The natural history and antiviral treatment of hepatitis C in haemophilia

People with haemophilia who received non-virucidally treated large-pool clotting factor before 1986 were infected with hepatitis C virus (HCV), previously referred to as non-A, non-B hepatitis. Approximately one-tenth of patients have been shown to clear infection naturally and shown persistently negative HCV PCR. Patients have been infected with genotypes 1, 2 and 3 reflecting the plasma donors in Northern Europe and the United States. Several studies have shown that HCV mono-infection has a very slow progression. Co-infection with human immunodeficiency virus (HIV), however, can hasten the progression to cirrhosis and liver failure. Genotype 1 and older age at first infection also increase the progression rate. Candidates with detectable HCV RNA are candidates for therapy. The combination of standard interferon-alpha and ribavirin doubles the effectiveness of interferon-alpha alone and is the current standard of care for the treatment of chronic hepatitis C. The duration of therapy depends on the genotype and level of viraemia. Patients with genotypes 2 or 3 should have 6 months' therapy while those with genotype 1 and > 2 million copies mL-1 should have 1 year of therapy. Pegylated interferon is an emerging therapy. Patients co-infected with HIV, in whom treatment has stabilized the HIV infection, may be able to tolerate therapy for HCV infection. Liver transplantation is indicated for patients with haemophilia who have decompensated hepatitis C infection.     

Hepatitis C virus genotypes and severity of chronic liver disease in haemophiliacs

Summary. We studied the activity and stage of chronic liver disease in 45 HCV-seropositive/HIV-seronegative patients with severe haemophilia followed for at least 10 years. HCV-RNA was detected in serum in 36 patients (80%) Viraemic cases were further analysed for HCV genotypes: 10 (28%) were infected by type la, 10 (28%) by type lb, seven (19%) by type 2, four (11%) by type 3, four (11%) had mixed infections (one by la + lb, one by la 4- 2, one by type 2+3, and one by la + 2 + 3). ALT levels were within the normal range in 55% of the HCV-RNA negative patients but in only 11% of the viraemic cases. Results show a trend for higher levels of ALT in HCV-RNA-positive patients compared with those without viraemia (98 ± 56 v 60 ± 61), and particularly with patients with type 3 HCV infection (148 ± 44). We suggest that a slow progression of chronic liver disease occurs in haemophilic HCV-positive/HiV-negative patients and conclude that presence of HCV-RNA in serum correlates well with cytolitic damage but, in the time-scale of our follow-up period, commonly used clinical-laboratory parameters cannot predict the chronic evolution of liver infection or identify differences in disease progression in relation to specific HCV subtypes.     

The role for liver biopsy in haemophiliacs infected with the hepatitis C virus

Assessment of chronic hepatitis C virus infection requires a liver biopsy in most circumstances. There is a reluctance to perform liver biopsy in haemophiliacs because of a perceived risk of haemorrhage, although with adequate factor concentrate replacement in patients without factor concentrate inhibitors it should be safe. We report a 4-year experience of liver biopsy in patients with haemophilia infected with chronic hepatitis C virus. Of 55 patients seropositive for anti-HCV, 35 have undergone liver biopsy; the median age of this group was 33 years (range 13–68). Seven patients had a normal liver. 22 had portal tract inflammation, four with lymphoid aggregates. Mild piecemeal necrosis was observed in only two and no bile duct injury was found. 11 patients had mild mixed micro- and macro-vesicular fat. 19 patients had no evidence of fibrosis despite an estimated median duration of disease of 20 years (range 8–43). In the remaining 16 patients the maximum degree of fibrosis achieved was stage III. Patients with more significant fibrosis could not be identified on the basis of ALT or HCV RNA. There were no complications of liver biopsy in this series. Liver biopsy following a well-defined protocol in chronic hepatitis C virus haemophiliac carriers is safe in the absence of factor concentrate inhibitors. In this young group of patients without HIV infection there was no evidence of significant liver disease despite a considerable duration of disease. Performing liver biopsy allows accurate information to be given to the patient and avoids unnecessary therapy. The relative youth of this group may be important in the light of the benign histology.     

