Hepatitis: Shiffman ML

Yilmaz N, Shiffman ML. · No affiliation provided · Liver Transpl. · Pubmed #19109836 No free full text.

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Shiffman ML. · No affiliation provided · Liver Transpl. · Pubmed #17663409 links to  free full text

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Shiffman ML, Rustgi VK. · No affiliation provided · Gastroenterology. · Pubmed #17030201 No free full text.

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Shiffman ML. · No affiliation provided · Liver Transpl. · Pubmed #14526397 links to  free full text

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Zeuzem S, Rizzetto M, Ferenci P, Shiffman ML. · JW Goethe University Hospital, Frankfurt, Germany. · Antivir Ther. · Pubmed #19430089 No free full text.

Abstract: Current guidelines recommend a full 24-week regimen for all patients undergoing treatment for genotype 2 or 3 hepatitis C virus (HCV) infection. Recent data from two large randomized studies, one with pegylated interferon-alpha2a plus ribavirin (RBV) and one with pegylated interferon-alpha2b plus RBV assessed treatment duration and on-treatment predictors, such as rapid virological response (RVR; HCV RNA <50 IU/ml at week 4) or sustained virological response rates. Overall, these studies have shown that abbreviated regimens are generally less effective than standard 24-week regimens in genotype 2 or 3 patients because of a higher rate of relapse. However, abbreviated treatment might be offered to selected patients with an RVR provided that they have a low baseline viral load and minimal hepatic fibrosis.

Shiffman ML. · Hepatology Section, Virginia Commonwealth University Medical Center, Richmond, VA 23298, USA. · Liver Int. · Pubmed #19207968 No free full text.

Abstract: The optimal therapy for patients with the chronic hepatitis C virus (HCV) is a combination of peginterferon and ribavirin. Treating HCV without ribavirin or prematurely discontinuing, frequently missing doses of ribavirin is associated with a significant decline in virological response, and an increase in both breakthrough viraemia and relapse. The major limitation of ribavirin is adverse events, the most common of which is haemolytic anaemia. Haemolysis is modest when ribavirin is utilized as monotherapy, but is significantly increased when combined with interferon or peginterferon. For these reasons, attempts to replace ribavirin with a less toxic alternative have been advanced. Unfortunately, even when ribavirin is replaced by a potent protease inhibitor, relapse is significantly increased and SVR is reduced. The future of HCV treatment is to combine peginterferon and ribavirin with several protease and/or polymerase inhibitors. Whether this strategy will allow ribavirin to be removed from the treatment paradigm remains to be proven. However, based on the results of clinical trials conducted to date, it is much more likely that peginterferon, not ribavirin, could be expendable.

Shiffman ML. · Hepatology Section, Virginia Commonwealth University Medical Center, Richmond, VA 23298, USA. <> · Clin Liver Dis. · Pubmed #18625425 No free full text.

Abstract: Achieving a sustained virologic response depends on the patient achieving three sequential independent milestones: virologic response, maintaining this response throughout treatment, and not relapsing after treatment has been completed. The ability to achieve these milestones depends on the doses of interferon/peginterferon and ribavirin used and on whether treatment with these medications is adjusted, interrupted, or prematurely discontinued in response to adverse events. This review discusses strategies to optimize peginterferon and ribavirin dosing and the impact that growth factors may have on the ability to achieve a sustained virologic response.

McHutchison JG, Manns MP, Brown RS, Reddy KR, Shiffman ML, Wong JB. · Duke Clinical Research Institute, Division of Gastroenterology Duke University, Durham, North Carolina 27705, USA. · Am J Gastroenterol. · Pubmed #17397412 No free full text.

Abstract: Anemia is a common side effect that begins soon after the initiation of peginterferon/ribavirin in the treatment of hepatitis C virus (HCV) infection. It can cause symptoms that negatively impact quality of life (QOL) and is the most common reason for reducing the dose and temporarily or permanently discontinuing ribavirin. Such dose modifications have been shown to reduce the efficacy of treatment. Administering erythropoietin can improve anemia caused by peginterferon and ribavirin therapy and is more effective than dose reduction at improving QOL during treatment. However, erythropoietin, which is not approved by the U.S. Food and Drug Administration (FDA) for use in patients with HCV infection, adds another parenteral drug to the patient's treatment regimen, and is associated with additional costs, inconvenience, and potential side effects. A new ribavirin analog, viramidine, is expected to be associated with a lower incidence of anemia and, if proven effective, may eventually be substituted for ribavirin in combination with peginterferon to treat chronic hepatitis C. In the meantime, physicians must make the best possible use of the available options for managing anemia, especially in select patient groups who are most at risk for anemia and its complications.

