This document addresses the treatment of Hepatitis C infection with pegylated interferon therapy, peginterferon alfa-2a or peginterferon alfa-2b as monotherapy, as dual therapy in combination with ribavirin, or as triple therapy utilizing ribavirin and a serine protease inhibitor (boceprevir or telaprevir).

• CG-DRUG-13 Hepatitis B Interferon Antiviral Therapy

Medically Necessary:

Note: for the purposes of this document, the following definitions apply:

Dual Therapy – pegylated interferon in combination with ribavirin
Triple Therapy – pegylated interferon in combination with ribavirin and a serine protease inhibitor (boceprevir or telaprevir)

Medically Necessary:

1. Treatment of Hepatitis C Virus (HCV) Genotype 1:
   1. Initial triple therapy – through week 12:
      Pegylated interferon as part of a planned triple therapy is considered medically necessary in individuals with confirmed HCV genotype 1 for up to an initial 12 weeks of therapy when all of the following criteria have been met:
      1. Detectable HCV ribonucleic acid (RNA); AND
      2. Compensated liver disease; AND
      3. Individual has not received previous treatment for HCV with triple therapy.
   2. Continuation of triple therapy – through week 48:
      Pegylated interferon as part of triple therapy is considered medically necessary in individuals with HCV genotype 1 currently receiving a 12 week course of  triple therapy who require up to an additional 36 weeks of treatment (to complete up to a total of 48 weeks) of therapy when one of the following criteria has been met:
      1. Decrease in HCV RNA to less than 1000 IU/mL for telaprevir-based triple therapy at week 4 and 12 of initial therapy, or
      2. Decrease in HCV RNA to less than100 IU/mL for boceprevir-based triple therapy at week 12 of initial therapy.
   3. Initial dual therapy – through week 12:
      Pegylated interferon as part of dual therapy is considered medically necessary in individuals with confirmed HCV genotype 1 for up to an initial 12 weeks of therapy when all of the following criteria have been met:
      1. Detectable HCV RNA; AND
      2. Compensated liver disease; AND
      3. When one of the following criteria has been met:
         1. Individual has not received previous treatment with pegylated interferon in combination with ribavirin.; or
         2. Individual with significant fibrosis or cirrhosis who has received one of the following treatments without any demonstrated response, or have relapsed:
            1. non-pegylated interferon monotherapy, or
            2. Non-pegylated interferon with ribavirin, or
            3. Pegylated monotherapy.
   4. Continuation of dual therapy – through week 48:
      Pegylated interferon as part of dual therapy is considered medically necessary in individuals with HCV genotype 1 currently receiving a 12 week course of dual therapy who require an additional 36 weeks of treatment (to complete a total of 48 weeks) of therapy when one of the following criteria has been met:
      1. Documented early viral response (EVR). An EVR is defined as a decrease in HCV RNA greater than 2 log from baseline; or
      2. Decrease in HCV RNA to undetectable levels at week 12 of initial therapy.
   5. Slow responders to initial dual therapy:
      Pegylated interferon as part of dual therapy is considered medically necessary in individuals with HCV genotype 1 who are slow responders, defined as HCV RNA test becomes negative between weeks 12 and 24 of initial dual therapy, for a maximum treatment duration of 72 weeks.
2. Treatment of HCV Genotype 2 or 3
   1. Dual therapy – through week 24:
      Pegylated interferon as part of dual therapy is considered medically necessary in individuals with confirmed HCV genotype 2 or 3, for an initial course of treatment not to exceed 24 weeks in duration for individuals with all the following conditions:
      1. Detectable HCV RNA; AND
      2. Compensated liver disease; AND
      3. Individual has not received previous therapy with pegylated interferon in combination with ribavirin.
   2. Dual therapy  – through week 48:
      Pegylated interferon as part of dual therapy is considered medically necessary in individuals with confirmed HCV genotype 2 or 3, for a course of treatment not to exceed 48 weeks in duration for individuals who meet both of the following conditions:
      1. Detectable HCV RNA; AND
      2. Individual has HIV coinfection, or demonstrated no response to initial dual therapy, or has relapsed after treatment with one of the following:
         1. Non-pegylated interferon monotherapy; 
         2. Non-pegylated interferon with ribavirin; or
         3. Pegylated monotherapy.
3. Treatment of HCV Genotype 4, 5 or 6
   1. Initial dual therapy – through week 12:
      Pegylated interferon as part of dual therapy is considered medically necessary in individuals with confirmed HCV genotype 4, 5 or 6 for up to an initial 12 weeks of therapy when all of the following criteria have been met:
      1. Detectable HCV RNA; AND
      2. Compensated liver disease; AND
      3. When one of the following criteria has been met:
         1. Individual has not received previous treatment with pegylated interferon in combination with ribavirin; or
         2. Individual with significant fibrosis or cirrhosis who has received one of the following treatments without any demonstrated response, or has relapsed:
            1. Non-pegylated interferon monotherapy, or
            2. Non-pegylated interferon with ribavirin, or
            3. Pegylated monotherapy.
   2. Continuation of dual therapy – through week 48:
      Pegylated interferon as part of dual therapy is considered medically necessary in individuals with HCV genotype 4, 5 or 6 currently receiving a 12 week course of combination pegylated interferon and ribavirin therapy who require an additional 36 weeks of treatment (to complete a total of 48 weeks) of therapy when one of the following criteria has been met:
      1. Documented EVR. An EVR is defined as a decrease in HCV RNA greater than 2 log from baseline; or
      2. Decrease in HCV RNA to undetectable levels at week 12 of initial therapy.
4. HCV antiviral therapy in individuals with a contraindication to Ribavirin:
   Pegylated interferon monotherapy is considered medically necessary in individuals with a contraindication to ribavirin and confirmed HCV with compensated liver disease for up to 48 weeks when all of the following criteria have been met:
   1.  Any genotype; AND
   2. Detectable HCV RNA; AND
   3. When one of the following criteria has been met:
      1. Individual has not received previous treatment with pegylated interferon monotherapy; or
      2. Individual has received previous non-pegylated interferon monotherapy with no response or relapse has occurred.

