Is there discrimination in access to therapy for HCV patients?
Authors: Silvio Garattini
Journal: Journal of Hepatology (2008)

Hepatitis C virus (HCV) eradication with interferon (IFN)-ribavirin (RBV) combination therapy is the therapeutic paradigm for patients with chronic hepatitis C. Since the empirical choice to use interferon alfa in 1986, therapy for chronic hepatitis C has, in fact, evolved substantially over the past two decades. In fact the attainable sustained virological response (SVR) rates have consistently increased over the years, the major improvement in the treatment of HCV infection being the addition of RBV to IFN-based therapy [1Pawlotsky J.M. Therapy of hepatitis C: from empiricism to eradication.Hepatology. 2006; 43: S207-S220Crossref PubMed Scopus (167) Google Scholar, 2EASL International Consensus Conference on hepatitis C. Paris, 26–27 February 1999. Consensus statement. J Hepatol 1999;31(Suppl. 1):3–8.Google Scholar]. While its mechanism of action still remains unclear, and even if RBV monotherapy actually shows no antiviral effect in vitro, the combination of IFN and RBV gave SVR rates of 30–35% in HCV genotype 1 patients and 75–80% in HCV-2 and 3 patients, exceeding by far those obtained with IFN monotherapy [3Poynard T. Marcellin P. Lee S.S. Niederau C. Minuk G.S. Ideo G. et al.Randomised trial of interferon alpha2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alpha2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus International Hepatitis Interventional Therapy Group (IHIT).Lancet. 1998; 352: 1426-1432Abstract Full Text Full Text PDF PubMed Scopus (2410) Google Scholar, 4McHutchison J.G. Gordon S.C. Schiff E.R. Shiffman M.L. Lee W.M. Rustgi V.K. et al.Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C Hepatitis Interventional Therapy Group.N Engl J Med. 1998; 339: 1485-1492Crossref PubMed Scopus (3366) Google Scholar]. The latest change in anti-HCV treatment has been the pegylation of the IFN molecule, and pegylated IFN (PegIFN) has become the standard of care for chronic hepatitis on account of its more potent acute antiviral effect, especially in HCV-1 patients, and also its "user-friendly" once-a-week administration. Two forms of PegIFN exist (α2a and α2b) which differ significantly in terms of pharmacokinetics and dynamics, however, whether these peculiarities translate into different efficacy rates is still unknown, the latest data suggesting that SVR rates obtained by the two compounds combined with RBV are comparable in HCV-1 patients [[5]Sulkowski M, Lawitz E, Shiffman ML, Muir AJ, Galler G, McCone J, et al. Final results of the IDEAL (Individualized Dosing Efficacy Versus Flat Dosing to Assess Optimal Pegylated Interferon Therapy) Phase IIIB Study. Presented at: 43rd Annual Meeting of the European Association for the Study of the Liver, April 23–27, Milan, Italy; 2008.Google Scholar]. Preliminary evidence is gathering that both types of PegIFN can be alternatively used as standard of care in naı¨ve HCV patients [6Strader D.B. Wright T. Thomas D.L. Seeff L.B. Diagnosis, management, and treatment of hepatitis C.Hepatology. 2004; 39: 1147-1171Crossref PubMed Scopus (1593) Google Scholar, 7Dienstag J.L. McHutchison J.G. American Gastroenterological Association technical review on the management of hepatitis C.Gastroenterology. 2006; 130: 231-264Abstract Full Text Full Text PDF PubMed Scopus (350) Google Scholar], but we ignore the percentage of infected patients that ultimately do receive PegIFN/RBV therapy. Lettmeier et al. in the paper which appears in this issue of the Journal, present a careful analysis concerning the sales of PegIFN α2a and 2b in 21 countries for the treatment of chronic hepatitis induced by HCV [[8]Lettmeier B. Mühlberger N. Schwarzer R. Sroczynski G. Wright D. Zeuzem S. et al.Market uptake of new antiviral drugs for the treatment of hepatitis C.J Hepatol. 