Ribavirin with interferons

Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, Goodman ZD, Koury K, Ling M, Albrecht JK (2001) Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C a randomised trial. Lancet 358 958-965... 

BriUanti S, Garson J, FoU M, Whitby K, Deaville R, Masci C, MigUoU M, Barbara L (1994) A pilot study of combination therapy with ribavirin plus interferon alfa for interferon alfa-resistant chronic hepatitis C. Gastroenterology 107 812-817... 

Hong SH, Cho O, Kim K, Shin HJ, Kotenko SV, Park S (2007) Effect of interferon-lambda on replication of hepatitis B virus in human hepatoma cells. Virus Res 126 245-249 Hoofnagle JH, Mullen KD, Jones DB, Rustgi V, Di BiscegUe A, Peters M, Waggoner JG, Park Y, Jones EA (1986) Treatment of chronic non-A, non-B hepatitis with recombinant human alpha interferon. A preliminary report. N Engl J Med 315 1575-1578 Horiike N, Onji M (2003) Combination therapy with interferon-alpha and ribavirin as im-munomodulators in patients with chronic hepatitis C. J Gastroenterol 38 302-304... 

Adherence to therapy is another important factor in increasing and maintaining SVR. Patients who were adherent with interferon and ribavirin therapy (taking more than 80% of doses for more than 80% of the treatment duration) had an SVR of 52% whereas those who were not compliant had an SVR of 44% 42... 

About 10% to 25% of patients treated with interferon and ribavirin require dosage reductions when hemoglobin levels decrease or they develop intolerable symptoms such as shortness of breath or severe fatigue. If warranted, erythropoietin may be used as adjunctive therapy for ribavirin-induced hemolytic anemia.45... 

Monitor patients carefully during treatment with interferon or pegylated interferon with or without ribavirin. 

Vidigal, P. G., Germer, J. J., and Zein, N. N., Polymorphisms in the interleukin-10, tumor necrosis factor-alpha, and transforming growth factor-betal genes in chronic hepatitis C patients treated with interferon and ribavirin, J. Hepatol., 36, 271, 2002. 

Interferon is the approved treatment for hepatitis C. In general, there are four different treatments (1) IFN-a, (2) combination therapy of IFN-a and another drug called ribavirin, (3) pegylated IFN-a, and (4) pegylated IFN-a with ribavirin. Pegylated interferon contains polyethylene glycol, which increases the half-Ufe (see Section 5.3.5) from 6 hours to 45 hours and slows down the body s absorption of interferon. In this way, a more controlled release of interferon is achieved to prolong absorption. Instead of a subcutaneous injection of three times weekly, the frequency can be reduced to once weekly. 

The safety and efficacy of ribavirin capsules or oral solution with interferons other than interferon alfa-2b or peginterferon alfa-2b products have not been established. 

The recommended duration of treatment for patients previously untreated with ribavirin and interferon is 24 to 48 weeks. 

Capsules/Tablets/Oral solution - Ribavirin monotherapy is not effective for the treatment of chronic HCV infection. The safety and efficacy of ribavirin capsules and oral solution have only been established when used together with interferon alfa-2b, recombinant as interferon alfa-2b/ribavirin capsule combination therapy or with peginterferon alfa-2b injection. 

Capsules/Tablets/Oral solution - Pulmonary symptoms, including dyspnea, pulmonary infiltrates, pneumonitis, and pneumonia have been reported during therapy with ribavirin and interferon. Occasional cases of fatal pneumonia have occurred. In addition, sarcoidosis or the exacerbation of sarcoidosis has been reported. 

Chronic hepatitis C Alone or in combination with ribavirin tablets for the treatment of adults with chronic hepatitis C who have compensated liver disease and have not been treated previously with interferon alfa. 

Chronic hepatitis C For use alone or in combination with ribavirin capsules for the treatment of chronic hepatitis C in patients with compensated liver disease who have not been previously treated with interferon alpha and are at least 18 years of age. When used in combination with ribavirin, refer to ribavirin monograph for additional prescribing information. 

Mitchell Jones, a 35-year-old man, began treatment for hepatitis C with interferon-a-2b and ribavirin (Rebetron) 4 weeks ago. On returning to his doctor... 

Chronic hepatitis C PO (capsule or oral solution in combination with interferon alfa-2b) 1,000-1,200 mg/day in 2 divided doses. PO (capsules in combination with peginterferon alfa-2b) 800 mg/day in 2 divided doses. PO (tablets in combination with peginterferon alfa-2b) 800-1,200 mg/day in 2 divided doses. Ribavirin with peginterferon alfa-2b requires individualized dosing. 

