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Predictive factors of response to interferon-α (IFN) in chronic hepatitis C: What factors for what response?
174A
269
AASLD ABSTRACTS
LONG-TERM BIOCHEMICAL, VIROLOGICAL, AND HISTOLOGICAL FOLLOW-UP IN PATIENTS WITH CHRONIC HEPATITIS C TREATED WITH INTERFERON. M Takahashi, G Y a m a d a , H Tsugeno. H Endo. F Kishi. M T a k a t a n i . K M a n a b e . M Mizuno, a n d T Tsuii. 1st Dept. of I n t e r n a l Medicine, O k a y a m a U n i v e r s i t y Medical School, O k a y a m a , J a p a n .
270
PREDICTORS OF RESPONSE TO ALPHA INTERFERON THERAPY I N CHRONIC HEPATITIS C : A MULTIVARIATE ANALYSIS IN 287 PATIENTS. M. Martinet. P. Marcellin. M. Pouteau. C. Caslelnau. N. Bover. I. Randrianatoavina. V. Le Breton. JP. Benhamou. and S. Erlin~er. INSERM U24 et Service d'Htpatologie, Htpital Beaujon, Clichy, France. The objective of this study was to assess, in a large population of patients, the relevance of pretreatment serum HCV RNA level and HCV genotype to predict sustained response to interferon CIFN)therapy. Patients and Methods: we studied 287 patients with chronic hepatitis C included in four consecutive randomized trials of IFN lymphoblastcYfd(96) (WeUferon, Wellcome), IFN alpha 2b (64) (IntronA, Schering Plough) and IFN alpha 2a (127)(Roferon, Roche). Two response groups were defined according to ALT response: 42 patients had a sustained response (SR) defined by normal serum ALT at the end of treatment and during the 6-month post-treatment follow-up ; 245 patients were non responders CNR) defined by increased serum ALT at the end of treatment or during the 6-month post: treatment follow-up. Sex, age, source of infection, duration of the disease, treatment schedule, 343T, serum ferritin, liver histology, pretreatment serum ALT and HCV RNA levels and HCV gcnotype were studied. Serum HCV RNA was quantified with the bDNA signal amplification assay (Quantiplex, CHIRON). Genotyping was perfonaed with the reverse hybridization assay (LiPA) (INN0-LIPA, InGeN). Results: By univariale analysis: age, source of infection, TGT levels, pretreatment serum HCV RNA levels and HCV genotype were significantly different in the two response groups. Characleristics found differenl with Io~oislicm~ression analysis. Variable OR-(95%CI) source of infection transfusion 1 others 3.2 (1.2 ; 8.3) Gtnotype
HCV RNA (xl06 gdnomes/ml)
1, In, lb 2a 3a 4 or 5
1 7.5 (2.2 ; 25) 9.7 (3.5 ; 26.9) 2.3 (3.5 ; 26.9)
>3.3 l 0.35-3.3 3.4 (1 ; 11.4) <0.35 25.1 (6.9 ; 90.5) C0n¢losion: In patients with chronic hepatitis C, source of infection, pretreatment serum HCV RNA and HCV genotype are the main independent predictors of sustained response to alpha IFN therapy.
L O N G T E R M F O L L O W - U P OF 364 P A T I E N T S T R E A T E D W I T H I N T E R F E R O N c~-2A F O R C H R O N I C H E P A T I T I S C: R O L E OF G E N O T Y P E A N D V I R E M I A . W G E Cookslev. the International Heoatitis Study G r o u o and L Wolfe, R o c h e M o l e c u l a r Systems, Somerville NJ and Royal Brisbane Hospital, Australia. Little is known on longterm remissions in patients with chronic hepatitis C ( C H C ) t r e a t e d with interferon. A n e c d o t a l e v i d e n c e indicated that some m a y relapse. The aim of the study was to follow 3-monthly, for 3 to 5 years 466 patients previously enrolled in 2 multicenter trials using interferon c~-2A (Roferon®-A; H o f f m a n n - L a Roche, Basel/Switzerland). T r e a t m e n t in the initial study used Placebo, 1,3,4.5,6 or 9 M I U tiw for 12 months. H C V R N A concentrations were measured by a quantitative RT-PCR (Amplicor@H C V Monitor@). Genotyping was by full sequencing 244 nucleotides from the 5'utr. 364 patients (79%) participated in the longterm followup. 58 of these had a sustained response (SR): normal A L T sustained for 3 or 6 m o n t h s after the end of t r e a t m e n t ( E O T ) , 52 (90%) subsequently had a long term response (LTR). In the 306 non r e s p o n d e r s (NR) there w e r e no s p o n t a n e o u s remissions during longlerm follow-up but 3 patients (1%) died from H C C (2) and hepatic failure (1). 317 patients h a d sequential H C V R N A determinations, at E O T 31/35 tested L T R s were negative vs 17/31 tested relapsers w h o were positive. 283 patients were genotyped: 1a/55, 1 b/167, 2a/24, 2b/3, 3a/31,4a/3 reflecting the high prevalence of lb in European patients, especially those o v e r 35. 7% of l b had a I~TR vs 20, 17 and 16% of la, 2a and 3a. Ib had the highest viremia and a higher proportion of cirrhotics. Further analysis showed that lb with LTR had low v i r e m i a similar to other genotypes with L T R indicating ihe poor response in ib to be due to higher viremia rather than genotype per se. In conclusion 1) the great majority of patients with SR also had a b i o c h e m i c a l L T R , 2) L T R are c o n f i r m e d virologically, 3) L T R s have m a r k e d l y lower v i r e m i a than NR, 4) relative resistance of 1b to interferon appears due to higher viremia.
