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Decreased functional liver cell mass in serum-HCV-RNA positive compared to serum-HCV-RNA negative patients with chronic hepatitis C (CAH-C)
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H E P A T I T I S C V I R U S T Y P I N G IN H A E M O P H I L I A P A T I E N T S , PRE- AND POST-TREATMENT WITH ALPHA-INTERFERON.
DECREASED FUNCTIONAL LIVER CELL MASS IN SERUM-HCVRNA POSITIVE COMPARED TO SERUM-HCV-RNA NEGATIVE PATIENTS WITH CHRONIC HEPATITIS C (CAH-C)
HI.. Devereux, PT Telfer~ GM Dusheiko, CA Lee. Haemophilia Centre and Dept of Medicine, Royal Free Hospital School of Medicine, London NW3 2QG. Transmission of the hepatitis C virus (HCV) has been a major clinical problem associated with the use of blood products. The 5'NCR of the HCV genome is relatively constant and RFLP analysis within this region is used to distinguish the three main types (1, 2 and 3) prevalent in the U.K. population. In this study we determined the HCV type of 24 anti-HCV positive haemophilic patients undergoing treatment with u-interferon. Serum samples were tested six months pre-treatment, week 0 and during the six months post-treatment. RT-PCR was performed using primers specific to the 5'NCR. The PCR product was digested with ScrFI, and also with a combination of H a e I I I and RsaI. The fragments were separated and visualised on a 12% polyacrylamide gel. Week 0 results showed that 17/24 patients (71%) were type I, 1/24 (4%) type 2, 5/24 (21%) type 2 and 1/24 (4%) types 1+2. Post-treatment results showed that 15/24 patients (62%) were type 1, 5/24 (21%) type 3 and 4/24 (17%) types 1+3. Pre-treatment 3/22 patients {14%) showed a change in HCV type and post-treatment 9/24 patients (38%) showed a change. These patients have received many infusions of unsterilised clotting factor concentrates so a higher prevalence of mixed infections might have been expected. This method may be insensitive to mixed infections if one type is present at a much higher concentration. 4/5 patients (80%) who showed a complete clinical response (normalisation of ALT levels) had either types 2 or 3. This supports current evidence that type i is least likely to respond to u-interferon. Treatment with u-interferon seems to be associated with a higher rate of change of predominant HCV types. The clinical significance of this change is not clear as yet.
A. D~llenbach. E. L. Renner. M. Solioz. L. Bianchi. M. Schmid & J. Reichen. Deptartment of Clinical Pharmacology, University of Berne, Switzedand While a large number, but not all, patients with CAH-C exhibit HCV viramia, its effects on the course of the disease are unknown. AIM: To compare liver function in patients with serum-HCV-RNA positive (RNA+) and serum-HCV-RNA negative (RNA-) CAH-C. METHODS: 37 RNA- patients (10F, 27M; aged 42+SD14yr) and 45 RNA+ patients (10F, 35M; aged 45+13yr) with CAH-C evaluated prior to interferon treatment were retrospectively analyzed. Diagnosts was based on positive serum-HCV-antibodies, the exclusion of other liver diseases by appropriate lab tests and a compatible histology. SerumHCV-RNA was determined by nested PCR using primers to the 5' non-coding region. At biopsy, routine liver function tests (RLFTs) were pedormed and the functional liver cell mass quantitated by the galactose elimination capacity (GEC). Biopsy findings were graded by scoring portal inflammation, p i e c e meal necrosis, Iobular inflammation and fibrosis. ~ None of the scored histologic characteristics, nor total biopsy scores differed in RNA+ and RNApatients, and a similar proportion of both groups, i.e. 27/45 and 23/37, had cirrhosis. While RLFTs including ALAT, ASAT, serum bilirubin, prothrombine time and serum albumin were not significanty different, GEC was lower in RNA+ than in RNA- patients (5.2±1.4 vs. 5.9±1.5 mg/min" kg; p<0.05). A trend to lower GEC in RNA+ compared to RNA- patients remained present when non-cirrhotics (5.6+1.2 vs. 6.3±1.3 mg/min'kg) and cirrhotics (4.9¢1.4 vs. 5.6+1.6 mg/min'kg) were analysed separately; due to small sample size, this failed, however, to reach statistical significance. RNA- cirrhotics were -16yr, RNA+ cirrhotics ~8yr older than the corresponding nonc i r r h o t i c s (48±12 vs. 32.+13 and 48±13 vs. 4 0 + 1 2 y r ) . CONCLUSION: HCV viremia is associated with a decreased functional liver cell mass. Inasmuch as GEC is of prognostic value in CAH (Schweiz Mad Wschr 121:970, 1991), this may imply a worse prognosis for RNA+ than for RNA- CAH-C and is compatible with the apparently faster cirrhogenesis in the former.
