Viral Eradication Research Articles

HIV cure trial mergers: Spotlighting the epigenetics of latency reversal.

Developing a scalable approach to cure HIV-1 infection remains a high priority.1 In recent years, pivotal advances have pushed the field toward such a cure – which could be realized as complete virus eradication or sustained antiretroviral therapy-free HIV-1 remission.2 Many of these advances have arisen from small, interventional clinical trials.3 However, a notable challenge in the field of HIV cure research has been the lack of relevant control arms in these clinical studies.4

2-Deoxy-D-Glucose and its Derivatives for the COVID-19 Treatment: An Update.

Treatment choices for the “severe acute respiratory syndrome‐related coronavirus‐2 (SARS‐CoV‐2)” are inadequate, having no clarity on efficacy and safety profiles. Currently, no established intervention has lowered the mortality rate in the “coronavirus disease 2019 (COVID‐19)” patients. Recently, 2-deoxy-D-glucose (2-DG) has evaluated as a polypharmacological agent for COVID-19 therapy owing to its influence on the glycolytic pathway, interaction with viral proteins, and anti-inflammatory action. In May 2020, the Indian drug regulatory authority approved 2-DG as an emergency adjunct therapy in mild to severe COVID-19 patients. Clinical studies of 2-DG corroborate that it aids in faster recovery of hospitalized patients and decreases supplemental oxygen. Herein, we describe the development process, synthesis, mechanism of viral eradication, and preclinical and clinical development of 2-DG and its derivatives as molecularly targeted therapeutics for COVID-19 treatment.

Clinical and Molecular Basis of Hepatocellular Carcinoma after Hepatitis C Virus Eradication.

Hepatocellular carcinoma (HCC) arises in the background of chronic liver diseases, including hepatitis and liver cirrhosis caused by hepatitis C virus (HCV) infection. It is well known that HCV eradication using antiviral drugs can efficiently inhibit hepatocarcinogenesis. Recent advances in and development of direct-acting antiviral (DAA) drugs has revolutionized the treatment of HCV infection, and the vast majority of HCV patients can achieve HCV eradication using DAAs. However, mounting evidence clearly indicates that HCC inevitably occurs in a subset of patients after successful viral eradication using DAA therapy. Cancer is a genetic disease, and the accumulation of genetic and epigenetic aberrations may cause hepatocarcinogenesis in chronically damaged liver, even after virus elimination. In this review, we highlight HCC development after HCV eradication and discuss the current understanding of the molecular mechanisms of tumorigenesis after virus elimination, focusing on the genetic and epigenetic background of chronically damaged liver tissues.

Compositions of gut microbiota before and shortly after hepatitis C viral eradication by direct antiviral agents

It is unclear whether dysbiosis in hepatitis C virus (HCV) infected patients results from the viral infection per se or develops as a result of hepatic dysfunction. We aimed to characterize compositions in gut microbiome before and shortly after HCV clearance. In this prospective cohort study, adult patients with confirmed HCV viremia were screened before receiving direct antiviral agents. Those with recent exposure to antibiotics or probiotics (within one month), prior abdominal surgery, or any malignancy were ineligible. Stool was collected before antiviral therapy started and at 12 weeks after the treatment completed. From the extracted bacterial DNA, 16 s rRNA gene was amplified and sequenced. Each patient was matched 1:2 in age and sex with uninfected controls. A total of 126 individuals were enrolled into analysis. The gut microbiome was significantly different between HCV-infected patients (n = 42), with or without cirrhosis, and their age-and sex-matched controls (n = 84) from the levels of phylum to amplicon sequence variant (all p values < 0.01 by principal coordinates analysis). All patients achieved viral eradication and exhibited no significant changes in the overall composition of gut microbiome following viral eradication (all p values > 0.5), also without significant difference in alpha diversity (all p values > 0.5). For the purpose of exploration, we also reported bacteria found differently abundant before and after HCV eradication, including Coriobacteriaceae, Peptostreptococcaceae, Staphylococcaceae, Morganellaceae, Pasteurellaceae, Succinivibrionaceae, and Moraxellaceae. Gut microbiota is altered in HCV-infected patients as compared with uninfected controls, but the overall microbial compositions do not significantly change shortly after HCV eradication.

Safety of direct acting antiviral treatment for hepatitis C in oncologic setting: A clinical experience and a literature review.

With a globally estimated 58 million people affected by, chronic hepatitis C virus (HCV) infection still represents a hard challenge for scientific community. A chronic course can occur among patients with a weak innate ad adaptive response with cirrhosis and malignancies as main consequences. Oncologic patients undergoing chemotherapy represent a special immunocompromised population predisposed to HCV reactivation (HCVr) with undesirable changes in cancer treatment and outcome. Aim of the study highlight the possibility of HCVr in oncologic population eligible to chemotherapy and its threatening consequences on cancer treatment; underline the importance of HCV screening before oncologic therapy and the utility of direct aging antivirals (DAAs). A comprehensive overview of scientific literature has been made. Terms searched in PubMed were: “HCV reactivation in oncologic setting” “HCV screening”, “second generation DAAs”. Pharmacokinetic and Pharmacodynamics characteristics of DAAs are reported, along with drug - drug interactions among chemotherapeutic drug classes regimens and DAAs. Clinical trials conducted among oncologic adults with HCV infection eligible to both chemotherapy and DAAs were analyzed. Viral eradication with DAAs in oncologic patients affected by HCV infection is safe and helps liver recovery, allowing the initiation of cancer treatment no compromising its course and success.

Carbon dioxide sterilization in critical/subcritical condition as an alternative to modern methods of eradication of bacteria, fungi and viruses on medical items (literature review)

Infections associated with the provision of medical care (ISMP) are a global problem that require the close attention of medical and preventive institutions. Therefore, strict compliance with the anti-infective safety regime, as well as the development of decontamination methods, materials and medical devices are an urgent approach to minimizing the risk of nosocomial infections.&#x0D; The purpose of the study is to provide an analytical assessment of the antimicrobial effectiveness of sterilization of medical materials and instruments with carbon dioxide in a supercritical and sub-supercritical state in comparison with other modern regulated methods of sterilization.&#x0D; Materials and methods. A meta-analysis of 1027 publications identified 67 publications, which are presented and analyzed in this literature review.&#x0D; Results and discussion. An updated review of experimental protocols based on supercritical sterilization and efficiency results sorted by strains of microorganisms and processed materials was carried out. The multidimensional effect of this sterilization method on microbial cells, spores, fungi and viruses is analyzed. Advantages and disadvantages in comparison with other sterilization technologies (autoclaving and its analogues, plasma sterilization, gamma rays) have been established conclusion.&#x0D; Conclusion. The use of carbon dioxide in supercritical/sub-supercritical states is a promising method that ensures high reliability of sterilization and the safety of processing objects.

Carbon dioxide sterilization in critical/subcritical condition as an alternative to modern methods of eradication of bacteria, fungi and viruses on medical items (literature review)

Infections associated with the provision of medical care (ISMP) are a global problem that require the close attention of medical and preventive institutions. Therefore, strict compliance with the anti-infective safety regime, as well as the development of decontamination methods, materials and medical devices are an urgent approach to minimizing the risk of nosocomial infections.&#x0D; The purpose of the study is to provide an analytical assessment of the antimicrobial effectiveness of sterilization of medical materials and instruments with carbon dioxide in a supercritical and sub-supercritical state in comparison with other modern regulated methods of sterilization.&#x0D; Materials and methods. A meta-analysis of 1027 publications identified 67 publications, which are presented and analyzed in this literature review.&#x0D; Results and discussion. An updated review of experimental protocols based on supercritical sterilization and efficiency results sorted by strains of microorganisms and processed materials was carried out. The multidimensional effect of this sterilization method on microbial cells, spores, fungi and viruses is analyzed. Advantages and disadvantages in comparison with other sterilization technologies (autoclaving and its analogues, plasma sterilization, gamma rays) have been established conclusion.&#x0D; Conclusion. The use of carbon dioxide in supercritical/sub-supercritical states is a promising method that ensures high reliability of sterilization and the safety of processing objects.

Generation of an avian influenza DIVA vaccine with a H3-peptide replacement located at HA2 against both highly and low pathogenic H7N9 virus

ABSTRACT A differentiating infected from vaccinated animals (DIVA) vaccine is an ideal strategy for viral eradication in poultry. Here, according to the emerging highly pathogenic H7N9 avian influenza virus (AIV), a DIVA vaccine strain, named rGD4HALo-mH3-TX, was successfully developed, based on a substituted 12 peptide of H3 virus located at HA2. In order to meet with the safety requirement of vaccine production, the multi-basic amino acid located at the HA cleavage site was modified. Meanwhile, six inner viral genes from a H9N2 AIV TX strainwere introduced for increasing viral production. The rGD4HALo-mH3-TX strain displayed a similar reproductive ability with rGD4 and low pathogenicity in chickens, suggesting a good productivity and safety. In immuned chickens, rGD4HALo-mH3-TX induced a similar antibody level with rGD4 and provided 100% clinical protection and 90% shedding protection against highly pathogenic virus challenge. rGD4HALo-mH3-TX strain also produced a good cross-protection against low pathogenic AIV JD/17. Moreover, serological DIVA characteristics were evaluated by a successfully established competitive inhibition ELISA based on a 3G10 monoclonal antibody, and the result showed a strong reactivity with antisera of chickens vaccinated with H7 subtype strains but not rGD4HALo-mH3-TX. Collectedly, rGD4HALo-mH3-TX is a promising DIVA vaccine candidate against both high and low pathogenic H7N9 subtype AIV.

Changes in Liver Steatosis Using Controlled Attenuation Parameter among Patients with Chronic Hepatitis C Infection Treated with Direct-Acting Antivirals Therapy Who Achieved Sustained Virological Response.

Chronic hepatitis C virus (HCV) infection induces hepatic steatosis due to viral and host factors. However, information regarding the effects of direct-acting antivirals (DAAs) therapy on liver steatosis and fibrosis is limited. Vibration-controlled transient elastography (VCTE) with a controlled attenuation parameter (CAP) represents a non-invasive method, which has been used in the last few years for the detection of hepatic steatosis and fibrosis before and at a sustained virological response at 12 weeks (SVR12). The aim of this study was to assess the modifications of liver steatosis and fibrosis in HCV-infected patients who achieved SVR12. Consecutive patients with chronic HCV infection that were treated with DAAs in a tertiary gastroenterology center from Romania were included. Demographics, laboratory data, and VCTE evaluation were recorded in all patients. Patients with previous hepatic decompensation and those who did not achieve SVR were excluded. Two hundred and eighty patients (67.1% females) who achieved SVR12 were included. Regarding the changes in biological parameters, including liver enzymes such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST), reduced to normal levels at SVR12 compared to the baseline (28.72 ± 24.71 U/L vs. 40.72 ± 27.34 U/L for ALT, p < 0.013 and 27.21 ± 11.15 U/L vs. 33.35 ± 23.37 U/L for AST, p = 0.029). On the contrary, the levels of triglycerides increased significantly from the baseline to SVR12 (124.03 ± 113.49 mg/dL to 153.78 ± 94.53, p = 0.004). Regarding hepatic steatosis by CAP evaluation, at SVR12, 186 (66.4%) of the individuals had a CAP score of ≥248 dB/m, an increase of 4.6% from the baseline. After viral eradication with DAAs, we observed an increase in hepatic steatosis. Hence, a long-term follow-up is mandatory to identify HCV-infected patients with hepatic steatosis post-SVR and the risk factors for more severe outcomes.

A reflection on health and disease amid COVID-19 pandemic.

Coronavirus disease 2019 pandemic is persisting for more than a year and it's still far from being controlled. It is making a big impact not only on physical illness but also on mental and social aspects. In this situation, we need to reflect on current medical society's view of disease and health. The dominant paradigm in contemporary medicine is the reductionist view of disease and the biomedical model of health. As a result, the healthcare system seems to be more focused on virus eradication than on patient care. We need to look back on this position in view of humanities and ethics and broaden our perspective to an ecological view of disease and the sociomedical model of health. The quarantine and health care policy also needs to be re‐built with more focus on patient care.

Topical pharmacologic interventions versus placebo for epidemic keratoconjunctivitis.

Topical pharmacologic interventions versus placebo for epidemic keratoconjunctivitis.

Innate and Adaptive Immunopathogeneses in Viral Hepatitis; Crucial Determinants of Hepatocellular Carcinoma.

Simple SummaryInfections with Hepatitis B and Hepatitis C viruses are usually asymptomatic and although some patients undergo resolution of infection, the majority do not. Chronic hepatitis leads to continuous cycles of inflammation that can cause complications including liver fibrosis, cirrhosis, and eventually liver cancer. This review summarizes the changes in liver immunity in acute and chronic Hepatitis B and C infections, as well as in liver cancer patients who developed their malignancy within a viral hepatitis background, aiming to better understand the disease biology. This review provides researchers in the field of chronic liver diseases with immune insights into viral hepatitis and hopes to be of help in developing better prophylactic approaches for cancer management.Viral hepatitis B (HBV) and hepatitis C (HCV) infections remain the most common risk factors for the development of hepatocellular carcinoma (HCC), and their heterogeneous distribution influences the global prevalence of this common type of liver cancer. Typical hepatitis infection elicits various immune responses within the liver microenvironment, and viral persistence induces chronic liver inflammation and carcinogenesis. HBV is directly mutagenic but can also cause low-grade liver inflammation characterized by episodes of intermittent high-grade liver inflammation, liver fibrosis, and cirrhosis, which can progress to decompensated liver disease and HCC. Equally, the absence of key innate and adaptive immune responses in chronic HCV infection dampens viral eradication and induces an exhausted and immunosuppressive liver niche that favors HCC development and progression. The objectives of this review are to (i) discuss the epidemiological pattern of HBV and HCV infections, (ii) understand the host immune response to acute and chronic viral hepatitis, and (iii) explore the link between this diseased immune environment and the development and progression of HCC in preclinical models and HCC patients.

Two cases of rapid progression of esophageal varices after atezolizumab-bevacizumab treatment for hepatocellular carcinoma.

We report two cases of rapid progression of esophageal varices after atezolizumab-bevacizumab treatment for hepatocellular carcinoma (HCC). Case 1: a man in his 60s with hepatitis C-related liver cirrhosis after viral eradication by direct acting antiviral. He was diagnosed with HCC 8years previously. He had undergone surgical resection 4 times, radio-frequency ablation (RFA) several times, and transcatheter arterial chemoembolization (TACE). However, HCC progressed and could not be controlled by locoregional treatment. Systemic chemotherapy was, therefore, selected. Atezolizumab-bevacizumab was administered after lenvatinib and sorafenib failure. Before starting treatment, his liver function was preserved (Child-Pugh score 5 and class A). His alpha fetoprotein and des-gamma-carboxyprothrombin levels were 3.6ng/mL and 443 mAU/mL, respectively. Esophagogastroduodenoscopy showed no remarkable esophageal varices before atezolizumab-bevacizumab treatment. Nine months after the initiation of atezolizumab-bevacizumab, the patient was admitted for hematemesis from esophageal varices. The disease control of HCC was classified as stable disease (SD) for the liver and lung metastases, and partial response for the lymph node metastases. Neither AST nor ALT was markedly elevated in the clinical course. Endoscopic variceal ligation (EVL) for the spurting point of large esophageal varices with red wale signs was able to successfully achieve hemostasis. Atezolizumab-bevacizumab was stopped and additional EVL eradicated the esophageal varices. However, the post-banding ulcer was prolonged in comparison to usual cases. Case 2: a man in his 60s with hepatitis C-related liver cirrhosis after viral eradication by direct acting antiviral therapy. He was diagnosed with HCC 6years previously. He had received RFA 2 times and TACE 7 times. Atezolizumab-bevacizumab was administered after lenvatinib failure. The disease control of HCC was classified as SD; however, the esophageal varices ruptured after 15 courses of atezolizumab-bevacizumab. Neither AST nor ALT were markedly elevated in the clinical course. The esophageal varices of these patients did not require treatment before atezolizumab-bevacizumab; however, they rapidly worsened and ruptured during atezolizumab-bevacizumab treatment. Although rare, similar cases with rapid progression of portal hypertension after atezolizumab-bevacizumab have been reported. We should pay attention to the worsening of esophageal varices during atezolizumab-bevacizumab treatment and poor wound healing after EVL.

Sofosbuvir/velpatasvir or glecaprevir/pibrentasvir for treating patients with hepatitis C virus reinfection following direct‐acting antiviral‐induced sustained virologic response

AbstractData regarding the patient characteristics of hepatitis C virus (HCV) reinfection following viral eradication by a prior course of direct‐acting antivirals (DAAs) and the clinical performance of pangenotypic DAAs to retreat such patients are lacking. The demographics and potential routes of transmission were shown in 22 patients with confirmed reinfection following HCV clearance by a prior course of DAAs. Twenty patients received retreatment with pangenotypic sofosbuvir/velpatasvir (SOF/VEL) or glecaprevir/pibrentasvir (GLE/PIB) according to label recommendations. The sustained virologic response (SVR12) rates and the tolerance following treatment were reported. The incidence rates of reinfection among human immunodeficiency virus (HIV)‐positive and HIV‐negative patients were 8.33 per 100 person‐years (95% CI: 5.33‐12.78) and 0.30 per 100 person‐years (95% CI: 0.12‐0.77), respectively. Eighteen (81.8%) patients had HIV coinfection. The elapsed time between SVR12 and reinfection ranged from 3 to 36 months. Twenty (90.9%) patients had different viral genotypes/subtypes before and after HCV reinfection. Prior to reinfection, 15 (68.2%) patients achieved SVR12 using SOF/VEL or GLE/PIB. Twelve and eight patients were retreated with SOF/VEL for 12 weeks and GLE/PIB for 8 weeks, respectively, in whom SVR12 was all achieved. All patients completed the assigned course of retreatment without interruption and all had excellent tolerance. The risk of HCV reinfection is higher in HIV‐positive patients than HIV‐negative patients following DAA‐induced SVR. Treating reinfected patients with SOF/VEL or GLE/PIB as DAA‐naïve patients has excellent effectiveness and tolerance, irrespective of the type of prior DAA exposure or viral genotypes/subtypes.

Duration and cost-effectiveness of hepatocellular carcinoma surveillance in hepatitis C patients after viral eradication

Successful treatment of chronic hepatitis C with oral direct-acting antivirals (DAAs) leads to virological cure, however, the subsequent risk of hepatocellular carcinoma (HCC) persists. Our objective was to evaluate the cost-effectiveness of biannual surveillance for HCC in patients cured of hepatitis C and the optimal age to stop surveillance. We developed a microsimulation model of the natural history of HCC in individuals with hepatitis C and advanced fibrosis or cirrhosis who achieved virological cure with oral DAAs. We used published data on HCC incidence, tumor progression, real-world HCC surveillance adherence, and costs and utilities of different health states. We compared biannual HCC surveillance using ultrasound and alpha-fetoprotein for varying durations of surveillance (from 5 years to lifetime) vs. no surveillance. In virologically cured patients with cirrhosis, the incremental cost-effectiveness ratio (ICER) of biannual surveillance remained below $150,000 per additional quality-adjusted life year (QALY) (range: $79,500-$94,800) when surveillance was stopped at age 70, irrespective of the starting age (40-65). Compared with no surveillance, surveillance detected 130 additional HCCs in 'very early'/early stage and yielded 51 additional QALYs per 1,000 patients with cirrhosis. In virologically cured patients with advanced fibrosis, the ICER of biannual surveillance remained below $150,000/QALY (range: $124,600-$129,800) when surveillance was stopped at age 60, irrespective of the starting age (40-50). Compared with no surveillance, surveillance detected 24 additional HCCs in 'very early'/early stage and yielded 12 additional QALYs per 1,000 patients with advanced fibrosis. Biannual surveillance for HCC in patients cured of hepatitis C is cost-effective until the age of 70 for patients with cirrhosis, and until the age of 60 for patients with stable advanced fibrosis. Individuals who are cured of hepatitis C using oral antiviral drugs remain at risk of developing liver cancer. The value of lifelong screening for liver cancer in these individuals is not known. By simulating the life course of hepatitis C cured individuals, we found that ultrasound-based biannual screening for liver cancer is cost-effective up to age 70 in those with cirrhosis and up to age 60 in those with stable advanced fibrosis.

The Novel Finding of Dynamic Change in eGFR Up to One Year after End of Treatment in HCV-Infected Patients Receiving Sofosbuvir and Velpatasvir.

Background: The results of long-term renal evolution in HCV-infected patients using sofosbuvir and velpatasvir (SOF/VEL), with or without ribavirin (RBV), are lacking. Aims: We evaluated the renal safety for HCV-infected patients receiving SOF/VEL. Methods: Between 1 June 2019 and 6 July 2020, we included 594 HCV-infected patients receiving SOF/VEL +/− RBV for 12 weeks in Taiwan. Viral eradication rate (defined by sustained virological response at week 12 post-treatment; SVR12) and changes to renal function were considered. Results: SVR12 was achieved in 99.3% (590/594) upon per-protocol analysis. Patients saw improved hepatobiliary function and fibrosis after the start of SOF/VEL therapy. For renal function, those with baseline estimated glomerular filtration rate (eGFR) ≥ 60 (mL/min/1.73 m2) experienced transient on-treatment reduction in renal function that improved upon ending treatment, but recurrent eGFR degradation during one-year follow-up. The use of RBV (OR = 5.200, 95% CI: 1.983–13.634, p = 0.001) was a significant risk factor at SVR24, while diabetes mellitus (OR = 2.765, 95% CI: 1.104–6.922, p = 0.030) and the use of RBV (OR = 3.143, 95% CI: 1.047–9.435, p = 0.041) were identified as significant risk factors of worsening renal function at SVR48. SOF/VEL did not worsen renal function among those with stage 4–5 chronic kidney disease (CKD) who were not receiving dialysis. Conclusions: A trend of decline in eGFR at 1 year after SOF/VEL treatment was observed among diabetic patients with baseline eGFR ≥ 60 (mL/min/1.73 m2) and concomitant use of RBV. The close monitoring of renal function is warranted. Further study should be conducted in order to weigh the risks and benefit of RBV.

Beneficial Effects of Silybin Treatment After Viral Eradication in Patients With HCV-Related Advanced Chronic Liver Disease: A Pilot Study.

Introduction and Aims: HCV eradication by direct-acting antivirals (DAAs) improves liver outcomes and reduces overall liver mortality. However, patients with advanced chronic liver disease (ACLD) may experience a progression of liver disease despite viral clearance. Silybin has shown hepatoprotective effects in experimental models, but clinical data are limited. The aim of this study is to evaluate the effect of a highly bioavailable form of silybin on liver fibrosis in patients with HCV-related ACLD after viral eradication with DAAs, in comparison with the standard of care. Methods: In this multicenter and prospective study, HCV patients with ACLD achieving SVR12 were treated with the combination of silybinphospholipid complex with vitamin D and vitamin E (Realsil 100D®, Ibi Lorenzini S.p.A., Aprilia, Italy) for 12 months (R group) compared to controls (C group). Patients were submitted to transient elastography (TE) and to the enhanced liver fibrosis (ELF) test at baseline, week 24, and week 48. Results: One hundred sixteen patients were enrolled, 56 in the R group and 60 in the C group. The median age was 68 years, and 53% were male, with no differences between groups. In both groups, liver stiffness improved at 6 and 12 months compared to baseline. However, patients in the R group compared to those in the C group showed a higher reduction of liver stiffness after 6 months (−2.05, 95% CI −3.89 to −0.22, p < 0.05) and 12 months of treatment (−2.79, 95% CI −4.5 to −1.09, p < 0.01) in comparison with baseline. No significant difference in the reduction of ELF was observed between the two groups. During the follow-up, four patients developed HCC, all in the C group. Conclusions: In HCV-related ACLD, the hepatoprotective effects of silybin may represent a tool to counteract liver disease progression.

Prediction of hepatocellular carcinoma using age and liver stiffness on transient elastography after hepatitis C virus eradication

Liver stiffness measurement (LSM) is a useful tool for assessing advanced liver fibrosis, an important risk factor for hepatocellular carcinoma (HCC) following hepatitis C (HCV) eradication. This study aimed to clarify the non-invasive factors associated with HCC following sustained virological response (SVR) and to identify the low-risk group. 567 patients without history of HCC who achieved SVR at 24 weeks (SVR24) after IFN-free treatment were retrospectively analyzed. The cumulative incidence of HCC and the risk factors were examined using pre-treatment and SVR24 data. The median observation period was 50.2 months. Thirty cases of HCC were observed, and the 4-year cumulative incidence of HCC was 5.9%. In multivariate analysis, significant pre-treatment factors were age ≥ 71 years (hazard ratio [HR]: 3.402) and LSM ≥ 9.2 kPa (HR: 6.328); SVR24 factors were age ≥ 71 years (HR: 2.689) and LSM ≥ 8.4 kPa (HR: 6.642). In cases with age < 71 years and LSM < 8.4 kPa at the time of SVR24, the 4-year cumulative incidence of HCC was as low as 1.1%. Both pre-treatment LSM (≥ 9.2 kPa) and SVR24 LSM (≥ 8.4 kPa) and age (≥ 71 years) are useful in predicting the risk of HCC after SVR with IFN-free treatment. Identification of low-risk individuals may improve the efficiency of follow-up.

Hepatitis C virus eradication prolongs overall survival in hepatocellular carcinoma patients receiving molecular-targeted agents.

The aim of this multicenter retrospective study was to evaluate the impact of the eradication of hepatitis C virus (HCV) on the clinical outcomes of patients with hepatocellular carcinoma (HCC) treated with molecular-targeted agents (MTAs). Among 877 patients who received any MTA as first-line systemic therapy for HCC between June 2009 and March 2019, 569 patients with HCV-related HCC were enrolled in this retrospective study. Of these, 109 patients achieved sustained virological response (SVR) before starting MTA. After propensity score matching, the clinical outcomes of 109 patients in the SVR group and 109 patients in the non-SVR group were compared. The median time to progression in the SVR group (7.8months) was similar to that in the non-SVR group (5.6months) (p = 0.212). The median time to treatment failure in the SVR group (5.3months) was longer than that in the non-SVR group (2.8months) (p = 0.059), and post-progression survival and overall survival in the SVR group were significantly longer than those in the non-SVR group (12.0months vs 7.2months; p = 0.039, and 18.1months vs 11.3months; p = 0.019). At the end of first-line MTA therapy, the albumin-bilirubin (ALBI) score in the SVR group ( - 2.25) was significantly lower than that in the non-SVR group ( - 2.10) (p = 0.008). The eradication of HCV before MTA therapy maintained liver function and led to a prolonged treatment period and improved overall survival of HCV-related HCC patients. We should not overlook the benefits of HCV eradication in HCC patients.

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.