Announcements
On 6 June 2017, the World Health Organization (WHO) published updates to its ‘Essential Medicines List’ (EML). Read more here.

Eurosurveillance is on the updated list of the Directory of Open Access Journals and in the SHERPA/RoMEO database. Read more here.

Follow Eurosurveillance on Twitter: @Eurosurveillanc


In this issue


Home Eurosurveillance Edition  2017: Volume 22/ Issue 30 Article 3
Back to Table of Contents
Previous Download (pdf)
Next

Eurosurveillance, Volume 22, Issue 30, 27 July 2017
Research article
Sanna, Le Strat, Roudot-Thoraval, Deuffic Burban, Carrieri, Delarocque-Astagneau, and Larsen: Severe liver disease related to chronic hepatitis C virus infection in treatment-naive patients: epidemiological characteristics and associated factors at first expert centre visit, France, 2000 to 2007 and 2010 to 2014

+ Author affiliations


Citation style for this article: Sanna A, Le Strat Y, Roudot-Thoraval F, Deuffic Burban S, Carrieri P, Delarocque-Astagneau E, Larsen C. Severe liver disease related to chronic hepatitis C virus infection in treatment-naive patients: epidemiological characteristics and associated factors at first expert centre visit, France, 2000 to 2007 and 2010 to 2014. Euro Surveill. 2017;22(30):pii=30582. DOI: http://dx.doi.org/10.2807/1560-7917.ES.2017.22.30.30582

Received:06 December 2016; Accepted:14 May 2017


Introduction

French public health policies have targeted hepatitis C virus (HCV) infection since the mid-1990s. Health authorities have promoted HCV-screening among individuals at risk of infection, and have enhanced and improved access to specialised care and antiviral treatment. They have also effectively reduced HCV transmission in the following contexts: blood transfusion [1], healthcare and PWID (people who inject drugs) [2].

France is a low endemic country for HCV infection. In 2004, the prevalence of chronic HCV infection in the general population was estimated at 0.53% (95% confidence interval (CI): 0.40–0.70), corresponding to 232,196 adults (95% CI: 167,869–296,523) 18–80 years of age, nearly 43% of whom were unaware of their infection [3]. Among the infected PWID population, 91% were aware of their infection, but among the blood transfusion recipients, only 50.7% were [3]. Prevalence has tended to decrease since then, with prevalence in 2011 being 0.42% (192,700 adults) [4]. In addition, the estimated number of undiagnosed chronically HCV-infected individuals has also decreased (72,102 adults in 2014) [5].

Chronic HCV infection can evolve into cirrhosis in 10–20% of cases over a period of 20 to 30 years. Cirrhosis is its main complication, along with hepatocellular carcinoma (HCC) [6]. Alcohol abuse, hepatitis B virus (HBV) and human immunodeficiency virus (HIV) co-infections, as well as metabolic disorders have all been shown to be major determinants of liver disease progression to cirrhosis, but individual-specific variations exist because of virus-host interactions. Cirrhosis and HCC have a significant impact on morbidity and mortality related to chronic HCV infection [6]. However, successful treatment of the viral infection can stop evolution to severe liver disease (SLD), can limit the risk of cirrhosis decompensation and its associated liver-related mortality [7] and can even lead to fibrosis regression [8].

Results from treatment with new direct-acting antivirals (DAAs) show very high success rates (sustained virologic response (SVR) rates can reach up to 95–99% with slight variations according to the viral genotype), good tolerance and short therapeutic course [9].

In most European countries, access to these drugs is limited because of their high cost. Priority is given to patients with significant liver fibrosis or cirrhosis (METAVIR score F2-F4), extra-hepatic complications, or HBV or HIV co-infection [10]. However, to increase treatment effectiveness, treatment before the occurrence of cirrhosis (i.e. before METAVIR score F4) is preferable. In fact, SLD is an important negative predictor of SVR in DAAs-based therapy. Moreover, SVR in patients with a METAVIR score of F4 do not necessarily protect from further hepatic complications (e.g. decompensated cirrhosis, HCC) [9].

In France, hepatology expert centres have a pivotal role in chronic HCV infection evaluation and treatment. Until June 2016, their approval was necessary for any HCV antiviral drugs prescription [11].

Given these points, a better understanding of factors associated with late-stage liver disease in patients seeking care at an expert centre for the first time would help inform public health policymaking. It would indeed allow patients identified as at risk of developing hepatic complications to benefit from closer follow-up, and earlier referral and treatment access. Concrete interventions could include increasing HCV screening coverage, comorbidity prevention, and training of physicians involved in the follow-up of such patients.

The main objective of our study is to describe the chronic HCV-infected population seeking care at the hepatology expert centres in France from 2000 to 2007 and from 2010 to 2014, and to identify the factors associated with having HCV infection-related SLD at the time of their first evaluation there.

Methods

Study population

For the present analysis, we included data from patients who sought care for chronic HCV infection at hepatology expert centres across France from two periods: 2000 to 2007 and 2010 to 2014.

Patients with first visit to an expert centre in 2000–2007

For the period 2000 to 2007, patients were recruited by the hepatitis C hospital service-based surveillance network coordinated by Santé publique France (the French National Public Health Agency) [11]. A total of 26 of the 30 hepatology expert centres located in university hospitals throughout France participated in the network. Every newly-referred adult (≥ 18 years of age) patient with anti-HCV antibodies visiting any of these 26 centres (as an outpatient or inpatient) for the first time was included after consent and without further inclusion criteria.

Patients with first visit to an expert centre in 2010–2014

For the period 2010 to 2014, patients who agreed to participate in the nationwide multi-centre cohort study ANRS (France Recherche Nord & Sud Sida-HIV Hépatites) CO22 HEPATHER (ClinicalTrials.gov, number: NCT01953458) [12] that actively recruited individuals infected with HBV or HCV in 2012–2014, were also included. A total of 32 expert centres were involved in cohort recruitment, 26 of which had participated in the former hepatitis C surveillance network. Every adult (≥ 18 years of age) attending centres for HCV or HBV infection follow-up in 2012–2014 was eligible for inclusion in the cohort, regardless of infection duration and duration of the follow-up at the expert centre, with the exception of HIV co-infected patients, pregnant women and adults who could not independently provide consent to participate.

For our analyses, data for patients from these two populations that met the following criteria were included: we selected individuals (i) seeking care for chronic hepatitis C as defined in the following section, (ii) with no history of liver biopsy at the time of first expert centre visit, (iii) who were antiviral treatment naive, and (iv) whose first expert centre visit occurred in the 24 months preceding inclusion in the ANRS CO22 HEPATHER cohort study so as to avoid overlap between the two study periods. Analyses were also restricted to patients who (v) were HIV-negative and (vi) 18 years of age or older.

Data collection

For all patients in the study, standardised forms were used to collect data from the visit (interview and patient assessment) on the following: sociodemographic characteristics; history of HCV infection; HCV infection risk factors; stage of liver disease when first examined at expert centre (liver fibrosis was evaluated by METAVIR score, clinical signs and liver biochemical markers such as alanine aminotransferase (ALT)); comorbidities such as alcohol consumption and HBV–co-infection; HCV-RNA viral load; and HCV genotype. We analysed data collected at the time of patients’ first visit to the centres or, when this was not possible, the earliest available data from a consultation after the first visit.

