Hepatitis C treatment failure is associated with increased risk of hepatocellular carcinoma

Sustained virological response (SVR) to antiviral therapy for hepatitis C (HCV) reduces risk of hepatocellular carcinoma (HCC), but there is little information regarding how treatment failure (TF) compares to lack of treatment. We evaluated the impact of treatment status on risk of HCC using data from the Chronic Hepatitis Cohort Study (CHeCS–an observational study based in four large US health systems, with up to 7 years of follow‐up on patients). Multivariable analyses were used to adjust for bias in treatment selection, as well as other covariates, followed by sensitivity analyses. Among 10 091 HCV patients, 3681 (36%) received treatment, 2099 (57%) experienced treatment failure (TF), and 1582 (43%) of these achieved sustained virological response (SVR). TF patients demonstrated almost twice the risk of HCC than untreated patients [adjusted hazard ratio (aHR) = 1.95, 95% confidence interval (CI) 1.50–2.53]; this risk persisted across all stages of fibrosis. Several sensitivity analyses validated these results. Although African Americans were at increased risk of treatment failure, they were at lower risk for HCC and all‐cause mortality compared to White patients. SVR patients had lower risk of HCC than TF patients (aHR = 0.48, CI 0.31–0.73), whereas treatment – regardless of outcome – reduced all‐cause mortality (aHR = 0.45, CI 0.34–0.60 for SVR patients; aHR = 0.78, CI 0.65–0.93 for TF patients).     

Impact of hepatitis C treatment status on risk of Parkinson's disease and secondary parkinsonism in the era of direct-acting antivirals

Research suggests a possible link between chronic infection with hepatitis C virus (HCV) and the development of Parkinson's Disease (PD) and secondary Parkinsonism (PKM). We investigated the impact of antiviral treatment status (untreated, interferon [IFN] treated, direct-acting antiviral [DAA] treated) and outcome (treatment failure [TF] or sustained virological response [SVR]) on risk of PD/PKM among patients with HCV. Using data from the Chronic Hepatitis Cohort Study (CHeCS), we applied a discrete time-to-event approach with PD/PKM as the outcome. We performed univariate followed by a multivariable modelling that used time-varying covariates, propensity scores to adjust for potential treatment selection bias and death as a competing risk. Among 17,199 confirmed HCV patients, we observed 54 incident cases of PD/PKM during a mean follow-up period of 17 years; 3753 patients died during follow-up. There was no significant association between treatment status/outcome and risk of PD/PKM. Type 2 diabetes tripled risk (hazard ratio [HR] 3.05; 95% CI 1.75–5.32; p < .0001) and presence of cirrhosis doubled risk of PD/PKM (HR 2.13, 95% CI 1.31–3.47). BMI >30 was associated with roughly 50% lower risk of PD/PKM than BMI <25 (HR 0.43; 0.22–0.84; p = .0138). After adjustment for treatment selection bias, we did not observe a significant association between HCV patients' antiviral treatment status/outcome on risk of PD/PKM. Several clinical risk factors—diabetes, cirrhosis and BMI—were associated with PD/PKM.     

Real‐world impact following initiation of interferon‐free hepatitis C regimens on liver‐related outcomes and all‐cause mortality among patients with compensated cirrhosis

