• Only 15-20% of patients with chronic hepatitis C achieve a sustained virological response with interferon therapy alone.
• interferon alfa-2b (3 MU/t.i.w.) + ribavirin (1, 200 mg/d) for 48 weeks has led to virus eradication in up to 43% of a large treatment-naive patient population.
  
• Compared with interferon therapy alone, interferon alpha-2b plus ribavirin doubles the virologic response rate in previously untreated patients infected with hepatitis C virus.
• The International Hepatitis Interventional Therapy Group, led by Dr. Thierry Poynard, of Universite Paris VI, in France, compared the virologic response of 832 treatment-naive, chronic hepatitis C patients receiving combination therapy versus standard interferon monotherapy for 24 and 48 weeks.
• Group A) : 3 (MU) interferon alpha2b t.i.w + 1000-1200 mg ribavirin per day for 48 weeks;
  Group B): 3 MU interferon alpha2b t.i.w. + 1000-1200 mg ribavirin per day for 24 weeks;
  Group C): 3 MU interferon alpha2b t.i.w. + placebo for 48 weeks.
• After treatment was completed, patients were followed up on weeks 4, 8, 12, and 24.
• The primary endpoint was loss of detectable HCV-RNA (serum HCV-RNA <100 copies/mL) ... at week 24 after treatment.
• At 24 weeks post-treatment, a "sustained virologic response" in 43% of patients who received combination therapy for 48 weeks, in 35% of those who received combination therapy for 24 weeks, and in 19% of those administered interferon monotherapy for 48 weeks were observed.
  Group A): 119 (43%) of the 277 patients
  Group B): 97 (35%) of the 277 patients (p=O.055)
  Group C): 53 (19%) of the 278 patients (p<0.001 vs both combination regimens, intention-to-treat analysis).
• Five independent factors significantly associated with response: 1) genotype 2 or 3, 2) viral load less than 2 million copies/mL, 3) age 40 years or less, 4) minimal fibrosis stage, and 5) female sex.
• Only the known side effects of each drug given as monotherapy were observed. Discontinuation of therapy for adverse events was more frequent with combination (19%) and monotherapy (13%) given for 48 weeks than combination therapy given for 24 weeks (8%).
  Poynard, T; et al.:

• Background. Only 15 to 20 percent of patients with chronic hepatitis C have a sustained virologic response to interferon therapy. Authors compared the efficacy and safety of recombinant interferon alfa-2b alone with those of a combination of interferon alfa-2b and ribavirin for the initial treatment of patients with chronic hepatitis C.
• 912 patients with chronic hepatitis C to receive standard-dose interferon alfa-2b alone or in combination with ribavirin (1000 or 1200 mg orally per day, depending on body weight) for 24 or 48 weeks.
• Efficacy was assessed by measurements of serum hepatitis C virus (HCV) RNA and serum aminotransferases and by liver biopsy.
• Group A) : 3 (MU) interferon alpha2b t.i.w + 1000-1200 mg ribavirin per day for 48 weeks;
  Group B): 3 MU interferon alpha2b t.i.w. + 1000-1200 mg ribavirin per day for 24 weeks;
  Group C): 3 MU interferon alpha2b t.i.w. alone for 48 weeks;
  Group D): 3 MU interferon alpha2b t.i.w. alone for 24 weeks.
• Results:
  • The rate of sustained virologic response (defined as an undetectable serum HCV RNA level 24 weeks after treatment was completed) was higher in Group A) --- 87/228 (38%) and B) --- 70/228 (31%) than in Group C) --- 29/225 (13%) and D) --- 13/231 (6%). (P<0.001 for the comparison of interferon alone with both 24 weeks and 48 weeks of combination treatment).
  • Among patients with HCV genotype 1 infection, the best response occurred in those who were treated for 48 weeks with interferon and ribavirin.
  • Histologic improvement was more common in patients who were treated with combination therapy for either 24 weeks (57 percent) or 48 weeks (61 percent) than in those who were treated with interferon alone for either 24 weeks (44 percent) or 48 weeks (41 percent).
  • The drug doses had to be reduced and treatment discontinued more often in patients who were treated with combination therapy.
• Conclusions. In patients with chronic hepatitis C, initial therapy with interferon and ribavirin was more effective than treatment with interferon alone.

