Use of Hematopoietic Growth Factors as Adjuvant Therapy for Anemia and Neutropenia in the Treatment of Hepatitis C

Abstract

Spanish

French

Objective:

To review the hematologic adverse effects of hepatitis C virus (HCV) therapy and adjuvant treatment with epoetin alfa and granulocyte colony-stimulating factor (ie, filgrastim).

Data Sources:

Medical literature indexed in MEDLINE (1966–January 2007) and EMBASE (1980–January 2007) was searched, and published conference abstracts were reviewed.

Study Selection and Data Extraction:

Peer-reviewed articles and relevant conference abstracts regarding the use of epoetin alfa and granulocyte colony-stimulating factor were reviewed.

Data Synthesis:

Ribavirin induces a dose-dependent hemolytic anemia. Studies using epoetin alfa 40 000 units subcutaneously once weekly have demonstrated efficacy in maintaining hemoglobin, ribavirin dose, and quality of life scores, but clear benefit shown with sustained virologic response (SVR) is lacking. The hemoglobin threshold for initiation of epoetin alfa used in studies may not adequately reflect values used in clinical practice. Treatment-related neutropenia is caused primarily by interferon or peg interferon. Few studies have investigated the impact of granulocyte or granulocyte-macrophage colony-stimulating factor derivatives on neutropenia. Results of dose maintenance evaluation vary, and studies reporting data on SVR showed no effect from growth factor therapy. The frequency of bacterial infections was not reported.

Conclusions:

The role and benefit of hematopoietic growth factors in HCV therapy have not been conclusively determined to date. However, the possibility of a benefit to individual patients seen on an outpatient basis remains, and an individualized treatment approach is recommended.

Keywords

epoetin filgrastim hepatitis C

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References

Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related disease. MMWR Morb Mortal Wkly Rep 1998;47(RR-19):1–40.

Alter

Kruszon-Moran

Nainan

. The prevalence of hepatitis C virus infection in the United States, 1988 through 1994. N Engl J Med 1999;341:555–62.

Kim

. The burden of hepatitis C in the United States. Hepatology 2002;36(suppl 1):S30–4.

Afdhal

. The natural history of hepatitis C. Semin Liver Dis 2004;24(suppl 2):S3–8.

World Health Organization. Hepatitis C fact sheet N°164. www.who.int/mediacentre/factsheets/fs164/en/print/html (version current at September 16, 2005).

Manns

McHutchison

Gordon

. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomized trial. Lancet 2001;358:958–65.

Fried

Shiffman

Reddy

. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002;347:975–82.

Hadziyannis

Sette

Jr.

Morgan

. Peginterferon-α2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med 2004;140:346–55.

Dalgard

Bjoro

Helium

. Treatment with pegylated interferon and ribavarin in HCV infection with genotype 2 or 3 for 14 weeks: a pilot study. Hepatology 2004;40:1260–5.

10.

Mangia

Santoro

Minerva

. Peginterferon alfa-2b and ribavirin for 12 vs 24 weeks in HCV genotype 2 or 3. N Engl J Med 2005;352:2609–17.

11.

von Wagner

Huber

Berg

. Peginterferon-alpha-2a (40 KD) and ribavirin for 16 or 24 weeks in patients with genotype 2 or 3 chronic hepatitis C. Gastroenterology 2005;129:522–7.

12.

Jensen

Morgan

Marcellin

. Early identification of HCV genotype 1 patients responding to 24 weeks peginterferon alfa-2a (40kd)/ribavirin therapy. Hepatology 2006;43:954–60.

13.

Stader

Wright

Thomas

Seeff

. AASLD Practice Guideline: diagnosis, management, and treatment of hepatitis C. Hepatology 2004;39:1147–70.

14.

McHutchison

Manns

Patel

. Adherence to combination therapy enhances sustained response in genotype-1-infected patients with chronic hepatitis C. Gastroenterology 2002;123:1061–9.

15.

Davis

Wong

McHutchison

. Early virologic response to treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C. Hepatology 2003;38:645–52.

16.

Homma

Matsuzaki

Inoue

. Marked elevation of erythrocyte ribavirin levels in interferon and ribavirin-induced anemia. Clin Gastroenterol Hepatol 2004;2:337–9.

17.

Glue

. The clinical pharmacology of ribavirin. Semin Liver Dis 1999;19(suppl 1):S17–24.

18.

De Franceschi

Fattovich

Turrini

. Hemolytic anemia induced by ribavirin therapy in patients with chronic hepatitis C virus infection: role of membrane oxidative damage. Hepatology 2000;31:997–1004.

19.

Sulkowski

. Anemia in the treatmentof hepatitis C virus infection. Clin Infect Dis 2003;37(suppl 4):S315–22.

20.

Bruchfeld

Lindahl

Schvarcz

Ståhle

. Dosage of ribavirin in patients with hepatitis C should be based on renal function: a population pharmacokinetic analysis. Ther Drug Monit 2002;24:701–8.

21.

