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995 A dynamic model to predict sustained virological response to combination peginterferon alfa-2A (40KD) (PEGASYS(®)) and ribavirin (COPEGUS(®)) therapy in patients with chronic hepatitis C
HEPATOLOGY, Vol. 38, No. 4, Suppl. 1, 2003
AASLD ABSTRACTS
baseline differences in HVR1 variation between drug-sensitive and drug-resistant patients. Patients were chronically infected with HCV genotype 1 and were untreated prior to this prospective trial of combination therapy (pegylated interferon-alpha-2b and ribavirin). The treatment protocol entailed 48 weeks of therapy plus an additional 24 weeks of follow-up. The circulating quasispecies was studied at baseline and at multiple time points during and subsequent to therapy. Description of the quasispecies was based on HVR1 sequence of 20 i n d e p e n d e n t clones from each sample. Although enrollment of subjects is ongoing, 20 subjects have either completed the 72-week regimen or reached a time point that allows outcome to be predicted. Due to the manner in which this comparison group was constructed, the observed proportions do not reflect a success rate for therapy. Of the 20 subjects, eight successfully cleared virus (responders), and 12 subjects failed to clear virus (nonresponders). The following parameters of genetic variability were compared in baseline samples from responders vs. nonresponders: viral load, genetic complexity of the quasispecies as measured by Shannon entropy, and genetic diversity. Genetic diversity was measured as mean genetic distance for synonymous substitutions per synonymous site (Ka) and mean genetic distance for nonsynonymous substitutions per nonsynonymous site (K~). The intrasample ratio (Ka/K~) was calculated and served as an indicator of host selection pressure. In comparing responders and nonresponders at baseline, responders exhibited significantly higher Ka/K~ ratios, with a mean (SE) of 2.46 (0.63) for responders and 0.70 (0.51) for nonresponders (p-0.04). The K~ measure reflects genetic drift resulting from random mutation, whereas Ka measures differences at the amino acid level. The relative increase in Ka for responders indicates that, even prior to the onset of therapy, there were host pressures in play that caused selection at the amino acid level. The relative increase in selection pressure may have predisposed these patients to achieve virologic response once therapy was initiated. Other parameters did not vary significantly, either between responders and nonresponders or evolutionarily in nonresponders. These results suggest that selection pressure caused by intrinsic host factors, such as sustained immune pressure, may be an important component contributing to therapeutic success in chronically infected patients. This work was supported by NIAID U19 AI-48216 and UTHSC GCRC M01 RR-00211 Disclosures: Jaquelyn Fleckenstein - No relationships to disclose Julia Krushkal - No relationships to disclose Rongling Li - No relationships to disclose Barbara Mason - No relationships to disclose Swapna Menon - No relationships to disclose Vicki Park - No relationships to disclose Caroline Riely - No relationships to disclose
635A
(EVR), defined as either a ->2-1ogre drop in viral load or complete disappearance of HCV RNA in serum by 12 weeks of therapy, failed to achieve an SVR. This information is useful because it allows for the early termination of treatment in those unlikely to respond to a full course of treatment. Purpose: To refine the ability to predict the likelihood of achieving a sustained virological response after treatment with peginterferon alfa-2a (40KD) and ribavirin, based on virological response data obtained at week 4 and week 12 of therapy. Methods: The dynamic model is based on data from patients treated with peginterferon alfa-2a (40KD) 180 /~g/week and ribavirin 1000 or 1200 rag/day for 48 weeks in a large, international randomized trial (Fried et al. N~ nglJMed. 