Definitions

Chronic hepatitis C was defined as testing positive for anti-HCV antibodies with persistent detection of HCV-RNA for at least six months after diagnosis.

Liver fibrosis was assessed either by invasive (liver biopsy) or validated non-invasive methods based on serum biomarkers (FibroTest) or based on liver stiffness measurement by transient elastography (FibroScan) [13]. Liver fibrosis assessments were considered for the present analysis if they were performed not more than 12 months before or after the first visit to an expert centre.

In the absence of liver fibrosis assessment, cirrhosis was assessed by a clinical evaluation, which included a physical examination, biochemical tests and imaging, mainly abdominal ultrasound (Table 1). Clinical evaluation was taken into account if performed at the time of first expert centre visit or in the 24 months before inclusion in the ANRS CO22 HEPATHER cohort.

Table 1

Study criteria for presence of cirrhosis, France, 2000–2007 and 2010–2014

Liver fibrosis
assessment
Criteria for cirrhosis
Yes Liver biopsy: METAVIR score F4
Serum biomarker (in absence of liver biopsy): FibroTest ≥ 0.75 [34]
Transient elastography (in absence of liver biopsy and serum biomarkers): FibroScan liver stiffness ≥ 12.5 kPa (cut-off correlated with METAVIR score F4) [35]
No Clinical evidence of cirrhosis: association of clinical signs, laboratory findings and imaging [36].

SLD was defined by the diagnosis of either cirrhosis or HCC.

Excessive alcohol intake was defined as more than 140 g of pure ethanol per week for women and more than 210 g per week for men, corresponding to 14 and 21 glasses of wine, respectively. Both present and past consumption were recorded at the time of the interview.

Endemicity of HCV infection in countries of birth was defined according to anti-HCV prevalence estimated by Gower et al. [14] and Lavanchy et al. [15]. Global HCV prevalence data were then categorised in five quintiles: ≤ 0.85%, 0.86–1.4% and 1.5–2% (low HCV prevalence), 2.1–3.2% (intermediate HCV prevalence), and > 3.2% (high HCV prevalence).

Patients’ referral years were categorised into three periods: 2000 to 2003, 2004 to 2007 and 2010 to 2014.

The ALT ratio was calculated as function of the upper limit of normal; during the first two periods, this data was already reported as a ratio and during the last period, it was calculated using an upper limit of normal compatible with that used by clinicians during the first period (35 IU/L).

Statistical methods

Patient characteristics were presented as numbers and proportions for each category of qualitative data, and as medians and interquartile ranges (IQR) for quantitative data. For each variable, the number and proportion of missing data were also reported.

Bivariate analyses according to the stage of the liver disease (SLD or not) were performed using Poisson regression models. Bivariate modelling of explanatory variables was performed by introducing fractional polynomials to find the best relationship between risk of SLD and the independent variable [16].

Missing data were considered as resulting from a missing at random (MAR) mechanism. A multiple imputation was performed using chained equation [17]. We included all the variables from the multivariate model in the imputation model to ensure that both models (for imputation and analyses) were congenial [17]. For each non-Gaussian continuous variable, we applied the transformation proposed by Nevalainen et al. [18]. We generated 100 imputed datasets. The distributions before and after imputation were compared for every selected variable and were found to be similar.

Factors associated with SLD were identified using multivariate Poisson regression [19] with robust variance and fractional polynomials for continuous explanatory variables [16,20]. The following co-variables were identified a priori and were included in the multivariable model if they had a p value < 0.20 in the bivariate analyses: sex, country of birth, age at HCV diagnosis, circumstances of HCV diagnosis, time between HCV diagnosis and first expert centre visit, French area/region of first expert centre visit, study period at time of first expert centre visit, HCV infection risk factor, excessive alcohol intake, HCV genotype, HBV co-infection and ALT ratio. They were selected using a manual stepwise backward approach. The area/region of referral was forced into the model as an adjustment variable, in order to partially take into account a potential centre effect. We tested interactions between sex and risk factors, sex and excessive alcohol intake, and risk factors and excessive alcohol intake. We also tested interactions between the study period and, respectively, excessive alcohol consumption, HCV infection risk factors, circumstances of diagnosis and HCV genotype. These analyses were performed on both complete cases and after imputation to estimate adjusted prevalence ratios (aPR), their 95% confidence intervals (95% CI) and p values.

All the analyses were performed with STATA 12 (StataCorp, College Station, Texas, United States) and R (version 3.2.3) statistical software. All tests were considered significant with a two-tailed p value ≤ 0.05. The Stata user-written programme ICE was used to perform the imputation process.

Ethical statements

Protocols for the two studies were approved by the French data protection authority (CNIL) and explained to all patients meeting the case definition, and who provided written consent when enrolled.

Results

A total of 16,851 patients matched our inclusion criteria: 15,529 from the hepatitis C surveillance network and 1,322 from the ANRS CO22 HEPATHER study (Table 2). Of these patients, 55.7% were men, 72.5% were born in low-endemic areas for HCV infection (HCV infection prevalence ≤ 2%), mostly France and other European countries, and 8.1% were born in areas with high HCV prevalence. The proportion of patients born in areas with high HCV prevalence varied from 6.1% in 2000–2003 to 15% in 2010–2014. The median age at diagnosis was 44 years (IQR: 35-56), corresponding to a median age of 43, 44 and 49 years in the three study periods, respectively.

Table 2

Characteristics of patients with chronic hepatitis C at time of their first visit to a hepatology expert centre, France, 2000–2007 and 2010–2014 (n = 16,851).

