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Data on extrahepatic cancers (EHCs) in compensated viral cirrhosis are limited. The objective of the prospective multicenter Agence Nationale de Recherche sur le SIDA et les Hépatites virales CO12 CirVir cohort was to assess the occurrence of all clinical events in patients with compensated viral cirrhosis, including all types of cancer. Patients with the following inclusion criteria were enrolled in 35 French centers: (1) biopsy-proven hepatitis B virus (HBV) or hepatitis C virus (HCV) cirrhosis, (2) Child-Pugh A, or (3) absence of previous liver complications including primary liver cancer (PLC). Patients were followed up prospectively every 6 months. The standardized mortality ratio (SMR) was calculated according to age and gender using 5-year periods. The impact of sustained viral response (SVR) in HCV patients and maintained viral suppression in HBV patients were assessed using time-dependent analysis. A total of 1,671 patients were enrolled between 2006 and 2012 (median age, 54.9 years; men, 67.3%; HCV, 1,323; HBV, 317; HCV-HBV, 31). Metabolic features and excessive alcohol and tobacco consumption were recorded in 15.2%, 36.4%, and 56.4% of cases, respectively. After a median follow-up of 59.7 months, 227 PLCs were diagnosed (5-year cumulative incidence [CumI] 13.4%) and 93 patients developed EHC (14 patients with lymphoid or related tissue cancer and 79 with solid tissue cancer; 5-year EHC CumI, 5.9%). Compared to the general French population, patients were younger at cancer diagnosis, with significantly higher risk of EHC in HCV patients (SMR, 1.31; 95 confidence interval [CI], 1.04-1.64; P = 0.017) and after SVR (SMR = 1.57; 95% CI, 1.08-2.22; P = 0.013). EHC was the fourth leading cause of death in the whole cohort and the first in patients with viral control/eradication., Conclusion: Compared to the general French population, HCV cirrhosis is associated with a higher risk of EHC and the first cause of death in patients with viral cirrhosis who achieve virological control/eradication. (Hepatology 2018)., (© 2018 by the American Association for the Study of Liver Diseases.)

Unlabelled: The aim of this work was to develop an individualized score for predicting hepatocellular carcinoma (HCC) in patients with hepatitis C (HCV)-compensated cirrhosis. Among 1,323 patients with HCV cirrhosis enrolled in the French prospective ANRS CO12 CirVir cohort, 720 and 360 were randomly assigned to training and validation sets, respectively. Cox's multivariate model was used to predict HCC, after which a nomogram was computed to assess individualized risk. During follow-up (median, 51.0 months), 103 and 39 patients developed HCC in the training and validation sets, respectively. Five variables were independently associated with occurrence of HCC: age > 50 years (hazard ratio [HR], 1.94; 95% confidence interval [CI], 1.16; 3.25; P = 0.012); past excessive alcohol intake (HR, 1.55; 95% CI, 1.02; 2.36; P = 0.041); low platelet count (<100 Giga/mm(3) : HR, 2.70; 95% CI, 1.62; 4.51; P < 0.001; [100; 150] Giga/mm(3) : HR, 1.87; 95% CI, 1.10; 3.18; P = 0.021); gamma-glutamyl transpeptidase above the upper limit of normal (HR, 1.96; 95% CI, 1.11; 3.47; P = 0.021); and absence of a sustained virological response during follow-up (HR, 3.02; 95% CI, 1.67; 5.48; P < 0.001). An 11-point risk score was derived from the training cohort and validated in the validation set. Based on this score, the population was stratified into three groups, in which HCC development gradually increased, from 0% to 30.1% at 5 years for patients with the lowest (≤3) and highest (≥8) scores (P < 0.001). Using this score, a nomogram was built enabling individualized prediction of HCC occurrence at 1, 3, and 5 years., Conclusion: This HCC score can accurately predict HCC at an individual level in French patients with HCV cirrhosis. (Hepatology 2016;64:1136-1147)., (© 2016 by the American Association for the Study of Liver Diseases.)

