Ombitasvir/paritaprevir/ritonavir plus ribavirin for 24 weeks in patients with HCV GT4 and compensated cirrhosis (AGATE-I Part II).

BACKGROUND AND AIMS: AGATE-I Part I previously reported high sustained virologic response rates in hepatitis C genotype 4 patients with cirrhosis, with 12 and 16 weeks' treatment with a combination of two direct-acting antivirals, ombitasvir and paritaprevir (codosed with ritonavir), plus ribavirin. Part II, reported here, extended the trial to include a 24-week treatment arm to fully assess treatment duration in patients with chronic hepatitis C genotype 4 infection and compensated cirrhosis. METHODS: Enrollment took place between June and November of 2015. Treatment-naive and interferon-experienced patients with chronic hepatitis C genotype 4 infection and compensated cirrhosis were enrolled into Arm C; patients previously treated with a sofosbuvir-based regimen were enrolled into Arm D. All patients received a 24-week treatment with ombitasvir, paritaprevir, and ritonavir plus ribavirin. The primary outcome was the proportion of patients with a sustained virologic response (hepatitis C virus RNA < 25 IU/mL) at posttreatment week 12 in the intention-to-treat population. The safety population included all patients who received at least one dose of study drug. RESULTS: In total, 64 patients were enrolled into AGATE-I Part II. Sustained virologic response at posttreatment week 12 was achieved in 57 of 61 patients (93.4%; 97.5% confidence interval, 92.6-97.7) in Arm C and 3 of 3 patients (100%) in Arm D. Two patients were missing SVR12 data, and two prematurely discontinued treatment. The most common adverse events for Arm C were fatigue (16 [26%]) and asthenia (15 [25%]). Results were comparable with those reported in Part I. CONCLUSIONS: AGATE-I Part II indicates that extending treatment beyond 12 weeks in genotype 4-infected patients with compensated cirrhosis does not offer additional benefit.

Predictors of hepatocellular carcinoma in HCV cirrhotic patients treated with direct acting antivirals.

BACKGROUND: Despite the dramatic improvement in viral eradication rates that has been reached with direct antiviral agents (DAAs), the real benefit of viral eradication after DAAs on hepatocellular carcinoma (HCC) development is still controversial. AIM: To prospectively assess the risk of HCC occurrence and early recurrence in a large cohort of DAA-treated HCV-cirrhotic patients and to identify potential predictors of HCC development. METHODS: We analyzed data prospectively collected from 1927 consecutive HCV-infected cirrhotic patients treated with DAA from January to December 2015 in 10 tertiary liver centers in Italy and followed-up for one year after therapy. 161 patients had a previous HCC. RESULTS: 38/161 subjects developed tumor recurrence during the follow-up (recurrence rate = 24.8 per 100-year), patients with SVR had a significantly lower rate of recurrence. Lack of SVR and alpha-fetoprotein (AFP) were independent predictors of HCC recurrence. 50/1766 patients without a previous HCC history developed HCC during follow-up (incidence rate = 2.4 per 100-year). Lack of SVR was the strongest predictor of HCC development. Furthermore, patients with SVR and no stigmata of portal hypertension have a lower incidence rate of HCC (1.0 per 100-year). CONCLUSIONS: SVR is associated with a significant decrease of recurrent or de novo HCC. Baseline AFP and signs of portal hypertension can help to stratify the risk of HCC.

Real life experiences in HCV management in 2018.

INTRODUCTION: Hepatitis C virus (HCV) infection is a major cause of chronic liver disease, with approximately 71 million chronically infected individuals worldwide. Treatment of chronic hepatitis C has considerably improved in the last few years thanks to the introduction of direct-acting antivirals able to achieve sustained virological response in more than 95% of patients. Successful anti-HCV treatment can halt liver disease progression and solve the HCV-related extra-hepatic manifestations, eventually reducing liver-related and overall mortality. Areas covered: With the aim to respond to unmet needs in patient's identification, universal access to antiviral therapy and treatment optimization in specific setting of HCV-infected patients, a group of Italian experts met in Stresa in May 2018. The summary of the considerations arising from this meeting and the final statements are reported in this paper. Expert commentary: All the advances on HCV cure may have a real clinical impact not only in individual patients but also at the social health level if they are applied to all infected patients, independently from the stage of liver disease. Further improvements are needed in order to attain HCV elimination, such as the development of an enhanced screening program working in parallel to the present treatment options.

