These authors shared senior authorship.
Evaluation of liver disease progression in the German hepatitis C virus (1b)-contaminated anti-D cohort at 35 years after infection
Article first published online: 18 NOV 2013
© 2013 by the American Association for the Study of Liver Diseases
Volume 59, Issue 1, pages 49–57, January 2014
How to Cite
Wiese, M., Fischer, J., Löbermann, M., Göbel, U., Grüngreiff, K., Güthoff, W., Kullig, U., Richter, F., Schiefke, I., Tenckhoff, H., Zipprich, A., Berg, T., Müller, T. and for the East German HCV Study Group (2014), Evaluation of liver disease progression in the German hepatitis C virus (1b)-contaminated anti-D cohort at 35 years after infection. Hepatology, 59: 49–57. doi: 10.1002/hep.26644
Potential conflict of interest: Dr. Schiefke advises Baxter and received grants from Gilead and MSD. Dr. Löbermann is on the speakers' bureau and owns stock in Janssen-Cilag and Gilead. She received grants and owns stock in Roche.
This work was supported by the German Competence Network for Viral Hepatitis (Hep-Net), funded by the German Ministry of Education and Research (BMBF; grant no.: 01 KI 0437; project no.: 10.1.3; core project no.: 10.1; Genetic host factors in viral hepatitis and Genetic Epidemiology Group in viral hepatitis), by the EU-Vigilance network of excellence combating viral resistance (VIRGIL; project no.: LSHM-CT-2004-503359), and by the BMBF Project: Host and viral determinants for susceptibility and resistance to hepatitis C virus infection (grant no.: 01KI0787)
- Issue published online: 20 DEC 2013
- Article first published online: 18 NOV 2013
- Accepted manuscript online: 8 AUG 2013 07:53AM EST
- Manuscript Accepted: 16 JUL 2013
- Manuscript Received: 6 MAR 2013
Vol. 61, Issue 4, 1446–1447, Article first published online: 13 FEB 2015
The natural course of HCV infection remains controversial. The German HCV (1b)-contaminated anti-D cohort provides an ideal population to investigate the natural course of HCV infection in a large, homogenous cohort of young women from the date of HCV inoculation. Our previous follow-up studies at 20 and 25 years after infection suggested slow fibrosis progression rates in this unique cohort. The aim of our prospective, community-based, multicenter study was to reevaluate the liver disease progression in 718 patients of the original anti-D cohort at 35 years after infection. Patients with self-limited HCV infection (n = 189) were compared to those who failed to eliminate the virus spontaneously (n = 529), comprising patients who were treatment naïve (n = 197) or achieved a sustained virological response (SVR; n = 149), respectively, failed to clear the virus (non-SVR; n = 183) after antiviral therapy. In the overall cohort, 9.3% of patients showed clinical signs of liver cirrhosis at 35 years after infection. Liver disease progression largely depended on HCV infection status. The highest proportion of patients with clinical signs of end-stage liver disease was observed in the non-SVR group (15.3%), whereas decreased cirrhosis rates were detected in the SVR group (6%) and in patients with self-limited HCV infection (1.1%; P = 6.2 × 10−6). Overall survival was significantly enhanced after SVR, compared to treatment-naïve patients or non-SVR (P = 0.027). Conclusion: The present study provides further evidence for a mild, but significant, disease progression at 35 years after infection in the German HCV (1b)-contaminated anti-D cohort. Patients with self-limited HCV infection or SVR after antiviral treatment were protected from progressive liver disease and showed the best clinical long-term outcome. (Hepatology 2014;58:49–57)
body mass index
chronic hepatitis C
end-stage liver disease
hepatitis C virus
sustained virological response
World Health Organization.
