Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial

 Michael P Manns, John G McHutchison, Stuart C Gordon, Vinod K Rustgi, Mitchell Shiffman, Robert Reindollar, Zachary D Goodman, Kenneth Koury, Mei-Hsiu Ling, Janice K Albrecht, and the International Hepatitis Interventional Therapy Group*

 THE LANCET • Vol 358 • September 22, 2001

 ABSTRACT:

1530 patients with chronic hepatitis C were assigned interferon alfa-2b (3 MU subcutaneously three times per week) plus ribavirin 1000–1200 mg/day orally, peginterferon alfa-2b 1·5 g/kg each week plus 800 mg/day ribavirin, or peginterferon alfa-2b 1·5 g/kg per week for 4 weeks then 0·5 g/kg per week plus ribavirin 1000–1200 mg/day for 48 weeks. The primary endpoint was

the SVR rate (undetectable hepatitis C virus [HCV] RNA in serum at 24-week follow-up). Analyses were based on patients who received at least one dose of study medication.

 The SVR rate was significantly higher (p=0·01 for both comparisons) in the higher-dose peginterferon group (274/511 [54%]) than in the lower-dose peginterferon (244/514 [47%]) or interferon (235/505 [47%]) groups. Among patients with HCV genotype 1 infection, the corresponding SVR rates were 42% (145/348), 34% (118/349), and 33% (114/343). The rate for patients with genotype 2 and 3 infections was about 80% for all treatment groups. Secondary analyses identified bodyweight as an important predictor of SVR, prompting comparison of the interferon regimens after adjusting ribavirin for bodyweight (mg/kg). Side-effect profiles were similar between the treatment groups.

 REPORT

 Histological response was assessed for inflammation and fibrosis by the Knodell histological activity index. 16,17 The inflammation score was obtained by combining scores for the first three components of the Knodell index: portal, periportal, and lobular inflammation (range 0–18, with higher scores indicating more severe abnormalities); improvement was defined as a decrease in the inflammation score of at least 2 units. The Knodell fibrosis scores are 0 (no fibrosis), 1 (portal fibrosis), 3 (bridging fibrosis), and 4 (cirrhosis). 16,17 An improvement in fibrosis was defined as a decrease of 1 or more from the pretreatment to post-treatment Knodell fibrosis score, and a worsening of fibrosis was defined as an increase in this score of 1 unit or more.

 RESULTS

 Patients’ characteristics Enrolment began in March, 1998, and the trial was completed in October, 2000. A total of 2316 patients were screened, and 1530 were enrolled and treated (figure 1). All efficacy and safety analyses were based on the 1530 patients who received at least one dose of medication.

 Responses

 The SVR rate was significantly higher for the group receiving peginterferon alfa-2b at the higher dose of 1·5 g/kg per week than for the other two treatment groups (54 vs 47%, table 2). The benefit of the higher-dose regimen was most apparent for patients with genotype 1 infection, the subgroup that is most common and difficult to treat. The biochemical (alanine aminotransferase) response rates at the end of treatment were similar in the three treatment groups: 65%, 63%, and 69% for the higher-dose peginterferon, lower-dose peginterferon, and interferon groups, respectively. The sustained response rates in terms of alanine aminotransferase were higher (54%) among the group assigned the higher dose of peginterferon than in those assigned the lower dose of peginterferon (48%) or interferon alfa-2b (47%). Nearly all patients who had SVRs also had normal alanine aminotransferase values at the end of follow-up: 97% of the higher-dose peginterferon group, 92% of the lower-dose peginterferon group, and 97% of the group. The proportion of patients who cleared virus but who relapsed by the end of follow-up was low in all treatment groups (18%, 16%, and 14%, respectively). As previously shown for therapy with interferon alfa-2b plus ribavirin, late viral clearance at week 12 or 24 and subsequent SVR were also observed in patients receiving peginterferon alfa-2b plus ribavirin. In the group assigned the higher dose of peginterferon alfa-2b, 75% of patients who were HCV RNA negative for the first time at week 12 achieved SVRs, and 32% of patients who lost HCV RNA for the first time at week 24 of therapy achieved SVRs. Previous studies with interferon alfa-2b plus ribavirin have shown that, in general, if patients do not respond by

 treatment week 24, an SVR will not be achieved; a similar pattern is observed with peginterferon alfa-2b plus ribavirin. Among the patients who had no detectable viral RNA for the first time more than 24 weeks after the start of treatment, few patients achieved SVRs (four patients treated with higher-dose peginterferon alfa-2b; none treated with lower-dose peginterferon alfa-2b; and one treated with interferon alfa-2b). Biopsy samples from before and after treatment were available in 1034 (68%) patients. Histological inflammation improved in all three treatment groups (table 3). Histological improvement was also greatest in sustained responders; 90% of this subgroup had histological improvement, irrespective of the treatment regimen they received. Among non-responders, 44% (205/464) also had some evidence of histological. Improvement in fibrosis was observed in about 20% of patients in each treatment group.

