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Does hepatitis C viral (HCV) genotype or initial HCV RNA titer predict induction of response to interferon alfa 2a in chronic hepatitis C
176A
277
AASLD ABSTRACTS
GENOTYPE DEPENDENT RESPONSE TO INrERFERON¢{-2a IN PATIL WITH CHRONIC HEPATITIS C. V Carre~o1 with the International Heoatl,~ Study Group and L Wolfe2 with the HCV PCR Diaonostic Grouo. 1Hepatology Unit, Fundaci6n Jim(mez Diaz, Madrid, Spain. 2Roche Molecular Systems, Somerville, NJ.
278 DOES HEPATITIS C VIRAL (HCV) GENOTYPE OR INITIAL HCV RNA TITER PREDICT INDUCTION OF RESPONSE TO INTERFERON ALFA 2a IN CHRONIC HEPATITIS C? WM Lee with the Hepatitis Study Group, Roche Clinical Research and Roche Molecular Systems, Nutley and Branchburg, NJ, and the University of Texas Southwestern Med School, Dattas, TX Quantify!ng and genotyping hepatitis C virus RNA might help predict responses to interferon therapy. We evaluated the 244nucleotide amplicon obtained after a 40-cycle rtPCR of pretreatment sara from 367 non-cirrhotic patients enrolled in a treatment trial in 19 centers from 18 cities in 11 states. Samples were genotyped by sequence analysis of the 5' UTR, with comparison to known prototype sequences, and analyzed by quantitative PCR. Results were analyzed by initial patient response of the first 249 patients to 6 MiU interferon alfa 2a (Roferon A ®) TIW for each genotype group. Complete responses (CR) = normal ALT's at 12 weeks' treatment, with all others grouped as NR. GenotvDe 1a 1b 2a 2b 3a 4 Total (%~ CR." N 47 42 1 19 22 1 132(53)
Obiective: to explore the effect of HCV genotypa and viremia on response of chronic hepatitis C to treatment with IFN=-2a in a new human serum albumin free liquid formulation (RoferonR-A, HoffmanmLa Roche, Switzerland). Patients and methods. 81 patients recruited in an international multicenter trial received IFN=-2a 5MIU tiw for three months and responding (CR) patients 3 MlU tiw for further three months. Genotype was determined by matching 244 nucleotide sequence from the 5' utr region to known prototype sequences. Results: 1a/20 lb/43 2a/1 3a/12 4a/5 AII/81 Genotype/n 9 (45) 24 (56) 0(-) 10 (83) 5 (-) 48 (59) Male: n (%) ALT quotient n (%): ,16(80) 29(67) 1(100) 7 (58) 3 (75) 56 (70) <3.0N 2 (10) 12(28) 5 (42) 1 (25) 20 (25) 3.0 - 7.0 2 (10) 2 (5) --7 -4 (5) > 7.0 Histology n (%): 3 (15) 6 (14) -1 (8) -10 (12) mild activity 17(85) 36(84) 1(100) 11 (92) 5(100) 70 (86) moderate activity 7 (36) 12(28) -8 (67) 1 (20) 28 (35) Complete response 1 (5) 2 (6) .... 1 (20) 4 (5) Partial response (Response: 2 consecutive measurements at months 5 and 6) Neutralizing antibodies to IFN= were detected in 7/81 (9%) patients at peak concentrations between 588 and 10,380 INUs (WHO standard). Conclusions: Genotype lb was isolated most frequently in this population. Patients with this genotype had lower CR rates than la or 3a.
279 CORRELATION OF HEPATITIS C VIRUS GENOTYPE WITH THE NUMBER OF INTERFERON-a RECEPTORS AND 2',5'OLIGOADENYLATE SYNTHErASE INDUCTION OF PBMC. S Nakaiima, T Kuroki, C Kawamura, T Takeda, S Nishipuchi. K Kobayashi. Third Dept. of Internal Medicine, Osaka City Univ., Japan Patients with hepatitis C virus genotype III are reported to respond better to IFN-a treatment than those with genotype II (genotype classified by Okamoto's method). To clarify the reason for this, we measured interferon (IFN)-a receptors and the activity of 2',5'-oligoadenylate synthetase (2-5AS) of peripheral blood mononuclear cells (PBMC). The binding of 1251-labeled IFN-a to cells for 120 min at 4 °C was measured. The number of IFN-a receptors was calculated from Scatchard analysis. Activity of 2-5AS was assayed with an RIA kit. PBMC were cultured for 18 hours at 37 C ° with IFN-a at a concentration of 1000 IU/ml or without IFN. We expressed the activity of 2-5AS in PBMC cultured with IFN relative to the value of PBMC cultured without IFN. IFN-a receptor numbers per cell Induction of 2-5AS
(fo d)
type II 1070 + 240 (n = 19) 4.4 + 2.0
type III 1530+380 * (n = 17) 7.3 + 2.8*
(n = 25) (n = 16) * p < 0.05. Values are mean ± S.D. Conclusion: We suggested that increases in the number of IFN-a receptors and induction of 2-5AS of PBMC in patients with genotype III contributed to their good response to IFN-a therapy.
