Tobacco Smoking and Liver Cancer Risk: Potential Avenues for Carcinogenesis

Smoking a cigarette generates over 4000 chemicals that have a deleterious impact on each part of the human body. It produces three main severe effects on the liver organ: oncogenic, immunological, and indirect or direct toxic effects. It results in the production of cytotoxic substances, which raises fibrosis and necro-inflammation. Additionally, it also directs the production of pro-inflammatory cytokines tumour necrosis factor alfa (TNF-α) and interleukins (IL-1β, IL-6) that will be responsible for the chronic liver injury. Furthermore, it gives rise to secondary polycythemia and successively raises the turnover and mass of red cells, which might be a common factor responsible for the development of oxidative stress in the liver due to iron overload. It also produces chemicals that are having oncogenic properties and raises the risk of liver cancer especially in sufferers of chronic hepatitis C. Smoking modulates both humoral and cell-mediated responses by restricting the proliferation of lymphocytes and inducing their apoptosis and ultimately decreasing the surveillance of cancer cells. Moreover, it has been determined that heavy smoking impacts the response of hepatitis C patients to interferon (IFN) therapy through different mechanisms, which can be improved by phlebotomy. Efforts are being made in different nations in decreasing the prevalence of smoking to improve premature death and ill effects of their nation’s individuals.

GANAB as a Novel Biomarker in Multiple Sclerosis: Correlation with Neuroinflammation and IFI35

Multiple sclerosis (MS) still lacks reliable biomarkers of neuroinflammation predictive for disease activity and treatment response. Thus, in a prospective study we assessed 55 MS patients (28 interferon (IFN)-treated, 10 treated with no-IFN therapies, 17 untreated) and 20 matched healthy controls (HCs) for the putative correlation of the densitometric expression of glucosidase II alpha subunit (GANAB) with clinical/paraclinical parameters and with interferon-induced protein 35 (IFI35). We also assessed the disease progression in terms of the Rio Score (RS) in order to distinguish the responder patients to IFN therapy (RS = 0) from the non-responder ones (RS ≥ 1). We found GANAB to be 2.51-fold downregulated in the IFN-treated group with respect to the untreated one (p < 0.0001) and 3.39-fold downregulated in responder patients compared to the non-responders (p < 0.0001). GANAB correlated directly with RS (r = 0.8088, p < 0.0001) and lesion load (LL) (r = 0.5824, p = 0.0014) in the IFN-treated group and inversely with disease duration (DD) (r = −0.6081, p = 0.0096) in the untreated one. Lower mean values were expressed for GANAB than IFI35 in IFN responder (p < 0.0001) and higher mean values in the non-responder patients (p = 0.0022). Inverse correlations were also expressed with IFI35 in the overall patient population (r = −0.6468, p < 0.0001). In conclusion, the modular expression of GANAB reflects IFI35, RS, DD, and LL values, making it a biomarker of neuroinflammation that is predictive for disease activity and treatment response in MS.

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.

Interferon and Hepatitis B: Current and Future Perspectives

Chronic hepatitis B virus (HBV) infection remains a major health burden worldwide for which there is still no effective curative treatment. Interferon (IFN) consists of a group of cytokines with antiviral activity and immunoregulatory and antitumor effects, that play crucial roles in both innate and adaptive immune responses. IFN-α and its pegylated form have been used for over thirty years to treat chronic hepatitis B (CHB) with advantages of finite treatment duration and sustained virologic response, however, the efficacy is limited and side effects are common. Here, we summarize the status and unique advantages of IFN therapy against CHB, review the mechanisms of IFN-α action and factors affecting IFN response, and discuss the possible improvement of IFN-based therapy and the rationale of combinations with other antiviral agents in seeking an HBV cure.

