Aetna considers ribavirin (Virazole) medically necessary for the treatment of respiratory syncytial virus (RSV) infection in immunosuppressed and high risk children and adults, and for the treatment of viral hemorrhagic fever (Crimean-Congo, Ebola, Lassa, and Marburg), Rift valley fever and Hantaan, a hanta virus.
Aetna considers ribavirin in combination with interferon alpha or pegylated interferon alpha medically necessary for persons with chronic hepatitis C according to the criteria set forth in CPB 0404 - Interferons. Clinical research suggests that there are synergistic effects of ribavirin and interferon alpha in the treatment of chronic hepatitis.
Aetna considers ribavirin monotherapy for the treatment of persons with chronic hepatitis C infection experimental and investigational because there is insufficient evidence to support the effectiveness of this approach.
Aetna considers ribavirin experimental and investigational for all other indications (e.g., acute myeloid leukemia, hepatitis E infection, multiple sclerosis; not an all-inclusive list) because its effectiveness for indications other than the ones listed above has not been established.
Ribavirin is indicated for use in the treatment and prevention of certain viral infections in selected patients. Ribavirin is marketed as a inhalation solution (Virazole), oral capsule (Rebetol) and tablet (Copegus), but can also be prepared for intravenous administration.
Mallet et al (2010) reported 2 patients in whom ribavirin therapy seemed to alter the natural history of chronic hepatitis E virus (HEV) infection. A kidney and pancreas transplant recipient and a patient with idiopathic CD4(+) T lymphocytopenia, both with biopsy-proven chronic HEV infection were included in this study. Patients received oral ribavirin, 12 mg/kg of body weight daily for 12 weeks. Liver function tests, detection of HEV RNA (viremia and stool shedding) by reverse transcriptase polymerase chain reaction, and anti-HEV IgM and IgG antibodies wer performed. Both patients had normalized liver function test results after 2 weeks of treatment and cleared HEV after 4 weeks of treatment. Hepatitis E virus RNA remained undetectable in the serum and stools throughout follow-up (3 months and 2 months for the 1st and 2nd patient, respectively). Side effects were considered mild. The authors concluded that ribavirin is a potentially effective treatment of HEV infection and should be evaluated in patients with chronic HEV infection. The main drawback of this study was that given the relatively short follow-up, the achievement of HEV eradication could not be claimed.
In a pilot study, Kamar and colleagues (2010) evaluated the ant-iviral effect of ribavirin monotherapy in patients with chronic HEV infection following kidney transplantation. A total of 6 patients who received kidney transplants and were positive for HEV RNA (infected with HEV for 36.5 months; [range of 11 to 46 months]) were given ribavirin monotherapy for 3 months. Ribavirin was given at 600 to 800 mg/day in 2 separate doses, based on the patient's ability to clear creatinine. Median serum concentration of HEV RNA at baseline was 5.77 log copies/mL (range of 4.35 to 7.35 log copies/ml). Three months after ribavirin therapy commenced, HEV RNA was undetectable in serum samples from all patients. A sustained virologic response was observed in 4 patients; the other 2 patients relapsed at 1 and 2 months after ribavirin therapy ended. At the end of the study, all patients had normal levels of alanine and aspartate aminotransferase. Anemia was the main side effect caused by ribavirin therapy. The authors concluded that ribavirin monotherapy inhibits the replication of HEV in vivo and might induce a sustained virological response in patients with chronic HEV infections. They stated that further studies are needed to determine the optimal duration of ribavirin therapy.
Kamar et al (2014) noted that there is no established therapy for HEV infection. In a retrospective, multi-center case-series study, these researchers evaluated the effects of ribavirin as monotherapy for solid-organ transplant (SOT) recipients with prolonged HEV viremia. They examined the records of 59 patients who had received a solid-organ transplant (37 kidney-transplant recipients, 10 liver-transplant recipients, 5 heart-transplant recipients, 5 kidney and pancreas-transplant recipients, and 2 lung-transplant recipients). Ribavirin therapy was initiated a median of 9 months (range of 1 to 82) after the diagnosis of HEV infection at a median dose of 600 mg per day (range of 29 to 1,200), which was equivalent to 8.1 mg/kg body weight/day (range of 0.6 to 16.3). Patients received ribavirin for a median of 3 months (range of 1 to 18); 66 % of the patients received ribavirin for 3 months or less. All the patients had HEV viremia when ribavirin was initiated (all 54 in whom genotyping was performed had HEV genotype 3). At the end of therapy, HEV clearance was observed in 95 % of the patients. A recurrence of HEV replication occurred in 10 patients after ribavirin was stopped. A sustained virologic response, defined as an undetectable serum HEV RNA level at least 6 months after cessation of ribavirin therapy, occurred in 46 of the 59 patients (78 %). A sustained virologic response was also observed in 4 patients who had a recurrence and were re-treated for a longer period. A higher lymphocyte count when ribavirin therapy was initiated was associated with a greater likelihood of a sustained virologic response. Anemia was the main identified side effect and required a reduction in ribavirin dose in 29 % of the patients, the use of erythropoietin in 54 %, and blood transfusions in 12 %. The authors concluded that the findings of this retrospective, multi-center study showed that ribavirin as monotherapy may be effective in the treatment of chronic HEV infection; a 3-month course seemed to be an appropriate duration of therapy for most patients.