2008; 49: 528-536Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar]. These data were then utilized to estimate the number of patients treated and to conclude that the access to PegIFNs may differ considerably in the various countries. The authors have the merit of translating sales into number of patients treated by developing for the first time an algorithm that takes account of genotype distribution, patient characteristics and practice patterns. For reasons of simplification, instead of reporting the sales figures for single countries they have preferred to group them into four categories: EU founder members, countries that joined the EU before 2000, after 2000 and non-EU states. It is hard to see the rationale for this grouping. For a more rational comparison of the results, it would have been better to analyze sales in relation to the prevalence of HCV cases in the single countries. It is in fact reasonable to suppose that comparisons of access to therapy are more meaningful in relation to the dimensions of the infection in the various countries: the problem is different in the Czech Republic, the Netherlands and Sweden where the prevalence of HCV ranges between 0.2% and 0.5% while in Spain, Italy and Romania the range is 1.5–4.5%. An important omission in this paper is data concerning the utilization of standard IFNs because in some countries low access to PegIFNs may possibly be counterbalanced by the sales of standard IFNs. The authors seem to overlook this aspect because they state in the discussion that "PegIFNs in combination with RBV (are) the state-of-the art drugs for treatment of chronic hepatitis". This statement can be challenged because, although this is the current opinion, it must be stressed that there is virtually a vacuum of randomized clinical trials comparing either the two PegIFNs now on the market, or the single PegIFNs with the corresponding standard IFN. The studies available are biased by their low numbers, lack of blinding and the authorship and sponsorship of the companies producing PegIFNs. Furthermore, there seems to be no agreement about the doses: the weekly dose of PegIFN α2a may range from 1.5 μg/kg [[9]Crespo M. Sauleda S. Esteban J.I. Juarez A. Ribera E. Andreu A.L. et al.Peginterferon alpha-2b plus ribavirin vs interferon alpha-2b plus ribavirin for chronic hepatitis C in HIV-coinfected patients.J Viral Hepat. 2007; 14: 228-238Crossref PubMed Scopus (59) Google Scholar] to 2.5 μg/kg, this latter extrapolated from a dose of 180 μg for an average person weighing 70 kg. [10Chung R.T. Andersen J. Volberding P. Robbins G.K. Liu T. Sherman K.E. et al.Peginterferon Alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons.N Engl J Med. 2004; 351: 451-459Crossref PubMed Scopus (847) Google Scholar, 11Mangia A. Ricci G.L. Persico M. Minerva N. Carretta V. Bacca D. et al.A randomized controlled trial of pegylated interferon alpha-2a (40 KD) or interferon alpha-2a plus ribavirin and amantadine vs interferon alpha-2a and ribavirin in treatment-naive patients with chronic hepatitis C.J Viral Hepat. 2005; 12: 292-299Crossref PubMed Scopus (48) Google Scholar] similarly to PegIFN α2b [12Lee S.D. Yu M.L. Cheng P.N. Lai M.Y. Chao Y.C. Hwang S.J. et al.Comparison of a 6-month course peginterferon alpha-2b plus ribavirin and interferon alpha-2b plus ribavirin in treating Chinese patients with chronic hepatitis C in Taiwan.J Viral Hepat. 2005; 12: 283-291Crossref PubMed Scopus (78) Google Scholar, 13Perrillo R. Rothstein K.D. Rubin R. Alam I. Imperial J. Harb G. et al.Comparison of quality of life, work productivity and medical resource utilization of peginterferon alpha 2a vs the combination of interferon alpha 2b plus ribavirin as initial treatment in patients with chronic hepatitis C.J Viral Hepat. 2004; 11: 157-165Crossref PubMed Scopus (45) Google Scholar]. The dose of the standard IFNs can also be 3 M I.U. twice [[12]Lee S.D. Yu M.L. Cheng P.N. Lai M.Y. Chao Y.C. Hwang S.J. et al.Comparison of a 6-month course peginterferon alpha-2b plus ribavirin and interferon alpha-2b plus ribavirin in treating Chinese patients with chronic hepatitis C in Taiwan.J Viral Hepat. 2005; 12: 283-291Crossref PubMed Scopus (78) Google Scholar] or three times [14Liu C.H. Liang C.C. Lin J.W. Chen S.I. Tsai H.B. Chang C.S. et al.Pegylated interferon alpha-2a versus standard interferon alpha-2a for treatment-naive dialysis patients with chronic hepatitis C: a randomised study.Gut. 2008; 57: 525-530Crossref PubMed Scopus (66) Google Scholar, 15Pockros P.J. Carithers R. Desmond P. Dhumeaux D. Fried M.W. Marcellin P. et al.Efficacy and safety of two-dose regimens of peginterferon alpha-2a compared with interferon alpha-2a in chronic hepatitis C: a multicenter, randomized controlled trial.Am J Gastroenterol. 