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HCV-RNA titers in the early course after orthotopic liver transplantation in patients with chronic hepatitis C
134A
109
AASLD
HCV GENOTYPES AND QUANTITATION OF HCV RNA : RELATIONSHIP WITH HCV RECURRENCE AFTER LIVER TRANSPLANTATION G.P. Paaeaux. J. Ducos. V. Coste. A.M. Mondain. J.M. Fabre. J. Domnrque, D. Larre~.'A. Serre. H. Michel. Departments of Hepatogastroenterology. Immunology; Surgery, HOpital Saint-Eloi. 34295 Montpellier. France.
ABSTRACTS
ii0
Recurrence of hepatitis C is a well-known event following liver transplantation (L'I'). It has been suggested that HCV ganotype l b is associated with more aggressive recurrent liver disease than other genotypes. On the other hand. there are contradictory results concerning the relation between HCV RNA levels following LT and recurrent histological hepatitis. Aim : to examine the relationship between genotypa, quantitation of HCV viremia and recurrent hepatitis C after LT. Methods : twenty-two patients were transplanted for HCV cirrhosis. Mean follow-up was 39 months (range 10 - 74). HCV RNA quantity was determined in serums samples by nested-PCR assay. HCV genotype (Simmonds classification) was determined with line probe assay (Inno-LIPA), Liver biopsies were performed for abnormal liver tests and yearly thereafter. They we.re compiled as normal, chronic obular hepatitis (CLH), chronic active hepatitis (CAH). cirrhosis. Results : the relationship between genotype and recurrent hepatitis is illustrated in the table, Ganotypa 1a (n = 1) I b (n = 12) 2a in = 6) 3 (n = 3) Histology Normal 5 1 2 CLH 3 5 1 CAH 1 3 Cirrhosis 1 HCV genotype l b was the predominant type (12 of 22 pts.). Recurrent hepatitis was common, whatever the genotype, but only patients with genotype l b and l a had severe histological lesions : CAH in 3 of the 12 ;)atients 1 b and in the patient 1 a. cirrhosis in 1 patient I b. HCV RNA quantity was very high in patients t a and 1 b (mean > 1.000,000 copies/ml) and weak in patients 2a and 3 (mean < 100.000 copies/ml). HCV RNA quantity was very high in patients without recurrent hepatitis and high in patients with recurrent hepatitis (mean > 100.000 and < 1.000.000 copies/ml). Conclusion : recurrent HCV hepatitis after LT was frequent whatever the genotype but more severe in patients with genntype lb. Though levels of viral replication were higher in these patients 1 b than in patients with other genotype, there was no relationship between HCV RNA quantity and recurrent hepatitis.
111
HCV-RNA titers in the early course after orthotopic liver transplantation in patients with chronic hepatitis C. T Fukumoto,2 T B e r gl. U Naumann.2 V KOni~.1 WO Bechstein.2 P Lemmens,2 H K e c k2, P Neuhaus 2. U Hoof t. Virdaow-Hospital, Dept. of Internal Medicine t, Dept. of Surgery, 2I2Iumboldt University, Berlin, Germany. Graft reinfection aiter liver traasplantation (OLT) occurs in nearly all patients with chronic hepatitis C. However, the time of reinfection and the onset of HCV replication in the graft is still unknown. We quantitatively measured serum HCV RNA in the early course after OLT. Patients: 6 male patients were investigated (mean age 43, 27-58). All patients were anti-HCV and HCV-RNA (PCR) positive and received. OLT due to dew,ompensated liver cirrhosis. Immanosuppmssion consisted of Azathioprine, ATG, steroids and FK506 or cyclosporin A. Sara were collected one day before OLT and daily from postoperative day 1 (POD 1) to POD 30 andwere stored at -80°C until used. Methods: HCV-RNA titers were measured using quantitative PCR (HCVMonitor, Roche Diagnostic Systems). Results: M e ~ preoperative HCV-RNA levels (1.65i-0.6 x 10s copies/ml + stand, error) were significantly higher, than those of POD 1 to 3 (p<0.05) (Table). Up to POD 6; HCV-RNA concentrations remained at low levels. On POD 7, HCV-RNA levels increased and exceeded preoperative levels. At POD 10, HCV-RNA levels were significantly higher than that of POD 6 (p<0.05) and gradually increased until POD 30. Mean HCV-RNA titers in 6 patients with chronic hepatitis C after OLT POD # 1 3 6 7 10 15 30 HCV 0.16 0.36 0.48 1.37 3.78 3.57 10.08 level* i-0.10 _+0.06 :L-0.49 I0.96 +1.01 +_2.03 +3.64 *HCV-RNAlevelis givenas meancopies/m1x 105+ standarderror. ~postoperativ¢day Conclusion: The low HCV-RNA titers at the first day after OLT compared to the preoperative levels might be explained by a short life time of HCV in serum. The liver therefore seems to be the main site of replication. The increase in HCV-RNA titers one week after OLT indicates reinfection of the gra~ within the first week.