Unlabelled: Various critical events, liver related or not, occur in patients with compensated cirrhosis, but their respective burden remains to be prospectively assessed. The aim of this prospective cohort study involving 35 French centers was to capture the whole spectrum of complications occurring in compensated viral cirrhosis (VC) using competing risks analyses. Inclusion criteria were: histologically proven cirrhosis resulting from hepatitis C virus (HCV) or hepatitis B virus (HBV); Child-Pugh A; and no previous hepatic complications. The cohort was considered as a multistate disease model, cumulative incidences (CumIs) of events were estimated in a competing risks framework. A total of 1,654 patients were enrolled from 2006 to 2012 (HCV, 1,308; HBV, 315; HCV-HBV, 31). During a median follow-up of 34 months, at least one liver nodule was detected in 271 patients, confirmed as hepatocellular carcinoma (HCC) in 128 (4-year cumI: 10.5%) and cholangiocarcinoma in 3. HCC incidence was higher in HCV (4-year cumI: 11.4% vs. 7.4%; P = 0.05). HCC fulfilled Milan criteria in 79.3%, leading to curative treatment in 70.4%. Liver decompensation occurred more frequently in HCV patients (4-year cumI: 10.8% vs. 3.6%; P = 0.0004). Virological eradication/control was achieved in 34.1% of HCV and 88.6% of HBV patients and was associated with a marked decrease in HCC, decompensation, and bacterial infection incidences. Survival was shorter in HCV patients (4-year cumI: 91.6% vs. 97.2%; P = 0.0002). Death (n = 102; missing data: 6) was attributed to liver disease in 48 (47%; liver cancer: n = 18; miscellaneous, n = 30) and extrahepatic causes in 48 (47%; bacterial infection: n = 13; extrahepatic cancers: n = 10; cardiovascular events: n = 5; miscellaneous, n = 20)., Conclusion: After 3 years of follow-up, extrahepatic events still explained half of deaths in patients with compensated VC. A strong decrease in complications was linked to virological eradication/control., (© 2015 by the American Association for the Study of Liver Diseases.)

Unlabelled: Response-guided pegylated interferon (peg-IFN) plus ribavirin (P/R) therapy trials on genotype (G)1 and G2/G3 hepatitis C virus-infected patients provide contradictory results. We conducted meta-analyses of randomized, controlled trials to address (1) the benefit of a 72-week extended-duration therapy in G1-slow responders and (2) adequate shortened duration therapy in G1 and G2/G3-rapid responders. Seventeen trials were selected, including 624 G1 rapid responders, 570 G1 slow responders, and 2,062 G2/G3 rapid responders. Virologic outcomes and treatment discontinuation data were collected from published articles and by asking investigators. Pooled estimates of sustained virologic response (SVR), relapse, and dropouts were calculated using the random effects model, considering the variability of shortened duration, ribavirin dose, genotype, and baseline viral load. In G1 slow responders, a 72-week extended duration increased SVR (+10.7%; 95% CI [confidence interval]: +4.4% to + 17.1%), decreased relapse (-12.3%; 95% CI: -25.4% to 0%), and did not significantly increase drop-out rates (+4.5%; 95% CI: -0.6% to + 9.6%). The benefit of extended duration was lower when using a weight-based ribavirin regimen (+8.7%; 95% CI: +1.7% to + 15.8%). In G1 rapid responders, a 24-week shortened duration decreased SVR (-12.5%; 95% CI: -19.2% to -5.8%) and increased relapse rates (+8.8%; 95% CI: +2.9% to + 14.8%). Such differences were not significant in patients with baseline viral load <400,000 UL/mL (-4.4%; 95% CI: -9.8% to + 1%). In G2/G3 rapid responders, SVR was more common for standard 24-week duration than for shortened durations (+4.1%; 95% CI: +0.1% to + 8.5), but this benefit was not significant when ribavirin was weight-adjusted and the short duration was 16 weeks (-1.7%; 95% CI: -6.1% to + 2.7%) and for G2 patients (+1.6%; 95% CI: -0.2% to + 5.5%)., Conclusion: Long durations of P/R therapy improve SVR, regardless of genotype. This effect is nonetheless negligible in rapid responders, with the most favorable conditions for SVR (G2, G1 with low viral load, and G3 with weight-adjusted ribavirin regimen)., (Copyright © 2011 American Association for the Study of Liver Diseases.)