Safety and efficacy of ombitasvir/paritaprevir/ritonavir/dasabuvir plus ribavirin in patients over 65 years with HCV genotype 1 cirrhosis.

PURPOSE: To analyse safety and efficacy of treatment based on ombitasvir/paritaprevir/ritonavir/dasabuvir plus ribavirin in the sub-group of GT1 patients older than 65 years. METHODS: We collected data extracted from the ABACUS compassionate-use nationwide Italian programme, in patients with cirrhosis due to hepatitis C virus (HCV) Genotype-1 (GT1) or 4 and at high risk of decompensation. GT1-HCV-infected patients received once-daily ombitasvir/paritaprevir, with the pharmacokinetic enhancer ritonavir (25/150/100 mg) and twice-daily dasabuvir (250 mg) plus Ribavirin (RBV) (OBV/PTV/r + DSV + RBV) for 12 (GT1b) or 24 (GT1a) weeks. Endpoints were to evaluate safety and efficacy, the latter defined as HCV RNA negative 12 weeks after the end of treatment (SVR12). RESULTS: Patients who suffered any adverse event (AE) were 74/240 (30.8%); 13/240 (5.4%) discontinued the treatment. A multivariate analysis found albumin < 3.5 g/dL (OR 2.04: 95% CI 1.0-4.2, p < 0.05) and hypertension (OR 4.6: 95% CI 2.3-9.2, p < 0.001) as variables independently associated with AE occurrence. The SVR12 was 95% (228/240). Multivariate analysis identified baseline bilirubin < 2 mg/dL (OR 4.9: 95% CI 1.17-20.71, p = 0.029) as the only variable independently associated with SVR12. CONCLUSION: Our findings suggest that OBV/PTV/r + DSV + RBV is safe and effective in real-life use in patients with compensated cirrhosis, HCV-GT1 infection, and age over 65.

Liver Angiopoietin-2 Is a Key Predictor of De Novo or Recurrent Hepatocellular Cancer After Hepatitis C Virus Direct-Acting Antivirals.

Recent reports suggested that direct acting antivirals (DAAs) might favor hepatocellular carcinoma (HCC). In study 1, we studied the proangiogenic liver microenvironment in 242 DAA-treated chronic hepatitis C patients with advanced fibrosis. Angiopoietin-2 (ANGPT2) expression was studied in tissue (cirrhotic and/or neoplastic) from recurrent, de novo, nonrecurrent HCC, or patients never developing HCC. Circulating ANGPT2,vascular endothelial growth factor (VEGF), and C-reactive protein (CRP) were also measured. In study 2, we searched for factors associated with de novo HCC in 257 patients with cirrhosis of different etiologies enrolled in a dedicated prospective study. Thorough biochemical, clinical, hemodynamic, endoscopic, elastographic, and echo-Doppler work-up was performed in both studies. In study 1, no patients without cirrhosis developed HCC. Of 183 patients with cirrhosis, 14 of 28 (50.0%) with previous HCC recurred whereas 21 of 155 (13.5%) developed de novo HCC. Patients with recurrent and de novo HCCs had significantly higher liver fibrosis (LF) scores, portal pressure, and systemic inflammation than nonrecurrent HCC or patients never developing HCC. In recurrent/de novo HCC patients, tumor and nontumor ANGPT2 showed an inverse relationship with portal vein velocity (PVv; r = -0.412, P = 0.037 and r = -0.409, P = 0.047 respectively) and a positive relationship with liver stiffness (r = 0.526, P = 0.007; r = 0.525, P = 0.003 respectively). Baseline circulating VEGF and cirrhotic liver ANGPT2 were significantly related (r = 0.414, P = 0.044). VEGF increased during DAAs, remaining stably elevated at 3-month follow-up, when it significantly related with serum ANGPT2 (r = 0.531, P = 0.005). ANGPT2 expression in the primary tumor or in cirrhotic tissue before DAAs was independently related with risk of HCC recurrence (odds ratio [OR], 1.137; 95% confidence interval [CI], 1.044-1.137; P = 0.003) or occurrence (OR, 1.604; 95% CI, 1.080-2.382; P = 0.019). In study 2, DAA treatment (OR, 4.770; 95% CI, 1.395-16.316; P = 0.013) and large varices (OR, 3.857; 95% CI, 1.127-13.203; P = 0.032) were independent predictors of de novo HCC. CONCLUSION: Our study indicates that DAA-mediated increase of VEGF favors HCC recurrence/occurrence in susceptible patients, that is, those with more severe fibrosis and splanchnic collateralization, who already have abnormal activation in liver tissues of neo-angiogenetic pathways, as shown by increased ANGPT2. (Hepatology 2018; 00:000-000).