HCV GENOTYPES AND LONG-TERM RESPONSE TO INTERFERON TREATMENT IN CI~,ONIC HEPATITIS C.
LONG-TERM OUTCOME AFTER HBe-SEROCONVERSION: INTERFERON ENHANCES EARLY HBs-SEROCONVERSION.
G.Diodati, P.Bonetti, F.Tremolada, C.Casarin, *A.Ta)zlzer, *M.L.Ribero, *G.Realdi end ARuol. Istitute of Clinical Medicine, Padova {Italy), *Isttitute of Virology, Milan (Italy) end Istitute of General Medicine, Sassari (Italy). In order to evaluate the response to Interferon ([FN) in cin-onic hepatitis C (either sporadic or post-trensfusion) in relation to different genot.vpes of hepatitis C virus (HCV), we studied seriated serum samples from 35 patients enrolled in a randomized controlled trial of rlFN (one year of treatment followed by six months without therapy). All serum samples ~ere tested lbr HCV-RNA by nested PCR, using primers from 5'UTR end the positive sera were then studied for different genotypes of HCV, according to Simmonds' classification: major HCV genot.xl~es were identified by nested type-specific primers from core region. Five patients were type la, 12 type lb and 18 t',l~e 2. None of the patients of type I (either la or lb) were HCV-RNA negative at the end of follow-up period whereas I I of 18 patients oft)pc 2 (61.1%) showed HCV-RNA clearance, with a statistically sgnificant difference (p<0.01). In relation to the response to IFN, we observed that all the patients with long-term response (LTR) were ot type 2: on the contrast, the patients with transient (TR) or no (NR) response were either of type I or of type 2. During a period of 3 .','ears sfter tbllow-up period, further 5 patients of type 2 lost viremia, independently of the response to therapy:
IA Eland I , RA de Man I . RA Heiitink 2, J Boot I, W H o p 3, S W Schalm j . Dept. of Internal Medicine II t, Virology:, Biostatistics3, Erasmus University Rotterdam, The Netherlands, To evaluate the long-term outcome after spontaneous or interferoninduced HBe-seroconversion, 102 patients with chronic hepatitis B and HBe--sernconversion (loss of HBeAg) between 1979-1992 were followed regularly (mean; 3.75 yr). Among them, 33 had HBe-seroconversion during or within 3 months of interferon therapy and 69 lost HBe spontaneously. IFN-treated patients (88% men, mean age 45 yr) had a shorter follow-up (mean, 2.5 yr) than spontaneous HBe-seroconverters (83% men, mean age 45 yr, mean follow-up 4.25 yr). HBe-reactivation was defined by one or more positive HBeAg tests (Abbott, KIA), HBs-seroconversion by loss of HBsAg (Abbott, ILIA). Cumulative percentage of HBe-reaetivation and HBs-seroconversion were: Follow-up (years) 0.5 I 2 3 HBe-reactivation ira-treated 6% 15% 18% 18% spontaneous 9% 19% 25% 26% HBs-seroconversion ifn-treated 18% 24% 27% 30% spontaneous 6% 7 % 12% 13% Conclusions: Interferon therapy tripled the HBs seroconverston m the first year after HBe seroconversion with thereafter return toe spontaneous rate of 2-4%/yr. Early HBe-reactivation was 15-20% and independent of IFN therapy; late HBe reactivation was 1-4 %/yr. Long-term follow-up did not show loss of early effects of IFN therapy.
HCV gen. la(5cases) lb(12cases) 2 ( 18 cases)
HCV-RNA LTR + 0 0 0 0 0 6
(at the end of follow-up) TR NR + + 2 0 3 0 7 0 5 0 4 5 3 0
Among 19 HCV-RNA positive patients after the first cycle of IFN, 7 (2 of t',qge lb and 5 of type 2) were re-treated for further 6 menth and only one of them became negative (type l b). In conclusion, in our experience genotype 2 of HCV is more often related to a positive virological and biochemical response to IFN therapy, so that we may suggest that submitting patients to HCV genotyping may be useful to predict the response to treatment itself.