Patient characteristics Overall Period of first visit at expert centre following referral
2000–2003a 2004–2007a 2010–2014a
n or
(median)
% or
 (IQR) 
n or
(median)
% or
 (IQR) 
n or
(median)
% or
 (IQR) 
n or
(median)
% or
 (IQR) 
Total number of patients 16,851 NA 8,648 NA 6,881 NA 1,322 NA
Sex Female 7,374 43.8 3,848 44.5% 3,011 43.8 515 39
Male 9,386 55.7 4,709 54.5 3,870 56.2 807 61
Missing 91 0.5 91 1.1 0 0 0 0
Country of birth France 10,615 63 5,762 66.6 3,988 58 865 65.4
Europe (outside France) 818 4.9 336 3.9 380 5.5 102 7.7
North Africa and Middle East 973 5.8 430 5 426 6.2 117 8.9
Sub-Saharan Africa 802 4.8 327 3.8 330 4.8 145 11
Asia, Pacific, Americas 622 3.7 229 2.6 304 4.4 89 6.7
Missing 3,021 17.9 1,564 18.1 1,453 21.1 4 0.3
HCV endemicity in country of birth b ≤ 0.85% 10,722 63.6 5,812 67.2 4,029 58.6 881 66.6
0.86–1.4% 738 4.4 318 3.7 295 4.3 125 9.5
1.5–2% 751 4.5 364 4.2 299 4.3 88 6.7
2.1–3.2% 219 1.3 64 0.7 129 1.9 26 2
> 3.2% 1,363 8.1 526 6.1 639 9.3 198 15
Missing 3,058 18.1 1,564 18.1 1,490 21.7 4 0.3
Age at HCV infection diagnosis Years (44) (35–56) (43) (34–56) (44) (35–55) (49) (40–57)
Circumstances of HCV infection diagnosis Systematic screening 8,344 49.5 3,911 45.2 3,466 50.4 967 73.1
Exposure to a HCV infection risk 3,145 18.7 1,871 21.6 1,182 17.2 92 7
Symptoms or laboratory findings 3,551 21.1 2,037 23.6 1,292 18.8 222 16.8
Unknown 1,811 10.7 829 9.6 941 13.7 41 3.1
Time between HCV diagnosis and first expert centre visit Months (4) (2–32) (4) (1–27) (5) (2–39) (5) (2–38)
French area/region of first visit Paris area 3,481 20.7 1,775 20.5 1,259 18.3 447 33.8
North-West 3,825 22.7 2,200 25.4 1,504 21.9 121 9.2
North-East 2,978 17.7 1,545 17.9 1,184 17.2 249 18.8
South-West 2,586 15.3 1,370 15.8 1,039 15.1 177 13.4
South-East 3,746 22.2 1,644 19 1,788 26 314 23.8
French Caribbean islands 235 1.4 114 1.3 107 1.6 14 1.1
HCV infection risk factor Intravenous drug use 5,234 31.1 2,756 31.9 2,105 30.6 373 28.2
Nasal drug use 347 2.1 151 1.7 139 2 57 4.3
Blood-derived product transfusion
before 1991
4,402 26.1 2,427 28.1 1,679 24.4 296 22.4
Other risk factors 4,029 23.9 1,863 21.5 1,574 22.9 592 44.8
No risk factor found 2,839 16.8 1,451 16.8 1,384 20.1 4 0.3
HBV co-infection at first visit No 12,283 72.9 5,764 66.7 5,523 80.3 996 75.3
Yes 315 1.9 149 1.7 141 2 25 1.9
Missing 4,253 25.2 2,735 31.6 1,217 17.7 301 22.8
Excessive alcohol intake c None 10,946 65 5,459 63.1 4,742 68.9 745 56.4
Current 466 2.8 288 3.3 178 2.6 0 0
Current and past 1,293 7.7 815 9.4 426 6.2 52 3.9
Past 2,303 13.7 1,049 12.1 910 13.2 344 26
Missing 1,843 10.9 1,037 12 625 9.1 181 13.7
HCV genotype 1 7,023 41.7 3,198 37 3,142 45.7 683 51.7
2 1,391 8.3 683 7.9 601 8.7 107 8.1
3 2,402 14.3 1,125 13 1,065 15.5 212 16
4 1,146 6.8 471 5.4 511 7.4 164 12.4
5, 6 or 7 281 1.7 132 1.5 118 1.7 31 2.3
Missing 4,608 27.3 3,039 35.1 1,444 21 125 9.5
ALT ratio d Times the upper limit of normal (1.5) (1–2.5) (1.5) (1–2.5) (1.5) (1–2.3) (1.71) (1.03–2.91)
Severe liver diseasee None 13,566 80.5 7,053 81.6 5,622 81.7 891 67.4
Cirrhosis 1,798 10.7 710 8.2 748 10.9 340 25.7
Hepatocellular carcinoma 151 0.9 57 0.7 66 1 28 2.1
Missing 1,336 7.9 828 9.6 445 6.5 63 4.8
Severe liver disease diagnostic tool No severe liver disease 13,566 80.5 7,053 81.6 5,622 81.7 891 67.4
Liver biopsy 834 4.9 485 5.6 283 4.1 66 5.0
FibroTest 391 2.3 0 NA 301 4.4 90 6.8
FibroScan 107 0.6 0 NA 0 NA 107 8.1
Clinical evaluation 617 3.7 282 3.3 230 3.3 105 7.9
Missing 1,336 7.9 828 9.6 445 6.5 63 4.8

ALT: alanine aminotransferase; HCV: hepatitis C virus; IQR: interquartile range; NA: not applicable.

a Data for the time periods 2000–2003 and 2004–2007 came from France’s hepatitis C surveillance network while that for the time period 2010–2014 came from the nationwide multi-centre cohort study ANRS CO22 HEPATHER.

b Endemicity of HCV in countries of birth was defined according to anti-HCV prevalence estimated by Gower et al. [14] and Lavanchy et al. [15]. Global HCV prevalence data were then categorised into 5 quintiles: ≤ 0.85%, 0.86–1.4% and 1.5–2% (low HCV prevalence), 2.1–3.2% (intermediate HCV prevalence) and > 3.2% (high HCV prevalence).

c Excessive alcohol intake was defined as consumption of more than 140 g of pure ethanol per week for women and 210 g of pure ethanol per week for men, corresponding to 14 and 21 glasses of wine, respectively. Present and past consumption were recorded at the moment of the interview.

d The ALT ratio was calculated as function of the upper limit of normal; during the first two periods, this data was already reported as a ratio and during the last period, it was calculated using an upper limit of normal compatible with that used by clinicians during the first period (35 IU/L).

e Severe liver disease (SLD) was defined by the diagnosis of either cirrhosis or hepatocellular carcinoma.

Overall, a history of intravenous drug use and blood transfusion before 1991 were found in 31.1% and 26.1% of patients respectively.

In 18.7% of all patients, known exposure to a HCV risk factor was what led to HCV infection diagnosis (ranging from 21.6% in 2000–2003 to 7% in 2010–2014) and in 49.5% of cases, it came through systematic screening such as blood donor screening, pre-surgery and pre-transfusion screening, prenatal testing, screening for insurance contract (ranging from 45.2% in 2000–2003 to 73.1% in 2010–2014).

The median time between diagnosis and referral to the expert centre was 4 months (IQR: 2-32) and seemed homogeneous across the three periods, as did the ALT ratio at referral (1.5 times higher than the upper limit of normal) and the proportion of patients with a HBV-co-infection (1.9%). Patients were mainly infected by HCV genotype 1 and 3, with this being in 57.3% and 19.6% of patients with a known genotype, respectively. Of note, the proportion of patients infected with an unknown genotype varied from 35.1% in the first study period to 9.5% in the third.

Of all patients, 10.5% were found to declare a current excessive consumption of alcohol at the time of the interview.

Overall, cirrhosis diagnosis was present at first visit in 10.7% of the patients and HCC was present in 0.9%. Among patients recruited during the third study period, cirrhosis and HCC were present in 25.7% and 2.1% of patients, respectively.

