V. Boccaccio

Survival of patients with HCV cirrhosis and sustained virologic response is similar to the general population

BACKGROUND & AIMS Life expectancy of patients with compensated hepatitis C virus (HCV) cirrhosis achieving sustained virologic response (SVR) is limited by liver events as compared to the general population. Thus, survival benefit of SVR remains to be measured. METHODS The study includes prospective surveillance data from three cohorts of Italian patients with compensated HCV cirrhosis who achieved SVR on an interferon-based (IFN) regimen, compared to simultaneously observed non-SVR, untreated and decompensated patients. Overall survival was calculated from the date of start of IFN to death. The number of deaths expected during the at-risk period was determined by applying age- and sex-specific mortality rates recorded in Italy for person-years adequate for the enrolment period. The standardized mortality ratio (SMR) determined the relative risk of death over that of the age and sex matched general population. RESULTS Overall, 28/181 patients followed-up for a median period of 9.6years (range 1-25years) died. The 10 and 20-year overall survival rates for the whole series were 90.9% (95% CI, 84.3-94.8) and 62.9% (95% CI, 45.9-75.9), respectively. The number of expected deaths in the corresponding age and sex matched general population was 28.1, corresponding to a SMR=1.00 (95% CI, 0.72-1.35), with an SMR for non-SVR patients of 3.85 (95% CI, 3.43-4.30), for untreated of 3.01 (95% CI, 2.64-3.42) and for decompensated of 6.70 (95% CI, 5.39-8.22). CONCLUSIONS Patients with compensated HCV cirrhosis achieving SVR by IFN obtain a main benefit levelling their survival curve to that of the general population. Wider applicability of IFN-free regimens will possibly make this achievement more generalizable.

Hepatocellular carcinoma recurrence in patients with curative resection or ablation: impact of HCV eradication does not depend on the use of interferon

In HCV‐infected cirrhotic patients with successfully treated early hepatocellular carcinoma (HCC), the time to HCC recurrence and the effects of sustained viral eradication (SVR) by interferon (IFN)‐based or IFN‐free regimens on HCC recurrence remain unclear.

Management of HCV patients with cirrhosis with direct acting antivirals

In recent years, several studies have clearly shown that sustained virological response (SVR) achieved by interferon‐based therapies may delay or reduce the risk of hepatocellular carcinoma, liver decompensation and all‐causes of mortality in all categories of patients with HCV‐related cirrhosis, a condition characterized by a wide heterogeneity of clinical features, especially in patients with compensated disease. Unfortunately, the advanced fibrosis stage has been shown to be associated with poor SVR rates and poor tolerance with Peg‐interferon and ribavirin. Therefore, on the basis of its risk/efficacy evaluation, most patients are considered to be ineligible for antiviral therapy with these molecules.

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

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.

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

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.

Interferon lambda-3 is not associated with clinical outcome in patients with HCV-induced compensated cirrhosis: a long-term cohort study.

BACKGROUND Interferon Lambda-3 (IFN-λ3) gene polymorphism is associated with spontaneous clearance of hepatitis C virus (HCV) and response to IFN-based therapy (IFN). However, very few data are available about its value in predicting sustained virologic response (SVR) in patients with cirrhosis, and whether IFN-λ3 genotype influences liver disease progression remains unclear. METHODS We determined IFN-λ3 genotype by PCR in a cohort of patients with compensated HCV-related cirrhosis, enrolled between 1989 and 1992. Person-years follow-up was calculated for each individual from the date of enrolment to the development of first episode of decompensation, HCC, liver transplant, death or end of follow-up. The follow-up of patients who achieved SVR was censored at the time of IFN initiation. Kaplan-Meier curves and Cox regression analyses were used to assess the association between IFN-λ3 genotype and clinical outcome. RESULTS IFN-λ3 was determined in 264 patients (52% males, mean age 57±8 years, 67% HCV genotype (G)1, while CC, CT and TT genotypes were 36%, 50% and 14%, respectively. During a median follow-up of 14.8 years, 149 (56%) patients received IFN. Overall, SVR was achieved in 31 (21%) patients, 40% among those with CC genotype (22% in G1 and 61% in G2, respectively) compared to 10% and 13% among patients with CT and TT genotypes (p<0.0001). Univariate and multivariate analyses found no association between IFN-λ3 (CC vs. non-CC genotype) and disease progression. CONCLUSION IFN-λ3 determination is fundamental for allocating cirrhotic patients to be treated with IFN, while it has no value in predicting the outcome of the disease.

