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1.
Serum miRNAs Predicting Sustained HBs Antigen Reduction 48 Weeks after Pegylated Interferon Therapy in HBe Antigen-Negative Patients.
Fujita, K, Mimura, S, Iwama, H, Nakahara, M, Oura, K, Tadokoro, T, Nomura, T, Tani, J, Yoneyama, H, Morishita, A, et al
International journal of molecular sciences. 2018;(7)
Abstract
The therapeutic goal for hepatitis B virus (HBV) infection is HBs antigen (HBsAg) seroclearance, which is achieved through 48-week pegylated interferon (Peg-IFN) therapy. This study aimed to identify predictive biomarkers for sustained HBsAg reduction by analyzing serum microRNAs. Twenty-two consecutive chronic HBV infection patients negative for HBe antigen (HBeAg) with HBV-DNA levels <5 log copies/mL, alanine aminotransferase (ALT) <100 U/L, and compensated liver functions, were enrolled. The patients were subcutaneously injected with Peg-IFNα-2a weekly for 48 weeks (treatment period), followed by the 48-week observation period. HBsAg 1-log drop relative to baseline levels recorded at the end of the observation period was considered effective. Sera were obtained at weeks 0 and 24 during the treatment period analyzed for microRNAs. The microRNA (miRNA) antiviral activity was evaluated in vitro using Huh7/sodium taurocholate cotransporting polypeptide (NTCP) cells. As a result, six patients achieved the HBsAg 1-log drop after the observation periods. Comparison of serum microRNA levels demonstrated that high miR-6126 levels at week 24 predicted HBsAg 1-log drop. Furthermore, miR-6126 reduced HBsAg in culture medium supernatants and intracellular HBV-DNA quantities in Huh7/NTCP cells. In conclusion, high serum miR-6126 levels during Peg-IFN therapy predicted the HBsAg 1-log drop 48 weeks after the completion of therapy. In vitro assays revealed that miR-6126 was able to suppress HBsAg production and HBV replication.
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2.
Combined effect of pegylated interferon α with adefovir on renal function in Chinese patients with chronic hepatitis B.
Su, Q, Liu, Y, Li, J
Medicine. 2018;(34):e12089
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Abstract
BACKGROUND Long-term safety of treatment with hepatitis B virus (HBV) polymerase inhibitors is a concern. Adefovir dipivoxil (ADV) and/or interferon alfa (IFN-α) therapies have previously been associated with impairment of renal function. Limited data are available on the safety of combination therapy with nucleos (t)ide analogues (NAs) and IFN-α. The aim of this analysis was to assess the renal function during combined therapy with pegylated interferon α-2b (PEG-IFN-α-2b) and ADV versus PEG-IFN-α-2b alone in patients with chronic hepatitis B (CHB). METHODS We performed a multicenter, prospective, open-label, randomized-controlled trial of renal function data to investigate the efficacy of 48 weeks of therapy with PEG-IFN-α-2b and ADV versus PEG-IFN-α-2b alone in 102 patients with CHB in Anhui, China. Glomerular filtration rates (GFRs) were calculated by Cockcroft-Gault (CG), abbreviated Modification of Diet in Renal Disease (MDRD) study, and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, and were tested by repeated-measures 1-way analysis of variance within groups. A linear mixed effects model for repeated measures was also used to evaluate the association between baseline information and estimated glomerular filtration rate (eGFR) changes overtime in all enrolled patients. The model considered the baseline age, sex, HBV DNA, aminotransferase, treatment group, time, and group-by-time interaction as fixed effects and incorporated random effects for individual subjects. RESULTS After 48 weeks of therapy and further 24 weeks of follow-up, the eGFR decreased both in patients given PEG-IFN-α-2b single therapy and combined therapy. Age, HBV DNA, and combined therapy were significant negative predictive factors for eGFR changes. CONCLUSION The incidence of renal adverse events in both groups was low, and the combination therapy may have delayed, but reversible renal impairment.
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Minimal residual disease or cure in MPNs? Rationales and perspectives on combination therapy with interferon-alpha2 and ruxolitinib.
