- Email: [email protected]
RIBAVIRIN IN HCV (GT1)-INFECTED PATIENTS
POSTERS (cEVR; mutually exclusive groups), defined as undetectable HCV RNA (<15 IU/mL) at week 4 and 12, respectively, were assessed for each group. Baseline predictors of RVR and cEVR, including fibrosis categories, were explored by multiple logistic regression (MLR) analyses (stepwise selection). Results: 1609 patients were analysed; 86% were Caucasian, 52% male and mean HCV RNA was 5.98 log10 IU/mL. F3/4 patients were older with higher baseline ALT levels and lower platelet counts versus F0–2 patients (Table). There was a marked step-wise decline in virological response (RVR and cEVR) by fibrosis stage, with RVR and cEVR rates declining with increasing severity of fibrosis (Table). MLR analyses showed METAVIR fibrosis score to be associated with RVR/cEVR (p < 0.05); odds ratios (95% CI) for RVR/cEVR versus F4 patients were 2.27 (1.10–4.69), 2.14 (1.41–3.25) and 1.38 (0.90– 2.12) for patients with F0, F1–2 and F3, respectively. Conclusion: This interim analysis demonstrates that the degree of fibrosis strongly influences treatment response to PegIFNa-2a/ribavirin in G1 patients. Acknowledgement: Funded by Roche, Basel, Switzerland Fibrosis categories
Baseline parameters Mean age, yrs (range) Mean HCV RNA, log10 IU/mL Mean ALT, IU/L ALT ratio >3.0, n (%) Mean platelets, ×109 /L
F0: No fibrosis (n = 62)
F1–2; Mild–moderate (n = 893)
F3: Moderate–severe (n = 503)
F4: Complete cirrhosis (n = 151)
40 (20–61) 5.72
47 (18–76) 6.05
50 (21–78) 5.87
54 (18–86) 6.00
54.2 8 (13)
65.2 162 (18)
78.7 150 (30)
74.1 33 (22)
242
Platelets <140×109 /L, n (%) 2 (3) On-treatment virological response, n (%) RVR 16 (25.8) cEVR 27 (43.5)
228
206
148
60 (7)
86 (17)
72 (48)
201 (22.5) 331 (37.1)
85 (16.9) 174 (34.6)
21 (13.9) 33 (21.9)
433 FREQUENCIES OF RESISTANCE-ASSOCIATED AMINO ACID VARIANTS DETECTED BY 454-SEQUENCING DURING COMBINATION TREATMENT WITH BOCEPREVIR PLUS PEGINTRON (PEGINTERFERON ALFA-2B)/RIBAVIRIN IN HCV (GT1)-INFECTED PATIENTS J.A. Howe1 , P. Qiu2 , R.A. Ogert2 , P. Mendez1 , C.A. Brass1 , J. Albrecht1 , R. Ralston2 , R.J.O. Barnard2 , D. Hazuda2 . 1 Merck & Co., Inc., Kenilworth, 2 Merck & Co., Inc., Whitehouse Station, NJ, USA E-mail: [email protected] Background: The HCV-NS3 protease inhibitor boceprevir (BOC) combined with PEGINTRON plus ribavirin (PR) is effective for treatment of HCV genotype 1 infection. We performed a detailed 454-sequencing analysis of 23 non-SVR and 6 SVR patients from the phase 2 SPRINT-1 study. Methods: SVR and non-SVR patients who had single and multiple variants at boceprevir resistant loci (NS3 aa positions V36, T54, R155, A156 and/or V170) by population sequencing from the SPRINT-1 study were selected for 454-sequence analysis. Sequences were obtained at baseline and/or 2–4 post-baseline time points. ~2200 clones were sequenced for each time point, giving a lower limit of RAV detection of 2.5%. Results: Of the 23 non-SVR patients, 12 experienced virological breakthrough (BT), 3 experienced an incomplete virological response (IVR), 5 were relapsers (RL), and 3 were non-responsive (NR) patients. Very few additional RAVs were identified by 454 sequencing that were undetected by population sequencing and these were detected at frequencies of <10% of the circulating viral population. In general, non-SVR patients with individual RAVs detected by population sequencing also had very high levels of detectable variants (>65%) at or near to the time of virological failure using 454 sequencing. Following BOC/PR treatment, the levels of RAVs declined during the follow-up period, although the rate of decline was different for each RAV. Also, in viruses with S176