Few studies have investigated clinical outcomes among patients with cirrhosis who were treated with interferon (IFN)‐free direct‐acting antiviral (DAA). We aimed to quantify treatment impact on first decompensated cirrhosis hospital admission, first hepatocellular carcinoma (HCC) admission, liver‐related mortality and all‐cause mortality among a national cohort of cirrhotic patients. Through record linkage between Scotland's HCV Clinical Database and inpatient/day‐case hospitalization and deaths records, a study population comprising chronic HCV‐infected patients with compensated cirrhosis and initiated on IFN‐free DAA between 1 March 2013 and 31 March 2018 was analysed. Cox regression evaluated the association of each clinical outcome with time‐dependent treatment status (on treatment, responder, nonresponder or noncompliant), adjusting for patient factors including Child‐Pugh class. Among the study population (n = 1073) involving 1809 years of follow‐up, 75 (7.0%) died (39 from liver‐related causes), 47 progressed to decompensated cirrhosis, and 28 developed HCC. Compared with nonresponders, treatment response (96% among those attending their 12 weeks post‐treatment SVR test) was associated with a reduced relative risk of decompensated cirrhosis (hazard ratio [HR] = 0.14; 95% CI: 0.05‐0.39), HCC (HR = 0.17; 95% CI: 0.04‐0.79), liver‐related death (HR = 0.13; 95% CI: 0.05‐0.34) and all‐cause mortality (HR = 0.30; 95% CI: 0.12‐0.76). Compared with responders, noncompliant patients had an increased risk of liver‐related (HR = 6.73; 95% CI: 2.99‐15.1) and all‐cause (HR = 5.45; 95% CI: 3.07‐9.68) mortality. For HCV patients with cirrhosis, a treatment response was associated with a lower risk of severe liver complications and improved survival. Our findings suggest additional effort is warranted to address the higher mortality among the minority of cirrhotic patients who do not comply with DAA treatment or associated RNA testing.     

Effects of interferon therapy on development of hepatocellular carcinoma in patients with hepatitis C-related cirrhosis: A meta-analysis of randomized controlled trials

Aim: The role of interferon (IFN) therapy on prevention of hepatocellular carcinoma (HCC) in patients with hepatitis C virus (HCV)‐related cirrhosis remains controversial. This meta‐analysis aimed to determine whether IFN therapy reduced the incidence of HCC in HCV‐related cirrhotic patients. Methods: We performed a meta‐analysis including eight randomized controlled trials (RCT) (a total of 1505 patients) to assess the effect of IFN therapy on prevention of HCC in patients with HCV‐related cirrhosis. The pooled odds ratios (OR) were calculated using a random or fixed effects model. Results: Our results showed that IFN therapy significantly decreased the overall HCC incidence in HCV‐related cirrhotic patients (OR, 0.29; 95% confidence interval [CI], 0.10–0.80; P = 0.02). HCC risk in patients who failed to achieve sustained virological response (SVR) in the initial IFN‐based treatment was also reduced by maintenance IFN therapy (OR, 0.54; 95% CI, 0.32–0.90; P = 0.02). Subgroup analysis indicated that IFN therapy decreased HCC incidence in HCV‐related cirrhotic patients during long‐term follow up (>48 months) evidently (OR, 0.25; 95% CI, 0.09–0.67; P = 0.006). However, subgroup analysis of four RCT with short‐term follow up (≤48 months) did not demonstrate the significant difference in HCC incidence between IFN‐treated cirrhotic patients and controls (OR, 0.78; 95% CI, 0.39–1.55; P = 0.48). Conclusion: The present study suggested that IFN therapy could efficiently reduce HCC development in patients with HCV‐related cirrhosis; this effect was more evident in the subgroup of patients with long‐term follow up (>48 months). Patients who received maintenance IFN therapy had a lower risk of HCC than controls.     

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

BackgroundDespite 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.MethodsWe 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.ResultsAmong 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).ConclusionsOur 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.     

Impact of sustained virologic response on risk of type 2 diabetes among hepatitis C patients in the United States

