Effect of Ribavirin in Genotype 1 Patients With Hepatitis C Responding to Pegylated Interferon Alfa-2a Plus Ribavirin
2006; Elsevier BV; Volume: 131; Issue: 4 Linguagem: Inglês
10.1053/j.gastro.2006.07.022
ISSN1528-0012
AutoresJean‐Pierre Bronowicki, Denis Ouzan, Tarik Asselah, Hervé Desmorat, Jean–Pierre Zarski, Juliette Foucher, Marc Bourlière, Christophe Renou, Albert Tran, P. Mélin, Christophe Hézode, M Chevalier, Magali Bouvier‐Alias, Stéphane Chevaliez, François Montestruc, Isabelle Lonjon‐Domanec, Jean‐Michel Pawlotsky,
Tópico(s)Liver Disease Diagnosis and Treatment
ResumoBackground & Aims: Pegylated interferon alfa-ribavirin combination is the standard treatment for chronic hepatitis C, but the mechanisms by which ribavirin enhances the rate of sustained hepatitis C virus (HCV) eradication remain unknown. We aimed to investigate the role of ribavirin in HCV clearance during therapy and to evaluate the consequences of ribavirin discontinuation in patients infected with genotype 1 hepatitis C who cleared HCV RNA at week 24. Methods: A total of 516 patients were treated with pegylated interferon alfa-2a, 180 μg/wk, plus ribavirin, 800 mg/day. Seventy percent were RNA negative at week 24. They were randomized to continue with the combination or receive pegylated interferon alone. Results: Responders at week 24 who stopped ribavirin had a significantly higher rate of breakthroughs during, and relapses after, therapy (sustained virologic response, 52.8% vs 68.2%; P = .004), but their side-effect profile and quality of life tended to improve. Multiple logistic regression analysis in the pegylated interferon alfa monotherapy group allowed identification of responders at week 24 who could stop ribavirin without losing their chance of a sustained virologic response, based on baseline viral load and age. Forty-eight weeks of ribavirin may not be needed when HCV RNA is undetectable at week 2. Conclusions: We made 3 conclusions from this study. First, ribavirin primarily acts by sustaining the virologic response to pegylated interferon alfa; second, ribavirin must be administered for the full treatment duration in most genotype 1–infected patients who respond; third, baseline parameters may help identify patients who could discontinue ribavirin or reduce the dose without losing their chance of success. Background & Aims: Pegylated interferon alfa-ribavirin combination is the standard treatment for chronic hepatitis C, but the mechanisms by which ribavirin enhances the rate of sustained hepatitis C virus (HCV) eradication remain unknown. We aimed to investigate the role of ribavirin in HCV clearance during therapy and to evaluate the consequences of ribavirin discontinuation in patients infected with genotype 1 hepatitis C who cleared HCV RNA at week 24. Methods: A total of 516 patients were treated with pegylated interferon alfa-2a, 180 μg/wk, plus ribavirin, 800 mg/day. Seventy percent were RNA negative at week 24. They were randomized to continue with the combination or receive pegylated interferon alone. Results: Responders at week 24 who stopped ribavirin had a significantly higher rate of breakthroughs during, and relapses after, therapy (sustained virologic response, 52.8% vs 68.2%; P = .004), but their side-effect profile and quality of life tended to improve. Multiple logistic regression analysis in the pegylated interferon alfa monotherapy group allowed identification of responders at week 24 who could stop ribavirin without losing their chance of a sustained virologic response, based on baseline viral load and age. Forty-eight weeks of ribavirin may not be needed when HCV RNA is undetectable at week 2. Conclusions: We made 3 conclusions from this study. First, ribavirin primarily acts by sustaining the virologic response to pegylated interferon alfa; second, ribavirin must be administered for the full treatment duration in most genotype 1–infected patients who respond; third, baseline parameters may help identify patients who could discontinue ribavirin or reduce the dose without losing their chance of success. See editorial on page 1339.The combination of pegylated interferon (IFN) alfa plus ribavirin is now recognized as standard treatment for patients with chronic hepatitis C.1National Institutes of Health Consensus Development Conference Statement: management of hepatitis C: 2002—June 10-12, 2002.Hepatology. 