Anti-tumour necrosis factor-α antibodies and B cell homeostasis in human inflammatory bowel diseases.

BACKGROUND: The expression of CD70 on T cells is greatly enhanced by antigen-presenting cell (APC)-associated signals, such as tumour necrosis factor(TNF)-α, which is constitutionally high in patients with inflammatory bowel disease (IBD). Experimentally, the chronic activation of CD27 as a result of the constitutive expression of CD70 leads to the demise of B cells in bone marrow (BM) and the secondary lymphoid organs. The aim of this study was to assess the number and phenotype of circulating B cell in untreated IBD patients and their counterparts treated with biological anti-TNF drugs. METHODS: The study involved 13 untreated IBD patients, 36 IBD patients treated with biological drugs, and 10 healthy controls. The B cell phenotypes were assessed by means of flow cytometry using monoclonal antibodies specific for CD20, CD19, CD3, CD27 and CD43. In order to evaluate B cell development in bone marrow and peripheral B cell activation, we identified four B cell subsets: hematogones (HBs: CD20+19+3-27-43+), memory B cells (MBs: CD20+19+3-27+43-), pre-plasmablasts (PPBs: CD20+19+3-27+43+), and plasmablasts (PBs: CD20-19+3-27+43+). RESULTS: The total number of B cells in the untreated patients was three times lower than that in the patients treated with biological drug (p<0.001), and half that in the healthy controls (p=0.03). The between-group differences (including the healthy donors) were statistically significant in the case of HBs and MBs, but not in the case of PPBs and PBs. Only one treated patient showed a transiently large increase in PPBs. There were statistically significant differences in all of the parameters between the untreated patients and those receiving biological therapy, and in some cases between the untreated patients and healthy controls, but never between the controls and the treated patients. Four non-responders to anti-TNF therapy had a smaller number of total circulating B cells than the untreated patients. CONCLUSIONS: Anti-TNF drugs disinhibit B cell production in IBD patients, but maintain the constant homeostasis of circulating B cells. The presence of individual variations may allow the activity of anti-TNF drugs to be monitored by studying B cell subgroups.

Surgical Resection vs. Ablative Therapies Through a Laparoscopic Approach for Hepatocellular Carcinoma: a Comparative Study.