Unzueta and Rakela (2014) stated that HEV infection (genotype 3) has been described in developed countries as a cause of chronic hepatitis in recipients of SOT. Immunosuppression seems to play a major role in the pathogenesis of chronic infections. The current gold standard for the diagnosis of HEV infection is the detection of HEV RNA in serum, stools, or both. In liver transplant recipients, HEV infection is considered an uncommon disease; however, a high index of suspicion is needed for patients with graft hepatitis of an unclear etiology. Liver transplant recipients seem more likely to develop chronic HEV after an acute infection, and there is accelerated progression to advanced fibrosis and cirrhosis. A decrease in immunosuppression is considered the first line of treatment, and pegylated interferon can be considered the second line of treatment for liver transplant recipients. At the present time, there are not enough data to recommend treatment with ribavirin for adult liver transplant recipients, although this has been tried in other SOT populations.
An UpToDate review on “Hepatitis E virus infection” (Umashanker and Chopra, 2014) states that “Case reports and series have suggested a benefit from ribavirin monotherapy in solid-organ transplant recipients with chronic HEV, but prospective studies are needed to confirm these findings and to determine the dose, duration, and timing of ribavirin therapy”.
CPT Codes / HCPCS Codes / ICD-9 Codes
Other CPT codes related to the CPB:
Respiratory syncytial virus, monoclonal antibody, recombinant, for intramuscular use, 50 mg, each
Other HCPCS codes related to the CPB:
J9213, J9214, J2915
Interferon alpha-2a, 2b, and n3
ICD-9 codes covered if selection criteria are met:
Crimean hemorrhagic fever [CHF Congo virus]
Other specified arthropod-borne hemorrhagic fever (e.g., mite-borne hemorrhagic fever)
Other mosquito-borne fever (e.g., Rift valley)
Chronic hepatitis C without mention of hepatic coma [not covered for ribavirin monotherapy]
Other specified diseases due to viruses (e.g., Marburg disease, Tanapox)
Respiratory syncytial virus (RSV)
Acute bronchiolitis due to respiratory syncytial virus (RSV)
ICD-9 codes not covered for indications listed in the CPB:
Hepatitis E with hepatic coma
Hepatitis E without mention of hepatic coma
205.00 - 205.92
Acute myeloid leukemia
The above policy is based on the following references:
American Society of Health-System Pharmacists (ASHSP). AHFS Drug Information 98. Bethesda, MD: ASHSP; 1998.
Davis GL, Esteban-Mur R, Rustgi V, et al. Interferon alpha-2b alone or in combination with ribavirin for the treatment of relapse of chronic hepatitis C. N Engl J Med. 1998;339(21):1493-1499.
Hepatitis C Foundation. Rebetron™ combination therapy fact sheet. Warminster, PA: Hepatitis C Foundation; November 7, 1998.
McHutchison JG, Gordon SC, Schiff ER, et al. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. N Engl J Med. 1998;339(21):1485-1492.
U.S. Pharmacopeial Convention, Inc. Ribavirin (systemic). In: US PDI Volume I: Drug Information for the Health Care Professional. 24th ed. Greenwood Village, CO: Micromedex; revised December 18, 2003.
Cummings KJ, Lee SM, West ES, et al. Interferon and ribavirin vs interferon alone in the re-treatment of chronic hepatitis C previously nonresponsive to interferon: A meta-analysis of randomized trials. JAMA. 2001;285(2):193-199.
Shepherd J, Waugh N, Hewitson P. Combination therapy (interferon alfa and ribavirin) in the treatment of chronic hepatitis C: A rapid and systematic review. Health Technol Assess. 2000;4(33):1-67.
Shigeta S. Recent progress in antiviral chemotherapy for respiratory syncytial virus infections. Expert Opin Investig Drugs. 2000;9(2):221-235.
DeVincenzo JP. Therapy of respiratory syncytial virus infection. Pediatr Infect Dis J. 2000;19(8):786-790; discussion 802-804, 811-813.
Swedish Consensus Group. Management of infections caused by respiratory syncytial virus. Scand J Infect Dis. 2001;33(5):323-328.
Kjaergard LL, Krogsgaard K, Gluud C. Ribavirin with or without alpha interferon for chronic hepatitis C. Cochrane Database Syst Rev. 2002;(2):CD002234.