HEPATOLOGY O c t o b e r 1995
HEPATITIS-C-VIRAL GENOTYPES: ASSOCIATION WITH THE POSTOPERATIVE COURSE AFTER LIVER TRANSPLANTATION J.C. Arnold. ll.M. Mtiller. T. Goeser, WJ. Hofmann~ U. T6x, G. 0tto~ W. Stremmel, L. Theilmann. Dept. of Medicine, Surgery and Pathology; University of Heidelberg, FRG. Recurrent hepatitis-C-virus (HCV) infection occurrs frequently after liver transplantation (OLT) for HCV induced hepatic failure. HCV genotypes appear tO differ in their clinical effects, although these differences are controversial ar/d not yet fully understood. We evaluated the postoperative course with regard to different HCV genotyps. Methods: 19 liver allograft recipients (pat.), surviving > 6 months were followed 9-81 months postoperatively. The diagnosis of HCV infection was based on clinical, serological and histological findings and detectable HCV- RNA in serum. The genotypes were evaluated by a "reverse line probe" assay (n=18 pat.). Furthermore sequence analysis of amplified PCR products werepefformed before and after OLT (n=3 pat.). Results: HCV-RNA was detectable after OLT in serum of 18/19 pat. (95%). 9/18 pat. were clinically asymptomatic. 9/18 pat. had an acute hepatitis (1127 weeks post OLT), of those 8 pat. developed a chronic hepatitis "with progression to cirrhosis in 2 pat., 6/8 pat. had mild clinical courses, the remainder a resolutive acute hepatitis (genotype lb). None of the patients developed a chronic allograft rejection. Genotyp lb was predominant 00/18 pat.).Genotypes of HCV and sequence analysis of amplified PCR products were identical before and after OLT in all patients studied. The postoperative course with regard tothe HCV ~enotyp is listed in the table. genotyp: clinical course: type la type lb type 2 type 3 asymptomatic: chronic hepatits, mild course: chronic hepatits, cirrhosis:
n=3
n=7 n=2 n=l
n= 1
n= 1 n=l
n=l
Conclusion: Identical HCV genotypes and sequence analysis of amplified PCR products before and after OLT indicate a recurrent rather than a postoperatively aquired HCV infection of the allograft. Different HCV genotypes were not associated with specific clinical courses of recurrent HCV infection after OLT. In contrast to other studies HCV genotyp lb was not consistent with more aggressive liver disease after OLT than other genotypes.