Factors associated with severe liver disease (SLD)

All selected variables, except for HBV co-infection, were significantly associated with the risk of SLD at patients’ first visit based on the bivariate analysis, and were introduced in the initial regression models. These statistically significant associations were confirmed by the multivariable analysis of imputed data. (Table 3)

Table 3

Estimation of adjusted prevalence ratios of severe liver disease in patients with chronic hepatitis C at first visit in hepatology expert centres in France using multivariate models in a complete cases analysis and after multiple imputation, France, 2000–2007 and 2010–2014

Patient characteristics Complete cases multivariate analysis
(n = 8,171)
Multiple imputation multivariate analysis
(n = 16,851)
Number of patients with SLD/total number patients per strata % SLDa per strata   aPR        95% CI       p value    aPR        95% CI       p value 
Sex Female 341/3,472 9.8 1 Ref < 0.001 1 Ref < 0.001
Male 744/4,699 15.8 1.58 1.40–1.75 1.53 1.40–1.67
Country of birth France NA NA NA NA NA 1 Ref 0.002
Europe (outside France) NA NA NA NA NA 1.06 0.89–1.26 0.504
North Africa and Middle East NA NA NA NA NA 1.34 1.16–1.56 < 0.001
Sub-Saharan Africa NA NA NA NA NA 1.00 0.80–1.26 0.975
Asia, Pacific, Americas NA NA NA NA NA 0.98 0.78–1.22 0.827
Age at HCV infection diagnosis 18 years 0/35 0.0 1 Ref < 0.001 1 Ref < 0.001
19–30 years (25)b 37/1,118 3.3 2.36 2.17–2.57 2.23 2.10–2.38
31–40 years (35)b 124/2,002 6.2 5.69 4.80–6.75 5.09 4.47–5.79
41–50 years (45)b 309/2,175 14.2 10.98 8.68–13.89 9.40 7.87–11.24
51–60 years (55)b 285/1,416 20.1 18.56 13.93–24.72 15.36 12.36–19.09
61–70 years (65)b 196/899 21.8 28.73 20.66–39.94 23.11 18.01–29.67
71–90 years (80)b 133/482 27.6 49.44 33.72–72.50 38.41 28.74–51.33
Circumstances of HCV infection diagnosis Systematic screening 555/4,585 12.1 1 Ref < 0.001 1 Ref < 0.001
Exposure to a HCV infection risk 119/1,629 7.3 0.90 0.74–1.08 0.254 0.90 0.78–1.05 0.176
Symptoms or laboratory findings 411/1,957 21.0 1.41 1.26–1.58 < 0.001 1.47 1.34–1.61 < 0.001
Time between HCV diagnosis and first expert centre visit 0 months 124/672 18.5 1 Ref < 0.001 1 Ref < 0.001
1–6 months (3)b 496/4,098 12.1 1.02 1.01–1.02 1.01 1.01–1.02
7–12 months (9)b 105/754 13.9 1.05 1.04–1.06 1.04 1.04–1.05
13–24 months (18)b 64/504 12.7 1.11 1.09–1.13 1.09 1.07–1.11
25–48 months (36)b 72/527 13.7 1.22 1.18–1.27 1.19 1.15–1.23
48–96 months (72)b 94/770 12.2 1.50 1.39–1.61 1.42 1.33–1.50
97–192 months (144)b 104/770 13.5 2.24 1.94–2.58 2.01 1.78–2.26
193–288 months (240)b 26/76 34.2 3.83 3.02–4.86 3.19 2.61–3.90
French area/region of first visit Paris area 229/1,466 15.6 1 Ref 0.047 1 Ref < 0.001
North-West 214/1,833 11.7 0.96 0.81–1.13 0.600 1.25 1.10–1.42 0.001
North-East 190/1,417 13.4 1.00 0.84–1.17 0.955 1.21 1.06–1.39 0.004
South-West 156/1,510 10.3 0.82 0.68–0.98 0.026 1.14 0.99–1.31 0.071
South-East 271/1,777 15.3 1.08 0.93–1.25 0.316 1.38 1.23–1.55 < 0.001
French Caribbean islands 25/168 14.9 1.19 0.83–1.69 0.343 1.53 1.13–2.09 0.007
Study period at first visit 2000–2003 c 358/3,602 9.9 1 Ref < 0.001 1 Ref < 0.001
2004–2007 c 451/3,697 12.2 1.23 1.08–1.39 0.001 1.31 1.20–1.43 < 0.001
2010–2014 c 276/872 31.7 2.14 1.84–2.49 < 0.001 2.39 2.13–2.69 < 0.001
HCV infection risk factor Intravenous drug use 282/2,631 10.7 1 Ref 0.038 1 Ref 0.004
Nasal drug use 31/200 15.5 1.21 0.91–1.61 0.196 1.14 0.88–1.48 0.325
Blood product transfusion
before 1991
327/2,152 15.2 1.18 0.99–1.40 0.058 1.19 1.04–1.37 0.011
Other risk factors 284/2,104 13.5 1.01 0.86–1.19 0.889 1.00 0.87–1.15 0.967
No risk factor found 161/1,084 14.9 1.25 1.03–1.51 0.026 1.27 1.09–1.47 0.002
Excessive alcohol intake d None 624/5,926 10.5 1 Ref < 0.001 1 Ref < 0.001
Current 35/257 13.6 1.48 1.08–2.03 0.015 1.39 1.09–1.78 0.009
Current and past 129/637 20.3 2.15 1.81–2.56 < 0.001 2.18 1.90–2.49 < 0.001
Past 297/1,351 22.0 1.90 1.67–2.17 < 0.001 2.08 1.87–2.31 < 0.001
HCV genotype 1 643/4,701 13.7 1 Ref < 0.001 1 Ref < 0.001
2 103/919 11.2 0.81 0.67–0.98 0.027 0.84 0.72–0.98 0.031
3 229/1,602 14.3 1.36 1.19–1.57 < 0.001 1.29 1.15–1.45 < 0.001
4 84/765 11.0 1.07 0.88–1.31 0.487 0.99 0.82–1.19 0.887
5, 6 or 7 26/184 14.1 0.77 0.55–1.08 0.127 0.76 0.57–1.00 0.054
ALT ratio e 1 51/1,133 4.5 1 Ref < 0.001 1 Ref < 0.001
1–2.5 (2)b 463/3,684 12.6 1.68 1.52–1.86 1.61 1.50–1.72
2.5–10 (6.5)b 476/1,936 24.6 2.96 2.54–3.45 2.87 2.55–3.22
> 10 (20)b 11/60 18.3 1.40 0.66–2.97 1.80 1.06–3.04

ALT: alanine aminotransferase; aPR: adjusted prevalence ratio; CI: confidence interval; HCV: hepatitis C virus; NA: not available, not applicable or not known; Ref: reference group for comparison; SLD: severe liver disease.

a Severe liver disease (SLD) was defined by the diagnosis of either cirrhosis or hepatocellular carcinoma.

b Numbers in brackets are the middle value of the category, used to estimate the aPR.

c Data for the time periods 2000–2003 and 2004–2007 came from France’s hepatitis C surveillance network while that for the time period 2010–2014 came from the nationwide multi-centre cohort study ANRS CO22 HEPATHER.

d Excessive alcohol intake was defined as consumption of more than 140 g of pure ethanol per week for women and 210 g of pure ethanol per week for men, corresponding to 14 and 21 glasses of wine, respectively. Present and past consumption were recorded at the moment of the interview.

e The ALT ratio was calculated as function of the upper limit of normal; during the first two periods, this data was already reported as a ratio and during the last period, it was calculated using an upper limit of normal compatible with that used by clinicians during the first period (35 IU/L).