HEPATOLOGYOctober 1995
NR: N 52 37 2 15 11 0 117(47) Total N (%) 99(39) 79(32) 3(1.2) 34(14) 33(13) 1(0.4) 249(100) Genotype prevalences in this multi-site study are similar to those i d e n t i f i e d p r e v i o u s l y . R e g i o n a l d i f f e r e n c e s in g e n o t y p e prevalence w e r e not found. ALT's and histologic severity scores w e r e also similar for all genotypes. No significant differences were discerned between response rates by genotype except that 3a patients w e r e s o m e w h a t better responders than either l a or l a / l b groups. M e a n b a s e l i n e P C R titers for C R (511,000 copies/ml) and NR (615,000 copies/ml) groups w e r e similar (N=210). Neither g e n o t y p e nor viral titer a p p e a r e d to play an important role in determining induction of response to interferon alfa 2a in this interim analysis of a US non-cirrhotic patient group.
280
NUMBER OF HCV INFECTED HEPATOCYTESAND QUANTITATION OF LIVER HCV RNA: RELATION TO HCV GENOTYPES, HCV VIREMIA AND RESPONSE TO IFN TREATMENT. G Ballardini ~ *A Manzin~ R Francesconi. F Gioetra, P Greff. *L Solforesi, S Ghatti. A Grusi, D Zauli~ *M Clementiv FB BianchL Semeiotica Medica II, Pol. S. O~ola, University of Bologna. *Institute of Microbiology, University of Ancona, Italy. No information is at present available on the relation between the number of hepatocyes positive for tissue HCV antigens (t-HCV Ag) and the amount of HCV RNA in tissue (t-HCV RNA). Thidy~one consecutive HCV patients were selected on the basis of the availability of frozen liver tissue for t-HCV Ag (immunohistochemiatry with FITC-conjugated human anti-HCV IgG) and t-HCV RNA quantitation (competitive RT PCR, results expressed as 1x103 copy number/ug of RNA extra~cted). Five patients turned out to be infected by genotybe la, 12 by lb, 8 by 2a, 5 by 3a and 1 by 4a (INNO UPA). Plasma HCV RNA level (competitive RT PCR, expressed in lx103 copy numberlml) was available in 26 cases. The short term response pattern to IFN treatment was at the moment defined in 28 (16 non responders and 12 responders). Viremia levels were available in 23 ot these 28 cases (12 non responders and 11 responders). A significant correlation (p<0.005) was found between t-HCV RNA and the number of HCV infected cells (visually scored from 0 to 3). These parameters were not significantly correlated with viremia levels. The median amount of tissue HCV RNA was 1.200 in l b (p
277
AASLD ABSTRACTS
GENOTYPE DEPENDENT RESPONSE TO INrERFERON¢{-2a IN PATIL WITH CHRONIC HEPATITIS C. V Carre~o1 with the International Heoatl,~ Study Group and L Wolfe2 with the HCV PCR Diaonostic Grouo. 1Hepatology Unit, Fundaci6n Jim(mez Diaz, Madrid, Spain. 2Roche Molecular Systems, Somerville, NJ.
278 DOES HEPATITIS C VIRAL (HCV) GENOTYPE OR INITIAL HCV RNA TITER PREDICT INDUCTION OF RESPONSE TO INTERFERON ALFA 2a IN CHRONIC HEPATITIS C? WM Lee with the Hepatitis Study Group, Roche Clinical Research and Roche Molecular Systems, Nutley and Branchburg, NJ, and the University of Texas Southwestern Med School, Dattas, TX Quantify!ng and genotyping hepatitis C virus RNA might help predict responses to interferon therapy. We evaluated the 244nucleotide amplicon obtained after a 40-cycle rtPCR of pretreatment sara from 367 non-cirrhotic patients enrolled in a treatment trial in 19 centers from 18 cities in 11 states. Samples were genotyped by sequence analysis of the 5' UTR, with comparison to known prototype sequences, and analyzed by quantitative PCR. Results were analyzed by initial patient response of the first 249 patients to 6 MiU interferon alfa 2a (Roferon A ®) TIW for each genotype group. Complete responses (CR) = normal ALT's at 12 weeks' treatment, with all others grouped as NR. GenotvDe 1a 1b 2a 2b 3a 4 Total (%~ CR." N 47 42 1 19 22 1 132(53)
Obiective: to explore the effect of HCV genotypa and viremia on response of chronic hepatitis C to treatment with IFN=-2a in a new human serum albumin free liquid formulation (RoferonR-A, HoffmanmLa Roche, Switzerland). Patients and methods. 81 patients recruited in an international multicenter trial received IFN=-2a 5MIU tiw for three months and responding (CR) patients 3 MlU tiw for further three months. Genotype was determined by matching 244 nucleotide sequence from the 5' utr region to known prototype sequences. Results: 1a/20 lb/43 2a/1 3a/12 4a/5 AII/81 Genotype/n 9 (45) 24 (56) 0(-) 10 (83) 5 (-) 48 (59) Male: n (%) ALT quotient n (%): ,16(80) 29(67) 1(100) 7 (58) 3 (75) 56 (70) <3.0N 2 (10) 12(28) 5 (42) 1 (25) 20 (25) 3.0 - 7.0 2 (10) 2 (5) --7 -4 (5) > 7.0 Histology n (%): 3 (15) 6 (14) -1 (8) -10 (12) mild activity 17(85) 36(84) 1(100) 11 (92) 5(100) 70 (86) moderate activity 7 (36) 12(28) -8 (67) 1 (20) 28 (35) Complete response 1 (5) 2 (6) .... 1 (20) 4 (5) Partial response (Response: 2 consecutive measurements at months 5 and 6) Neutralizing antibodies to IFN= were detected in 7/81 (9%) patients at peak concentrations between 588 and 10,380 INUs (WHO standard). Conclusions: Genotype lb was isolated most frequently in this population. Patients with this genotype had lower CR rates than la or 3a.
