Ribavirin Capsules and Interferon alfa-2b

By William T. Elliott, MD and James Chan, PharmD, PhD

Hepatitis c is one of this country’s greatest public health concerns. Some 4 million Americans are chronically infected with the virus, of which 20-50% will go on to develop chronic liver inflammation and cirrhosis. As many as 30% of those will develop liver failure or liver cancer as a result of the disease. The disease is so prevalent that hepatitis C infection has become the leading reason for liver transplantation in the United States.1

Interferon (alfa-2 and alfacon-1) has been the mainstay of therapy for hepatitis C, but the results have been variable, and the treatment is often poorly tolerated. Now, the FDA has approved a new treatment, a combination product involving interferon alfa-2b and the antiviral drug ribavirin.

Interferon alfa-2b is a large, water soluble protein produced by recombinant DNA technology using a strain of E. coli bacteria. Interferon is believed to have immunomodulating activity. The drug must be given parenterally and is generally given subcutaneously. Ribavirin is an oral nucleoside analog antiviral agent with in vitro activity against respiratory syncytial virus, influenzae virus, and herpes simplex virus. The combination is being marketed by Schering-Plough under the name Rebetron. It is approved by the FDA only for patients who have relapsed on conventional interferon treatment.

Indications

Rebetron is indicated for the treatment of chronic hepatitis C in patients with compensated liver disease who have relapsed following alpha interferon therapy.

Dosage

For patients who are less than 75 kg: 3 million IU of interferon injected subcutaneouly three times weekly for 24 weeks. Ribavirin is administered orally as 400 mg (2 × 200 mg) in the morning and 600 mg (3 × 200 mg) in the evening. The drug may be taken without regards to meals.

For patients greater than 75 kg: 3 million IU of interferon injected subcutaneouly three times weekly for 24 weeks. Ribavirin is administered orally as 600 mg 3 × 200 mg) in the morning and 600 mg (3 × 200 mg) in the evening.

The recommended regimen is six months (24 weeks). Safety and efficacy have not been established beyond 24 weeks of treatment.2

Rebetron is supplied as six single dose vials (3 million IU each) or as 18 million IU multidose vials with 84, 70, or 42 capsules of ribavirin. Each unit is a 14-day supply.

Potential Advantages

Interferon and ribavirin have been reported to produce a decrease in hepatitis C viral RNA and normalization of alanine aminotransferase compared to retreatment with intereron alfa-2b in patients who relapse after interferon therapy.1,2 In phase III studies, retreatment with interferon and ribavirin was compared with interferon and placebo. Sustained virological response (no detectable virus 24 weeks after end of treatment) was 43-48% vs. 4-5%, respectively, and histological response of 49-51% vs. 31-36%, respectively.2 Histological response was defined as improvement in liver, Knodell histology activity index (HAI) of 2 points or greater. The combination has also been shown to be more effective than interferon alone in interferon-naïve patients in sustaining virological response.3 While the response rates (no detectable HCV RNA by PCR) after therapy were identical, the responses 48 weeks later were 46% for the combination and 21% for monotherapy (P = 0.02).3 Normalization of ALT was 44% for the combination and 24% for monotherapy 24 weeks posttreatment (P = 0.057).

Potential Disadvantages

Anemia was observed in 10% of interferon/ribavirin patients in clinical trials. This adverse event usually occurred within 1-2 weeks of initiation of therapy. In a recently published trial, the mean hemoglobin concentration decreased from 14.7 to 12.1 g/dL in the interferon/ribavirin group, compared to a decrease of 14.5-13.8 g/dL in the interferon/placebo group (P < 0.001).3 Ribavirin has significant teratogenic and/or embryocidal potential and is contraindicated in women who are or may become pregnant.2 Pulmonary symptoms, including dyspnea, pulmonary infiltrates, pneumonitis, and pneumonia, including fatality, have been reported during interferon/ribavirin therapy.2 Nausea is more common with the combination than interferon alone (34% vs 12%; P = 0.02).3 Severe psychiatric reactions including depression and suicidal behavior have been reported with alpha interferon monotherapy and interferon/ribavirin.2