Data regarding the impact of hepatitis C (HCV) therapy on incidence of type 2 diabetes mellitus are limited. We used the data from the longitudinal Chronic Hepatitis Cohort Study—drawn from four large US health systems—to investigate how response to HCV treatment impacts the risk of subsequent diabetes. Among HCV patients without a history of type 2 diabetes mellitus or hepatitis B, we investigated the incidence of type 2 diabetes from 12 weeks post‐HCV treatment through December 2015. Cox proportional hazards models were used to test the effect of treatment status (sustained virologic response [SVR] or treatment failure) and baseline risk factors on the development of diabetes, considering any possible risk factor‐by‐SVR interactions, and death as a competing risk. Among 5127 patients with an average follow‐up of 3.7 years, diabetes incidence was significantly lower among patients who achieved SVR (231/3748; 6.2%) than among patients with treatment failure (299/1379; 21.7%; adjusted hazard ratio [aHR] = 0.79; 95% CI: 0.65‐0.96). Risk of diabetes was higher among African American and Asian American patients than White patients (aHR = 1.82 and 1.75, respectively; P < .05), and among Hispanic patients than non‐Hispanics (aHR = 1.86). Patients with BMI ≥ 30 and 25‐30 (demonstrated higher risk of diabetes aHR = 3.62 and 1.72, respectively; P < .05) than those with BMI < 25; patients with cirrhosis at baseline had higher risk than those without cirrhosis (aHR = 1.47). Among a large US cohort of patients treated for HCV, patients who achieved SVR demonstrated a substantially lower risk for the development of type 2 diabetes mellitus than patients with treatment failure.     

Suppression of hepatocellular carcinoma development in hepatitis C patients given interferon‐based antiviral therapy

The advance of antiviral treatment for chronic hepatitis C has brought a high sustained virological response (SVR) rate. In this review article, the suppressive effect of interferon (IFN)‐based therapy on the development of hepatocellular carcinoma (HCC), risk factors for developing HCC and the characteristics of HCC development after SVR among chronic hepatitis C patients given IFN‐based therapy were studied. The HCC incidence has been revealed to decrease with IFN‐based antiviral therapy, especially in SVR, and the risk factors for developing HCC were older age, advanced liver fibrosis and male sex. α‐Fetoprotein levels at 24 weeks after the end of IFN‐based treatment was associated strongly with HCC incidence irrespective of virological response. In patients with SVR, other risk factors were glucose metabolism disorders, lipid metabolism disorders and alcohol intake. Extra attention to the possibility of HCC incidence should be required for these SVR patients. Antiviral therapy with a combination of HCV‐specific direct‐acting antivirals (DAA) is expected to be utilized in the future. However, it is not known whether DAA‐based treatment can suppress HCC to the level of IFN‐based treatment. Further research is required to clarify this.     

Tenofovir versus entecavir for tertiary prevention of hepatocellular carcinoma in chronic hepatitis B infection after curative therapy: A systematic review and meta-analysis

Entecavir (ETV) and Tenofovir disoproxil fumarate (TDF) are the first-line drugs for the treatment of chronic hepatitis B virus (HBV). However, the impact of these two antiviral agents on the outcome of HBV-related hepatocellular carcinoma (HCC) after curative therapy remains to be explored. The purpose of the present study was to compare the effect of ETV and TDF on recurrence and mortality after curative treatment for HBV-related HCC. A comprehensive literature search of multiple electronic databases was conducted from 2000 to January 2022 for studies comparing ETV and TDF for HBV-related HCC patients after curative therapy. The adjusted hazard ratios (aHR) were pooled using a random-effects model. A total of nine studies with 5298 patients were included in the final meta-analysis. TDF was associated with a lower risk of HCC recurrence [aHR 0.73, 95% confidence interval (CI) 0.65–0.81] compared to HCC. TDF reduced the risk of late recurrence compared to ETV (aHR 0.58, 95% CI 0.45–0.76) but not early recurrence (aHR 0.88, 95% CI 0.76–1.02). The mortality risk was also lower with TDF compared to ETV (aHR 0.62, 95% CI 0.50–0.77). TDF was associated with a lower risk of recurrence and mortality than ETV after resection or ablation of HBV-related HCC. Further prospective randomized controlled studies are warranted to validate these results.     

Is HCV elimination among persons living with HIV feasible? Data from the NoCo study in the setting of the ICONA cohort

Background and Aims

Whether the HCV test-and-treat strategy impacted on the rate of new HCV infections among PLWH in Italy is unknown.