2002; 36: S3-S20Crossref PubMed Scopus (267) Google Scholar The mechanisms by which IFN alfa acts include: (1) the establishment of a nonspecific antiviral state in both infected and noninfected cells, through activation of multiple intracellular pathways after binding to the IFN receptor located on the surface of target cells; and (2) complex interactions with the immune system that likely accelerate the clearance of infected cells.2Pawlotsky J.M. Mechanisms of antiviral treatment efficacy and failure in chronic hepatitis C.Antiviral Res. 2003; 59: 1-11Crossref PubMed Scopus (127) Google Scholar In contrast, the mechanisms by which ribavirin enhances the rate of sustained hepatitis C virus (HCV) eradication when added to standard3Poynard T. Marcellin P. Lee S.S. Niederau C. Minuk G.S. Ideo G. Bain V. Heathcote J. Zeuzem S. Trepo C. Albrecht J. Randomised trial of interferon alpha2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alpha2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus.Lancet. 1998; 352: 1426-1432Abstract Full Text Full Text PDF PubMed Scopus (2393) Google Scholar, 4McHutchison J.G. Gordon S.C. Schiff E.R. Shiffman M.L. Lee W.M. Rustgi V.K. Goodman Z.D. Ling M.H. Cort S. Albrecht J.K. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C.N Engl J Med. 1998; 339: 1485-1492Crossref PubMed Scopus (3343) Google Scholar or pegylated5Manns M.P. McHutchison J.G. Gordon S.C. Rustgi V.K. Shiffman M. Reindollar R. Goodman Z.D. Koury K. Ling M. Albrecht J.K. 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 (5873) Google Scholar, 6Fried M.W. Shiffman M.L. Reddy K.R. Smith C. Marinos G. Goncales Jr, F.L. Haussinger D. Diago M. Carosi G. Dhumeaux D. Craxi A. Lin A. Hoffman J. Yu J. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection.N Engl J Med. 2002; 347: 975-982Crossref PubMed Scopus (5861) Google Scholar IFNs remain unknown. Ribavirin recently was shown to exert a moderate and transient antiviral effect during the first few days of administration, which could play at least a partial role in increasing the rate of on-treatment HCV clearance when combined with standard IFN alfa administered 3 times per week.7Pawlotsky J.M. Dahari H. Neumann A.U. Hezode C. Germanidis G. Lonjon I. Castera L. Dhumeaux D. Antiviral action of ribavirin in chronic hepatitis C.Gastroenterology. 2004; 126: 703-714Abstract Full Text Full Text PDF PubMed Scopus (221) Google Scholar However, this modest antiviral effect is unlikely to explain the significantly increased rate of sustained virologic eradication when ribavirin is added to standard or pegylated IFN alfa.Although ribavirin significantly improves the virologic results of HCV therapy, its administration can be associated with severe side effects, the most frequent being dose-related hemolytic anemia.3Poynard T. Marcellin P. Lee S.S. Niederau C. Minuk G.S. Ideo G. Bain V. Heathcote J. Zeuzem S. Trepo C. Albrecht J. Randomised trial of interferon alpha2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alpha2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus.Lancet. 1998; 352: 1426-1432Abstract Full Text Full Text PDF PubMed Scopus (2393) Google Scholar, 4McHutchison J.G. Gordon S.C. Schiff E.R. Shiffman M.L. Lee W.M. Rustgi V.K. Goodman Z.D. Ling M.H. Cort S. Albrecht J.K. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C.N Engl J Med. 1998; 339: 1485-1492Crossref PubMed Scopus (3343) Google Scholar, 5Manns M.P. McHutchison J.G. Gordon S.C. Rustgi V.K. Shiffman M. Reindollar R. Goodman Z.D. Koury K. Ling M. Albrecht J.K. 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 (5873) Google Scholar, 6Fried M.W. Shiffman M.L. Reddy K.R. Smith C. Marinos G. Goncales Jr, F.L. Haussinger D. Diago M. Carosi G. Dhumeaux D. Craxi A. Lin A. Hoffman J. Yu J. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection.N Engl J Med. 2002; 347: 975-982Crossref PubMed Scopus (5861) Google Scholar, 8Hadziyannis S.J. Sette Jr, H. Morgan T.R. Balan V. Diago M. Marcellin P. Ramadori G. Bodenheimer Jr, H. Bernstein D. Rizzetto M. Zeuzem S. Pockros P.J. Lin A. Ackrill A.M. Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose.Ann Intern Med. 2004; 140: 346-355Crossref PubMed Scopus (2740) Google Scholar Dose reductions or the use of hematopoietic growth factors may help control ribavirin-induced anemia,9Fried M.W. Side effects of therapy of hepatitis C and their management.Hepatology. 2002; 36: S237-S244Crossref PubMed Google Scholar, 10Afdhal N.H. Role of epoetin alfa in maintaining ribavirin dose.Gastroenterol Clin North Am. 2004; 33: S25-S35Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar but discontinuation of ribavirin is sometimes necessary for patients who continue to experience side effects. In this context, it is pertinent to ask whether administration of ribavirin over the entire treatment period is absolutely necessary in all patients. Indeed, if the principal mode of action of ribavirin is to enhance the antiviral effect of IFN alfa, it could be discontinued easily in patients who experience a virologic response during the first 24 weeks of therapy while IFN alfa’s immunomodulatory properties would facilitate the host immune response to eliminate infected cells. Shortening the period of ribavirin administration thus could improve both tolerance and the quality of life of treated patients, and reduce treatment costs, without altering the rate of sustained virologic response (SVR). In contrast, if ribavirin plays a pivotal role in the elimination of HCV-infected cells, its administration throughout the treatment period would be necessary.We report here the results of a prospective, multicenter, randomized, clinical trial designed to evaluate the consequences of ribavirin discontinuation in patients infected with HCV genotype 1 receiving pegylated IFN alfa-2a (40 kilodaltons)/ribavirin combination therapy who responded by clearing HCV RNA ( 600 IU/mL), increased ALT levels documented on at least 2 occasions within the previous 6 months, liver biopsy findings consistent with chronic hepatitis C obtained within 18 months before therapy (Metavir scores of at least A1 and F1, as assessed by a single pathologist [M.C.]), and compensated liver disease. The initial genotype screening was performed locally, but the genotype was checked in all patients in the central virology laboratory (S.C.) and the 8 patients infected with HCV genotype non-1 subsequently were excluded from the analysis. Patients with cirrhosis had no hepatocellular carcinoma, as confirmed by ultrasound, computerized tomography, or magnetic resonance imaging, and had an α-fetoprotein level of less than 50 ng/mL. Female patients were required to have negative urine or serum pregnancy tests at baseline and during treatment. All fertile male and female patients were required to use 2 forms of effective contraception during treatment and for 6 months after treatment. HCV-RNA quantification was performed at baseline by means of Cobas Amplicor HCV Monitor v2.0 after automated extraction with the Cobas Ampliprep device (Roche Molecular Systems, Pleasanton, CA). All samples greater than 100,000 IU/mL were retested after 1/10 or 1/100 dilution for accurate quantification.11Gourlain K. Soulier A. Pellegrin B. Bouvier-Alias M. Hezode C. Darthuy F. Remire J. Pawlotsky J.M. Dynamic range of hepatitis C virus RNA quantification with the Cobas Ampliprep-Cobas Amplicor HCV Monitor v2.0 assay.J Clin Microbiol. 2005; 43: 1669-1673Crossref PubMed Scopus (18) Google Scholar All HCV-RNA quantification tests were performed in the central virology laboratory at Henri Mondor Hospital (M.B.-A., J.