Title: Side effects of therapy for chronic hepatitis C
Abstract: Chronic hepatitis C remains one of the leading causes of chronic liver disease in the United States, and great emphasis has been placed on treatment of this potentially life-threatening illness. Therapy has steadily improved over the last decade, such that sustained virological response can now be achieved in over 50% of individuals treated with the combination of long-acting pegylated interferon and ribavirin.1Fried M.W. Shiffman M.L. Reddy K.R. Smith C. Marinos G. Goncales F.L. Haussinger D. et al.Combination of peginterferon alfa-2a plus ribavirin in patients with chronic hepatitis C virus infection.N Engl J Med. 2002; 347: 975-982Crossref PubMed Scopus (5961) Google Scholar, 2Manns M.P. McHutchison J.G. Gordon S.C. Rustgi V.K. Shiffman M. Reindollar R. Goodman Z.D. 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: 958-965Abstract Full Text Full Text PDF PubMed Scopus (5957) Google Scholar Although these newer agents are significantly more effective than earlier versions of standard interferon, the side effect profile of interferon-based therapies has remained largely unchanged. All interferon agents approved for the treatment of chronic hepatitis C produce similar types of side effects, although the frequency of certain adverse events may vary by preparation.1Fried M.W. Shiffman M.L. Reddy K.R. Smith C. Marinos G. Goncales F.L. Haussinger D. et al.Combination of peginterferon alfa-2a plus ribavirin in patients with chronic hepatitis C virus infection.N Engl J Med. 2002; 347: 975-982Crossref PubMed Scopus (5961) Google Scholar, 3Fried M.W. Side effects of therapy for hepatitis C and their management.Hepatology. 2002; 36: S237-S244Crossref PubMed Google Scholar Recent data have suggested that improved adherence to combination regimens will favorably affect sustained virologic response rates. This review will focus on the management of common side effects associated with the use of pegylated interferon and ribavirin combination therapies. Peginterferonα-2a and peginterferonα-2b in combination with ribavirin yield the highest sustained virologic responses (SVRs) compared with earlier therapies for chronic hepatitis C.1Fried M.W. Shiffman M.L. Reddy K.R. Smith C. Marinos G. Goncales F.L. Haussinger D. et al.Combination of peginterferon alfa-2a plus ribavirin in patients with chronic hepatitis C virus infection.N Engl J Med. 2002; 347: 975-982Crossref PubMed Scopus (5961) Google Scholar, 2Manns M.P. McHutchison J.G. Gordon S.C. Rustgi V.K. Shiffman M. Reindollar R. Goodman Z.D. 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: 958-965Abstract Full Text Full Text PDF PubMed Scopus (5957) Google Scholar, 4National Institutes of Health Consensus Development Conference Statement Management of hepatitis C 2002 (June 10–12, 2002).Gastroenterology. 2002; 123: 2082-2099Abstract Full Text Full Text PDF PubMed Scopus (225) Google Scholar Results from 2 large registration trials show that SVR can be achieved in 54%–56% of subjects.1Fried M.W. Shiffman M.L. Reddy K.R. Smith C. Marinos G. Goncales F.L. Haussinger D. et al.Combination of peginterferon alfa-2a plus ribavirin in patients with chronic hepatitis C virus infection.N Engl J Med. 2002; 347: 975-982Crossref PubMed Scopus (5961) Google Scholar, 2Manns M.P. McHutchison J.G. Gordon S.C. Rustgi V.K. Shiffman M. Reindollar R. Goodman Z.D. 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: 958-965Abstract Full Text Full Text PDF PubMed Scopus (5957) Google Scholar Furthermore, among those participants who achieve an early virologic response (negative or ≥2-log decrease in HCV RNA by week 12), sustained virologic response is best when full adherence to the prescribed regimen is maintained (SVR = 75%).5Ferenci P. Shiffman M.L. Fried M.W. Sulkowski M.S. Haeussinger D. Zarski J.