Methods

Prospective study of PLWH in the ICONA network. At baseline, PLWH were tested for HCV-Ab; HCV-RNA (if HCV-Ab positive) and, if positive, treated with DAA. SVR12 indicated eradication. Seroconversions and re-infections were evaluated yearly in HCV-Ab neg and HCV-RNA neg at first screening. We estimated the following: HCV seroconversions, incidence of HCV reinfections, and access to DAA and SVR12 rates tighter with factors associated with each outcome. Data were analysed by Cox regression, Poisson regression and logistic regression models.

Results

Sixteen thousand seven hundred and forty-three PLWH were included; 27.3% HCV-Ab positive; of these, 39.3% HCV-RNA positive. HCV seroconversion incidence: .48/100 PYFU (95% CI: .36–.65); re-infections incidence: 1.40/100 PYFU (95% CI: .91–2.04). The risk factor for HCV re-infection was young age: aIRR 1.85, 95% CI: 1.17–2.95) per 10 years younger. 86.4% of HCV viremic in follow-up started DAA. PWID vs. heterosexuals (aHR .75, 95% CI .62–.90), HIV-RNA >50 copies/mL (aHR .70, 95% CI .56–.87), HCV genotype other than G1, G2, G3, G4 or with multiple/missing HCV genotype and post-COVID-19 calendar periods were associated with lower DAA access. 922/965 (95.5%) PLWH achieved SVR12. We estimated 72% reduction of chance to achieve SVR12 in PLWH with a CD4 count <200/mm³ (vs. CD4 ≥200/mm³ aOR .18, 95% CI: .07–.46). 95.5% of DAA-treated individuals eradicated HCV, but they represent only 53.2% of HCV viremic PLWH and 66.4% of those in follow-up. HCV-RNA positivity by year decreased from 41.7% in 2017 to 11.7% in 2022.

Conclusions

The screening-and-treat campaign implemented in Italy, even if only partially effective, resulted in a dramatic drop in HCV circulation in our cohort.     

Does HCV antiviral therapy decrease the risk of hepatocellular carcinoma?

Whether antiviral therapy for hepatitis C virus (HCV) infection can prevent hepatocellular carcinoma (HCC) independent of a sustained virologic response (SVR) has been debated since a randomized trial from Japan in 1995. Incidence of HCC in patients with chronic hepatitis C with SVR is reduced through cirrhosis prevention, but HCC is also prevented in cirrhosis by reduction of necroinflammatory activity and possibly cell turnover. However, HCV patients with cirrhosis who achieve an SVR still have a risk, although a lower one, of HCC, so surveillance must continue. The potential antiproliferative effect of interferon (IFN) with respect to HCC has been discounted by a prospective randomized clinical trial in nonresponders to IFN (Hepatitis C Antiviral Long-term Treatment Against Cirrhosis [HALT-C]), in which IFN did not modify any outcomes. Thus, the best strategy to reduce HCC is to treat HCV-infected patients before they develop cirrhosis and to increase the SVR rate.     

Hepatocellular carcinoma occurrence in DAA-treated hepatitis C virus patients: Correlated or incidental? A brief review

Hepatitis C virus(HCV) chronic infection induces liver fibrosis and cirrhosis but is also responsible for a significant portion of hepatocellular carcinoma(HCC) occurrence. Since it was recognized as a causative factor of chronic hepatitis,there have been multiple efforts towards viral eradication,leading to the first-generation HCV treatment that was based on interferon(IFN)-α and its analogs,mainly PEGylated interferon-α(PEG IFNα). Sustained virological response(SVR),defined as the absence of detectable RNA of HCV in blood serum for at least 24 wk after discontinuing the treatment,was accepted as a marker of viral clearance and was achieved in approximately one-half of patients treated with PEG IFNα regimens. Further research on the molecular biology of HCV gave rise to a new generation of drugs,the so-called direct antiviral agents(DAAs). DAA regimens,as implied by their name,interfere with the HCV genome or its products and have high SVR rates,over 90%,after just 12 wk of per os treatment. Although there are no questions about their efficacy or their universality,as they lack the contraindication for advanced liver disease that marks PEG IFNα,some reports of undesired oncologic outcomes after DAA treatment raised suspicions about possible interference of this treatment in HCC development. The purpose of the present review is to investigate the validity of these concerns based on recent clinical studies,summarize the mechanisms of action of DAAs and survey the updated data on HCV-induced liver carcinogenesis.     