The following factors were associated with an increased risk of SLD at the time of first visit: male sex (aPR = 1.53; 95% CI: 1.40–1.67); being born in North Africa or the Middle East (aPR = 1.34; 95% CI: 1.16–1.56) compared with being born in France; blood product transfusion before 1991 (aPR = 1.19; 95% CI 1.04–1.37) and no other known HCV risk factor (aPR = 1.27; 95% CI: 1.09–1.47) compared with intravenous drug use; current and/or past excessive alcohol intake (p < 0.001); and symptom-based HCV diagnosis compared with diagnosis from systematic screening (aPR = 1.47; 95% CI: 1.34–1.61).

Compared with genotype 1, genotype 2 was found to be negatively associated with SLD while genotype 3 was found to be associated with an increased risk of SLD in both complete case and multiple imputed data analyses.

Age at diagnosis and time between diagnosis and first expert centre visit were linked by a positive nonlinear relationship with the risk of SLD (Table 3). The ALT ratio (cf.d with the upper limit of normal) was linked by a nonlinear non-monotonic relation with the risk of SLD (Table 3).

The prevalence of SLD significantly changed across the three study periods (p < 0.001 in both analyses) and doubled between the first period (2000–2003) and the last (2010–2014).

Apart from the country of birth, which was not significantly associated with the risk of SLD in the complete cases analysis, results from the complete cases multivariate analysis (n = 8,171) and multiple imputation multivariate analysis (n = 16, 851) were similar.

We found no statistically significant interaction.

Discussion

Our observational multi-centre study allows us to describe factors associated with SLD in patients with chronic hepatitis C at the time of their first visit to a hepatology expert centre in France from 2000 to 2007 and 2010 to 2014. It confirms the influence of several known risk factors for SLD in chronic hepatitis C, including male sex, a history of excessive alcohol intake, age at diagnosis and HCV genotype 3 [6,11,21].

During the overall study period we observed a general increase in the percentage of SLD at first visits. This trend is consistent with those observed via the French Hospital Discharge Data System (PMSI) from 2004 to 2011, where both diagnosis of cirrhosis and of HCC among the HCV-infected hospitalised population increased from 17.8% to 33.7% and from 4.0% to 7.3%, respectively [22]. During the same period, the prevalence of chronic hepatitis C tended to decrease in the hospitalised population (from 0.45% to 0.33%) and general population (from 0.53% to 0.42%) in France [22]. These opposing trends could reflect an ageing of patients infected with HCV in recent decades and fewer new HCV infections in France. Patients’ evaluation at an expert centre was a key moment before specific treatment, and in general, patients with SLD may have been referred for follow-up and treatment more frequently than non-severe patients. During the 2012–2014 period, which corresponds with the start of HCV treatment with DAAs, patients with severe liver fibrosis or SLD had priority access to these innovative treatments. In this context, patients with SLD were probably referred to expert centres for treatment by their general practitioner more frequently than in the past. It may therefore be the case that the evolution observed in our data reflects increased attractiveness of specialised care services during the last period. In addition, it is possible that patients with SLD were more likely to have been included in the ANRS CO22 HEPATHER cohort by the expert centres themselves as one of the cohort’s objectives is to evaluate and measure the impact of new drug associations on the course of chronic hepatitis C. Consequently, it is possible that the burden of SLD we observed in our study is overestimated, especially for the third period of study, although the change in SLD prevalence might be consistent with an existing trend in French chronic hepatitis C epidemiology.

We found that the longer the time between HCV infection diagnosis and first hepatology expert centre visit, the higher the probability was of having SLD. This highlights the urgent need to raise the awareness among patients and general practitioners about the need for both close monitoring of chronic HCV infection after diagnosis and earlier referral for treatment.

Interestingly, our results suggest a protective effect of genotype 2 on the risk of SLD at a patient’s first expert centre visit. Indeed, there is already some evidence linking genotype 2 to a lower prevalence of liver fibrosis [23] and to slower progression to cirrhosis [24,25] compared with other genotypes. We also confirmed the relationship between genotype 3 and liver cirrhosis shown by others [21,25].

Place of birth appears to be linked to the risk of SLD at first hepatology expert centre visit, especially for patients born in North Africa or the Middle East. Although an association between migration and poorer prognosis in hepatitis C has already been described [26,27], it is not well understood and needs further investigation. One possible reason for this observed association is the lack of information concerning comorbidities such as type 2 diabetes and metabolic syndrome, which are potentially not homogeneously prevalent among different ethnic groups. In addition, the evolution of chronic hepatitis C in this sub-group of patients could be different. Age at infection, mode of contamination, lifestyle, access to HCV screening and care may all influence the course of disease progression [28,29]. Another possible reason for the association between place of birth (as a proxy for patients’ country) and the risk of SLD at first hepatology expert centre visit could be that people from France might be referred to an expert centre even when not severely ill, while patients from foreign countries (especially those that are mainly francophone) might more frequently seek treatment at an expert centre in France only when they become severely ill.

Age at diagnosis had a positive relationship with the risk of SLD in our study. This variable takes the age of the patient, a known risk factor for the evolution to cirrhosis [30], into account. Age at diagnosis may also reflect the duration of infection: the older the patient at diagnosis, the more likely he or she has been infected longer. The importance of early diagnosis is indicated by the increased risk of SLD at the time of first expert centre visit for patients whose diagnosis is based on hepatic or digestive symptoms (clinical or biochemical).

In addition, our study showed that patients with no identified HCV infection risk factor tended to have a greater probability of SLD at their first visit than well-identified at-risk groups, such as drug users and blood transfusion recipients before 1991. This finding suggests that when both patients and practitioners are unaware of the risk of viral hepatitis, the former tend to be referred when they already have late stage disease and a poorer prognosis.

The limitations of our study include: (i) its cross-sectional design, with retrospective and self-reported assessment of several exposures, including alcohol consumption and risk behaviours, (ii) the inclusion of one group of patients via systematic surveillance and the other via a cohort study, with different recruitment and with slight differences in the forms’ wording and structure, that has probably lead to a difference in the quality of data and in missing data proportions, and (iii) other factors known to be associated with fibrosis (e.g. obesity, metabolic syndrome, type 2 diabetes, duration of infection) were not collected for all the periods, with these factors therefore not included in our analysis. Furthermore, our data could only provide estimations on a select population (chronic hepatitis C patients referred to a hepatology expert centre), not necessarily reflecting the characteristics of the overall population of patients with chronic hepatitis C.

Despite these study limitations, our work provides interesting insights in the context of chronic hepatitis C patient care evolution.

First, it underlines the importance of early diagnosis and providing the general population with better information about HCV infection risk factors. In fact, severe disease was more frequently diagnosed when symptoms or biochemical liver abnormalities triggered testing. To increase people’s awareness about their HCV infection status, screening recommendations and guidelines were revised [31,32] to emphasise both targeted and mass screening. Accordingly, the utilisation of HCV rapid tests has been authorised in the context of healthcare facilities and approved charities.