Variables associated with SVR

 (Comments from Jules Levin: the question of whether or not ribavirin dosing should be weight based has been controversial. In this study, the authors take a retrospective look at the concentration of ribavirin based on the weight of the patient. And they find the higher the concentration of ribavirin the better the response to treatment. But they also find that baseline weight (lighter) is associated with SVR. To me, this makes it difficult to conclude which may be the reason for better response —lighter weight or receiving higher concentrations of ribavirin or both. The authors make a case below that concentration of ribavirin was a significant factor upon further statistical analysis. Nonetheless, these studies are retrospective and the FDA did not approve ribavirin weight based dosing when PegIntron/RBV was recently approved. The European regulatory authorities did, however, approve ribavirin weight based dosing.  Schering is conducting a large prospective study to establish the usefulness of RBV weight based dosing).

 To examine the influence of potentially important prognostic factors on SVR, factors known to affect response (HCV genotype, baseline viral load, cirrhosis, age, sex, baseline weight) were first examined individually by univariate logistic regression analysis on each factor for all treatment groups combined. HCV genotype (other than genotype 1), the baseline viral load (log; lower viral load), baseline weight (lighter), and age (younger) were clearly associated with SVR (p<0·0001), as were sex (p=0·01) and, to a lesser extent, the absence of cirrhosis (p=0·07). Since only 5–7% of patients had cirrhosis at baseline, this analysis may not have been sensitive enough to detect a clear relation between cirrhosis and SVR. However, the absence of bridging fibrosis/cirrhosis was

significantly associated with SVR (p=0·001). To assess the independence of these factors, a backward elimination procedure was then used. All variables identified by univariate analyses were retained in the final multivariate

model, except sex. Specifically, although weight was retained (p=0·03), sex was no longer significant when weight was taken into account (p=0·35). Doses of peginterferon alfa-2b are given according to the patient’s weight, because of the previous observation with interferon alfa-2b that among patients receiving 3 MU three times per week, lighter patients have higher SVR rates than heavier patients. In this study, logistic regression analysis showed that baseline weight was an important predictor of SVR. Because a single dose of ribavirin (800 mg) was used with the higher dose of peginterferon alfa-2b, the effect of the ribavirin dose adjusted for bodyweight (mg/kg) was explored. Logistic regression analyses were used to characterise further the relation between SVR and the doses of both peginterferon alfa-2b and ribavirin. The two doses of peginterferon alfa-2b were treated as a categorical variable, and the dose of ribavirin as a continuous variable, with each patient’s ribavirin dose expressed as mg/kg. The results indicate that the doses of both drugs are important and significantly predict SVR (odds ratio 1·7, p=0·002 for higher-dose vs lower-dose peginterferon alfa-2b, and slope 0·07, p=0·015 for ribavirin). Thus, the likelihood of SVR increases as ribavirin dose increases. Also, when the dose of ribavirin is controlled on a mg/kg basis, the estimated effect of the higher dose of peginterferon alfa-2b compared

 
 with the lower dose was larger (odds ratio 1·7) than the estimate obtained from the primary (as-randomised) analysis (1·3). To account for possible interaction between the two drugs, a term for the product of the two doses was included in the model. Fitted regression lines are shown in figure 2, which also shows that the observed response rates (moving average) generally increase as ribavirin dose increases up to about 13 mg/kg. The observed response rates were almost flat between 13 and 15 mg/kg; although the number of patients was small, the observed response rates did not increase after 15 mg/kg. From these results, the ribavirin dose range that allowed for adequate interpretation of both safety and efficacy data was 11–15mg/kg. Thus, for an average 75 kg man, doses of

10·6 mg/kg, 13·2 mg/kg, and about 15 mg/kg represent daily doses of 800 mg, 1000 mg, and 1200 mg ribavirin, respectively. SVR rates are presented in table 4 according to weight-based ribavirin dose (10·6 mg/kg or less, and more than 10·6 mg/kg) according to treatment group and stratification factors. The SVR rate was higher in all groups when the dose of ribavirin was greater than 10·6 mg/kg bodyweight, which is the lower end of the optimum dose range. For genotype 1 patients who received more than 10·6 mg/kg ribavirin the SVR rate was in the higher-dose peginterferon group than in the other two groups.

  Influence of other prognostic or potentially confounding factors

 Both the fitted regression lines and the observed response rates show that the likelihood of an SVR can be increased in patients treated with the higher dose of peginterferon alfa-2b by increasing the ribavirin dose into the range obtained by the 1000–1200 mg dosing schedule in the other two treatment groups. However, because these analyses were not based on direct comparisons of the as randomised treatment groups, we had to assess the potential for imbalances in important prognostic factors to bias the assessment of treatment effects. An obvious potential confounding factor is sex, since women tend to weigh less than men and therefore receive higher doses of ribavirin per unit of bodyweight. To confirm the importance of treatment effects after the potentially confounding factors were taken into account, multivariate logistic regression analyses were done. Each analysis included treatment effects, interferon alfa-2b dose (1·5 g/kg per week vs others), and ribavirin dose (mg/kg), as well as HCV genotype and (log) baseline viral load. Other potential confounding factors identified above (ie, sex, age, bridging fibrosis/cirrhosis) were then added one at a time. In each case, both treatment effects (peginterferon alfa-2b and ribavirin) remained significant after all other factors were taken into account, and both genotype and baseline viral load were independent predictors of response (p<0·0001). When the dose of ribavirin was expressed as mg/kg, sex was not significant (p=0·54). Similarly, weight was no longer significant (p=0·30) after control for ribavirin dose (mg/kg). Age and the presence of bridging fibrosis/cirrhosis remained independent predictors of response (p<0·01).