-M.P.).Patients with the following conditions were excluded: chronic liver disease other than that attributed to HCV infection; evidence of decompensated liver disease (cirrhosis with a Child–Pugh stage B or C); co-infection with hepatitis B virus or human immunodeficiency virus; absolute neutrophil count less than 1500/mm3; platelet count less than 90,000/mm3; hemoglobin level less than 12 g/dL in women or less than 13 g/dL in men, or any patient with an increased risk of anemia; serum creatinine level greater than 1.5 times the upper limit of normal; severe psychiatric disease, especially depression; significant comorbid medical conditions; and/or pregnancy, breast-feeding, or unwillingness to practice contraception. Patients also were excluded if they had previously received IFN alfa (conventional or pegylated) or ribavirin. Alcohol consumption was strongly discouraged and patients were expected to consume on average less than 20 g/day of alcohol. Patients were recruited and enrolled by the investigators.Study DesignThis randomized, multicenter, parallel-group, open-label study was conducted at secondary and tertiary hepatology centers in France between December 18, 2000, and April 9, 2003. All patients received pegylated IFN alfa-2a (40 kilodaltons) (Pegasys; Roche, Basel, Switzerland), 180 μg once weekly subcutaneously, plus ribavirin (Copegus; Roche) 400 mg twice daily orally, for 24 weeks. At week 24, HCV RNA was analyzed by means of a sensitive qualitative polymerase chain reaction assay (Cobas Amplicor HCV v2.0; Roche Molecular Systems) with a lower limit of detection of 50 IU/mL. The patients were seen at week 26 with the result of their HCV RNA detection.Patients with undetectable HCV RNA at week 24 were randomized at week 26 (according to a 1:1 ratio) to a further 22 weeks of treatment (ie, until week 48) with either pegylated IFN alfa-2a 180 μg once weekly without ribavirin, or continuation of pegylated IFN alfa-2a 180 μg once weekly in combination with ribavirin 400 mg twice daily. Adaptive centralized randomization was performed (minimization method) to balance minimization factors of frequencies (center, sex, and fibrosis score) and means (viral load, weight, or age). The remaining patients who had detectable HCV RNA at week 24 stopped therapy because they had a low chance of achieving an SVR with continued treatment.12Davis G.L. Wong J.B. McHutchison J.G. Manns M.P. Harvey J. Albrecht J. Early virologic response to treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C.Hepatology. 2003; 38: 645-652Crossref PubMed Scopus (788) Google Scholar, 13Ferenci P. Fried M.W. Shiffman M.L. Smith C.I. Marinos G. Goncales Jr, F.L. Haussinger D. Diago M. Carosi G. Dhumeaux D. Craxi A. Chaneac M. Reddy K.R. Predicting sustained virological responses in chronic hepatitis C patients treated with peginterferon alfa-2a (40 KD)/ribavirin.J Hepatol. 2005; 43: 425-433Abstract Full Text Full Text PDF PubMed Scopus (484) Google Scholar These patients were followed-up for 24 weeks after their last dose of study medication for safety monitoring.The protocol was approved by the local ethics committee (Comité Consultatif de Protection des Personnes dans la Recherche Biomédicale) of the University Hospital of Nancy on October 24, 2000. All patients provided written informed consent. The study was conducted according to the guidelines of the Declaration of Helsinki, under provisions of Good Clinical Practices, or both. Data were collected by the study group, and analyzed by the authors with the help of the sponsor. The authors had unlimited access to the data and no limitation on publication was imposed by any party.HCV Genotype DeterminationThe HCV genotype was determined in all patients by direct sequence analysis of the nonstructural 5B gene followed by phylogenetic analysis. Briefly, RNA was extracted from 200 μL of serum using the High Pure Viral RNA kit (Roche Molecular Biochemicals, Mannheim, Germany). Complementary DNA synthesis was performed for 1 hour at 50°C with 5 μL of viral RNA, 50 ng of random hexamers, and 200 U of Superscript III reverse transcriptase (Invitrogen, Carlsbad, CA). A nested polymerase chain reaction technique was used to amplify a 286-bp fragment located in the nonstructural 5B gene. The first round used external sense and antisense primers Sn755 and Asn1121,14Morice Y. Roulot D. Grando V. Stirnemann J. Gault E. Jeantils V. Bentata M. Jarrousse B. Lortholary O. Pallier C. Deny P. Phylogenetic analyses confirm the high prevalence of hepatitis C virus (HCV) type 4 in the Seine-Saint-Denis district (France) and indicate seven different HCV-4 subtypes linked to two different epidemiological patterns.J Gen Virol. 