Hepatitis C Information Central

Background

Only a small fraction of chronic Hepatitis C virus (HCV) infected patients will achieve long-term benefit with viral eradication from standard interferon treatment. ^1-3 Furthermore, patients with autoimmune disorders, thyroid dysfunctions, decompensated cirrhosis, thrombocytopenia, and posttransplant patients, usually are withheld from interferon therapy due to the risk of serious adverse reactions. Thus, the need for alternative treatments for chronic HCV infection is evident. Presently, ribavirin (1-beta-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide), a guanosine analogue with a broad spectrum of activity against several RNA and DNA viruses including the flavivirus family, is the most extensively evaluated and promising alternative. ⁴ Ribavirin is usually well tolerated and has the advantage of oral administration. The exact mode of action is poorly understood. Possible mechanisms include depletion of the intracellular triphosphate pools through the direct inhibition of inosine monophosphate dehydrogenase, inhibition of the 5'-cap structure of viral mRNA, and inhibition of the viral dependent RNA polymerases. Moreover, it has recently been proposed that ribavirin does not act as an antiviral drug, but rather as an inhibitor of macrophage pro-inflammatory cytokines and as an immune modulator preserving the Th1 and reducing the Th2 cytokine production. ⁵ Unfortunately, it is not possible to test drugs including ribavirin for antiviral effect against HCV in vitro, since no tissue culture system is readily available for HCV replication.

Ribavirin Monotherapy Studies

Ribavirin as therapy for chronic HCV infection was first suggested 1991 in a pilot study from Sweden. ⁶ Ten HCV patients were treated with oral ribavirin at a dose of 1000 - 1200 mg/day for 12 weeks. A significant reduction of mean serum transaminase levels during treatment, with a subsequent relapse when treatment was withdrawn, was seen. The effect on HCV replication, as measured by polymerase chain reaction (PCR) in serum, was disappointing. No patient cleared viremia during treatment in spite of normalization of transaminases. ⁷ Several uncontrolled studies later confirmed these initial results. ^8,9

Recently, two randomized, double-blind, placebo-controlled ribavirin trials were reported. ^{10, 11} The results were consistent with previous uncontrolled studies. Thus, a biochemical response with reduction of transaminase levels during treatment was seen in ribavirin treated patients, whereas no virological eradication was achieved (Table 1). However, a slight but significant decline of serum HCV RNA levels during treatment as measured by branched DNA assay was seen in the ribavirin group. ¹¹ After treatment, rebound to pretreatment levels was noted. The necro-inflammatory activity, particularly periportal and intralobular inflammation, was significantly reduced for patients treated with ribavirin when liver biopsies from before and at the end of treatment were compared. The predominant adverse events noted were hemolysis (necessitating a dose reduction in 13 percent of patients), nervous system disorders (fatigue, depression, insomnia, and vertigo), gastrointestinal disorders (anorexia and nausea), and skin disorders (pruritus, rash, and eczema).

Interferon / Ribavirin Combination Studies

In order to improve response rates and to minimize drug resistance, combination therapy is of value in many infectious diseases. The combination of interferon and ribavirin as therapy for chronic HCV infection thus seemed reasonable. Pilot studies have shown that approximately 80 percent of relapsers and 10-25 percent of nonresponders to previous interferon therapy will have a sustained virological and biochemical response when ribavirin is combined with interferon during a 24-week treatment course. ^12-14 In an Italian study, 45 interferon-naive chronic HCV patients were randomized in three groups (1:1:1) to receive either alpha interferon alone, ribavirin alone, or alpha interferon in combination with ribavirin. Standard doses of interferon (3 million units [MU] thrice weekly) and ribavirin (1,000-1,200 mg/day) were used. The sustained virological response rate was 0 percent in the ribavirin group, 13 percent in the interferon group, and 47 percent in the combination group. ¹⁵ Similar results were obtained in an open study from Sweden where 7/14 (50 percent) of interferon-naive patients had a sustained response to combination treatment. ¹⁶ Furthermore, a recent long-term followup study from Taiwan reported sustained virological response 2 years after stopping treatment in 9/21 (43 percent) of patients treated with interferon / ribavirin vs. only 1/19 (6 percent) of patients treated with interferon alone (p=0.017). ¹⁷