The impact of hepatic steatosis on the natural history of chronic hepatitis C infection

Summary.  Since patients with hepatitis C virus (HCV) often have hepatic steatosis, this retrospective analysis aimed to assess whether steatosis influences fibrosis progression. We studied 112 HCV RNA positive subjects (median age 44, IQR 39–51 years), who had two liver biopsies performed (median biopsy interval 50, 34–74 months). Fibrosis was staged using the Ishak method and steatosis by the Kleiner system (<5% steatosis = S0, 5–33% = S1, 33–66% = S2, and >66% = S3). The subjects were untreated because they had mild fibrosis ( n =  59), declined therapy ( n =  48), or had co-existing disease precluding treatment ( n  =   5). On first liver biopsy, 60 (54%) had S0, 34 (30%) had S1, 12 (11%) had S2, and 6 (5%) had S3. Steatosis was associated with genotype 3, odds ratio 4.8 (95% CI 1.3–16.7, P =  0.02). Twenty-three patients (21%) had disease progression on the second biopsy, defined as an increase in Ishak score by ≥1 stage. On univariate analysis, fibrosis progression was associated with older age ( P =  0.004), higher AST ( P =  0.04), and steatosis ( P =  0.005) but on multivariate analysis, only baseline steatosis was significant, odds ratio 14.3 (2.1–111.1, P =  0.006). Kaplan-Meier analysis demonstrated that steatosis impacted on time to progression to both significant fibrosis (Ishak ≥F3) and cirrhosis (Ishak F5-6) ( P =  0.001 and P =  0.049, respectively). The finding that steatosis was significantly associated with fibrosis progression indicates that, independent of baseline fibrosis stage, patients should be considered for anti-viral treatment if steatosis is present. Furthermore, strategies to reduce steatosis may have a beneficial effect on fibrosis progression and, therefore, patient outcome.     

The influence of host factors on the natural history of chronic hepatitis C viral infections

The natural history of hepatitis C is variable, with some patients progressing rapidly to cirrhosis and others showing no significant fibrosis over many decades. A number of studies have examined the factors that influence disease progression. Age at time of infection, gender, alcohol abuse and, perhaps, route of transmission, appear to have the greatest influence on the natural history of the hepatitis C virus with the possible exception of alcohol, the mechanism whereby these factors influence disease progression has yet to be determined.     

The natural course of chronic hepatitis C: implications for clinical practice

Hepatitis C is an important public health problem with high rates of chronic infection ensuing after viral acquisition. The spectrum of the disease ranges from mild to severe chronic hepatitis, cirrhosis and hepatocellular carcinoma. Extra-hepatic manifestations may occur. The disease is complex and predictions about long-term prognosis for individual patients remain difficult. It is generally accepted that 10–20% of patients with chronic hepatitis C will develop cirrhosis within 10 years of first infection: identifying the group of patients at greatest risk remains a primary challenge for clinicians. Older age of infection, duration of infection, degree of liver inflammation at first biopsy and cofactors such as alcohol abuse, all appear to be predictors of a poorer prognosis. The following paper aims to identify some of the features of the natural history of hepatitis C most relevant to the clinician.     

Persistent hepatitis C virus RNA replication in haemophiliacs: role of co-infection with human immunodeficiency virus

Summary. In order to evaluate the evolution of transfusional hepatitis C in haemophiliacs, we performed a retrospective study of ALT levels and HCV viraemia with a RNA PCR assay in 57 patients. We found that the vast majority of HCV-infected patients remained viraemic (43/57=75%) and higher ALT levels correlated with HCV viraemia. Although indicators of the transfusional viral load (age, severity of haemophilia) and HBV co-infection did not correlate with HCV RNA replication, HIV seropositivity was strongly associated with persistence of HCV viraemia (23/25 = 92% in HIV-positive versus 20/32 = 62% in HIV-negative patients), without any correlation with CD4 counts. Genotyping of HCV in the 43 viraemic patients shows more frequent genotype 1 in the HIV-seropositive group (14/23) than in the seronegative group (6/20). Our data emphasize that besides the role of the immunodeficiency status, the genotypes of HCV might be involved in the differences observed in terms of HCV RNA replication between the HIV-seropositive and seronegative haemophiliacs.     