T h i s s t u d y i n v e s t i g a t e d t h e l o n g - t e r m p r o g n o s i s in p a t i e n t s w i t h chronic h e p a t i t i s C t r e a t e d w i t h i n t e r f e r o n ([FN). [ S u b j e c t s a n d M e t h o d s ] We s t u d i e d 139 p a t i e n t s w i t h chronic h e p a t i t i s C who w e r e followed biochemically, virologically, a n d histologically, o v e r 2 y e a r s ( m e a n follow-up: 4.1 y e a r s ) a f t e r I F N t r e a t m e n t . L e v e l s of h e p a t i t i s C v i r u s (HCV) R N A w e r e m e a s u r e d b y b D N A signal a m p l i f i c a t i o n assay. G e n o t y p e s of H C V ( H e p a t o l o g y 19: 1347, 1994) w e r e classified a s g r o u p I o r II. [ R e s u l t s ] I n 52 pat i e n t s (group I:19, II:25, I+II:3, n e g a t i v e 3, N D 2), s e r u m a l a n i n e a m i n o t r a n s f e r a s e (ALT) n o r m a l i z e d a n d t h e r e s p o n s e l a s t e d for m o r e t h a n One y e a r a f t e r t r e a t m e n t cessation. T h i r t y . n i n e of t h e 52 l o n g - t e r m r e s p o n d e r s w e r e n e g a t i v e for H C V R N A ( n e s t e d RTPCR) a f t e r t r e a t m e n t , a n d h a d n o r m a l A L T d u r i n g follow-up. Neit h e r l i v e r cirrhosis (LC) n o r h e p a t o c e l l u l a r c a r c i n o m a (HCC) w e r e d e t e c t e d d u r i n g follow:up. A m o n g r e s p o n d e r s w i t h histological findings of l o b u l a r distortion before t r e a t m e n t , t h e i m p r o v e m e n t of fibrosis w a s o b s e r v e d in s o m e p a t i e n t s , while p o r t a l i n f l a m m a tion r e m a i n e d on 5 - y e a r follow-up in others. A m o n g t h e 1 3 res p o n d e r s w i t h positive H C V R N A (group 1:7, IT :3, I+ 1T:2, negative 1), 5 d e v e l o p e d r e c u r r e n c e of hepatitis. T h e r e w e r e no differences in t h e g e n o t y p e s o r in t h e H C V R N A levels of t h e p a t i e n t s w i t h r e c u r r e n c e . Fifty-two of t h e 87 n o n - r e s p o n d e r s ( group 1:54, ]I: 12, I + ]1:2, n e g a t i v e 5, N D 14) r e c e i v e d a d d i t i o n a l I F N t r e a t m e n t a n d 10 p a t i e n t s h a d n o r m a l i z e d A L T t h e r e a f t e r . Five nonr e s p o n d e r s ( group 1:4, I +l1:1) d e v e l o p e d LC, a n d 5 ( g r o u p 1:4, n e g a t i v e 1) HCC. [ C o n c l u s i o n ] P a t i e n t s w i t h s u s t a i n e d n o r m a l A L T a f t e r I F N t r e a t m e n t s h o w e d no p r o g r e s s i o n of disease. H o w e v e r , s o m e n o n - r e s p o n d e r s s h o w e d p r o g r e s s i o n : 5 pat i e n t s d e v e l o p e d L C a n d 5 HCC.