Hepatitis C virus (HCV) infection is the leading cause of end-stage liver disease (ESLD) in the world and represents a major burden for national health systems. The World Health Organisation (WHO) and international consensus conferences refer to the high chronification rate of HCV infection, the risk of subsequent HCV-related complications, including end-stage liver cirrhosis and hepatocellular carcinoma (HCC) and the high costs for antiviral therapy, respectively, liver transplantation (LT).[2, 3]
It is estimated that HCV-related morbidity and mortality will increase in the next decade.[4-6] The predicted cumulative probability of cirrhosis approximates 20% at 20 years after HCV infection and increases to 45% at 30 years after infection. However, recent estimates on the natural fibrosis progression rates of hepatitis C largely depend on study design, study setting, and the selected study population. In theory, prospective multicenter, community-based long-term follow-up studies in large representative patient cohorts with a defined onset of HCV infection from a single identified source constitute the optimal setting for the evaluation of the natural course of chronic HCV infection. Therefore the well-documented iatrogenic single-source HCV outbreaks in recipients of HCV-contaminated anti-D immunoglobulin (Ig) in Ireland (1977-1978) and Germany (1978-1979) provided valuable insight into the acute and chronic course of HCV infection in the past.[9-12] We have previously reported on the outcome of the German HCV (1b)-contaminated anti-D cohort at 20 and 25 years after infection and demonstrated a very low cirrhosis rate of only 0.5% in the overall cohort at 25 years after infection.[11, 12] The aim of the present 35-year follow-up study was to reevaluate the liver disease progression in this unique cohort after another decade of data accrual in our prospective, community-based, multicenter study. We also report on the effect of antiviral treatment on liver disease progression and survival probability. Relevant comorbid conditions, which have been shown to interfere with the natural and the treatment-induced course of HCV infection,[13-15] were also assessed.
Patients and Methods
Characteristics of the German Anti-D Cohort
In 1978-1979, a large outbreak of HCV (1b)-infections in young women occurred in East Germany after legal administration of anti-D Ig after pregnancy. We have previously reported on the acute course and the long-term disease outcome at 20 and 25 years after infection.[11, 12, 16]
Clinical and Laboratory Data Collection
This 35-year interim analysis of our prospective, multicenter, population-based long-term study was conducted by the treating hepatologists from 2011 to 2012 in the original referral centers throughout East Germany, including liver units in Leipzig, Dresden, Rostock, Chemnitz, Potsdam, Berlin, Magdeburg, Cottbus, Jena, Erfurt, and Halle. The present study comprises 718 women of the original cohort of 1978-1979, among them 181 patients who had not been included in our previous follow-up studies at 20 and 25 years after infection (Fig. 1). Data collection during regular follow-up visits in the referral centers comprised the assessment of the women's clinical status and included the documentation of relevant biochemical parameters, such as alanine aminotransferase (ALT) and gamma-glutamyl transferases (GGTs), HCV serology (Architect Anti-HCV; Abbott, Wiesbaden, Germany), and HCV RNA (COBAS AmpliPrep/COBAS TaqMan HCV; Roche Diagnostics, Mannheim, Germany).
Determination of Clinical Outcome
The individual HCV infection status at 35 years after infection was determined as follows: HCV RNA-positive (HCV+), patients who failed to clear the virus spontaneously and patients with non-SVR (sustained virologic response) after antiviral therapy; and HCV RNA-negative (HCV−), patients with spontaneous or treatment-induced clearance of HCV infection. The HCV RNA-negative group comprised 171 women with self-limited HCV infection and 18 patients with persistently normal ALT levels and negative tests for HCV markers throughout the observation period who were classified as inoculated patients without hepatitis. For the subsequent analyses, these 18 patients were added to the larger cohort of patients with self-limited HCV infection. In addition, 149 patients with SVR after antiviral treatment were included in the HCV RNA-negative group. The clinical outcome at 35 years after infection was defined as follows: spontaneous recovery, presence of anti-HCV antibodies (Abs) in the absence of HCV RNA; chronic hepatitis, presence of positive HCV RNA and histological evidence of chronic hepatitis or elevated ALT activity; advanced liver disease, histological Ishak stage 3-4 or transient elastography values >9.6 kPa (F3); and cirrhosis, histological stage Ishak 5-6 or transient elastography values >14.5 kPa (F4) or definitive ultrasound (US) signs, respectively, clinical signs of cirrhosis, including splenomegaly, palpable blunt liver margins, ascites, caput medusae, and esophageal varices. The development of HCC and all deaths were systemically documented over the entire observation period since 1978-1979.