Not Medically Necessary: 

Treatment of HCV with ribavirin as monotherapy is considered not medically necessary for the treatment of hepatitis C.

Treatment of HCV with pegylated interferon as monotherapy, or as part of dual or triple therapy is considered not medically necessary when any of the criteria specified above are not met, or in individuals when any of the following contraindications are present:

1. Uncontrolled depression (for example, suicide risk); or
2. Autoimmune hepatitis or other condition known to be exacerbated by interferon and ribavirin; or
3. Pregnant women or those who may become pregnant; or
4. Severe concurrent diseases including, but not limited to, severe hypertension, heart failure, significant coronary artery disease, poorly controlled diabetes or obstructive pulmonary disease; or
5. Untreated hyperthyroidism; or
6. Children under 3 years of age; or
7. Known hypersensitivity to drugs used to treat hepatitis C; or
8. A recipient of kidney, heart, or other solid organ transplant except liver transplant (note: antiviral therapy post liver transplantation should be undertaken with caution and performed under the supervision of a physician experienced in transplantation).

Treatment of HCV genotype 1 with pegylated interferon is considered not medically necessary when the criteria specified above are not met, or for any of the following:

1. Triple therapy beyond 48 weeks;
2. Dual therapy beyond 48 weeks when there was a response to initial therapy;
3. Dual therapy beyond 72 weeks for slow responders.

Treatment of HCV genotype 2, 3, 4, 5, and 6 with pegylated interferon beyond 48 weeks is considered not medically necessary.

The following codes for treatments and procedures applicable to this document are included below for informational purposes.  Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy.  Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

Future ICD-10 coding (effective 10/01/2013)
A draft of ICD-10 Coding related to this document, as it might look today, is available for reference and comments at: Appendix 1: Future ICD-10 coding

The hepatitis C virus (HCV) was identified in 1989 and found to account for most infections previously termed "non-A, non-B hepatitis." It is a common and serious disease accounting for approximately 15 percent of reported cases of acute viral hepatitis, 60 to 70 percent of chronic hepatitis, and up to 50 percent of cirrhosis, end-stage liver disease, and liver cancer (hepatocellular carcinoma [HCC]). Approximately 1.8 percent of the U.S. population (3.8 million persons exposed and 2.7 million persons chronically infected) revealed antibodies to HCV, indicating ongoing or previous infection with the virus and resulting in an estimated 10,000 to 12,000 deaths annually. A distinct and major characteristic of hepatitis C is its tendency to cause chronic liver disease and liver failure.

Liver failure from chronic hepatitis C is one of the most common indications for liver transplantation in the United States. It is estimated that 70% of all HCV-infected individuals will eventually go on to develop chronic liver disease; at least 20 percent will develop cirrhosis, a process that takes 10 to 20 years. After 20 to 40 years, a smaller percentage of those individuals with chronic disease develop liver cancer (hepatocellular carcinoma [HCC]). The population identified as high-risk for developing HCC includes males, people with a history of substance abuse; those diagnosed with cirrhosis, people over age 40, and those infected for 20 to 40 years.