BACKGROUND: When compatible with the liver functional reserve, laparoscopic hepatic resection remains the treatment of choice for hepatocellular carcinoma while laparoscopic ablation therapies appear as a promising less invasive alternative. The aim of the study is to compare two homogeneous groups of patients submitted to either hepatic resection or thermoablation for the treatment of single hepatocellular carcinoma (≤ 3 cm). METHODS: We enrolled 264 cirrhotic patients out of 905 cases consecutively evaluated for hepatocellular carcinoma. We performed 59 hepatic resections and 205 thermoablations through a laparoscopic approach, and they were then followed for similar follow-up (41.7 ± 31.5 months for laparoscopic hepatic resection vs. 38.7±32.3 for laparoscopic ablation therapy). Outcomes included short- and long-term morbidities, tumoral recurrence, and overall survival. RESULTS: Short-term morbidity was significantly higher in the resection group (but the two groups had similar rates for severe complications) while, during follow-up, recurrence was more frequent in patients treated with thermoablation, with a clear disadvantage in terms of survival. At multivariate analysis, only the type of surgical treatment was an independent predictor of disease recurrence, while plasmatic alpha-fetoprotein and Hb values, model for end-stage liver disease score, time to recurrence, and the type of surgical treatment were independent predictors of overall survival. CONCLUSION: Our data ultimately support some therapeutic advantages for hepatic resection in patients with a single nodule and preserved liver function. However, thermoablation is an adequate alternative in patients with nodules that would require complex surgical resections or imply a poor prognosis that might therefore better tolerate a less invasive procedure.

Current and future challenges in HCV: insights from an Italian experts panel.

BACKGROUND: The recent availability of direct acting antiviral drugs (DAAs) has drastically changed hepatitis C virus (HCV) treatment scenarios, due to the exceedingly high rates of sustained virological response (SVR) and excellent tolerability allowing for treatment at all disease stages. METHODS: A panel of Italian experts was convened twice, in November 2016 and January 2017, to provide further support on some open issues and provide guidance for personalized HCV care, also in light of forthcoming regimens. RESULTS AND CONCLUSIONS: Treatment recommendations issued by international and national liver societies to guide clinicians in the management of HCV infection are constantly updated due to accumulating new data. Such recommendations may not be applicable to all healthcare settings for a variety of reasons. Moreover, some gaps still remain and the spectrum of patients to be treated is also evolving.

Intraoperative ultrasound for prediction of hepatocellular carcinoma biological behaviour: Prospective comparison with pathology.

BACKGROUND & AIMS: Preoperative prediction of both microinvasive hepatocellular carcinoma and histological grade of hepatocellular carcinoma is pivotal to treatment planning and prognostication. The aim of this study was to evaluate whether some intraoperative ultrasound features correlate with both the presence of same histological patterns and differentiation grade of hepatocellular carcinoma on the histological features of the primary resected tumour. METHODS: All patients with single, small hepatocellular carcinoma that underwent hepatic resection were included in this prospective double-blind study: the intraoperative ultrasound patterns of nodule were registered and compared with similar histological features. RESULTS: A total of 179 patients were enclosed in this study: 97 (54%) patients (34% in HCC ≤2 cm) had a microinvasive hepatocellular carcinoma at ultrasound examination, while 82 (46%) patients (41% in HCC ≤2 cm) at histological evaluation. Statistical analysis showed that diameters ≤2 cm, presence of satellites and microinvasive hepatocellular carcinoma at ultrasound examination were the variables with the strongest association with the histological findings. In the multivariate analysis, the vascular microinfiltration and infiltrative hepatocellular carcinoma aspect were independent predictors for grading. CONCLUSIONS: In patients with cirrhosis and hepatocellular carcinoma, the prevalence of microinvasive hepatocellular carcinoma is high, even in cases of HCC ≤2 cm. Intraoperative ultrasound findings strongly correlated with histopathological criteria in detecting microinvasive patterns and are useful to predict neoplastic differentiation. The knowledge of these features prior to treatment are highly desired (this can be obtained by an intraoperative ultrasound examination), as they could help in providing optimal management of patients with hepatocellular carcinoma.

Premature ovarian senescence and a high miscarriage rate impair fertility in women with HCV.

