Boceprevir for Chronic HCV Genotype 1 Infection

Correspondence
Boceprevir for Chronic HCV Genotype 1 Infection
N Engl J Med 2011; 365:176-178July 14, 2011
Article

Related Links;
Boceprevir for Untreated Chronic HCV Genotype 1 Infection
Boceprevir for Previously Treated Chronic HCV Genotype 1 Infection

To the Editor:
Poordad et al. and Bacon et al. (March 31 issue)1,2 (See Related Links Above) report improved rates of sustained virologic response among patients with chronic infection with the hepatitis C virus (HCV) who received boceprevir. Although these rates are similar to those seen among patients who received telaprevir,3-5 the telaprevir studies did not allow erythropoietin use, so there are important distinctions between the two protease inhibitors. In the boceprevir studies, despite erythropoietin use in 41 to 49% of the patients, 2 to 3% of the patients required treatment discontinuation because of anemia. The telaprevir studies3-5 showed similar discontinuation rates without erythropoietin use.
Clinically significant anemia might not be tolerated in a larger population of patients with cirrhosis. Erythropoietin carries a Food and Drug Administration black-box warning for possible increases in thromboembolic events.

Alpna R. Limaye, M.D.Peter V. Draganov, M.D.Roniel Cabrera, M.D.University of Florida College of Medicine, Gainesville, FL cabrer@medicine.ufl.edu
No potential conflict of interest relevant to this letter was reported.5 References

1
Poordad F, McCone J Jr, Bacon BR, et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 2011;364:1195-1206Full Text Web of Science Medline
2
Bacon BR, Gordon SC, Lawitz E, et al. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med 2011;364:1207-1217Full Text Web of Science Medline
3
McHutchison JG, Everson GT, Gordon SC, et al. Telaprevir with pegylated interferon and ribavirin for chronic HCV genotype 1 infection. N Engl J Med 2009;360:1827-1838[Erratum, N Engl J Med 2009;361:1516.]Full Text Web of Science Medline
4
McHutchison JG, Manns MP, Muir AJ, et al. Telaprevir for previously treated chronic HCV infection. N Engl J Med 2010;362:1292-1303[Erratum, N Engl J Med 2010;362:1647.]Full Text Web of Science Medline
5
Jacobson IM, McHutchison JG, Dusheiko GM, et al. Telaprevir in combination with peginterferon and ribavirin in genotype 1 HCV treatment-naive patients: final results of Phase 3 ADVANCE study. Hepatology 2010;52:Suppl:427A-427AWeb of Science

To the Editor:
Poordad et al. report that the addition of boceprevir to standard therapy with peginterferon−ribavirin was associated with significant increases in the rates of sustained virologic response and anemia among previously untreated patients with chronic HCV genotype 1 infection. Although subgroups with different predictors of sustained virologic response were evaluated in this study, patients were not stratified according to the presence or absence of the interleukin-28B (IL28B) genotype, a favorable genotype that is known to be the most important pretreatment predictor of sustained virologic response and to be associated with viral kinetics.1 This host genetic variation may alter the interpretation of the results. In addition, inosine triphosphatase (ITPA) gene variants, which may protect against anemia and affect therapeutic outcomes,2 were not evaluated. This study showed an improved therapeutic efficacy after the addition of boceprevir to peginterferon−ribavirin; however, the clinical usefulness in patients with favorable IL28B genotypes (such as most Asian patients) or in patients with anemia-prone ITPA gene variants remains unclear, and the concept of genomic variation−guided therapy deserves further examination.

Ching-Sheng Hsu, M.D., Ph.D.Buddhist Tzu Chi General Hospital, Taipei, Taiwan
Jia-Horng Kao, M.D., Ph.D.National Taiwan University Hospital, Taipei, Taiwan kaojh@ntu.edu.tw
Dr. Kao reports receiving consulting fees from Bristol-Myers Squibb, GlaxoSmithKline, Novartis, Omrix, Roche, and Schering-Plough, and serving on the speakers bureau for Roche, Bristol-Myers Squibb, GlaxoSmithKline, Novartis, and Schering-Plough.
No other potential conflict of interest relevant to this letter was reported.2 References

1
Hsu CS, Hsu SJ, Chen HC, et al. Association of IL28B gene variations with mathematical modeling of viral kinetics in chronic hepatitis C patients with IFN plus ribavirin therapy. Proc Natl Acad Sci U S A 2011;108:3719-3724CrossRef Web of Science Medline
2
Ochi H, Maekawa T, Abe H, et al. ITPA polymorphism affects ribavirin-induced anemia and outcomes of therapy -- a genome-wide study of Japanese HCV virus patients. Gastroenterology 2010;139:1190-1197CrossRef Web of Science Medline

Author/Editor Response
Anemia is increased when boceprevir is added to peginterferon and ribavirin. This class effect is also seen with telaprevir; 40% of patients in the 12-week groups of the phase 3 trials (ADVANCE [A New Direction in HCV Care: A Study of Treatment-Naive Hepatitis C Patients with Telaprevir; ClinicalTrials.gov number, NCT00627926] and ILLUMINATE [Illustrating the Effects of Combination Therapy with Telaprevir, NCT00758043]) had decreases in hemoglobin levels below 10 g per deciliter, as compared with 49% in SPRINT-2 (Serine Protease Inhibitor Therapy 2, NCT00705432).1 The use of erythropoietin was allowed at the discretion of investigators in the boceprevir studies; however, in patients with only a reduction in the dose of ribavirin in SPRINT-2 and HCV RESPOND-2 (Retreatment with HCV Serine Protease Inhibitor Boceprevir and PegIntron/Rebetol 2, NCT00708500), the sustained virologic response was the same as in those who received erythropoietin (79% vs. 76%). Similarly, a reduction in the dose of ribavirin did not hamper the sustained virologic response in patients in the ADVANCE trial (76% vs. 72%), but 12% of the patients in whom anemia developed required blood transfusions, as compared with 3% in SPRINT-2.1 Drug discontinuation because of anemia occurred in 4% of patients in the telaprevir trials as compared with 1% in the boceprevir trials.
Clinicians in practice prescribe erythropoietin in 28% of patients treated with peginterferon interferon and ribavirin.2 It is likely that this use will continue with both protease inhibitors. As noted, it is important for clinicians to be aware of the potential adverse events and the black-box warning associated with erythropoietin.
As noted by Hsu and Kao, patients were not stratified according to the IL28B polymorphism,3 which was first described in the IDEAL trial (Individualized Dosing Efficacy versus Flat Dosing to Assess Optimal Pegylated Interferon Therapy, NCT00081770) conducted by Schering-Plough (now Merck), nor has this stratification occurred in any large trial to date. In SPRINT-2 and HCV RESPOND-2, which were ongoing at the time of the discovery of this polymorphism, patients provided consent prospectively for pharmacogenomic testing. Boceprevir improved the sustained virologic response in patients with all variants.4 ITPA gene variants, first described and reported in 2010,5 were assessed in both boceprevir studies. We agree that individualized and response-guided therapies are important evolving concepts, and the SPRINT-2 and HCV RESPOND-2 trials were designed with this in mind.

Fred Poordad, M.D.Cedars−Sinai Medical Center, Los Angeles, CA fred.poordad@cshs.org
Bruce R. Bacon, M.D.Saint Louis University School of Medicine, St. Louis, MO
Clifford A. Brass, M.D., Ph.D.Merck, Whitehouse Station, NJ
Since publication of their article, the authors report no further potential conflict of interest.5 References