-P. Goncales F.L. et al.Early prediction of response to 40KDA peginterferon alfa-2a (PEGASYS) plus ribavirin in patients with chronic hepatitis C.Hepatology. 2001; 34: 351ACrossref PubMed Scopus (101) Google Scholar Patients who are less adherent to therapy, receiving <80% of the prescribed treatment, have a substantially decreased rate of SVR (48%). Within this group, those who discontinued therapy prematurely for whatever reasons had dismal sustained response rates of 12% compared with 65% of those who continued on therapy despite dose reduction.5Ferenci P. Shiffman M.L. Fried M.W. Sulkowski M.S. Haeussinger D. Zarski J.-P. Goncales F.L. et al.Early prediction of response to 40KDA peginterferon alfa-2a (PEGASYS) plus ribavirin in patients with chronic hepatitis C.Hepatology. 2001; 34: 351ACrossref PubMed Scopus (101) Google Scholar This analysis underscores the importance of developing strategies to monitor and encourage adherence among patients who are being treated with combination therapies. One of the barriers to adherence in combination therapy for chronic hepatitis C is the incidence of treatment-associated adverse events that can lead to dose reductions or sometimes premature discontinuation.1Fried M.W. Shiffman M.L. Reddy K.R. Smith C. Marinos G. Goncales F.L. Haussinger D. et al.Combination of peginterferon alfa-2a plus ribavirin in patients with chronic hepatitis C virus infection.N Engl J Med. 2002; 347: 975-982Crossref PubMed Scopus (5961) Google Scholar, 2Manns M.P. McHutchison J.G. Gordon S.C. Rustgi V.K. Shiffman M. Reindollar R. Goodman Z.D. 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: 958-965Abstract Full Text Full Text PDF PubMed Scopus (5957) Google Scholar, 3Fried M.W. Side effects of therapy for hepatitis C and their management.Hepatology. 2002; 36: S237-S244Crossref PubMed Google Scholar Table 1, Table 2 show the types and frequency of adverse events reported by participants treated with peginterferon combination therapies during trials of peginterferon alfa-2a (180 mics, Pegasys) or peginterferon alfa-2b (1.5 mics/kg, Peg-Intron). For both studies, the control arm was standard interferon alfa-2b and ribavirin.Table 1Frequency of Adverse Events of Peginterferon Alfa-2a and Ribavirin Compared With Standard Interferon Alfa-2b and Ribavirin (>20%)1Fried M.W. Shiffman M.L. Reddy K.R. Smith C. Marinos G. Goncales F.L. Haussinger D. et al.Combination of peginterferon alfa-2a plus ribavirin in patients with chronic hepatitis C virus infection.N Engl J Med. 2002; 347: 975-982Crossref PubMed Scopus (5961) Google Scholar, 3Fried M.W. Side effects of therapy for hepatitis C and their management.Hepatology. 2002; 36: S237-S244Crossref PubMed Google ScholarPeginterferon Alfa-2a and Ribavirin (%)Interferon Alfa-2b and Ribavirin (%)Fatigue5455Headache4752Pyrexia4356Myalgia4250Rigors2435Insomnia3739Nausea2933Alopecia2834Irritability2428Arthralgia2725Anorexia2122Dermatitis2118Depression2230Fatigue5455 Open table in a new tab Table 2Frequency of Adverse Events of Peginterferon Alfa-2b and Ribavirin Compared With Standard Interferon Alfa-2b and Ribavirin (>20%)2Manns M.P. McHutchison J.G. Gordon S.C. Rustgi V.K. Shiffman M. Reindollar R. Goodman Z.D. 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: 958-965Abstract Full Text Full Text PDF PubMed Scopus (5957) Google Scholar, 3Fried M.W. Side effects of therapy for hepatitis C and their management.Hepatology. 