Possible biomarkers of therapy effective

Administration of the disease modifying therapy in patients with multiple sclerosis is associated with alterations in immune system reactivity. Interferon’s IFN-β-1a and IFN-β-1b are included in the first-line treatment for multiple sclerosis cure. However, as protein substances, they are potentially immunogenic, hence neutralizing antibodies (Nab) can appear after 3–6 months in the serum of a multiple sclerosis patient, reducing IFN-molecules activity. Detection of the NAb to the administrated IFN-medication enables to change the patient management strategy. The level of inflammatory and apoptotic caspases in serum and cerebrospinal fluid may also be considered as a prognostic biomarker for the IFN-therapy efficiency. In addition, the level of microRNA, neurofilaments in serum and secreted glycoproteins (chitinases) in cerebrospinal fluid have certain prognostic value. Increasing of medical substances action specificity, searching for new pathogenesis links as targets for the therapeutic action and identification of the effective prognostic biomarkers are the main strategies of multiple sclerosis treatment nowadays.

Loss of HBsAg in Patients with High Levels of HBV-DNA During Treatment with Nucleoside or Nucleotide Analogs

Background: HBsAg is synthesized in the endoplasmic reticulum and is necessary for the formation of complete HBV particles. A decreased synthesis of this antigen leads to an intracellular inhibition of virus production. Methods: The study aimed to assess the incidence of HBsAg elimination among 1,290 patients who suffered from chronic HBV infection undergoing an antiviral treatment with nucleoside or nucleotide analogs (NAs). Furthermore, possible predictive factors for this elimination were analyzed. Results: A permanent HBsAg loss was confirmed in 3% of the patients, which was more frequent in men than in women (4.4% vs. 1.9%; P = 0.009). The HBsAg elimination occurred in 5% of HBeAg (+) patients and 2.8% of HBeAg (-) patients. The age of patients whose HBsAg was eliminated was higher than the age of the remaining patients (60 vs. 51 y/o). The effect of initially used pegylated interferon alfa (PEG-IFN) therapy on the HBsAg elimination was not observed. It occurred with the use of entecavir (ETV) and tenofovir (TDF); however, among patients treated with ETV, HBsAg was significantly more often eliminated in HBeAg (+) patients. Conclusions: The HBsAg elimination in patients undergoing antiviral treatment occurs more often in men, patients with positive HBeAg before treatment, individuals above 60 years, and patients treated with ETV.

Interferon-Alpha (IFN) Therapy Discontinuation Is Feasible in Myeloproliferative Neoplasm (MPN) Patients with Complete Hematological Remission

