SILS 2009 - The 5th Seoul International Liver Symposium -

Symposium Ⅲ Cu r r e n t a n d f u t u r e i s s u e s i n h e p a t i t i s C t r e a t m e n t

Side effects of peginterferon and treatment for 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) .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 ane- mia and neutropenia. Reducing ribavirin dose corresponded to a decline in the SVR rate.4 Like this, dose mod- ification 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 conven- tional 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, in- somnia, 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 SILS 2009 - The 5th Seoul International Liver Symposium - 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.8

2. 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 con- jugates 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 eryth- ropoiesis 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 re- duction (≥1.5 g/dL decrease at week 2) were known to be factors associated with anemia.12‐14

4. 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/mm3) 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/mm3, and the drug is permanently dis-

44 SILS 2009 - The 5th Seoul International Liver Symposium - continued when the ANC falls below 500/mm3. For peginterferon alfa‐2a, on the other hand, the dose is re- duced to 135 mg when the ANC falls below 750/mm3 and stopped when the ANC falls below 500/mm3. 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. con- trol 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 tol- erated 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 discon- tinuation.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 supple- mentation 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 ribavirin‐ induced 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 de- pends 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 SILS 2009 - The 5th Seoul International Liver Symposium - 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 treat- ment of chronic hepatitis C. It is a guanosine analogue that preferentially targets the liver and is rapidly con- verted 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 in- cidence of anemia was approximately four‐fold significantly lower, fixed doses of viramidine failed to demon- strate 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 bleed- ing has not been observed in patients with low platelet counts (<50,000/mm3) 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/mm3 (peginterferon alfa‐2b) or <50,000/mm3 (peginterferon alfa‐2a) and permanent treatment discontinuation for platelets <50,000/ mm3 (peginterferon alfa‐2b) or <25,000/mm3 (peginterferon alfa‐2a). Few studies have explored thrombopoietic growth factor for treatment of interferon‐induced thrombo- cytopenia. Oprelvekin (a recombinant human interleukin‐11) is a thrombopoietic growth factor. Oprelvekin im- proved 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. Eltrombo- pag 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 ef- fects with the first few doses of interferon. Fortunately, these symptoms generally resolve or become less se- vere 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 SILS 2009 - The 5th Seoul International Liver Symposium - ing antiviral therapy, and once after therapy is completed.2 Numerous case reports exist documenting other ad- verse 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 treat- ment, patients should be fully informed of the potential side effects, and arrangements should be made for mon- itoring 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

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