Incidence of Hepatocellular Carcinoma After Direct Antiviral Therapy for HCV in Patients With Cirrhosis Included in Surveillance Programs.

Retrospective studies have found an unexpectedly high incidence of hepatocellular carcinoma (HCC) among patients with hepatitis C virus (HCV)-associated cirrhosis who received direct-acting antiviral (DAA) agents. We analyzed data from the ANRS CO12 CirVir cohort to compare the incidence of HCC in patients with cirrhosis who received DAA therapy vs patients treated with interferon (IFN). Data were collected from 1270 patients with compensated biopsy-proven HCV-associated cirrhosis recruited from 2006 through 2012 at 35 centers in France. For descriptive purpose, patients were classified as follows: patients who received DAA treatment (DAA group, n = 336), patients who achieved a sustained virologic response (SVR) following an IFN-based regimen (SVR-IFN group, n = 495), or patients who never received DAA treatment and never had an SVR following IFN therapy (non-SVR group, n = 439). The patients were included in HCC surveillance programs based on ultrasound examination every 6 months, and clinical and biological data were recorded. To account for confounding by indication due to differences in patient characteristics at treatment initiation, we constructed a time-dependent Cox regression model weighted by the inverse probability of treatment and censoring (IPTCW) to assess the treatment effects of DAA on time until HCC. Compared with patients in the SVR-IFN group, patients in the DAA group were older, higher proportions had diabetes or portal hypertension, and liver function was more severely impaired. The crude 3-year cumulative incidences of HCC were 5.9% in the DAA group, 3.1% in the SVR-IFN group, and 12.7% in the non-SVR group (overall P < .001; unadjusted hazard ratio [HR] for HCC 2.03; 95% confidence interval [CI] 1.07-3.84; P = .030 for the DAA group vs the SVR-IFN group). HCC characteristics were similar among groups. Among patients with HCC, the DAA group received less-frequent HCC screening than the other 2 groups (P = .002). After Cox analyses weighted by the IPTCW, we found no statistically significant increase in risk of HCC associated with DAA use (HR 0.89; 95% CI 0.46-1.73; P = .73). Analysis of data from the ANRS CO12 CirVir cohort reveals that the apparent increase in HCC incidence observed in patients with cirrhosis treated with DAAs compared with patients who achieved SVR following an IFN therapy can be explained by patient characteristics (age, diabetes, reduced liver function) and lower screening intensity.

Nahon P ，Layese R ，Bourcier V ，Cagnot C ，Marcellin P ，Guyader D ，Pol S ，Larrey D ，De Lédinghen V ，Ouzan D ，Zoulim F ，Roulot D ，Tran A ，Bronowicki JP ，Zarski JP ，Riachi G ，Calès P ，Péron JM ，Alric L ，Bourlière M ，Mathurin P ，Blanc JF ，Abergel A ，Serfaty L ，Mallat A ，Grangé JD ，Attali P ，Bacq Y ，Wartelle C ，Dao T ，Thabut D ，Pilette C ，Silvain C ，Christidis C ，Nguyen-Khac E ，Bernard-Chabert B ，Zucman D ，Di Martino V ，Sutton A ，Roudot-Thoraval F ，Audureau E ，ANRS CO12 CirVir Group ... -  《-》

Eradication of Hepatitis C Virus Infection in Patients With Cirrhosis Reduces Risk of Liver and Non-Liver Complications.

We performed a prospective study to investigate the effects of a sustained viral response (SVR) on outcomes of patients with hepatitis C virus (HCV) infection and compensated cirrhosis. We collected data from 1323 patients included in the prospective Agence Nationale pour la Recherche sur le SIDA et les hépatites virales (ANRS) viral cirrhosis (CirVir) cohort, recruited from 35 clinical centers in France from 2006 through 2012. All patients had HCV infection and biopsy-proven cirrhosis, were Child-Pugh class A, and had no prior liver complications. All patients received anti-HCV treatment before or after inclusion (with interferon then with direct antiviral agents) and underwent an ultrasound examination every 6 months, as well as endoscopic evaluations. SVR was considered as a time-dependent covariate; its effect on outcome was assessed by the Cox proportional hazard regression method. We used a propensity score to minimize confounding by indication of treatment and capacity to achieve SVR. After a median follow-up period of 58.2 months, 668 patients (50.5%) achieved SVR. SVR was associated with a decreased incidence of hepatocellular carcinoma (hazard ratio [HR] compared with patients without an SVR, 0.29; 95% confidence interval [CI], 0.19-0.43; P < .001) and hepatic decompensation (HR, 0.26; 95% CI, 0.17-0.39; P < .001). Patients with SVRs also had a lower risk of cardiovascular events (HR, 0.42; 95% CI, 0.25-0.69; P = .001) and bacterial infections (HR, 0.44; 95% CI, 0.29-0.68; P < .001). Metabolic features were associated with a higher risk of hepatocellular carcinoma in patients with SVRs, but not in patients with viremia. SVR affected overall mortality (HR, 0.27 compared with patients without SVR; 95% CI, 0.18-0.42; P < .001) and death from liver-related and non-liver-related causes. Similar results were obtained in a propensity score-matched population. We confirmed a reduction in critical events, liver-related or not, in a prospective study of patients with HCV infection and compensated cirrhosis included in the CirVir cohort who achieved an SVR. We found an SVR to reduce overall mortality and risk of death from liver-related and non-liver-related causes. A longer follow-up evaluation is required to accurately describe and assess specific risk factors for complications in this population.