BACKGROUND & AIMS: Premenopausal women who are HCV positive (HCV+) have failing ovarian function, which is likely to impact their fertility. Thus, we investigated the reproductive history, risk of infertility, and pregnancy outcomes in women of childbearing age who were HCV+. METHODS: Three different groups were studied: (1) Clinical cohort: 100 women who were HCV+ and also had chronic liver disease (CLD), age matched with 50 women who were HBV+ with CLD and with 100 healthy women; all women were consecutively observed in three gastroenterology units in hospitals in Italy; (2) 1,998 women who were HCV+ and enrolled in the Italian Platform for the Study of Viral Hepatitis Therapies (PITER); (3) 6,085 women, who were mono-infected with HCV, and 20,415 women, who were HCV-, from a large de-identified insurance database from the USA. MEASUREMENTS: total fertility rate (TFR) defined as the average number of children that a woman would bear during her lifetime. To define the reproductive stage of each participant, levels of anti-Müllerian hormone (AMH) and 17ß-estradiol were measured. RESULTS: Clinical cohort: women who were either HCV+ or HBV+ had similar CLD severity and age at first pregnancy. Based on a multivariate analysis, women who were HCV+ had a higher risk of miscarriage than those who were HBV+ (odds ratio [OR] 6,905; 95% CI 1.771-26.926). Among women who were HCV+, incidence of miscarriage was correlated with median AMH level (1.0 ng/ml). Achieving a sustained virologic response (SVR) after antiviral treatment reduced the risk of miscarriage (OR 0.255; 95% CI 0.090-0.723). In the PITER-HCV cohort, miscarriage occurred in 42.0% of women (44.6% had multiple miscarriages). TFR for women who were HCV+ and between 15 and 49 years of age was 0.7 vs. 1.37 of Italian population of the same age range. In the US cohort: compared with women who were HCV-, women who were HCV+ positive were significantly more likely to have infertility (OR 2.439; 95% CI 2.130-2.794), premature birth (OR 1.34; 95% CI 1.060-1.690), gestational diabetes (OR 1.24; 95% CI 1.020-1.510), and pre-eclampsia (OR 1.206; 95% CI 0.935-1.556), and were less likely to have a live birth (OR 0.754; 95% CI 0.622-0.913). CONCLUSIONS: Ovarian senescence in women of childbearing age who are HCV+ is associated with a lower chance of live birth, greater risk of infertility, gestational diabetes, pre-eclampsia and miscarriage. Such risks could be positively influenced by successful HCV cure. LAY SUMMARY: Most new cases of HCV infection are among people who inject drugs, many of whom are young women in their childbearing years. Women of reproductive age who are HCV+ display markers of ovarian senescence. This is associated with an increased burden in terms of infertility and adverse pregnancy outcomes, including stillbirth, miscarriage, fewer live births, and gestational diabetes. Early viral suppression with therapy is likely to mitigate these risks.

Safety and efficacy of a fixed-dose combination regimen of grazoprevir, ruzasvir, and uprifosbuvir with or without ribavirin in participants with and without cirrhosis with chronic hepatitis C virus genotype 1, 2, or 3 infection (C-CREST-1 and C-CREST-2, part B): two randomised, phase 2, open-label trials.