Optimal management of patients with chronic hepatitis C and comorbidities

Although HCV infection mainly induces liver injury, chronic disease is systemic. Moreover, host and viral factors, as well as comorbidities, may influence the chance of achieving a sustained virological response or disease outcome. Although there are sufficient data on the use of peg‐interferon and ribavirin in patients with comorbidities, there is very little data on first generation protease inhibitors, which include significant drug–drug interactions and have therefore been administered with caution in these patients. The availability of new, more effective direct acting antivirals should significantly change this scenario. All these issues are discussed in this review.

P465 SVR IS ASSOCIATED WITH NO RISK REDUCTION OF HCC DEVELOPMENT IN PATIENTS WITH HCV-RELATED CIRRHOSIS. A PROSPECTIVE, UP-TO 23 YEARS, COHORT FOLLOW-UP STUDY

Methods: Sixty-five patients with cirrhosis tested for ETP with/without TM. Clinical, endoscopic variables, presence/absence of PVT by Doppler-US and/or TC examination were collected at basal evaluation and up to 4 years. The incidence of de novo PVT was the primary clinical end-point. We also considered transplantation freesurvival. ETP-ratio upper than the 95° percentile of 173 healthycontrols defined TM-resistance. Results: ETP-ratio was not different by comparing patients with (n =12) vs without PVT (n =53) at basal evaluation. Among no-PVT patients, 11 developed de novo PVT in the follow-up. The incidence of PVT was higher in those patients with TM-resistance (n =36) also after adjustment for Child-score (HR:7.68; 90%-CI: 1.32–44.54, p = 0.017). Seventeen patients experienced at least one PHT-related complication and 23 patients died or were transplanted. The mean survival time-free of transplantation was 2.7 vs 3.6 years by comparing, respectively, patients with vs without TM-resistance (p = 0.005, log-rank test). However, only Child-score independently predicted transplantation free-survival. Conclusions: The occurrence of PVT should be explained, in part, by the pro-coagulant imbalance described in patients with advanced liver disease. TM-resistance could be a potential modifiable factor to improve survival in patients with cirrhosis.

Frequent NS5A and multiclass resistance in almost all HCV genotypes at DAA failures: what are the chances for second-line regimens?

Velia Chiara Di Maio, Valeria Cento, Marianna Aragri, Stefania Paolucci, Teresa Pollicino, Nicola Coppola, Bianca Bruzzone, Valeria Ghisetti, Maurizio Zazzi, Maurizia Brunetto, Ada Bertoli, Silvia Barbaliscia, Silvia Galli, William Gennari, Fausto Baldanti, Giovanni Raimondo, Carlo Federico Perno, Francesca Ceccherini-Silberstein, on behalf of treatment team of the HCV Virology Italian Resistance Network (VIRONET-C),

12 weeks of interferon-based therapy is feasible in patients with hepatitis C-related cirrhosis and thrombocytopenia: A post hoc analysis of eltrombopag studies

BACKGROUND A 24-48-week course of interferon-based therapy poorly tolerated in hepatitis C virus (HCV) cirrhosis patients with thrombocytopenia. Aim of the study was to identify patients at low-risk of liver-related complications over a 12-week course of interferon-based therapy. METHODS We assessed the rate of complications and death during the first 12 weeks of interferon-based therapy in HCV cirrhotics with thrombocytopenia (platelets ≤75×10(9)/L) enrolled in the ENABLE-1 and -2 phase 3 randomised controlled trials. RESULTS Overall, among 1441 patients, 89 complications (6.9%) and 10 deaths (0.7%) were observed within the first 12 weeks of therapy. At univariate analysis baseline albumin levels and Model for End Stage Liver Disease (MELD) score (≤35 g /L, p<0.001, and ≥10, p<0.001, respectively) were the only predictors associated with occurrence of complications and death. Of the 1026 patients with serum albumin >35 g/L (71.2%), one patient died (0.1%) and 17 experienced liver-related complications (1.7%). Among 667 patients with serum albumin >35 g/L and MELD score <10, no deaths occurred and 4 experienced liver-related complications (0.6%). CONCLUSION Among HCV cirrhotic patients with thrombocytopenia, albumin levels and MELD score can identify patients who may safely receive a 12-week course of interferon-based therapy with a low risk of complications.