2002;347:975-982). For the purpose of this analysis, an early virological response (EVR) was defined as undetectable HCV RNA by qualitative polymerase chain reaction (PCR) assay (<50 IU/mL; COBAS AMPLICOR ® HCV Test, v2.0; Roche Diagnostics) or a decrease of ->2 logm in HCV RNA levels as determined by quantitative PCR (COBAS AMPLICOR HCV MONITOR ®Test, v2.0; Roche Diagnostics) after 12 weeks of treatment. For this analysis SVR was defined as a single undetectable HCV RNA level by qualitative PCR on or after week 60. Treatment was to be stopped in patients with detectable HCV RNA after 24 weeks. Results: A total of 453 patients were randomized to treatment with peginterferon alfa-2a (40KD) and ribavirin and received study medication. The disposition of patients who were HCV RNA negative after 24 weeks of treatment is shown in the Table and grouped according to their HCV RNA status at week 4, 12 and 24. Patients with missing data at any of these time points were not included in the analysis. Patients with ->2-1ogre drop in HCV RNA levels at a given time point, and who were negative at the previous and following time point, were grouped with patients assessed as HCV RNA negative at that time point (n - 8). The probability of achieving an SVR increased in inverse proportion to the time taken to achieve undetectable HCV RNA levels. Thus, the highest SVR rate (89%) and, correspondingly, the lowest relapse rate during follow-up (8%), was obtained in patients who were consistently HCV RNA negative at weeks 4, 12 and 24. Conclusions: The outcome of combination therapy with peginterferon alfa-2a (40KD) (PEGASYS ®) and ribavirin (COPEGUS ®) is highly dependent on the rapidity of the virological response. Patients who become HCV RNA negative after 4 weeks have the best chance for achieving an SVR. It may be hypothesized that to decrease the frequency of relapse in the remaining patients, treatment longer than 48 weeks may be required. This approach should be tested in a prospective trial. F~V*RNA Sta~s
EOT
995
A DYNAMIC MODEL TO PREDICT SUSTAINED VIROLOGICAL RESPONSE TO COMBINATION PEGINTERFERON ALFA-2A (40KD) (PEGASYS (R)) AND RIBAVIRIN (COPEGUS (R)) THERAPY IN PATIENTS WITH CHRONIC HEPATITIS C. Peter Ferenci, University of Vienna,
Vienna, Austm'a; Michael W Fried, University of North Carolina, Chapel Hill, NC; Monique Chaneac, Roche Diagnostics, Basel, Switzerland Background: Overall, 56% of patients achieved sustained virological responses (SVR) after 48 weeks of treatment with the combination of peginterferon alfa-2a (40KD) (PEGASYS®) 180 /~g/week and ribavirin (COPEGUS ®) 1000 or 1200 rag/day in a large international randomized, phase 3 triaL(Fried et al. N~ ngl J Med. 2002;347:975-982). In this study, 97% of patients without an early virological response
N~atl~e
N~a~tve N~,~ti"ve:11Z 96
~00 (~¾~
;~2,1~g {t~Op
~4e~at~ve N~stf~e 132 H~
~ ~7~) 24 (~1%)
?~%)
~r~ ¢~rop
d~op
End of treatment response (EOT) -
"
HCV RNA negative at week 48
Disclosures: Monique Chaneac - Roche: Employee Peter Ferenci - Roche: Investigator Michael W Fried - Roche: Investigator
AASLD ABSTRACTS
baseline differences in HVR1 variation between drug-sensitive and drug-resistant patients. Patients were chronically infected with HCV genotype 1 and were untreated prior to this prospective trial of combination therapy (pegylated interferon-alpha-2b and ribavirin). The treatment protocol entailed 48 weeks of therapy plus an additional 24 weeks of follow-up. The circulating quasispecies was studied at baseline and at multiple time points during and subsequent to therapy. Description of the quasispecies was based on HVR1 sequence of 20 i n d e p e n d e n t clones from each sample. Although enrollment of subjects is ongoing, 20 subjects have either completed the 72-week regimen or reached a time point that allows outcome to be predicted. Due to the manner in which this comparison group was constructed, the observed proportions do not reflect a success rate for therapy. Of the 20 subjects, eight successfully cleared virus (responders), and 12 subjects failed to clear virus (nonresponders). The following parameters of genetic variability were compared in baseline samples from responders vs. nonresponders: viral load, genetic complexity of the quasispecies as measured by Shannon entropy, and genetic diversity. Genetic diversity was measured as mean genetic distance for synonymous substitutions per synonymous site (Ka) and mean genetic distance for nonsynonymous substitutions per nonsynonymous site (K~). The intrasample ratio (Ka/K~) was calculated and served as an indicator of host selection pressure. In comparing responders and nonresponders at baseline, responders exhibited significantly higher Ka/K~ ratios, with a mean (SE) of 2.46 (0.63) for responders and 0.70 (0.51) for nonresponders (p-0.04). The K~ measure reflects genetic drift resulting from random mutation, whereas Ka measures differences at the amino acid level. The relative increase in Ka for responders indicates that, even prior to the onset of therapy, there were host pressures in play that caused selection at the amino acid level. The relative increase in selection pressure may have predisposed these patients to achieve virologic response once therapy was