Unlabelled: We conducted a national retrospective survey on hospital practitioners to evaluate the magnitude of erythropoietin (EPO) or granulocyte colony-stimulating factor (G-CSF) prescriptions in patients treated for chronic hepatitis C. Four hundred seventy-one questionnaires were sent, and 274 practitioners (58.2%) responded. Forty-six percent of practitioners used EPO, and 31% used G-CSF. The total number of HCV-infected patients receiving antiviral therapy per year was estimated at 6,630 patients, of whom 8.8% and 4% received EPO and G-CSF, respectively. EPO-beta was the main EPO molecule prescribed at a median dose of 30,000 IU/wk (range: 2,000-80,000). The indications for prescribing EPO varied greatly, including "fragile patients" (34%), "low" Hb level (8-11 g/dL) (19%), "rapid decline" in Hb level (2-5 g/dL during the first month of therapy) (12%), and symptomatic anemic patients (7%). G-CSF was mainly prescribed for a "low" level of neutrophils ranging from 400 to 750 neutrophils/mm3. In multivariate analysis, independent predictors of EPO and G-CSF prescription were age of practitioner less than 45 years (EPO: OR = 1.96, P = 0.03; G-CSF: OR = 2.27, P = 0.004), practice in university hospital (EPO: OR = 5.89, P < 0.0001; G-CSF: OR = 2.39, P = 0.003), and the high number of CHC treated/year (EPO: OR = 6.18, P < 0.0001; G-CSF: OR = 2.58, P = 0.002)., Conclusion: Our survey reveals an important rate of EPO and G-CSF prescriptions but with considerable disparity in the schedule of injections, the molecules used, and above all the indications. The suitable role of EPO and G-CSF as complements to HCV therapy urgently needs to be clarified.

Female sex is a protective factor for the progression of fibrosis in patients with chronic hepatitis C virus (HCV) infection. Experimental data suggest that estrogens may have an antifibrotic effect. The objective of this study was to evaluate the influence of past pregnancies, oral contraceptives, menopause, and hormone replacement therapy (HRT) on liver fibrosis progression in HCV-infected women. Four hundred seventy-two HCV-infected women received a survey regarding prior pregnancies, menopause, and the use of oral contraceptives and HRT. The impact of these variables on liver fibrosis and its progression were evaluated using multivariate analyses considering all putative confounding factors. Two hundred one women completed the survey (43% response rate), 157 of whom had an estimated date of HCV infection (96 postmenopausal women, 96 women with previous pregnancies, and 105 women with past use of oral contraceptives). Through multivariate analyses, the estimated rate of fibrosis progression was higher in postmenopausal (P < .05) and nulliparous (P = .02) women and was associated with greater histological activity (P < .001). Prior use of oral contraceptives had no significant influence. Among postmenopausal women, the estimated rate of fibrosis progression (+/-SE) was lower in women who received HRT compared with untreated patients (0.099 +/- 0.016 vs. 0.133 +/- 0.006 METAVIR units/yr; P = .02) and was similar to that of premenopausal women (0.093 +/- 0.012 METAVIR units/yr; P value not significant). In conclusion, menopause appears to be associated with accelerated liver fibrosis progression in HCV-infected women, an effect that may be prevented by HRT. Pregnancies may have a beneficial impact on the long-term progression of liver fibrosis.

Despite the rising incidence of obesity and diabetes, there is little emphasis on morbidity and mortality from obesity-related cirrhosis, usually considered a rare and asymptomatic condition. Our aim was to assess survival and the occurrence of hepatocellular carcinoma and complications of hepatic insufficiency in obesity-related cryptogenic cirrhosis compared with cirrhosis of other origins. We analyzed retrospectively 27 overweight patients with cryptogenic cirrhosis (CC-O), 10 lean patients with cryptogenic cirrhosis (CC-L) and 391 patients with hepatitis C virus-related cirrhosis (C-HCV). In CC-O patients, cirrhosis was detected later in life than in C-HCV and CC-L patients. Severe liver disease was as frequent in CC-O as in C-HCV patients as indicated by the proportion of Child B or C or of episodes of hepatic decompensation. Survival of CC-O patients was lower than that of untreated, age- and sex-matched C-HCV controls (P <.02 at 30 months), with a higher mortality of Child B or C patients. Hepatocellular carcinoma was detected in 8 of 27 (27%) CC-O patients versus 21% of matched C-HCV controls with a similar age cumulated incidence, suggesting a comparable carcinogenic potential. In conclusion, obesity-related cirrhosis should now be recognized as a distinct entity that can cause severe liver disease and death. Increased awareness of and better diagnostic strategies for nonalcoholic steatohepatitis in overweight patients are urgently needed.