2001; 82: 1001-1012Crossref PubMed Scopus (92) Google Scholar and consisted of 45 polymerase chain reaction cycles at 95°C for 30 seconds, 60°C–50°C for 30 seconds, and 70°C for 30 seconds. The second round used internal sense primer nonstructural 5B–SI766 (5′-CTGYTTTGACTCCACNGTRAC-3′, nt 8252–8272) and antisense primer nonstructural 5B–ASI1110 (5′-CATAGCCTCCGTGAAGGCTC-3′, nt 8596–8615), and consisted of 45 cycles at 95°C for 30 seconds, 60°C–50°C for 30 seconds, and 70°C for 30 seconds. Polymerase chain reaction products were sequenced directly by using the Big-Dye Terminator Cycle v3.1 sequencing kit on the ABI 3100 sequencer (Perkin-Elmer Applied Biosystems, Foster City, CA) according to the manufacturer’s protocol. Phylogenetic analyses were performed using different prototype HCV genotype 1–6 isolate sequences by using software from the Phylogeny Inference Package (PHYLIP) version 3.65. This method allows precise determination of the genotype and the subtype.15Simmonds P. Bukh J. Combet C. Deleage G. Enomoto N. Feinstone S. Halfon P. Inchauspe G. Kuiken C. Maertens G. Mizokami M. Murphy D.G. Okamoto H. Pawlotsky J.M. Penin F. Sablon E. Shin I.T. Stuyver L.J. Thiel H.J. Viazov S. Weiner A.J. Widell A. Consensus proposals for a unified system of nomenclature of hepatitis C virus genotypes.Hepatology. 2005; 42: 962-973Crossref PubMed Scopus (1215) Google ScholarEnd Point AssessmentSerum HCV RNA was sought by means of the qualitative, nonquantitative Cobas Amplicor HCV v2.0 assay (lower limit of detection, 50 IU/mL) at weeks 2, 4, 12, 24, 36, and 48 of treatment, and 12 weeks (week 60) and 24 weeks (week 72) after treatment withdrawal. The primary efficacy end point was SVR, defined as an undetectable serum HCV-RNA level (<50 IU/mL) 24 weeks after treatment withdrawal. Patients without HCV-RNA assessment at the end of the follow-up period were considered to be nonresponders. All of the virologic tests were performed in the central virology laboratory (M.B.-A., J.-M.P.).Secondary end points included serum ALT normalization at the end of the follow-up period, assessment of health-related quality of life with the Hepatitis Quality of Life Questionnaire, and assessment of fatigue with the Fatigue Severity Scale. These assessments were performed at baseline and at weeks 24, 48, and 72.Safety AssessmentsSafety was assessed by means of physical examination, laboratory tests, and spontaneous reports of clinical adverse events in clinical visits during treatment and follow-up evaluation. Stepwise dose reductions of pegylated IFN alfa-2a to 135 or 90 μg/wk and of ribavirin to 600 mg/day were permitted to manage clinically significant adverse events or laboratory abnormalities, according to a predefined protocol. If the side-effect improved or resolved, a return to the initial dose of pegylated IFN was permitted. Patients could continue on pegylated IFN alfa-2a monotherapy if ribavirin was discontinued, but ribavirin monotherapy was not allowed. The use of colony-stimulating factors and erythropoietin to manage hematologic adverse events was not permitted.Statistical AnalysisEnrollment of 500 patients was scheduled to ensure that 340 virologic responders at week 24 would be randomized after 24 weeks of treatment. The objective was to show the noninferiority of pegylated IFN alfa-2a monotherapy compared with pegylated IFN alfa-2a plus ribavirin in virologic responders at week 24 with the following hypotheses: an SVR rate of 50% in both arms; a maximum allowed difference Δ = 15%; a 1-sided 95% confidence interval (CI) power; a per-protocol population between weeks 26 and 72 of 80%; and 20% of patients not responding to the combination of pegylated IFN alfa-2a plus ribavirin at week 24 (detectable HCV RNA).The intention-to-treat population was defined as all patients randomized who had at least one evaluation after randomization. The per-protocol population was defined as the intention-to-treat patients without major deviation of protocol. The safety population comprised all patients who received at least one dose of study drug. The Review Committee of September 8, 2003, categorized the patients into these groups