112
LONG TERM OUTCOME OF HEPATITIS C VIRUS INFECTION AFTER LIVER TRANSPLANTATION. K.H.W.B6ker. M.J.Bahr. G:Dallev. H.Maschek: H.L.TiUmann. K. Oldhaver. Ch.Trautwein. R.Pichhhavr and M.P. Manns. Dept. of Gastroenterology, Dept. of Transplant-surgei'y and Institute of Pathology, Medizinische Hochschule Hannover, D-30623 Hannover, Germany We analyzed the long time survival and clinical course of 71 patients with HCV-RNA positive hepatitis C virus (HCV) infection after liver transplantation. Patients had either been transplanted for HCV related liver disease and had suffered reinfection, or had aquired de novo HCV infection at transplantation. Frozen sera were retrospectively analyzed to identify infected patients, who were then followed for up to 11 years. Cumulative survival for patients with HCV infection'of the graft at 2, 5 and 10 years (67%; 62%; and 62% rasp.) was not significantlydifferent from that in patients with other nonmalignant transplant indications (62%, 57%, and 52% resp.)who had no HCV infection. The main factor determining long term survival was hepatocellular carcinoma (HCC) at transplantation. 5 year survival for HCV patients with or without HCC was 35% vs. 73% rasp. Deaths in the first year after transplantation were mostly due to severe bacterial infection, while deaths after more than l year were exclusively due to recurrence of HCC. Biochemical and histological evidence of hepatitis was found in the majority of the patients. Only 15% had normal ALAT values throughout and only 12% of biopsies raken did not show signs of chronic inflammation. The clinical course was mild. Only 22% of patients complained of symptoms, with hepatitis C baaing the cause in 82% of these. Most symptomatic patients had aditional health problems however, hepatitis C alone caused symptoms in only 6% of infected patients. 27% of all hospital admissions were.caused by chronic hepatitis C, 22% by acute or chronic rejection, 19% by bile duct problems, and 32% by miscellaneousother Causes unrelated to hepatitis C. Histology showed inflammatory changes in 88% of all biopsies and signs of fibroproliferation in 24%. There Was a tendency towards slow progression of fibrosis with time after transplantation. Porto-portal bridging was observed in 10%, 1 patient developed cirrhosis 2 years after transplantation We conclude that mild chronic hepatitis develops in the majority of patients with HCV infection after liver transplantation. "Healthy carrier states" withont biochemical or histological abnormalities are observed in ca.15 %, laboratory abnormalities without symptoms are seen in 60%, and mptomatic disease develops in a quarter of patients. The prognosis for the st ten years is quite good and the course closely resembles that seen in HCV infection without transplantation.
~y
109
AASLD
HCV GENOTYPES AND QUANTITATION OF HCV RNA : RELATIONSHIP WITH HCV RECURRENCE AFTER LIVER TRANSPLANTATION G.P. Paaeaux. J. Ducos. V. Coste. A.M. Mondain. J.M. Fabre. J. Domnrque, D. Larre~.'A. Serre. H. Michel. Departments of Hepatogastroenterology. Immunology; Surgery, HOpital Saint-Eloi. 34295 Montpellier. France.
ABSTRACTS
ii0
Recurrence of hepatitis C is a well-known event following liver transplantation (L'I'). It has been suggested that HCV ganotype l b is associated with more aggressive recurrent liver disease than other genotypes. On the other hand. there are contradictory results concerning the relation between HCV RNA levels following LT and recurrent histological hepatitis. Aim : to examine the relationship between genotypa, quantitation of HCV viremia and recurrent hepatitis C after LT. Methods : twenty-two patients were transplanted for HCV cirrhosis. Mean follow-up was 39 months (range 10 - 74). HCV RNA quantity was determined in serums samples by nested-PCR assay. HCV genotype (Simmonds classification) was determined with line probe assay (Inno-LIPA), Liver biopsies were performed for abnormal liver tests and yearly thereafter. They we.re compiled as normal, chronic obular hepatitis (CLH), chronic active hepatitis (CAH). cirrhosis. Results : the relationship between genotype and recurrent hepatitis is illustrated in the table, Ganotypa 1a (n = 1) I b (n = 12) 2a in = 6) 3 (n = 3) Histology Normal 5 1 2 CLH 3 5 1 CAH 1 3 Cirrhosis 1 HCV genotype l b was the predominant type (12 of 22 pts.). Recurrent hepatitis was common, whatever the genotype, but only patients with genotype l b and l a had severe histological lesions : CAH in 3 of the 12 ;)atients 1 b and in the patient 1 a. cirrhosis in 1 patient I b. HCV RNA quantity was very high in patients t a and 1 b (mean > 1.000,000 copies/ml) and weak in patients 2a and 3 (mean < 100.000 copies/ml). HCV RNA quantity was very high in patients without recurrent hepatitis and high in patients with recurrent hepatitis (mean > 100.000 and < 1.000.000 copies/ml). Conclusion : recurrent HCV hepatitis after LT was frequent whatever the genotype but more severe in patients with genntype lb. Though levels of viral replication were higher in these patients 1 b than in patients with other genotype, there was no relationship between HCV RNA quantity and recurrent hepatitis.