2004; 99: 1298-1305Crossref PubMed Scopus (68) Google Scholar] a week. In some cases, IFN α2a has been used at the dose of 6 M I.U. three times a week for 12 weeks followed by 3 M I.U. [[10]Chung R.T. Andersen J. Volberding P. Robbins G.K. Liu T. Sherman K.E. et al.Peginterferon Alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons.N Engl J Med. 2004; 351: 451-459Crossref PubMed Scopus (847) Google Scholar]. It is clear that since no dose ranging has been done, no comparison can be made at optimal doses for the two classes of IFNs. In addition, it would be important to establish how much RBV has been sold and utilized, to check whether in many cases PegIFNs were used alone. Another point not adequately discussed is whether PegIFNs induce more adverse effects than standard IFNs [12Lee S.D. Yu M.L. Cheng P.N. Lai M.Y. Chao Y.C. Hwang S.J. et al.Comparison of a 6-month course peginterferon alpha-2b plus ribavirin and interferon alpha-2b plus ribavirin in treating Chinese patients with chronic hepatitis C in Taiwan.J Viral Hepat. 2005; 12: 283-291Crossref PubMed Scopus (78) Google Scholar, 16Brady M. Siebert U. Sroczynski G. Murphy G. Husereau D.R. Sherman M. et al.Pegylated interferon combined with ribavirin for chronic hepatitis C virus infection: an economic evaluation.Health Technol Assess. 2007; 82: 1-42Google Scholar, 17Simin M. Brok J. Stimac D. Gluud C. Gluud L.L. Cochrane systematic review: pegylated interferon plus ribavirin vs interferon plus ribavirin for chronic hepatitis C.Aliment Pharmacol Ther. 2007; 25: 1153-1162Crossref PubMed Scopus (54) Google Scholar] such as neutropenia, thrombocytopenia, arthralgia and injection-site reactions. The authors explain the different access to PegIFNs by considering in particular that reduced access to therapy was common in low-resource countries. This may not be the only reason if the Czech Republic treats about 11% of prevalent cases with PegIFNs while Belgium, Italy, UK and Denmark use them for less than 4%. Important differences exist between the use of the α2a and 2b PegIFNs: for instance in Switzerland α2a largely predominates while in France the winner is α2b. This is probably explained by the task force of detailmen of the producers in the various countries. Previous studies about the access to treatment with IFNs and RBV – without distinctions among the type of IFN utilized – have shown that US patients were less likely to receive treatment if they were older, single, anemic, with hepatic dysfunctions, had HCV genotype 1 and if they were evaluated by less experienced providers [[18]Kanwal F. Hoang T. Spiegel B.M. Eisen S. Dominitz J.A. Gifford A. et al.Predictors of treatment in patients with chronic hepatitis C infection – role of patient versus nonpatient factors.Hepatology. 2007; 46: 1741-1749Crossref PubMed Scopus (103) Google Scholar]. In Canada, where PegIFNs and IFNs are similarly priced, a technology report from the Canadian Agency for Drugs and Technologies in Health [[16]Brady M. Siebert U. Sroczynski G. Murphy G. Husereau D.R. Sherman M. et al.Pegylated interferon combined with ribavirin for chronic hepatitis C virus infection: an economic evaluation.Health Technol Assess. 2007; 82: 1-42Google Scholar] is particularly interesting. On the basis of the literature, it concluded that PegIFNs and RBV attain a higher overall sustained virological response rate, particularly for genotypes 2 and 3, than standard IFNs and RBV. However it is not known whether this will translate into real advantages in the natural history of chronic hepatitis which frequently develops in an unpredictable way over decades. For the moment, the report states that the two treatments do not present detectable differences in all-cause mortality or withdrawals due to adverse effects although the treatment of PegIFNs and RBV is associated with a significantly higher rate of non-fatal serious adverse effects than the standard combination. Clearly Lettmeier et al. [[8]Lettmeier B. Mühlberger N. Schwarzer R. Sroczynski G. Wright D. Zeuzem S. et al.Market uptake of new antiviral drugs for the treatment of hepatitis C.J Hepatol. 2008; 49: 528-536Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar] have opened the way to discussing HCV patients' access to therapy in different countries but establishing the best therapy in terms of benefit-risk in relation to cost still requires a lot of independent clinical research.