in blinded conditions. To take into account the switching between noninferiority and superiority resolution adopted by Committee for Proprietary Medicinal Products in July 2000, the Review Committee decided to analyze efficacy data with a 2-sided 95% CI. If this CI excludes 0, superiority can be concluded. If the CI does not include Δ = 15%, noninferiority can be concluded.Multiple logistic regression analyses were performed to identify the predictors of virologic response. They included univariate followed by multivariate analysis. The latter was performed by entering into the model all of the parameters associated with a P value <.10 with less than 20% missing data. Strongly related variables (eg, weight and daily ribavirin dose in mg/kg) were not added to the model. The most discriminant variables for viral kinetics were introduced into the model. Interactions of the multivariate model were duly explored.Covariance analyses adjusted on baseline values were used to analyze the Fatigue Severity Scale and Hepatitis Quality of Life Questionnaire scores.ResultsA total of 516 patients with HCV genotype 1 infection were enrolled between December 18, 2000, and December 17, 2001. All patients were treated with pegylated IFN alfa-2a (40 kilodaltons), 180 μg/week, plus ribavirin, 800 mg/day. The study was terminated on April 9, 2003. A total of 358 of the 516 patients (69%) were HCV RNA negative at week 24 of combination therapy. Six patients were excluded because of ribavirin-related side effects and 3 were lost to follow-up evaluation. Overall, 349 patients were randomized, including 173 patients who were assigned to receive the combination of pegylated IFN alfa-2a plus ribavirin, and 176 who were assigned to receive pegylated IFN alfa-2a alone after week 26. Baseline characteristics of the patients are shown in Table 1. No significant difference was found between the groups for any of the baseline parameters.Table 1Patient Characteristics at BaselineAll enrolled and treated patients (n = 516)Nonvirologic responders at week 24 (n = 167)Randomized virologic responders at week 24 (N = 349)Continue on pegylated IFN alfa-2a + ribavirin (n = 173)Continue on pegylated IFN alfa-2a alone (n = 176)Sex: male/female (%)306/210108/59 (64.7)98/75 (56.6)100/76Age, y46.2 ± 11.549.2 ± 12.444.2 ± 10.645.4 ± 10.8Weight, kg70.8 ± 14.873.2 ± 14.469.0 ± 12.670.2 ± 16.8Body mass index, kg/m224.6 ± 4.425.3 ± 4.324.2 ± 3.724.5 ± 5.1Mode of infection: n (%) Transfusion180 (34.9)60 (35.9)62 (35.8)58 (33.0) Injection drug use155 (30.0)44 (26.3)53 (30.6)58 (33.0) Other/unknown181 (35.1)63 (37.7)58 (33.6)60 (34.1)Serum ALT level (U/L)94.2 ± 66.999.8 ± 62.791.1 ± 66.391.8 ± 71.1Log serum HCV-RNA level6.2 ± 0.86.3 ± 0.66.1 ± 0.96.2 ± 0.8HCV RNA354 (70.2)124 (77.5)106 (62.4)124 (71.3) >800,000 IU/mL n (%) Fibrosis score, no. (%) F1157 (30.7)39 (23.4)59 (34.3)59 (34.1) F2176 (34.4)45 (26.9)66 (38.4)65 (37.6) F3135 (26.4)60 (35.9)36 (20.9)39 (22.5) F444 (8.6)23 (13.8)11 (6.4)10 (5.8) Missing4013HCV subtype, no (%) 1a85 (50.3)83 (48.0) 1b84 (49.7)86 (49.7) 1d0 (0.0)3 (1.7) 1e0 (0.0)1 (0.6) Unknown43NOTE. Absolute numbers (percentages) and mean SDs are given when appropriate. Open table in a new tab The average daily dose of ribavirin administered to the 516 enrolled patients until week 24 was 786 ± 48 mg/day. In the patients who subsequently were randomized, the average daily dose of ribavirin received between start of treatment and week 24 was 787 ± 49 mg/day in the patients who remained on combination therapy vs 786 ± 47 mg/day in those who received pegylated IFN alfa-2a monotherapy after week 26 (not significantly different).Virologic ResponseAs shown in Figure 1, the proportion of patients who achieved an SVR at the end of the follow-up period (primary efficacy end point) was significantly smaller in the patients who stopped ribavirin at week 26 than in those who continued under combination therapy (93/176 [52.8%] vs 118/173 [68.2%]; P = .004).By definition, all randomized patients were HCV RNA negative at week 24. Figure 2 shows the cumulative proportion of patients with detectable HCV RNA (>50 IU/mL) at different time points during therapy