Effectiveness of direct-acting antiviral therapy among Aboriginal and Torres Strait Islander peoples with HCV infection in Australia: A national real-world cohort (REACH-C)

Aboriginal and Torres Strait Islander peoples experience a disproportionate burden of hepatitis C virus (HCV) infection. This study assessed the effectiveness of direct-acting antiviral (DAA) therapy among Aboriginal peoples in the three years following universal access in Australia. REACH-C, a national multicentre prospective cohort study, evaluated HCV treatment outcomes from sequential DAA initiations across 33 health services between March 2016 and June 2019. DAA effectiveness was assessed by sustained virological response (SVR) in the total (full analysis set) and effectiveness (modified analysis set excluding those lost to follow-up) populations. Overall, 915 (10%) Aboriginal and 8095 (90%) non-Indigenous people commenced DAA therapy, of whom 30% and 16% reported current injecting drug use and 73% and 42% were treated in primary care, respectively. SVR in the total and effectiveness populations was 74% and 94% among Aboriginal people and 82% and 94% among non-Indigenous people, with loss to follow-up contributing to lower SVR in the total population analysis (22% Aboriginal, 13% non-Indigenous). Among Aboriginal people, returning for follow-up was positively associated with older age (aOR 1.20; 95% CI 1.04, 1.39) and SVR was negatively associated with cirrhosis (aOR 0.39; 95% CI 0.19, 0.80) and prior DAA treatment (aOR 0.14; 95% CI 0.04, 0.49). Factors reflecting higher vulnerability or inequity were not associated with returning for testing or SVR. DAA therapy was highly effective among Aboriginal peoples with HCV treated through primary and tertiary services. Tailored community-led interventions are necessary to optimize follow-up and engagement. Sustained DAA uptake and equitable access to care, treatment and prevention are required for HCV elimination.     

The impact of SVR from direct‐acting antiviral‐ and interferon‐based treatments for HCV on hepatocellular carcinoma risk

We evaluated the effect of sustained virologic response (SVR) from direct‐acting antiviral (DAA)‐ and interferon‐based treatments on hepatocellular carcinoma (HCC) risk in a large population‐based cohort in Canada. We used data from the BC Hepatitis Testers Cohort, which includes ~1.3 million individuals tested for HCV since 1990, linked with healthcare administrative and registry datasets. Patients were followed from the end of HCV treatment to HCC, death or 31 December 2016. We assessed HCC risk among those who did and did not achieve SVR by treatment type using proportional hazard models. Of 12 776 eligible individuals, 3905 received DAAs while 8871 received interferon‐based treatments, followed for a median of 1.0 [range: 0.6‐2.7] and 7.9 [range: 4.4‐17.1] years, respectively. A total of 3613 and 6575 achieved SVR with DAAs‐ and interferon‐based treatments, respectively. Among DAAs‐treated patients, HCC incidence rate was 6.9 (95%CI: 4.7‐10.1)/1000 person yr (PY) in SVR group (HCC cases: 26) and 38.2 (95%CI: 20.6‐71.0) in the no‐SVR group (HCC cases: 10, P < .001). Among interferon‐treated individuals, HCC incidence rate was 1.8 (95%CI: 1.5‐2.2) in the SVR (HCC cases: 99) and 13.9 (95%CI: 12.3‐15.8) in the no‐SVR group (HCC cases: 239, P < .001). Compared with no‐SVR from interferon, SVR from DAA‐ and interferon‐based treatments resulted in significant reduction in HCC risk (adjusted subdistribution hazard ratio (adjSHR) DAA = 0.30, 95%CI: 0.19‐0.48 and adjSHR interferon = 0.2, 95%CI: 0.16‐0.26). Among those with SVR, treatment with DAAs compared to interferon was not associated with HCC risk (adjSHR = 0.93, 95%CI: 0.51‐1.71). In conclusion, similar to interferon era, DAA‐related SVR is associated with 70% reduction in HCC risk.     