271
HEPATOLOGYOctober 1995
272
PREDICTIVE FACTORS OF RESPONSE TO INTERFERON-a (IFN) IN CHRONIC HEPATITIS C : WHAT FACTORS FOR WHAT RESPONSE ? JM. Pawlotskv1. F. RoudotThoraval2. A. Bastie~-. C. Pellet1. G. Babanv4. J. Duvalj-. D. Dhumeaux~-. Departments of
1Bacteriology-Virology,2Epidemiology,3Hepatology-Gastroenterology,Htpital Henri Mender, Univeralt6Paris XII, Cr~teil,France ; 4RocheLaboratories,Neuilly/Seine,France. Several parameters have been reported to be associated with the response to IFN in patients with chronic hepatitisC. They include factorsrelated to the infectedindividual(age, sex, body weight), to the features of liver disease (ALT and 7-GT levels, cirrhosis), and to the characteristics of the infective viral strain (HCV genotypa, viral burden, anti-HCV IgM, a parimaetersignificantlyrelated to HCV genotypa),However,the definition of the response to IFN varies from one study to another,in terms of both response criteria and time of evaluation.The objective'of this study was to determine to what kind of response to IFN these predictive parameterswere wary related. Methods. 113 consecutivepatients (75M, 38F, mean age 46 yr) with chronic hepatitisC were treated with 3 MU of IFN alpha-2a (Roferon-A,Roche) for at least 3 months, and until month 6 when they had normal ALT at month 3. Three types of response were taken into consideration : early biochemical response (normal ALT at month 3 : BR3); biochemical response at treatmentwithdrawal(normalALT at month 6 : BR6); sustained virologicalresponse (normalALT and negativePCR at month 12 : VR12). The pretreatmentparametersstudied were: sex, age, body weight, route of transmission, disease duration when available, ALT and 7-GT activities,cirrhosis on liver biopsy, HCV genotypa(Inno-LiPAHCV. Itmogenetics),viral burden (Quantiplex HCV RNA, Chiron), presenceof anti-HCVcore lgM (HCVIgM EIA, Abbott). Results. BR3 (43%)
BR6 (30%)
VR12 (6%)
Univariate Multivariate Univariate Multivariate Univariate Multivariate Sex p<0.00l p
269
AASLD ABSTRACTS
LONG-TERM BIOCHEMICAL, VIROLOGICAL, AND HISTOLOGICAL FOLLOW-UP IN PATIENTS WITH CHRONIC HEPATITIS C TREATED WITH INTERFERON. M Takahashi, G Y a m a d a , H Tsugeno. H Endo. F Kishi. M T a k a t a n i . K M a n a b e . M Mizuno, a n d T Tsuii. 1st Dept. of I n t e r n a l Medicine, O k a y a m a U n i v e r s i t y Medical School, O k a y a m a , J a p a n .
270
PREDICTORS OF RESPONSE TO ALPHA INTERFERON THERAPY I N CHRONIC HEPATITIS C : A MULTIVARIATE ANALYSIS IN 287 PATIENTS. M. Martinet. P. Marcellin. M. Pouteau. C. Caslelnau. N. Bover. I. Randrianatoavina. V. Le Breton. JP. Benhamou. and S. Erlin~er. INSERM U24 et Service d'Htpatologie, Htpital Beaujon, Clichy, France. The objective of this study was to assess, in a large population of patients, the relevance of pretreatment serum HCV RNA level and HCV genotype to predict sustained response to interferon CIFN)therapy. Patients and Methods: we studied 287 patients with chronic hepatitis C included in four consecutive randomized trials of IFN lymphoblastcYfd(96) (WeUferon, Wellcome), IFN alpha 2b (64) (IntronA, Schering Plough) and IFN alpha 2a (127)(Roferon, Roche). Two response groups were defined according to ALT response: 42 patients had a sustained response (SR) defined by normal serum ALT at the end of treatment and during the 6-month post-treatment follow-up ; 245 patients were non responders CNR) defined by increased serum ALT at the end of treatment or during the 6-month post: treatment follow-up. Sex, age, source of infection, duration of the disease, treatment schedule, 343T, serum ferritin, liver histology, pretreatment serum ALT and HCV RNA levels and HCV gcnotype were studied. Serum HCV RNA was quantified with the bDNA signal amplification assay (Quantiplex, CHIRON). Genotyping was perfonaed with the reverse hybridization assay (LiPA) (INN0-LIPA, InGeN). Results: By univariale analysis: age, source of infection, TGT levels, pretreatment serum HCV RNA levels and HCV genotype were significantly different in the two response groups. Characleristics found differenl with Io~oislicm~ression analysis. Variable OR-(95%CI) source of infection transfusion 1 others 3.2 (1.2 ; 8.3) Gtnotype
HCV RNA (xl06 gdnomes/ml)
1, In, lb 2a 3a 4 or 5
1 7.5 (2.2 ; 25) 9.7 (3.5 ; 26.9) 2.3 (3.5 ; 26.9)
>3.3 l 0.35-3.3 3.4 (1 ; 11.4) <0.35 25.1 (6.9 ; 90.5) C0n¢losion: In patients with chronic hepatitis C, source of infection, pretreatment serum HCV RNA and HCV genotype are the main independent predictors of sustained response to alpha IFN therapy.
