Sequential versus concomitant administration of ribavirin and interferon alfa-n3 in patients with chronic hepatitis C not responding to interferon alone: Results of a randomized, controlled trial

Abstract

We conducted a three-arm, randomized trial in 96 patients with chronic hepatitis C who did not respond to interferon alfa to compare treatments. Group 1 (33 patients) received ribavirin alone (1,000 mg/daily for 6 months) followed by interferon alfa n-3 alone (3 MU thrice weekly for 6 months); group 2 (33 patients) received ribavirin plus interferon alfa n-3 for 6 months at the above doses; and group 3 (30 patients) received interferon alfa n-3 alone (3 MU thrice weekly for 6 months). At the end of treatment, 3 patients (10%) in group 1, 13 (41%) in group 2, and 5 (17%) in group 3 had normal alanine transaminase (ALT) levels (group 2 vs. groups 1 and 3, P ‫؍‬ .008). After 6 months of follow-up, only 4 patients (12.5%) in group 2 still had normal ALT values (P ‫؍‬ .03). At the end of therapy, hepatitis C virus (HCV) RNA was no longer detectable by polymerase chain reaction in 4 (13%), 9 (27%), and 2 (7%) patients, respectively, in groups 1, 2, and 3 (P ‫؍‬ NS). Six months posttherapy, only 5 (15%) patients in group 2 were still HCV RNA negative (P ‫؍‬ .02). At the time of follow-up liver biopsy, performed 6 months after the end of treatment, a significant improvement of the necroinflammatory scores was observed among group 2 patients (P ‫؍‬ .01) but not in the other two groups. Side effects reflected the profile of each drug as monotherapy; mild hemolytic anemia was the most frequent side effect caused by ribavirin. In conclusion, concomitant administration of ribavirin and interferon alfa n-3 was significantly superior to the sequential schedule or interferon alfa n-3 monotherapy in inducing a sustained response in patients with chronic hepatitis C who had not responded to interferon alone. However, combination therapy at the dose and duration adopted in this study is capable of modifying the natural course of the disease in only a minority of these patients. (HEPATOLOGY 1998;28:341-346.)Interferon (IFN) monotherapy induces a permanent remission in a minority of treated patients with chronic hepatitis C. 1 Patients in whom IFN monotherapy is not effective do not respond to either initial or repeat IFN therapy. Their alanine transaminase (ALT) levels do not normalize, even during IFN administration. 2,3 Thus, retreatment of nonresponders with IFN alone generally is considered ineffective. 4 Pilot studies 5,6 using ribavirin (a broad-spectrum antiviral drug given by mouth) with IFN have reported sustained responses in approximately 40% of patients who had a relapse or no response to IFN alone. Further studies have shown that the response to combination therapy is significantly different between patients who had no response to IFN and those who had a response while undergoing therapy but then relapsed; with combination therapy a sustained response is observed in most relapsers but in only few nonresponders. 7,8 A recent meta-analysis 9 has shown that the estimated probability of sustained response after IFN-ribavirin combination therapy is approximately 16% for previous IFN nonresponders; the standard schedule curr...

Efficacy of interferon alpha-2b induction therapy before retreatment for chronic hepatitis C

“…In Study 2, the rates of SVR by ITT analysis were 20% for induction vs. 24% for non-induction, and 45% vs. 46% by non-ITT analysis. The rates of SVR observed here are comparable with the results of other studies demonstrating low response rates (11-18%) for retreatment of chronic hepatitis C, especially among previous nonresponders to IFN monotherapy or IFN plus ribavirin combination therapy (7,8,10,11). The rationale for induction therapy is that higher IFN doses are correlated with a faster decline of viral load, which in turn appears to correlate with higher rates of SVR (12)(13)(14).…”

Meta‐analysis: ribavirin‐induced haemolytic anaemia in patients with chronic hepatitis C

“…Only 17 studies clearly presented the haematological outcome information of interest and were included in our analysis. 3,4,[14][15][16][17][18][19][20][21][22][23][24][25][26][27][28] These 17 studies, published between 1993 and 1999, with the number of study subjects ranging from 20 to 912, and a total of 3520 chronic hepatitis C patients, are summarized in Table 1. Their quality scores were in the range 4-12.…”

“…The mean age of the patients ranged from 33 to 49 years, and the proportion of male patients ranged from 40% to 100%. The proportion of patients with liver cirrhosis enrolled in each study varied: 45% and 25% in the studies of Brillanti et al 18 and Sostegni et al, 28 respectively, compared with 0% in those of Lai et al 25 and Chemello et al 19 None of these 17 studies provided results of the haematological outcome of interest separately for males vs. females, or for patients with cirrhosis vs. those without cirrhosis. The treatment regimens employed in these studies were quite diverse with different types of interferon being used in combination with ribavirin simultaneously or sequentially.…”

Potential Benefits of Sequential Inhibitor-Mutagen Treatments of RNA Virus Infections

“…Subsequent treatments, once HCV had been identified, involved IFN-α alone or in combination with R [92],[93]. Some early clinical trials documented benefits of a combination [IFN-α,+R] treatment versus either treatment with IFN-α alone, or sequential treatment first with R and then with IFN-α, in chronic HCV infections [94]. More recent trials established a higher efficacy of PEG-IFN-α over conventional IFN-α, in combination treatments with R [95].…”