AGA Clinical Practice Update on Interaction Between Oral Direct-Acting Antivirals for Chronic Hepatitis C Infection and Hepatocellular Carcinoma: Expert Review.

The purpose of this clinical practice update is to evaluate the evidence describing the interaction between direct-acting antiviral (DAA) therapy for hepatitis and hepatocellular carcinoma (HCC) with regard to HCC incidence, HCC recurrence, and DAA efficacy, and to summarize best practice advice regarding HCC surveillance and timing of DAA therapy. The recommendations outlined in this expert review are based on available published evidence, including observational studies and systematic reviews, and incorporates expert opinion where applicable. BEST PRACTICE ADVICE 1: DAA treatment is associated with a reduction in the risk of incident HCC. The relative risk reduction is similar in patients with and without cirrhosis. BEST PRACTICE ADVICE 2: Patients with advanced liver fibrosis (F3) or cirrhosis should receive surveillance imaging before initiating DAA treatment. BEST PRACTICE ADVICE 3: Patients with advanced liver fibrosis (F3) or cirrhosis at the time of DAA treatment represent the highest-risk group for HCC after DAA-induced sustained virologic response. These patients should stay in HCC surveillance. BEST PRACTICE ADVICE 4: HCC surveillance should be performed using ultrasound with or without α-fetoprotein every 6 months. Current data do not support shorter surveillance intervals or the use of alternative surveillance modalities. BEST PRACTICE ADVICE 5: Future studies may show a reduction in HCC risk over time after DAA-induced sustained virologic response. However, in the interim, HCC surveillance should continue indefinitely if patients are otherwise eligible for potentially curative therapy. BEST PRACTICE ADVICE 6: The presence of active HCC is associated with a small but statistically significant decrease in sustained virologic response with DAA therapy. BEST PRACTICE ADVICE 7: Patients with HCC who are eligible for potentially curative therapy with liver resection or ablation should defer DAA therapy until after HCC treatment is completed. BEST PRACTICE ADVICE 8: Timing of DAA therapy for patients with HCC who are listed for liver transplantation should be determined with consideration of median wait times, availability of hepatitis C virus-positive organs, and degree of liver dysfunction. BEST PRACTICE ADVICE 9: There are insufficient data evaluating benefits and cost-effectiveness of DAA therapy in patients with active intermediate or advanced HCC. Decisions regarding DAA treatment in these patients should be considered in light of HCC tumor burden, degree of liver dysfunction, life expectancy, and patient preferences. BEST PRACTICE ADVICE 10: There are no conclusive data that DAA therapy is associated with increased or decreased risk, differential time to recurrence, or aggressiveness of recurrent HCC in patients with complete response to HCC therapy. BEST PRACTICE ADVICE 11: DAA therapy should not be withheld from patients with complete response to HCC therapy; however, DAA therapy can be deferred 4-6 months to confirm response to HCC therapy. BEST PRACTICE ADVICE 12: Patients with complete response to HCC therapy who are treated with DAAs have a continued risk of HCC recurrence and require HCC surveillance, which should be conducted indefinitely with dynamic contrast-enhanced computed tomography or magnetic resonance imaging every 3-6 months. Current data do not support more frequent surveillance in these patients. This Clinical Practice Update was produced by the AGA Institute.

Singal AG ，Lim JK ，Kanwal F 《-》

Hepatocellular carcinoma incidence post direct-acting antivirals in hepatitis C-related advanced fibrosis/cirrhosis patients in Australia.

Despite efficacy in HCV eradication, direct-acting antiviral (DAA) therapy has raised controversies around their impact on hepatocellular carcinoma (HCC) incidence. Herein we reported the first Australian data on HCC incidence in DAA-treated HCV patients with advanced fibrosis/cirrhosis. We conducted a retrospective single center study of DAA-treated HCV patients with advanced fibrosis/cirrhosis from April 2015 to December 2017. Patients with prior HCC were included if they had complete response to HCC treatment. Among 138 patients who completed DAA therapy, 133 (96.4%) achieved sustained virologic response (median follow-up 23.8 months). Ten had prior HCC and 5/10 (50.0%) developed recurrence, while de novo HCC developed in 7/128 (5.5%). Median time from DAA to HCC diagnosis was 34 weeks in recurrent HCC vs. de novo 52 weeks (P = 0.159). In patients with prior HCC, those with recurrence (vs. without) had shorter median time between last HCC treatment and DAA (12 vs. 164 weeks, P < 0.001). On bivariate analysis, failed sustained virologic response at 12 weeks (SVR12) (P = 0.011), platelets (P = 0.005), model for end-stage liver disease (MELD) score (P = 0.029), alpha fetoprotein (AFP) (P = 0.013), and prior HCC (P < 0.001) were associated with HCC post-DAA. On multivariate analysis, significant factors were prior HCC (OR = 4.80; 95% CI: 1.47-48.50; P = 0.010), failed SVR12 (OR = 2.83; 95% CI: 1.71-16.30; P = 0.016) and platelets (OR = 0.97; 95% CI: 0.95-0.99; P = 0.009). Our study demonstrates a high incidence of recurrent HCC in HCV patients with advanced fibrosis/cirrhosis treated with DAA. Factors associated with HCC development post-DAA were more advanced liver disease, failed SVR12 and prior HCC, with higher rates of recurrence in those who started DAA earlier.