L O N G T E R M F O L L O W - U P OF 364 P A T I E N T S T R E A T E D W I T H I N T E R F E R O N c~-2A F O R C H R O N I C H E P A T I T I S C: R O L E OF G E N O T Y P E A N D V I R E M I A . W G E Cookslev. the International Heoatitis Study G r o u o and L Wolfe, R o c h e M o l e c u l a r Systems, Somerville NJ and Royal Brisbane Hospital, Australia. Little is known on longterm remissions in patients with chronic hepatitis C ( C H C ) t r e a t e d with interferon. A n e c d o t a l e v i d e n c e indicated that some m a y relapse. The aim of the study was to follow 3-monthly, for 3 to 5 years 466 patients previously enrolled in 2 multicenter trials using interferon c~-2A (Roferon®-A; H o f f m a n n - L a Roche, Basel/Switzerland). T r e a t m e n t in the initial study used Placebo, 1,3,4.5,6 or 9 M I U tiw for 12 months. H C V R N A concentrations were measured by a quantitative RT-PCR (Amplicor@H C V Monitor@). Genotyping was by full sequencing 244 nucleotides from the 5'utr. 364 patients (79%) participated in the longterm followup. 58 of these had a sustained response (SR): normal A L T sustained for 3 or 6 m o n t h s after the end of t r e a t m e n t ( E O T ) , 52 (90%) subsequently had a long term response (LTR). In the 306 non r e s p o n d e r s (NR) there w e r e no s p o n t a n e o u s remissions during longlerm follow-up but 3 patients (1%) died from H C C (2) and hepatic failure (1). 317 patients h a d sequential H C V R N A determinations, at E O T 31/35 tested L T R s were negative vs 17/31 tested relapsers w h o were positive. 283 patients were genotyped: 1a/55, 1 b/167, 2a/24, 2b/3, 3a/31,4a/3 reflecting the high prevalence of lb in European patients, especially those o v e r 35. 7% of l b had a I~TR vs 20, 17 and 16% of la, 2a and 3a. Ib had the highest viremia and a higher proportion of cirrhotics. Further analysis showed that lb with LTR had low v i r e m i a similar to other genotypes with L T R indicating ihe poor response in ib to be due to higher viremia rather than genotype per se. In conclusion 1) the great majority of patients with SR also had a b i o c h e m i c a l L T R , 2) L T R are c o n f i r m e d virologically, 3) L T R s have m a r k e d l y lower v i r e m i a than NR, 4) relative resistance of 1b to interferon appears due to higher viremia.