In this study we analyzed the influence of human immunodeficiency virus (HIV) infection on the course of chronic hepatitis C through multivariate analysis including age, alcohol consumption, immune status, and hepatitis C virus (HCV)-related virologic factors. Eighty HIV-positive and 80 HIV-negative injection drug users included between 1980 and 1995 were matched according to age, gender, and duration of HCV infection and followed-up during 52 months. The progression to cirrhosis was the primary outcome measure. The impact of HIV on HCV-RNA load, histologic activity index, response to interferon therapy, and liver-related death was also considered. In HIV-positive patients, chronic hepatitis C was characterized by higher serum HCV-RNA levels (P =.012), higher total Knodell score (P =.011), and poorer sustained response to interferon therapy (P =.009). High serum HCV-RNA level was associated with low CD4-lymphocyte count (P =.001). Necroinflamatory score was higher in HIV-positive patients (P =.023) independently of the CD4-lymphocyte count, whereas increased fibrosis was related to decreased CD4-lymphocyte count (P =.011). The progression to cirrhosis was accelerated in HIV-positive patients with low CD4 cell count (RR = 4.06, P =.024) and in interferon-untreated patients (RR = 4.76, P =.001), independently of age at HCV infection (P =.001). Cirrhosis caused death in 5 HIV-positive patients. The risk of death related to cirrhosis was increased in heavy drinkers (RR = 10.8, P =.001) and in HIV-positive patients with CD4 cell count less than 200/mm(3) (RR = 11.9, P =.007). In this retrospective cohort study, HIV coinfection worsened the outcome of chronic hepatitis C, increasing both serum HCV-RNA level and liver damage and decreasing sustained response to interferon therapy. Age and alcohol were cofactors associated with cirrhosis and mortality. Interferon therapy had a protective effect against HCV-related cirrhosis no matter what the patient's HIV status was.

Hepatitis C virus (HCV)-related liver fibrosis progression is accelerated in human immunodeficiency virus (HIV)-infected patients. The effect of protease inhibitor (PI) therapy on liver fibrosis is unknown. The aim of this work was to analyze the impact of PI therapy on HCV-related liver fibrosis in HIV/HCV coinfected patients. We evaluated in a long-term follow-up retrospective cohort study the influence of antiretroviral therapy containing PI on liver fibrosis in 182 consecutive HIV/HCV coinfected patients. At liver biopsy, 63 patients had received PI and 119 patients had never been treated with PI. Relationships between liver histologic features, age, alcohol consumption, CD4 cell count, HIV-RNA load, and antiretroviral regimens were analyzed. Liver fibrosis stage was lower in patients receiving PIs by comparison with patients who had never received PIs (P =.03). The 5-, 15-, and 25-year cirrhosis rates were 2% versus 5%, 5% versus 18%, and 9% versus 27%, respectively, in patients who had received PIs compared with PI-untreated patients (P =.0006). Multivariate analysis identified 4 independent predictors of progression to cirrhosis: absence of protease inhibitor therapy (relative risk [RR] = 4.74, 95% confidence interval [CI], 1.34-16.67), heavy alcohol consumption (> or = 50 g daily) (RR = 4.71, 95% CI, 1.92-11.57), low CD4 cell count (<200/microL) (RR = 2.74, 95% CI, 1.17-6.41), and age at HCV contamination (> or = 20 years) (RR = 2.37, 95% CI, 1.04-5.38). In conclusion, protease inhibitor therapy might not accelerate progression to HCV-related cirrhosis. Furthermore, chronic use of antiretroviral therapy containing PI together with reduction of alcohol consumption and maintenance of high CD4 count could have a beneficial impact on liver fibrosis progression in HIV/HCV coinfected patients.

Hepatitis B virus (HBV) resistance to lamivudine has not been extensively documented in human immunodeficiency virus (HIV)-infected patients. We studied the long-term incidence of HBV resistance to lamivudine in HIV-positive patients. Sixty-six HIV-HBV-coinfected patients were studied while receiving lamivudine (150 mg twice daily) as a part of antiretroviral therapy. All these patients had a detectable serum HBV DNA at the beginning of lamivudine therapy. Serum HBV DNA was quantified by molecular hybridization. Sequence analysis of the HBV polymerase was performed in patients who became resistant to lamivudine. After 2 months of lamivudine, HBV DNA became undetectable in 57 patients (86.4%, 95% CI: 75.7%-93.6%). After 2 years of lamivudine, 47% +/- 18.6% of the patients, had sustained HBV-DNA suppression. All the 22 tested patients with HBV resistance developed mutation at position 550 in the YMDD motif of the DNA polymerase. None of the following variables were associated with an increased risk of lamivudine resistance: age, associated protease inhibitor therapy, Center for Disease Control (CDC) stage C, known HIV-infection duration, serum HBV-DNA level at baseline, CD4 cell count and serum alanine transaminase levels at baseline and at HBV-replication suppression (2 months of lamivudine). Lamivudine (300 mg/d) is effective for the inhibition of HBV replication in HIV-infected patients. However, emergence of lamivudine-resistant HBV may occur in 20% of patients per year.

