To review the literature regarding current strategies for the management of anemia associated with treatment for chronic viral hepatitis C (HCV) in adults.
DATA SOURCES:
The MEDLINE/PubMed, EMBASE, and Cochrane databases were searched (January 1980-October 2012) for articles in English using the search terms anemia, ribavirin, dose reduction, erythropoietin stimulating agents, hepatitis C, HIV, liver transplant, telaprevir, and boceprevir.
STUDY SELECTION AND DATA EXTRACTION:
All relevant original studies, meta-analyses, systematic reviews, guidelines, and review articles were assessed for inclusion. References from pertinent articles were examined for additional content not found during the initial search.
DATA SYNTHESIS:
Standard of care for patients infected with HCV genotype 1 now requires a triple therapy regimen including an HCV NS3 protease inhibitor. These regimens lead to significantly higher rates of anemia compared to prior dual therapy regimens. Development of an optimal management strategy should begin with risk stratification. Ribavirin dose reductions have been recommended in the package inserts for the pegylated interferon products and studies have demonstrated the need for maintenance of 80% of the initial ribavirin dose to achieve optimal sustained virologic response (SVR) with dual therapy. The use of erythropoietin-stimulating agents has been shown to be effective for anemia caused by peginterferon and ribavirin without compromising SVR rates. Limited data have been published regarding the management of anemia with triple therapy; however, efficacy studies for boceprevir and telaprevir have used ribavirin dose reduction and erythropoietin-stimulating agents to successfully manage anemia.
CONCLUSIONS:
Anemia is a common adverse event associated with the use of ribavirin, and, more recently, the new HCV protease inhibitors. Ribavirin dose reduction should continue to be used as an initial anemia management strategy, with the use of erythropoietin alfa 40,000 units once weekly reserved for patients whose hemoglobin does not adequately respond to initial management strategies.
DavisGLAlterMJEl-SeragHPoynardTJenningsLW. Aging of hepatitis C virus (HCV)–infected persons in the United States: A multiple cohort model of HCV prevalence and disease progression. Gastroenterology2010; 138: 513–21, 521.e1–6. doi: 10.1053/j.gastro.2009.09.067
3.
LyKNXingJKlevensRMJilesRBWardJWHolmbergSD. The increasing burden of mortality from viral hepatitis in the United States between 1999 and 2007. Ann Intern Med2012; 156: 271–8. DOI: 10.1059/0003-4819-156-4-201202210-00004
4.
WongJBMcQuillanGMMcHutchisonJGPoynardT. Estimating future hepatitis C morbidity, mortality, and costs in the United States. Am J Public Health2000; 90: 1562–9.
5.
PoordadFLawitzEShiffmanML, Virologic response rates of weight-based taribavirin versus ribavirin in treatment-naive patients with genotype 1 chronic hepatitis C. Hepatology2010; 52: 1208–15. DOI: 10.1002/hep.23827
6.
JacobsonIMMcHutchisonJGDusheikoG, Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med2011; 364: 2405–16. DOI: 10.1056/NEJMoa1012912
7.
PoordadFMcConeJJrBaconBR, Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med2011; 364: 1195–206. DOI: 10.1056/NEJMoa1010494
8.
ZeuzemSAndreonePPolS, Telaprevir for retreatment of HCV infection. N Engl J Med2011; 364: 2417–28. DOI: 10.1056/NEJMoa1013086
9.
BaconBRGordonSCLawitzE, Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med2011; 364: 1207–17. DOI: 10.1056/NEJMoa1009482
10.
McHutchisonJGMannsMPLongoDL. Definition and management of anemia in patients infected with hepatitis C virus. Liver Int2006; 26: 389–98. DOI: 10.1111/j.1478–3231.2006.01228.x
11.
SulkowskiMSWassermanRBrooksLBallLGishR. Changes in haemoglobin during interferon alpha-2b plus ribavirin combination therapy for chronic hepatitis C virus infection. J Viral Hepat2004; 11: 243–50. DOI: 10.1111/j.1365–2893.2004.00490.x
12.
HiramatsuNKurosakiMSakamotoN, Pretreatment prediction of anemia progression by pegylated interferon alpha-2b plus ribavirin combination therapy in chronic hepatitis C infection: Decision-tree analysis. J Gastroenterol2011; 46: 1111–9. DOI: 10.1007/s00535-011-0412-z
TakakiSTsubotaAHosakaT, Factors contributing to ribavirin dose reduction due to anemia during interferon alfa2b and ribavirin combination therapy for chronic hepatitis C. J Gastroenterol2004; 39: 668–73. DOI: 10.1007/s00535-003-1363-9
15.