Second, our results highlight that a long delay between diagnosis and first visit to a hepatology expert centre increases the risk of having late stage disease when starting specialised care and antiviral treatment. This in turn is associated with a lower probability of treatment success and the continued risk of further complications even after successful treatment. In this light, the French National Authority for Health (HAS) issued new recommendations for treatment in June and December 2016, broadening the eligibility parameters for DAAs treatment to include patients with a METAVIR score of F0-F1, incorporating both individual and collective objectives for HCV infection eradication [32,33], and allowing the prescription of DAAs outside the expert centres. Health authorities should also urge general practitioners to refer patients with HCV infections to a hepatology specialist or unit as early as possible in order to ensure their steady treatment. As now recommended in France, all adults diagnosed with hepatitis C should be immediately referred for evaluation and HCV treatment.

Finally, particular attention should be paid to migrant patient as they could be at greater risk of already having late stage disease when referred to specialised care. Early referral is even more important for patients with supplementary risk factors such as a history of alcohol excessive consumption, HCV infection diagnosis at an older age, male sex and HCV genotype 3.

These findings originating from French epidemiological data may be important for other European countries dealing with similar challenges in HCV infection care. Indeed, effective tertiary prevention of HCV complications, which have been made possible thanks to the extension of DAAs treatment to new populations, is an ethical obligation of our modern healthcare systems. In this light, effective large-scale screening and earlier referral of HCV-infected patients are two very important public health tools.


Acknowledgements

We thank all members of the ANRS (France Recherche Nord & Sud Sida-HIV Hépatites) CO22 HEPATHER study group, and all the members of the Santé publique France Hepatitis C surveillance network. We especially thank all the physicians and nurses who were involved in the inclusions, and all patients who took part in these studies. Finally, we thank Jude Sweeney for the English revision and editing of our manuscript.

The Santé publique France Hepatitis C surveillance network:

D Capron, E Nguyen-Khac (Amiens); P Cales, I Hubert-Fouchard (Angers); V Di Martino (Besançon); J Foucher, V de Ledinghen (Bordeaux); MT Dao, C Guillemard (Caen); A Abergel (Clermont-Ferrand); N Boyer, P Marcellin, MP Ripault (Clichy); D Dhumeaux, C Hezode, F Roudot-Thoraval (Créteil); P Hillon, A Minello (Dijon); A Edouard (Fort de France); MN Hilleret, V Leroy, JP Zarski (Grenoble); V Canva, P Mathurin (Lille), V Loustaud-Rati (Limoges); P Pradat, C Trepo (Lyon); JJ Raabe (Metz); D Larrey (Montpellier); JP Bronowicki (Nancy); J Gournay (Nantes); E Marine-Barjoan, A Tran (Nice); X Causse (Orléans); B Nalpas, S Pol (Paris); C Silvain (Poitier); G Thiefin (Reims); H Danielou, D Guyader (Rennes); O Goria, P Michel (Rouen); L Alric, K Barange, S Metivier (Toulouse); Y Bacq, L D’Alteroche, EH Metman (Tours).

The ANRS CO22 HEPATHER study group:

Laurent Alric, Delphine Bonnet, Virginie Sicart (CHU Purpan, Toulouse); Fabien Zoulim, François Bailly, Marjolaine Beaudoin, Dominique Giboz, Kerstin Hartig-Lavie, Marianne Maynard (Hospices Civils de Lyon, Lyon); Eric Billaud, Morane Cavellec, Marjorie Cheraud-Carpentier, Jérome Gournay, François Raffi, Florian Vivrel (Hôpital Hôtel-Dieu, Nantes); Isabelle Hubert, Jaouad Benhida, Jérôme Boursier, Paul Calès, Françoise Lunel, Frédéric Oberti (CHU Angers, Angers); Patrick Marcellin, Nathalie Boyer, Audrey Gilibert, Nathalie Giuily (Hôpital Beaujon, Clichy); Giovanna Scoazec (Hôpital Beaujon, Clichy and Hôpital Henri Mondor, Créteil); Stanislas Pol, Hélène Fontaine, Sandrine Fernandes, Sylvie Keser, Philippe Sultanik, Anaïs Vallet-Pichard (Hôpital Cochin, Paris); Victor De Ledinghen, Juliette Foucher, Jean-Baptiste Hiriart, Aurore Mathias, Julien Vergniol (Hôpital Haut-Lévêque, Pessac, Bordeaux); Marc Bourlière, Chrystelle Ansaldi, Laëtitia Chouquet, Emilie De Luca, Valérie Oules (Hôpital Saint Joseph, Marseille); Albert Tran, Rodolphe Anty, Eve Gelsi, Régine Truchi (CHU de Nice, Nice); Elena Luckina, Nadia Messaoudi, Joseph Moussali, Dominique Thabut (Groupe Hospitalier Pitié-Salpétrière, Paris); Xavier Causse, Barbara De Dieuleveult, Damien Labarriere, Pascal Poter, Si Nafa Si Ahmed (CHR La Source, Orléans); Nathalie Ganne-Carrié, Véronique Grando-Lemaire, Pierre Nahon, Valérie Bourcier, Alan Peltier, Judith Ung (Hôpital Jean Verdier, Bondy); Dominique Guyader, Mariette Gougeon, Anne Guillygomarch, Caroline Jezequel (CHU Rennes, Rennes); Romain Moirand, Thomas F Baumert, Michel Dofföel, Catherine Mutter, François Habersetzer, Pauline Simo-Noumbissie (Hôpitaux Universitaires de Strasbourg, Strasbourg); Hélène Barraud, Mouni Bensenane, Abdelbasset Nani, Sarah Hassani-Nani (CHU de Nancy, Vandoeuvre-lès-Nancy); Jean-Pierre Bronowicki, Marie-Albertine Bernard (CHU de Nancy, Vandoeuvre-lès-Nancy and Centre Hospitalier Régional, Metz); Dominique Larrey, Georges-Philippe Pageaux, Michael Bismuth, Ludovic Caillo, Stéphanie Faure, Marie Pierre Ripault (Hôpital Saint Eloi, Montpellier); Sophie Métivier, Karl Barange, Christophe Bureau, Jean Marie Peron, Marie Angèle Robic, Léa Tarallo (CHU Purpan, Toulouse); Jean-Pierre Zarski, Marine Faure, Bruno Froissart, Marie-Noelle Hilleret, Vincent Leroy (CHU de Grenoble, Grenoble); Ghassan Riachi, Odile Goria, Victorien Grard, Hélène Montialoux (CHU Charles Nicolle, Rouen); Christophe Hézode, Muriel François, Christian Ouedraogo, Christelle Pauleau, Anne Varault (Hôpital Henri Mondor, Créteil); Olivier Chazouillères, Tony Andreani, Bénédicte Angoulevant, Azeline Chevance, Lawrence Serfaty (Hôpital Saint-Antoine, Paris); Didier Samuel, Teresa Antonini, Audrey Coilly, Jean-Charles Duclos Vallée, Mariagrazia Tateo (Hôpital Paul Brousse, Villejuif); Armand Abergel, Corinne Bonny, Chanteranne Brigitte, Géraldine Lamblin, Léon Muti (Hôpital Estaing, Clermont-Ferrand); Abdenour Babouri, Claire Geist, Virginie Filipe (Centre Hospitalier Régional, Metz); Camille Barrault, Laurent Costes, Hervé Hagège, Soraya Merbah, Isabelle Rosa (Centre Hospitalier Intercommunal, Créteil); Véronique Loustaud-Ratti, Paul Carrier, Maryline Debette-Gratien, Jérémie Jacques (CHU Limoges, Limoges); Philippe Mathurin, Florent Artu, Valérie Canva, Sébastien Dharancy, Alexandre Louvet (CHRU Claude Huriez, Lille); Anne Minello, Marc Bardou, Donya Da Costa Souhiel, Patrick Hillon, Marianne Latournerie (Dijon University Hospital, Dijon); Louis D’Alteroche, Yannick Bacq, Didier Barbereau, Charlotte Nicolas (CHU Trousseau, Tours); Nisserine Ben Amara, Danièle Botta-Fridlund, Isabelle Portal (CHU Timone, Marseille); Moana Gelu-Simeon, Marie-Josée Lafrance, Eric Saillard (CHU de Pointe-à-Pitre, Pointe-à-Pitre, Guadeloupe); Fabrice Carrat, Céline Dorival, Georges Haour (UPMC & INSERM U1136); Ventzislava Petrov-Sanchez, Alpha Diallo, Mélanie Simony, Carole Cagnot, Imane Amri (ANRS).