Comments

Hepatitis C virus is an RNA virus of the Flaviviridae family. It does not exist as a homogenous species but, rather, as a closely related heterogenous population of viral genomes or quasispecies. This genetic heterogeneity may explain variations in clinical course, lack of response, and difficulty in vaccine development.6 There are several genotypes and subtypes of the virus, with type 1 being the dominant genotype.7 Current therapy of chronic hepatitis C are alfa interferon and alfacon-1 interferon. Efficacy of treatment is defined as reduction in hepatitis viremia, normalization of serum ALT, and mean changes in liver histology score. Sustained response is generally assessed 24-48 weeks after the end of a 24-week course of therapy.

Typical response rates are 27-35% for virological response and 37-42% in biochemical response at the end of treatment. Sustained responses are 11-12% and 20%, respectively, 24 weeks after treatment.8 There appears to be a higher response rate in patients infected with genotype 2 and 3 compared to genotype 1.8 In addition, patients with lower serum HCV RNA (< 1,000,000 copies/mL) and absence of cirrhosis may be predictive of response to therapy.6 Selection of quasispecies may occur during interferon therapy.10 For nonresponders, treatment with a newer alfacon-1 interferon at a higher dose (15 mcg TIW compared to 9 mcg TIW) and longer duration (48 weeks) provides marginal benefit (13% sustained response). Retreatment of relapse patients at a higher dose produced a sustained response of 28% after a 24-week treatment and 58% after a 48-week treatment.8

Interferon/ribavirin appears to offer some promise in relapse patients, as well as interferon-naïve patients. A sustained response rate of 47% has been reported in relapse patients and 36% in treatment-naïve patients.2,3 While data are limited, it appears that patients who fail to achieve a sustained effect with interferon may have favorable response to the combination, but success in non-responders is limited.4,9

Clinical Implications

It is estimated that nearly 4 million Americans are infected with hepatitis C. Given the high prevalence of infected individuals, it is urgent that effective intervention (i.e., education, vaccine, and antiviral drugs) be developed to prevent future infections and delay the progression of liver disease after infections.

Currently, the options are limited. Treatment is recommended for patients with chronic hepatitis who are at the greatest risk for developing cirrhosis. Characteristics of these patients include consistently elevated ALT, HCV viremia, and evidence of portal or bridging fibrosis and moderate degrees of inflammation and necrosis.6

Treatment success with interferon monotherapy has been limited. Prior to the approval of interferon/ribavirin, the NIH had recommended initial therapies of 12-month duration to improve the rate of sustained response.6 The combination of ribavirin and interferon provides an important option. It is currently approved by the FDA for patients who relapsed on interferon but is soon expected to gain approval for treatment-naïve patients. Resistance to interferon is still problematic and the combination does not appear to be the solution. More active anti-HCV agents are needed, and combination therapy similar to those used for HIV therapy may improve efficacy.

Interferon/ribavirin is expensive. Wholesale cost for a 24-week therapy is $6120-$6720. This is about three times the cost for interferon alone.

References

1. Mereno-Monteagudo, et al. Aliment Pharmacol Ther 1998;12(8):717-723.

2. Rebetron Product Information. Schering Corporation. May 1998.

3. Reichard O, et al. Lancet 1998;351:83-87.

4. Schvarcz R, et al. J Hepatol 1995;23(suppl 2):17-21.

5. Gonzalez-Peralta RP, et al. J Med Virol 1996;49:242-247.

6. National Institutes of Health Alfacon-1 Development Statement. Management of Hepatitis C. Hepatology 1997;26(suppl 1):2S-10S.

7. Mahaney K, et al. Hepatology 1994;20:1405-1411.

8. Keeffe EB, et al. Hepatology 1997;26(suppl 1):101S-107S.

9. Schalm S, et al. J Hepatol 1997;26:961-966.

10. Sakuma I, et al. Arch Virol 1996;141(10):1921-1932.