2002; 36: S237-S244Crossref PubMed Google ScholarPeginterferon Alfa-2b and Ribavirin (%)Interferon Alfa-2b and Ribavirin (%)Fatigue6460Headache6258Pyrexia4633Myalgia5650Rigors4841Insomnia4041Nausea4333Alopecia3632Irritability3534Arthralgia3428Anorexia/weight loss3227Weight loss2920Depression3134Injection site reaction5836Injection site inflammation2518 Open table in a new tab In general, the adverse events were all predictable based on previous experience with interferon and ribavirin combination therapy, and no unexpected new classes of side effects were observed in these trials. In the study of peginterferon alfa-2a and ribavirin, the majority of adverse events in subjects treated with these agents were of similar or lower frequency than for those treated with standard interferon and ribavirin. Thus, influenza-like symptoms (fever, myalgia, and rigors) and depression occurred significantly less often in the peginterferon alfa-2a combination arm compared with standard interferon and ribavirin.1Fried M.W. Shiffman M.L. Reddy K.R. Smith C. Marinos G. Goncales F.L. Haussinger D. et al.Combination of peginterferon alfa-2a plus ribavirin in patients with chronic hepatitis C virus infection.N Engl J Med. 2002; 347: 975-982Crossref PubMed Scopus (5961) Google Scholar, 3Fried M.W. Side effects of therapy for hepatitis C and their management.Hepatology. 2002; 36: S237-S244Crossref PubMed Google Scholar Similar rates of adverse events were shown in a second registration trial of peginterferon alfa-2a and ribavirin, reported in preliminary form by Hadziyannis.6Hadziyannis S.J. Hepatology. 2002; PubMed Google Scholar In studies of peginterferon alfa-2b and ribavirin, similar types of adverse events were reported in comparison to standard interferon combination therapy.2Manns M.P. McHutchison J.G. Gordon S.C. Rustgi V.K. Shiffman M. Reindollar R. Goodman Z.D. 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: 958-965Abstract Full Text Full Text PDF PubMed Scopus (5957) Google Scholar, 3Fried M.W. Side effects of therapy for hepatitis C and their management.Hepatology. 2002; 36: S237-S244Crossref PubMed Google Scholar Most adverse events were reported with similar frequencies in both treatment groups (Table 2). Injection-site reactions and injection-site inflammation were more common, although it was noted that these were generally mild and rarely dose limiting.2Manns M.P. McHutchison J.G. Gordon S.C. Rustgi V.K. Shiffman M. Reindollar R. Goodman Z.D. 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: 958-965Abstract Full Text Full Text PDF PubMed Scopus (5957) Google Scholar Table 3 provides a summary of the frequency of premature discontinuation of therapy or dose reduction from 2 registration trials of either peginterferon alfa-2a or peginterferon alfa-2b.1Fried M.W. Shiffman M.L. Reddy K.R. Smith C. Marinos G. Goncales F.L. Haussinger D. et al.Combination of peginterferon alfa-2a plus ribavirin in patients with chronic hepatitis C virus infection.N Engl J Med. 2002; 347: 975-982Crossref PubMed Scopus (5961) Google Scholar, 2Manns M.P. McHutchison J.G. Gordon S.C. Rustgi V.K. Shiffman M. Reindollar R. Goodman Z.D. 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: 958-965Abstract Full Text Full Text PDF PubMed Scopus (5957) Google Scholar, 3Fried M.W. Side effects of therapy for hepatitis C and their management.Hepatology. 2002; 36: S237-S244Crossref PubMed Google Scholar Premature withdrawal from therapy because of laboratory abnormalities or adverse events was generally low in the combination arms treated with either peginterferon alfa-2a (10%) or peginterferon alfa-2b (14%) and was comparable in both studies to their control arms of standard interferon alfa-2b and ribavirin (11% and 13%, respectively) (Table 3). Dose reductions (temporary or permanent) of either peginterferon for any adverse event were required in 32%–42% of patients compared with 27%–34% in those treated with standard interferon. Laboratory abnormalities such as neutropenia, anemia, and thrombocytopenia were the most frequent indications for dose reduction. The frequency of dose reduction for neutropenia was greater with both peginterferon agents compared with standard interferon (20% vs. 5%, peginterferon alfa-2a, and 18% vs. 10%, peginterferon alfa-2b). Among these participants, approximately 4%–5% experienced grade 4 neutropenia (<500 cells/mm3) in both studies. Thrombocytopenia was also more common with