It is estimated that nearly 4 million Americans have hepatitis C, related predominantly to prior intravenous drug abuse or blood transfusions prior to 1990 when routine screening of all blood donations began. Of these 4 million, 70% will have chronic hepatitis and 15% to 20% will develop cirrhosis. Cirrhosis related to hepatitis C is now the most common indication for liver transplant. Hepatitis C, a single-stranded RNA virus, is genetically complex with several recognized genotypes. Genotypes 1, 2, and 3 are the most frequently encountered genotypes worldwide. Type 1a is most frequently found in Northern Europe and North America, while 1b is most common in Japan and Southern and Eastern Europe. Genotype 1 has been associated with a poorer response to interferon and/or ribavirin compared to other genotypes.

Interferon alfa has been considered the only effective treatment of hepatitis C. A total of 40% of patients will show an initial response to interferon alfa, but most patients relapse soon after stopping treatment. Ribavirin (Rebetron), a synthetic nucleoside analogue with antiviral activity, has also been investigated as a treatment of hepatitis C. Currently, oral ribavirin, in combination with interferon alfa, has received approval from the U.S. Food and Drug Administration (FDA) for treatment of hepatitis C that has relapsed after initial treatment with interferon alfa alone and recently as a first-line therapy of hepatitis C. A pegylated form of interferon, designed to have a longer duration of action permitting once weekly dosing, has also received FDA approval for the treatment of hepatitis C.

Interferon alfa or peginterferon, in combination with ribavirin, may be considered medically necessary as an initial treatment of hepatitis C, or as salvage treatment of relapsed hepatitis C.

Interferon alfa or peginterferon alone may be considered medically necessary as an initial treatment of hepatitis C, or as salvage treatment of relapsed hepatitis C. (Note that combination therapy [see above] is the therapy of choice.)

Genotyping of hepatitis C virus may be considered medically necessary as a technique to determine duration of interferon therapy.

Patients treated with interferon alfa alone typically receive 3 to 6 million units 3 times a week for up to 18 months.

Patients treated with interferon alfa combined with ribavirin typically receive interferon alfa, as described here, in addition to oral ribavirin administered twice daily at a total daily dose of 1,000 to 1,200 mg. As initial therapy, patients may be treated for up to 12 months. As salvage therapy, patients may be treated for up to 6 months.

Dosages of ribavirin and peginterferon are based on weight.

Response to treatment may be monitored by serial measurement of viral function tests or serum HCV RNA levels (see policy No. 2.04.10.) Discontinuation of treatment should be considered in any patient who has not achieved an HCV RNA below the limit of detection of the assay after 24 weeks of therapy.

Ribavirin is associated with a reversible, hemolytic anemia in some patients, and interferon is associated with bone marrow suppression; thus, periodic hematologic monitoring is warranted with these drugs.

Note:This policy was originally issued in 1999 to address the new commercial availability of combination therapy of interferon and ribivarin. It was not the intent of this policy, then or now, to provide detailed guidelines for the treatment of hepatitis C, either in terms of treatment of naïve, nonresponding, or relapsing patients, or the selection of which of the commercially available interferons might be optimal.

BlueCard/National Account Issues

Coverage of interferon and ribavirin for the treatment of hepatitis C may be adjudicated under the pharmacy benefits.

Two recently published randomized, placebo-controlled clinical trials have focused on the treatment of hepatitis C. Davis and colleagues reported on the use of interferon alfa and ribavirin in patients with relapsed hepatitis C. (1) A total of 172 patients were randomly assigned to receive interferon alone with oral placebo; 173 were assigned to receive interferon alfa plus ribavirin. Both groups were treated for 6 months. Patients treated with combined therapy experienced higher rates of sustained virologic, biochemical, and histological response compared to patients treated with ribavirin alone. Treatment of relapsed hepatitis C with combined interferon alfa and ribavirin is an FDA-approved labeled indication for ribavirin.

McHutchison and colleagues reported on the use of combined interferon alfa and ribavirin therapy as an initial treatment of hepatitis C. (2) A total of 933 patients were assigned to 1 of 4 treatment arms; interferon alfa plus placebo for 24 or 48 weeks, or interferon alfa plus ribavirin for 24 or 48 weeks. The rate of sustained virologic response was significantly higher among patients who received the combination therapy for either 24 or 48 weeks compared to the control arm of interferon alfa alone. The combined therapy was also found to be effective in particularly high-risk patients, i.e., those with high viral burdens, those with genotype 1 infection (found in about 70% of U.S. patients), or advanced fibrosis or cirrhosis. The duration of treatment, either 24 or 48 weeks, is still uncertain. McHutchison’s study found only a minimal difference in response rates between those treated for 24 or 48 weeks with the combination therapy. High-risk patients, i.e., those with high viral loads, or those with genotype 1 infections may be those who would benefit most from a 48-week course of therapy. (3)

