Side effects of peginterferon and ribavirin treatment for hepatitis C and their management

Transcription

1 Symposium Ⅲ Current and future issues in hepatitis C treatment Side effects of peginterferon and ribavirin treatment for hepatitis C and their management Seung Woon Paik Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea Introduction Side effects of peginterferon and ribavirin affect virtually all patients who receive antiviral treatment due to hepatitis C virus (HCV) infection. 1 The most common side effects include fatigue, influenza like symptoms, gastrointestinal disturbances, neuropsychiatric symptoms, and hematologic abnormalities. These side effects not only can impair patients quality of life, but also can lead to dose reductions or sometimes premature discontinuation. 2 Sustained virologic response (SVR) is best when full adherence to the prescribed regimen is maintained. 3 The most common indications for dose modification were hematologic abnormalities, such as anemia and neutropenia. Reducing ribavirin dose corresponded to a decline in the SVR rate. 4 Like this, dose modification diminishes the efficacy of optimal treatment regimen for HCV and may have a negative impact on SVR. Thus, appropriate managements of adverse events have profound effect on treatment of HCV. Side effects of peginterferon and ribavirin The incidence and types of side effects of peginterferon plus ribavirin are similar to those caused by conventional interferon plus ribavirin. Side effects related to interferon include: cytopenia, abnormalities of thyroid function, depression, irritability, concentration and memory disturbances, visual disturbances, fatigue, muscle aches, headaches, nausea and vomiting, loss of appetite and weight, low grade fever and skin irritation, insomnia, hearing loss, tinnitus, interstitial fibrosis and hair thinning. Side effects associated with ribavirin include hemolytic anemia, fatigue, itching, rash, cough, gastrointestinal upset, pharyngitis, gout, and birth defects. It is essential that persons who take ribavirin practice strict contraception during treatment and for 6 months after the termination of treatment. 5 The most common adverse effects of peginterferon are muscle aches and fatigue, psychological side effects, and hematologic side effects such as anemia, neutropenia, and thrombocytopenia. 1 The frequency of premature discontinuation of therapy from 2 registration trial was 10% (peginerferon alfa 2a) or 14% (peginterferon alfa 2b). 6,7 Dose reductions (temporary or permanent) were required in 32~42% of 43

2 patients. Laboratory abnormalities such as neutropenia, anemia, and thrombocytopenia were the most frequent indications for dose reduction. 6,7 The frequency of dose reduction for neutropenia or thrombocytopenia was greater with peginterferon agents compared with standard interferon. 6,7 Management of common side effects - hematologic side effects 1. Mechanisms of hematologic changes by interferon Single high dose interferon therapy resulted in a significant drop in hemoglobin, leukocytes, and platelet count. Consecutive combination antiviral therapy aggravated the anemia but not the drop in leukocytes or thrombocytes. The drop in all 3 hematopoietic lineages through IFN treatment is caused by a combination of bone marrow inhibition and probably some other rapid acting mechanisms Mechanisms of ribavirin induced anemia Ribavirin accumulates in erythrocytes where it undergoes phosphorylation to its monophosphate, diphosphate and triphosphate, the pharmacologically active forms, via adenosine kinase. These ribavirin phosphate conjugates are unable to cross the erythrocyte cell membrane and are thus trapped intracellularly as a mixture of phosphorylated derivates and cleared slowly from red cells with a half life of 40 days; by contrast, elimination from plasma is much more rapid (half life 24 hours). 9 Increased susceptibility of erythrocytes to oxidative stress, increased removal of defective erythrocytes by the reticuloendothelial system, and inhibition of erythropoiesis involving down regulation of erythropoietin receptors have been suggested to explain ribavirin induced anemia. 9,10 3. Identifying high risk patients with hematologic side effects Identifying high risk patients is also important in managing hematologic side effects. These patients needs close monitoring and it may result in earlier identification, and earlier appropriate interventions. Weight and baseline neutrophil count was found to be independent factor for neutropenia. 11 Pretreatment hemoglobin level, age, baseline platelet level, gender, body weight, race, creatinine clearance, cirrhosis, and rapid hemoglobin reduction ( 1.5 g/dl decrease at week 2) were known to be factors associated with anemia Management of neutropenia Use of interferon or peginterferon is associated with neutropenia (about 22% to 45% drop from baseline white blood cell count). 15 Rapid decrease in neutrophil count may be seen within the first 2 weeks of initiation of therapy and usually stabilize over the next 4~6 weeks as steady state concentrations of pegylated interferon are achieved. 2 Grade 4 neutropenia (<500 cells/mm 3 ) is experienced in 4~5% of patients. 6,7 The major concern about neutropenia is the potential risk of increased infectious complications. However, studies have suggested that neutropenia is not necessarily associated with an increased risk for major bacterial infection. 16 Nevertheless, in general, patients who develop neutropenia are managed with dose reduction or permanent discontinuation of interferon as per guidelines provided in package inserts. For patients on peginterferon alfa 2b, a 50% dose reduction is recommended when the ANC falls below 750/mm 3, and the drug is permanently dis- 44