BACKGROUND: There is a need for hepatitis C virus (HCV) therapies with excellent efficacy across genotypes and in diverse populations. Part A of the C-CREST-1 and C-CREST-2 trials led to the selection of a three-drug regimen of grazoprevir (MK-5172; an HCV NS3/4A protease inhibitor; 100 mg/day) plus ruzasvir (MK-8408; an NS5A inhibitor; 60 mg/day) plus uprifosbuvir (MK-3682; an HCV NS5B polymerase inhibitor; 450 mg/day). Part B of the studies tested this combination as a single formulation in different treatment durations in a broader population. METHODS: Part B of these randomised, phase 2, open-label clinical trials enrolled individuals from 15 countries who were chronically infected with HCV genotypes 1-6 (HCV RNA ≥10 000 IU/mL) with or without compensated cirrhosis. Those with genotype 1, genotype 2, genotype 4, or genotype 6 were treatment-naive; those with genotype 3 could be treatment-naive or treatment-experienced with pegylated interferon and ribavirin. Randomisation occurred centrally using an interactive voice response system and integrated web response system. Participants were randomly assigned to receive treatment for 8, 12, or 16 weeks with a fixed-dose combination of grazoprevir, ruzasvir, and uprifosbuvir with or without ribavirin. The primary endpoint was the proportion of participants achieving sustained virological response 12 weeks after the end of all study therapy (SVR12), defined as HCV RNA less than the lower limit of quantification (either target detected unquantifiable or target not detected [<15 IU/mL]). The trials are registered at ClinicalTrials.gov, numbers NCT02332707 and NCT02332720. FINDINGS: 676 participants were randomly assigned between Feb 18, 2015, and Aug 16, 2016. In all 675 participants who received at least one dose of study drug (full analysis set), SVR12 for the 8-week regimen of grazoprevir, ruzasvir, and uprifosbuvir with and without ribavirin was achieved in 39 (93% [95% CI 81-99]) of 42 participants with genotype 1a, 45 (98% [88-100]) of 46 with genotype 1b, 54 (86% [75-93]) of 63 with genotype 2, 98 (95% [89-98]) of 103 with genotype 3, and seven (100% [59-100]) of seven participants with genotype 4. SVR12 for the 12-week regimen with and without ribavirin was achieved in 87 (99% [95% CI 94-100]) of 88 participants with genotype 1, 61 (98% [91-100]) of 62 with genotype 2, and four (100% [40-100]) of four with genotype 6. Among participants with cirrhosis who were infected with genotype 3, SVR12 for the 12-week regimen with and without ribavirin was achieved in 28 (97% [95% CI 82-100]) of 29 of those who were treatment-naive and 29 (100% [88-100]) of 29 who were treatment-experienced. SVR12 for the 16-week regimen with and without ribavirin was achieved in 26 (100% [95% CI 87-100]) of 26 participants with genotype 2 infection and 72 (96% [89-99]) of 75 participants with genotype 3 infection. The most common adverse events were headache (143 [22%] of 664), fatigue (129 [19%] of 664), and nausea (83 [13%] of 664). 16 (2%) of 664 participants had serious adverse events. INTERPRETATION: The combined regimen of grazoprevir (100 mg/day), ruzasvir (60 mg/day), and uprifosbuvir (450 mg/day) has the potential to provide a simplified treatment for HCV that is effective and well tolerated in most individuals infected with HCV, as well as a shorter duration of treatment in many individuals. FUNDING: Merck & Co, Inc.

Ombitasvir, paritaprevir, and ritonavir, with or without dasabuvir, plus ribavirin for patients with hepatitis C virus genotype 1 or 4 infection with cirrhosis (ABACUS): a prospective observational study.

