Pushing the treatment envelope for chronic hepatitis C?is more necessarily better?
Authors: Glen Lutchman, Marc Ghany
Journal: Hepatology (2005)

Ribavirin is a synthetic purine analogue that has a broad spectrum of antiviral activity and is approved for use in combination with interferon for the treatment of chronic hepatitis C. Clinically, it appears to act synergistically with interferon to result in a small increase in end-of-treatment response but more importantly a doubling of the sustained virological response (SVR) rate by preventing virological relapse. In vitro, ribavirin has been shown to act as an immunomodulator, a competitive inhibitor of inosine monophosphate dehydrogenase, a direct inhibitor of the viral RNA dependent RNA polymerase and as a viral mutagen. However, it is unclear which, if any, of these mechanisms is important for its antiviral effect in vivo. SVR, sustained virological rate. The recommended therapy for patients with chronic hepatitis C is the combination of either peginterferon alfa-2a or -2b once weekly plus daily ribavirin for 48 weeks.1, 2 The recommended dose of ribavirin is dependent on the preparation of peginterferon used. In the United States, ribavirin is approved for use with peginterferon alfa-2b at a fixed dose of 800 mg daily, but in combination with peginterferon alfa-2a, ribavirin is given in a dose of 1,000 or 1,200 mg based on whether body weight is less than or greater than 75 kg, respectively. In Europe, the approved daily dose is based on weight regardless of peginterferon preparation: 800 mg for patients below 65 kg; 1,000 mg for those between 65 and 85 kg; and 1,200 mg for patients heavier than 85 kg. The decision in the United States. to approve a lower, fixed dose of ribavirin in combination with peginterferon alfa-2b was based on Food and Drug Administration concerns about the lack of data on efficacy and more importantly, the safety of higher doses of ribavirin.3 However, in a secondary analysis of the peginterferon alfa-2b plus ribavirin registration trial, body weight was identified as an important predictor of response and the European regulatory agency chose to approve weight-based ribavirin.1 The approved regimens yield similar SVR rates ranging from 54% to 63%.1, 2, 4 In an effort to improve SVR rates, investigators have experimented with different regimens by varying the dose and duration of therapy. A theme emerging from recent studies is that therapy should be tailored to different groups of patients. The current data suggest that patients with genotype 1 should be treated for 48 weeks, whereas those infected with genotypes 2 and 3 might be treated for a shorter duration of 24 weeks and perhaps as short as 14 to 16 weeks in patients who achieve an early virological response (hepatitis C virus RNA negative at treatment week 4).5 A controversial issue in chronic hepatitis C therapy is the optimal dose of ribavirin to use in combination with peginterferon and whether higher doses of ribavirin are more effective. The initial evidence supporting higher doses of ribavirin was largely indirect and evolved from a secondary analysis of the large multicenter trial of peginterferon alfa-2b and ribavirin. A logistic regression analysis revealed that, if the ribavirin dose was expressed as mg/kg, patients who received higher doses experienced the highest SVR rates.1 Using an arbitrary ribavirin dose cutoff of 10.6 mg/kg, genotype 1 patients who received the standard dose of peginterferon alfa-2b (1.5 μg/kg/wk) and higher doses of ribavirin (>10.6 mg/kg) were shown to have higher SVR rates compared with those receiving lower doses (<10.6 mg/kg), 48% versus 38%. Although suggestive that higher doses of ribavirin were better, these data should be interpreted with caution because they were derived from a secondary analysis with the potential for confounding variables and the small numbers of patients within subgroups. More compelling data came from a recent randomized trial of peginterferon alfa-2a and ribavirin which was specifically designed to assess efficacy of low-dose versus standard dose ribavirin. The results clearly showed that for genotype 1 patients treated for 48 weeks the SVR rate was superior in those receiving standard dose (1,000 to 1,200 mg) compared with those receiving low-dose ribavirin (800 mg), 52% versus 41%.4 In contrast, both studies showed no difference in the SVR rate in patients with genotypes 2 and 3 infections using ribavirin doses ranging from 800 to 1,200 mg daily. Thus, the issue can be narrowed to optimizing therapy for genotype 1 patients. In this issue of HEPATOLOGY, Lindahl and coworkers provide some further data regarding the benefit of higher doses of ribavirin for genotype 1 patients.6 They conducted a small pilot study in which they treated 10 patients with standard doses of peginterferon alfa-2a and individualized the daily dose of ribavirin to achieve a target ribavirin concentration in serum of 15 μmol/mL. The primary goal was to evaluate the safety of using higher doses of ribavirin in patients with genotype 1 and high viral load (the difficult-to-treat patient profile). To achieve the targeted serum concentration, patients required a mean ribavirin dose of 2,540 mg/day (range 1,600-3,600 mg/day), which is more than twice the currently recommend maximum daily dose. However, in an intention-to-treat analysis of 10 patients, the SVR rate was an impressive 90%. Side effects were severe, particularly hemolysis and anemia. Every patient required erythropoietin, and two patients required blood transfusion on two separate occasions. The results of this study are indeed striking but a note of caution must be struck. Foremost is the issue of safety. One