A randomized double-blind placebo-controlled study comprising 100 interferon-naive chronic HCV patients has been performed by our group in Sweden. ¹⁸ All patients were treated with interferon alfa-2b 3 MU thrice weekly, in combination with either ribavirin 1,000-2,000 mg/day (n=50) or placebo (n=50) for 24 weeks. The followup period after treatment was 24 weeks. The study groups were comparable with regard to age, gender, mode of transmission, liver histology, pretreatment ALT level, pretreatment HCV RNA level, and genotype. Preliminary results confirmed those of previous pilot studies. Thus the sustained virological response rate was 45 percent in the combination group vs. 23 percent in the interferon group (p<0.05). In the combination group, significantly more patients either required reduction in dose or withdrew from treatment due to adverse events, primarily anemia, fatigue, and depression.

Moreover, in order to prevent recurrent HCV in the posttransplant setting, ribavirin alone or in combination with alpha interferon seems to offer promising results. ^{19, 20}

Discussion

Ribavirin alone is apparently not the answer to antiviral therapy for chronic HCV infection, since it does not achieve eradication of the viremia. Nevertheless, ALT levels frequently normalize, and more importantly, histological activity improves during therapy. Ribavirin is also generally well tolerated, with a mild, dose-dependent, and reversible hemolysis being the predominant adverse reaction. For nonresponders to interferon therapy, and for patients where interferon cannot be used, maintenance therapy with ribavirin could be an option. However, the long-term consequences of continuous hemolysis have not been fully elucidated. Hemolyzed red blood cells release iron, and significantly increased hepatic iron stores have been noted after prolonged ribavirin therapy. ²¹

Combination treatment with interferon and ribavirin for 24 weeks is clearly associated with higher sustained response rates than interferon alone. However, many questions remain to be solved. Should all HCV patients receive combination treatment as a first choice, regardless of genotype, pretreatment viral load, liver histology, or other factors shown to be predictive of sustained response to interferon monotherapy? What are the optimal dose and duration of combination therapy? Should relapsers of 24 weeks of combination therapy receive prolonged combination treatment courses? Do patients tolerate prolonged combination therapy? What is the optimal treatment for nonresponders to combination therapy? Should patients with unfavorable prognostic pretreatment factors like cirrhosis, genotype 1b, and/or high pretreatment viral loads receive more aggressive and prolonged combination treatment courses? Is the risk for drug resistance diminished by combination treatment?

Ongoing international, randomized, multicenter, placebo-controlled studies comparing 24- and 48-week treatment with interferon alone vs. combination treatment, in naive, chronic HCV patients, will answer some of these questions in the forthcoming years. Controlled combination studies in relapsers after prior interferon treatment, and ribavirin dose-finding studies, are also in progress.

References

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15. Chemello L, Cavaletto L, Bernardinello E, Guido M, Pontisso P, Alberti A. The effect of interferon alfa and ribavirin combination therapy in native patients with chronic Hepatitis C. J Hepatol 1995;23 (suppl 2):8-12.

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17. Lai M-Y, Kao J-H, Yang P-M, et al. Long-term efficacy of ribavirin plus interferon alfa in the treatment of chronic Hepatitis C. Gastroenterology 1996;111:1307-12.

18. Reichard O, Norkrans G, Fryden A, et al. Alfa-interferon and ribavirin versus alfa-interferon alone as therapy for chronic Hepatitis C: a randomized, double-blind, placebo-controlled study. Hepatology 1996;24:356A.

19. Gane E, Lo S, Portman B, Lau J, Naoumov N, Williams R. A randomized study of the safety and efficacy of ribavirin vs. intereron monotherapy for recurrent HCV infection in liver transplant recipients. Hepatology 1996;24:293A.

20. Bizzolon T, Palazzo U, Chevallier M, Dicerf C, Trepo C. HCV recurrence after OLT: a pilot study of ribavirin therapy following initial combination with IFN. Hepatology 1996;24:293A.

21. Di Bisceglie A, Bacon B, Kleiner D, Hoofnagle J. Increase in hepatic iron stores following prolonged therapy with ribavirin in patients with chronic Hepatitis C. J Hepatol 1994;21:1109-12.