Papers read by title
H E P A T I T I S C V I R U S T Y P I N G IN H A E M O P H I L I A P A T I E N T S , PRE- AND POST-TREATMENT WITH ALPHA-INTERFERON.
DECREASED FUNCTIONAL LIVER CELL MASS IN SERUM-HCVRNA POSITIVE COMPARED TO SERUM-HCV-RNA NEGATIVE PATIENTS WITH CHRONIC HEPATITIS C (CAH-C)
HI.. Devereux, PT Telfer~ GM Dusheiko, CA Lee. Haemophilia Centre and Dept of Medicine, Royal Free Hospital School of Medicine, London NW3 2QG. Transmission of the hepatitis C virus (HCV) has been a major clinical problem associated with the use of blood products. The 5'NCR of the HCV genome is relatively constant and RFLP analysis within this region is used to distinguish the three main types (1, 2 and 3) prevalent in the U.K. population. In this study we determined the HCV type of 24 anti-HCV positive haemophilic patients undergoing treatment with u-interferon. Serum samples were tested six months pre-treatment, week 0 and during the six months post-treatment. RT-PCR was performed using primers specific to the 5'NCR. The PCR product was digested with ScrFI, and also with a combination of H a e I I I and RsaI. The fragments were separated and visualised on a 12% polyacrylamide gel. Week 0 results showed that 17/24 patients (71%) were type I, 1/24 (4%) type 2, 5/24 (21%) type 2 and 1/24 (4%) types 1+2. Post-treatment results showed that 15/24 patients (62%) were type 1, 5/24 (21%) type 3 and 4/24 (17%) types 1+3. Pre-treatment 3/22 patients {14%) showed a change in HCV type and post-treatment 9/24 patients (38%) showed a change. These patients have received many infusions of unsterilised clotting factor concentrates so a higher prevalence of mixed infections might have been expected. This method may be insensitive to mixed infections if one type is present at a much higher concentration. 4/5 patients (80%) who showed a complete clinical response (normalisation of ALT levels) had either types 2 or 3. This supports current evidence that type i is least likely to respond to u-interferon. Treatment with u-interferon seems to be associated with a higher rate of change of predominant HCV types. The clinical significance of this change is not clear as yet.
A. D~llenbach. E. L. Renner. M. Solioz. L. Bianchi. M. Schmid & J. Reichen. Deptartment of Clinical Pharmacology, University of Berne, Switzedand While a large number, but not all, patients with CAH-C exhibit HCV viramia, its effects on the course of the disease are unknown. AIM: To compare liver function in patients with serum-HCV-RNA positive (RNA+) and serum-HCV-RNA negative (RNA-) CAH-C. METHODS: 37 RNA- patients (10F, 27M; aged 42+SD14yr) and 45 RNA+ patients (10F, 35M; aged 45+13yr) with CAH-C evaluated prior to interferon treatment were retrospectively analyzed. Diagnosts was based on positive serum-HCV-antibodies, the exclusion of other liver diseases by appropriate lab tests and a compatible histology. SerumHCV-RNA was determined by nested PCR using primers to the 5' non-coding region. At biopsy, routine liver function tests (RLFTs) were pedormed and the functional liver cell mass quantitated by the galactose elimination capacity (GEC). Biopsy findings were graded by scoring portal inflammation, p i e c e meal necrosis, Iobular inflammation and fibrosis. ~ None of the scored histologic characteristics, nor total biopsy scores differed in RNA+ and RNApatients, and a similar proportion of both groups, i.e. 27/45 and 23/37, had cirrhosis. While RLFTs including ALAT, ASAT, serum bilirubin, prothrombine time and serum albumin were not significanty different, GEC was lower in RNA+ than in RNA- patients (5.2±1.4 vs. 5.9±1.5 mg/min" kg; p<0.05). A trend to lower GEC in RNA+ compared to RNA- patients remained present when non-cirrhotics (5.6+1.2 vs. 6.3±1.3 mg/min'kg) and cirrhotics (4.9¢1.4 vs. 5.6+1.6 mg/min'kg) were analysed separately; due to small sample size, this failed, however, to reach statistical significance. RNA- cirrhotics were -16yr, RNA+ cirrhotics ~8yr older than the corresponding nonc i r r h o t i c s (48±12 vs. 32.+13 and 48±13 vs. 4 0 + 1 2 y r ) . CONCLUSION: HCV viremia is associated with a decreased functional liver cell mass. Inasmuch as GEC is of prognostic value in CAH (Schweiz Mad Wschr 121:970, 1991), this may imply a worse prognosis for RNA+ than for RNA- CAH-C and is compatible with the apparently faster cirrhogenesis in the former.