3 continued when the ANC falls below 500/mm 3. For peginterferon alfa 2a, on the other hand, the dose is reduced to 135 mg when the ANC falls below 750/mm 3 and stopped when the ANC falls below 500/mm 3. Dose adjustments effectively treat neutropenia, but the resulting suboptimal dosing and potential impact on virologic response are major concerns. Granulocyte colony stimulating factor (G CSF) has been used to treat or avoid interferon induced neutropenia. 17 G CSF use improve neutropenia, but impact on SVR is less clear. Recently published, one non randomized study showed potential benefit of G CSF use in neutropenic patients. There is no statistically significant difference in the SVR (61% vs 76%, p=0.18), between G CSF arm vs. control arm who received anti HCV therapy without developing neutropenia. 18 This study also shows that timing of G CSF administration did not make any significant impact on patients neutrophil counts but was better tolerated when given 2 days apart from peginterferon. 5. Management of anemia Anemia is the most frequent reported hematologic abnormality resulting from treatment with interferon and ribavirin, and it may be the most significant side effect. The stress of the sudden onset of anemia can induce myocardial infaction in persons with preexisting coronary artery disease or stroke in those with cerebrovascular disease. 1 Both interferon and ribavirin can cause anemia, but ribavirin induced anemia is most important. Ribavirin produces a dose dependent hemolytic anemia that is reversible within 4~8 weeks of drug discontinuation. 19 Conventional, nonpharmacologic management for treatment related anemia involves ribavirin dose reduction or permanent discontinuation per the manufacturer s guidelines. 10 These recommendations include ribavirin dose reduction when the hemoglobin (Hb) level reaches 8.5 to 10 g/dl, and permanent discontinuation for Hb <8.5 g/dl. But, again, the resulting suboptimal dosing and potential impact on virologic response are major concerns. Erythropoietic growth factors (epoetin alfa and darbepoetin alfa) effectively increase hemoglobin while maintain the optimal ribavirin dose and improving patients quality of life. 17,20,21 However, these agents exposes the patient to an additional injectable agent with potentially serious but uncommon adverse effects including thrombosis, hypertension, and pure RBC aplasia, and the impact of this adjunctive agent in terms of SVR remains to be determined. 19 A pilot trial tested the hypothesis that antioxidant supplementation may attenuate ribavirin induced hemolysis, which showed that antioxidant administration was associated with a milder and more gradual decrease in Hb. 9 But other study found no protective effect of antioxidant supplementation. 22 The effect of antioxidant supplementation remains to be determined. It has been suggested that ribavirin induced anemia is dose related and that higher doses are associated with a greater incidence and severity of hemolysis. Thus correct dosage would be important in preventing ribavirininduced anemia. Currently ribavirin dosage is recommended according to genotype and body weight. 23 Lindahl found that the decrease in Hb level with ribavirin therapy was not related to dose of ribavirin per body weight, but with the serum concentration of ribavirin. The authors concluded that the anemia induced by ribavirin depends primarily on the concentration of ribavirin rather than dose per body weight and proposed that ribavirin should be dosed according to renal function, not body weight. 24 Current recommended flat dose ribavirin dose result in higher ribavirin exposure, especially for low weight patients. We evaluated the effect of high ribavirin starting dose among Korean patients, which found that ribavirin dose >16 mg/kg is associated with more fre- 45