 Safety evaluation

 The side-effect profiles of peginterferon alfa-2b plus ribavirin and interferon alfa-2b plus ribavirin were similar; there were no new or unique adverse events (table 5). The rate of several influenza-like symptoms was higher in the higher-dose peginterferon group than in the interferon alfa-2b group, probably because a higher dose of interferon alfa-2b is administered via the peginterferon formulation. As previously reported with peginterferon alfa-2b monotherapy, there was a substantial increase in injection-site reactions compared with interferon alfa-2b. In all cases, the characteristics of the reaction were similar for both interferon alfa-2b and peginterferon alfa-2b. The typical event was generally mild, not treatment-limiting, and characterised by localised erythema. Anaemia is a well-recognised effect of ribavirin, and the pattern that has been previously observed was seen in this study. The optimum treatment regimen of peginterferon alfa-2b 1·5 g/kg plus ribavirin did not result in a greater fall in haemoglobin; the mean decreases at weeks 4–8 were the same (25 g/L), for both that group and the standard interferon group. A decrease in haemoglobin to less than 100 g/L, the protocol requirement for dose modification, occurred in 9% of patients receiving the higher-dose peginterferon alfa-2b plus ribavirin regimen and 13% of patients receiving interferon alfa-2b. Discontinuation for anaemia was rare.

 The frequency of dose reduction for neutropenia according to the protocol was 18% for the higher-dose peginterferon alfa-2b plus ribavirin regimen compared with 8% for interferon alfa-2b plus ribavirin. However, or 1% less of patients discontinued treatment for neutropenia, which suggests that the dose-modification schedule included in the protocol provided good protection for the patient. The effect of combination therapy on platelet counts reflects a balance between the effects of interferon alfa-2b and ribavirin; the former reduces platelet counts, while the latter is associated with a reactive thrombocytosis. 3% of patients in the higher-dose peginterferon group and 1% in the interferon alfa-2b group had a platelet decrease that reached the protocol-defined criterion for dose reduction. No patient discontinued therapy owing to thrombocytopenia. No significant increase in alanine aminotransferase (greater than five times baseline) was observed in any patient during the study. Rises in alanine aminotransferase more than two times baseline were infrequent, occurring in 3%, 2%, and 1% of patients receiving ribavirin in combination with higher-dose peginterferon, lower-dose peginterferon, and standard interferon alfa-2b, respectively. The safety profile for patients receiving a dose of more than 10·6 mg/kg ribavirin with either interferon formulation was similar. Only a few adverse events were more frequent (>10% difference) in this group (asthenia, weight loss, nausea, and alopecia).

 Among patients receiving more than 10·6 mg/kg ribavirin, dose modification was more frequent with alfa-2b than with interferon alfa-2b (49% vs 34%), with most of the difference due to neutropenia in the peginterferon alfa-2b group. By contrast, the discontinuation rate in the two treatment groups was similar, 14% vs 13%, respectively. A decrease in haemoglobin to less than 100 g/L or the need for dose reduction owing to anaemia were neither more frequent nor of greater severity in patients who received the higher dose of peginterferon alfa-2b and ribavirin more than 10·6 mg/kg.

 Discussion

 Late viral clearance was infrequently associated with eventual SVR in this study. Only one of 403 patients who received either dose of peginterferon alfa-2b plus ribavirin and who had detectable HCV RNA at week 24 of therapy showed an SVR, which is consistent with previous studies in patients treated with standard interferon alfa-2b plus ribavirin. This finding supports the current recommendation to consider stopping therapy at week 24 in genotype-1-infected patients with persistent viraemia. However, such a strategy does not take into account a report that hepatitis C patients treated with interferon-based regimens who do not achieve eradication of HCV RNA from serum or normalisation of liver enzymes may derive some short-term histological benefit.

20 Further prospective trials are in progress to find out whether these potential antifibrotic effects of interferon will be valuable in preventing disease and fibrosis progression. As in previous studies, 5% of patients had persistent rises in alanine aminotransferase during follow-up, but they had eradicated HCV RNA from serum and were classified as sustained responders. 21 The reasons for these discordant results remain unclear, but previous studies have also indicated that some of these patients may have steatosis or other potential causes for the persistently abnormal biochemical results. 14 The most effective therapy for the initial treatment of suitable patients with chronic hepatitis C according to this study is the combination of 1·5 g/kg per week of peginterferon alfa-2b with ribavirin. Because of the improved response rate and more convenient once-weekly administration schedule, this regimen will replace the current standard of interferon alfa-2b plus ribavirin.

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