There are six known genotypes of HCV with genotype 1 (75%), genotype 2 (approximately 10%) and genotype 3 (approximately 10%) being most common in the United States. People with genotypes 2 and 3 are almost three times more likely to respond to therapy than those with genotype 1. Genotyping can also be used to determine the duration of treatment for many people. For those with genotype 2 or 3, a 24-week course of combination therapy is usually sufficient. Individuals with genotype 1 who have responded at the end of 12 weeks of treatment may benefit from an additional 36 weeks of treatment. For those individuals with Genotype 1 who are identified as slow responders (HCV RNA test becomes negative between weeks 12 and 24), the American Association for the Study of Liver Disease (AASLD) has recommended extending treatment to 72 weeks (AASLD 2009). For those with genotype 4, the American Gastroenterological Association (AGA) recommends treatment for 48-weeks with combination therapy. The hepatitis C virus replicates inside its host every 7 to 9 hours and typically produces about 1 trillion viral copies per day. According to the National Institute for Health and Clinical Excellence (NICE, 2004) individuals infected with HCV genotype 5 or 6 the treatment should mirror that of HCV genotype 1 and 4 using pegylated therapy and ribavirin. According to recommendations individuals should receive an initial 12 weeks of treatment, if there is a decrease in HCV RNA greater than 2 log from baseline treatment is recommended until 48 weeks. The authors also concluded that "people infected with more than one genotype that includes one or more of genotypes 1, 4, 5, or 6 should be treated as genotype 1"

Chronic hepatitis C varies greatly in its course and outcome. At one end of the spectrum are individuals who exhibit no signs or symptoms of liver disease and have completely normal levels of serum liver enzymes. Liver biopsy has been used to determine the stage of fibrosis and the degree of inflammation, which assist in determining prognosis. Biopsy results usually show some degree of chronic hepatitis, but the degree of injury is usually mild, and the overall prognosis may be good. At the other end of the spectrum are individuals with severe hepatitis C who have symptoms, HCV RNA (ribonucleic acid) in serum, and elevated serum liver enzymes, and who ultimately develop cirrhosis and end-stage liver disease. In the middle of the spectrum are individuals who have few or no symptoms, mild to moderate elevations in liver enzymes, and an uncertain prognosis. For individuals with HCV genotype-1 infection, clinicians are more likely to proceed with liver biopsy as a guide for treatment. Whereas those with HCV genotype-2 or 3 are very likely to respond to therapy, the clinician may not resort to liver biopsy. (AASLD 2009)

Currently, combination therapy with oral ribavirin and pegylated interferon alfa 2a or 2b injection (Pegasys^®_, Hoffman-La Roche Inc., Nutley, NJ or PegIntron^®_, Schering Corporation, Kenilworth, NJ) is the standard of care for the treatment of chronic hepatitis C. Combination therapy with pegylated interferon products has been more effective than interferon alfa alone in interferon-naïve subjects. Treatment-naïve subjects have a 41%- 56% sustained viral response (SVR) with combination pegylated interferon and ribavirin (Rebetol^® Schering Corporation, Kenilworth, NJ, Copegus^®_, Roche Laboratories Inc., Nutley, NJ or Ribasphere^®_, Three Rivers Pharmaceuticals, LLC, Warrendale, PA) therapy. Subjects who have relapsed on previous non-pegylated interferon therapy have a 49% SVR, and non-responders to non-pegylated interferon monotherapy have a 25 to 40% response (Shepherd, 2004). According to the U.S. Food and Drug Administration label for ribavirin, the intended use for treatment of hepatitis C is in combination with peglyated-interferon and not as a monotherapy, when criteria are met. In May 2011, Incivek (Vertex Pharmaceuticals inc., Cambridge, MA) or Victrelis (Schering Corp., Whitehouse Station, NJ) were approved by the U.S. Food and Drug Administration for treatment of chronic hepatitis C genotype 1 infection, in combination with pegylated interferon and ribavirin, in adults with compensated liver disease, including cirrhosis, who are previously untreated or who have failed previous interferon and ribavirin therapy.

According to the 2011 AASLD update on treatment of genotype 1 chronic hepatitis C virus infection the use of pegylated interferon and ribavirin remain key components of therapy in treatment of this disease. The emergence of triple therapy with the addition of the serine protease NS3/4A (boceprevir and telaprevir) inhibitors provides options for the treatment-naïve and treatment-experienced individuals with HCV genotype 1 disease.