Nahon P ，Bourcier V ，Layese R ，Audureau E ，Cagnot C ，Marcellin P ，Guyader D ，Fontaine H ，Larrey D ，De Lédinghen V ，Ouzan D ，Zoulim F ，Roulot D ，Tran A ，Bronowicki JP ，Zarski JP ，Leroy V ，Riachi G ，Calès P ，Péron JM ，Alric L ，Bourlière M ，Mathurin P ，Dharancy S ，Blanc JF ，Abergel A ，Serfaty L ，Mallat A ，Grangé JD ，Attali P ，Bacq Y ，Wartelle C ，Dao T ，Benhamou Y ，Pilette C ，Silvain C ，Christidis C ，Capron D ，Bernard-Chabert B ，Zucman D ，Di Martino V ，Thibaut V ，Salmon D ，Ziol M ，Sutton A ，Pol S ，Roudot-Thoraval F ，ANRS CO12 CirVir Group ... -  《-》

Risk of Hepatocellular Cancer in HCV Patients Treated With Direct-Acting Antiviral Agents.

The risk of hepatocellular cancer (HCC) after sustained virological response (SVR) with direct-acting antivirals (DAA) is unclear. Our aim was to examine the risk and determinants of HCC in patients cured with DAA. We conducted a retrospective cohort study of hepatitis C virus patients who were treated with DAA in any of the 129 Veterans Health Administration hospitals between January 1, 2015 and December 31, 2015. We calculated the annual incidence rates of HCC by SVR. We used Cox regression models to compare the risk of HCC in patients with vs those without SVR and to identify factors associated with incident HCC among patients with SVR. We reviewed a sample of HCC patients for tumor size and stage at diagnosis. Among 22,500 patients treated with DAA (19,518 with SVR; 2982 without SVR), the mean (standard deviation) age was 61.6 (6.1) years, and 39.0% had cirrhosis. There were 271 new cases of HCC, including 183 in patients with SVR. Compared with patients without SVR, those with SVR had a significantly reduced risk of HCC (0.90 vs 3.45 HCC/100 person-years; adjusted hazard ratio, 0.28, 95% CI=0.22-0.36). Patients with cirrhosis had the highest annual incidence of HCC after SVR (1.82 vs 0.34/100 person-years in patients without cirrhosis; adjusted hazard ratio, 4.73. 95% CI, 3.34-6.68). Most (>44.8%) HCC were classified as stage I. Maximum size of the largest lesion was ≤5 cm in over 75% of cases. Among patients treated with DAA, SVR was associated with a considerable reduction in the risk of HCC. We did not find any evidence to suggest that DAAs promote HCC. However, in patients with SVR, the absolute risk of HCC remained high in patients with established cirrhosis. These patients should be considered for ongoing HCC surveillance.

Kanwal F ，Kramer J ，Asch SM ，Chayanupatkul M ，Cao Y ，El-Serag HB ... -  《-》

Long-term effect of sustained virological response on hepatocellular carcinoma in patients with hepatitis C in Canada.