Zeuzem S, Alberti A, Rosenberg W, Marcellin P, Diago M, Negro F, Prati D, Puoti C, Roberts SK, Shiffman ML. · Department of Internal Medicine, , Saarland University Hospital, 66421 Homburg/Saar, Germany. · Aliment Pharmacol Ther. · Pubmed #17014573 No free full text.

Abstract: BACKGROUND: Hepatitis C virus infection, a major cause of chronic liver disease, occurs with normal serum alanine aminotransferase activity in approximately 25% of patients. These patients have historically remained untreated but substantial evidence indicates liver damage, progression of disease and impaired quality of life in some individuals. AIM: To review the current management of patients with chronic hepatitis C and normal alanine aminotransferase activity. METHODS: This review represents the summary of discussions at a Clinical Workshop with a comprehensive literature searching of available databases (PubMed and Embase). RESULTS: Current limits defining normal serum alanine aminotransferase activity are not representative of a "healthy" status. Most patients with hepatitis C and normal alanine aminotransferase levels have histologically proven liver damage that, although generally mild, may be significant (> or =F2) in up to 20% of patients and progresses at approximately 50% of the rate in patients with elevated alanine aminotransferase levels. Some patients have persistently normal alanine aminotransferase activity and may have a more benign outcome, but a significant proportion (> or =20%) experience periods of increased serum alanine aminotransferase activity which may be associated with enhanced disease progression. CONCLUSIONS: A treatment approach that considers host and virus-related variables and optimizes patient and cost benefits may therefore provide more effective management of patients with chronic hepatitis C and normal alanine aminotransferase activity.

Shiffman ML. · Hepatology Section, Virginia Commonwealth University Medical Center, Box 980341, Richmond, VA 23298, USA. · Curr Gastroenterol Rep. · Pubmed #16510034 No free full text.

Abstract: Patients with chronic hepatitis C virus (HCV) who were nonresponders to previous treatment with pegylated interferon and ribavirin are a growing population. The vast majority have genotype 1, a high viral load, advanced fibrosis or cirrhosis, and are of African-American race. The evaluation of these patients should include a thorough review of the previous treatment record and characterization of the previous nonresponse. Patients with prior null response are likely resistant to the effects of interferon. In contrast, patients with partial virologic response, breakthrough, and relapse could potentially achieve sustained virologic response if one or more correctable factors that contributed to the prior nonresponse are identified and addressed before and during retreatment. Many HCV nonresponders, especially those with no fibrosis or mild fibrosis, have an excellent prognosis, are at low risk to develop cirrhosis, and should simply be monitored at periodic intervals until more effective therapy has been developed.

Sethi A, Shiffman ML. · Hepatology Section, Virginia Commonwealth University Medical Center, Box 980341, Richmond, VA 23298, USA. · Clin Liver Dis. · Pubmed #16023977 No free full text.

Abstract: The combination of peginterferon and ribavirin is the most effective therapy for patients with chronic hepatitis C virus (HCV) infection. Although more than half of all patients are able to achieve a sustained virologic response (SVR), a significant proportion of patients, particularly those with genotype 1, fail to have undetectable HCV RNA during treatment or relapse after completing therapy with return of detectable HCV RNA. The management of these patients creates a formidable challenge. This article outlines various strategies for patients who have failed to achieve SVR and discusses the merits of different approaches to management.

Shiffman ML. · Hepatology Section, Virginia Commonwealth, University Medical Center, Richmond, VA 23298, USA. · Minerva Gastroenterol Dietol. · Pubmed #15719005 No free full text.

Abstract: The treatment of patients with chronic hepatitis C virus (HCV) has improved dramatically over the past several years. Despite this nearly half of all patients fail to achieve a sustained virologic response (SVR) following therapy. The decision to retreat a non-responder depends upon several factors which include data regarding the response to the previous course of therapy and the likelihood that a favorable response can be achieved with retreatment. These factors must be balanced against the risk for fibrosis progression and developing cirrhosis in each individual patient before a decision is made for embark upon retreament. The management of patients who have failed to achieve SVR is therefore one of the most complicated in the spectrum of treating chronic HCV. This manuscript will review the factors to consider when assessing such patients, the likelihood of achieving an SVR with current therapy and options for patients who continue to manifest non-response.