Evaluation of the Effect of Antiviral Therapy on Disease Progression
In total, 332 (47%) patients of the current study population were treated with various (pegylated) interferon- and ribavirin-based combination regimens over the last few decades. Response to therapy was classified as SVR in patients who permanently cleared the virus after antiviral treatment and non-SVR in patients who failed to clear the virus after antiviral treatment, comprising patients with nonresponse, partial response, breakthrough, and relapse. In total, 149 women (46%) achieved SVR and 183 women failed to clear the virus after antiviral therapy.
The database was constructed with Microsoft Access within the German Network of Competence of Hepatitis. An informed consent was obtained from each patient, and the study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki. The Human Studies Committee of the University of Leipzig (Leipzig, Germany) approved the study. Statistical analysis was performed with SPSS 20.0 statistical software (SPSS, Inc., Chicago, IL) using contingence tables by Pearson's chi-square test and Fischer's exact test for dichotomous data and Mann-Whitney's U test for continuous data. The odds ratio (OR) and the 95% confidence interval (CI) were calculated. All tests were two-sided, and P values less than 0.05 were considered to be statistically significant. Survival curves were established according to Kaplan-Meier. Significance was tested using the log-rank test. Year of death was used to discriminate between the analyzed groups.
Characteristics of the Patients at 35 Years After Infection
Table 1 summarizes the clinical and biochemical characteristics of the German HCV (1b)-contaminated anti-D cohort at 35 years after infection (n = 718). HCV RNA-positive patients showed significantly increased ALT levels (P = 3.3 × 10−69) and GGT levels (P = 1.4 × 10−19) compared to HCV RNA negative patients. US signs suggesting liver cirrhosis were reported in 10.3% of treatment-naïve patients, 13.1% of non-SVR patients, and 5.4% of SVR patients. We noticed an increased proportion of patients exhibiting a body weight exceeding the normal range according to the actual WHO classification. In total, only 37% of the women exhibited a normal weight with a body mass index (BMI) <25 kg/m2, which was in sharp contrast to our previous reports at 20 years after infection with 90% normal-weight women. Approximately every fifth woman in our cohort was currently obese, sometimes of an extreme degree (BMI ≥40 kg/m2).
|Parameter||Inoculated Without Signs of Hepatitis||Spontaneously Recovered||CHC||Total|
|n = 18||n = 171||n = 197||n = 149||n = 183||n = 718|
|Age at HCV-infection, years, median/range||24/18-35||24/17-38||24/17-38||24/16-37||24/18-38||24 (16-38)|
|Age at 35 years after infection, years, median/range||57/51-68||57/50-72||57/50-71||57/49-70||57/51-73||57 (49-73)|
|BMI, kg/m2 (n = 710)|
|<25 (%)||8 (44.4)||73 (43.2)||58 (30.4)||64 (43.0)||60 (32.8)||263 (37.0)|
|25-29 (%)||7 (38.9)||57 (33.7)||98 (51.3)||60 (40.3)||92 (50.3)||314 (44.2)|
|30-39 (%)||2 (11.1)||36 (21.3)||32 (16.7)||23 (15.4)||29 (15.8)||122 (17.2)|
|≥40 (%)||1 (5.6)||3 (1.8)||3 (1.6)||2 (1.3)||2 (1.1)||11 (1.6)|
|Diabetes mellitus (%)||2 (11.1)||7 (4.1)||19 (9.6)||10 (6.7)||11 (6.0)||49 (6.8)|
|HBV (%)||0||1 (0.6)||0||0||0||1 (0.1)|
|HIV (%)||0 (0)||0||0||0||0||0 (0)|