initiated. Other parameters did not vary significantly, either between responders and nonresponders or evolutionarily in nonresponders. These results suggest that selection pressure caused by intrinsic host factors, such as sustained immune pressure, may be an important component contributing to therapeutic success in chronically infected patients. This work was supported by NIAID U19 AI-48216 and UTHSC GCRC M01 RR-00211 Disclosures: Jaquelyn Fleckenstein - No relationships to disclose Julia Krushkal - No relationships to disclose Rongling Li - No relationships to disclose Barbara Mason - No relationships to disclose Swapna Menon - No relationships to disclose Vicki Park - No relationships to disclose Caroline Riely - No relationships to disclose
635A
(EVR), defined as either a ->2-1ogre drop in viral load or complete disappearance of HCV RNA in serum by 12 weeks of therapy, failed to achieve an SVR. This information is useful because it allows for the early termination of treatment in those unlikely to respond to a full course of treatment. Purpose: To refine the ability to predict the likelihood of achieving a sustained virological response after treatment with peginterferon alfa-2a (40KD) and ribavirin, based on virological response data obtained at week 4 and week 12 of therapy. Methods: The dynamic model is based on data from patients treated with peginterferon alfa-2a (40KD) 180 /~g/week and ribavirin 1000 or 1200 rag/day for 48 weeks in a large, international randomized trial (Fried et al. N~ nglJMed. 2002;347:975-982). For the purpose of this analysis, an early virological response (EVR) was defined as undetectable HCV RNA by qualitative polymerase chain reaction (PCR) assay (<50 IU/mL; COBAS AMPLICOR ® HCV Test, v2.0; Roche Diagnostics) or a decrease of ->2 logm in HCV RNA levels as determined by quantitative PCR (COBAS AMPLICOR HCV MONITOR ®Test, v2.0; Roche Diagnostics) after 12 weeks of treatment. For this analysis SVR was defined as a single undetectable HCV RNA level by qualitative PCR on or after week 60. Treatment was to be stopped in patients with detectable HCV RNA after 24 weeks. Results: A total of 453 patients were randomized to treatment with peginterferon alfa-2a (40KD) and ribavirin and received study medication. The disposition of patients who were HCV RNA negative after 24 weeks of treatment is shown in the Table and grouped according to their HCV RNA status at week 4, 12 and 24. Patients with missing data at any of these time points were not included in the analysis. Patients with ->2-1ogre drop in HCV RNA levels at a given time point, and who were negative at the previous and following time point, were grouped with patients assessed as HCV RNA negative at that time point (n - 8). The probability of achieving an SVR increased in inverse proportion to the time taken to achieve undetectable HCV RNA levels. Thus, the highest SVR rate (89%) and, correspondingly, the lowest relapse rate during follow-up (8%), was obtained in patients who were consistently HCV RNA negative at weeks 4, 12 and 24. Conclusions: The outcome of combination therapy with peginterferon alfa-2a (40KD) (PEGASYS ®) and ribavirin (COPEGUS ®) is highly dependent on the rapidity of the virological response. Patients who become HCV RNA negative after 4 weeks have the best chance for achieving an SVR. It may be hypothesized that to decrease the frequency of relapse in the remaining patients, treatment longer than 48 weeks may be required. This approach should be tested in a prospective trial. F~V*RNA Sta~s
EOT
995
A DYNAMIC MODEL TO PREDICT SUSTAINED VIROLOGICAL RESPONSE TO COMBINATION PEGINTERFERON ALFA-2A (40KD) (PEGASYS (R)) AND RIBAVIRIN (COPEGUS (R)) THERAPY IN PATIENTS WITH CHRONIC HEPATITIS C. Peter Ferenci, University of Vienna,
Vienna, Austm'a; Michael W Fried, University of North Carolina, Chapel Hill, NC; Monique Chaneac, Roche Diagnostics, Basel, Switzerland Background: Overall, 56% of patients achieved sustained virological responses (SVR) after 48 weeks of treatment with the combination of peginterferon alfa-2a (40KD) (PEGASYS®) 180 /~g/week and ribavirin (COPEGUS ®) 1000 or 1200 rag/day in a large international randomized, phase 3 triaL(Fried et al. N~ ngl J Med. 2002;347:975-982). In this study, 97% of patients without an early virological response
N~atl~e
N~a~tve N~,~ti"ve:11Z 96
~00 (~¾~
;~2,1~g {t~Op
~4e~at~ve N~stf~e 132 H~
~ ~7~) 24 (~1%)
?~%)
~r~ ¢~rop
d~op
End of treatment response (EOT) -
"
HCV RNA negative at week 48
Disclosures: Monique Chaneac - Roche: Employee Peter Ferenci - Roche: Investigator Michael W Fried - Roche: Investigator