Bjørn, ME, Hasselbalch, HC
Expert review of hematology. 2017;(5):393-404
Abstract
The therapeutic landscape of the Philadelphia-negative myeloproliferative neoplasms (MPNs) is markedly changing consequent to the development of JAK-inhibitors and the use of ruxolitinib (RUX) in patients with myelofibrosis (MF) and patients with polycythemia vera (PV) who develop refractoriness or intolerance to hydroxyurea. The use of Interferon-alpha2 (IFN) is rapidly expanding in several countries, based upon favourable safety and efficacy profiles in several single-arm studies during the last 30 years, displaying complete hematological remissions in a large proportion of patients, a reduction in the JAK2V617 F and CALR mutational burden and in a subset of patients with PV with normalisation of the bone marrow after long-term treatment - even being sustained for several years after discontinuation of IFN. To this end the concept of chronic inflammation as the driving force for MPN disease progression is being increasingly recognized. This novel concept has initiated phase II studies in patients with PV and MF of combination therapy with IFN and RUX. Areas covered and Expert commentary: Herein we highlight the background, the rationales and perspectives for this novel combinatorial approach which is foreseen as the most encouraging and promising treatment for patients with MPNs - hopefully with the potential of cure - at least operational cure - in a subset of patients.
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Resveratrol in Hepatitis C Patients Treated with Pegylated-Interferon-α-2b and Ribavirin Reduces Sleep Disturbance.
Pennisi, M, Bertino, G, Gagliano, C, Malaguarnera, M, Bella, R, Borzì, AM, Madeddu, R, Drago, F, Malaguarnera, G
Nutrients. 2017;(8)
Abstract
BACKGROUND Hepatitis C virus infection and interferon treatment have shown to be risk factors for sleep disorder health-related quality of life. AIM: To determine whether the effects of resveratrol on sleep disorders were associated with different tests in subjects with chronic hepatitis C treated with Peg-IFN-α and RBV. PATIENTS AND METHODS In this prospective, randomized, placebo controlled, double blind clinical trial, 30 subjects (Group A) with chronic hepatitis received Pegylated-Interferon-α2b (1.5 mg/kg per week), Ribavirin and placebo (N-acetylcysteine 600 mg and lactoferrin 23.6 g), while 30 subjects (Group B) received the same dosage of Pegylated-Interferon-α2b, Ribavirin and association of N-acetylcysteine 600 mg, lactoferrin 23.6 g and Resveratrol 19.8 mg for 12 months. All subjects underwent laboratory exams and questionnaires to evaluate mood and sleep disorders (General Health Questionnaire (GHQ), Profile of Mood States (POMS), Pittsburgh Sleep Quality Inventory (PSQI), Epworth Sleepiness Scale (ESS)). RESULTS The comparison between Group A and Group B showed significant differences after six months in C-reactive protein (p < 0.0001); after 12 months in aspartate aminotransferase (AST) (p < 0.0001) Viremia (p < 0.0001), HAI (p < 0.0012) and C-reactive protein (p < 0.0001); and at follow up in AST (p < 0.0001), Viremia (p < 0.0026) and C-reactive protein (p < 0.0001). Significant differences were observed after 12 month and follow-up in General Health Questionnaire, after 1, 6, 12 and follow-up in Profile of Mood States, after 6, 12, follow-up in Pittsburgh Sleep Quality Inventory and Epworth Sleepiness Scale. CONCLUSIONS Supplementation with Resveratrol decreased General Health Questionnaire score and reduced sleep disorders in patients treated with Peg-IFN-α and RBV.
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Effect of Hops Derived Prenylated Phenols on TNF-α Induced Barrier Dysfunction in Intestinal Epithelial Cells.