Lindahl

Schvarcz

Bruchfeld

Ståhle

. Evidence that plasma concentration rather than dose per kilogram body weight predicts ribavirin-induced anaemia. J Viral Hep 2004;11:84–7.

22.

Maeda

Kiribayashi

Moriya

. Dosage adjustment of ribavirin based on renal function in Japanese patients with chronic hepatitis C. Ther Drug Monit 2004;26:9–15.

23.

Wong

Kaita

Gauthier

. A comparative trial of recombinant interferon alpha 2a versus alpha 2b on myelosuppression in healthy adult volunteers. Hepatogastroenterology 1996;43:301–5.

24.

Fried

. Side effects of therapy of hepatitis C and their management. Hepatology 2002;36(5 suppl 1): S237–44.

25.

Gaeta

Precone

Felaco

. Premature discontinuation of interferon plus ribavirin for adverse effects: a multicentre survey in ‘real world’ patients with chronic hepatitis C. Aliment Pharmacol Ther 2002;16:1633–9.

26.

Dieterich

Spivak

. Hematologic disorders associated with hepatitis C virus infection and their management. Clin Infect Dis 2003;37:533–41.

27.

Russo

Fried

. Side effects of therapy for chronic hepatitis C. Gastroenterology 2003;124:1711–9.

28.

Soza

Everhart

Ghany

. Neutropenia during combination therapy of interferon alfa and ribavirin for chronic hepatitis C. Hepatology 2002;36:1273–9.

29.

Juarez-Navarro

Vera-de-Leon

Navarro

. Incidence and severity of infections according to the development of neutropenia during combined therapy with pegylated interferon alfa-α2a plus ribavirin in chronic hepatitis C infection. Methods Find Exp Clin Pharmacol 2005;27:317–22.

30.

Hillman

. Hematopoietic agents. In: Hardman

Limbird

, eds. Goodman & Gilman's the pharmacological basis of drugs. Toronto: McGraw-Hill, 2001: 1311–40.

31.

Besarab

Bolton

Browne

. The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med 1998;339:584–90.

32.

NKF-K/DOQI clinical practice guidelines for anemia of chronic kidney disease: update 2000. Am J Kidney Dis 2001;37(1 suppl): s182–238.

33.

Stravitz

Chung

Sterling

. Antibody-mediated pure red cell aplasia due to epoetin alfa during antiviral therapy of chronic hepatitis C. Am J Gastroenterol 2005;100:1415–9.

34.

Dieterich

Wasserman

Brau

. 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 Gastroenterol 2003;98:2491–9.

35.

Afdhal

Dieterich

Pockros

. Epoetin alfa maintains ribavirin dose in HCV-infected patients: a prospective, double-blind, randomized controlled study. Gastroenterology 2004;126:1302–11.

36.

Pockros

Shiffman

Schiff

. Epoetin alfa improves quality of life in anemic HCV-infected patients receiving combination therapy. Hepatology 2004;40:1450–8.

37.

Shiffman

di Bisceglie

Lindsay

. Peginterferon alfa-2a and ribavirin in patients with chronic hepatitis C who have failed prior treatment. Gastroenterology 2004;126:1015–23.

38.

Spiegel

Chen

Chiou

. Erythropoietic growth factors for treatment-induced anemia in hepatitis C: a cost-effectiveness analysis. Clin Gastroenterol Hepatol 2005;3:1034–42.

39.

AHFS drug information 2005. Bethesda, MD: American Society of Health-System Pharmacists, 2005: 1486–506.

40.

Brown

Dale

. Spontaneous splenic rupture following administration of granulocyte colony-stimulating factor (G-CSF): occurrence in an allogeneic donor of peripheral blood stem cells (letter). Biol Blood Marrow Transplant 1997;3:341–3.

41.

Arshad

Seiter

Bilaniuk

. Side effects related to cancer treatment: case 2. Splenic rupture following pegfílgrastim. J Clin Oncol 2005;23:8533–4.

42.

Kuendgen

Fenk

Bruns

. Splenic rupture following administration of pegfilgrastim in a patient with multiple myeloma undergoing autologous peripheral blood stem cell transplantation. Bone Marrow Transplant 2006;38:69–70.

43.

Sood

Reddy

Russo

. Use of granulocyte colony stimulating factor (G-CSF) for interferon induced neutropenia in patients with chronic hepatitis C infection (abstract). Hepatology 2001;34:429A.

44.

Koliouskas

Didiropoulos

Masmanidou

. Comparative analysis and effect of GM-CSF on neutropenia in peg-interferon alpha-2b and ribavirin-treated chronic hepatitis C patients (abstract). Hepatology 2002;36:587A.

45.

Carey

Rosati

Anderson

. Use of G-CSF allows for optimal PEG-INF dosing during therapy for hepatitis C virus with pegylated interferon and ribavirin (abstract). Hepatology 2002;36:604A.

46.

Lebray

Nalpas

Vallet-Pichard

. The impact of haematopoietic growth factors on the management and efficacy of antiviral treatment in patients with hepatitis C. Antivir Ther 2005;10:769–76.