Medically Necessary:

Hepatitis C Genotype 1 or 4:
Pegylated interferon in combination with ribavirin is considered medically necessary in patients with confirmed hepatitis C (HCV) genotype 1 or 4 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. Patient has not received previous treatment with pegylated interferon in combination with ribavirin.; or
   2. Patients with significant fibrosis or cirrhosis who received one of the following and demonstrate no response or have relapsed:
      1. Previous treatment using non pegylated interferon monotherapy, or
      2. Non pegylated interferon with ribavirin, or
      3. Pegylated monotherapy.                                  

Hepatitis C Genotype 1 or 4 for patients who have had response to initial therapy:
Pegylated interferon in combination with ribavirin is considered medically necessary in patients with HCV genotype 1 or 4 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 early viral response (EVR). An EVR is defined as a decrease in HCV RNA > 2 log from baseline; or
2. Decrease in HCV RNA to undetectable levels at week 12 of initial therapy. 

Hepatitis C Genotype 1 for patients who are slow responders to initial therapy:
Pegylated interferon in combination with ribavirin is considered medically necessary in patients with HCV genotype 1 who are slow responders, defined as HCV RNA test becomes negative between weeks 12 and 24 of initial therapy, for a maximum treatment duration of 72 weeks.

Hepatitis C Genotype 2 or 3:
Pegylated interferon in combination with ribavirin is considered medically necessary in patients with confirmed hepatitis C (HCV) genotype 2 or 3, for an initial course of treatment not to exceed 24 weeks in duration for patients with all the following conditions:

1. Detectable HCV RNA; AND
2. Compensated liver disease; AND
3. Patient has not received previous therapy with pegylated interferon in combination with ribavirin. 

Hepatitis C (HCV) Genotype 2 or 3 in patients who have had no response to prior therapy or who have relapsed:
Pegylated interferon in combination with ribavirin is considered medically necessary in patients with confirmed hepatitis C (HCV) genotype 2 or 3, for a course of treatment not to exceed 48 weeks in duration for patients who meet both of the following conditions:

1. Detectable HCV RNA; AND
2. Patients who have demonstrated no response or have relapsed after treatment with one of the following:
   1. Non pegylated interferon monotherapy; or
   2. Non pegylated interferon with ribavirin; or
   3. Pegylated monotherapy.        

Hepatitis C Antiviral Therapy in Patients with a Contraindication to Ribavirin:
Pegylated interferon monotherapy is considered medically necessary in patients with a contraindication to ribavirin and confirmed hepatitis C (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. Patient has not received previous treatment with pegylated interferon monotherapy; or
   2. Patient has received previous non-pegylated interferon monotherapy with no response or relapse has occurred.

Hepatitis C (HCV) All Genotypes, co-infection with human immunodeficiency virus (HIV):
Pegylated interferon in combination with ribavirin is considered medically necessary in patients with confirmed hepatitis C (HCV) co-infected with human immunodeficiency virus (HIV) for a course of treatment not to exceed 48 weeks in duration.

Note: The published literature currently shows no trials directly comparing pegylated interferons to each other. Results using these agents separately are similar in national and international trials. There is no data to suggest one agent is preferable to another.

Not Medically Necessary: 

1. Treatment of HCV with ribavirin as monotherapy for the treatment of hepatitis C
   
2. Treatment of HCV with pegylated interferon as monotherapy or in combination with ribavirin in patients with any one or more of the following:
   1. Failure to respond to previous treatment with peginterferon alfa 2a, or peginterferon alfa 2b in combination with ribavirin; or
   2. Major, uncontrolled depressive illness; or
   3. Autoimmune hepatitis or other condition known to be exacerbated by interferon and ribavirin; or
   4. Pregnant women or those who may become pregnant; or
   5. Severe concurrent diseases including, but not limited to, severe hypertension, heart failure, significant coronary artery disease, poorly controlled diabetes or obstructive pulmonary disease; or
   6. Untreated hyperthyroidism; or
   7. Children under 3 years of age; or
   8. Known hypersensitivity to drugs used to treat hepatitis C; or
   9. Decompensated liver disease; or
   10. 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).
3. Treatment of HCV with pegylated interferon beyond 48 weeks for genotype 1 who had response to initial therapy.
4. Treatment of HCV with pegylated interferon beyond 48 weeks for genotype 2, 3, and 4.
5. Treatment of HCV with pegylated interferon beyond 72 weeks for genotype 1 slow responders.