peginterferon, although rarely required dose reductions. Despite the need for dose reductions, only a minority of patients discontinued therapy because of laboratory abnormalities (peginterferon alfa-2a and ribavirin = 3% and peginterferon alfa-2b = 2%).1Fried M.W. Shiffman M.L. Reddy K.R. Smith C. Marinos G. Goncales F.L. Haussinger D. et al.Combination of peginterferon alfa-2a plus ribavirin in patients with chronic hepatitis C virus infection.N Engl J Med. 2002; 347: 975-982Crossref PubMed Scopus (5961) Google Scholar, 2Manns M.P. McHutchison J.G. Gordon S.C. Rustgi V.K. Shiffman M. Reindollar R. Goodman Z.D. 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: 958-965Abstract Full Text Full Text PDF PubMed Scopus (5957) Google Scholar, 3Fried M.W. Side effects of therapy for hepatitis C and their management.Hepatology. 2002; 36: S237-S244Crossref PubMed Google ScholarTable 3Frequency of Discontinuation of Therapy or Dose Reduction in Patients Treated With Peginterferon and Ribavirin1Fried M.W. Shiffman M.L. Reddy K.R. Smith C. Marinos G. Goncales F.L. Haussinger D. et al.Combination of peginterferon alfa-2a plus ribavirin in patients with chronic hepatitis C virus infection.N Engl J Med. 2002; 347: 975-982Crossref PubMed Scopus (5961) Google Scholar, 2Manns M.P. McHutchison J.G. Gordon S.C. Rustgi V.K. Shiffman M. Reindollar R. Goodman Z.D. 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: 958-965Abstract Full Text Full Text PDF PubMed Scopus (5957) Google ScholarPEGα-2a + Ribavirin (%)IFNα-2b + Ribavirin (%)PEGα-2b + Ribavirin (%)IFNα-2b + Ribavirin (%)Premature discontinuation10111413Adverse events7101212Lab abnormalities3121Dose modifications3242 Open table in a new tab It is evident from the above discussion that treatment for chronic hepatitis C has a significant impact on the quality of life of those undergoing therapy. From personal discussions with patients who are contemplating starting therapy, these issues are the greatest source of anxiety surrounding their decision to embark on treatment. These concerns are heightened in many cases by skewed information, is readily available on the Internet, from poor experiences anecdotal in nature, of other patients (and healthcare providers) with whom they have communicated, or from other sources (M. Fried, personal communication). Thus, it is important to have a frank discussion with the patient before beginning treatment outlining the most common side effects and plans for monitoring and managing those symptoms. It is imperative that patients on treatment for hepatitis C are regularly evaluated by experienced healthcare providers so that adverse events can be identified early and appropriate interventions undertaken with the goal to maximize adherence to therapy while minimizing the detrimental effects of these agents on the patients' quality of life. Proper patient selection as candidates for treatment is important to ensuring optimal responses to treatment. Absolute and relative contraindications to therapy with pegylated interferon and ribavirin are noted in the package inserts of these products. It should also be emphasized that the above data concerning adverse events with the new pegylated interferons reflect the experiences of a highly selected, idealized group of patients enrolled in clinical trials. For entry into these studies, patients had to meet strict inclusion and exclusion criteria. Patients were excluded if they had significant psychiatric illnesses, active substance abuse, or comorbid medical conditions that could compromise tolerability of the agents under investigation. These criteria are very appropriate for clinical trials in which safety issues are paramount. However, in clinical practice, there is much greater diversity among patients, and we must regularly weigh the risks and benefits of therapy in individual patients who may be less ideal candidates for treatment than those included in clinical trials. Indeed, the recent National Institutes of Health Consensus Statement4National Institutes of Health Consensus Development Conference Statement Management of hepatitis C 2002 (June 10–12, 2002).Gastroenterology. 