Scott LJ, Perry CM. Interferon-alpha-2b plus ribavirin: A review of its use in the management of chronic hepatitis C. Drugs. 2002;62(3):507-556.
Agence Nationale d'Accreditation et d'Evaluation en Sante (ANAES). Consensus conference. Treatment of hepatitis C. Gastroenterol Clin Biol. 2002;26 Spec No 2:B303-B320.
Scottish Health Purchasing Information Centre (SHPIC). Ribavirin and interferon alfa in the treatment of chronic hepatitis C. Aberdeen, Scotland, UK: SHPIC; 2002.
Gebo K, Jenckes M, Chander G. Management of chronic hepatitis C. Evidence Report/Technology Assessment 60. Rockville, MD: Agency for Healthcare Research and Quality (AHRQ); 2002.
Zein CO, Zein NN. Advances in therapy for hepatitis C infection. Microbes Infect. 2002;4(12):1237-1246.
Chander G, Sulkowski MS, Jenckes MW, et al. Treatment of chronic hepatitis C: A systematic review. Hepatology. 2002;36(5 Suppl 1):S135-S144.
Colgan R, Michocki R, Greisman L, Moore TA. Antiviral drugs in the immunocompetent host: Part II. Treatment of influenza and respiratory syncytial virus infections. Am Fam Physician. 2003;67(4):763-766, 675.
Wejstal R, Alaeus A, Fischler B, et al. Chronic hepatitis C: Updated Swedish consensus. Scand J Infect Dis. 2003;35(8):445-451.
Cross JT, Campbell GD. Therapy for nosocomial pneumonia. Med Clin North Am. 2001;85(6):1583-1594.
San Miguel R, Guillen F, Cabases JM, Buti M. Meta-analysis: Combination therapy with interferon-alpha 2a/2b and ribavirin for patients with chronic hepatitis C previously non-responsive to interferon. Aliment Pharmacol Therapeut. 2002;16(9):1611-1621.
Institute for Clinical Systems Improvement (ICSI). Antiviral treatment for chronic hepatitis C. Technology Assessment Report No. 43. Bloomington, MN: Institute for Clinical Systems Improvement (ICSI); 2005.
Danish Centre for Evaluation and Health Technology Assessment (DACEHTA). Chronic hepatitis C. Combination therapy IFN and ribavirin. Copenhagen, Denmark: DACEHTA; 2002.
National Institute for Clinical Excellence (NICE). Interferon alfa (pegylated and non-pegylated) and ribavirin for the treatment of chronic hepatitis C. Technology Appraisal Guidance No.75. London, UK: NICE; 2004.
Husereau D, Bassett K, Koretz R. Inteferon-based therapies for chronic hepatitis C virus infection: An assessment of clinical outcomes. Technology Report Issue 47. Ottawa, ON: Canadian Coordinating Office for Health Technology Assessment (CCOHTA); 2004.
Shepherd J, Brodin H, Cave C, et al. Pegylated interferon alpha-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): iii-iv, 1-125.
Shiffman ML. Retreatment of patients who do not respond to initial therapy for chronic hepatitis C. Cleve Clin J Med. 2004;71 Suppl 3:S13-S16.
Ventre K, Randolph AG. Ribavirin for respiratory syncytial virus infection of the lower respiratory tract in infants and young children. Cochrane Database Syst Rev. 2007;(1):CD000181.
Lozano JM. Bronchiolitis. In: Clinical Evidence. London, UK: BMJ Publishing Group; October 2004.
Tien PC; Veterans Affairs Hepatitis C Resource Center Program; National Hepatitis C Program Office. Management and treatment of hepatitis C virus infection in HIV-infected adults: Recommendations from the Veterans Affairs Hepatitis C Resource Center Program and National Hepatitis C Program Office. Am J Gastroenterol. 2005;100(10):2338-2354.
Brok J, Gluud LL, Gluud C. Ribavirin plus interferon versus interferon for chronic hepatitis C. Cochrane Database Syst Rev. 2005;(3):CD005445.
Siebert U, Sroczynski G; German Hepatitis C Model GEHMO Group; HTA Expert Panel on Hepatitis C. Effectiveness and cost-effectiveness of initial combination therapy with interferon/peginterferon plus ribavirin in patients with chronic hepatitis C in Germany: A health technology assessment commissioned by the German Federal Ministry of Health and Social Security. Int J Technol Assess Health Care. 2005;21(1):55-65.
Dienstag JL, McHutchison JG. American Gastroenterological Association medical position statement on the management of hepatitis C. Gastroenterol. 2006;130:225-230.
Mohsen A, Norris S. Hepatitis C (chronic). In: Clinical Evidence. London, UK: BMJ Publishing Group; May 2005.