HCV GENOTYPES AND LONG-TERM RESPONSE TO INTERFERON TREATMENT IN CI~,ONIC HEPATITIS C.
LONG-TERM OUTCOME AFTER HBe-SEROCONVERSION: INTERFERON ENHANCES EARLY HBs-SEROCONVERSION.
G.Diodati, P.Bonetti, F.Tremolada, C.Casarin, *A.Ta)zlzer, *M.L.Ribero, *G.Realdi end ARuol. Istitute of Clinical Medicine, Padova {Italy), *Isttitute of Virology, Milan (Italy) end Istitute of General Medicine, Sassari (Italy). In order to evaluate the response to Interferon ([FN) in cin-onic hepatitis C (either sporadic or post-trensfusion) in relation to different genot.vpes of hepatitis C virus (HCV), we studied seriated serum samples from 35 patients enrolled in a randomized controlled trial of rlFN (one year of treatment followed by six months without therapy). All serum samples ~ere tested lbr HCV-RNA by nested PCR, using primers from 5'UTR end the positive sera were then studied for different genotypes of HCV, according to Simmonds' classification: major HCV genot.xl~es were identified by nested type-specific primers from core region. Five patients were type la, 12 type lb and 18 t',l~e 2. None of the patients of type I (either la or lb) were HCV-RNA negative at the end of follow-up period whereas I I of 18 patients oft)pc 2 (61.1%) showed HCV-RNA clearance, with a statistically sgnificant difference (p<0.01). In relation to the response to IFN, we observed that all the patients with long-term response (LTR) were ot type 2: on the contrast, the patients with transient (TR) or no (NR) response were either of type I or of type 2. During a period of 3 .','ears sfter tbllow-up period, further 5 patients of type 2 lost viremia, independently of the response to therapy:
IA Eland I , RA de Man I . RA Heiitink 2, J Boot I, W H o p 3, S W Schalm j . Dept. of Internal Medicine II t, Virology:, Biostatistics3, Erasmus University Rotterdam, The Netherlands, To evaluate the long-term outcome after spontaneous or interferoninduced HBe-seroconversion, 102 patients with chronic hepatitis B and HBe--sernconversion (loss of HBeAg) between 1979-1992 were followed regularly (mean; 3.75 yr). Among them, 33 had HBe-seroconversion during or within 3 months of interferon therapy and 69 lost HBe spontaneously. IFN-treated patients (88% men, mean age 45 yr) had a shorter follow-up (mean, 2.5 yr) than spontaneous HBe-seroconverters (83% men, mean age 45 yr, mean follow-up 4.25 yr). HBe-reactivation was defined by one or more positive HBeAg tests (Abbott, KIA), HBs-seroconversion by loss of HBsAg (Abbott, ILIA). Cumulative percentage of HBe-reaetivation and HBs-seroconversion were: Follow-up (years) 0.5 I 2 3 HBe-reactivation ira-treated 6% 15% 18% 18% spontaneous 9% 19% 25% 26% HBs-seroconversion ifn-treated 18% 24% 27% 30% spontaneous 6% 7 % 12% 13% Conclusions: Interferon therapy tripled the HBs seroconverston m the first year after HBe seroconversion with thereafter return toe spontaneous rate of 2-4%/yr. Early HBe-reactivation was 15-20% and independent of IFN therapy; late HBe reactivation was 1-4 %/yr. Long-term follow-up did not show loss of early effects of IFN therapy.
HCV gen. la(5cases) lb(12cases) 2 ( 18 cases)
HCV-RNA LTR + 0 0 0 0 0 6
(at the end of follow-up) TR NR + + 2 0 3 0 7 0 5 0 4 5 3 0
Among 19 HCV-RNA positive patients after the first cycle of IFN, 7 (2 of t',qge lb and 5 of type 2) were re-treated for further 6 menth and only one of them became negative (type l b). In conclusion, in our experience genotype 2 of HCV is more often related to a positive virological and biochemical response to IFN therapy, so that we may suggest that submitting patients to HCV genotyping may be useful to predict the response to treatment itself.