multiple RAVs, each individual variant declined at different rates. Six SVR patients with RAVs detected at baseline by population sequencing were also selected for 454 analysis. The frequency of individual baseline RAVs was found to vary in these patients from 4.5% to as high as 99.9%. Conclusions: RAVs were detected at a high frequency at or close to the time of virological failure in patients not achieving SVR. RAVs did decline following BOC/PR treatment, but the rate of decline was specific to each RAV. RAVs were also detected at baseline in 6 patients that subsequently achieved SVR, indicating that baseline RAVs do not preclude the possibility of achieving SVR and could be related to the interferon responsiveness of these patients. 434 IMPROVEMENT OF GLUCOSE ABNORMALITIES IN PREDIABETIC CHRONIC HEPATITIS C PATIENTS AFTER PEGINTERFERON-ALPHA PLUS RIBAVIRIN THERAPY J.-F. Huang1 , C.-Y. Dai2 , M.-L. Yu3 , W.-L. Chuang2 . 1 Department of Internal Medicine, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung Medical University, 2 Hepatobiliary Section, Department of Internal Medicine, Kaohsiung Medical University Hospital, 3 Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University, Kaohsiung City, Taiwan R.O.C. E-mail: [email protected] Background and Aim: Pre-diabetes is an insulin resistance state and carries risk for development of type 2 diabetes and cardiovascular disease. We aimed to elucidate the impact of treatment response to antiviral therapy on sequential changes of glucose abnormalities in pre-diabetic chronic hepatitis C (CHC) patients. Methods: CHC patients with their baseline A1C range of 5.7 to 6.4% and achieved 80/80/80 adherence were recruited. All received peginterferon plus ribavirin combination therapy with a 24-week follow-up period according to the current treatment recommendations. The primary outcome measurement was their A1C level at end-of-follow-up (EOF). The interaction between sequential A1C changes and sustained virological response (SVR) was also analyzed. Results: A total of 181 consecutive CHC (106 males, mean age = 53.6±10.5 years) were enrolled. They included 92 (50.8%) patients of genotype-1 (G-1) and 89 patients of G-non-1 infection. Those 154 (85.1%) patients who achieved SVR significantly had a lower age, a lower histological activity index score, and a lower viral load than their counterparts. The mean A1C at EOF was 5.8±0.4%, which was significantly lower than baseline level (5.9±0.2%, P < 0.001). The improvement was observed in those G-non-1 (from 5.9±0.2 to 5.8±0.3%, P < 0.001), but not in G-1 (from 5.9±0.2 to 5.9±0.5%, P = 0.1) patients. At EOF, the incidences of diabetes, pre-diabetes and normoglycemia were 5.5%, 59.7% and 34.8%, respectively. The SVR rates of 63 normoglycemics and 108 pre-diabetics at EOF were 92.1% and 84.3%, respectively, which were significantly higher than 10 diabetics (50%) (P = 0.003, and 0.02, respectively). Achievement of an SVR was the only predictive factor associated with the development of normoglycemia at EOF in multivariate logistic regression analysis (Odds ratio = 2.6, 95% confidence interval = 1.1–6.8, P = 0.04). Conclusion: Successful eradication of HCV improves glucose abnormalities in pre-diabetic CHC patients.
Journal of Hepatology 2011 vol. 54 | S61–S208
Baseline parameters Mean age, yrs (range) Mean HCV RNA, log10 IU/mL Mean ALT, IU/L ALT ratio >3.0, n (%) Mean platelets, ×109 /L
F0: No fibrosis (n = 62)
F1–2; Mild–moderate (n = 893)
F3: Moderate–severe (n = 503)
F4: Complete cirrhosis (n = 151)
40 (20–61) 5.72
47 (18–76) 6.05
50 (21–78) 5.87
54 (18–86) 6.00
54.2 8 (13)
65.2 162 (18)
78.7 150 (30)
74.1 33 (22)
242
Platelets <140×109 /L, n (%) 2 (3) On-treatment virological response, n (%) RVR 16 (25.8) cEVR 27 (43.5)
228
206
148
60 (7)
86 (17)
72 (48)
201 (22.5) 331 (37.1)
85 (16.9) 174 (34.6)
21 (13.9) 33 (21.9)
433 FREQUENCIES OF RESISTANCE-ASSOCIATED AMINO ACID VARIANTS DETECTED BY 454-SEQUENCING DURING COMBINATION TREATMENT WITH BOCEPREVIR PLUS PEGINTRON (PEGINTERFERON ALFA-2B)/RIBAVIRIN IN HCV (GT1)-INFECTED PATIENTS J.A. Howe1 , P. Qiu2 , R.A. Ogert2 , P. Mendez1 , C.A. Brass1 , J. Albrecht1 , R. Ralston2 , R.J.O. Barnard2 , D. Hazuda2 . 