Fibrosis progression in initially mild chronic hepatitis C

The natural history of chronic hepatitis C presenting with no/minimal liver fibrosis is uncertain with controversies on risk of progression and need for antiviral treatment. We studied rates and determinants of fibrosis progression in initially mild chronic hepatitis C. One hundred and six patients (mean age 41.65 +/- 12.83 years) with chronic hepatitis C virus infection and no/minimal fibrosis in the initial liver biopsy (F0/F1 by METAVIR score) were followed prospectively while untreated with repeated biopsy after 5 or more years (mean interval 7.8 +/- 1.51 years). Patients showing fibrosis progression were compared with nonprogressors for baseline and follow-up parameters. Sixty-four patients (60.4%) showed fibrosis progression including 13 of 27 (49%) with F0 and 51 of 79 (65%) with F1. Progression to F3 or cirrhosis was seen in 36% of those with F1 initially. Fibrosis progression (DeltaF/year) was associated with age (P < 0.0001), baseline and follow-up alanine aminotransferase (ALT) (P = 0.005), histological activity (P = 0.004) and steatosis (P = 0.002) in the initial biopsy and use of alcohol (P = 0.008). Thus liver fibrosis progression occurs in two-thirds of patients with initially mild chronic hepatitis C within 5-10 years and advanced fibrosis/cirrhosis develops in one-third of those with F1 initially. Fibrosis is facilitated by older age and alcohol and associated with inflammatory activity and ALT levels. Antiviral therapy should be considered in mild chronic hepatitis C.     

Natural history of initially mild chronic hepatitis C

The hepatitis C virus is a leading cause of chronic liver disease, cirrhosis and hepatocellular carcinoma in western countries. Chronic hepatitis C is highly heterogeneous and many patients present with a mild form of liver disease. Population-based studies have indeed demonstrated that around 50% of hepatitis C virus carriers have persistently normal ALT and two-third have mild histological liver lesions. Studies on the natural history of initially mild chronic disease indicate that the short-term outcome is always benign. However, progression of liver fibrosis can be observed at long-term (>5-7 years) follow-up, particularly in those cases who have elevated and/or fluctuating transaminase levels. Observational prospective studies and outcome modelling projections indicate that the risk of liver disease progression towards severe fibrosis/cirrhosis is minimal at 10-15 years in hepatitis C virus carriers with persistently normal ALT, around 5-10% in patients with elevated ALT and F0 (no fibrosis) in the initial biopsy but >30-40% in chronic carriers with elevated ALT and F1 (portal fibrosis) in the initial biopsy. Cofactors like age at infection, alcohol, coinfections and liver steatosis accelerate disease progression. On the basis of these findings, patients with initially mild chronic hepatitis C and elevated ALT should be proposed for antiviral therapy in the absence of contraindications.     

Chronic hepatitis C in children--review of natural history at a National Centre

The natural history of hepatitis C virus (HCV) infection in adults has been established, but less is known about outcome in children. We conducted a retrospective review of patients referred to Birmingham Children's Hospital Liver Unit, from 1991 till 2008, with the diagnosis of HCV was undertaken. Only children with documented positive HCV RNA and a minimum duration of follow-up of 6 months were included. One hundred and thirty-three children were identified. The route of transmission was transfusion acquired in 47%, vertically acquired in 49% and transplantation in 2%. Since 2000, most children were infected vertically. The overall rate of spontaneous viral clearance was 17.5% with higher clearance (27%) in the transfusion group compared to the vertically acquired group (9%). Seventy-six had a liver biopsy at diagnosis. There was no evidence of fibrosis in 46%, mild fibrosis in 50% and moderate to severe fibrosis in 4%. None had cirrhosis. There was a statistically significant relationship between fibrosis score and older age at the time of biopsy (P = 0.02) and longer duration of infection (P = 0.05). Eighty children received treatment for HCV. Sustained viral response (SVR) was influenced by viral genotypes, with significantly increased response rates in genotypes (G) 2 and 3 compared to G 1 and 4. Vertical infection is now the major route of HCV infection in children in the UK. Histological changes were mild at diagnosis, but the severity of fibrosis progressed with age. Consideration should be given to improve detection and diagnosis to refer children to specialist centres for management and antiviral therapy before developing fibrosis.     

