www.elsevier.com/locate/jhep

Journal of Hepatology 47 (2007) 7–9

Editorial

Anemia and clinical outcomes in hepatitis C q

Yves Benhamou*

Service d’Hepato-Gastroenterologie, Groupe Hospitalier Pitie-Salpetriere and Universite Pierre et Marie Curie,

47 Boulevard de l’Hopital, 75651 Paris Cedex 13, France

See Article, pages 51–59

Combination therapy with pegylated interferon andribavirin is currently the most effective treatment forchronic hepatitis C (CHC), and rates of sustained viro-logical response (SVR) now exceed 50% [1,2]. Yet asSVR rates have increased, so have rates of treatment-related anemia. Anemia is a common consequence ofantiviral treatment for CHC and may occur in as manyas half of all treated patients [3–5]. In two recent clinicaltrials, dose reductions due to anemia occurred in 0–3%of patients treated with 48 weeks of standard or pegylat-ed interferon monotherapy, in up to 19% of patientstreated with a combination of standard interferon andribavirin, and in up to 22% of patients treated withpegylated interferon and ribavirin [1,2]. Dose reductionshave also been demonstrated in as many as 36% ofpatients treated with pegylated interferon and ribavirinin a clinical practice setting [6].

Both standard and pegylated interferon have beenshown to cause mild anemia, mediated by bone marrowsuppression, and may reduce hemoglobin concentra-tions by at least 2 g/dL in approximately 25–30% ofpatients [4,5]. Ribavirin is associated with a well-described, dose-dependent hemolytic anemia that leadsto hemoglobin decreases of at least 2 g/dL in as manyas 80% of patients and maximum decreases of at least4 g/dL in as many as 20% of patients [7]. This anemiais mediated by the transport of ribavirin into the eryth-rocyte, which does not contain the phosphatases neces-sary to hydrolyze ribavirin metabolites. These

0168-8278/$32.00 � 2007 European Association for the Study of the Liver.

doi:10.1016/j.jhep.2007.04.007

q Prof. Yves Benhamou declares that he was the prime investigatorof one of the pivotal studies with taribavirin and he has participated onadvisory boards organized by Valeant 2 years ago.

* Tel.: +33 1 42161041; fax: +33 1 42161425.E-mail address: ybenhamou@teaser.fr

accumulate and eventually lead to extravascular hemo-lysis [8]. The anemia associated with ribavirin is mostsevere early in the course of therapy and typicallyresolves within 4–8 weeks of ribavirin discontinuation[3].

Anemia is associated with fatigue and decreased qual-ity of life, and has a substantial negative impact on anti-viral outcomes, as it frequently necessitates dosereduction, which leads to lower rates of SVR [2,9].Recent studies demonstrate that ribavirin dose reduc-tions early in therapy may especially compromise SVRrates [10–12]. Therefore, it is essential to maintain riba-virin dose in patients undergoing antiviral therapy forCHC [9].

A common strategy to maintain ribavirin dosewhen anemia occurs is the use of recombinant humanerythropoietin (rHuEPO). While generally consideredto be safe and effective at reversing ribavirin-inducedanemia, rHuEPO adds to the cost of treatment andis associated with rare side effects [13]. In addition,no current evidence demonstrates increased SVR ratesamong patients with ribavirin-associated anemia trea-ted with rHuEPO [14].

Alternate adjunctive therapies with lower associatedrates of anemia in conjunction with pegylated interferonmay decrease the risk of ribavirin-related hemolytic ane-mia, thereby decreasing the rate of dose reductions anddrug discontinuations in patients treated with combina-tion antiviral therapy. Taribavirin (previously known asviramidine; Valeant Pharmaceutical International,Costa Mesa, CA, USA) is a liver-targeting, syntheticnucleoside (guanosine) analogue that is converted intoribavirin by adenosine deaminase present primarily inhepatocytes [15,16]. Taribavirin is preferentially takenup in the liver and thus specifically targets the primary

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8 Y. Benhamou / Journal of Hepatology 47 (2007) 7–9

site of hepatitis C virus (HCV) infection. It is not trans-ported efficiently into red blood cells, which may explainthe lower rates of anemia when compared with ribavirin[17,18].