|IL28B rs12979860||n = 10||n = 101||n = 101||n = 93||n = 121||n = 426|
|CC (%)||5 (50)||66 (65)||22 (22)||28 (30)||24 (20)||145 (34.1)|
|CT (%)||3 (30)||31 (31)||62 (61)||50 (54)||74 (61)||220 (51.6)|
|TT (%)||2 (20)||4 (4)||17 (17)||15 (16)||23 (19)||61 (14.3)|
|ALT, µkat/L (n = 688)|
|Normal (%)||14 (87.5)||133 (81.1)||41(22.3)||123 (83.1)||17 (9.7)||328 (47.7)|
|Fluctuating elevation (%)||1 (6.25)||12 (7.3)||4 (2.2)||1 (0.7)||7 (4.0)||25 (3.6)|
|Permanent elevation (%)||1 (6.25)||19 (11.6)||139 (75.5)||24 (16.2)||152 (86.3)||335 (48.7)|
|GGT, µkat/L (n = 485)|
|Normal (%)||8 (72.7)||79 (71.2)||63 (47.7)||84 (83.2)||55 (42.3)||289 (59.6)|
|Elevated (%)||3 (27.3)||32 (28.8)||69 (52.3)||17 (16.8)||75 (57.7)||196 (40.4)|
|Anti-HCV positive (%)||0||130 (76.0)||184 (100)||149 (100)||183 (100)||646 (90)|
|HCV PCR (n = 688)|
|Negative (%)||16 (100)||164 (100)||148(100)||328 (47.7)|
|Positive (%)||184 (100)||176 (100)||360 (52.3)|
|US (n = 688)|
|Normal (%)||16 (100)||161 (98.2)||158 (85.9)||139 (93.9)||147 (83.5)||621 (90.3)|
|Precirrhotic signs (%)||0||2 (1.2)||5 (2.7)||1 (0.7)||6 (3.4)||14 (2.0)|
|Signs of cirrhosis (%)||0||1 (0.6)||19 (10.3)||8 (5.4)||23 (13.1)||51 (7.4)|
|HCC (%)||0||0||2 (1.1)||0||0||2 (0.3)|
Clinical Outcome at 35 Years After Infection
Clinical signs of liver cirrhosis were detected in 67 patients (9.3%) of the overall cohort (Fig. 2). Further subgroup analysis revealed the highest proportion of patients with clinical signs of cirrhosis in the non-SVR group (15.3%) and treatment-naïve patients (14.2%). Only 6% of patients in the SVR group showed clinical signs of liver cirrhosis rates (P = 0.021; naïve vesus SVR: P = 0.021; non-SVR versus SVR: P = 0.008). Comparison of clinical outcome at 20, 25, and 35 years after infection unravelled a slowly accelerating disease progression over the observation period (Supporting Fig. 1). Advanced fibrosis stages (F3) increased from 0% at 20 years to 1.5% at 25 years and 1.5% at 35 years after infection. The proportion of patients with clinical signs of liver cirrhosis increased from 0.4% at 20 years to 0.5% at 25 years and 7.8% at 35 years after infection (P = 1.1 × 10−35; 20 years after infection versus 25 years after infection: P = 0.783; 25 years after infection versus 35 years after infection: P = 1.9 × 10−29). Transient elastography (Supporting Fig. 2) and liver biopsies (Supporting Fig. 3) further confirmed that the long-term outcome in this otherwise healthy young female cohort depended on the natural respectively treatment-induced course of HCV infection.
Risk Factors for Fibrosis and Cirrhosis Progression at 35 Years After Infection
Characteristics of women with advanced (F3) fibrosis, respectively, end-stage liver cirrhosis, compared to women without significant liver disease at 35 years after infection, are shown in Table 2. Factors associated with fibrosis and cirrhosis progression in the univariate analysis are depicted in Table 3. In the multivariate analysis, cirrhosis was associated with the BMI (OR, 1.125; 95% CI: 1.038-1.22; P = 0.004), spontaneous HCV elimination (OR, 0.05; 95% CI: 0.006-0.365; P = 0.003), and SVR (OR, 0.05; 95% CI: 0.019-0.09; P = 0.019). Further analysis confirmed significant differences in the disease progression in relation to the individual BMI of the patients at 35 years after infection (Fig. 3).
