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)
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.
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.