Subsequent analysis of stored serum samples showed reduction of HCV RNA levels during treatment and durable eradication of virus in some cases [38]. These early results were confirmed by randomized controlled trials in patients with chronic hepatitis C [39-41]. Durable viral eradication (termed sustained virologic response, or SVR) was achieved in 6% to 15% of patients after six months of treatment with recombinant interferon at doses of 3 to 6 MU administered subcutaneously three times per week. SVR increased to 13% to 25% if treatment was extended to 12 months [41]. The combination of the oral nucleoside analogue ribavirin with recombinant interferon increased SVR to 41% [42-44]. Ribavirin, however, is potentially embryotoxic and induces a dose-dependent hemolytic anemia, a situation that calls for close monitoring during therapy. 

Treatment of patients with chronic HCV infection is recommended for those with an increased risk for progression to cirrhosis. The parameters for selection are complex. In those who are to be treated, however, the current standard of treatment is once-weekly pegylated interferon alfa in combination with daily oral ribavirin. Pegylated interferon alfa-2a and -2b have replaced their unmodified interferon alfo counterparts because of superior efficacy in combination with ribavirin, regardless of genotype. It is also clear that combination therapy with oral ribavirin is more effective than monotherapy with either interferon or ribavirin alone. Therefore, monotherapy with pegylated interferon alfa is recommended only in patients who cannot tolerate ribavirin. Factors associated with a favorable response to therapy include HCV genotype 2 or 3, absence of cirrhosis on liver biopsy, and low pretreatment HCV RNA levels. 

In addition to oral administration for hepatitis C infection in combination with interferon alfa, aerosolized ribavirin is administered by nebulizer (20 mg/mL for 12-18 hours per day) to children and infants with severe respiratory syncytial virus (RSV) bronchiolitis or pneumonia to reduce the severity and duration of illness. Aerosolized ribavirin has also been used to treat influenza A and infections but has not gained widespread use. Systemic absorption is low (< 1%). Aerosolized ribavirin is generally well tolerated but may cause conjunctival or bronchial irritation. Health care workers should be protected against extended inhalation exposure. The aerosolized drug may precipitate on contact lenses. 

The occurrence of thyroid dysfunction in 72 patients treated with interferon alfa plus ribavirin (1.0-1.2 g/day) has been compared with that of 75 age- and sex-matched patients treated with interferon alfa alone for chronic hepatitis C (523). Of the former, 42 patients, and of the latter, 40 patients had received previous treatment with interferon alfa alone. There was no difference in the rate of thyroid autoimmunity (antithyroglobulin, antithyroid peroxidase, and thyroid-stimulating hormone receptor... 

In three middle-aged patients, diabetes was diagnosed after 3-7 months of treatment with interferon alfa-2b and ribavirin, and two presented with severe ketoacidosis (534,535). There was a family history of diabetes in one patient and two had high titers of glutamic acid decarboxylase antibodies before treatment. One patient never had diabetes-related serum autoantibodies before or after interferon alfa therapy. All three required permanent insulin treatment despite withdrawal of interferon alfa. 

In a randomized trial in 74 patients with chronic hepatitis C treated with interferon alfa-2b and ribavirin, plus placebo or amantadine, two developed glutamic acid decarboxylase (GAD) autoantibodies, but none developed IA-2 or insulin autoantibodies (543). One had an increased titer of GAD autoantibodies during a first sequence of interferon alfa monotherapy, then a further rise during subsequent combination therapy, and finally developed diabetes mellitus after 5 months of treatment. The authors suggested that repetitive treatment with interferon alfa could increase the risk of type 1 diabetes in patients previously positive for islet antibodies. 

A severe acute flare of porphyria cutanea tarda has been reported in a 61-year-old man after 4 months of treatment with interferon alfa-2b plus ribavirin for chronic hepatitis C (553). No further relapse was observed after chloroquine treatment, despite continuation of the antiviral drugs. 

Carella C, Mazziotti G, Morisco F, Rotondi M, Cioffi M, Tuccillo C, Sorvillo F, Caporaso N, Amato G. The addition of ribavirin to interferon-alpha therapy in patients with hepatitis C virus-related chronic hepatitis does not modify the thyroid autoantibody pattern but increases the risk of developing hypothyroidism. Eur J Endocrinol 2002 146(6) 743-9. 

Antiviral Efficacy and Clinical Use. Ribavirin (Vira-zole) is active against several RNA and DNA viruses, including respiratory syncytial virus (RSV).106 Clinically, this drug is used to treat severe RSV pneumonia in infants and young children,106 and RSV in certain adult populations, including the elderly, people with cardiopulmonary problems, and people with a compromised immune system.29 Ribavirin may also be useful as a secondary agent in the treatment of influenza A and B in young adults. The combination of ribavirin and interferons (see section on Interferons, later) is often the treatment of choice in chronic hepatitis C infection.30 72... 

In addition to oral administration for hepatitis C infection in combination with interferon alfa (see above), aerosolized ribavirin is administered by nebulizer (20 mg/mL for 12-18 hours per day for... 

Ribavirin Interference with viral messenger RNA Lassa fever, hantavirus (hemorrhagic fever renai syndrome), hepatitis C (in chronic cases in combination with interferon a) 30-60... 

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