Chan PPY ，Levy MT ，Shackel N ，Davison SA ，Prakoso E ... -  《Hepatobiliary & Pancreatic Diseases International》

Direct-Acting Antiviral Therapy Not Associated With Recurrence of Hepatocellular Carcinoma in a Multicenter North American Cohort Study.

There is controversy over the effects of direct-acting antiviral (DAA) therapies for hepatitis C virus (HCV) infection on hepatocellular carcinoma (HCC) recurrence and tumor aggressiveness. We compared HCC recurrence patterns between DAA-treated and untreated HCV-infected patients who had achieved a complete response to HCC treatment in a North American cohort. We conducted a retrospective cohort study of patients with HCV-related HCC with a complete response to resection, local ablation, transarterial chemo- or radioembolization, or radiation therapy from January 2013 through December 2017 at 31 health systems throughout the United States and Canada. Cox regression was used to examine the association between DAA therapy and time to recurrence after a complete response, with DAA therapy analyzed as a time-varying exposure. We also estimated the association between DAA therapy and risk of early HCC recurrence (defined as 365 days after complete response). Of 793 patients with HCV-associated HCC, 304 (38.3%) received DAA therapy and 489 (61.7%) were untreated. HCC recurred in 128 DAA-treated patients (42.1%; early recurrence in 52 patients) and 288 untreated patients (58.9%; early recurrence in 227 patients). DAA therapy was not associated with HCC recurrence (hazard ratio 0.90, 95% confidence interval 0.70-1.16) or early HCC recurrence (hazard ratio 0.96, 95% confidence interval 0.70-1.34) after we adjusted for study site, age, sex, Child-Pugh score, α-fetoprotein level, tumor burden, and HCC treatment modality. In DAA-treated and untreated patients, most recurrences were within the Milan criteria (74.2% vs 78.8%; P = .23). A larger proportion of DAA-treated than untreated patients received potentially curative HCC therapy for recurrent HCC (32.0% vs 24.6%) and achieved a complete or partial response (45.3% vs 41.0%) but this did not achieve statistical significance. In a large cohort of North American patients with complete response to HCC treatment, DAA therapy was not associated with increased overall or early HCC recurrence. HCC recurrence patterns, including treatment response, were similar in DAA-treated and untreated patients.

Singal AG ，Rich NE ，Mehta N ，Branch A ，Pillai A ，Hoteit M ，Volk M ，Odewole M ，Scaglione S ，Guy J ，Said A ，Feld JJ ，John BV ，Frenette C ，Mantry P ，Rangnekar AS ，Oloruntoba O ，Leise M ，Jou JH ，Bhamidimarri KR ，Kulik L ，Tran T ，Samant H ，Dhanasekaran R ，Duarte-Rojo A ，Salgia R ，Eswaran S ，Jalal P ，Flores A ，Satapathy SK ，Wong R ，Huang A ，Misra S ，Schwartz M ，Mitrani R ，Nakka S ，Noureddine W ，Ho C ，Konjeti VR ，Dao A ，Nelson K ，Delarosa K ，Rahim U ，Mavuram M ，Xie JJ ，Murphy CC ，Parikh ND ... -  《-》

Direct-acting antivirals after successful treatment of early hepatocellular carcinoma improve survival in HCV-cirrhotic patients.

The effectiveness of direct-acting antivirals (DAAs) against hepatitis C virus (HCV), following successful treatment of early hepatocellular carcinoma (HCC), has been studied extensively. However, the benefit in terms of overall survival (OS) remains to be conclusively demonstrated. The aim of this study was to assess the impact of DAAs on OS, HCC recurrence, and hepatic decompensation. We prospectively enrolled 163 consecutive patients with HCV-related cirrhosis and a first diagnosis of early Barcelona Clinic Liver Cancer stage 0/A HCC, who had achieved a complete radiologic response after curative resection or ablation and were subsequently treated with DAAs. DAA-untreated patients from the ITA.LI.CA. cohort (n = 328) served as controls. After propensity score matching, outcomes of 102 DAA-treated (DAA group) and 102 DAA-untreated patients (No DAA group) were compared. In the DAA group, 7/102 patients (6.9%) died, HCC recurred in 28/102 patients (27.5%) and hepatic decompensation occurred in 6/102 patients (5.9%), after a mean follow-up of 21.4 months. OS was significantly higher in the DAA group compared to the No DAA group (hazard ratio [HR] 0.39; 95% CI0.17-0.91; p = 0.03). HCC recurrence was not significantly different between the DAA and No DAA groups (HR0.70; 95% CI0.44-1.13; p = 0.15). A significant reduction in the rate of hepatic decompensation was observed in the DAA group compared with the No DAA group (HR0.32; 95% CI0.13-0.84; p = 0.02). In the DAA group, sustained virologic response was a significant predictor of OS (HR 0.02; 95% CI 0.00-0.19; p <0.001), HCC recurrence (HR 0.25; 95% CI 0.11-0.57; p <0.001) and hepatic decompensation (HR 0.12; 95% CI 0.02-0.38; p = 0.02). In patients with HCV-related cirrhosis who had been successfully treated for early HCC, DAAs significantly improved OS compared with No DAA treatment. We aimed to determine whether direct-acting antivirals (DAAs) significantly improve overall survival in patients with hepatitis C virus-related compensated cirrhosis and a first diagnosis of hepatocellular carcinoma (HCC) which has been successfully treated with curative resection or ablation. Using propensity-score matched patients, we found that DAAs improved overall survival and reduced the risk of hepatic decompensation. However, the risk of HCC recurrence was not significantly reduced.

Cabibbo G ，Celsa C ，Calvaruso V ，Petta S ，Cacciola I ，Cannavò MR ，Madonia S ，Rossi M ，Magro B ，Rini F ，Distefano M ，Larocca L ，Prestileo T ，Malizia G ，Bertino G ，Benanti F ，Licata A ，Scalisi I ，Mazzola G ，Di Rosolini MA ，Alaimo G ，Averna A ，Cartabellotta F ，Alessi N ，Guastella S ，Russello M ，Scifo G ，Squadrito G ，Raimondo G ，Trevisani F ，Craxì A ，Di Marco V ，Cammà C ，Rete Sicilia Selezione Terapia – HCV (RESIST-HCV) and Italian Liver Cancer (ITA.LI.CA.) Group ... -  《-》

Impact of direct-acting antivirals on early recurrence of HCV-related HCC: Comparison with interferon-based therapy.

It remains controversial whether direct-acting antivirals (DAAs) accelerate the recurrence of hepatitis C-related hepatocellular carcinoma (HCC) after curative therapy. This study aimed to evaluate HCC recurrence after DAA treatment of chronic hepatitis C. We enrolled patients with a history of successful radiofrequency ablation treatment for hepatitis C-related HCC who received antiviral therapy with DAAs (DAA group: 147 patients) or with interferon (IFN)-based therapy (IFN group: 156 patients). We assessed HCC recurrence rates from the initiation of antiviral therapy using the Kaplan-Meier method and evaluated risk factors for HCC recurrence by multivariate Cox proportional hazard regression analysis. The recurrence pattern was categorized as follows: intrahepatic recurrence with a single tumor <2 cm (stage 0), a single tumor or up to 3 tumors ≤3 cm (stage A), multinodular (stage B), and extrahepatic metastasis or macrovascular invasion (stage C). The recurrence rates at 1 and 2 years were 39% and 61% in the IFN group and 39% and 60% in the DAA group, respectively (p = 0.43). Multivariate analysis identified higher lens culinaris agglutinin-reactive fraction of alpha-fetoprotein level, a history of multiple HCC treatments, and a shorter interval between HCC treatment and initiation of antiviral therapy as independent risk factors for HCC recurrence. HCC recurrence in stage 0, A, B, and C was found in 56 (41%), 60 (44%), 19 (14%), and 1 (0.7%) patients in the IFN group and 35 (44%), 32 (40%), 11 (14%), and 2 (2.5%) patients in the DAA group, respectively (p = 0.70). HCC recurrence rates and patterns after initiation of antiviral therapy did not differ between patients who received IFN-based therapy and DAA therapy. We detected no significant difference in early hepatocellular carcinoma (HCC) recurrence rates and patterns between patients who received interferon-based and direct-acting antiviral therapy after HCC treatment. High lens culinaris agglutinin-reactive fraction of alpha-fetoprotein level, short recurrence-free period, and a history of multiple HCC treatments were independent risk factors for early HCC recurrence after the initiation of antiviral therapy.

Nishibatake Kinoshita M ，Minami T ，Tateishi R ，Wake T ，Nakagomi R ，Fujiwara N ，Sato M ，Uchino K ，Enooku K ，Nakagawa H ，Asaoka Y ，Shiina S ，Koike K ... -  《-》