Shiffman ML. · Hepatology Section, Virginia Commonwealth University Medical Center, Box 980341, Richmond, VA 23298, USA. · Cleve Clin J Med. · Pubmed #15468612 links to  free full text

Abstract: Despite improvements in the treatment of chronic hepatitis C virus (HCV) infection, nearly half of all patients do not respond to initial therapy. Retreatment of these patients with pegylated interferon and ribavirin has been successful in only a limited percentage of cases. Factors associated with sustained virologic response (SVR) following retreatment include prior treatment with interferon monotherapy, HCV genotype 2 or 3, a low serum HCV RNA level, and the absence of cirrhosis. Fewer than 6% of nonresponders who were previously treated with interferon and ribavirin and who have cirrhosis, genotype 1, and a high viral load achieve SVR following retreatment with pegylated interferon and ribavirin. No therapy has been shown to yield SVR in patients who do not respond to pegylated interferon and ribavirin. Long-term maintenance therapy with pegylated interferon is currently being evaluated in nonresponders with advanced fibrosis and cirrhosis. Its use should be considered investigational at this time.

Ferreira-Gonzalez A, Shiffman ML. · Division of Molecular Diagnostics, Department of Pathology, Virginia Commonwealth University Medical Center, Richmond, Virginia 23298, USA. · Semin Liver Dis. · Pubmed #15346241 No free full text.

Abstract: Serological and virological testing for the hepatitis C virus (HCV) is essential in the management of patients with chronic HCV infection. Recent advances in molecular virology tests and the development of a new international unit standard have greatly simplified the use and interpretation of these tests. In the absence of treatment, baseline serum HCV RNA does not change over time and does not correlate with the severity of hepatic inflammation or fibrosis on liver biopsy. In contrast, changes in serum HCV RNA level are important predictors of virological response to treatment with pegylated interferon and ribavirin.

Shiffman ML. · Hepatology Section, Virginia Commonwealth University Medical Center, Richmond, VA, USA. · Rev Gastroenterol Disord. · Pubmed #15184821 No free full text.

Abstract: The treatment of patients with chronic hepatitis C virus infection has improved dramatically over the past several years. Despite this, more than half of all patients with genotype 1 fail to achieve a sustained virologic response (SVR) following therapy. The decision to retreat a nonresponder should balance two major factors: the likelihood that the patient will achieve an SVR during retreatment and the likelihood that the patient will develop progressive fibrosis and cirrhosis within the next 5 to 10 years (before more effective therapy is developed). Recent data have demonstrated that about 18% of all patients with previous nonresponse to standard interferon therapy (with or without ribavirin) will achieve an SVR when retreated with peginterferon and ribavirin. However, no therapy has been shown to be effective for patients with nonresponse to peginterferon and ribavirin. The approach to such patients is based on correcting the factors that led to this nonresponse. Maintenance peginterferon therapy is currently being explored but is likely to be of benefit in only a select group of nonresponders. The management of patients who have failed to achieve SVR is, therefore, one of the most complicated issues in the spectrum of treating chronic hepatitis C. This article reviews the factors to consider when assessing nonresponders for additional therapy and options for patients with continued nonresponse.

Shiffman ML. · Hepatology Section, Virginia Commonwealth University Medical Center, Richmond, 23298, USA. · Ann Hepatol. · Pubmed #15118573 No free full text.

Abstract: The treatment of chronic hepatitis C virus (HCV) has improved greatly over the past decade. Over half of all patients treated with the combination of peginterferon and ribavirin have the opportunity to achieve sustained virologic response. The major factors which interfere with this goal are the side effects of therapy which require that the doses of peginterferon or ribavirin be reduced or that these medications be discontinued. While some of these side effects can be overcome and treatment continued, some side effects are severe and potentially life threatening. Appropriate recognition and management of these side effects will both improve response to therapy and avoid unnecessary morbidity and mortality.

Fontana RJ, Everson GT, Tuteja S, Vargas HE, Shiffman ML. · Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA. · Clin Gastroenterol Hepatol. · Pubmed #15017601 No free full text.

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Shiffman ML. · Hepatology Section, Virginia Commonwealth University Health System, Medical College of Virginia, Richmond, VA 23298, USA. · Hepatology. · Pubmed #12407586 No free full text.