Brok J, Gluud LL, Gluud C. Ribavirin monotherapy for chronic hepatitis C infection: A Cochrane Hepato-Biliary Group systematic review and meta-analysis of randomized trials. Am J Gastroenterol. 2006;101(4):842-847.
National Institute for Health and Clinical Excellence (NICE). Peginterferon alfa and ribavirin for the treatment of mild chronic hepatitis C. Technology Appraisal Guidance 106. London: National Institute for Health and Clinical Excellence (NICE); 2006.
Wright M, Grieve R, Roberts J, et al. Health benefits of antiviral therapy for mild chronic hepatitis C: Randomised controlled trial and economic evaluation. Health Technol Assess. 2006;10(21):1-130.
Shepherd J, Jones J, Hartwell D, et al. Interferon alpha (pegylated and non-pegylated) and ribavirin for the treatment of mild chronic hepatitis C: A systematic review and economic evaluation. Health Technol Assess. 2007;11(11):1-205, iii.
Simin M, Brok J, Stimac D, et al. Cochrane systematic review: Pegylated interferon plus ribavirin vs. interferon plus ribavirin for chronic hepatitis C. Aliment Pharmacol Ther. 2007;25(10):1153-1162.
Fabrizi F, Bruchfeld A, Mangano S, et al. Interferon therapy for HCV-associated glomerulonephritis: Meta-analysis of controlled trials. Int J Artif Organs. 2007;30(3):212-219.
Brady B, Siebert U, Sroczynski G, et al. Pegylated interferon combined with ribavirin for chronic hepatitis C virus infection: An economic evaluation. Technology Report No 82. Ottawa, ON: Canadian Agency for Drugs and Technologies in Health (CADTH); 2007.
Centers for Disease Control and Prevention; Infectious Disease Society of America; American Society of Blood and Marrow Transplantation. Guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients. MMWR Recomm Rep. 2000;49(RR-10):1-125, CE1-7.
Franchini M, Mengoli C, Veneri D, et al. Treatment of chronic hepatitis C in haemophilic patients with interferon and ribavirin: A meta-analysis. J Antimicrob Chemother. 2008;61(6):1191-1200.
Escudero A, Rodríguez F, Serra MA, et al. Pegylated alpha-interferon-2a plus ribavirin compared with pegylated alpha-interferon-2b plus ribavirin for initial treatment of chronic hepatitis C virus: Prospective, non-randomized study. J Gastroenterol Hepatol. 2008;23(6):861-866.
Shiffman ML. What future for ribavirin? Liver Int. 2009;29 Suppl 1:68-73.
Reddy KR, Nelson DR, Zeuzem S. Ribavirin: Current role in the optimal clinical management of chronic hepatitis C. J Hepatol. 2009;50(2):402-411.
Zhu X, Ma Y, Liu D. Novel agents and regimens for acute myeloid leukemia: 2009 ASH annual meeting highlights. J Hematol Oncol. 2010;3:17.
Mangas A, Coveñas R, Geffard M. New drug therapies for multiple sclerosis. Curr Opin Neurol. 2010;23(3):287-292.
Soares-Weiser K, Thomas S, Thomson G, Garner P. Ribavirin for Crimean-Congo hemorrhagic fever: Systematic review and meta-analysis. BMC Infect Dis. 2010;10:207.
Brok J, Gluud LL, Gluud C. Ribavirin plus interferon versus interferon for chronic hepatitis C. Cochrane Database Syst Rev. 2010;(1):CD005445.
Mallet V, Nicand E, Sultanik P, et al. Brief communication: Case reports of ribavirin treatment for chronic hepatitis E. Ann Intern Med. 2010;153(2):85-89.
Kamar N, Rostaing L, Abravanel F, et al. Ribavirin therapy inhibits viral replication on patients with chronic hepatitis e virus infection. Gastroenterology. 2010;139(5):1612-1618.
Hauser G, Awad T, Brok J, et al. Peginterferon plus ribavirin versus interferon plus ribavirin for chronic hepatitis C. Cochrane Database Syst Rev. 2014;2:CD005441.
Kamar N, Izopet J, Tripon S, et al. Ribavirin for chronic hepatitis E virus infection in transplant recipients. N Engl J Med. 2014;370(12):1111-1120.
Unzueta A, Rakela J. Hepatitis E infection in liver transplant recipients. Liver Transpl. 2014;20(1):15-24.
Umashanker R, Chopra S. Hepatitis E virus infection. UpToDate [serial online]. Waltham, MA: UpToDate; reviewed October 2014.
Copyright Aetna Inc. All rights reserved. Clinical Policy Bulletins are developed by Aetna to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. This Clinical Policy Bulletin contains only a partial, general description of plan or program benefits and does not constitute a contract. Aetna does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Aetna or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. This Clinical Policy Bulletin may be updated and therefore is subject to change.