|Parameter||Cirrhosis (n = 67)||F3 Fibrosis (n = 14)||No Liver Disease (n = 637)||Cirrhosis Versus None P Value||F3 Fibrosis Versus None P Value|
|Age at HCV-infection*||24/17-35||25/17-34||24/16-38||n.s.||n.s.|
|Age at 35 years after infection*||57/50-68||58/50-67||57/49-73||n.s.||n.s.|
|Clinical outcome (%)|
|Spontaneously recovered||2 (3.0)||4 (11.4)||183 (29.7)|
|Treatment naïve||28 (41.8)||8 (22.9)||161 (26.1)||3.4 × 10−5||0.046|
|SVR||9 (13.4)||12 (34.3)||128 (20.8)|
|Non-SVR||28 (41.8)||11 (31.4)||144 (23.4)|
|BMI, kg/m2||1.3 × 10−9||0.031|
|Median/range||29.7 (16.1-40.0)||29.4 (20.3-41.0)||25.8 (16.7-50.6)|
|<25 (%)||10 (14.9)||9 (32.1)||244 (39.7)|
|25-29.9 (%)||28 (41.8)||9 (31.1)||277 (45.0)|
|30-39.9 (%)||28 (41.8)||8 (28.6)||86 (14.0)|
|≥40 (%)||1 (1.5)||2 (7.2)||8 (1.3)|
|IL28B rs12970860 (%)|
|CC||4 (13.8)||5 (26.3)||126 (36.0)|
|CT||18 (62.1)||11 (57.9)||178 (50.9)||0.035||n.s.|
|TT||7 (24.1)||3 (15.8)||46 (13.1)|
|ALT, µkat/L||1.2 × 10−8||1.6 × 10−5|
|Normal (%)||9 (17.7)||5 (17.8)||314 (51.6)|
|Fluctuating elevation (%)||4 (7.8)||1 (3.6)||20 (3.3)|
|Permanent elevation (%)||38 (74.5)||22 (75.6)||275 (45.1)|
|GGT, µkat/L||8.5 × 10−10||2.3 × 10−5|
|Normal (%)||4 (12.1)||4 (21.1)||281 (64.9)|
|Elevated (%)||29 (87.9)||15 (78.9)||152 (35.1)|
|Parameter||Cirrhosis||F3 Fibrosis||No Liver Disease||Cirrhosis Versus None P Value||F3 Fibrosis Versus None P Value|
|Age at infection*||24 (17-35)||25 (17-34)||24 (16-38)||0.974||0.100|
|Age at 35 years after infection*||57 (50-68)||58 (50-67)||57 (49-73)||0.974||0.100|
|ALT||1.2 × 10−9||1.6 × 10−5|
|GGT||8.5 × 10−10||2.3 × 10−5|
|BMI, kg/m2||8.3 × 10−9||0.031|
|Spontaneous HCV recovery||2||4||187||6.2 × 10−6||0.189|
Mortality at 35 Years After Infection
Figure 4 summarizes the overall mortality of the German HCV (1b)-contaminated anti-D cohort at 35 years after infection in relation to the HCV infection status. In total, 30 patients (4.2%) of the actual study cohort died since 1979. In the group of HCV RNA-negative patients, 10 (3.0%) died, among them 2 who were classified as inoculated patients without hepatitis, 7 with spontaneous recovery from HCV infection, and 1 with SVR after treatment who died of a malignant disease other than HCC. In the group of HCV RNA-positive patients, 20 (5.3%) died, among them 9 (1.3%) who succumbed to definite HCV-related end-stage liver complications, such as esophageal variceal bleeding or hepatic coma. The remaining 11 HCV RNA-positive patients (1.5%) died from additional non-liver-related causes, such as cardiac failure, nonliver malignancy, apoplectic insult, or accident.
Kaplan-Meyer's analysis was used to describe overall survival probability in relation to individual HCV infection status at 35 years after infection. Survival was significantly improved in patients showing SVR after antiviral treatment, compared to chronic viremic treatment-naïve patients (Fig. 5A). The highest mortality was observed in the group of non-SVR patients who failed to clear the virus after antiviral therapy (P = 0.027). Irrespective of HCV infection status, obese and overweight patients showed higher cirrhosis rates (P = 4.7 × 10−8; P = 0.017, data not shown), higher probability to develop liver cirrhosis (P = 0.031, data not shown), and decreased survival probability (p = 0.007), compared to patients with a normal BMI (Fig. 5B).
