Fighting fatigue

1. Fighting fatigue Hepatitis C treatment-Related Anemia

2. Global Prevalence of Hepatitis C Virus The graph is based on data submitted to the WHO as of June 1999.

3. Anemia A common adverse effect of hepatitis C antiviral therapy Bone marrow suppression Hemolysis of Red Blood Cells

4. Erythropoiesis in CKD Erythropoietin Iron SCF, IL-1, IL-3, IL-6, IL-11 SCF, GM-CSF, IL-3 Transferrin Receptors Erythropoiesis Epo Vit D About 8 Days PluripotentStem Cell Burst-Forming Unit-Erythroid Cells (BFU-E) Colony-FormingUnit-ErythroidCells (CFU-E) Proerythro-blasts Erythro-blasts Reticulocytes RBCs Papayannopoulou T, et al. In: Hoffman R, et al., ed. Hematology: Basic Principles and Practice. 4th ed. 2005;267-288.

5. Ribavirin • Transported from plasma to RBCs • Phosphorylated to mono,di & triphosphate analogs • Neither metabolized nor transported out of RBCs • Accumolation of ribavirin 100 fold its extracellular concentration • Oxidative damage • Extra vascular death of RBCs

6. Ribavirin • 54% of treated patients experienced decline in Hg level of over 3 g/dl • 10% of men & 7% of women experienced a decline of over 5 g/dl • RBCs lifespan from 107 + 22 days in HCV patients not exposed to Ribavirin • to 39 + 13 days in HCV patients exposed to Ribavirin - -

7. Ribavirin To maximize the benefits Make the balance Antiviral activity TREATMENT LIMITING SIDE EFFECT Hemolytic anemia

8. The Hemoglobin Sweet Spot Risk At 10 g/dl 80% of ribavirin dose 8.5 g/dl Stop treatment 100% 50% Hb g/dL 9 11 12 13

9. Anemia treatment OBJECTIVES Maintain higher ribavirin doses No reduction in Sustained Virologic Response (SVR) Improve patient quality of life

10. Anemia Patient selection • Before considering using Erythropoietin • Evaluate other causes of anemia • (bleeding-Hereditary) • Obtain CBC • Assess for adequate iron stores • Ferritin 50 ng/ml or more • TS 20% or more • Thyroid function tests • Thyroid dysfunction affect Epo response

11. Iron therapy treatment selection

12. Not affected by gastric acidity Affected by gastric acidity Limited absorption Higher absorption

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14. How to assess Iron store Ferritin kits < 10 ng/ml 50 ng/ml 100 ng/ml > 100 ng/ml invalid

15. Anemia Patient selection Hemoglobin less than 10g/dl Or Symptomatic and have Hemoglobin less than 11g/dl Or Hemoglobin less than 12g/dl with comorbid cardiovascular or hypoxemic pulmonary diseases

16. Hemoglobin From monitor to Close monitor Step 1 Insert the TEST CARD Step 2 Apply the SAMPLE Step 3 Read the RESULT in 2 min

17. Anemia Patient selection Sever anemia persists within 2 weeks After reducing the dose of Ribavirin by 200 mg/day from their initial dose

18. Anemia Goals of therapy Resolution of sever anemia with target Hb 12 g/dl Maintain target ribavirin dose (not less than 80% of original dose) Reduce need for transfusion and or hospitalization Enhance treatment adherence

19. erythropoietin Energy to live … not just to survive Initiate therapy with Erythropoietin 150 IU/Kg/W Recheck Hgb every 2 weeks Till goals of therapy achieved

20. erythropoietin ESA Partial responder Hgb increase less than1gm/dl After 4 weeks If Hgb at 6-8 weeks is still not at goal .consider further reduction In Ribavirin dose and maintain Epo as needed Monitor Hb accordingly check iron stores If iron stores are adequate Increase Epo dose 25-50%

21. erythropoietin ESA responder Hgb increase more than1gm/dl with Hgb less than 12g/dl in any 2 week period If patient not at target ribavirin dose Maintain Epo dose and increase Ribavirin dose Monitor Hgb accordingly if at target ribavirin dose maintain Epo dose

22. erythropoietin ESA responder Hgb increase more than 12gm/dl If not at target Ribavirin dose Continue Epo and increase Ribavirin dose Monitor Hb accordingly If at target Ribavirin dose decrease Epo dose 25%

23. March 9, 2007