4 quent dose modifications while improvement of SVR was not seen. Our findings suggest that some patients might benefit from lowering starting dose of ribavirin to reduce ribavirin induced anemia. 25 Viramidine is a novel ribavirin prodrug being developed for administration with peginterferon for the treatment of chronic hepatitis C. It is a guanosine analogue that preferentially targets the liver and is rapidly converted to ribavirin by adenosine deaminase. Viramidine less accumulates in erythrocytes, thus may reduce risk of anemia without reducing the probability of achieving SVR. However, in phase III trial, although the incidence of anemia was approximately four fold significantly lower, fixed doses of viramidine failed to demonstrate noninferiority to ribavirin in producing SVR rates. 26 A weight based dosing trial of viramidine is currently under way. 6. Management of thrombocytopenia Thrombocytopenia occurs in 3% to 6% of patients treated for chronic hepatitis C. 27 However, because bleeding has not been observed in patients with low platelet counts (<50,000/mm 3 ) and interferon discontinuation or dose modification is relatively rare in patients with thrombocytopenia, the clinical implications of modest thrombocytopenia have been questioned. The package insert of these products recommends dose reduction based on established guidelines, ie, 50% dose reduction for platelets <80,000/mm 3 (peginterferon alfa 2b) or <50,000/mm 3 (peginterferon alfa 2a) and permanent treatment discontinuation for platelets <50,000/ mm 3 (peginterferon alfa 2b) or <25,000/mm 3 (peginterferon alfa 2a). Few studies have explored thrombopoietic growth factor for treatment of interferon induced thrombocytopenia. Oprelvekin (a recombinant human interleukin 11) is a thrombopoietic growth factor. Oprelvekin improved platelet count, but due to side effect (fluid retention), there is currently little enthusiasm for its use. 15 Eltrombopag is a new, orally active thrombopoietin receptor agonist that stimulates thrombopoiesis. Eltrombopag therapy increases platelet counts in patients with thrombocytopenia due to HCV related cirrhosis, thereby permitted the initiation of antiviral therapy. 28 Management of common side effects other than hematologic side effects The most common adverse effects of peginterferon are constitutional symptoms, such as fatigue, headache, fever, myalgia, and arthralgia. Virtually all patients will experience at least one of these influenza like side effects with the first few doses of interferon. Fortunately, these symptoms generally resolve or become less severe after the first month of therapy. Acetaminophen or ibuprofen taken at the time of injection may ameliorate the myalgias, arthralgias, headache, and fever. Simple interventions such as maintaining adequate hydration and a light moderate exercise program and altering dosing schedules to coincide with scheduled days off from work or a lighter work load help minimize these side effects. 2 Adverse events that is more difficult to manage are the psychological side effects, such as depression, anxiety, irritability, sleep disturbance, and difficulty concentrating. These side effects typically are managed with counseling, antidepressant drugs, or anxiolytic agents, with variable success. 1 Interferon treatment is associated with the development of hypo or hyperthyroidism. It is generally recommended that thyroid function test be checked before, every 12 weeks dur- 46

5 ing antiviral therapy, and once after therapy is completed. 2 Numerous case reports exist documenting other adverse events during therapy. Specific management for these less common adverse events must be individualized based on their severity. 2,27 Conclusion Side effects affect virtually all patients who receive treatment with peginterferon and ribavirin. Before treatment, patients should be fully informed of the potential side effects, and arrangements should be made for monitoring of symptoms and blood counts. 1 Early identification and early appropriate interventions of adverse event will maximize patients adherence to treatment, while minimizing detrimental effects on the patients quality of life, leading to ultimate goal of successful treatment of hepatitis C virus. References 1. Hoofnagle JH, Seeff LB. Peginterferon and ribavirin for chronic hepatitis C. N Engl J Med 2006;355: Russo MW, Fried MW. Side effects of therapy for chronic hepatitis C. Gastroenterology 2003;124: McHutchison JG, Manns M, Patel K, Poynard T, Lindsay KL, Trepo C, et al. Adherence to combination therapy enhances sustained response in genotype 1 infected patients with chronic hepatitis C. Gastroenterology 2002;123: Shiffman ML, Di Bisceglie AM, Lindsay KL, Morishima C, Wright EC, Everson GT, et al. Peginterferon alfa 2a and ribavirin in patients with chronic hepatitis C who have failed prior treatment. Gastroenterology 2004;126: ; discussion Asian Pacific Association for the Study of the Liver (APASL) Hepatitis C Working Party, McCaughan GW, Omata M, Amarapurkar D, Bowden S, Chow WC, et al. Asian Pacific Association for the Study of the Liver consensus statements on the diagnosis, management and treatment of hepatitis C virus infection. J Gastroenterol Hepatol 2007;22: Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, et al. Peginterferon alfa 2b plus ribavirin compared with interferon alfa 2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001;358: Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Gonçales FL Jr, et al. Peginterferon alfa 2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002;347: Peck-Radosavljevic M, Wichlas M, Homoncik-Kraml M, Kreil A, Hofer H, Jessner W, et al. Rapid suppression of hematopoiesis by standard or pegylated interferon alpha. Gastroenterology 2002;123: Kowdley KV. Hematologic side effects of interferon and ribavirin therapy. J Clin Gastroenterol 2005;39:S3 S De Franceschi L, Fattovich G, Turrini F, Ayi K, Brugnara C, Manzato F, et al. Hemolytic anemia induced by ribavirin therapy in patients with chronic hepatitis C virus infection: role of membrane oxidative damage. Hepatology 2000;31: Rotman Y, Katz L, Cohen M, Cohen-Ezra O, Manhaim V, Braun M, et al. Low weight predicts neutropenia and peginterferon alfa 2a dose reductions during treatment for chronic hepatitis C. J Viral Hepat 2009;16: Takaki S, Tsubota A, Hosaka T, Akuta N, Someya T, Kobayashi M, et al. Factors contributing to ribavirin dose reduction due to anemia during interferon alfa2b and ribavirin combination therapy for chronic hepatitis C. J Gastroenterol 2004;39: Hung CH, Lee CM, Lu SN, Wang JH, Chen CH, Hu TH, et al. Anemia associated with antiviral therapy in chronic 47