我国丙型肝炎肝硬化患者DAA治疗现状及短期预后的研究

目的了解丙型肝炎肝硬化患者直接抗病毒药物(DAA)治疗现状、短期预后和影响因素。方法选取2015年1月至2019年11月期间于瑞金医院感染科诊治的丙型肝炎肝硬化患者,收集其数据,研究基线特征、DAA方案及疗效和预后的关系。结果共入组161例,DAA治疗者149例;代偿组122例,失代偿组27例;两组在年龄、性别、HCV基因型及干扰素治疗史等方面无显著性差别;两组疗效与安全性均良好,其中SVR12率(99.17%比96.25%,P=0.325)和SVR24率(96.64%比92.0%,P=0.614)均无明显差异;基线肝硬化失代偿期患者中发生肝病进展的比例明显高于代偿期患者(50%vs.13.75%,P=0.000);基线肝硬化失代偿是DAA治疗后短期预后的独立危险因素(HR 6.765,95%Cl:2.866~15.969,P=0.000)。结论基线肝硬化失代偿是DAA治疗后短期预后的独立预测因素。     

Direct-acting antivirals and hepatocellular carcinoma in chronic hepatitis C: A few lights and many shadows

With the introduction of direct-acting antiviral agents(DAA), the rate of sustained virological response(SVR) in the treatment of hepatitis C virus(HCV) has radically improved to over 95%. Robust scientific evidence supports a beneficial role of SVR after interferon therapy in the progression of cirrhosis, resulting in a decreased incidence of hepatocellular carcinoma(HCC). However, a debate on the impact of DAAs on the development of HCC is ongoing. This review aimed to analyse the scientific literature regarding the risk of HCC in terms of its recurrence and occurrence after the use of DAAs to eradicate HCV infection. Among 11 studies examining HCC occurrence, the de novo incidence rate ranged from 0 to 7.4%(maximum follow-up: 18 mo). Among 18 studies regarding HCC recurrence, the rate ranged from 0 to 54.4%(maximum "not well-defined" followup: 32 mo). This review highlights the major difficulties in interpreting data and reconciling the results of the included studies. These difficulties include heterogeneous cohorts, potential misclassifications of HCC prior to DAA therapy, the absence of an adequate control group, short follow-up times and different kinds of follow-up. Moreover, no clinical feature-based scoring system accounts for the molecular characteristics and pathobiology of the tumours. Nonetheless, this review does not suggest that there is a higher rate of de novo HCC occurrence or recurrence after DAA therapy in patients with previous HCV infection.     

Hepatocellular carcinoma and hepatitis C virus treatments: The bold and the beautiful

The occurrence of hepatocellular carcinoma (HCC) is one of the most serious complications of hepatitis C virus (HCV) infection. Recently, effective antiviral medications have made sustained viral response (SVR) or cure a realistic therapeutic goal for most chronic HCV patients. Given HCV's tumorigenic propensity, it is not surprising that achieving SVR is helpful in preventing HCC. This review briefly summarizes and discusses the existing evidence on the relationship between hepatic carcinogenesis and viral eradication by antivirals, which is mainly divided into interferon-based and direct-acting antivirals (DAAs) based therapy. DAAs have changed the treatment landscape of chronic HCV, reaching high rates of SVR even in patients with advanced cirrhosis, with few contraindications and little side effects. Although some early reports suggested that DAA treatment increased the chance of HCC occurrence, more subsequent observational studies have refuted this theory. The probability of HCC recurrence after HCV eradication appears to be decreasing over time following SVR. Despite virological suppression/cure, individuals with liver cirrhosis are still at risk of HCC and should be monitored. There is a considerable need for markers/scores to predict the long-term risk of HCC in patients with HCV-related liver disease who attain SVR with direct-acting antivirals.     