In this issue of the Journal, Gish et al. examine thesafety and efficacy of taribavirin in treating patientswho have CHC [19]. This phase II, multicenter, random-ized, active-controlled study was conducted in 180 treat-ment-naıve patients with CHC and assessed virologicoutcomes and safety of taribavirin. Patients were ran-domized in a 1:1:1:1 ratio to receive pegylated interferonalfa-2a 180 lg once weekly (Pegasys�, Hoffmann-LaRoche Inc., Nutley, NJ, USA) plus taribavirin in a fixeddose of 800, 1200, or 1600 mg given QD or ribavirin(Rebetol�, Schering Corporation, Kenilworth, NJ,USA) in a weight-based dose of 1000 mg or 1200 mg/day QD. The efficacy end points of this study includedthe proportion of patients with undetectable serumHCV RNA concentrations at treatment week 12, rateof SVR, and SVR broken out by viral genotype. Safetyvariables included the proportion of patients with 2.5 g/dL or greater decrease in hemoglobin concentration attreatment week 4, as well as the proportion of patientswith hemoglobin concentrations less than 10 g/dL anytime during treatment.

A total of 191 patients were screened and random-ized, and 180 received at least one dose of the studydrug. Analysis of the efficacy variables revealed no sig-nificant differences between any treatment groups inthe proportion of patients with undetectable HCVRNA at any of the time points assessed, regardless ofHCV genotype. There were also no significant differ-ences in SVR rates between any of the treatment groups.Differences did exist, however, in rates of anemia. Com-pared with those treated with ribavirin, patients treatedwith taribavirin 800 or 1200 mg had significantly lowerrates of hemoglobin (<10 g/dL) at any point in thestudy. In addition, significantly fewer patients treatedwith any dose of taribavirin had hemoglobin decreasesof 25% or less from baseline to the end of treatment thanthose treated with ribavirin.

The authors concluded that taribavirin, especially at adose of 1200 mg/day, is as effective as ribavirin whenused in combination with pegylated interferon alfa-2aand is associated with lower rates of anemia. It wasbecause of these results that the 600 mg BID dose oftaribavirin was chosen for the subsequent phase IIIVISER (VIramidine’s [taribavirin’s] Safety and Efficacyversus Ribavirin) trials. VISER 1 and 2 examined thesafety and efficacy of taribavirin in combination withpegylated interferon alfa-2b or alfa-2a, respectively.Safety results from these trials were consistent with thecurrent phase II trial in demonstrating lower rates ofanemia for the taribavirin groups compared with ribavi-rin (5–6% versus 22–24%) [16,20]. Neither trial, however,met its primary non-inferiority efficacy end point (SVR).

Although the results of the current study are promis-ing, the subsequent phase III trials raise questions aboutthe sufficiency of the taribavirin 1200 mg/day dose incombination with pegylated interferon for treatingCHC. It is possible that the lack of weight-based dosingfor taribavirin in these trials was responsible for theobserved outcomes. Dosing by weight is accepted prac-tice in the treatment of CHC, and recent data haveshown a direct correlation between increasing bodyweight and decreasing rate of SVR during fixed-weightdosing [21]. The weight-based dosing of ribavirin inthe VISER studies may have therefore conferred anadvantage to patients treated with that regimen. A phaseIIb study utilizing weight-based dosing has been under-taken to resolve any questions regarding the efficacy oftaribavirin.

The mechanism by which ribavirin acts to enhanceSVR remains obscure. There is no doubt that inter-feron-based therapy will remain the backbone of futureanti-HCV regimens. While many believe that ribavirin iscurrently necessary to optimize SVR, it is unknownwhether it will maintain the same importance in theera of anti-HCV treatment with protease and polymer-ase inhibitors. Ongoing studies with new antiviral agentswill provide more data on the importance of ribavirin(or eventually taribavirin) in the future treatment ofchronic hepatitis C.

The current study shows that taribavirin is as effectiveas ribavirin when used in combination with pegylatedinterferon alfa-2a to treat CHC and has a significantlybetter hematologic profile. Because of taribavirin’sliver-targeting mechanism of action, there should beno reason to believe that it would be any less efficaciousthan ribavirin, which makes the results of the VISER tri-als all the more surprising. The ongoing phase IIb trialshould substantially clarify taribavirin’s role in the treat-ment of CHC.

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[2] Manns MP, McHutchison JG, Gordon SC, Rustgi VK, ShiffmanM, Reindollar R, et al. Peginterferon alfa-2b plus ribavirincompared with interferon alfa-2b plus ribavirin for initial treat-ment of chronic hepatitis C: a randomised trial. Lancet2001;358:958–965.

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