Background: Although patients with MPN may achieve complete hematological remission (CHR) with cytoreductive therapy (CRT), lifelong treatment represents a major burden for these chronically ill patients. IFN has emerged as a major MPN therapy thought to positively alter the natural history of MPN and appears to be the only drug that can provide long-term CHR after discontinuation in some patients (Hasselbalch HC et al., Seminars in Immunopathology, 2019). In this study, we aimed to identify clinical and molecular factors associated with long-term CHR after IFN treatment discontinuation and to compare clinical outcome of patients who discontinued therapy, to patients who continued IFN treatment despite achieving a CHR. Methods: All MPN patients followed between January 2000 and May 2020 in our institution who received at least 3 months of IFN were included. Logistic regression analysis was performed to identify variables associated with long-term CHR after discontinuation. Cumulative incidence of relapse was calculated from time of IFN discontinuation, considering death without relapse as a competitive event. Overall survival (OS) and thrombotic/hemorrhagic events free survival (EFS) curves were estimated using the Kaplan-Meier method and compared by cause-specific hazard Cox models. Results: 381 patients treated with IFN were included in the study. Median age at MPN diagnosis was 44 years [interquartile range: 33-54]. 171 had polycythemia vera (PV), 169 essential thrombocythemia (ET) and 34 primary myelofibrosis (PMF). JAK2V617F was the most frequent driver mutation (78.8% of patients), while CALR and MPL were mutated in 15.5%, and 2.9% of patients respectively. Median driver variant allele frequency (VAF) at time of IFN therapy initiation was 34% [12; 51]. Reasons to start IFN included age younger than 50 years in 44.9%, intolerance/resistance to previous therapies in 17.8% or pregnancy in 1.8% patients. CHR was achieved with IFN in 77.2% of patients. After a median follow-up of 72.4 months [28.4; 119.7] from IFN initiation, 131 patients were still on IFN treatment, while 250 patients had discontinued therapy. No significant difference was observed between continued and discontinued IFN patients in terms of MPN subtype, initial clinical, biological or molecular characteristics. Reasons for discontinuation were toxicity in 128 (50.4%), prolonged hematological CHR in 76 (29.9%), failure in 16 (6.3%) and other in 30 (11.8%) patients. At time of IFN discontinuation, 170 (66.9%) patients were in CHR and the median driver mutation VAF was 12% [3; 35]. Of note, IFN was re-introduced in 61 patients who lost CHR with a second CHR rate of 83.6%, arguing for the absence of development of IFN resistance in post-discontinuation relapses. In multivariate logistic regression analysis, stopping for prolonged CHR (OR 3.52, 95%CI [1.18; 10.56], p=0.024) was associated with a higher CHR without CRT rate, while VAF ≥ 10% at time of IFN discontinuation (OR 0.26, 95%CI [0.1; 0.65], p=0.004) was associated with lower long-term CHR without CRT. Accordingly, VAF ≥ 10% at time of IFN discontinuation (HR 3.06 [1.59; 5.90], p=0.001) was independently associated with a higher cumulative incidence of relapse after IFN discontinuation (Figure A). Driver VAF at IFN discontinuation time was available for 117 patients. 53 patients (45.3%) had a driver VAF &lt; 10% at IFN discontinuation. Finally, we compared discontinued IFN patients who stopped IFN for CHR (n=76) to patients who obtained CHR and are still on IFN therapy (n=116). Hematological transformation could not be evaluated due to very low incidence of events: 2 patients from each group progressed to myelofibrosis while leukemic progression was only observed in 1 patient. Importantly, OS (HR 0.23, 95%CI [0.5; 1.14], p=0.07) and EFS (HR 0.53, 95%CI [0.19; 1.45], p=0.217) were not significantly different between patients who discontinued and those who continued IFN. Conclusion: Overall, our study demonstrates that IFN discontinuation represents a safe strategy in MPN patients who achieved CHR, and particularly in patients with a driver VAF lower than 10% at time of discontinuation. Importantly, relapsed patients did not develop IFN resistance. Our data contributes to set the frame for future clinical trials evaluating the possibility of IFN treatment holidays in good responding MPN patients. Disclosures Benajiba: Gilead Foundation: Research Funding. Kiladjian:Abbvie: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees.

Immune mechanisms of SARS-CoV-2 and potential drugs in the prevention and treatment of COVID-19

The lack of specific vaccines against SARS-CoV-2, as well as chemotherapy, significantly affected the spread of infection and the number of adverse outcomes of COVID-19. With the discovery of the pathogenesis of coronavirus infection, especially immune mechanisms, the important role of the innate immunity system in interacting with the virus is obvious. The presence of comorbid conditions, as well as the aging of the body, lead to disturbances in the immune response mechanism, low interferon induction, depletion of CD8+ -lymphocytes and natural killers and suppression of the effectiveness of both innate and adaptive immunity. The review discusses various mechanisms of antiviral activity associated with the induction of interferon (IFN) production, the use of direct IFN therapy, the use of antiviral drugs, and immunotropic therapy (synthetic immunomodulators), as promising in the prevention and treatment of COVID-19.

Development of Hepatocellular Carcinoma in a Patient with Chronic Hepatitis C 21 Years after Achieving a Sustained Virological Response to Interferon Therapy

A 77-year-old man with chronic hepatitis C (CH-C) infection, who achieved a sustained virological response (SVR) to interferon (IFN) therapy, was followed up regularly. Before IFN therapy, he did not have metabolic diseases, and the histological diagnosis of his chronic hepatitis was stage-3 fibrosis. After achieving SVR, the fibrosis-4 (FIB-4) index level dropped once but gradually increased. 21 years after SVR, hepatocellular carcinoma (HCC) was diagnosed by dynamic computed tomography. The HCC was 12 mm in diameter. The HCC was treated with radiofrequency ablation. CH-C patients with advanced fibrosis require long-term follow-up, even after achieving SVR.