Differences in background characteristics of patients with chronic hepatitis C who achieved sustained virologic response with interferon‐free versus interferon‐based therapy and the risk of developing hepatocellular carcinoma after eradication of hepatitis C virus in Japan

We compared the background characteristics of patients with chronic hepatitis C who achieved eradication of hepatitis C virus (HCV), that is sustained virologic response (SVR), with interferon (IFN)‐based versus IFN‐free antiviral therapy in Japan. In addition, we used a previously reported risk assessment model to compare the incidence of hepatocellular carcinoma (HCC) after SVR by treatment type. Pretreatment characteristics of 1533 patients who achieved SVR with IFN‐based therapy and 1086 patients with IFN‐free therapy from five institutions across Japan were compared. The risk of HCC after SVR was assessed based on pretreatment characteristics, and the incidence of HCC after SVR was estimated in both groups. Age and serum alpha‐fetoprotein levels were higher, platelet count was lower, and liver fibrosis was more advanced in patients who achieved SVR with IFN‐free therapy compared with IFN‐based therapy. The incidence of HCC after SVR in the IFN‐free group was estimated to be more than twofold higher than in the IFN‐based therapy group (7.29% vs. 3.09%, and 6.23% vs. 3.01% when excluding patients who have underwent curative treatment for HCC). There are large differences in pretreatment characteristics between patients who achieved SVR with IFN‐based and IFN‐free therapies in Japan, which are associated with differential risk of HCC after SVR. These differences can influence the incidence of HCC after SVR and should be taken into consideration when comparing IFN‐based and IFN‐free therapies in terms of hepatocarcinogenesis suppression with HCV eradication.     

Trends in hepatocellular carcinoma incidence and survival among people with hepatitis C: An international study

This study evaluates trends in hepatitis C virus (HCV)‐related hepatocellular carcinoma (HCC) incidence and survival in three settings, prior to introduction of direct‐acting antiviral (DAA) therapies. HCV notifications from British Columbia (BC), Canada; New South Wales (NSW), Australia; and Scotland (1995‐2011/2012/2013, respectively) were linked to HCC diagnosis data via hospital admissions (2001‐2012/2013/2014, respectively) and mortality (1995‐2013/2014/2015, respectively). Age‐standardized HCC incidence rates were evaluated, associated factors were assessed using Cox regression, and median survival time after HCC diagnosis was calculated. Among 58 487, 84 529 and 31 924 people with HCV in BC, NSW and Scotland, 734 (1.3%), 1045 (1.2%) and 345 (1.1%) had an HCC diagnosis. Since mid‐2000s, HCC diagnosis numbers increased in all jurisdictions. Age‐standardized HCC incidence rates remained stable in BC and Scotland and increased in NSW. The strongest predictor of HCC diagnosis was older age [birth <1945, aHR in BC 5.74, 95% CI 4.84, 6.82; NSW 9.26, 95% CI 7.93, 10.82; Scotland 12.55, 95% CI 9.19, 17.15]. Median survival after HCC diagnosis remained stable in BC (0.8 years in 2001‐2006 and 2007‐2011) and NSW (0.9 years in 2001‐2006 and 2007‐2013) and improved in Scotland (0.7 years in 2001‐2006 to 1.5 years in 2007‐2014). Across the settings, HCC burden increased, individual‐level risk of HCC remained stable or increased, and HCC survival remained extremely low. These findings highlight the minimal impact of HCC prevention and management strategies during the interferon‐based HCV treatment era and form the basis for evaluating the impact of DAA therapy in the coming years.     