The National Institute of Health consensus statement on HCV states pegylated-interferon in combination with ribavirin is an appropriate therapy for non-responders and for those who relapse after previous interferon monotherapy or in combination with ribavirin. The yield of retreatment may be as small as 15 to 20% of non-responders to standard interferon.

At this time, there is a paucity of evidence to support the retreatment of individuals who have relapsed after previous treatment with pegylated interferon/ribavirin combination therapy.

There is limited peer reviewed literature addressing the net health outcomes in individuals with decompensated cirrhosis with evidence of clinical complications and/or profound thrombocytopenia or leukopenia. However, for a subset of individuals with cirrhosis and decompensation (generally MELD [Model for End-stage Liver Disease] score less than 18), low accelerating doses of interferon and ribavirin combination therapy, with or without growth factors, may slow progression or prevent complications, therefore such cases should be reviewed on an individual basis.

In several uncontrolled studies, results report individuals with acute HCV, as confirmed by HCV RNA, who fail to spontaneously clear the virus within 12 weeks of the onset of symptomatic disease, may also benefit from pegylated interferon therapy and such cases will be considered on an individual basis. Due to the lack of controlled studies in this population, definitive recommendations regarding the initiation, dosing of pegylated interferon or duration of therapy have yet to be determined.

Child-Pugh Score: (also known as Child-Turcotte-Pugh score): A scoring system for severity of liver disease and likelihood of survival based on the presence of: degenerative disease of the brain (encephalopathy), the escape or accumulation of fluid in the abdominal cavity (ascites), laboratory measures of various substances in the blood (see table below), and the presence of other co-existing diseases; after calculating the CTP score using a table similar to the one below, individuals can be classified into one of three categories:

• Childs A (5-6 points): 10 year survival 80-90%;
• Childs B (7-9 points): 5 year survival 60-80% and
• Childs C (10-15 points): 2 year survival less than 50%.

Compensated liver disease: Child-Pugh score less than or equal to 6 (class A) in cirrhotic individuals before or during treatment.

Decompensated liver disease: Child-Pugh score greater than 6 (class B or class C) in cirrhotic individuals before or during treatment.

Peer Reviewed Publications:

1. Ahmed F, Jacobson IM. Treatment of relapsers after combination therapy for chronic hepatitis C. Gastroenterol Clin North Am. 2004; 33(3):513-526.
2. Arenas JI, Vargas HE. Hepatitis C antiviral therapy in patients with cirrhosis. Gastroenteroly Clin North Am. 2004; 33(3):549-562.
3. Berenguer M, Wright T. Treatment strategies for hepatitis C: intervention prior to liver transplant, pre-emptively or after established disease. Clinics in Liver Disease. 2003; 7(3):631-650.
4. DeFrancesco R, Rice CM. New therapies on the horizon for hepatitis C. Clinics in Liver Disease. 2003; 7(1):211-242.
5. Dove, L. A general approach to the management of chronic hepatitis C. Gastroenterol Clin North Am. 2004; 33(3):463-477.
6. Flamm SL. Chronic hepatitis C virus infection. JAMA. 2003; 289(18):2413-2417.
7. Fontana RJ. Nonresponders to hepatitis C virus therapy: pegylated interferons and beyond. Gastroenterol Clin North Am.2004; 33(3):527-547.
8. Hadziyannis SJ, Sette H, Morgan TR, et al. Peginterferon-a2a and ribavirin combination therapy in chronic hepatitis C. Ann Internal Med. 2004; 140:346-355.
9. Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomized trial. Lancet. 2001; 358:958-965.
10. Oh S, Afdhal NH. Antiviral therapy for treatment naïve patients with hepatitis C virus. Gastroenterol Clin North Am. 2004; 33(3):497-511.
11. Shepard J, Brodin H, Cave C, et al. Pegylated interferon µ-2a and -2b in combination with ribavirin in the treatment of chronic hepatitis C: a systematic review and economic evaluation. Health Technol Assess. 2004; 8(39).
12. Ward RP, Kugelmas M, Libsch KD. Management of hepatitis C: evaluating suitability for drug therapy. Am Fam Physician. 2004: 69(6):E1429-1438. Available at: http://www.aafp.org/afp/20040315/1429.html. Accessed on October 6, 2011.