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) possess antibody to HCV, indicating ongoing or previous infection with the virus and causing 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. Researchers estimate 70% of all HCV-infected patients will eventually go on to develop chronic liver disease; at least 20 percent of patients will develop cirrhosis, a process that takes 10 to 20 years. After 20 to 40 years, a smaller percentage of patients 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. Patients 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 patients 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.

Chronic hepatitis C varies greatly in its course and outcome. At one end of the spectrum are patients 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 patients 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 patients who have few or no symptoms, mild to moderate elevations in liver enzymes, and an uncertain prognosis. For patients 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 Peg-Intron^®, 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 patients. Treatment-naïve patients 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^® DSM Pharmaceuticals, Greenville, NC) therapy. Patients 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).

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 patients who have relapsed after previous treatment with pegylated interferon/ribavirin combination therapy.

There is limited peer reviewed literature addressing the net health outcomes in patients with decompensated cirrhosis with evidence of clinical complications and/or profound thrombocytopenia or leukopenia. However, for a subset of patients with cirrhosis and decompensation (generally MELD [Model for End-stage Liver Disease] score < 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 patients 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 know 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, patients 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 < 50%.

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 June 24, 2009.

Government Agency, Medical Society, and Other Authoritative Publications:

1. 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 June 24, 2009.
2. American Hospital Formulary Services^® (AHFS). AHFS Drug Information 2009^®. Bethesda, MD: American Society of Health-System Pharmacists^®; 2009.
3. Boyer JL, Chang EB Collyar DE, et al. Management of Hepatitis C: National Institutes of Health Consensus Development Conference Statement. 2002.
4. Copegus [Product Information], Nutley, NJ. Roche Laboratories, Inc.; April 2009. Available at: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=9558 Accessed on June 24, 2009.
5. 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 September 30, 2008.
6. 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 June 24, 2009.
7. Hayes Inc. Hayes Medical Technology Directory. Interferon/Ribavirin Therapy for Hepatitis C. Lansdale, PA: Hayes, Inc.; March 2004. Search Updated August 23, 2008.
8. Pegasys [Product Information], Nutley, NJ. Hoffman-La Roche Inc; October 2008. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/103964s5147,%20103964s5163lbl.pdf Accessed June 24, 2009.
9. Peginterferon Alfa-2a (systemic). In: DrugPoints System [Internet database]. Greenwood Village, CO: Thomson Healthcare. Updated periodically. Available at: http://www.thomsonhc.com. Accessed on June 18, 2009.
10. Peginterferon Alfa-2b (systemic). In: DrugPoints System [Internet database]. Greenwood Village, CO: Thomson Healthcare. Updated periodically. Available at: http://www.thomsonhc.com. Accessed on June 18, 2009.
11. Peg Intron [Product Information], Kenilworth, NJ. Schering Corporation; May 2009. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/103949s5172lbl.pdf  Accessed on June 24, 2009.
12. Rebetol [Product Information], Kenilworth, NJ. Schering Corporation. December 2007. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/020903s040lbl.pdf Accessed on July10, 2009.
13. Ribasphere [Product Information], Greenville, NC. DSM Pharmaceuticals, Inc; April 2004. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/76203LBL_Ribasphere.pdf Accessed on June 24, 2009.
14. Ribavirin (systemic). In: DrugPoints System [Internet database]. Greenwood Village, CO: Thomson Healthcare. Updated periodically. Available at: http://www.thomsonhc.com. Accessed on June 24, 2009.

Appendix A¹

Testing for Hepatitis C