of the major limitations to combination therapy is the high frequency of side effects, some of which may be serious and life-threatening. In the two large multicenter registration trials, 10% to 14% of patients required discontinuation of therapy and 32% to 42% required dose modification for serious or severe side effects.1, 2 Higher doses of ribavirin would undoubtedly lead to more side effects. Hemolytic anemia is the major risk associated with ribavirin, and, if defined as a hemoglobin level less than 10g/ dL, occurred in 7 of 10 patients. All patients required hemopoetic growth factor, two required blood transfusion and four required dose reduction or temporary discontinuation of the drug to manage side effects. Furthermore, all patients experienced a reduction in ability to work, although, quality-of-life was not specifically assessed. The need for erythropoietin, blood transfusion, and loss of work are not trivial matters particularly in the typical patient with hepatitis C who has few if any symptoms and is largely fully functional. Anemia caused by ribavirin can induce cardiovascular and cerebrovascular incidents in susceptible patients. Thus, even with intensive monitoring this high-dose ribavirin regimen can be life-threatening. Second, we should recognize that the study by Lindahl et al. was a small, nonrandomized pilot one without a control group. Finally, difficult-to-treat patients such as African Americans, those with significant comorbidities and patients with cirrhosis, all of whom have been shown to have lower SVR rates, were not included.7, 8 Another concern in today's practice environment is the cost associated with this treatment regimen. A 48-week course of standard treatment without the need for supplementary therapy or testing costs approximately 24,000 U.S. dollars.9 The additional cost associated with a high-dose ribavirin regimen would not be insignificant and include paying for a greater quantity of ribavirin, the need to monitor ribavirin levels, more frequent laboratory monitoring, use of erythropoietin, blood transfusion, additional clinic visits, hospitalizations, and time missed from work. The obvious question is whether the additional risks and costs are worth the increase in SVR. For genotype 2 and 3 patients who already have high SVR rates with standard peginterferon and low-dose ribavirin, the incremental benefit of higher ribavirin doses is likely to be minimal and not worth the added risks and costs. Similarly, it would be difficult to justify this high-dose ribavirin regimen for treatment naïve genotype 1 patients given a SVR rate of 42% to 47% with standard therapy. Such an approach would unnecessarily expose close to 50% of genotype 1 patients to a potentially more toxic therapy. For the moment, we would suggest that until more data and experience are available, this regimen should not be offered outside the setting of a clinical trial. Ideally, this approach should be evaluated in a prospective controlled trial using patients who have failed to respond to standard therapy. The finding of Lindahl and colleagues that higher doses of ribavirin may improve the SVR rate suggests that a safer ribavirin preparation is required and that ribavirin-like compounds with better safety profiles may have a role to play in therapy. Viramidine, a prodrug of ribavirin that specifically targets the liver, is associated with less hemolysis than ribavirin, and in preliminary clinical studies, seems to have similar efficacy.10 Levovirin, the L-enantiomer of ribavirin, has been disappointing thus far in clinical trials but higher doses have not been tested.11 The apparent increase in effectiveness of high-dose ribavirin over standard dose is intriguing from a mechanistic view. At higher doses, ribavirin may either augment previously proposed antiviral pathways, act through a novel mechanism or, perhaps, at higher doses more patients achieve a critical threshold of intracellular ribavirin concentration. Unfortunately, the results of Lindahl and coworkers seem to raise more questions than to provide answers as to the mechanism of action of ribavirin. Clearly more research is needed in this area. Future studies should address the dosing, pharmacokinetics, and mechanism of action of ribavirin. The rationale for choosing a target concentration of 15 μmol/L appeared to be arbitrary and not based on good pharmacokinetic and pharmacodynamic data. Lower plasma concentrations may have been as effective but it also raises the question as to whether ribavirin should continue to be administered based on body weight or dosed to achieve a target serum concentration. Another possibility is that inter-individual variations in the metabolism of ribavirin may account for differences in clinical efficacy. Thus, patients who are nonresponders to weight-based therapy may be receiving subtherapeutic doses of ribavirin. This possibility may to a certain extent explain the low SVR rates observed in two trials of peginterferon and ribavirin in human immunodeficiency virus coinfected patients12, 13 and a recent Spanish Trial of 72 weeks versus 48 weeks of peginterferon plus ribavirin for patients who fail to achieve virological clearance at week four.14 In summary, Lindahl et al.'s article is an important study whose results probably provoke more thought about ribavirin's mechanism of action than provide a practical therapeutic approach for patients with chronic hepatitis C. At present, this strategy should be reserved for the setting of controlled clinical trials and not become part of standard clinical practice. The authors are grateful to Jay Hoofnagle, M.D., for helpful discussion and suggestions during the conceptual phase of this editorial.