survival of patients with stage III/IVA tumor from 24% to 68% (p = 0.038).  The authors concluded that in a group of patients with predominantly hepatitis B-related HCC, adjuvant interferon therapy showed a trend for survival benefit, primarily in those with pTNM stage III/IVA tumors.  They stated that further larger randomized trials stratified for stage are needed.  An editorial that accompanied the afore-mentioned article stated that any new strategy to prevent HCC recurrence following resection must still be tested in randomized controlled studies, including a control group without treatment (Clavien, 2007).

Guidelines from the National Comprehensive Cancer Network (2008) recommend use of interferon alpha in desmoid tumors, as a low-dose single agent for gross residual disease following surgery or for unresectable disease either as an initial treatment or for recurrence.  NCCN guidelines cite for support the results of a nonrandomized, retrospective study of 13 patients with extra-abdominal desmoid tumors, which found encouraging response rates with interferon alpha treatment. Seven of the patients included in the study also received tretinoin.  After a mean of 27 months of treatment, local control was seen in 11 of 13 patients (85%). Seven patients had no evidence of disease at a mean disease-free interval of 22 months; in two patients progressive disease occurred after only 7 and 9 months, respectively, of observation. In another four patients, progression of the desmoid tumor was stabilized.  The investigators concluded that these data suggest that treatment with interferon may be effective in prolonging the disease-free interval of patients with desmoid tumors after intralesional or marginal surgery.