The natural course of HCV infection remains controversial. Recent studies provided a wide range of cirrhosis rates in chronically HCV-infected patients over varying observation periods. A large variety of environmental and host-related factors, such as gender, transmission mode of infection, age at infection, duration of infection, and subsequent aging of the HCV-infected patient, have been shown to influence the natural course of HCV infection. The German HCV (1b)-contaminated anti-D cohort is considered an ideal population to investigate the natural and treatment-induced course of HCV infection. We have previously reported low rates of liver disease progression at 20 and 25 years after infection in this unique cohort, showing only 0.5% end-stage liver cirrhosis at 25 years after infection.[11, 12] In the actual study, we extended our previous observations and presented the long-term follow-up data at 35 years after infection obtained from our prospective community-based multicenter study, comprising 718 patients of the original anti-D cohort.
The present study provides further evidence for a slow disease progression in the German anti-D cohort, which was in line with our previous findings at 20 and 25 years after infection. Our present analysis revealed that liver disease progression at 35 years after infection largely depended on HCV infection status. Spontaneously recovered women and those who permanently cleared the virus after antiviral treatment were protected from liver fibrosis progression. The highest proportion of ESLD was observed in the group of patients with chronic HCV infection who failed to eliminate the virus after antiviral treatment. However, the overall liver cirrhosis rate in this group was well below the predicted natural cirrhosis progression rate of 45% at 30 years after infection. Decreased rates of advanced liver fibrosis and cirrhosis were also detected in patients who achieved SVR after antiviral treatment over the last few decades. Analysis of the overall survival probability confirmed enhanced survival in the group of patients showing SVR after antiviral therapy, compared to non-SVR patients and treatment-naïve patients. Overweight and obese women exhibited significantly decreased survival probability likely as a result of increased liver-related death rates because all deceased obese women (n = 8) were suffering from liver cirrhosis, among them 3 with documented alcohol abuse (data not shown). Previous community-based long-term studies have already shown that chronic HCV infection increases mortality from hepatic and extrahepatic diseases. Multivariate analysis confirmed that overweight and obesity constituted an increased risk for fibrosis progression and decreased survival probability, which was in line with previous reports suggesting an association between obesity and the development of liver cirrhosis.
There are notable differences between the present study and previous attempts to characterize the natural and treatment-induced course of HCV infection. The slow disease progression in chronically HCV-infected women of the German anti-D cohort is at variance to the poorer outcome reported in other studies. However, these studies comprised either young males with increased alcohol consumption or patients who contracted their HCV infection after blood transfusions and were likely prone to the selection bias of tertiary centres, which include more “difficult-to-treat” patients, compared to nontertiary community-based observational studies. Of note, male gender, concomitant alcohol consumption, and HCV transmission after blood transfusion have been identified as potential risk factors for an aggressive course of HCV infection, whereas female gender and young age at infection have been associated with a benign course of HCV infection.[7, 21, 22]
Current projections predict that the prevalence of HCV-related ESLD and its associated complications will continue to increase in patients older than 60 years. Fibrosis progression has been shown to be nonlinear and stage specific, likely accelerating after prolonged disease duration. Despite the mean duration of follow-up of 35 years in the present study, the participating patients were still relatively young, with a mean age of 57 years, and had not reached the 40-year disease duration, which has been reported to be critical for liver fibrosis progression to ESLD in women who were infected at a young age. Therefore, we cannot exclude that cirrhosis progression rates will accelerate within in the next decade. Further follow-up studies in this unique cohort are clearly warranted to examine the natural and treatment-induced course of HCV infection.