Evidence is limited on hepatocellular carcinoma (HCC) risk after sustained virological response (SVR) to interferon-based treatment of hepatitis C virus (HCV) infection. We evaluated the effect of SVR on the risk of HCC and estimated its incidence in post-SVR HCV patients from a large population-based Canadian cohort. The British Columbia Hepatitis Testers Cohort includes individuals tested for HCV between 1990-2013 linked with data on their medical visits, hospitalizations, cancers, prescription drugs and mortality. Patients receiving interferon-based HCV treatments were followed from the end of treatment to HCC diagnosis, death or December 31, 2012. We examined HCC risk among those who did and did not achieve SVR using multivariable proportional hazard models with the Fine and Gray modification for competing risks. Of 8147 individuals who received HCV treatment and were eligible for analysis, 4663 (57%) achieved SVR and 3484 (43%) did not. Each group was followed for a median of 5.6years (range: 0.5-12.9) for an HCC incidence rate of 1.1/1000 person-years (PY) among the SVR and 7.2/1000 PY among the no SVR group. The HCC incidence rate was higher among those with cirrhosis (SVR: 6.4, no SVR: 21.0/1000 PY). In the multivariable model, SVR was associated with a lower HCC risk (subdistribution hazard ratio [SHR]=0.20, 95% CI: 0.13-0.3), while cirrhosis (SHR=2.61, 95% CI: 1.68-4.04), age ⩾50years, being male and genotype 3 infection were associated with a higher HCC risk. Among those who achieved SVR, cirrhosis, age ⩾50years and being male were associated with a higher HCC risk. SVR after interferon-based treatment substantially reduces but does not eliminate HCC risk, which is markedly higher among those with cirrhosis and age ⩾50years at treatment initiation. Treatment of patients at an advanced fibrosis stage with new highly effective drugs will warrant continued surveillance for HCC post-SVR. We assessed the effect of successful hepatitis C treatment with older interferon-based treatment on the occurrence of liver cancer (hepatocellular carcinoma) and found that successful treatment prevents liver cancer. However, more people with cirrhosis and older age continued to develop liver cancer after successful treatment. Thus, treatment with new drugs among those with cirrhosis will require continued monitoring for liver cancer.

Janjua NZ ，Chong M ，Kuo M ，Woods R ，Wong J ，Yoshida EM ，Sherman M ，Butt ZA ，Samji H ，Cook D ，Yu A ，Alvarez M ，Tyndall M ，Krajden M ... -  《-》

Incidence of Hepatocellular Carcinoma in Patients With HCV-Associated Cirrhosis Treated With Direct-Acting Antiviral Agents.

Studies have produced conflicting results of the incidence of hepatocellular carcinoma (HCC) in patients with hepatitis C virus-associated cirrhosis treated with direct-acting antivirals (DAAs). Data from clinics are needed to accurately assess the occurrence rate of HCC in patients with cirrhosis in the real world. We collected data from a large prospective study of 2,249 consecutive patients (mean age = 65.4 years, 56.9% male) with hepatitis C virus-associated cirrhosis (90.5% with Child-Pugh class A and 9.5% with Child-Pugh class B) treated with DAAs from March 2015 through July 2016 at 22 academic and community liver centers in Sicily, Italy. HCC occurrence was evaluated by Kaplan-Meier curves. Cox regression analysis was used to identify variables associated with HCC development. A sustained virologic response (SVR) was achieved by 2,140 patients (total = 95.2%; 95.9% with Child Pugh class A and 88.3% with Child Pugh class B; P < .001). Seventy-eight patients (3.5%) developed HCC during a mean follow-up of 14 months (range = 6-24 months). At 1 year after exposure to DAAs, HCC developed in 2.1% of patients with Child-Pugh class A with an SVR and 6.6% of patients with no SVR and in 7.8% of patients with Child-Pugh class B with an SVR and 12.4% of patients with no SVR (P < .001 by log-rank test). Albumin level below 3.5 g/dL (hazard ratio = 1.77, 95% confidence interval = 1.12-2.82, P = .015), platelet count below 120 × 109/L (hazard ratio = 3.89, 95% confidence interval = 2.11-7.15, P < .001), and absence of an SVR (hazard ratio = 3.40, 95% confidence interval = 1.89-6.12, P < .001) were independently associated increased risk for HCC. The mean interval from exposure to DAAs to an HCC diagnosis was 9.8 months (range = 2-22 months) and did not differ significantly between patients with (n = 64, 9.2 months) and without (n = 14, 12.0 months) an SVR (P = .11). A larger proportion of patients with an SVR had a single HCC lesion (78% vs 50% without an SVR; P = .009) or an HCC lesion smaller than 3 cm (58% vs 28% without an SVR; P = .07). In an analysis of data from a large prospective study of patients with hepatitis C virus-associated compensated or decompensated cirrhosis, we found that the SVR to DAA treatment decreased the incidence of HCC over a mean follow-up of 14 months.

Calvaruso V ，Cabibbo G ，Cacciola I ，Petta S ，Madonia S ，Bellia A ，Tinè F ，Distefano M ，Licata A ，Giannitrapani L ，Prestileo T ，Mazzola G ，Di Rosolini MA ，Larocca L ，Bertino G ，Digiacomo A ，Benanti F ，Guarneri L ，Averna A ，Iacobello C ，Magro A ，Scalisi I ，Cartabellotta F ，Savalli F ，Barbara M ，Davì A ，Russello M ，Scifo G ，Squadrito G ，Cammà C ，Raimondo G ，Craxì A ，Di Marco V ，Rete Sicilia Selezione Terapia–HCV (RESIST-HCV) ... -  《-》