279 CORRELATION OF HEPATITIS C VIRUS GENOTYPE WITH THE NUMBER OF INTERFERON-a RECEPTORS AND 2',5'OLIGOADENYLATE SYNTHErASE INDUCTION OF PBMC. S Nakaiima, T Kuroki, C Kawamura, T Takeda, S Nishipuchi. K Kobayashi. Third Dept. of Internal Medicine, Osaka City Univ., Japan Patients with hepatitis C virus genotype III are reported to respond better to IFN-a treatment than those with genotype II (genotype classified by Okamoto's method). To clarify the reason for this, we measured interferon (IFN)-a receptors and the activity of 2',5'-oligoadenylate synthetase (2-5AS) of peripheral blood mononuclear cells (PBMC). The binding of 1251-labeled IFN-a to cells for 120 min at 4 °C was measured. The number of IFN-a receptors was calculated from Scatchard analysis. Activity of 2-5AS was assayed with an RIA kit. PBMC were cultured for 18 hours at 37 C ° with IFN-a at a concentration of 1000 IU/ml or without IFN. We expressed the activity of 2-5AS in PBMC cultured with IFN relative to the value of PBMC cultured without IFN. IFN-a receptor numbers per cell Induction of 2-5AS
(fo d)
type II 1070 + 240 (n = 19) 4.4 + 2.0
type III 1530+380 * (n = 17) 7.3 + 2.8*
(n = 25) (n = 16) * p < 0.05. Values are mean ± S.D. Conclusion: We suggested that increases in the number of IFN-a receptors and induction of 2-5AS of PBMC in patients with genotype III contributed to their good response to IFN-a therapy.
HEPATOLOGYOctober 1995
NR: N 52 37 2 15 11 0 117(47) Total N (%) 99(39) 79(32) 3(1.2) 34(14) 33(13) 1(0.4) 249(100) Genotype prevalences in this multi-site study are similar to those i d e n t i f i e d p r e v i o u s l y . R e g i o n a l d i f f e r e n c e s in g e n o t y p e prevalence w e r e not found. ALT's and histologic severity scores w e r e also similar for all genotypes. No significant differences were discerned between response rates by genotype except that 3a patients w e r e s o m e w h a t better responders than either l a or l a / l b groups. M e a n b a s e l i n e P C R titers for C R (511,000 copies/ml) and NR (615,000 copies/ml) groups w e r e similar (N=210). Neither g e n o t y p e nor viral titer a p p e a r e d to play an important role in determining induction of response to interferon alfa 2a in this interim analysis of a US non-cirrhotic patient group.
280
NUMBER OF HCV INFECTED HEPATOCYTESAND QUANTITATION OF LIVER HCV RNA: RELATION TO HCV GENOTYPES, HCV VIREMIA AND RESPONSE TO IFN TREATMENT. G Ballardini ~ *A Manzin~ R Francesconi. F Gioetra, P Greff. *L Solforesi, S Ghatti. A Grusi, D Zauli~ *M Clementiv FB BianchL Semeiotica Medica II, Pol. S. O~ola, University of Bologna. *Institute of Microbiology, University of Ancona, Italy. No information is at present available on the relation between the number of hepatocyes positive for tissue HCV antigens (t-HCV Ag) and the amount of HCV RNA in tissue (t-HCV RNA). Thidy~one consecutive HCV patients were selected on the basis of the availability of frozen liver tissue for t-HCV Ag (immunohistochemiatry with FITC-conjugated human anti-HCV IgG) and t-HCV RNA quantitation (competitive RT PCR, results expressed as 1x103 copy number/ug of RNA extra~cted). Five patients turned out to be infected by genotybe la, 12 by lb, 8 by 2a, 5 by 3a and 1 by 4a (INNO UPA). Plasma HCV RNA level (competitive RT PCR, expressed in lx103 copy numberlml) was available in 26 cases. The short term response pattern to IFN treatment was at the moment defined in 28 (16 non responders and 12 responders). Viremia levels were available in 23 ot these 28 cases (12 non responders and 11 responders). A significant correlation (p<0.005) was found between t-HCV RNA and the number of HCV infected cells (visually scored from 0 to 3). These parameters were not significantly correlated with viremia levels. The median amount of tissue HCV RNA was 1.200 in l b (p