Natural course of HGV infection in haemophiliacs

The natural course of hepatitis G virus (HGV) infection was clarified in 70 haemophiliacs by testing for HGV RNA and antibodies against HGV envelope protein (anti-E2). None of 12 patients treated with only virus-inactivated coagulation factors were infected with HGV. Of 58 patients who received non-inactivated products, 28 (48%) were positive for HGV RNA and/or anti-E2. Of 16 patients with anti-E2, 14 were negative for the viral RNA, and had recovered from HGV infections. HCV antibodies were detected in 59 patients, and eight patients were successively negative for HCV RNA. Thus, the recovery rate of HGV infection (14/28, 50%) was higher than that of HCV (8/59, 14%) ( P  < 0.001). Longitudinal study revealed that anti-E2 developed either during viraemia or some years after seronegativity for HGV RNA. Hence the antibody response itself seemed not to play a major role in the clearance of HGV, though anti-E2 was associated with the clearance of HGV RNA. In conclusion, HGV and HCV are prevalent in patients treated with unsterilized coagulation factor concentrates. However, in contrast to HCV, spontaneous recovery is frequently observed in HGV infections.     

Interferon and ribavirin in HIV-negative haemophiliacs with chronic hepatitis C who were nonresponders to a previous interferon treatment

Between January 1999 and December 2001, 33 HIV-negative haemophiliacs with interferon-nonresponsive chronic hepatitis C were treated with interferon (IFN) alpha2b (5 MU three times weekly) and ribavirin (1-1.2 g daily) for 12 months. Four patients (12.1%) dropped out of the study due to adverse effects. At the end of therapy, normalization of ALT occurred in 14/33 treated patients (42.4%) and HCV-RNA was cleared in 12 (36.4%). Eleven patients (33.3%) became sustained responders. Genotype 1 was the only factor associated with a poor response to therapy (P < 0.001). Our study shows that IFN and ribavirin combination therapy is effective in HIV-negative chronically HCV-infected haemophiliacs who do not respond to a previous IFN treatment.     

Liver biopsy in patients with inherited disorders of coagulation and chronic hepatitis C

Liver biopsy plays a pivotal role in the management of patients with a variety of liver diseases, including chronic hepatitis C virus. The major risk of the procedure is the potential for significant haemorrhagic complications. Although the data are limited, the procedure does not appear to pose excessive risk to the patient with inherited disorders of coagulation, provided that adequate haemostasis can be achieved prior to the liver biopsy. This requires close coordination of care between the hepatologist and the haematologist. Indications for liver biopsy should be the same in patients with haemophilia as in other populations.     

Historical features are poor predictors of liver fibrosis in Canadian patients with chronic hepatitis C