HuCCWengCHLinCL, Predictors of changes in hemoglobin levels in patients with chronic hepatitis C treated with ribavirin plus pegylated interferon-alpha. Ren Fail2012; 34: 429–34. DOI: 10.3109/0886022X.2011.650562
16.
Van Vlierbergh H, Delanghe JR, De Vos M, Leroux-Roel G, BASL Steering Committee. Factors influencing ribavirin-induced hemolysis. J Hepatol2001; 34: 911–6.
17.
FellayJThompsonAJGeD, ITPA gene variants protect against anaemia in patients treated for chronic hepatitis C. Nature2010; 464: 405–8. DOI: 10.1038/nature08825
18.
ThompsonAJFellayJPatelK, Variants in the ITPA gene protect against ribavirin-induced hemolytic anemia and decrease the need for ribavirin dose reduction. Gastroenterology2010; 139: 1181–9. DOI: 10.1053/j.gastro.2010.06.016
19.
OchiHMaekawaTAbeH, ITPA polymorphism affects ribavirin-induced anemia and outcomes of therapy—a genome-wide study of Japanese HCV virus patients. Gastroenterology2010; 139: 1190–7. DOI: 10.1053/j.gastro.2010.06.071
20.
DomingoPGuardiolaJMSalazarJ, Association of ITPA gene polymorphisms and the risk of ribavirin-induced anemia in HIV/hepatitis C virus (HCV)-coinfected patients receiving HCV combination therapy. Antimicrob Agents Chemother2012; 56: 2987–93. DOI: 10.1128/AAC.06473–11
21.
EskesenANMelumEMoghaddamA, Genetic variants at the ITPA locus protect against ribavirin-induced hemolytic anemia and dose reduction in an HCV G2/G3 cohort. Eur J Gastroenterol Hepatol2012; 24: 890–6. DOI: 10.1097/MEG.0b013e3283546efd
22.
KurosakiMTanakaYTanakaK, Relationship between polymorphisms of the inosine triphosphatase gene and anaemia or outcome after treatment with pegylated interferon and ribavirin. Antivir Ther2011; 16: 685–94. DOI: 10.3851/IMP1796
23.
SakamotoNTanakaYNakagawaM, ITPA gene variant protects against anemia induced by pegylated interferon-alpha and ribavirin therapy for Japanese patients with chronic hepatitisC. Hepatol Res2010; 40: 1063–71. DOI: 10.1111/j.1872–034X.2010.00741.x
24.
NaggieSRallonNIBenitoJM, Variants in the ITPA gene protect against ribavirin-induced hemolytic anemia in HIV/HCV-coinfected patients with all HCV genotypes. J Infect Dis2012; 205: 376–83. DOI: 10.1093/infdis/jir754
25.
RallonNIMorelloJLabargaP, Impact of inosine triphosphatase gene variants on the risk of anemia in HIV/hepatitis C virus—coinfected patients treated for chronic hepatitis C. Clin Infect Dis2011; 53: 1291–5. DOI: 10.1093/cid/cir665
McHutchisonJGMannsMPatelK, Adherence to combination therapy enhances sustained response in genotype-1–infected patients with chronic hepatitis C. Gastroenterology2002; 123: 1061–9.
29.
BenhamouYAfdhalNHNelsonDR, A phase III study of the safety and efficacy of viramidine versus ribavirin in treatment-naive patients with chronic hepatitis C: ViSER1 results. Hepatology2009; 50: 717–26. DOI: 10.1002/hep.23073
30.
GishRGAroraSReddyK Rajender, Virological response and safety outcomes in therapy-naive patients treated for chronic hepatitis C with taribavirin or ribavirin in combination with pegylated interferon alfa-2a: A randomized, phase 2 study. J Hepatol2007; 47: 51–9. DOI: 10.1016/j.jhep.2007.02.018
31.
MarcellinPGishRGGitlinN, Safety and efficacy of viramidine versus ribavirin in ViSER2: Randomized, double-blind study in therapy-naive hepatitis C patients. J Hepatol2010; 52: 32–8. DOI: 10.1016/j.jhep.2009.10.015
32.
KaushanskyKKippsTJ. Hematopoietic agents, growth factors, minerals, and vitamins. In: ChabnerBABruntonLLKnollmannBC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 12th ed.New York: McGraw-Hill Medical, 2011.
33.
DieterichDTWassermanRBrauN, Once-weekly epoetin alfa improves anemia and facilitates maintenance of ribavirin dosing in hepatitis C virus—infected patients receiving ribavirin plus interferon alfa. Am J Gastroenterol2003; 98: 2491–9. DOI: 10.1111/j.1572–0241.2003.08700.x
34.
AfdhalNHDieterichDTPockrosPJ, Epoetin alfa maintains ribavirin dose in HCV-infected patients: A prospective, double-blind, randomized controlled study. Gastroenterology2004; 126: 1302–11.