Conflict of interest

None declared.

Authors’ contributions

AS, CL and EDA conceived and designed the study. CL, EDA, YLS and PC supervised the study. FRT, SDB, PC, EDA and CL participated in the design of at least one of the two studies (the hepatitis C surveillance network and/or the ANRS CO22 HEPATHER cohort). AS and YLS performed the statistical analysis. AS drafted the manuscript. All the authors interpreted the data, critically revised the manuscript and gave their final approval of the version to be published.


References

  1. Pillonel J, Laperche S. Trends in risk of transfusion-transmitted viral infections (HIV, HCV, HBV) in France between 1992 and 2003 and impact of nucleic acid testing (NAT).Euro Surveill. 2005;10(2):5-8.PMID: 15735313

  2. Delarocque-Astagneau E, Meffre C, Dubois F, Pioche C, Le Strat Y, Roudot-Thoraval F,  et al.  The impact of the prevention programme of hepatitis C over more than a decade: the French experience. J Viral Hepat. 2010;17(6):435-43. DOI: 10.1111/j.1365-2893.2009.01196.x PMID: 19780936

  3. Meffre C, Le Strat Y, Delarocque-Astagneau E, Dubois F, Antona D, Lemasson J-M,  et al.  Prevalence of hepatitis B and hepatitis C virus infections in France in 2004: social factors are important predictors after adjusting for known risk factors. J Med Virol. 2010;82(4):546-55. DOI: 10.1002/jmv.21734 PMID: 20166185

  4. Pioche C, Pelat C, Larsen C, Desenclos J-C, Jauffret-Roustide M. Estimation de la prévalence de l’hépatite C en population générale, France métropolitaine, 2011. [Estimation of hepatitis C prevalence in the general population, metropolitan France, 2011]. Bull Epidemiol Hebd (Paris). 2016; (13-14):224-9. French. Available from: http://invs.santepubliquefrance.fr/beh/2016/13-14/2016_13-14_1.html

  5. Brouard C, Le Strat Y, Larsen C, Jauffret-Roustide M, Lot F, Pillonel J. The undiagnosed chronically-infected HCV population in France. Implications for expanded testing recommendations in 2014.PLoS One. 2015;10(5):e0126920. DOI: 10.1371/journal.pone.0126920 PMID: 25961575

  6. Westbrook RH, Dusheiko G. Natural history of hepatitis C.J Hepatol. 2014;61(1) Suppl;S58-68. DOI: 10.1016/j.jhep.2014.07.012 PMID: 25443346

  7. Morgan TR, Ghany MG, Kim H-Y, Snow KK, Shiffman ML, De Santo JL,  et al. , HALT-C Trial Group. Outcome of sustained virological responders with histologically advanced chronic hepatitis C.Hepatology. 2010;52(3):833-44. DOI: 10.1002/hep.23744 PMID: 20564351

  8. George SL, Bacon BR, Brunt EM, Mihindukulasuriya KL, Hoffmann J, Di Bisceglie AM. Clinical, virologic, histologic, and biochemical outcomes after successful HCV therapy: a 5-year follow-up of 150 patients.Hepatology. 2009;49(3):729-38. DOI: 10.1002/hep.22694 PMID: 19072828

  9. Zopf S, Kremer AE, Neurath MF, Siebler J. Advances in hepatitis C therapy: What is the current state - what come’s next?World J Hepatol. 2016;8(3):139-47. DOI: 10.4254/wjh.v8.i3.139 PMID: 26839638

  10. European Association for the Study of the Liver. EASL Recommendations on Treatment of Hepatitis C 2016.J Hepatol. 2017;66(1):153-94. DOI: 10.1016/j.jhep.2016.09.001 PMID: 27667367

  11. Delarocque-Astagneau E, Roudot-Thoraval F, Campèse C, Desenclos J-C. Past excessive alcohol consumption: a major determinant of severe liver disease among newly referred hepatitis C virus infected patients in hepatology reference centers, France, 2001.Ann Epidemiol. 2005;15(8):551-7. DOI: 10.1016/j.annepidem.2004.12.006 PMID: 16117999

  12. Pol S, Bourliere M, Lucier S, Hezode C, Dorival C, Larrey D,  et al.  Safety and efficacy of daclatasvir-sofosbuvir in HCV genotype 1-mono-infected patients. J Hepatol. 2017;66(1):39-47. DOI: 10.1016/j.jhep.2016.08.021 PMID: 27622858

  13. European Association for Study of Liver, Asociacion Latinoamericana para el Estudio del Higado. EASL-ALEH Clinical Practice Guidelines: Non-invasive tests for evaluation of liver disease severity and prognosis.J Hepatol. 2015;63(1):237-64. DOI: 10.1016/j.jhep.2015.04.006 PMID: 25911335

  14. Gower E, Estes C, Blach S, Razavi-Shearer K, Razavi H. Global epidemiology and genotype distribution of the hepatitis C virus infection.J Hepatol. 2014;61(1) Suppl;S45-57. DOI: 10.1016/j.jhep.2014.07.027 PMID: 25086286

  15. Lavanchy D. Evolving epidemiology of hepatitis C virus.Clin Microbiol Infect. 2011;17(2):107-15. DOI: 10.1111/j.1469-0691.2010.03432.x PMID: 21091831

  16. Royston P, Ambler G, Sauerbrei W. The use of fractional polynomials to model continuous risk variables in epidemiology.Int J Epidemiol. 1999;28(5):964-74. DOI: 10.1093/ije/28.5.964 PMID: 10597998

  17. Sterne JAC, White IR, Carlin JB, Spratt M, Royston P, Kenward MG, et al. Multiple imputation for missing data in epidemiological and clinical research: potential and pitfalls. BMJ. 2009;338(jun29 1):b2393.PMID: 19564179