Abstract: Significant advances have been made in the treatment of chronic hepatitis C virus (HCV) infection during the past 5 years. As a consequence, there is continuing enthusiasm for retreating patients who did not achieve sustained virological response (SVR) with previous therapy. Retreatment of non-responders to standard interferon monotherapy using interferon and ribavirin has yielded SVR rates of 12% to 15%. Retreatment with peginterferon and ribavirin has been more effective; achieving SVR rates of 34% to 40%. Retreatment of patients who relapsed after interferon monotherapy using standard interferon and ribavirin yielded SVR rates of 47%, whereas retreatment with peginterferon and ribavirin resulted in an SVR rate of about 60%. The major factors associated with a higher likelihood of an SVR after retreatment include previous relapse, previous treatment with interferon monotherapy, HCV genotypes 2 or 3, lower serum levels of HCV RNA, and having a significant decrease in HCV RNA levels during the initial course of therapy. These results help to focus retreatment with peginterferon and ribavirin on subsets of patients who are most likely to benefit.

Shiffman ML. · Hepatology Section, Virginia Commonwealth University Health System, Richmond, Virginia, USA. · Clin Liver Dis. · Pubmed #11685793 No free full text.

Abstract: Despite improvements in the therapies for chronic hepatitis C virus (HCV) over the past several years, many patients still fail to become hepatitis C virus ribonucleic acid (HCV-RNA) undetectable during treatment and are classified as nonresponders. Providing treatment recommendations for these patients requires that the likelihood of achieving any benefit from another course of therapy be balanced with the natural history of chronic HCV. The management of nonresponders represents the most challenging of all aspects in the care of patients with chronic HCV. Retreatment of interferon non-responders with interferon and ribavirin has yielded a long-term virologic benefit in only 10% to 25% of patients. The efficacy of peginterferon and peginterferon with ribavirin for nonresponders has yet to be defined.

Shiffman ML. · Hepatology Section, Medical College of Virginia Commonwealth University, Box 980341, Richmond, VA 23298, USA. · Curr Gastroenterol Rep. · Pubmed #11177692 No free full text.

Abstract: The primary therapy for patients with chronic hepatitis C virus (HCV) infection is interferon alfa. However, use of interferon for treatment of chronic HCV has several shortcomings that limit its effectiveness. Interferon has a very short half-life, must be administered multiple times weekly, and is associated with significant side effects. "PEGylation" is a process whereby the inert polymer, polyethylene glycol (PEG), is attached to a protein pharmaceutical. This process has been shown to alter the properties of PEGylated proteins in a manner that significantly extends half-life, reduces immunogenicity, and enhances biologic activity when compared with the native protein. In recent years, several PEGylated forms of interferon alfa have been developed. Recent studies have demonstrated that PEG-interferons have a significantly prolonged half-life and sustained virologic response when compared with standard interferon. Studies to evaluate the effects of combining PEG-interferons with ribavirin are currently underway. The role PEG-interferons will play in patients who have either relapsed or failed to respond to previous interferon or interferon/ribavirin therapy remains to be defined.

Shiffman ML. · Medical College of Virginia Commonwealth University, Richmond 23298, USA. · Semin Liver Dis. · Pubmed #10349690 No free full text.

Abstract: High-dose interferon therapy is defined as any treatment regimen that provides more than 3 million Units (MU) of interferon three times weekly (TIW), or more than 9 MU on a weekly basis. Such treatment could be achieved with either a fixed dose of interferon administered daily (QD) or TIW, an induction regimen in which doses greater than 3 MU QD are administered for several weeks to months followed by a reduction in the dose or dosing frequency, or by escalation in the interferon dose. Each of these high-dose regimens appears to increase end-of-treatment response. Unfortunately, sustained response and virologic "cure" following treatment with high-dose interferon appear no better than what could be achieved with standard-dose interferon therapy. Whether sustained response can be improved by utilizing ribavirin in combination with high-dose interferon remains to be determined.

Bacon BR, Shiffman ML, Mendes F, Ghalib R, Hassanein T, Morelli G, Joshi S, Rothstein K, Kwo P, Gitlin N. · Saint Louis University Liver Center, Saint Louis University School of Medicine, St. Louis, MO 63110-0250, USA. · Hepatology. · Pubmed #19291790 No free full text.