BACKGROUND: We ran a compassionate use nationwide programme (ABACUS) to provide access to ombitasvir, paritaprevir, and ritonavir, with dasabuvir, plus ribavirin for hepatitis C virus (HCV) genotype 1 infection and ombitasvir, paritaprevir, and ritonavir, plus ribavirin for HCV genotype 4 infection in patients with cirrhosis at high risk of decompensation while approval of these regimens was pending in Italy. METHODS: In this prospective observational study, we collected data from a compassionate use nationwide programme from March 17, 2014, to May 28, 2015. Patients with HCV genotype 1 infection and cirrhosis at high risk of decompensation were given coformulated ombitasvir (25 mg), paritaprevir (150 mg), and ritonavir (100 mg) once daily and dasabuvir (250 mg) twice daily for 12 weeks (patients with HCV genotype 1b infection) or 24 weeks (patients with HCV genotype 1a infection). Patients with HCV genotype 4 infection were given coformulated ombitasvir (25 mg), paritaprevir (150 mg), and ritonavir (100 mg) once per day for 24 weeks. All patients were given weight-based ribavirin. The primary efficacy endpoint was sustained virological response at week 12 after the end of treatment (SVR12), analysed by intention-to-treat. Univariate and multivariate logistic regression analyses were used to identify baseline characteristics associated with SVR12. Adverse events were recorded throughout the study. FINDINGS: 728 (96%) of 762 patients with cirrhosis who were given ombitasvir, paritaprevir, and ritonavir, with or without dasabuvir, plus ribavirin therapy for 12 or 24 weeks achieved SVR12. Logistic regression analyses identified that bilirubin concentrations of less than 2 mg/dL were associated with SVR12 (odds ratio [OR] 4·76 [95% CI 1·83-12·3]; p=0·001). 166 (23%) of 734 patients included in safety analyses had an adverse event. 25 (3%) patients discontinued treatment because of adverse events. Asthenia was the most commonly reported adverse event, occurring in 36 (5%) patients. INTERPRETATION: Our findings suggest that the safety and effectiveness of ombitasvir, paritaprevir, and ritonavir, with or without dasabuvir, plus ribavirin in patients with HCV genotype 1 or 4 infection and cirrhosis at high risk of decompensation in a real-life setting are similar to those reported in clinical trials. The concordance with clinical trials provides reassurance that the reported efficacy of this treatment in clinical trials will translate to its use in routine clinical practice. FUNDING: Dipartimento Biomedico di Medicina Interna e Specialistica dell'Universita di Palermo.

Improved survival of patients with hepatocellular carcinoma and compensated hepatitis C virus-related cirrhosis who attained sustained virological response.

BACKGROUND: Few studies examined the outcome of patients with hepatitis C virus (HCV)-related cirrhosis who developed hepatocellular carcinoma (HCC). The relative weight as determinant of death for cancer vs end-stage liver disease (ESLD) and the benefit of HCV eradication remain undefined. This multicentre, retrospective analysis evaluates overall survival (OS), rate of decompensation and tumour recurrence in compensated HCC patients treated with interferon (IFN) according to HCV status since HCC diagnosis. METHODS: Two groups of patients with HCV-related cirrhosis and HCC were followed since HCC diagnosis: (i) compensated cirrhotics with prior sustained virological response (SVR) on IFN-based regimens (N=19); (ii) compensated cirrhotics without SVR (viraemic) (N=156). RESULTS: Over a median follow-up of 3.0 years since the onset of HCC, OS was longer for HCC patients with SVR than for viraemic patients (log-rank P=.004). The 5-year OS rate was 65.9% in patients with SVR vs 31.9% in viraemic patients. Similar trends were reported for hepatic decompensation (log-rank P=.01) and tumour recurrence (log-rank P=.01). These findings were confirmed at multivariable and propensity score analysis. At propensity analysis, 0/19 compensated patients with SVR died for ESLD vs 7/19 (37%) viraemic patients (P=.004). HCC mortality was similar in the two groups. CONCLUSIONS: Hepatocellular carcinoma patients with prior SVR and compensated cirrhosis at the time of tumour diagnosis have prolonged OS than viraemic patients. Given the lack of cirrhosis progression, no SVR patient ultimately died for ESLD while this condition appears the main cause of death among viraemic patients.

Risk of cirrhosis-related complications in patients with advanced fibrosis following hepatitis C virus eradication.