2002; 123: 2082-2099Abstract Full Text Full Text PDF PubMed Scopus (225) Google Scholar suggested that treatment be cautiously expanded to and studied in certain populations in which data are limited in terms of safety and efficacy (liver transplant recipients, children, human immunodeficiency virus coinfected, injecting drug users). The impact on safety, tolerability, and efficacy in these special populations is yet to be determined. Constitutional symptoms, such as fatigue, headache, fever, myalgia, and arthralgia, are the most common side effects in patients treated with pegylated interferons.1Fried M.W. Shiffman M.L. Reddy K.R. Smith C. Marinos G. Goncales F.L. Haussinger D. et al.Combination of peginterferon alfa-2a plus ribavirin in patients with chronic hepatitis C virus infection.N Engl J Med. 2002; 347: 975-982Crossref PubMed Scopus (5961) Google Scholar, 2Manns M.P. McHutchison J.G. Gordon S.C. Rustgi V.K. Shiffman M. Reindollar R. Goodman Z.D. 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: 958-965Abstract Full Text Full Text PDF PubMed Scopus (5957) Google Scholar, 3Fried M.W. Side effects of therapy for hepatitis C and their management.Hepatology. 2002; 36: S237-S244Crossref PubMed Google Scholar 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. Other drugs may be used, such as cyclooxygenase-2 inhibitors, but there are no data suggesting this class of medications is superior to acetaminophen or ibuprofen in this group of patients. 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.3Fried M.W. Side effects of therapy for hepatitis C and their management.Hepatology. 2002; 36: S237-S244Crossref PubMed Google Scholar Hematologic adverse events are the most common laboratory abnormalities leading to dose modifications or discontinuation.1Fried M.W. Shiffman M.L. Reddy K.R. Smith C. Marinos G. Goncales F.L. Haussinger D. et al.Combination of peginterferon alfa-2a plus ribavirin in patients with chronic hepatitis C virus infection.N Engl J Med. 2002; 347: 975-982Crossref PubMed Scopus (5961) Google Scholar, 2Manns M.P. McHutchison J.G. Gordon S.C. Rustgi V.K. Shiffman M. Reindollar R. Goodman Z.D. 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: 958-965Abstract Full Text Full Text PDF PubMed Scopus (5957) Google Scholar, 3Fried M.W. Side effects of therapy for hepatitis C and their management.Hepatology. 2002; 36: S237-S244Crossref PubMed Google Scholar Standard and pegylated interferons are associated with rapid suppression of hematopoiesis. After administration of high doses of interferon alpha-2b followed by daily interferon or weekly pegylated interferon in 46 patients with chronic hepatitis C, there was a significant drop in hemoglobin followed by increases in erythropoietin.7Peck-Radosavljevic M. Wichlas M. Homoncik-Kraml M. Kreil A. Hofer H. Jessner W. Gangl A. et al.Rapid suppression of hematopoiesis by standard or pegylated interferon-alpha.Gastroenterology. 2002; 123: 141-151Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar Peginterferon alpha-2b had a greater effect on hemoglobin levels compared with standard interferon alpha-2b. Interestingly, the reticulocyte count recovered more quickly in the peginterferon group compared with the daily standard interferon group.7Peck-Radosavljevic M. Wichlas M. Homoncik-Kraml M. Kreil A. Hofer H. Jessner W. Gangl A. et al.Rapid suppression of hematopoiesis by standard or pegylated interferon-alpha.Gastroenterology. 