Abstract: Up to 50% of patients with chronic hepatitis C fail to respond to initial therapy with pegylated interferon (PEG-IFN) and ribavirin (RBV). With unsuccessful viral eradication, these patients remain at risk for developing progression of their liver disease. Retreatment with PEG-IFN/RBV yields sustained virologic response (SVR) rates that are under 10%. A wholly synthetic interferon, interferon alfacon-1 or consensus interferon (CIFN) given with RBV, was evaluated in patients who failed initial PEG-IFN/RBV therapy. The intent-to-treat analysis included 487 patients; 245 received CIFN 9 microg/day and RBV, and 242 received CIFN 15 microg/day and RBV. Within this group of patients, 59.3% had documented advanced fibrosis at baseline liver biopsy (stage F3 or F4). SVR rates were 6.9% (17/245 patients) in the 9 microg group and 10.7% (26/242) in the 15 microg group. In the intent-to-treat analysis, SVR rates were higher among patients with a >2-log(10) decrease in hepatitis C virus RNA during prior PEG-IFN/RBV therapy: 11% (4/38) in the 9 mug group and 23% (7/31) in the 15 microg group. Among patients with lower baseline fibrosis scores (F0-F3), SVR rates were 7.8% (15/192) in the 9 microg group and 13.1% (23/175) in the 15 microg group. In this same group of patients (F0-F3), if a >2-log(10) decrease in hepatitis C virus RNA with previous PEG-IFN/RBV treatment was achieved, SVR rates improved to 10.7% and 31.6% in the 9 microg and 15 microg groups, respectively. CIFN/RBV combination retreatment was safe and well tolerated. CONCLUSION: Retreatment of PEG-IFN and RBV nonresponders with CIFN and RBV is safe and efficacious and can be considered a retreatment strategy for patients failing previous therapy with PEG-IFN/RBV, especially in interferon-sensitive patients with lower baseline fibrosis scores.

Marcellin P, Heathcote EJ, Buti M, Gane E, de Man RA, Krastev Z, Germanidis G, Lee SS, Flisiak R, Kaita K, Manns M, Kotzev I, Tchernev K, Buggisch P, Weilert F, Kurdas OO, Shiffman ML, Trinh H, Washington MK, Sorbel J, Anderson J, Snow-Lampart A, Mondou E, Quinn J, Rousseau F. · Hôpital Beaujon, Assistance Publique Hôpitaux de Paris, University of Paris 7 and INSERM Unité 773, Centre de Recherches Claude Bernard sur les Hepatites Virales, Clichy, France. · N Engl J Med. · Pubmed #19052126 links to  free full text

Abstract: BACKGROUND: Tenofovir disoproxil fumarate (DF) is a nucleotide analogue and a potent inhibitor of human immunodeficiency virus type 1 reverse transcriptase and hepatitis B virus (HBV) polymerase. METHODS: In two double-blind, phase 3 studies, we randomly assigned patients with hepatitis B e antigen (HBeAg)-negative or HBeAg-positive chronic HBV infection to receive tenofovir DF or adefovir dipivoxil (ratio, 2:1) once daily for 48 weeks. The primary efficacy end point was a plasma HBV DNA level of less than 400 copies per milliliter (69 IU per milliliter) and histologic improvement (i.e., a reduction in the Knodell necroinflammation score of 2 or more points without worsening fibrosis) at week 48. Secondary end points included viral suppression (i.e., an HBV DNA level of <400 copies per milliliter), histologic improvement, serologic response, normalization of alanine aminotransferase levels, and development of resistance mutations. RESULTS: At week 48, in both studies, a significantly higher proportion of patients receiving tenofovir DF than of those receiving adefovir dipivoxil had reached the primary end point (P<0.001). Viral suppression occurred in more HBeAg-negative patients receiving tenofovir DF than patients receiving adefovir dipivoxil (93% vs. 63%, P<0.001) and in more HBeAg-positive patients receiving tenofovir DF than patients receiving adefovir dipivoxil (76% vs. 13%, P<0.001). Significantly more HBeAg-positive patients treated with tenofovir DF than those treated with adefovir dipivoxil had normalized alanine aminotransferase levels (68% vs. 54%, P=0.03) and loss of hepatitis B surface antigen (3% vs. 0%, P=0.02). At week 48, amino acid substitutions within HBV DNA polymerase associated with phenotypic resistance to tenofovir DF or other drugs to treat HBV infection had not developed in any of the patients. Tenofovir DF produced a similar HBV DNA response in patients who had previously received lamivudine and in those who had not. The safety profile was similar for the two treatments in both studies. CONCLUSIONS: Among patients with chronic HBV infection, tenofovir DF at a daily dose of 300 mg had superior antiviral efficacy with a similar safety profile as compared with adefovir dipivoxil at a daily dose of 10 mg through week 48. (ClinicalTrials.gov numbers, NCT00116805 and NCT00117676.)