2002-5 Update

Since this policy was issued in 1999, combination therapy with interferon and ribavirin has become preferred choice for the initial treatment of hepatitis C and a salvage therapy for patients who have failed to respond or have relapsed after treatment with interferon alone. (4) In addition, long-acting peginterferon has become commercially available. Randomized studies comparing peginterferon with conventional interferon alfa suggest that peginterferon is associated with improved virologic responses. (5, 6) Studies of the combination of peginterferon and ribavirin showed a similar safety profile compared to peginterferon alone, with the expected improvement in virologic response. (7, 8) In addition, combined peginterferon and ribavirin may be effective in patients who have failed prior courses of interferon therapy. (9) Recent clinical trials have focused on the treatment of HCV inpatients co-infected with HIV, (10, 11) in different subpopulations of patients (12), and with different schedules of interferon or peginterferon. (13-16)

Genotyping of the hepatitis C virus is now routinely performed to determine whether genotype 1 is present and to determine the duration of interferon therapy. Patients with genotype 1 are commonly treated with 48 weeks of therapy instead of 24. (17,18) There has also been research interest in daily high-dose interferon, compared to the conventional 3 times a week dose, in patients with unfavorable characteristics, including genotype 1. (9)

A review of the literature for the period of 2003 through 2005 identified many clinical trials whose focus was the refinement of treatment strategies using various combinations and durations of therapy of interferon and ribavirin in different populations of patients; i.e. naive, non-responders, and relapsers. It is not the intent of this policy to determine the precise regimen for hepatitis C nor the optimal selection of the commercially available interferon. This policy was originally developed when interferon and ribavirin were first emerging as therapy for hepatitis C. This therapy is now considered the gold standard therapy. Therefore, no further review is scheduled for this policy.

References:

1. Davis GL, Esteban-Mur R, Rustgi V et al. Interferon alfa-2b alone or in combination with ribavirin for the treatment of relapse of chronic hepatitis C. N Engl J Med 1998; 339(21):1493-9.
2. 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):1485-92.
3. Liang TJ. Combination therapy for hepatitis C infection. N Engl J Med 1998; 339(21):1549-50.
4. 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):507-56.
5. Lindsay KL, Trepo C, Heintges T et al. A randomized, double-blind trial comparing pegylated interferon alfa-2b to interferon alfa-2b as initial treatment for chronic hepatitis C. Hepatology 2001; 34(2):395-403.
6. Reddy KR, Wright TL, Pockros PJ et al. Efficacy and safety of pegylated (40-kd) interferon alpha-2a compared with interferon alpha-2a in noncirrhotic patients with chronic hepatitis C. Hepatology 2001; 33(2):433-48.
7. Glue P, Rouzier-Panis R, Raffanel C et al. A dose-ranging study of pegylated interferon alfa-2b and ribavirin in chronic hepatitis C. The Hepatitis C Intervention Therapy Group. Hepatology 2000; 32(3):646-53.
8. Cornberg M, Wedemeyer H, Manns MP. Treatment of chronic hepatitis C with PEGylated interferon and ribavirin. Curr Gastroenterol Rep 2002; 4(1):23-30.
9. Shiffman ML, Di Bisceglie AM, Lindsay KL et al. Peginterferon alfa-2a and ribavirin in patients with chronic hepatitis C who have failed prior treatment. Gastroenterology 2004; 126(4):1015-23.
10. Chung RT, Andersen J, Volberding P et al. Peginterferon alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons. N Engl J Med 2004; 351(5):451-9.
11. Torriani FJ, Rodriguez-Torres M, Rockstroh JK et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients. N Engl J Med 2004; 351(5):438-50.
12. Muir AJ, Bornstein JD, Killenberg PG. Peginterferon alfa-2b and ribavirin for the treatment of chronic hepatitis C in blacks and non-Hispanic whites. N Engl J Med 2004; 350(22):2265-71.
13. Pockros PJ, Carithers R, Desmond P et al. Efficacy and safety of two-dose regimens of peginterferon alpha-2a compared with interferon alpha-2a in chronic hepatitis C: a multicenter, randomized controlled trial. Am J Gastroenterol 2004; 99(7):1298-305.
14. Van Vlierberghe H, Leroux-Roels G, Adler M et al. Daily induction combination treatment with alpha 2b interferon and ribavirin or standard combination treatment in naïve chronic hepatitis C patients. A multicentre randomized controlled trial. J Viral Hepat 2003; 10(6):460-6.
15. Portal I, Bourliere M, Halfon P et al. Retreatment with interferon and ribavirin vs interferon alone according to viraemia in interferon responder-relapse hepatitis C patients: a prospective multicentre randomized controlled study. J Viral Hepat 2003; 10(3):215-23.
16. Poynard T, Marcellin P, Bissery A et al. Reinforced interferon alpha-2b and ribavirin is more effective than standard combination therapy in the retreatment of chronic hepatitis C previously nonresponse to interferon: a randomized trial. J Viral Hepat 2003; 10(3):197-204.
17. Hadziyannis SJ, Sette H, Morgan TR et al. Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med 2004; 140(5):346-55.
18. Fried MW, Shiffman M, Sterling RK et al. A multicenter, randomized trial of daily high-dose interferon-alfa 2b for the treatment of chronic hepatitis C: pretreatment stratification by viral burden and genotype. Am J Gastroenterol 2000; 95(11):3225-9.

Hepatitis C, Treatment
Interferon Alfa, Hepatitis C Treatment
Ribavirin