Luescher, S, Urmann, C, Butterweck, V
Journal of natural products. 2017;(4):925-931
Abstract
For the prenylated hops phenols 6- and 8-prenylnaringenin (1 and 2), xanthohumol (3), and isoxanthohumol (4), a variety of biological activities has been described. In the current study, a transwell based in vitro model using the human intestinal epithelial cell line Caco-2 was developed to assess potential beneficial effects of compounds 1-4 on TNF-α-induced impairment of tight junction (TJ) permeability. Transepithelial electrical resistance (TEER) was measured using the latest cellZScope online monitoring device. TNF-α treatment (25 ng/mL) induced a significant decrease in TEER values (204.71 ± 4.57 at 72 h) compared to that in control values (245.94 ± 1.68 at 72 h). To determine preventive effects on TNF-α-induced impairment of TJ permeability, 1-4 were added to the apical compartment of Caco-2 monolayers 1 h before TNF-α treatment; afterward, TNF-α was added to the basolateral compartment to induce TJ dysfunction and incubated for a further 72 h. Using this setting, only 1 and 2 prevented epithelial disruption induced by TNF-α. To evaluate restorative effects of 1-4, TNF-α was added to the basolateral compartment of Caco-2 cell monolayers. After 48 h of incubation, 1-4 were added to the apical side, and TEER values were monitored online for a further 72 h. Under these experimental conditions, only 2 restored TNF-α induced barrier dysfunction.
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Overview of Targeted Therapies for Adult T-Cell Leukemia/Lymphoma.
Nasr, R, Marçais, A, Hermine, O, Bazarbachi, A
Methods in molecular biology (Clifton, N.J.). 2017;:197-216
Abstract
Adult T-Cell Leukemia/lymphoma (ATL) is the first human malignancy associated with a chronic infection by a retrovirus, the human T-cell lymphotropic virus type I (HTLV-I). ATL occurs, after a long latency period, only in about 5% of 10-20 millions infected individuals. ATL has a dismal prognosis with a median survival of less than 1 year, mainly due to its resistance to chemotherapy and to a profound immunosuppression. The viral oncoprotein, Tax, plays a major role in ATL oncogenic transformation by interfering with cell proliferation, cell cycle, apoptosis, and DNA repair. The diversity in ATL clinical features and prognosis led to Shimoyama classification of ATL into four clinical subtypes (acute, lymphoma, chronic, and smoldering) requiring different therapeutic strategies. Clinical trials, mainly conducted in Japan, demonstrated that combination of chemotherapy could induce acceptable response rate in the lymphoma subtype but not in acute ATL. However, long-term prognosis remains poor for both subtypes, due to a high relapse rate. Similarly, whether managed by a watchful waiting or treated with chemotherapy, the indolent forms (smoldering and chronic) have a poor long-term outcome. An international meta-analysis showed improved survival in the leukemic subtypes of ATL (chronic, smoldering as well as a subset of the acute subtype) with the use of two antiviral agents, zidovudine and interferon-alpha, and accordingly, this combination should be considered the standard first-line treatment in this context. ATL patients with lymphoma subtype benefit from induction chemotherapy, given simultaneously or sequentially with an antiviral combination of zidovudine and interferon-alpha. Allogeneic hematopoietic stem cells transplantation remains a promising and potentially curative approach but is limited to a small number of patients. Novel drugs such as arsenic trioxide in combination with interferon-alpha or monoclonal antibodies such as anti-CXCR4 have shown promising results and warrant further investigation.
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Association of hepatic oxidative stress and iron dysregulation with HCC development after interferon therapy in chronic hepatitis C.
