HCV genotype 3: An independent predictor of fibrosis progression in chronic hepatitis C
Authors: Stella De Nicola, Alessio Aghemo, Maria Grazia Rumi, Massimo Colombo
Journal: Journal of Hepatology (2009)

The multi-centre study, by Bochud et al. [[1]Bochud P.-Y. Cai T. Overbeck K. Bochud M. Dufour J.-F. Müllhaupt B. et al.Genotype 3 is associated with accelerated fibrosis progression in chronic hepatitis C.J Hepatol. 2009; 51: 655-666Abstract Full Text Full Text PDF PubMed Scopus (231) Google Scholar], demonstrating an association between hepatitis C virus (HCV) genotype 3 and rapid progression of liver fibrosis in chronically infected patients, amplifies the potential clinical meaning of HCV genotypes, originally identified as predictors of interferon therapy outcome. The report from Switzerland corroborates the increasing evidence that the natural history of hepatitis C may be also influenced by the genotype of HCV in addition to host and environmental co-factors of morbidities. The road to HCV genotype being a modifier of the course of HCV infection was opened a long time ago by HCV-1, shown to be associated with rapid progression of recurrent hepatitis C in liver transplanted patients [[2]Féray C. Gigou M. Samuel D. Paradis V. Mishiro S. Maertens G. et al.Influence of the genotypes of hepatitis C virus on the severity of recurrent liver disease after liver transplantation.Gastroenterology. 1995; 108: 1314-1317Abstract Full Text PDF PubMed Scopus (299) Google Scholar], and with increased risk of hepatocellular carcinoma (HCC) in patients with cirrhosis [[3]Nousbaum J.B. Pol S. Nalpas B. Landais P. Berthelot P. Bréchot C. Hepatitis C virus type 1b (II) infection in France and Italy. Collaborative Study Group.Ann Intern Med. 1995; 122: 161-168Crossref PubMed Scopus (517) Google Scholar], and by HCV-2 associated with ALT flares that ultimately accelerate the course of chronic hepatitis in untreated patients [[4]Rumi M.G. De Filippi F. La Vecchia C. Donato M.F. Gallus S. Del Ninno E. et al.Hepatitis C reactivation in patients with chronic infection with genotypes 1b and 2c: a retrospective cohort study of 206 untreated patients.Gut. 2005; 54: 402-406Crossref PubMed Scopus (55) Google Scholar]. In this context, the paper by Bochud et al. adds nicely to these findings, as it shows HCV-3 to be associated with an accelerated deposition of fibrosis in the liver.To externally validate these findings we assessed a cohort of patients prospectively followed at our centre between December 2008 and May 2009. Of the 3566 patients with chronic HCV infection consecutively admitted to our centre for biochemical and clinical evaluation, 327 (9%) knew the date of infection and had undergone at least one liver biopsy before any antiviral treatment. All liver biopsy specimens were considered adequate for fibrosis assessment [[5]Bedossa P. Dargère D. Paradis V. Sampling variability of liver fibrosis in chronic hepatitis C.Hepatology. 2003; 38: 1356-1358Crossref PubMed Scopus (1950) Google Scholar]. Fibrosis was quantified by the Ishak staging system, with scores ranging from 0, representing no fibrosis to 6 representing cirrhosis [[6]Ishak K. Baptista A. Bianchi L. Callea F. De Groote G. Gudat F. et al.Histological grading and staging of chronic hepatitis.J Hepatol. 1995; 22: 696-699Abstract Full Text PDF PubMed Scopus (4079) Google Scholar].At variance with the study population described by Bochud et al. where the majority of patients acquired HCV through intra-venous drug abuse (IVDA), two-thirds of our patients with the known data of infection identified blood transfusions as the relevant risk factor for HCV infection (Table 1). Compared to Bochud's study, our patients were slightly older (median age at biopsy 47 vs. 42 years) while they had a comparable duration of HCV infection in years (23 vs. 21 years). Consistent with Bochud's observation, we noticed a faster progression of liver fibrosis in HCV-3 patients. Among the 327 patients of our cohort 134 (41%) developed a significant degree of fibrosis, defined as an Ishak staging score ⩾3. While the proportion of patients developing a significant fibrosis was not influenced by HCV genotype (HCV-1: 68/143, 48%; HCV-2: 28/104, 27%; HCV-3: 38/80, 47%), when comparing the mean disease duration in these patients significant differences emerged. In fact, the mean time lag necessary to develop a significant fibrosis was 28.3 years for HCV-1, 24.2 years for HCV-2 patients and 21.8 years for HCV-3 infected patients (p = 0.03). We omitted to calculate the pace of fibrosis progression in units per year since we think that it is intrinsically flawed, as the authors correctly point out, since not only it assumes that fibrosis progression is constant over time, a finding that has been proven incorrect [[7]Poynard T. Mathurin P. Lai C.L. Guyader D. Poupon R. Tainturier M.H. et al.A comparison of fibrosis progression in chronic liver diseases.J Hepatol. 2003; 38: 257-265Abstract Full Text Full Text PDF PubMed Scopus (370) Google Scholar], but also it transforms a qualitative variable, such as the pattern of fibrosis deposition in the liver, into a quantitative variable [[8]Standish R.A. Cholongitas E. Dhillon A. Burroughs A.K. Dhillon A.P. et al.An appraisal of the histopathological assessment of liver fibrosis.Gut. 2006; 55: 569-578Crossref PubMed Scopus (324) Google Scholar].Table 1Baseline and clinical characteristics of the 327 patients.PatientsOverall (n = 327)HCV-1 (n = 143)HCV-2 (n = 104)HCV-3 (n = 80)paCategorical values were compared using a chi-square test and continuous variables were compared using a median test.Male gender192 (58%)75 (52%)49 (47%)53 (66%)0.03Median age at biopsy (years)47485342.5<0.001Median age at infection (years)212124190.09Median infection duration (years)232524.5200.001HCV genotype 1143 (43%)––– 2104 (31%)––– 380 (24%)–––HCV reported risks<0.001 IVDAbIVDA, intra-venous drug abuse.94 (29%)25 (17%)5 (4%)64 (81%) Transfusion228 (69%)117 (81%)99 (95%)12 (13%) Others5 (1%)1 (0%)1 (0%)4 (5%)Biopsy fibrosis stage (Ishak)0.01 06 (1%)5 (3%)1 (0%)0 (0%) 185 (26%)32 (22%)36 (34%)17 (21%) 2102 (31%)38 (22%)39 (37%)25 (31%) 344 (13%)17 (12%)12 (11%)15 (18%) 426 (8%)13 (9%)4 (4%)9 (11%) 528 (8%)17 (12%)7 (7%)4 (5%) 636 (11%)21 (15%)5 (5%)10 (12%)a Categorical values were compared using a chi-square test and continuous variables were compared using a median test.b IVDA, intra-venous drug abuse. Open table in a new tab The demonstration that HCV-3 genotype is a relevant modifier of the natural history of chronic infection further supports anticipated treatment of these patients, whenever possible. The multi-centre study, by Bochud et al. [[1]Bochud P.-Y. Cai T. Overbeck K. Bochud M. Dufour J.-F. Müllhaupt B. et al.Genotype 3 is associated with accelerated fibrosis progression in chronic hepatitis C.J Hepatol. 2009; 51: 655-666Abstract Full Text Full Text PDF PubMed Scopus (231) Google Scholar], demonstrating an association between hepatitis C virus (HCV) genotype 3 and rapid progression of liver fibrosis in chronically infected patients, amplifies the potential clinical meaning of HCV genotypes, originally identified as predictors of interferon therapy outcome. The report from Switzerland corroborates the increasing evidence that the natural history of hepatitis C may be also influenced by the genotype of HCV in addition to host and environmental co-factors of morbidities. The road to HCV genotype being a modifier of the course of HCV infection was opened a long time ago by HCV-1, shown to be associated with rapid progression of recurrent hepatitis C in liver transplanted patients [[2]Féray C. Gigou M. Samuel D. Paradis V. Mishiro S. Maertens G. et al.Influence of the genotypes of hepatitis C virus on the severity of recurrent liver disease after liver transplantation.Gastroenterology. 