The natural history of hepatitis C virus (HCV) infection in human immunodeficiency virus (HIV)-infected patients has never been studied according to the concept of liver fibrosis progression. The aim of this work was to assess the fibrosis progression rate in HIV-HCV coinfected patients and in patients infected by HCV only. A cohort of 122 HIV-HCV coinfected patients was compared with a control group of 122 HIV-negative HCV-infected patients. Groups were matched according to age, sex, daily alcohol consumption, age at HCV infection, and duration and route of HCV infection. The fibrosis progression rate was defined as the ratio between fibrosis stage (METAVIR scoring system) and the HCV duration. The prevalence of extensive liver fibrosis (METAVIR fibrosis scores 2, 3, and 4) and moderate or severe activity were higher in HIV-infected patients (60% and 54%, respectively) than in control patients (47% and 30%, respectively; P <.05 and P <.001, respectively). The median fibrosis progression rate in coinfected patients and in control patients was 0.153 (95% confidence interval [CI], 0.117-0.181) and 0.106 (95% CI, 0.084-0.125) fibrosis units per year, respectively (P <.0001). HIV seropositivity (P <.0001), alcohol consumption (>50 g/d, P =.0002), age at HCV infection (<25 years old, P <.0001), and severe immunosuppression (CD4 count 50 g/d), CD4 count (

Recurrence of hepatitis C after liver transplantation is common and can lead to severe liver diseases. Although immunosuppression and high levels of viremia suggest a direct pathogenicity of hepatitis C virus (HCV), the relations between viral replication and long-term histological course are still unknown. Thirty-three patients with a mean histological follow-up of 3.5 years (3 months - 8.6 years) were analyzed. Nineteen patients were infected by genotype 1b. Liver HCV RNA was determined in parallel with the quantitation of an internal control (28S ribosomal RNA) by competitive polymerase chain reaction (PCR). Lobular hepatitis (LH) and chronic active hepatitis (CAH) occurred in 27 and 19 patients, respectively. Levels of liver HCV RNA determined in 84 biopsies were higher in cases of LH than in the other patterns (82 +/- 123 vs. 19 +/- 38; P < .01) and were unrelated to the genotype. Progression from LH to CAH was associated with a highly significant decrease of liver HCV RNA (P = .006), which was not observed in patients with stable histology. Among patients with CAH, those infected by genotype 1b had more severe liver damage and lower levels of liver HCV RNA than others (P = .04). Multivariate analysis showed that high levels of liver HCV RNA at the time of the first posttransplantation biopsy was an independent predictor of CAH (P = .01). After liver transplantation, the progression to CAH together with a decrease of liver HCV RNA suggests that a host's response is involved in the long-term viral pathogenicity. This response may be stronger and liver disease more severe in patients with high levels of replication at the time of LH and in those infected by genotype 1b.

Arterial hypertension is frequent in liver transplant recipients on cyclosporine A (CsA). Nicardipine is a calcium channel blocker (CCB) that has been shown to be efficient in controlling postoperative hypertension. However, its use has been limited in organ recipients because of its reported interaction with CsA metabolism. In this report, we studied the results of the long-term use of nicardipine after liver transplantation. Forty-nine consecutive liver transplant recipients with a follow-up longer than 2 years were studied. Immunosuppressive regimen was based on CsA and prednisone. Patients with immediate postoperative hypertension received intravenous nicardipine, secondarily switched to oral nicardipine (group 1, n = 27). Patients with delayed hypertension (i.e., >2 weeks posttransplant) received other antihypertensive drugs which did not interact with CsA metabolism. These patients and those without hypertension formed group 2 (n = 22). The two groups were similar for age, sex, body weight, and transplantation indications. Interaction of nicardipine with CsA metabolism was confirmed. Whereas cyclosporine blood levels were similar in both groups at any time during the study, the mean cyclosporine daily dose required to achieve such levels was 30% lower in group 1 compared with group 2 (P < .01). This resulted in a significant cost-containment. The use of nicardipine was not associated with an increased incidence of graft rejection or CsA toxicity episodes. The results in liver transplant recipients showed that nicardipine interacts with CsA metabolism, leading to a 30% reduction in CsA dose and does not increase the risk of CsA toxicity or graft rejection. Nicardipine can be used safely for the treatment of arterial hypertension after liver transplantation with a potential cost-containment.