The progression of fibrosis in chronic hepatitis C infection (HCV) is related to host factors including age, gender and alcohol consumption. Due to the morbidity and potential mortality of liver biopsy, a noninvasive method of assessing hepatic fibrosis is needed. The aim of this study was to assess the utility of historical features in predicting fibrosis using published rates of fibrosis progression. The charts of 239 untreated patients with HCV were reviewed; patients who had a liver biopsy and whose duration of infection could be estimated (n=106) were categorized according to gender, age at infection (≤ or > 40 years) and peak alcohol consumption (< or ≥ 50 g/day). Estimates of fibrosis were calculated using the product of the interval between infection and biopsy and published rates of fibrosis progression. Estimates were compared with liver biopsies staged according to the Metavir system (F0–F4; F0=no fibrosis; F4= cirrhosis). The mean age of patients was 42 ± 8 years, 61% were male and 36% consumed > 50 g of alcohol daily. The mean duration of infection was 19 ± 9 years (range, 1–40) and ALT was elevated > 1.5 times upper normal in 63%. When patients were classified into those with mild (F0–F2) and severe (F3–F4) fibrosis, the sensitivity, specificity, positive predictive value and negative predictive value of an estimate of mild fibrosis was 60%, 55%, 78% and 34%, respectively. An estimate of severe fibrosis had a sensitivity of 55%, specificity of 60%, positive predictive value of 34% and negative predictive value of 78%. Agreement between fibrosis estimates and actual histological stages was poor (kappa = 0.13, P=0.08). The prediction of hepatic fibrosis in HCV infection using historical features and published rates of fibrosis progression is poor in a Canadian clinical practice setting. Alternate noninvasive methods of predicting hepatic fibrosis are needed.     

Percutaneous liver biopsy in adult haemophiliacs with hepatitis C virus: safety of outpatient procedure and impact of human immunodeficiency virus coinfection on the spectrum of liver disease

Both HCV and HIV are common in haemophiliacs previously treated with non-viral-inactivated clotting factor concentrates. Because of increased bleeding risks, little data are available on the safety of percutaneous outpatient liver biopsy (LBx) and impact of HIV coinfection in this population. This study aims at reporting our experience with percutaneous LBx in a cohort of haemophiliacs infected with HCV and describe the spectrum of disease and impact of HIV coinfection. A retrospective review of consecutive patients with haemophilia and HCV who underwent percutaneous LBx was performed. All patients were positive for HCV RNA by commercial assay and received factor concentrate prior to biopsy. A total of 29 male patients (mean age 36, 24 haemophilia A, five haemophilia B, and 44% coinfected with HIV) underwent successful outpatient percutaneous LBx without bleeding complication. Histologic activity index was 6.44 with advanced fibrosis (bridging fibrosis/cirrhosis) in 31%. When patients were stratified by HIV positive (n = 13) vs. HIV negative (n = 16), coinfected patients had higher fibrosis scores and higher proportion advanced fibrosis (54% vs. 12%; P = 0.0167) with no differences in age, demographic or other laboratory parameters. Multivariate logistic regression found that HIV positivity was independently associated with advanced fibrosis (OR = 3.7; 95% CI: 1.17-11.8; P = 0.026). Outpatient percutaneous LBx can be safely performed in patients with haemophilia. Despite similar age, HIV coinfection was an independent predictor of advanced fibrosis. These data support the hypothesis that HIV accelerates fibrosis progression in those coinfected with HCV and highlights the importance of liver histology in this population.     

Histological progression during short-term follow-up of patients with chronic hepatitis C virus infection

Assessment of prognosis from hepatitis requires liver histology. When the fibrosis stage is known, and if the fibrosis progression rate can be established, time to development of cirrhosis can be calculated. The fibrosis progression rate can be calculated from a single biopsy when duration of infection prior to biopsy is known. Sequential biopsies can also be examined. In this work, we studied histological activity and fibrosis stage in liver biopsies of 157 hepatitis C virus (HCV)-infected patients, including 92 for whom the approximate duration of infection was known. The mean fibrosis progression rate was 0.09 units per year, and was not influenced by mode of infection or viral genotype. Forty-six patients who had very mild histological changes in the initial biopsy underwent repeat biopsy 2 years later (with no intervening anti-viral treatment). Comparison of paired biopsies confirmed a tendency to histological progression and increasing hepatic fibrosis (mean, 0.15 fibrosis units per year). A normal baseline alanine aminotransferase (ALT) value was associated with slow fibrosis progression before baseline biopsy and between biopsies. These data do not differ from published cross-sectional and longitudinal studies, and suggest that histological progression will be observed during follow-up of most patients, including those with mild histological changes at time of initial assessment.