111
HCV-RNA titers in the early course after orthotopic liver transplantation in patients with chronic hepatitis C. T Fukumoto,2 T B e r gl. U Naumann.2 V KOni~.1 WO Bechstein.2 P Lemmens,2 H K e c k2, P Neuhaus 2. U Hoof t. Virdaow-Hospital, Dept. of Internal Medicine t, Dept. of Surgery, 2I2Iumboldt University, Berlin, Germany. Graft reinfection aiter liver traasplantation (OLT) occurs in nearly all patients with chronic hepatitis C. However, the time of reinfection and the onset of HCV replication in the graft is still unknown. We quantitatively measured serum HCV RNA in the early course after OLT. Patients: 6 male patients were investigated (mean age 43, 27-58). All patients were anti-HCV and HCV-RNA (PCR) positive and received. OLT due to dew,ompensated liver cirrhosis. Immanosuppmssion consisted of Azathioprine, ATG, steroids and FK506 or cyclosporin A. Sara were collected one day before OLT and daily from postoperative day 1 (POD 1) to POD 30 andwere stored at -80°C until used. Methods: HCV-RNA titers were measured using quantitative PCR (HCVMonitor, Roche Diagnostic Systems). Results: M e ~ preoperative HCV-RNA levels (1.65i-0.6 x 10s copies/ml + stand, error) were significantly higher, than those of POD 1 to 3 (p<0.05) (Table). Up to POD 6; HCV-RNA concentrations remained at low levels. On POD 7, HCV-RNA levels increased and exceeded preoperative levels. At POD 10, HCV-RNA levels were significantly higher than that of POD 6 (p<0.05) and gradually increased until POD 30. Mean HCV-RNA titers in 6 patients with chronic hepatitis C after OLT POD # 1 3 6 7 10 15 30 HCV 0.16 0.36 0.48 1.37 3.78 3.57 10.08 level* i-0.10 _+0.06 :L-0.49 I0.96 +1.01 +_2.03 +3.64 *HCV-RNAlevelis givenas meancopies/m1x 105+ standarderror. ~postoperativ¢day Conclusion: The low HCV-RNA titers at the first day after OLT compared to the preoperative levels might be explained by a short life time of HCV in serum. The liver therefore seems to be the main site of replication. The increase in HCV-RNA titers one week after OLT indicates reinfection of the gra~ within the first week.