2002; 123: 141-151Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar Hemolytic anemia occurs to some extent in all patients treated with ribavirin, although the degree of anemia is variable. Lower pretreatment platelet count and haptoglobin phenotype are reported to be associated with a greater drop in hemoglobin.8Van Vlierbergh H. Delanghe J.R. De Vos M. Leroux-Roel G. Factors influencing ribavirin-induced hemolysis.J Hepatol. 2001; 34: 911-916Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar The hemolytic anemia associated with ribavirin is caused by impaired antioxidant defenses and red blood cell oxidative damage, promoting extravascular hemolysis via the reticuloendothelial system.9De Franceschi L. Fattovich G. Turrini F. Ayi K. Brugnara C. Manzato F. Noventa 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: 997-1004Crossref PubMed Scopus (414) Google Scholar Ribavirin is taken up by erythrocytes and activated to ribavirin triphosphate. Erythrocytes are unable to hydrolyze ribavirin triphosphate, and ribavirin triphosphate remains trapped in erythrocytes in which concentrations remain 60-fold greater compared with plasma concentrations.9De Franceschi L. Fattovich G. Turrini F. Ayi K. Brugnara C. Manzato F. Noventa 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: 997-1004Crossref PubMed Scopus (414) Google Scholar Erythropoieitin has been used to improve hemoglobin levels in patients who develop symptomatic hemolytic anemia with ribavirin. Interim results of a study of HCV-infected subjects treated with interferon alfa-2b plus ribavirin or peginterferon alpha-2b plus ribavirin showed that epoetin alfa effectively treats the hemolytic anemia associated with ribavirin and improves quality of life.10Dieterich D.T. Pockros P. Schiff E.R. et al.Interim results of a randomized, double-blind placebo-controlled study demonstrates that epoietin-alfa (PROCRIT) allows maintenance of ribavirin dosing.Hepatology. 2002; (abstr): 493Google Scholar Preliminary data have been presented from 48 subjects who were randomized to placebo (n = 25) or epoetin alfa (40,000 U/week) (n = 23) after developing anemia (<12 g/dL) while on antiviral therapy. The epoetin group had a 2.1 g/dL increase in hemogloblin level compared with a −0.20 decrease in the placebo group (P < 0.001). This translated to greater maintenance of ribavirin dose; at week 9 of antiviral therapy, 96% of the epoetin group was able to maintain the initial ribavirin dose compared with only 63% in the placebo group (P < 0.01).10Dieterich D.T. Pockros P. Schiff E.R. et al.Interim results of a randomized, double-blind placebo-controlled study demonstrates that epoietin-alfa (PROCRIT) allows maintenance of ribavirin dosing.Hepatology. 2002; (abstr): 493Google Scholar Although quality of life appears to be significantly improved with epoetin alfa in ribavirin induced anemia, the impact of this adjunctive agent in terms of sustained virologic response remains to be determined. Thus, an examination of the costs and benefits provided by epoetin alfa are warranted.11Devine E.B. Kowdley K.V. Veenstra D.L. Sullivan S.D. Management strategies for ribavirin-induced hemolytic anemia in the treatment of hepatitis C clinical and economic implications.Value Health. 2001; 4: 376-384Abstract Full Text PDF PubMed Scopus (20) Google Scholar At the present time, we have reserved the use of epoetin alfa for those patients with markedly symptomatic anemia who require significant reductions in ribavirin dose to maintain an acceptable level of hemoglobin above 10 g/dL or in whom discontinuation of ribavirin is imminent because of severe anemia (between 8.5 and 10 g/dL). Initial management of these patients with severe anemia still requires transient ribavirin dose reduction and close monitoring until the hemoglobin values increase, generally within 1–2 weeks, after the administration exogenous epoetin alfa. The incidence of neutropenia in patients treated with peginterferons is greater than that seen with standard interferon regimens and is a frequent indication for dose reduction.1Fried M.W. Shiffman M.L. Reddy K.R. Smith C. Marinos G. Goncales F.L. Haussinger D. et al.Combination of peginterferon alfa-2a plus ribavirin in patients with chronic hepatitis C virus infection.N Engl J Med. 2002; 347: 975-982Crossref PubMed Scopus (5961) Google Scholar, 2Manns M.P. McHutchison J.G. Gordon S.C. Rustgi V.K. Shiffman M. Reindollar R. Goodman Z.D. 