Government Agency, Medical Society, and Other Authoritative Publications:

1. American Association for the Study of Liver Disease (AASLD). Ghany MG, Nelson DR, Strader DB, et al. An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 Practice Guideline by the American Association for the Study of Liver Diseases. Available at: http://www.aasld.org/practiceguidelines/Documents/2011UpdateGenotype1HCVbyAASLD24641.pdf. Accessed on October 6, 2011.
2. American Association for the Study of Liver Disease (AASLD). Ghany MG, Strader DB, Thomas DL, Seeff LB. Diagnosis, management and treatment of hepatitis C: an update. 2009. Available at: http://www.aasld.org/practiceguidelines/Documents/Bookmarked%20Practice%20Guidelines/Diagnosis_of_HEP_C_Update.pdf. Accessed on October 6, 2011.
3. American Hospital Formulary Services^® (AHFS). AHFS Drug Information 2011^®_.  Bethesda, MD: American Society of Health-System Pharmacists^®_; 2011.
4. Boceprevir (systemic). In: DrugPoints System [Internet database]. Greenwood Village, CO: Thomson Healthcare. Updated August 4, 2011. Available at: http://www.thomsonhc.com. Accessed on October 10, 2011.
5. Boyer JL, Chang EB Collyar DE, et al. Management of Hepatitis C: National Institutes of Health Consensus Development Conference Statement. 2002.
6. Copegus [Product Information], Nutley, NJ. Roche Laboratories, Inc.; August 2011. Available at: http://www.gene.com/gene/products/information/pegasys/pdf/copegus_pi.pdf.  Accessed on October 6, 2011.
7. Dienstag JL, McHutchison JG. American Gastroenterological Association medical position statement on the management of hepatitis C. Gastroenterology 2006; 130(1):225-230. Available at: http://www.gastrojournal.org/article/PIIS0016508505022717 Accessed on October 6, 2011.
8. Dienstag JL, McHutchison JG. American Gastroenterological Association technical review on the management of hepatitis C. Gastroenterology. 2006; 130 (1):231-264. Available at: http://www.gastrojournal.org/article/PIIS0016508505022705 Accessed on October 6, 2011.
9. Incivek [product Information], Cambridge, MA. Vertex Pharmaceuticals Inc.; May 2011. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/201917lbl.pdf. Accessed on October 6. 2011.
10. National Institute for Health and Clinical Excellence. Technology appraisal guidance 75. Interferon alfa (pegylated and non-pegylated) and ribavirin for the treatment of chronic hepatitis C. (Review and extension of technology appraisal guidance 14). January 2004. Available at: http://www.nice.org.uk/nicemedia/live/11524/32809/32809.pdf. Accessed on October 6, 2011.
11. Pegasys [Product Information], Nutley, NJ. Hoffman-La Roche Inc; August 2011. Available at: http://www.gene.com/gene/products/information/pegasys/pdf/pi.pdf. Accessed October 6, 2011.
12. Peginterferon Alfa-2a (systemic). In: DrugPoints System [Internet database]. Greenwood Village, CO: Thomson Healthcare. Updated August 25, 2011. Available at: http://www.thomsonhc.com. Accessed on October 10, 2011.
13. Peginterferon Alfa-2b (systemic). In: DrugPoints System [Internet database]. Greenwood Village, CO: Thomson Healthcare. Updated May 19, 2011. Available at: http://www.thomsonhc.com. Accessed on October 10, 2011.
14. PegIntron [Product Information], Kenilworth, NJ. Schering Corporation; May 2009. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/103949s5172lbl.pdf Accessed on October 6, 2011.
15. Rebetol [Product Information], Kenilworth, NJ. Schering Corporation. October 2010. Available at: http://www.spfiles.com/pirebetol.pdf. Accessed on October 6, 2011.
16. Ribasphere [Product Information], Warrendale, PA. Three Rivers Pharmaceuticals, Inc; April 2011. Available at: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=41798. Accessed on September 20, 2011.
17. Ribavirin (systemic). In: DrugPoints System [Internet database]. Greenwood Village, CO: Thomson Healthcare. Updated September 15, 2011. Available at: http://www.thomsonhc.com. Accessed on October 10, 2011.
18. Telaprevir (systemic). In: DrugPoints System [Internet database]. Greenwood Village, CO: Thomson Healthcare. Updated August 27, 2011. Available at: http://www.thomsonhc.com. Accessed on October 10, 2011.
19. Victrelis [Product Information], Whitehouse Station, NJ. Schering Corporation; May 2011. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/202258lbl.pdf. Accessed on October 6, 2011.

Boceprevir
Copegus^®
Hepatitis C
Peginterferon alfa 2-a [Pegasys^®]
Peginterferon alfa-2b [PegIntron^®]
Pegylated Interferon Therapy
Rebetol^®
Ribasphere^®
Ribavirin
Telaprevir

The use of specific product names is illustrative only.  It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

Appendix A¹

Testing for Hepatitis C