• Background. Interferon alfa is the only effective treatment for patients with chronic hepatitis C. Forty percent of patients have an initial response to this therapy, but most subsequently relapse. Authors compared the effect of interferon alone with that of interferon plus oral ribavirin for relapses of chronic hepatitis C.
• A total of 345 patients with chronic hepatitis C who relapsed after interferon treatment.
  Group A): 173 patients --- standard-dose recombinant interferon alfa-2b concurrently + ribavirin (1000 to 1200 mg orally per day, depending on body weight) for six months
  Group B): 172 patients --- interferon + placebo.
• Results:
  • At the completion of treatment, serum levels of hepatitis C virus (HCV) RNA were undetectable in Group A) --- 141/173 (82%), and in Group B) --- 80/172 (47%), P<0.001).
  • Serum HCV RNA levels remained undetectable 24 weeks after the end of treatment in 84 patients (49 percent) in Group A), but in only 8 patients (5 percent) in Group B), (P<0.001).
  • Sustained normalization of serum alanine aminotransferase concentrations and histologic improvement were highly correlated with virologic response.
  • Base-line serum HCV RNA levels of 2 x 106 copies per milliliter or less were associated with higher rates of response in both treatment groups.
  • Viral genotypes other than type 1 were associated with sustained responses only in the combination-therapy group.
  • Combined therapy caused a predictable fall in hemoglobin concentrations but otherwise had a safety profile similar to that of interferon alone.
• Conclusions. In patients with chronic hepatitis C who relapse after treatment with interferon, therapy with interferon and oral ribavirin results in higher rates of sustained virologic, biochemical, and histologic response than treatment with interferon alone.

• Treatment with the standard dose of interferon alfa (3 million U three times a week for 12 months) normalizes aminotransferase concentrations and leads to the disappearance of HCV RNA from serum in approximately 40 percent of patients with chronic hepatitis C.
• However, this response is transient in the majority of patients; only 10 to 15 percent have a sustained response after treatment is stopped.
• Although longer duration (18 to 24 months) of treatment, higher doses of interferon alfa (up to 30 million U per week), and treatment with other types of interferon may improve the response, many patients still relapse. Moreover, these alternatives are costly or poorly tolerated.
• Two studies in this issue of the Journal address the role of interferon alfa-2b in combination with ribavirin for the treatment of chronic hepatitis C.
• McHutchison et al. studied the effect of this combination as an initial treatment, and Davis et al. as a treatment after relapse. The findings of both studies indicate that this combination therapy represents an important advance.
• These large multicenter, randomized, controlled trials expanded on the findings of earlier, small studies that the combination of interferon and ribavirin was more efficacious than interferon alone. Both studies reported impressive rates of sustained virologic response, defined as the absence of serum HCV RNA 24 weeks after treatment was completed, with combination therapy.
• The rate was 31 to 38 percent when combination therapy was used as the initial treatment and 49 percent when it was used for the treatment of relapse. These rates are 5 to 10 times as high as those achieved with monotherapy. The rates of histologic response were similar to the rates of virologic and biochemical response.
• The factors associated with a response to combination therapy were similar to those that predict a response to treatment with interferon alone: a low viral titer before treatment, an HCV genotype other than 1 (there are at least six genotypes), and the absence of cirrhosis before treatment.
• An interesting paradox emerges from these studies. In patients treated with interferon alone, early clearance of the virus (after 4 or 12 weeks of treatment) has been associated with a sustained virologic response. Davis et al. also found this to be true with the use of interferon and ribavirin for the treatment of relapse. In contrast, McHutchison et al. reported that in at least 50 percent of patients with a sustained response after initial treatment with interferon and ribavirin for either 24 or 48 weeks, HCV RNA was not cleared from serum until after week 12 or 24 of therapy.
• Surprisingly, there was also no significant association between early viral clearance and a sustained virologic response among patients treated with interferon alone; up to 52 percent of such patients had late viral clearance and a sustained response. Therefore, the recommendation that an early virologic response should be used as a guide to the duration of therapy should be reevaluated.
• Why is the combination of interferon and ribavirin much more effective than interferon alone for the treatment of chronic hepatitis C, and what is the mechanism of action? Unfortunately, there are no readily available answers. Treatment with ribavirin alone has no effect on serum HCV RNA levels, although it does lead to a transient decrease in aminotransferase concentrations. Therefore, ribavirin may enhance the effect of interferon, leading to a more vigorous immune response against HCV.
• McHutchison et al. found that the difference in the overall rates of sustained response between the group treated with 24 weeks of combination therapy and the group treated with 48 weeks was barely significant. The patients who would benefit the most from 48 weeks of therapy are probably those with factors that are associated with a poor response, including HCV genotype 1 and high viral titers and cirrhosis before treatment.
• In the study by McHutchison et al., 21 percent of the patients assigned to combination therapy for 48 weeks discontinued treatment because of severe side effects.
• Since the studies by McHutchison et al. and Davis et al. were carefully monitored clinical trials in tertiary academic centers and the patients were presumably highly motivated, the use of this combination in routine practice may be associated with a lower rate of efficacy, more severe side effects, and greater noncompliance.

5) Other reports on combination therapy:

• 43% sustained responder (96 wks post-teatment).
  Lai MY, Kao JH, Yang PM, et al; Long-term efficacy of ribavirin plus interferon alfa in the treatment of chronic hepatitis C. (Gastroenterology 1996 Nov;111(5):1307-12)
• 53% sustained responder if the dose of interferon in the first 12 wks has been increased to 6 MU/tiw (by Kao, JH, -- NTUH, 1998)
• Correspondence to Combination Therapy for Hepatitis C Infection.
  (New Eng J of Med: April 15, 1999 -- Vol. 340, No. 15)