Adjuvant ribavirin and longer direct‐acting antiviral treatment duration improve sustained virological response among hepatitis C patients at risk of treatment failure

The role of ribavirin (RBV) in the era of direct‐acting antivirals (DAA) is not clear, and DAA studies have been largely genotype‐ and regimen‐specific. Using data from the Chronic Hepatitis Cohort Study, we evaluated the role of RBV and increased DAA treatment duration among patients with chronic hepatitis C (HCV) in routine clinical care. We performed multivariable analysis of data from 4133 patients receiving any of the following: sofosbuvir (SOF); daclatasvir + SOF; grazoprevir + elbasvir; paritaprevir/ritonavir + ombitasvir; simeprevir + SOF; and SOF + ledipasvir; SOF + velpatasvir ± voxilaprevir; and glecaprevir + pibrentasvir—all with/ without RBV. Inverse probability treatment weighting was used to adjust for treatment selection bias. Sustained virological response (SVR) was defined by undetectable HCV RNA 12 weeks after end of therapy. The overall SVR rate was 95%. Mean treatment duration was 12 ± 4.5 weeks. The final model included treatment duration and diabetes, as well as the interaction of RBV with previous treatment status (treatment naïve, interferon treatment failure [TF] or previous DAA TF), cirrhosis status, and HCV genotype (GT). Each one‐month increment of treatment duration increased odds of SVR by 99% (aOR = 1.99). Diabetes, previous DAA TF, and decompensated cirrhosis significantly reduced odds of SVR. RBV significantly increased the likelihood of SVR among patients with decompensated cirrhosis (aOR = 5.05), previous DAA treatment failure (aOR = 5.43), and GT3 (aOR = 13.28). Among RBV‐free regimens, patients with GT3 were less likely to achieve SVR than those with GT1 or 2 (aOR 0.07). Diabetes, decompensated cirrhosis, and prior DAA TF independently reduced the likelihood of SVR. Longer treatment duration increased likelihood of SVR. Conclusion: RBV increased likelihood of SVR among patients with GT3, previous DAA TF, or decompensated cirrhosis.     

Interferon‐α/β for treatment of chronic hepatitis C infection in the era of direct‐acting antiviral agents

Type I interferons (IFN‐α/β), with or without ribavirin, have been the only agents that can eradicate the hepatitis C virus (HCV). An IFN‐free regimen combining oral direct‐acting antiviral agents (DAA) will be approved soon for genotype 1 patients. Here, we discuss the role of IFN‐α/β in the forthcoming “era of DAA” with consideration of limitations and concerns about IFN‐free therapies. First, the therapeutic efficacy of first‐generation DAA varies among the different subtypes. While the rate of sustained virological response (SVR) is 60–90% among patients with genotype 1b, the rate often falls short of 50% in patients with genotype 1a. IFN and ribavirin can still be indicated for patients with genotype 1a as a platform for combination with DAA. Second, there is concern about the emergence of drug‐resistance resulting from inappropriate use of DAA. The clinical significance of pre‐existing resistant variants has not been elucidated. Drug resistance may affect the efficacy of next‐generation treatments. An IFN and ribavirin backbone in combination with DAA is an effective measure to prevent the emergence of drug resistance and/or to suppress pre‐existing resistant viruses. Third, it remains unknown whether the incidence of hepatocellular carcinoma (HCC) will be reduced in patients who achieve SVR with IFN‐free regimens. In contrast, there are many reports in Japan demonstrating the preventive effects of IFN on the development of HCC. When patients do not achieve SVR with first‐generation DAA, low‐dose IFN maintenance therapy is a treatment option until the next‐generation therapy with pan‐genotypic potency and high genetic barrier become available.