6 hepatitis C: incidence, risk factors, and impact on treatment response. Liver Int 2006;26: Reau N, Hadziyannis SJ, Messinger D, Fried MW, Jensen DM. Early predictors of anemia in patients with hepatitis C genotype 1 treated with peginterferon alfa 2a (40KD) plus ribavirin. Am J Gastroenterol 2008;103: Collantes RS, Younossi ZM. The use of growth factors to manage the hematologic side effects of PEG interferon alfa and ribavirin. J Clin Gastroenterol 2005;39:S9 S Soza A, Everhart JE, Ghany MG, Doo E, Heller T, Promrat K, et al. Neutropenia during combination therapy of interferon alfa and ribavirin for chronic hepatitis C. Hepatology 2002;36: Younossi ZM, Nader FH, Bai C, Sjogren R, Ong JP, Collantes R, et al. 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 Hepat 2008;15: Koirala J, Gandotra SD, Rao S, Sangwan G, Mushtaq A, Htwe TH, et al. Granulocyte colony stimulating factor dosing in pegylated interferon alpha induced neutropenia and its impact on outcome of anti HCV therapy. J Viral Hepat 2007;14: McHutchison JG, Manns MP, Longo DL. Definition and management of anemia in patients infected with hepatitis C virus. Liver Int 2006;26: Afdhal NH, Dieterich DT, Pockros PJ, Schiff ER, Shiffman ML, Sulkowski MS, et al. Epoetin alfa maintains ribavirin dose in HCV infected patients: a prospective, double blind, randomized controlled study. Gastroenterology 2004;126: Pockros PJ, Shiffman ML, Schiff ER, Sulkowski MS, Younossi Z, Dieterich DT, et al. Epoetin alfa improves quality of life in anemic HCV infected patients receiving combination therapy. Hepatology 2004;40: Saeian K, Bajaj JS, Franco J, Knox JF, Daniel J, Peine C, et al. High dose vitamin E supplementation does not diminish ribavirin associated haemolysis in hepatitis C treatment with combination standard alpha interferon and ribavirin. Aliment Pharmacol Ther 2004;20: Dienstag JL, McHutchison JG. American Gastroenterological Association technical review on the management of hepatitis C. Gastroenterology 2006;130: ; quiz Lindahl K, Schvarcz R, Bruchfeld A, Ståhle L. Evidence that plasma concentration rather than dose per kilogram body weight predicts ribavirin induced anaemia. J Viral Hepat 2004;11: Sinn DH, Paik SW, Kim J, Shin SR, Gwak GY, Choi MS, et al. Flat dosing of ribavirin in Korean results in ribavirin dose over 16 mg/kg for significant proportion of patients, but is not associated with improved sustained virologic response. SILS 2009 poster. 26. Benhamou Y, Afdhal NH, Nelson DR, Shiffman ML, Halliman DG, Heise J, et al. A phase III study of the safety and efficacy of viramidine versus ribavirin in treatment naive patients with chronic hepatitis C: ViSER1 results. Hepatology 2009;50: [Epub ahead of print] 27. Fried MW. Side effects of therapy of hepatitis C and their management. Hepatology 2002;36:S237 S McHutchison JG, Dusheiko G, Shiffman ML, Rodriguez-Torres M, Sigal S, Bourliere M, et al. Eltrombopag for thrombocytopenia in patients with cirrhosis associated with hepatitis C. N Engl J Med 2007;357: