Re: Risk of extrahepatic cancer in a nationwide cohort of hepatitis C virus‐infected persons treated with direct‐acting antivirals: Public health impact amongst Swedish cohort in the Covid‐19 pandemic era

To the Editor: The study by Lybeck et al1 focusing on riskassessment of extrahepatic cancer (EHC) in a nationwide Swedish cohort of hepatitis C virus (HCV) infected persons treated with direct acting antivirals (DAAs) provides critical insights in the patientfriendly, costeffective, timelinebased clinical management of HCVmediated EHC (eg nonHodgkin lymphoma/intrahepaticcholangiocarcinoma) for eventual design/development of novel immunomodulatory drugs and predictive/prognostic biomarkers in “atrisk” susceptible populations of varying genetic landscapes. Inclusion/exclusioncriteria were welldefined with a biasfree interpretation of complex statistical datasets; large sample size (N = 19 685 HCVpositive cases), a major study strength, added adequate statistical power (≥80%) reducing the possibility of potential selection bias in risk assessment amongst subgroups of HCVinfected persons: 4013 DAAtreated/3071 interferon (IFN)treated/12 601 untreated, with maximal 3 years’ clinical followup time. EHC risk was compared between treatment groups using Cox regression analyses, with adjustment for age/Charlson Comorbidity Index (CCI); matched case– control studyapproach wherein HCVinfected groups were stringently compared with matched cohorts without HCV from general Swedish population, reduced possibility of populationadmixture. Healthy/diseasefree, age/ethnicitymatched controls from random population significantly adds to statisticalpower of case– control association studies in “gastrohepatic diseaseweb”pathophysiology research2,3; Pandey has elegantly emphasized the significance of age/ethnicitymatched diseasefree controls from the general random population in multicentric epidemiology/ pharmacogenetics/genomics studies for demystifying the cellular/ molecular/genetic basis of inflammatory gastrohepatic ailments in susceptible cohorts.4 Overall, the findings of this study on HCVmediated EHC management in Swedish cohort(s) convincingly demonstrated that the HCVpositivity trend amongst 341 EHCs was appreciable: 84/43/214 EHC in DAA/IFN/untreatedgroup respectively; EHCrisk in DAAtreated compared with IFNtreated was doubled, but after adjustment for age/CCI, hazards ratio (HR) was 1.07 (95% CI 0.741.56). Cox regression analysis with controls revealed that EHCHR in DAAgroup = 1.45 (CI 1.131.86), with difference remaining statistically significant after adjusting for CCI. These findings may be successfully replicated in future multicentric large sample sizebased case– control prospective studies adhering to core tenets of good practice ethical research with longterm patient satisfaction trends. Interestingly, data from the HCVinfected EHCcohort and matched comparisoncohort were linked to national registers with prospectively collected data (National Board of Health and Welfare: PrescriptionRegister (PrR)/PatientRegister (PR)/CancerRegister (CR)/CauseofDeathRegister (DR)), adding authenticity to the selectioncriteria of eligible studysubjects of Swedish ethnicity. Pharmacotherapy clinical evidence on prescriptions of pegylatedIFN (alfa2a/alfa2b)/2nd or 3rd wave DAAs: (sofosbuvir/simeprevir/daclatasvir/ombitasvir/paritaprevir/ritonavir/dasabuvir/ledipasvir/elbasvir/grazoprevir/velpatasvir/glecaprevir/pibrentasvir/voxilaprevir) were meticulously extracted to form specific treatmentgroups; individuals treated with 1st wave DAAs (telaprevir/boceprevir/n = 697) were excluded. Sensitivity analyses by adding cancers from PR and DR (when missing in CR) and with shorter followup times, to study HRs after 12 years of followup, were conducted; Kaplan– Meier curves estimated EHC free followup time for different treatmentgroups, stratified for agegroups (age at the start of followup: 3549/5064/≥65 years), and for matched general Swedish population, and logranktests to compare EHCfree followup time between these groups. Datasets implicated no increased risk for EHC associated with DAAtherapy after adjustment for age/CCI, and increased risk of EHC in DAAtreated compared with the general population. I would like to add that aberrant “metabolicflux” in the hypoxic/ vascularinsufficient/inflammatory heterogeneous tumourcore infiltrated with proliferative and/or necrotic/apoptotic/autophagic cells of distinct phenotypes, is a major hallmark of HCVmediated EHC/interrelated gastrohepaticcancers; therapeutic targeting of “immunogenic celldeath cascade(s)” viz. autophagynecrosisapoptosis, offers fascinating avenues for future HCVmediated EHC stem cells’translational research in the Covid19 pandemic era.