The strength of the present study is the knowledge of the exact HCV inoculation date, which provides a unique setting to study the natural and treatment-induced course of HCV infection in this large, homogenous study population from the date of infection onset in a prospective long-term community-based multicenter study. The only inclusion criteria in our study was that the enrolled patients had been infected in 1978-1979 by HCV (1b) anti-D-contaminated batches, which minimized a potential selection bias that has been observed in comparable studies in the past. However, several limitations of the present study must be acknowledged. First, a substantial proportion of the otherwise healthy young women of the original cohort was lost to follow-up at 35 years after infection, comprising 835 women with self-limited HCV infection, 399 who were treatment naïve, 34 with SVR, and 75 with non-SVR after antiviral therapy. Therefore, it appears to be unlikely that the rate of patients with advanced liver diseases might be unintentionally decreased in the present study because the majority of the women lost to follow-up represented patients who cleared the virus after infection. However, we cannot exclude an unintended selection bias in our present study because it appears likely that patients who suffered from an aggressive course of HCV infection were more readily considered for antiviral treatment during their scheduled follow-up visits, compared with patients with a mild disease course. Second, our study lacks the comparison of paired biopsy samples obtained at 20, 25, and 35 years after infection to evaluate the histological rate of fibrosis progression. However, our present findings are in agreement with a recent report showing slow histological fibrosis progression rates in paired biopsy samples obtained from treatment-naïve patients of the Irish anti-D cohort over a period of 5 years. Our findings are also consistent with another extensive histological follow-up study by Poynard et al., who reported similar slow fibrosis progression patterns in young women with chronic hepatitis C (CHC). In the Irish anti-D cohort, a 22-year follow-up study also showed mild fibrosis progression in affected women. Third, we could not reliably evaluate alcohol consumption in our patients over this long observation period. However, we observed only a minority of patients with excessive alcohol consumption in our 25-year follow-up study.
In summary, we provide evidence for a mild, but significant, disease progression at 35 years after infection in the German HCV (1b)-contaminated anti-D cohort, which largely depended on the HCV infection status of the participating patients. Patients with self-limited HCV infection or SVRs to antiviral treatment were protected from progressive liver fibrosis and showed the best clinical long-term outcome. The results of the present study will help attending physicians to counsel patients on the long-term outcome of CHC.
- 2EASL Clinical Practice Guidelines:management of hepatitis C virus infection. J Hepatol 2011;55:245-264..
- 4The increasing burden of mortality from viral hepatitis in the United States between 1999 and 2007. Ann InternMed 2012;156:271-278., , , , , .
Additional Supporting Information may be found in the online version of this article.
|hep26644-sup-0001-suppfig1.tif||1603K||Supporting Information Figure 1: Comparison of clinical outcomes at 20 years, 25 years and 35 years after infection.|
|hep26644-sup-0002-suppfig2.tif||1679K||Supporting Information Figure 2: Evaluation of liver fibrosis at 35 years after infection by transient elastography. Transient elastography (FibroScan®, Echosens, Paris) was used for non-invasive fibrosis assessment. The measurements were performed according to the manufacturer's instructions (10 valid results required). Fibrosis stages were defined as METAVIR F2 with measurements >8.7 kPa, F3 (advanced fibrosis) >9.6 kPa and F4 (cirrhosis) >14.5 kPa.|
|hep26644-sup-0003-suppfig3.tif||1595K||Supporting Information Figure 3: Evaluation of liver fibrosis at 35 years after infection by liver biopsy. Liver biopsies were recommended to all viremic women to assess the individual inflammatory activity and fibrosis stage. Biopsies were scored for inflammation (grading 0-18) and fibrosis (staging 0-6) according to the Ishak score by the pathologists assigned to the respective centers.|
|hep26644-sup-0004-suppfig4.tif||1878K||Supporting Information Figure 4: Comparison of histological fibrosis stages at 20 years, 25 years and 35 years after infection. Biopsies were scored for inflammation (grading 0-18) and fibrosis (staging 0-6) according to the Ishak score by the pathologists assigned to the respective centers.|
|hep26644-sup-0005-suppfig5.tif||1564K||Supporting Information Figure 5: Interleukin 28B (IL28B) polymorphism in relation to the natural and treatment-induced course of HCV infection. The IL28B gene polymorphism rs12979860 was determined by real-time polymerase chain reaction and melting curve analysis.|
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