T h i s s t u d y i n v e s t i g a t e d t h e l o n g - t e r m p r o g n o s i s in p a t i e n t s w i t h chronic h e p a t i t i s C t r e a t e d w i t h i n t e r f e r o n ([FN). [ S u b j e c t s a n d M e t h o d s ] We s t u d i e d 139 p a t i e n t s w i t h chronic h e p a t i t i s C who w e r e followed biochemically, virologically, a n d histologically, o v e r 2 y e a r s ( m e a n follow-up: 4.1 y e a r s ) a f t e r I F N t r e a t m e n t . L e v e l s of h e p a t i t i s C v i r u s (HCV) R N A w e r e m e a s u r e d b y b D N A signal a m p l i f i c a t i o n assay. G e n o t y p e s of H C V ( H e p a t o l o g y 19: 1347, 1994) w e r e classified a s g r o u p I o r II. [ R e s u l t s ] I n 52 pat i e n t s (group I:19, II:25, I+II:3, n e g a t i v e 3, N D 2), s e r u m a l a n i n e a m i n o t r a n s f e r a s e (ALT) n o r m a l i z e d a n d t h e r e s p o n s e l a s t e d for m o r e t h a n One y e a r a f t e r t r e a t m e n t cessation. T h i r t y . n i n e of t h e 52 l o n g - t e r m r e s p o n d e r s w e r e n e g a t i v e for H C V R N A ( n e s t e d RTPCR) a f t e r t r e a t m e n t , a n d h a d n o r m a l A L T d u r i n g follow-up. Neit h e r l i v e r cirrhosis (LC) n o r h e p a t o c e l l u l a r c a r c i n o m a (HCC) w e r e d e t e c t e d d u r i n g follow:up. A m o n g r e s p o n d e r s w i t h histological findings of l o b u l a r distortion before t r e a t m e n t , t h e i m p r o v e m e n t of fibrosis w a s o b s e r v e d in s o m e p a t i e n t s , while p o r t a l i n f l a m m a tion r e m a i n e d on 5 - y e a r follow-up in others. A m o n g t h e 1 3 res p o n d e r s w i t h positive H C V R N A (group 1:7, IT :3, I+ 1T:2, negative 1), 5 d e v e l o p e d r e c u r r e n c e of hepatitis. T h e r e w e r e no differences in t h e g e n o t y p e s o r in t h e H C V R N A levels of t h e p a t i e n t s w i t h r e c u r r e n c e . Fifty-two of t h e 87 n o n - r e s p o n d e r s ( group 1:54, ]I: 12, I + ]1:2, n e g a t i v e 5, N D 14) r e c e i v e d a d d i t i o n a l I F N t r e a t m e n t a n d 10 p a t i e n t s h a d n o r m a l i z e d A L T t h e r e a f t e r . Five nonr e s p o n d e r s ( group 1:4, I +l1:1) d e v e l o p e d LC, a n d 5 ( g r o u p 1:4, n e g a t i v e 1) HCC. [ C o n c l u s i o n ] P a t i e n t s w i t h s u s t a i n e d n o r m a l A L T a f t e r I F N t r e a t m e n t s h o w e d no p r o g r e s s i o n of disease. H o w e v e r , s o m e n o n - r e s p o n d e r s s h o w e d p r o g r e s s i o n : 5 pat i e n t s d e v e l o p e d L C a n d 5 HCC.
271
HEPATOLOGYOctober 1995
272
PREDICTIVE FACTORS OF RESPONSE TO INTERFERON-a (IFN) IN CHRONIC HEPATITIS C : WHAT FACTORS FOR WHAT RESPONSE ? JM. Pawlotskv1. F. RoudotThoraval2. A. Bastie~-. C. Pellet1. G. Babanv4. J. Duvalj-. D. Dhumeaux~-. Departments of
1Bacteriology-Virology,2Epidemiology,3Hepatology-Gastroenterology,Htpital Henri Mender, Univeralt6Paris XII, Cr~teil,France ; 4RocheLaboratories,Neuilly/Seine,France. Several parameters have been reported to be associated with the response to IFN in patients with chronic hepatitisC. They include factorsrelated to the infectedindividual(age, sex, body weight), to the features of liver disease (ALT and 7-GT levels, cirrhosis), and to the characteristics of the infective viral strain (HCV genotypa, viral burden, anti-HCV IgM, a parimaetersignificantlyrelated to HCV genotypa),However,the definition of the response to IFN varies from one study to another,in terms of both response criteria and time of evaluation.The objective'of this study was to determine to what kind of response to IFN these predictive parameterswere wary related. Methods. 113 consecutivepatients (75M, 38F, mean age 46 yr) with chronic hepatitisC were treated with 3 MU of IFN alpha-2a (Roferon-A,Roche) for at least 3 months, and until month 6 when they had normal ALT at month 3. Three types of response were taken into consideration : early biochemical response (normal ALT at month 3 : BR3); biochemical response at treatmentwithdrawal(normalALT at month 6 : BR6); sustained virologicalresponse (normalALT and negativePCR at month 12 : VR12). The pretreatmentparametersstudied were: sex, age, body weight, route of transmission, disease duration when available, ALT and 7-GT activities,cirrhosis on liver biopsy, HCV genotypa(Inno-LiPAHCV. Itmogenetics),viral burden (Quantiplex HCV RNA, Chiron), presenceof anti-HCVcore lgM (HCVIgM EIA, Abbott). Results. BR3 (43%)
BR6 (30%)
VR12 (6%)
Univariate Multivariate Univariate Multivariate Univariate Multivariate Sex p<0.00l p