BACKGROUND & AIMS: The risk of hepatocellular carcinoma (HCC) is reduced but not eradicated among patients with hepatitis C virus (HCV)-induced advanced hepatic fibrosis who attained sustained viral response (SVR). We aimed to assess the risk of cirrhosis-related complications in this specific group of patients. METHODS: Data from previously reported Western cohort studies including patients with chronic HCV infection and bridging fibrosis or cirrhosis who attained SVR were pooled for survival analyses on the individual patient level. The primary endpoint was HCC and the secondary endpoint was clinical disease progression, defined as liver failure, HCC or death. RESULTS: Included were 1000 patients with SVR. Median age was 52.7 (IQR 45.1-59.7) years, 676 (68%) were male and 842 (85%) had cirrhosis. Median follow-up was 5.7 (IQR 2.9-8.0) years. Fifty-one patients developed HCC and 101 had clinical disease progression. The cumulative 8-year HCC incidence was 1.8 (95% CI 0.0-4.3) among patients with bridging fibrosis and 8.7% (95% CI 6.0-11.4) among those with cirrhosis (p=0.058). Within the cirrhosis group, the 8-year HCC incidence was 2.6% (95% CI 0.0-5.5) among patients <45years, 9.7% (95% CI 5.8-13.6) among patients from 45-60years, and 12.2% (95% CI 5.3-19.1) among patients >60years of age at start of therapy (p=0.006). Multivariable Cox analyses indicated that higher age, lower platelet count and diabetes mellitus were independently associated with development of HCC. After 8years 4.2% (95% CI 0.1-8.3) of patients with bridging fibrosis and 15.8% (95% CI 12.3-19.3) of patients with cirrhosis experienced clinical disease progression (p=0.007). CONCLUSIONS: Patients with HCV-induced cirrhosis and SVR showed an annual risk of approximately 1% for HCC and 2% for clinical disease progression. Therefore, to prevent HCC surveillance, chronic HCV infection should preferably be treated before cirrhosis has developed. LAY SUMMARY: Patients with cirrhosis who were able to eradicate their chronic HCV infection remain at substantial risk of primary liver cancer. The risk of liver cancer increases with higher age, laboratory makers suggesting more severe liver disease, and presence of diabetes mellitus. Also after successful antiviral therapy patients with HCV-induced cirrhosis should thus remain included in follow-up for early detection of liver cancer.

Toward precision medicine in primary biliary cholangitis.

Primary biliary cholangitis is a chronic, cholestatic liver disease characterized by a heterogeneous presentation, symptomatology, disease progression and response to therapy. In contrast, clinical management and treatment of PBC is homogeneous with a 'one size fits all' approach. The evolving research landscape, with the emergence of the -omics field and the availability of large patient cohorts are creating a unique opportunity of translational epidemiology. Furthermore, several novel disease and symptom-modifying agents for PBC are currently in development. The time is therefore ripe for precision medicine in PBC. In this manuscript we describe the concept of precision medicine; review current approaches to risk-stratification in PBC, and speculate how precision medicine in PBC might develop in the near future.

Impact of virus eradication in patients with compensated hepatitis C virus-related cirrhosis: competing risks and multistate model.

BACKGROUND & AIMS: No published study to date has provided a careful analysis of the effects of a sustained viral response (SVR) on the outcomes of patients with compensated hepatitis C virus (HCV)-related cirrhosis in relation to the degree of portal hypertension. Therefore, we estimated the impact of achieving SVR on disease progression, hepatocellular carcinoma (HCC) development and mortality in a large cohort of HCV patients with cirrhosis with or without oesophageal varices (OVs) at the start of antiviral therapy. METHODS: A total of 535 Caucasian patients were prospectively recruited to this study. All patients had a clinical or histological diagnosis of compensated HCV-related cirrhosis and underwent interferon-based therapy. Competing risks and a multistate model were analysed according to the presence or absence of OVs at baseline. RESULTS: Compared to patients without SVR, a greater proportion of patients who achieved SVR showed no liver disease progression after 10 years (36.3% vs. 61.3% of patients without baseline OVs; 29.6% vs. 64.3% of patients with baseline OVs). Achievement of SVR was significantly associated with reduced occurrence rates of de-novo OVs, hepatic decompensation and HCC. Compared to patients without SVR, patients with SVR had lower likelihoods of liver-related death at 10 years (20.6% vs. 10.3% of patients without baseline OVs; 50.5% vs. 21.8% of patients with baseline OVs). CONCLUSIONS: In patients with compensated HCV-related cirrhosis with or without OVs at baseline, SVR is associated with reduced disease progression and liver-related mortality.