1995; 108: 1314-1317Abstract Full Text PDF PubMed Scopus (299) Google Scholar], and with increased risk of hepatocellular carcinoma (HCC) in patients with cirrhosis [[3]Nousbaum J.B. Pol S. Nalpas B. Landais P. Berthelot P. Bréchot C. Hepatitis C virus type 1b (II) infection in France and Italy. Collaborative Study Group.Ann Intern Med. 1995; 122: 161-168Crossref PubMed Scopus (517) Google Scholar], and by HCV-2 associated with ALT flares that ultimately accelerate the course of chronic hepatitis in untreated patients [[4]Rumi M.G. De Filippi F. La Vecchia C. Donato M.F. Gallus S. Del Ninno E. et al.Hepatitis C reactivation in patients with chronic infection with genotypes 1b and 2c: a retrospective cohort study of 206 untreated patients.Gut. 2005; 54: 402-406Crossref PubMed Scopus (55) Google Scholar]. In this context, the paper by Bochud et al. adds nicely to these findings, as it shows HCV-3 to be associated with an accelerated deposition of fibrosis in the liver. To externally validate these findings we assessed a cohort of patients prospectively followed at our centre between December 2008 and May 2009. Of the 3566 patients with chronic HCV infection consecutively admitted to our centre for biochemical and clinical evaluation, 327 (9%) knew the date of infection and had undergone at least one liver biopsy before any antiviral treatment. All liver biopsy specimens were considered adequate for fibrosis assessment [[5]Bedossa P. Dargère D. Paradis V. Sampling variability of liver fibrosis in chronic hepatitis C.Hepatology. 2003; 38: 1356-1358Crossref PubMed Scopus (1950) Google Scholar]. Fibrosis was quantified by the Ishak staging system, with scores ranging from 0, representing no fibrosis to 6 representing cirrhosis [[6]Ishak K. Baptista A. Bianchi L. Callea F. De Groote G. Gudat F. et al.Histological grading and staging of chronic hepatitis.J Hepatol. 1995; 22: 696-699Abstract Full Text PDF PubMed Scopus (4079) Google Scholar]. At variance with the study population described by Bochud et al. where the majority of patients acquired HCV through intra-venous drug abuse (IVDA), two-thirds of our patients with the known data of infection identified blood transfusions as the relevant risk factor for HCV infection (Table 1). Compared to Bochud's study, our patients were slightly older (median age at biopsy 47 vs. 42 years) while they had a comparable duration of HCV infection in years (23 vs. 21 years). Consistent with Bochud's observation, we noticed a faster progression of liver fibrosis in HCV-3 patients. Among the 327 patients of our cohort 134 (41%) developed a significant degree of fibrosis, defined as an Ishak staging score ⩾3. While the proportion of patients developing a significant fibrosis was not influenced by HCV genotype (HCV-1: 68/143, 48%; HCV-2: 28/104, 27%; HCV-3: 38/80, 47%), when comparing the mean disease duration in these patients significant differences emerged. In fact, the mean time lag necessary to develop a significant fibrosis was 28.3 years for HCV-1, 24.2 years for HCV-2 patients and 21.8 years for HCV-3 infected patients (p = 0.03). We omitted to calculate the pace of fibrosis progression in units per year since we think that it is intrinsically flawed, as the authors correctly point out, since not only it assumes that fibrosis progression is constant over time, a finding that has been proven incorrect [[7]Poynard T. Mathurin P. Lai C.L. Guyader D. Poupon R. Tainturier M.H. et al.A comparison of fibrosis progression in chronic liver diseases.J Hepatol. 2003; 38: 257-265Abstract Full Text Full Text PDF PubMed Scopus (370) Google Scholar], but also it transforms a qualitative variable, such as the pattern of fibrosis deposition in the liver, into a quantitative variable [[8]Standish R.A. Cholongitas E. Dhillon A. Burroughs A.K. Dhillon A.P. et al.An appraisal of the histopathological assessment of liver fibrosis.Gut. 2006; 55: 569-578Crossref PubMed Scopus (324) Google Scholar]. The demonstration that HCV-3 genotype is a relevant modifier of the natural history of chronic infection further supports anticipated treatment of these patients, whenever possible.