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: 958-965Abstract Full Text Full Text PDF PubMed Scopus (5957) Google Scholar, 3Fried M.W. Side effects of therapy for hepatitis C and their management.Hepatology. 2002; 36: S237-S244Crossref PubMed Google Scholar Rapid decreases in neutrophil counts 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. Neutrophil counts rapidly return to baseline after therapy is discontinued.3Fried M.W. Side effects of therapy for hepatitis C and their management.Hepatology. 2002; 36: S237-S244Crossref PubMed Google Scholar A recent study of 25 patients with hepatitis C given a single high dose of standard interferon followed by regular injections of standard or pegylated interferon detailed the hematologic effects of these drugs.7Peck-Radosavljevic M. Wichlas M. Homoncik-Kraml M. Kreil A. Hofer H. Jessner W. Gangl A. et al.Rapid suppression of hematopoiesis by standard or pegylated interferon-alpha.Gastroenterology. 2002; 123: 141-151Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar Leukocytes were the most affected cell lineage, and the peginterferons had a similar effect on neutrophils and lymphocytes with a median drop of 21% and 31%, respectively, after a single dose of interferon. During daily administration of interferon or weekly administration of peginterferon, the decline in neutrophil count was larger than the drop in lymphocyte count. Peginterferon had a greater effect on neutrophil count compared with standard interferon, consistent with the observations in clinical trials.7Peck-Radosavljevic M. Wichlas M. Homoncik-Kraml M. Kreil A. Hofer H. Jessner W. Gangl A. et al.Rapid suppression of hematopoiesis by standard or pegylated interferon-alpha.Gastroenterology. 2002; 123: 141-151Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar The major concern about neutropenia is the potential risk of increased infectious complications. An analysis of 119 subjects with hepatitis C who were treated with interferon and ribavirin showed a 34% decrease in neutrophil count with the steepest decline during the first 4 weeks of therapy.12Soza A. Everhart J.E. Ghany M.G. Doo E. Heller T. Promrat K. Park Y. et al.Neutropenia during combination therapy of interferon alfa and ribavirin for chronic hepatitis C.Hepatology. 2002; 36: 1273-1279Crossref PubMed Scopus (188) Google Scholar Of the 22 infections that occurred, the most common infections were sinusitis, pharyngitis, and urinary tract infection. One patient, a 72-year-old man with cirrhosis required hospitalization for cellulitis and lower-extremity edema. None of the patients who developed infections had preexisting neutropenia or a neutrophil count less than 750 cells/mm3 during any point in treatment.12Soza A. Everhart J.E. Ghany M.G. Doo E. Heller T. Promrat K. Park Y. et al.Neutropenia during combination therapy of interferon alfa and ribavirin for chronic hepatitis C.Hepatology. 2002; 36: 1273-1279Crossref PubMed Scopus (188) Google Scholar Similar analyses of databases from the registration trials of peginterferons also did not show a significant association between neutropenia and infectious complications.1Fried M.W. Shiffman M.L. Reddy K.R. Smith C. Marinos G. Goncales F.L. Haussinger D. et al.Combination of peginterferon alfa-2a plus ribavirin in patients with chronic hepatitis C virus infection.N Engl J Med. 2002; 347: 975-982Crossref PubMed Scopus (5961) Google Scholar, 2Manns M.P. McHutchison J.G. Gordon S.C. Rustgi V.K. Shiffman M. Reindollar R. Goodman Z.D. et al.Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribaviri