Direct-acting Antivirals Group Research Articles

Elucidating the association between direct-acting antivirals and Parkinson's disease in patients with hepatitis C virus infection

BackgroundSome epidemiological studies have found an increased association between Parkinson's disease (PD) and chronic hepatitis C virus (HCV) infection. Although a few studies have also found a decreased risk of PD with interferon-α therapy, the effect of direct-acting antivirals (DAAs) on Parkinson's disease remains unclear. The current study seeks to assess and elucidate the association between DAAs and PD in patients newly diagnosed with chronic HCV infection. MethodsWe conducted a retrospective cohort study of patients ≥18 years diagnosed with HCV using MarketScan Commercial and Medicare Supplemental database (2012–2019). Follow-up started with the initiation of DAA (or randomly assigned date for the non-DAA group) and ended at occurrence of PD, disenrollment, or end of the study period. A multivariable Cox proportional hazards model was used to estimate hazard ratios (HR) and 95% confidence intervals. ResultsWe identified 48,356 patients diagnosed with HCV. The mean follow-up time of the cohort was 1.31 years. The incidence rate of PD was 53 per 100,000 person-years for the DAA group and 48 per 100,000 person-years for the non-DAA group. The adjusted HR was 1.24 (95% CI = 0.56–2.73). Results were consistent across sensitivity and subgroup analyses. ConclusionThis study did not find an association between DAAs and PD among patients with HCV infection.

Hepatitis C Virus-Related One-Year Hepatocellular Carcinoma Recurrence After Directly Acting Antivirals: A Randomized Controlled Trial.

Available data on hepatocellular carcinoma (HCC) recurrence after direct-acting antivirals (DAAs) treatment for hepatitis C virus (HCV) are conflicting. No randomized trials were done. This study aims to compare the 1-year HCC recurrence rates in patients who received DAAs after tumor ablation versus those who postponed HCV treatment for 1year. Included patients were randomized after complete HCC ablation into two groups: a postponed DAAs group for whom DAAs initiation was postponed for 12months and a DAAs group who were given sofosbuvir/velpatasvir. Patients were followed for 1year. Eighty-four HCV patients with a mean age of 56.35 ± 8.12years were included; 78.57% of them were males. The number of lesions per patient ranged from 1 to 3 lesions, and the size of the largest lesion ranged from 1.5 to 5cm. There were no statistically significant differences between both groups regarding baseline characteristics. In the DAAs group (43 patients), 11 patients had HCC recurrence, while 25 patients in the postponed DAAs group (41 patients) had HCC recurrence. Using Kaplan-Meier analysis, the 1-year recurrence-free survival (RFS) was significantly higher in the DAAs group (72.2% vs. 38%, P = 0.001). On multivariate analysis, both higher albumin levels (HR 0.147, 95% CI 0.066-0.329) and receiving DAAs (HR 0.358, 95% CI 0.176-0.730) 1year after ablation were associated with significantly lower recurrence. Direct-acting antiviral usage after complete hepatocellular carcinoma ablation significantly decreases the 1-year HCC recurrence rates, but the risk of recurrence is still not eliminated.The study registration number on clinicaltrials.gov : NCT04653818 (initial release on 28/11/2020).

Immune Responses to Anti-Hepatitis C Virus Antibodies during Pre-Liver Transplantation Direct-Acting Antiviral Therapy in Hepatitis C Virus-Infected Recipients Associated with Post-Liver Transplantation Allograft Injury.

The impact of antibody responses following direct-acting antiviral (DAA) therapy in hepatitis C virus (HCV)-infected recipients before and after liver transplantation (LT) is still undetermined. In this observational cohort study, we aimed to explore the association between changes in anti-HCV antibody titers following pre-LT DAA therapy and allograft injury, including biliary complications (BCs) and acute cellular rejection (ACR). A total of 153 cases were enrolled from January 2015 to February 2021. Serum anti-HCV antibody titers were assessed before and after (day 30) LT. Among all recipients, 31/153 (20.3%) had pre-LT DAA therapy (the DAA group) and 122/153 (79.7%) did not undergo pre-LT DAA therapy (the DAA-naïve group). A higher incidence of post-LT BCs was observed in the DAA group (p = 0.028). Compared with the DAA-naïve group, the DAA group had a significantly higher mean level of anti-HCV titer upregulation (p = 0.0024); furthermore, among the recipients with BCs (n = 28) and ACR (n = 41), those in the DAA group exhibited significantly higher mean levels of anti-HCV antibody titer upregulation (p < 0.005). In conclusion, we speculate that the upregulation of anti-HCV antibody titers, which might have been induced via the restoration of HCV-specific immune responses through pre-LT DAA therapy, was associated with post-LT allograft injury.

Neuropsychiatric disorders in chronic hepatitis C patients after receiving interferon or direct-acting antivirals: a nationwide cohort study.

Background: Data on the neuropsychological outcomes after receiving direct-acting antivirals (DAAs) among chronic hepatitis C (CHC) patients have not been well-documented. Aim: This study aimed to evaluate the difference in incidence of neuropsychological disorders (NPDs) after treatment completion between CHC patients receiving interferon (IFN) therapy and DAA therapy. Methods: A nationwide retrospective cohort study was performed using Taiwan's National Health Insurance Research Database (NHIRD) between 2010 and 2018. CHC patients without pre-existing mental disorders were included and divided into the treatment (Tx)-naïve DAA group, retreatment (re-Tx) DAA group, and Tx-naïve IFN group based on their HCV therapy. Propensity score matching was used to balance baseline differences between groups. The primary outcome was the incidence of NPDs during 6 months after completion of therapy. Results: After one-to-one matching, there were 6,461 pairs of patients selected from the Tx-naïve DAA group and Tx-naïve IFN group and 3,792 pairs from the re-Tx DAA group and Tx-naïve IFN group. A lower incidence of NPDs was observed in the Tx-naïve DAA group than in the Tx-naïve IFN group (HR = 0.72, 95% CI = 0.55-0.94, and p = 0.017). The risk of NPDs did not differ between the re-Tx DAA group and the Tx-naïve IFN group (HR = 0.74, 95% CI: 0.52-1.05, and p = 0.092). Conclusion: DAA therapy was associated with lower risk of NPDs when compared with IFN therapy among Tx-naïve CHC patients in a 6-month period after treatment completion, especially among the patients less than 65 years, male gender, and cirrhosis.

Hepatocellular carcinoma, decompensation, and mortality based on hepatitis C treatment: A prospective cohort study.

BACKGROUNDProspective studies of the long-term outcomes of patients with hepatitis C virus (HCV) infection after treatment with interferon-based therapy (IBT) or direct-acting antivirals (DAA) are limited in many Asian countries.AIMTo elucidate the incidences of hepatocellular carcinoma (HCC) and death/transplantation based on treatment with IBT or DAA, to compare the outcomes of the sustained virologic response (SVR) to IBT and DAA, and to investigate outcome-determining factors after SVR.METHODSThis cohort included 2054 viremic patients (mean age, 57 years; 46.5% male; 27.4% with cirrhosis) prospectively enrolled at seven hospitals between 2007 and 2019. They were classified as the untreated group (n = 619), IBT group (n = 578), and DAA group (n = 857). Outcomes included the incidences of HCC and death/transplantation. The incidences of the outcomes for each group according to treatment were calculated using an exact method based on the Poisson distribution. A multivariate Cox regression analysis was performed to determine the factors associated with HCC or death/transplantation, followed by propensity score matching to confirm the results.RESULTSDuring a median of 4.1 years of follow-up, HCC and death/transplantation occurred in 113 and 206 patients, respectively, in the entire cohort. Compared with the untreated group, the incidences of HCC and death/transplantation were significantly lower in the IBT group [adjusted hazard ratio (aHR) 0.47, 95%CI: 0.28-0.80 and aHR 0.28, 95%CI: 0.18-0.43, respectively] and the DAA group (aHR 0.58, 95%CI: 0.35-0.96, and aHR 0.19, 95%CI: 0.20-0.68, respectively). Among 1268 patients who attained SVR with IBT (n = 451) or DAA (n = 816), the multivariable-adjusted analysis showed no differences in the risks of HCC (HR 2.03; 95%CI: 0.76-5.43) and death/transplantation (HR 1.38; 95%CI: 0.55-3.49) between the two groups. This was confirmed by a propensity score-matching analysis. Independent factors for HCC after SVR were age, genotype 1, and the presence of cirrhosis.CONCLUSIONTreatment and achieving SVR with either IBT or DAA significantly reduced the incidences of HCC and mortality in the Asian patients with HCV infection. The risks of HCC and mortality were not significantly different regardless of whether SVR was induced by IBT or DAA.

Efficacy of hepatitis C virus eradication after curative treatment for hepatocellular carcinoma in patients with advanced hepatocellular carcinoma and decreased hepatic functional reserve: A nationwide, multicentre study by the Japanese Red Cross Liver Study Group.

Improvements in the hepatocellular carcinoma (HCC) recurrence rate and survival have been frequently reported following virus eradication after hepatitis C virus (HCV)-related HCC cure. However, the efficacy of direct-acting antiviral (DAA) therapy in patients who included those with advanced HCC and decreased hepatic functional reserve is unknown. A comparative examination was retrospectively conducted of 141 patients with hepatitis C who started DAA therapy within 1 year after undergoing curative HCC treatment and showed a sustained viral response (SVR) and 327 patients who underwent curative treatment for HCV-related HCC and did not subsequently receive antiviral therapy. Whether DAA therapy was given was identified as an independent factor related to both HCC recurrence and survival. Both the recurrence and survival rates improved significantly with DAA therapy in Child-Pugh (CP)-A, whereas no difference in the recurrence rate was seen with DAA therapy in CP-B. However, the survival rate was significantly higher in the DAA group in this class. Similarly, dividing the patients by the Milan criteria showed significant improvements in the recurrence rate and survival with DAA therapy in patients within the Milan criteria. Patients with HCC beyond the Milan criteria showed no difference in recurrence rates, but the DAA group tended to have higher survival rates. Thus, DAA after curative therapy for HCC can be expected to improve survival in patients with advanced HCC or decreased hepatic functional reserve. HCV should be aggressively eradicated in all patients eligible for curative treatment of HCC.

The Impact of Direct-Acting Antiviral Therapy on the Risk of Recurrence after Curative Resection in Patients with Hepatitis-C-Virus-Related Early Stage Hepatocellular Carcinoma.

Background and Objectives: The impact of direct-acting antiviral (DAA)-based regimens on the recurrence of hepatocellular carcinoma (HCC) after successful curative hepatectomy is controversial. Aims: This study aimed to assess the association between DAAs treatment and recurrence risk in HCC after resection. Materials and Methods: We retrospectively assessed 152 cases of early stage (BCLC stage 0/A) hepatitis C virus (HCV)-related HCC (HCV-HCC) that underwent resection with curative intent between 2001 and 2019 at Kaohsiung Chang Gung Memorial Hospital; 48 cases achieved a sustained virological response (SVR) by DAA, and 104 cases were not treated with any antiviral therapy (non-treatment group). Recurrence-free survival (RFS) following curative resection was analyzed by using the log-rank test and Kaplan–Meier method. A Cox proportional hazards model was used to analyze the factors that impacted RFS and OS. Results: Five patients (10.4%) experienced HCC recurrence after DAA therapy. The cumulative HCC recurrence rate was significantly lower in the DAA group than the non-treatment group (p < 0.001). Multivariate analysis revealed a significant difference in RFS between the non-treatment group and DAA group (p = 0.001; hazard ratio (HR), 4.978; 95% CI, 1.976–12.542); liver cirrhosis (p = 0.005; HR, 2.062; 95% CI, 1.247–3.410), microvascular invasion (p = 0.001; HR, 2.331; 95% CI, 1.408–3.860) and AFP > 15 ng/mL (p = 0.022; HR, 1.799; 95% CI, 1.089–2.970) were also independent factors for HCC recurrence. ALBI stage II/III (p = 0.005; HR, 3.249; 95% CI, 1.418–7.443) and microvascular invasion (p < 0.001; HR, 4.037 95% CI, 2.071–7.869) were independent factors for OS; no significant difference in OS was observed between the DAA and no DAA treatment groups. Conclusions: DAA treatment could reduce the risk of recurrence after curative treatment for early stage HCC.

Dynamics of cytokines predicts risk of hepatocellular carcinoma among chronic hepatitis C patients after viral eradication.

BACKGROUNDChronic hepatitis C virus (HCV) infection induces profound alterations in the cytokine and chemokine signatures in peripheral blood. Clearance of HCV by antivirals results in host immune modification, which may interfere with immune-mediated cancer surveillance. Identifying HCV patients who remain at risk of hepatocellular carcinoma (HCC) following HCV eradication remains an unmet need. We hypothesized that antiviral therapy-induced immune reconstruction may be relevant to HCC development.AIMTo investigate the impact of differential dynamics of cytokine expression on the development of HCC following successful antiviral therapy.METHODSOne hundred treatment-naïve HCV patients with advanced fibrosis (F3/4) treated with direct-acting antivirals (DAAs) or peginterferon/ribavirin who achieved sustained virologic response [SVR, defined as undetectable HCV RNA throughout 12 wk (SVR12) for the DAA group or 24 wk (SVR24) for the interferon group after completion of antiviral therapy] were enrolled since 2003. The primary endpoint was the development of new-onset HCC. Standard HCC surveillance (abdominal ultrasound and α-fetoprotein) was performed every six months during the follow-up. Overall, 64 serum cytokines were detected by the multiplex immunoassay at baseline and 24 wk after end-of-treatment.RESULTSHCC developed in 12 of the 97 patients over 459 person-years after HCV eradication. In univariate analysis, the Fibrosis-4 index (FIB-4), hemoglobin A1c (HbA1c), the dynamics of tumor necrosis factor-α (TNF-α), and TNF-like weak inducer of apoptosis (TWEAK) after antiviral therapy were significant HCC predictors. The multivariate Cox regression model showed that ΔTNF-α (≤ -5.7 pg/mL) was the most important risk factor for HCC (HR = 11.54, 95%CI: 2.27-58.72, P = 0.003 in overall cases; HR = 9.98, 95%CI: 1.88-52.87, P = 0.007 in the interferon group). An HCC predictive model comprising FIB-4, HbA1c, ΔTNF-α, and ΔTWEAK had excellent performance, with 3-, 5-, 10-, and 13-year areas under the curve of 0.882, 0.864, 0.903, and 1.000, respectively. The 5-year accumulative risks of HCC were 0%, 16.9%, and 40.0% in the low-, intermediate-, and high-risk groups, respectively.CONCLUSIONDownregulation of serum TNF-α significantly increases the risk of HCC after HCV eradication. A predictive model consisting of cytokine kinetics could ameliorate personalized HCC surveillance strategies for post-SVR HCV patients.

Advances in the Era of Direct-Acting Antivirals for Hepatitis C in Patients with Unresectable Hepatocellular Carcinoma

Background: In patients with unresectable hepatocellular carcinoma (HCC), the advances in direct-acting antiviral (DAA) therapy for chronic hepatitis C remain unclear. We aimed to investigate the characteristics of DAA therapy, when compared to interferon (IFN) therapy. Methods: In this hospital-based study, all HCC patients in Barcelona Clinic Liver Cancer (BCLC) stage B or C, who received pegylated IFN or DAA, were retrospectively screened from 2009 to 2020. Patients without viremia, without HCC, or with HCC in BCLC stage 0, A, or D prior to antiviral therapy were excluded. Rates of and odds ratio (OR) for sustained virological response (SVR) achievement were analyzed. Results: Nineteen and 78 patients were recruited into the IFN and DAA groups, respectively. The median age was significantly older in the DAA group (DAA vs. IFN: 69.5 [25–75% IQR: 62.8–77.3] vs. 64.0 [25–75% IQR: 61.0–68.0]; p < 0.05). The SVR rates were higher in the DAA group as per protocol (DAA vs. IFN: 94.5% vs. 76.5%; p < 0.05) and in BCLC stage B (DAA vs. IFN: 95.2% vs. 76.5%; p < 0.05). All patients in BCLC stage C received DAA therapy, with the SVR rate being 90.9%. In multivariable regression analysis, the 4-week virological response (OR 5.6, 95% CI: 1.3–25.4) and HCC within the up-to-7 criteria (OR 3.7, 95% CI: 1.1–12.9) were independent factors associated with SVR (all p < 0.05). Conclusions: Compared to IFN therapy, more elderly patients with unresectable HCCs were able to receive DAA therapy, while achieving a significantly higher SVR rate.

Health care utilization and costs associated with direct-acting antivirals for patients with substance use disorders and chronic hepatitis C.

BACKGROUND: Patients with substance use disorders (SUD) and chronic hepatitis C virus infection (HCV) have limited access to direct-acting antivirals (DAAs) due to multilevel issues related to providers (eg, concern about reinfection); patients (eg, refusal); payers (eg, prior authorization); and health system structure, although clinical guidelines recommend timely DAA treatment for patients with SUD and HCV. Effects of DAAs on real-world health care utilization and costs among these patients is unknown. OBJECTIVE: To compare changes in medical service utilization and costs related to liver, SUD, and all-cause morbidity in patients with SUD and HCV treated with DAAs (DAA group) vs not treated with DAAs (non-DAA group). METHODS: We conducted a retrospective cohort study using MarketScan Commercial and Medicare Supplemental Claims databases (2012-2018) for newly diagnosed HCV treatment-naive adults with SUD. We used difference-in-differences analyses, stratified by cirrhosis status, to determine the adjusted ratio of rate ratio (RoRR) to assess the difference in the relative changes from the pre- to posttreatment periods between the 2 groups. RESULTS: 6,266 patients with SUD and HCV were identified. Of these patients who also had cirrhosis (n = 607), 49% (n = 298) initiated DAA therapy for HCV, whereas of those without cirrhosis (n = 5,659), 22% (n = 1,219) initiated DAAs. For patients with cirrhosis (n = 607), the liver-related costs decreased by $6,213 (95% CI = -$8,571, -$3,856) for the DAA group and $1,585 (95% CI = -$4,659, $1,490) for the non-DAA group. The relative decreases in the rate of liver-related costs were larger for the DAA group than for the non-DAA group, and the relative changes between groups were significantly different (RoRR = 0.37, 95% CI = 0.19-0.73). There was no difference in the relative changes after DAAs in the rate of SUD-related visits/costs or all-cause costs between the 2 groups. For patients without cirrhosis (n = 5,659), a similar association was observed. Besides, the relative decreases in the rate of SUD-related emergency department (ED) visits (RoRR = 0.54, 95% CI = 0.38-0.77); SUD-related long-term care visits (RoRR = 0.30, 95% CI = 0.13-0.73); all-cause ED visits (RoRR = 0.75, 95% CI = 0.64-0.88); and all-cause long term-care visits (RoRR = 0.36, 95% CI = 0.18-0.72) were larger in the DAA group than in the non-DAA group. CONCLUSIONS: DAAs are associated with a significant decrease in the rate of SUD-related ED visits and liver-related costs without increasing the rate of all-cause costs among patients with SUD and HCV, suggesting that the benefits of DAAs extended beyond liver-related outcomes, especially in this disadvantaged population. DISCLOSURES: Research reported in this publication was supported in part by the National Institute on Drug Abuse of the National Institutes of Health (K01DA045618). The funder did not have a role in the design, the execution, the analyses, the interpretation of the data, or the decision to submit the results of this study. The authors have no potential conflicts of interest.

Assessment of Left Ventricular Systolic Function by Speckle Tracking in Diabetic Patients Receiving Direct Acting Antiviral Drugs for Chronic HCV

Background: Diabetes mellitus [DB] is a well-known risk factor for cardiovascular disease. The co-existence of DM and microvascular abnormalities could lead to hypertrophy of left ventricle (LV) with diastolic and/or systolic dysfunction. However, early stages of the disease are asymptomatic due to its chronic nature and the effective control of diabetes. Aim of the work: This clinical cohort aimed to assess left ventricular systolic function in DM patients, receiving direct acting antiviral (DAA) drugs for chronic hepatitis-C virus by speckle tracking. Subjects and methods: This clinical cohort included 90 patients who were divided into three equal groups. Patients were recruited from Hepatology Outpatient Clinic of Kafr El-Shaikh University hospital, who were sent to the cardiovascular department for evaluation. Patients were evaluated just before, one month and three months after starting therapy. Results: No one in control group had diastolic dysfunction compared to 10.0% and 16.7% in DAAs and Non-DAAs groups, respectively. Conventional echocardiography returned statistically non-significant difference except significant increase of LVESD, IVST and LVPWT in study groups than control groups. However, the difference between DAAs and Non-DAAs groups was statistically non-significant. The basic strain parameters returned significant lower values at different windows in control than study groups. The strains were reduced in the follow up visits (first and third months) in DAAs groups, but not significantly reduced in non-DAAs group. Acute myocardial infarction was reported among one patient in non-DAAs group compared to none in DAAs group. Conclusion: The speckle tracking is a useful tool for early detection of subclinical left ventricular dysfunction in HCV diabetic patients and could be used for following up of response DAA treatment. DAAs therapy is associated with improvement, not of HCV disease, but also of cardiac dysfunction

Safe use of livers from deceased donors older than 70 years in recipients with HCV cirrhosis treated with direct-action antivirals. Retrospective cohort study

IntroductionThere is controversy regarding the use of older grafts for liver transplantation (LT) in HCV-infected patients, but the introduction of direct-acting antivirals (DAA) can radically change that debate. MethodsThe aim of this retrospective cohort study was to evaluate outcomes of the use of liver grafts from donors older than 70 years in recipients with HCV infection who underwent pre- or post-LT treatment with DAA. We compared two groups of patients who underwent LT using livers >70 years; the groups were defined according to antiviral therapy: non-DAA therapy group (n = 62; LT between May 1996 and December 2013), and DAA therapy group (n = 31; LT between January 2014 and December 2019). ResultsThirty (96.8%) patients of DAA therapy and nine (14.5%) of non-DAA therapy (21 patients underwent complete therapy with interferon-ribavirin) achieved sustained viral response (SVR). One, 3-, and 5-year patient survival were 83.9%, 67.7%, and 56.5% in the non-DAA group vs 93.5%, 88.4%, and 88.4% in the DAA group (P = 0.04); the 1-, 3-, and 5-year graft survival were 77.4%, 62.9%, and 51.6% in the non-DAA group vs. 88.6%, 83.7%, and 83.7% in the DAA group (P = 0.03). Multivariate analysis demonstrated donor female sex and DAA therapy as protective factors of graft survival. ConclusionsPre- or post-LT therapy with DAA in HCV-infected patients has achieved an almost overall SVR. The use of liver grafts >70 years in these patients treated with DAA was associated with significantly higher 5-year patient and graft survival in DAA group compared to non-DAA group. Thus, the introduction of DAA therapy has allowed the safe use of livers >70 years in HCV-positive recipients.

PMU66 Healthcare Utilization and Costs Associated with Direct-Acting Antivirals for Patients with Chronic Hepatitis C and Substance Use Disorders

Patients with substance use disorders (SUD) and chronic hepatitis C virus infection (HCV) have limited access to direct-acting antivirals (DAAs). The effects of DAAs on real-world health care utilization and costs among these patients is unknown. We aim to compare changes in medical service utilization and costs related to liver, SUD, and all-cause morbidity in patients with SUD and HCV treated with DAAs (DAA group) versus those not treated with DAAs (non-DAA group). We conducted a retrospective cohort study using MarketScan data (2012-2018) for newly diagnosed HCV-infected adults with SUD. After applying the stabilized inverse probability of treatment weights, we used difference-in-differences analyses, stratified by cirrhosis status, to determine the adjusted ratio of rate ratio (RRR) to assess the difference in the changes from the pre- to the post-treatment period between the DAA and non-DAA groups. Zero-inflated negative binomial regression and two-part models were used. 6266 patients with SUD and HCV were identified. For patients with cirrhosis (n=607), a greater decrease in liver-related costs after DAAs was observed for the DAA group compared to the non-DAA group (RRR=0.37; 95% confidence interval (CI)=0.19-0.73). The DAA group was associated with a significant decrease in all-cause office visits (RRR=0.70; 95% CI=0.60-0.81) compared to non-DAA group. There was no difference in the changes after DAAs in SUD-related visits/costs, or all-cause costs between groups. For patients without cirrhosis (n=5659), a similar trend was observed, except for the DAA group that experienced a significant decrease in SUD-related emergency department (ED) visits (RRR=0.54; 95%CI=0.38-0.77), and SUD-related long-term care visits (RRR=0.30; 95%CI=0.13-0.73). DAAs are associated with a significant decrease in SUD-related ED and long-term care visits, and liver-related costs without increasing all-cause costs among patients with SUD and HCV, suggesting the benefits of DAAs extended beyond liver-related outcomes, especially in this difficult-to-treat population.

Risk of extrahepatic cancer in a nationwide cohort of hepatitis C virus infected persons treated with direct‐acting antivirals

Background and aims Direct-acting antivirals (DAAs) against HCV have an immune modulatory effect, this could possibly lead to a decreased tumour control. We, therefore, aimed to assess the risk of extrahepatic cancer (EHC) during and the first years after DAA treatment. Methods and Results This is a nationwide cohort study with prospectively collected data for 19 685 persons with HCV, 4013 DAA treated, 3071 interferon (IFN) treated and 12 601 untreated, from 2008 to 2016. Follow-up time was maximum 3 years. The risk for EHC was compared between the groups using Cox regression analyses, with adjustment for age and Charlson Comorbidity Index (CCI). The HCV-infected groups were also compared with matched cohorts without HCV from the general population. In total 341 EHCs were identified, 84, 43 and 214 EHC in the DAA, IFN and untreated group respectively. The EHC risk in DAA treated compared with IFN treated was doubled, but when adjusted for age and CCI the HR was 1.07 (95% CI 0.74-1.56). Compared with the general population, the HR of EHC for the DAA group was 1.45 (CI 1.13-1.86), with the difference remaining statistically significant after adjusting for CCI. Conclusion We found no increased risk for EHC associated with DAA therapy after adjustment for age and CCI. An increased risk of EHC in DAA treated compared with the general population was though seen, and attention should be paid to this association in the ageing population with a history of HCV infection.

Comparison of the Prognosis of Decompensated Cirrhosis in Patients with and Without Eradication of HepatitisC Virus.

IntroductionIn patients with hepatitis C virus (HCV) infection and decompensated cirrhosis (DC), it is uncertain whether viral clearance is clinically meaningful and whether it decreases liver-related and non-liver-related mortality. The aim of this study was to assess whether viral eradication reduced liver-related and non-liver-related mortality in patients with HCV infection and DC.MethodsTo clarify the impact of viral eradication on liver-related and non-liver-related mortality, 364 patients with DC who received direct-acting antivirals (DAAs) and achieved sustained virological response (SVR) in the UK (DAA group) were compared with 249 patients with DC who did not receive DAAs and who underwent symptomatic treatment in Japan (non-DAA group). Propensity score matching and inverse probability weighting (IPW) were performed to adjust the baseline characteristics in the DAA and non-DAA groups. Liver-related and non-liver-related mortality were analyzed using the competing risks IPW cumulative incidence functions estimator.ResultsThe cumulative all-cause mortality rate in the DAA group was significantly lower than that in the non-DAA group (p < 0.0001, IPW-adjusted log-rank test). The cumulative incidence rates of both liver-related and non-liver-related mortality were significantly lower in the DAA group than those in the non-DAA group (p < 0.0001 for both).ConclusionDAA-mediated viral eradication reduced not only liver-related mortality but also non-liver-related mortality in patients with HCV infection and DC.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40121-021-00441-7.

Usefulness of serial FIB-4 score measurement for predicting the risk of hepatocarcinogenesis after hepatitis C virus eradication.

There is insufficient information to evaluate the correlation between fibrosis regression and hepatocellular carcinoma (HCC) risk after hepatitis C virus eradication. We analyzed serial changes in fibrosis (FIB)-4 scores after sustained virological response (SVR). The subjects were 717 patients who achieved SVR by interferon (IFN)-based therapy (IFN Group) and 635 patients who achieved SVR by direct-acting antiviral (DAA) therapy (DAA Group). We performed propensity score matching because the baseline characteristics differed between the IFN and DAA groups, and then applied inverse probability weighting (IPW). We compared the changes in FIB-4 scores between the IFN and DAA groups. We also investigated the dynamics of FIB-4 scores, which are useful for predicting hepatocarcinogenesis. Using time-dependent receiver operating characteristic curve analysis and an IPW-adjusted Cox proportional hazards model, we identified an FIB-4 cutoff of 1.50 for predicting hepatocarcinogenesis. The percentages of patients in the IFN and DAA groups who demonstrated IPW-adjusted cumulative reduction and increase in FIB-4 scores indicated no significant differences. No HCC developed during the 5-year follow-up period in 547 of the 1352 patients whose FIB-4 score was <1.50 at SVR or improved from ≥1.50 to <1.50 during follow-up. Only one patient developed HCC, at 7.3 years; this individual had diabetes mellitus and excessive alcohol intake. There was no difference in FIB-4 score reduction between the IFN and DAA groups. Patients whose FIB-4 scores improved to <1.50 or remained at <1.50 during follow-up after SVR had extremely low hepatocarcinogenesis rates.

Absence of differences in the recurrence rates of hepatitis C virus‑associated hepatocellular carcinoma between direct‑acting antivirals and interferon‑based treatments: A multicenter study

Direct‑acting antivirals (DAAs) have a high rate of achieving a sustained virological response (SVR) to hepatitis C virus (HCV). However, there is a possibility that the rapid elimination of HCV by DAAs can decrease internal interferon (IFN) secretion, resulting in an increased rate of hepatocellular carcinoma (HCC) recurrence than that observed with the current IFN‑based treatment. The present study aimed to retrospectively confirm the absence of differences in the recurrence rates of HCC between patients receiving DAAs and IFN‑based treatment, and to investigate the possible risk factors for recurrence. The HCC recurrence rate following treatment was compared between patients who underwent DAA therapy (DAA group, n=257) and those who received an IFN‑based regimen (IFN group, n=47). Kaplan‑Meier analysis and the log‑rank test were used to compare the groups, and baseline confounds were adjusted by Cox proportional methods. Further comparison of the HCC recurrence rate between the DAA and IFN groups was performed after adjusting these potential confounding variables using propensity score matching. Kaplan‑Meier analysis revealed no significant differences in the HCC recurrence rate between the two groups, as well as no significant difference following the adjustment of the confounding variables. In addition, significant independent risk factors were identified for recurrence in the DAA group, including proteins induced by vitamin K absence or antagonist‑II, the number of previous HCC treatments and the Forns index. Following the adjustment for risk factors for HCC recurrence among the patients in the DAA group, no significant differences in the rate were observed between the DAA and IFN groups. On the whole, these results suggested that HCC recurrence following curative treatment was equivalent in patients treated with DAAs and those treated with IFN. The Forns index was identified as a novel risk factor for HCC recurrence following DAA treatment.

Hepatocellular carcinoma recurrence after direct-acting antiviral therapy: an individual patient data meta-analysis

ObjectiveThe benefit of direct-acting antivirals (DAAs) against HCV following successful treatment of hepatocellular carcinoma (HCC) remains controversial. This meta-analysis of individual patient data assessed HCC recurrence risk following DAA administration.DesignWe...

A real-world observational study of drug utilization and clinical outcomes of direct-acting antivirals and interferon therapy for hepatitis C treatment in Taiwan

Objective In this study, we investigated the use of direct-acting antivirals (DAAs), medical expenses and clinical outcomes since the initiation of national health insurance coverage in Taiwan. Methods This was a retrospective observational study. We obtained claims data from Taiwan’s National Health Insurance Research Database in 2017. Patients diagnosed with hepatitis C with at least two physician visits or one hospitalization were included in the study. Cases were divided into three groups based on the treatment type: traditional treatment (interferon, INF), new drug treatment (DAA) and INF-experienced (INF followed by DAA). We compared the distributions of various cases based on individual demographic variables, hospital type and comorbidities. Trends in medical expenses by treatment type were estimated. We also analyzed clinical outcomes, including rehospitalization and liver function disorders, using a survival analysis method. Results Among patients with hepatitis C, the DAA group had a significantly higher proportion of females, a higher mean age and greater disease severity than the INF group. The growth rate of medical expenses was significantly lower in the DAA group. In addition, compared to the INF group, the DAA group and INF-experienced group had significantly lower rehospitalization rates, and the DAA group had a significantly lower risk of liver function disorders. Furthermore, the longer a patient received any form of treatment, the lower was their chance of rehospitalization and liver function disorders. Conclusions In conclusion, our results confirmed that insurance coverage of DAAs led to better clinical outcomes than INF, and this may reduce increases in medical expenses and the risks of rehospitalization and liver function disorders. What is known on this topic Interferon for hepatitis C has low efficacy with serious side effects, while the efficacy of new oral drugs (direct-acting antivirals, DAAs) is high. DAAs were approved for listing in Taiwan in December 2013, and they have been covered by National Health Insurance since January 2017. Little is known about DAA-related real-world evidence following the coverage of DAAs in Taiwan, including drug utilization, expenditures and safety. What this study adds This study explored three important issues related to DAAs: drug utilization, medical expenses and clinical outcomes following the insurance coverage by using the National Health Insurance Database. Cases were divided into three groups based on the treatment type: traditional treatment (interferon, INF), new drug treatment (DAA) and INF-experienced (INF followed by DAA). After the adjustment of various personal and hospital factors, the DAA group and INF-experienced group had significantly lower rehospitalization rates, and the DAA group had a significantly lower risk of liver function disorders, compared to the interferon group. There was a lower chance of rehospitalization and lower liver function disorder rates with longer treatment.

Impact of Obesity and Heavy Alcohol Consumption on Hepatocellular Carcinoma Development after HCV Eradication with Antivirals

Background and Aims: It remains unclear whether obesity increases the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C who achieved a sustained virological response (SVR) with antiviral therapy. Methods: In this multicenter cohort study, we enrolled patients with chronic hepatitis C who achieved SVR with interferon (IFN)-based therapy (IFN group) or direct-acting antiviral (DAA) therapy (DAA group) between January 1, 1990, and December 31, 2018. The patients underwent regular surveillance for HCC. Cumulative incidence of and the risk factors for HCC development after SVR were assessed using the Kaplan-Meier method and Cox proportional hazard regression analysis, respectively. Results: Among 2,055 patients (840 in the IFN group and 1,215 in the DAA group), 75 developed HCC (41 in the IFN group and 34 in the DAA group) during the mean observation period of 4.1 years. The incidence rates of HCC at 1, 2, and 3 years were 1.2, 1.9, and 3.0%, respectively. Multivariate analysis revealed that in addition to older age, lower albumin level, lower platelet count, higher alpha-fetoprotein level, and absence of dyslipidemia, obesity (body mass index ≥25 kg/m²) and heavy alcohol consumption (≥60 g/day) were independent risk factors for HCC development, with adjusted hazard ratio (HR) of 2.53 (95% confidence interval [CI]: 1.51–4.25) and 2.56 (95% CI: 1.14–5.75), respectively. The adjusted HR was not significant between the 2 groups (DAA vs. IFN; HR 1.19, 95% CI: 0.61–2.33). Conclusions: Obesity and heavy alcohol consumption increased the risk of HCC development after SVR.