after randomization and during posttreatment follow-up evaluation. The incidence of viral breakthroughs during therapy increased more rapidly in the patients who stopped ribavirin than in those who did not, and the difference was statistically significant at weeks 36 and 48 (Figure 2). Similarly, the incidence of posttreatment relapses was significantly greater in patients who stopped ribavirin than in those who did not. At the end of the follow-up period (week 72), the cumulative rate of relapse was 42.1% in the patients receiving monotherapy vs 28.7% in those receiving combination therapy for the full 48-week period (P = .02). Most posttreatment relapses in the monotherapy group occurred early after treatment withdrawal (ie, between weeks 48 and 52), whereas posttreatment relapses occurred later in the patients who had received combination therapy (ie, between weeks 52 and 60) (Figure 2). At the end of the follow-up period, serum ALT level had normalized in 117 of 160 patients treated with combination therapy (73.1%) and 105 of 162 patients treated with pegylated IFN alfa monotherapy (64.8%; P = .12).Figure 2Cumulative incidence (observed data) of patients in whom HCV RNA became detectable (≥50 IU/mL) after randomization at week 26, including the treatment period until week 48 (breakthroughs) and follow-up evaluation until week 72 (relapses).View Large Image Figure ViewerDownload (PPT)Baseline Parameters Associated With SVRMultiple logistic regression analysis was used to identify baseline parameters predictive of an SVR in these patients with undetectable HCV RNA at week 24. When patients with missing values were considered to be failures, 6 variables had a favorable influence on the SVR at a threshold P value of .1: ribavirin continuation after week 26, low HCV-RNA level at baseline, low body weight, young age, low fibrosis score, and a higher daily administered ribavirin dose per body weight before week 24. The body weight and the ribavirin dose per body weight before week 24 strongly correlated, so only the latter was included in subsequent analyses. Interestingly, no difference was found according to the subtype (1a or 1b) in this large cohort of patients in whom the subtype could be identified by direct sequence analysis of the nonstructural 5B region (Table 1).In multivariate analysis, only ribavirin continuation after week 26 (P = .0073; odds ratio, .53; 95% CI, .34–.85) and baseline HCV-RNA level (P < .0001; odds ratio, 2.32; 95% CI, 1.66–3.26) were significantly and independently associated with a higher SVR.Baseline Parameters Associated With an SVR in the Pegylated IFN Alfa-2a Monotherapy GroupStopping ribavirin administration was associated with a significant increase in viral breakthrough during, and relapses after, therapy. However, a substantial number of patients cleared infection in the pegylated IFN monotherapy arm. Thus, we aimed to identify which patients, among those who responded at week 24, could stop ribavirin without decreasing the likelihood of achieving an SVR. We therefore assessed which baseline parameters were associated significantly with SVR in the group of patients who stopped ribavirin at week 26. In a univariate analysis, 4 variables had a favorable influence on the SVR at a threshold P value of .1. These included a low baseline HCV-RNA level, route of HCV transmission other than transfusion, young age, and a higher daily administered ribavirin dose per body weight before week 24. In multivariate analysis, only baseline HCV-RNA level (P = .0004; odds ratio, 2.38; 95% CI, 1.48–3.84) and age less than 44 years (P = .03; odds ratio, .49; 95% CI, .26–.92) were significantly and independently associated with the SVR in this group of patients.By using this logistic model, the probability of an SVR after stopping ribavirin at week 26 could be calculated using the following formulas, according to age.Probability of an SVR (if age ≤ 44 y) = 1 ÷ 1 + exp (− 5.50 + .87 × log HCV RNA − .36); andProbability of an SVR (if age > 44 y) = 1 ÷ 1 + exp (− 5.50 + .87 × log HCV RNA).For example, a patient younger than 44 years with a baseline
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