35.
ShiffmanMLSalvatoreJHubbardS, Treatment of chronic hepatitis C virus genotype 1 with peginterferon, ribavirin, and epoetin alpha. Hepatology2007; 46: 371–9. DOI: 10.1002/hep.21712
36.
FalascaKUcciferriCMancinoPGorgorettiVPizzigalloEVecchietJ. Use of epoetin beta during combination therapy of infection with hepatitis C virus with ribavirin improves a sustained viral response. J Med Virol2010; 82: 49–56. DOI: 10.1002/jmv.21657
37.
BertinoGArdiriABoemiPM, Epoetin alpha improves the response to antiviral treatment in HCV-related chronic hepatitis. Eur J Clin Pharmacol2010; 66: 1055–63. DOI: 10.1007/s00228-010-0868-4
38.
YounossiZMNaderFHBaiC, A phase II dose finding study of darbepoetin alpha and filgrastim for the management of anaemia and neutropenia in chronic hepatitis C treatment. J Viral Hepat2008; 15: 370–8. DOI: 10.1111/j.1365–2893.2007.00956.x
39.
GergelyAELafargePFouchard-HubertILunel-FabianiF. Treatment of ribavirin/interferon-induced anemia with erythropoietin in patients with hepatitis C. Hepatology2002; 35: 1281–2. DOI: 10.1053/jhep.2002.32529
40.
TalalAHWeiszKHauTKreiswirthSDieterichDT. A preliminary study of erythropoietin for anemia associated with ribavirin and interferon-alpha. Am J Gastroenterol2001; 96: 2802–4. DOI: 10.1111/j.1572–0241.2001.04149.x
41.
CampbellMSunJLeeBKaplanDReddyK. Administration of erythropoietin for hepatitis C treatment-related anemia is not cost effective. Presented at: Programs and abstracts of the 56th Annual Meeting of the American Association for the Study of Liver Diseases, San Francisco, CA, November 11–15, 2005.
42.
DevineEBCrossJTKowdleyKVSullivanSD. The cost of treating ribavirin-induced anemia in hepatitis C: The impact of using recombinant human erythropoietin. Curr Med Res Opin2007; 23: 1463–72. DOI: 10.1185/030079907X188189
43.
DieterichDT. Hepatitis C virus and human immunodeficiency virus: Clinical issues in coinfection. Am J Med1999; 107: 79S–84S.
44.
VispoELabargaPGuardiolaJM, Preemptive erythropoietin plus high ribavirin doses to increase rapid virological responses in HIV patients treated for chronic hepatitis C. AIDS Res Hum Retroviruses2010; 26: 419–24. DOI: 10.1089/aid.2009.0120
45.
ButtAAUmblejaTAndersenJWChungRTShermanKE, ACTG A5178 Study Team. The incidence, predictors and management of anaemia and its association with virological response in HCV/HIV coinfected persons treated with long-term pegylated interferon alfa 2a and ribavirin. Aliment Pharmacol Ther2011; 33: 1234–44. DOI: 10.1111/j.1365–2036.2011.04648.x
46.
GaneE. Treatment of recurrent hepatitis C. Liver Transpl2002; 8: S28–37. DOI: 10.1053/jlts.2002.35860
47.
JainABEghtesadBVenkataramananR, Ribavirin dose modification based on renal function is necessary to reduce hemolysis in liver transplant patients with hepatitis C virus infection. Liver Transpl2002; 8: 1007–13. DOI: 10.1053/jlts.2002.36241
48.
ObaidSBrendonMJefferyS. Interferon-alpha 2B and ribavirin combination therapy in liver transplantation with recurrent hepatitis C. Hepatology2000; 32: 261A.
49.
ShermanKEFlammSLAfdhalNH, Response-guided telaprevir combination treatment for hepatitis C virus infection. N Engl J Med2011; 365: 1014–24. DOI: 10.1056/NEJMoa1014463
50.
PoordadFFLawitzEJReddyKR, A randomized trial comparing ribavirin dose reduction versus erythropoietin for anemia management in previously untreated patients with chronic hepatitis C receiving boceprevir plus peginterferon/ribavirin. Presented at: Program and abstracts of the 47th Annual Meeting of the European Association for the Study of the Liver. Barcelona, Spain, April 18–22, 2012.
51.
DebRoySKribs-ZaletaCMubayiA, Evaluating treatment of hepatitis C for hemolytic anemia management. Math Biosci2010; 225: 141–55. DOI: 10.1016/j.mbs.2010.02.005
52.
HezodeCForestierNDusheikoG, Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med2009; 360: 1839–50. DOI: 10.1056/NEJMoa0807650
