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Adding ribavirin to interferon alpha -2b for chronic Hepatitis C infection increased virological response and nausea

GUT 1998;43:602-602 ( November )


Reichard O, Norkrans G, Frydén A, et al, for the Swedish Study Group.

Randomised, double-blind, placebo-controlled trial of interferon alpha -2b with and without ribavirin for chronic Hepatitis C.

Lancet 1998 Jan 10;351:83-87


In patients with chronic Hepatitis C virus (HCV) infection, is the addition of ribavirin to interferon alpha -2b effective and safe?

48 week randomised, double blind, placebo controlled trial.

5 university hospitals in Sweden.

100 patients (mean age 40 y, 62% men) who had increased aminotransferase concentrations for >= 6 months, serum antibodies to HCV found by polymerase chain reaction (PCR), and a diagnosis of chronic hepatitis on a liver biopsy sample in the previous 12 months. Exclusion criteria included previous treatment with interferon alpha -2b or ribavirin, decompensated cirrhosis, autoimmune hepatitis, chronic Hepatitis B infection, HIV infection, current intravenous drug use, liver disease related to drug use, or pregnancy.

Patients were allocated to combination therapy (subcutaneous interferon alpha -2b, 3 MU three times/wk, plus ribavirin, 1000 mg daily in 2 divided doses) (n=50) or monotherapy (subcutaneous interferon alpha -2b plus a matching placebo) (n=50) for 24 weeks. Patients who weighed >= 75 kg received 1200 mg of ribavirin. 90% of patients completed 24 weeks of treatment.

Main outcome measures
Virological sustained response (absence of HCV RNA on PCR at weeks 24 and 48). Secondary outcomes were biochemical and histological responses and safety outcomes.

Main results
Analysis was by intention to treat. More patients allocated to combination therapy than to monotherapy had a virological sustained response (p=0.047) (table ). Combination therapy led to more patients with nausea (p=0.02) needing a dose reduction or discontinuing treatment than did monotherapy (p=0.03) (table ). No differences existed between groups for histological improvement.

In patients with chronic Hepatitis C infection, the addition of ribavirin to interferon alpha -2b led to an increase in sustained virological response but also to more dose reductions or treatment withdrawals and nausea.

To View This table

Interferon alpha -2b plus ribavirin (combination therapy) v interferon alpha -2b alone (monotherapy) at 48 weeks in chronic Hepatitis C virus infection*



Sources of funding: Schering-Plough AB, Sweden; Schering-Plough International.

For correspondence: Dr O Weiland, Department of Infectious Diseases, Karolinska Institute, Huddinge University Hospital, S-141 86 Huddinge, Sweden.


Treatment with alpha  interferon is widely recommended for chronic Hepatitis C.1 However, the clinically relevant outcome of sustained response---that is, no HCV RNA in serum by PCR and normalisation of alanine aminotransferase (ALT) persisting after treatment for more than 6 months---is found in only about 15% of patients. Lower response rates are observed in patients with genotype 1, those with a high viral load, or cirrhosis at start of therapy.2 Ribavirin is an oral nucleoside analogue that lowers serum ALT in chronic Hepatitis C but its effect on HCV replication is minimal.

Reichard et al carried out a large, double blind, randomised controlled trial to assess the efficacy and safety of combination therapy with interferon and ribavirin. One hundred consecutive patients without previous treatment with interferon or ribavirin entered the trial and received either alpha  interferon 3 MU three times weekly plus placebo daily, or interferon plus ribavirin 1-1.2 g daily for 24 weeks. Follow up lasted for another 24  weeks.

Significantly more patients on combination therapy (16/50) than on interferon monotherapy (6/50) needed a reduction in dose or discontinued treatment; depression, nausea and a decrease in haemoglobin were more common in the combination therapy group. A sustained response was seen in 18 (36%) patients on combination and in 9 (18%) on interferon monotherapy (p<0.05). Subgroup analysis indicated particularly enhanced efficacy of combination therapy in patients with a high viral load (>= 8 MEq/ml by bDNA, Chiron), whereas no effect could be shown in patients with genotype 1b.

This relatively large trial was designed and executed according to modern standards, and virological assays were of high quality. However, the number of patients inthe study was too small to allow subgroup analysis with confidence.

The potential clinical impact of the Swedish findings is that combination of interferon with ribavirin will be regarded as the treatment of choice for patients with chronic Hepatitis C and an indication for antiviral treatment. However, the greater number of side effects and the considerably higher cost of combination therapy compared with interferon monotherapy will mean that this treatment will probably not be universally applied. Interferon monotherapy will suffice for 10-20% of patients, and additional subgroup analysis is needed to identify those individuals. Furthermore, many patients do not respond to combination treatment, which should be suspended if HCV RNA is detected after 12 weeks. Such a cost effective strategy, coupled with the now appreciable chance to eradicate the virus as suggested by long term follow up studies,3 should widen the application of treatment in chronic Hepatitis C.


Department of Hepatogastroenterology, Erasmus University Hospital Rotterdam – Dijkzigt, PO Box 2040, 3000 CA Rotterdam, The Netherlands (email: devlaming@inw2.azr.nl)


  1. Anonymous. National Institutes of Health Consensus Development Conference Panel statement: management of Hepatitis C. Hepatology 1997;26(suppl 1):2-10S.
  2. Brouwer JT, Nevens F, Kleter B, et al. Efficacy of interferon dose and prediction of response in chronic Hepatitis C: Benelux study in 336 patients. J Hepatol 1998;28:951-959.
  3. Marcellin P, Boyer N, Gervais A, et al. Long-term histologic improvement and loss of detectable intrahepatic HCV RNA in patients with chronic Hepatitis C and sustained response to interferon-alpha therapy. Ann Intern Med 1997;127:875-881.

© 1998 by Gut