1 Merck & Co., Inc., Kenilworth, 2 Merck & Co., Inc., Whitehouse Station, NJ, USA E-mail: [email protected] Background: The HCV-NS3 protease inhibitor boceprevir (BOC) combined with PEGINTRON plus ribavirin (PR) is effective for treatment of HCV genotype 1 infection. We performed a detailed 454-sequencing analysis of 23 non-SVR and 6 SVR patients from the phase 2 SPRINT-1 study. Methods: SVR and non-SVR patients who had single and multiple variants at boceprevir resistant loci (NS3 aa positions V36, T54, R155, A156 and/or V170) by population sequencing from the SPRINT-1 study were selected for 454-sequence analysis. Sequences were obtained at baseline and/or 2–4 post-baseline time points. ~2200 clones were sequenced for each time point, giving a lower limit of RAV detection of 2.5%. Results: Of the 23 non-SVR patients, 12 experienced virological breakthrough (BT), 3 experienced an incomplete virological response (IVR), 5 were relapsers (RL), and 3 were non-responsive (NR) patients. Very few additional RAVs were identified by 454 sequencing that were undetected by population sequencing and these were detected at frequencies of <10% of the circulating viral population. In general, non-SVR patients with individual RAVs detected by population sequencing also had very high levels of detectable variants (>65%) at or near to the time of virological failure using 454 sequencing. Following BOC/PR treatment, the levels of RAVs declined during the follow-up period, although the rate of decline was different for each RAV. Also, in viruses with S176
multiple RAVs, each individual variant declined at different rates. Six SVR patients with RAVs detected at baseline by population sequencing were also selected for 454 analysis. The frequency of individual baseline RAVs was found to vary in these patients from 4.5% to as high as 99.9%. Conclusions: RAVs were detected at a high frequency at or close to the time of virological failure in patients not achieving SVR. RAVs did decline following BOC/PR treatment, but the rate of decline was specific to each RAV. RAVs were also detected at baseline in 6 patients that subsequently achieved SVR, indicating that baseline RAVs do not preclude the possibility of achieving SVR and could be related to the interferon responsiveness of these patients. 434 IMPROVEMENT OF GLUCOSE ABNORMALITIES IN PREDIABETIC CHRONIC HEPATITIS C PATIENTS AFTER PEGINTERFERON-ALPHA PLUS RIBAVIRIN THERAPY J.-F. Huang1 , C.-Y. Dai2 , M.-L. Yu3 , W.-L. Chuang2 . 1 Department of Internal Medicine, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung Medical University, 2 Hepatobiliary Section, Department of Internal Medicine, Kaohsiung Medical University Hospital, 3 Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University, Kaohsiung City, Taiwan R.O.C. E-mail: [email protected] Background and Aim: Pre-diabetes is an insulin resistance state and carries risk for development of type 2 diabetes and cardiovascular disease. We aimed to elucidate the impact of treatment response to antiviral therapy on sequential changes of glucose abnormalities in pre-diabetic chronic hepatitis C (CHC) patients. Methods: CHC patients with their baseline A1C range of 5.7 to 6.4% and achieved 80/80/80 adherence were recruited. All received peginterferon plus ribavirin combination therapy with a 24-week follow-up period according to the current treatment recommendations. The primary outcome measurement was their A1C level at end-of-follow-up (EOF). The interaction between sequential A1C changes and sustained virological response (SVR) was also analyzed. Results: A total of 181 consecutive CHC (106 males, mean age = 53.6±10.5 years) were enrolled. They included 92 (50.8%) patients of genotype-1 (G-1) and 89 patients of G-non-1 infection. Those 154 (85.1%) patients who achieved SVR significantly had a lower age, a lower histological activity index score, and a lower viral load than their counterparts. The mean A1C at EOF was 5.8±0.4%, which was significantly lower than baseline level (5.9±0.2%, P < 0.001). The improvement was observed in those G-non-1 (from 5.9±0.2 to 5.8±0.3%, P < 0.001), but not in G-1 (from 5.9±0.2 to 5.9±0.5%, P = 0.1) patients. At EOF, the incidences of diabetes, pre-diabetes and normoglycemia were 5.5%, 59.7% and 34.8%, respectively. The SVR rates of 63 normoglycemics and 108 pre-diabetics at EOF were 92.1% and 84.3%, respectively, which were significantly higher than 10 diabetics (50%) (P = 0.003, and 0.02, respectively). Achievement of an SVR was the only predictive factor associated with the development of normoglycemia at EOF in multivariate logistic regression analysis (Odds ratio = 2.6, 95% confidence interval = 1.1–6.8, P = 0.04). Conclusion: Successful eradication of HCV improves glucose abnormalities in pre-diabetic CHC patients.
Journal of Hepatology 2011 vol. 54 | S61–S208