Progression of the FIB-4 index among patients with chronic HCV infection and early liver disease.

BACKGROUND AND AIMS: Historical paired liver biopsy studies are likely to underestimate current progression of disease in patients with chronic hepatitis C virus (HCV) infection. We aimed to assess liver disease progression according to the non-invasive Fibrosis-4 (FIB-4) index in patients with chronic HCV and early disease. METHODS AND RESULTS: Patients diagnosed with chronic HCV and FIB-4 <3.25 from four international liver clinics were included in a retrospective cohort study. Follow-up ended at start of antiviral therapy resulting in sustained virological response, at time of liver transplantation or death. Primary outcome of advanced liver disease was defined as FIB-4 >3.25 during follow-up. Survival analyses were used to assess time to FIB-4 >3.25.In total, 4286 patients were followed for a median of 5.0 (IQR 1.7-9.4) years, during which 41 071 FIB-4 measurements were collected. At baseline, median age was 47 (IQR 39-55) years, 2529 (59.0%) were male, and 2787 (65.0%) patients had a FIB-4 <1.45. Advanced liver disease developed in 821 patients. Overall, 10-year cumulative incidence of advanced disease was 32.1% (95% CI 29.9% to 34.3%). Patients who developed advanced disease showed an exponential FIB-4 increase. Among patients with a presumed date of HCV infection, cumulative incidence of advanced disease increased 7.7-fold from 20 to 40 years as opposed to the first 20 years after HCV infection. CONCLUSIONS: The rate of advanced liver disease is high among chronic HCV-infected patients with early disease at time of diagnosis, among whom liver disease progression accelerated over time. These results emphasise the need to overcome any limitations with respect to diagnosing and treating all patients with chronic HCV across the globe.

Clinical outcomes following DAA therapy in patients with HCV-related cirrhosis depend on disease severity.

BACKGROUND & AIMS: HCV-infected patients with cirrhosis achieve high sustained virological response (SVR) rates with direct-acting antivirals (DAAs) even after hepatic decompensation. We aimed to assess the clinical outcome following DAAs among patients with compensated and decompensated cirrhosis in relation to SVR and changes in model for end-stage liver disease (MELD) score. METHODS: Consecutive DAA-treated chronic HCV-infected patients with cirrhosis from 4 hepatology clinics were included. The primary endpoint in survival analyses was clinical disease progression, defined as liver failure, hepatocellular carcinoma, liver transplantation or death. RESULTS: In total, 868 patients were included with a median age of 59 (IQR 54-65) years; 719 (83%) with Child-Pugh A cirrhosis and 149 (17%) with Child-Pugh B/C cirrhosis. SVR was attained by 647 (90%) Child-Pugh A patients and 120 (81%) Child-Pugh B/C patients. During a median follow-up of 28 (IQR 20-36) months, 102 (14%) Child-Pugh A patients and 96 (64%) Child-Pugh B/C patients experienced clinical disease progression. SVR was independently associated with an improved event-free survival in patients with Child-Pugh A cirrhosis (adjusted hazard ratio [HR] 0.47; 95% CI 0.27-0.82, p = 0.007), but not in patients with Child-Pugh B/C cirrhosis (adjusted HR 1.23; 95% CI 0.67-2.26; p = 0.51). Twelve weeks post-DAAs, 28 (19%) patients with Child-Pugh B/C cirrhosis had ≥2-point MELD decline, but their 2-year event-free survival did not differ from those with a stable MELD (47.9%; 95% CI 28.7-67.1 vs. 48.9%; 95% CI 38.1-59.7, respectively, p = 0.99). CONCLUSIONS: Among patients with chronic HCV infection, DAA-induced SVR was associated with a reduced risk of clinical disease progression in patients with Child-Pugh A cirrhosis but not in patients with Child-Pugh B/C cirrhosis. In Child-Pugh B/C cirrhosis, a ≥2-point MELD decline did not translate into improved clinical outcome. LAY SUMMARY: Chronic HCV infection can be cured with antiviral therapy. In this study, we evaluated the long-term effects of antiviral therapy on liver-related complications in patients with cirrhosis. Our results suggest that patients with compensated cirrhosis who were cured of their HCV infection have a lower rate of complications. In contrast, the rate of complications was not related to virological cure among those with decompensated cirrhosis. While these patients seem to remain in need of liver transplantation, antiviral therapy may lower their priority on the liver transplantation waiting list.

Ultra-Long-term Follow-up of Interferon Alfa Treatment for HBeAg-Positive Chronic Hepatitis B Virus Infection.

BACKGROUND AND AIMS: Interferon-alpha (IFN-α) treatment for chronic hepatitis B (CHB) virus infection is finite and leads to relatively higher functional cure rates (HBsAg loss) than nucleo(s)tide analogue (NA) therapy. Effects of pegylated (PEG)/conventional IFN-α treatment on clinical outcomes were evaluated in an ultra-long-term follow-up of CHB patients. METHODS: HBeAg-positive patients treated with (PEG)IFN-α at a tertiary referral centre between 1977-2014 were included. We reviewed medical charts and consulted the municipal registry for patient information. Patients were invited for a single visit at the outpatient clinic in the case of missing follow-up data. The endpoints included serum HBeAg/HBsAg loss and incidence of clinical events, using life table methods and person-years to analyze the incidence of events. Patients were censored upon retreatment. RESULTS: The study cohort included 267 patients, 67% male, 58% Caucasian, with a median age of 32 years. The median follow-up duration was 11.5 years. The 5 and 10-year cumulative incidence of HBsAg loss were 14% and 32%, respectively. Baseline factors associated with a higher rate of HBsAg loss were male sex, Caucasian race, genotype A, age ≥40 years, and cirrhosis. HBsAg loss rates did not differ significantly between those who received short-term (≤24 weeks) vs long-term (>24 weeks) therapy. Both HBeAg and HBsAg loss were significantly associated with improved clinical outcomes. Early response (HBeAg loss) was associated with more HBsAg loss and better patient outcomes. CONCLUSIONS: During long-term follow-up, high rates of HBsAg loss were observed from a single (PEG)IFN-α course. Its persistent effects suggest that a role for IFN-α remains, potentially in novel combination therapies in search of a functional cure.

Evaluation of Sustained Virologic Response as a Relevant Surrogate Endpoint for Long-term Outcomes of Hepatitis C Virus Infection.

BACKGROUND: The causal link of sustained virologic response (SVR) with outcome has been challenged. With improved SVR rates with direct-acting antivirals (DAAs), the benefit of SVR would be expected to diminish if the association with outcome is not causal. METHODS: Data were collected for patients starting treatment with interferon (IFN) or DAAs between June 2006 and December 2016. To control for disease severity, criteria for the IDEAL (Individualized Dosing Efficacy vs. Flat Dosing to Assess Optimal Pegylated Interferon Therapy) trial determined IFN-eligibility. Clinical events were decompensation, hepatocellular carcinoma, liver transplantation, and all-cause mortality. RESULTS: In 1078 IDEAL-eligible patients, 1306 treatments occurred (52% IFN, 49% DAAs). Cirrhosis was present in 30% DAAs vs 21% IFN (P < .001). SVR was 97% with DAAs vs 52% with IFN (P < .0001). The 24-month cumulative event-free survival was 99% for IFN and 97% for DAAs with SVR (P = .08) and 96% and 75%, respectively, for non-SVR (P = .01). SVR was associated with improved event-free survival with an adjusted hazard ratio of 0.21 (95% confidence interval, .06-.71; P = .01). Using inverse probability of treatment weighting to match IFN nonresponders with DAA-treated patients, the 24-month event-rate was 1.1% with DAAs compared to 3.4% in IFN nonresponders (P = .005), highlighting the clinical benefit of maximizing SVR. CONCLUSIONS: In IFN-eligible patients, SVR is more commonly achieved with DAAs and confers a similar clinical benefit as in those treated with IFN. The reduced event-rate with DAAs compared to IFN, despite similar disease severity, confirm that SVR alters prognosis leading to improved clinical outcomes.

Spontaneous Clearance After Relapse Following Direct-Acting Antiviral Treatment for Chronic HCV Infection.

BACKGROUND & AIMS: Direct-acting antivirals (DAAs) cure most cases of chronic hepatitis C virus (HCV) infection. However, a small percentage of patients relapse with reappearance of viremia after a full course of therapy. Although most who relapse require retreatment, some patients spontaneously clear HCV without additional therapy. We studied patients who relapsed with detectable HCV RNA after a full course of DAA therapy and then spontaneously cleared the HCV infection without retreatment. METHODS: We performed a case-control study of patients who spontaneously cleared chronic HCV infection following a documented relapse after DAA therapy at the Toronto Centre for Liver Disease, from January 2014 through December 2017. We collected clinical information at baseline, 12 weeks after treatment, and 6 months after relapse and compared data among spontaneous clearers, patients with persistent relapse, and patients who achieved a sustained virologic response to therapy 12 weeks after treatment (SVR12). The strength and breadth of interferon gamma cytokine secretion by HCV-specific T cells from peripheral blood were quantified using the ELISPOT assay. RESULTS: Of the 1032 individuals with chronic HCV infection who were treated with DAAs, 93 patients had a documented relapse. Of these patients, 12 patients (13%) spontaneously cleared HCV within 6 months after the documented relapse without additional therapy. The spontaneous clearers had low levels of HCV RNA (<4 log IU/mL in 11 of 12) and normal levels of alanine aminotransferase at the time of relapse, much like patients with an SVR12. There was no significant difference between the spontaneous clearance group and the SVR12 group in magnitude and breadth of HCV-specific T cell responses. CONCLUSIONS: In a case-control study of patients who spontaneously cleared chronic HCV infection following a relapse after DAA therapy, we found that it is important to confirm viremia prior to retreatment after the relapse-particularly for individuals with low levels of HCV RNA and normal or near-normal levels of alanine aminotransferase after treatment.

What Comes First: Treatment of Viral Hepatitis or Liver Cancer?

Chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection are the most important underlying causes for the development of hepatocellular carcinoma (HCC) worldwide. Determining the optimal approach for management of the viral infection and the HCC depends on the virus and the stage of the cancer. In patients with HCV-associated HCC, there are multiple reasons to first treat the HCC. Firstly, in case of a curable HCC, the urgency for HCC treatment is important to avoid progression during HCV treatment. Secondly, the presence of HCC itself appears to reduce the rates of sustained virological response (SVR) achieved with direct-acting antivirals (DAAs). And finally, the evidence does not support the concept of an increase in HCC recurrence due to DAAs, so a patient can safely be treated after HCC cure. For patients with very advanced HCC, the benefits of HCV therapy are questionable. In contrast, those who develop HCC in the setting of chronic HBV infection, treatment with nucleoside analogues (NAs) is recommended prior to treating HCC, to prevent further liver injury and reduce the risk for HCC recurrence. Ultimately, earlier diagnosis and treatment of HBV and HCV will hopefully reduce the incidence of HCC worldwide.