HEPATOLOGY O c t o b e r 1995
HEPATITIS-C-VIRAL GENOTYPES: ASSOCIATION WITH THE POSTOPERATIVE COURSE AFTER LIVER TRANSPLANTATION J.C. Arnold. ll.M. Mtiller. T. Goeser, WJ. Hofmann~ U. T6x, G. 0tto~ W. Stremmel, L. Theilmann. Dept. of Medicine, Surgery and Pathology; University of Heidelberg, FRG. Recurrent hepatitis-C-virus (HCV) infection occurrs frequently after liver transplantation (OLT) for HCV induced hepatic failure. HCV genotypes appear tO differ in their clinical effects, although these differences are controversial ar/d not yet fully understood. We evaluated the postoperative course with regard to different HCV genotyps. Methods: 19 liver allograft recipients (pat.), surviving > 6 months were followed 9-81 months postoperatively. The diagnosis of HCV infection was based on clinical, serological and histological findings and detectable HCV- RNA in serum. The genotypes were evaluated by a "reverse line probe" assay (n=18 pat.). Furthermore sequence analysis of amplified PCR products werepefformed before and after OLT (n=3 pat.). Results: HCV-RNA was detectable after OLT in serum of 18/19 pat. (95%). 9/18 pat. were clinically asymptomatic. 9/18 pat. had an acute hepatitis (1127 weeks post OLT), of those 8 pat. developed a chronic hepatitis "with progression to cirrhosis in 2 pat., 6/8 pat. had mild clinical courses, the remainder a resolutive acute hepatitis (genotype lb). None of the patients developed a chronic allograft rejection. Genotyp lb was predominant 00/18 pat.).Genotypes of HCV and sequence analysis of amplified PCR products were identical before and after OLT in all patients studied. The postoperative course with regard tothe HCV ~enotyp is listed in the table. genotyp: clinical course: type la type lb type 2 type 3 asymptomatic: chronic hepatits, mild course: chronic hepatits, cirrhosis:
n=3
n=7 n=2 n=l
n= 1
n= 1 n=l
n=l
Conclusion: Identical HCV genotypes and sequence analysis of amplified PCR products before and after OLT indicate a recurrent rather than a postoperatively aquired HCV infection of the allograft. Different HCV genotypes were not associated with specific clinical courses of recurrent HCV infection after OLT. In contrast to other studies HCV genotyp lb was not consistent with more aggressive liver disease after OLT than other genotypes.
112
LONG TERM OUTCOME OF HEPATITIS C VIRUS INFECTION AFTER LIVER TRANSPLANTATION. K.H.W.B6ker. M.J.Bahr. G:Dallev. H.Maschek: H.L.TiUmann. K. Oldhaver. Ch.Trautwein. R.Pichhhavr and M.P. Manns. Dept. of Gastroenterology, Dept. of Transplant-surgei'y and Institute of Pathology, Medizinische Hochschule Hannover, D-30623 Hannover, Germany We analyzed the long time survival and clinical course of 71 patients with HCV-RNA positive hepatitis C virus (HCV) infection after liver transplantation. Patients had either been transplanted for HCV related liver disease and had suffered reinfection, or had aquired de novo HCV infection at transplantation. Frozen sera were retrospectively analyzed to identify infected patients, who were then followed for up to 11 years. Cumulative survival for patients with HCV infection'of the graft at 2, 5 and 10 years (67%; 62%; and 62% rasp.) was not significantlydifferent from that in patients with other nonmalignant transplant indications (62%, 57%, and 52% resp.)who had no HCV infection. The main factor determining long term survival was hepatocellular carcinoma (HCC) at transplantation. 5 year survival for HCV patients with or without HCC was 35% vs. 73% rasp. Deaths in the first year after transplantation were mostly due to severe bacterial infection, while deaths after more than l year were exclusively due to recurrence of HCC. Biochemical and histological evidence of hepatitis was found in the majority of the patients. Only 15% had normal ALAT values throughout and only 12% of biopsies raken did not show signs of chronic inflammation. The clinical course was mild. Only 22% of patients complained of symptoms, with hepatitis C baaing the cause in 82% of these. Most symptomatic patients had aditional health problems however, hepatitis C alone caused symptoms in only 6% of infected patients. 27% of all hospital admissions were.caused by chronic hepatitis C, 22% by acute or chronic rejection, 19% by bile duct problems, and 32% by miscellaneousother Causes unrelated to hepatitis C. Histology showed inflammatory changes in 88% of all biopsies and signs of fibroproliferation in 24%. There Was a tendency towards slow progression of fibrosis with time after transplantation. Porto-portal bridging was observed in 10%, 1 patient developed cirrhosis 2 years after transplantation We conclude that mild chronic hepatitis develops in the majority of patients with HCV infection after liver transplantation. "Healthy carrier states" withont biochemical or histological abnormalities are observed in ca.15 %, laboratory abnormalities without symptoms are seen in 60%, and mptomatic disease develops in a quarter of patients. The prognosis for the st ten years is quite good and the course closely resembles that seen in HCV infection without transplantation.
~y