/EASL: 72 Weeks Pegasys/RBV for Genotype 1

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Mangia Study:In Patients Who Clear HCV RNA At Week 12 (between week 8 and 12): SVR is Higher After 72 Weeks Than After 48 Weeks Treatment: Results of a Randomized Controlled Trial- (04/23/07)72 Weeks Pegasys/RBV for Genotype 1 Achieves Higher SVR Rates When Week 12 Response is >2 log VL Reduction, in this Exploratory AnalysisReported by Jules LevinEASL, April 2007, Barcelona, Spain“How can we identify HCV genotype 1 patients who may benefit froman extended treatment duration with peginterferon alfa-2a (40KD)(PEGASYS) plus ribavirin (COPEGUS)?â€J.M. Sánchez-Tapias,1 P. Ferenci,2 M. Diago,3 M. Romero-Gómez,4 S. Zeuzem,5 T. Berg61Hospital Clinic Institut d'Investigacions Biomediques August Pi i Sunyer, Barcelona, Spain; 2Medical University of Vienna, Vienna, Austria; 3Hospital General, Valencia, Spain; 4Hospital Universitario de Valme, Sevilla, Spain;5J.W. Goethe-University Hospital, furt, Germany; 6Universitatsklinikum Charite, Campus Virchow-Klinikum, Universitatsmedizin Berlin, GermanyJules analysis: Mangia's prospective study at EASL reported patients with no response at week 4 or 8, but negative HCV by week 12 benefited from 72 weeks therapy compared to 48 weeks (63% vs 37%) SVR. This study outlined in this poster found patients with 2 log drop at week 12 also may benefit from 72 weeks rather than 48 weeks. So the poster here appears to perhaps extend the benefits of 72 week therapy for patients with 2 log drop at week 12 as well as HCV negatives at week 12; the poster analysis is a reospective analysis of several studies. Outcome of patients with a partial EVRIn contrast to the wide variation in complete EVR rates, the proportion of patients with a partial EVR (detectable HCV RNA but >2 log10 drop at week 12) was relatively constant across the various studies but ranged from 16-25% (Table 1).Among patients with a partial EVR, extension of treatment to 72 weeks resulted in consistent and considerable improvement in SVR rates that ranged from 13-28% when compared with the standard 48 week duration of treatment (Figure 4).Figure 4. SVR rates in patients with a partial EVR.INTRODUCTIONThe recommended treatment duration for chronic hepatitis C genotype 1 is 48 weeks with the combination of pegylated interferon plus ribavirin 1000 or 1200 mg/day.[1,2] However, between 40% and 50% of genotype 1 patients do not achieve a sustained virological response (SVR) with this regimen,[3,4] which has spurred researchers to investigate intensification of therapy to improve therapeutic outcomes for this important 'difficult-to-cure' group of patients. Extending the duration of treatment beyond 48 weeks is one such strategy that may increase SVR rates in select patients.[5-7] The ability to accurately identify patients most likely to benefit from extended treatment is important because this approach is less convenient and more expensive than standard duration therapy. In order to identify patients most likely to benefit from extended treatment, we investigated the relationship between virological response after 4 and 12 weeks of treatment and SVR rates in patients treated for 48 or 72 weeks with peginterferon alfa-2a (40KD) (PEGASYS) plus ribavirin (COPEGUS).CONCLUSIONThis exploratory analysis indicates that genotype 1 patients with a partial EVR (no RVR and detectable HCV RNA but >2 log10 drop at week 12) derive considerable benefit from extension of therapy with peginterferon alfa-2a (40KD) (PEGASYS) plus ribavirin (COPEGUS) from 48 to 72 weeks.The proportion of genotype 1 patients that might benefit from extended treatment seems to be approximately 20%, while the remaining 80% of patients will likely derive maximum benefit from the standard duration of treatment (48 weeks). The greatest SVR rate in patients with a partial EVR treated for 72 weeks was observed in the Ferenci study (69%) which used the currently recommended dose of ribavirin (1000/1200 mg/day) suggesting that ribavirin dose may influence SVR in patients with a partial EVR. This study indicates that measurement of complete EVR and partial EVR is a simple and reliable tool which allows us to tailor the individual duration of treatment. However, the use of this more precise definition of complete EVR to optimize treatment in genotype 1 patients requires confirmation in large prospective studies with standard dose ribavirin (1000 or 1200 mg/day).METHODSData included in this analysis are from three randomised, multicentre studies that compared 48 with 72 weeks of treatment with peginterferon alfa-2a (40KD) 180 _g/week plus ribavirin.