  18. Nevalainen J, Kenward MG, Virtanen SM. Missing values in longitudinal dietary data: a multiple imputation approach based on a fully conditional specification.Stat Med. 2009;28(29):3657-69. DOI: 10.1002/sim.3731 PMID: 19757484

  19. Barros AJD, Hirakata VN. Alternatives for logistic regression in cross-sectional studies: an empirical comparison of models that directly estimate the prevalence ratio.BMC Med Res Methodol. 2003;3(1):21. DOI: 10.1186/1471-2288-3-21 PMID: 14567763

  20. Morris TP, White IR, Carpenter JR, Stanworth SJ, Royston P. Combining fractional polynomial model building with multiple imputation.Stat Med. 2015;34(25):3298-317. DOI: 10.1002/sim.6553 PMID: 26095614

  21. Larsen C, Bousquet V, Delarocque-Astagneau E, Pioche C, Roudot-Thoraval F, Desenclos JC. Hepatitis C virus genotype 3 and the risk of severe liver disease in a large population of drug users in France.J Med Virol. 2010;82(10):1647-54. DOI: 10.1002/jmv.21850 PMID: 20827760

  22. Septfons A, Gautier A, Brouard C, Bernillon P, Nicolau J, Larsen C. Prévalence, morbidité et mortalité associées aux hépatites B et C chroniques dans la population hospitalisée en France, 2004-2011. [Prevalence, morbidity and mortality associated with chronic hepatitis B and C in the French hospitalized population (2004-2011)]. Bull Epidemiol Hebd (Paris). 2014;(12):202-9. French. Available from: http://invs.santepubliquefrance.fr//beh/2014/12/2014_12_1.html

  23. Leandro G, Mangia A, Hui J, Fabris P, Rubbia-Brandt L, Colloredo G,  et al.  Relationship between steatosis, inflammation, and fibrosis in chronic hepatitis C: a meta-analysis of individual patient data. Gastroenterology. 2006;130(6):1636-42. DOI: 10.1053/j.gastro.2006.03.014 PMID: 16697727

  24. Marabita F, Aghemo A, De Nicola S, Rumi MG, Cheroni C, Scavelli R,  et al.  Genetic variation in the interleukin-28B gene is not associated with fibrosis progression in patients with chronic hepatitis C and known date of infection. Hepatology. 2011;54(4):1127-34. DOI: 10.1002/hep.24503 PMID: 21721028

  25. 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(4):655-66. DOI: 10.1016/j.jhep.2009.05.016 PMID: 19665246

  26. Chen W, Tomlinson G, Krahn M, Heathcote J. Immigrant patients with chronic hepatitis C and advanced fibrosis have a higher risk of hepatocellular carcinoma.J Viral Hepat. 2012;19(8):574-80. DOI: 10.1111/j.1365-2893.2012.01583.x PMID: 22762142

  27. Chen W, Krahn M. Disease burden of chronic hepatitis C among immigrants in Canada.J Viral Hepat. 2015;22(12):1043-54. DOI: 10.1111/jvh.12432 PMID: 26110922

  28. Sharma S, Carballo M, Feld JJ, Janssen HL. Immigration and viral hepatitis.J Hepatol. 2015;63(2):515-22. DOI: 10.1016/j.jhep.2015.04.026 PMID: 25962882

  29. Hatzakis A, Wait S, Bruix J, Buti M, Carballo M, Cavaleri M,  et al.  The state of hepatitis B and C in Europe: report from the hepatitis B and C summit conference. J Viral Hepat. 2011;18(Suppl 1):1-16. DOI: 10.1111/j.1365-2893.2011.01499.x PMID: 21824223

  30. Poynard T, Bedossa P, Opolon P. Natural history of liver fibrosis progression in patients with chronic hepatitis C.Lancet. 1997;349(9055):825-32. DOI: 10.1016/S0140-6736(96)07642-8 PMID: 9121257

  31. Bottero J, Brouard C, Roudot-Thoraval F, Deuffic-Burban S, Hofliger P, Abergel A,  et al.  2014 French guidelines for hepatitis B and C screening: a combined targeted and mass testing strategy of chronic viruses namely HBV, HCV and HIV.Liver Int. 2016;36(10):1442-9.PMID: 27043826

  32. Haute Autorité de Santé. Prise en charge de l’hépatite C par les médicaments antiviraux d’action directe (AAD): Élargissement du périmètre de remboursement. [Treatment of HCV infection by direct-acting antivirals (DAAs): broadening of the eligibility criteria for of the public financing of costs]. 7 Dec 2016. French. Available from: http://www.has-sante.fr/portail/upload/docs/application/pdf/2016-12/recommandation_college_hepatite_c.pdf

  33. Haute Autorité de Santé. Avis de la Commission de Transparence: Antiviraux d’action directe. [Recommendations from the Transparency Committee: the direct-acting antivirals]. 8 Jun 2016. French. Available from: http://www.has-sante.fr/portail/upload/docs/application/pdf/2016-05/aad_avis_25052016_ct_25052016.pdf

  34. Poynard T, Imbert-Bismut F, Munteanu M, Messous D, Myers RP, Thabut D,  et al.  Overview of the diagnostic value of biochemical markers of liver fibrosis (FibroTest, HCV FibroSure) and necrosis (ActiTest) in patients with chronic hepatitis C. Comp Hepatol. 2004;3(1):8. DOI: 10.1186/1476-5926-3-8 PMID: 15387887

  35. Castéra L, Vergniol J, Foucher J, Le Bail B, Chanteloup E, Haaser M,  et al.  Prospective comparison of transient elastography, Fibrotest, APRI, and liver biopsy for the assessment of fibrosis in chronic hepatitis C. Gastroenterology. 2005;128(2):343-50. DOI: 10.1053/j.gastro.2004.11.018 PMID: 15685546

  36. Schuppan D, Afdhal NH. Liver cirrhosis.Lancet. 2008;371(9615):838-51. DOI: 10.1016/S0140-6736(08)60383-9 PMID: 18328931



Back to Table of Contents
Previous Download (pdf)
Next

The publisher’s policy on data collection and use of cookies.

Disclaimer: The opinions expressed by authors contributing to Eurosurveillance do not necessarily reflect the opinions of the European Centre for Disease Prevention and Control (ECDC) or the editorial team or the institutions with which the authors are affiliated. Neither ECDC nor any person acting on behalf of ECDC is responsible for the use that might be made of the information in this journal. The information provided on the Eurosurveillance site is designed to support, not replace, the relationship that exists between a patient/site visitor and his/her physician. Our website does not host any form of commercial advertisement. Except where otherwise stated, all manuscripts published after 1 January 2016 will be published under the Creative Commons Attribution (CC BY) licence. You are free to share and adapt the material, but you must give appropriate credit, provide a link to the licence, and indicate if changes were made. You may do so in any reasonable manner, but not in any way that suggests the licensor endorses you or your use.

Eurosurveillance [ISSN] - ©2007-2016. All rights reserved
 

This website is certified by Health On the Net Foundation. Click to verify. This site complies with the HONcode standard for trustworthy health information:
verify here.