Pockros PJ, Nelson D, Godofsky E, Rodriguez-Torres M, Everson GT, Fried MW, Ghalib R, Harrison S, Nyberg L, Shiffman ML, Najera I, Chan A, Hill G. · Division of Gastroenterology and Hepatology, Scripps Clinic, La Jolla, CA 92037, USA. · Hepatology. · Pubmed #18570306 No free full text.

Abstract: R1626, a prodrug of the hepatitis C virus (HCV) RNA polymerase inhibitor R1479, showed time-dependent and dose-dependent reduction of HCV RNA levels in a previous study. The present study evaluated the efficacy and safety of R1626 administered for 4 weeks in combination with peginterferon alfa-2a +/- ribavirin in HCV genotype 1-infected treatment-naive patients. Patients were randomized to: DUAL 1500 (1500 mg R1626 twice daily [bid] + peginterferon alfa-2a; n = 21); DUAL 3000 (3000 mg R1626 bid + peginterferon alfa-2a; n = 32); TRIPLE 1500 (1500 mg R1626 bid + peginterferon alfa-2a + ribavirin; n = 31); or standard of care (SOC) (peginterferon alfa-2a + ribavirin; n = 20). At 4 weeks HCV RNA was undetectable (<15 IU/mL) in 29%, 69%, and 74% of patients in the DUAL 1500, DUAL 3000, and TRIPLE 1500 arms, respectively, compared with 5% of patients receiving SOC, with respective mean reductions in HCV RNA from baseline to week 4 of 3.6, 4.5, 5.2, and 2.4 log(10) IU/mL. Synergy was observed between R1626 and peginterferon alfa-2a and between R1626 and ribavirin. There was no evidence of development of viral resistance. Adverse events (AEs) were mainly mild or moderate; seven patients had nine serious AEs (including one patient with one serious AE in SOC). The incidence of Grade 4 neutropenia was 48%, 78%, 39%, and 10% in DUAL 1500, DUAL 3000, TRIPLE 1500, and SOC, respectively, and was the main reason for dose reductions. Conclusion: A synergistic antiviral effect was observed when R1626 was combined with peginterferon alfa-2a +/- ribavirin; up to 74% of patients had undetectable HCV RNA at week 4. Dosing of R1626 was limited by neutropenia; a study of different dosages of R1626 in combination with peginterferon alfa-2a and ribavirin is underway.

Rustgi VK, Esposito S, Hamzeh FM, Shiffman ML. · Liver Transplantation Unit, Georgetown University Medical Center, Washington, DC, USA. · Aliment Pharmacol Ther. · Pubmed #18081737 No free full text.

Abstract: BACKGROUND: Peginterferon alfa-2a/ribavirin treatment resulted in fewer incidences of depression and flu-like symptoms than that of standard interferon/ribavirin, whereas peginterferon alfa-2b/ribavirin and standard interferon/ribavirin treatment resulted in similar incidences of these adverse events (AEs). AIM: To assess the efficacy and safety of peginterferon alfa-2a/ribavirin in genotype 1-infected patients treated for up to 12 weeks with peginterferon alfa-2b/ribavirin but not achieving early virologic response (EVR) (non-EVR) or nontolerant (NT) because of depression, fatigue, flu-like symptoms, or injection-site reactions. METHODS: Nontolerants were treated for an additional 36 weeks and non-EVRs for an additional 60 weeks with peginterferon alfa-2a (180 microg/week)/ribavirin (1000/1200 mg/day). Patients with detectable HCV RNA after 12 weeks were discontinued. RESULTS: Of 25 NTs, 23 (92%) were HCV-RNA negative after 12 weeks on peginterferon alfa-2a/ribavirin and 14 (56%) achieved sustained virologic response. Of 32 non-EVRs to peginterferon alfa-2b/ribavirin, four (13%) achieved EVR with peginterferon alfa-2a/ribavirin and one (3%) achieved sustained virologic response. Four non-EVRs and 0 NTs were withdrawn for AEs; 26 (81%) and 24 (96%), respectively, completed peginterferon alfa-2a/ribavirin treatment or were withdrawn for insufficient response at week 12. In NTs, depression, fatigue, flu-like symptoms, and injection-site reactions declined during treatment. CONCLUSION: Most patients who did not tolerate peginterferon alfa-2b/ribavirin because of AEs, and who completed the full 36-week course of peginterferon alfa-2a/ribavirin treatment, achieved sustained virologic response.