[5-7]Patients in all three studies were treatment naive, aged >18 years, had quantifiable hepatitis C virus (HCV) RNA in serum by polymerase chain reaction (PCR), elevated serum alanine aminotransferase (ALT) levels, liver biopsy consistent with a diagnosis of chronic hepatitis C and compensated liver disease.Patients received ribavirin at a dose of 800 mg/day in two studies;[5,6] the standard dose (1000 or 1200 mg/day) was used in the third.[7]The lower dose of ribavirin was used in two of the studies because they were initiated prior to the establishment of the optimal dose of ribavirin for patients with genotype 1 as 1000 or 1200 mg/day.[8]In the study by Berg et al.[5] genotype 1 patients were randomised at baseline to either 48 or 72 weeks of treatment. In the other two studies,[6,7] which were open to patients infected with non-1 genotypes, only patients without a rapid virological response (RVR), defined as undetectable HCV RNA levels [<50 IU/mL] at week 4, were randomized to 48 or 72 weeks of treatment.Overall, about 95% of patients had genotype 1 infection. In this analysis we compared SVR rates between patients who were HCV RNA positive at week 4 (i.e. without an RVR) and who met two different definitions of virological response at week 12 (Figure 1):--complete early virological response (cEVR) defined as undetectable HCV RNA (<50 IU/mL)--partial EVR, defined as detectable HCV RNA (>50 IU/mL) but with a >2 log10 drop in HCV RNA from baselineFigure 1. Definitions of virological response at week 4 and week 12.The end-point of each study was eradication of the virus, referred to as achievement of SVR and defined as undetectable HCV RNA (<50 IU/mL) as assessed by sensitive PCR assay at the end of a 24 week, untreatedfollow-up period.RESULTSThe overall SVR rates for patients without an RVR who were treated for 48 or 72 weeks ranged from 32-59% (Table 1, Figure 2).In two of three studies, there was no difference in SVR rates between 48 and 72 weeks' therapy duration.Table 1. Overall SVR rates and rates of response at week 12RVR = rapid virological responseSVR = sustained virological responseEVR = early virological responseaOverall ~95% had HCV genotype 1 infection (455/455;[5] 291/326;[6] 195/213[7])b90% patients infected with genotype 1c 88% patients infected with genotype 1dApproximately 10% of these patients had genotype 4 infectionFigure 2. Overall SVR rates.†90% and 88% of patients in 48 and 72-week groups infected with genotype 1,respectively*Includes small number of G4 (<10%) patientsOutcome of patients with a complete EVRThe proportion of patients with a complete EVR varied from 34-60% across the various studies (Table 1). This wide range likely reflects differences in ribavirin dose and whether or not patients with RVR were included or excluded from randomisation.Among patients who achieved a complete EVR, SVR rates exceeded 50% after 48 weeks of treatment and extension of treatment to 72 weeks did not provide a consistent pattern of improvement (Figure 3).Complete EVR = no RVR but HCV RNA <50 IU/mL at week 12* Includes small number of G4 (<10%) patientsREFERENCES1. Dienstag JL, McHutchison JG. American gastroenterological association medical position statement on the management of hepatitis C. Gastroenterology 2006; 130:225-302. Strader DB, T, DL, et al. Diagnosis, management, and treatment of hepatitis C. Hepatology 2004; 39: 1147-713. Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002; 347: 975-824. Manns MP, McHutchison JG, Gordon SC, 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: 958-655. Berg T, von Wagner M, Nasser S, et al. Extended treatment duration for hepatitis C virus type 1: comparing 48 versus 72 weeks of peginterferon-alfa-2a plus ribavirin. Gastroenterology 2006; 130: 1086-976. Sánchez-Tapias JM, Diago M, Escartín P, et al. Peginterferon-alfa2a plus ribavirin for 48 versus 72 weeks in patients with detectable hepatitis C virus RNA at week 4 of treatment. Gastroenterology 2006; 131: 451-607. Ferenci P, Laferl H, Scherzer T, et al. Customizing treatment with peginterferon alfa-2a (40KD) (Pegasys) plus ribavirin (Copegus) in patients with HCV genotype 1 or 4 infection. Interim results of a prospective randomized trial [abstract no. 390]. Hepatology 2006; 44 (Suppl. 1): 336A8. Hadziyannis SJ, Sette H, Jr., TR, et al. Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med 2004; 140: 346-55_______________________________________________