Nanba, S, Ikeda, F, Baba, N, Takaguchi, K, Senoh, T, Nagano, T, Seki, H, Takeuchi, Y, Moritou, Y, Yasunaka, T, et al
Journal of clinical pathology. 2016;(3):226-33
Abstract
BACKGROUND Oxidative stress may play pathogenic roles in the mechanisms underlying chronic hepatitis C (CHC). The impact of excessive oxidative stress and iron dysregulation on the development of hepatocellular carcinoma (HCC) after interferon therapy has not been established. METHODS We investigated the impact of oxidative stress and iron deposition on HCC development after therapy with pegylated interferon (PegIFN)+ribavirin in CHC patients. Systemic and intracellular iron homeostasis was evaluated in liver tissues, peripheral blood mononuclear cells and sera. RESULTS Of 203 patients enrolled, 13 developed HCC during the 5.6-year follow-up. High hepatic 8-hydroxy-2-deoxyguanosine (8-OHdG) levels were significantly associated with HCC development in multivariate analysis (p=0.0012) which was also significantly correlated with severity of hepatic iron deposition before therapy (p<0.0001). Systemic and intracellular iron regulators of hepcidin and F-box and leucine-rich repeat protein 5 (FBXL5) expression levels were significantly suppressed in CHC patients (p=0.0032 and p=0.016, respectively) despite their significantly higher levels of serum iron and ferritin compared with controls. However, intracellular iron regulators of FBXL5 and iron regulatory proteins were regulated in balance with hepatic iron deposition. Significant correlations were observed among IL-6, bone morphogenetic protein 6, hepcidin and ferroportin, as regards systemic iron regulation. CONCLUSIONS Measurement of hepatic oxidative stress before antiviral therapy is useful for the prediction of HCC development after interferon therapy. Low baseline levels of the intracellular iron regulators of FBXL5 in addition to a suppressed hepcidin level might be associated with severe hepatic iron deposition in CHC patients. TRIAL REGISTRATION NUMBER UMIN 000001031.
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Vitamin D Status and Virologic Response to HCV Therapy in the HALT-C and VIRAHEP-C Trials.
Loftfield, E, O'Brien, TR, Pfeiffer, RM, Howell, CD, Horst, R, Prokunina-Olsson, L, Weinstein, SJ, Albanes, D, Morgan, TR, Freedman, ND
PloS one. 2016;(11):e0166036
Abstract
Higher vitamin D status was not beneficially associated with responses to therapy; if anything, patients with higher vitamin D concentrations were less likely to attain SVR. Our data do not support a role for vitamin D supplementation as an adjuvant therapy for HCV.
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Does Epoetin Beta Still Have a Place in Peginterferon Alpha-2a Plus Ribavirin Treatment Strategies for Chronic Hepatitis C?
Veillon, P, Fouchard-Hubert, I, Larrey, D, Dao, MT, D'alteroche, L, Boyer-Darrigand, N, Picard, N, Le Guillou-Guillemette, H, Saulnier, P, Ducancelle, A, et al
Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research. 2016;(3):204-14
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Abstract
To investigate the impact of epoetin beta (EPO) on sustained virological response (SVR) in hepatitis C virus (HCV)-infected patients treated with peginterferon-ribavirin (RBV). Controlled, randomized, pragmatic multicenter study to assess 2 strategies, ie, the use (EPO group) or nonuse (control group) of EPO in terms of achieving SVR in treatment-naive, genotype non-2/non-3 HCV-infected patients receiving a 48-week treatment regimen of pegylated interferon α-2a (peg-IFN) plus RBV (randomization 2:1). The single-nucleotide polymorphisms of interferon lambda 3 (IFNL3) (rs12979860 and rs8099917), interferon lambda 4 (IFNL4) (ss469415590), and inosine triphosphatase (ITPA) (rs1127354 and rs7270101) were determined retrospectively. Two hundred twenty-seven patients were included in the study. In the global population (n = 227), the overall SVR rate was 52% (118/227). Nonresponse and relapse occurred in respectively 46/227 (20.3%) and 42/227 (18.5%) patients. In the intention-to-treat analysis, 55.5% of patients with anemia (n = 164) had a SVR, specifically 57.4% in the EPO group versus 52.4% in the control group, but the difference was not statistically significant. In the anemic population, independent factors associated with SVR were IFNL3 and IFNL4 polymorphisms, pretreatment HCV RNA level, iron level, and aspartate aminotransferase/alanine aminotransferase (AST/ALT) ratio. EPO has little impact on SVR in patients treated with peg-IFN+RBV and should be recommended only for patients with severe anemia.
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10.
Latest developments in the treatment of hepatitis B.
Dandri, M, Petersen, J
Minerva gastroenterologica e dietologica. 2016;(1):88-102
Abstract
Chronic hepatitis B virus (HBV) infection continues to be a major health burden worldwide. Currently available antiviral treatment options for chronic hepatitis B include pegylated interferon alpha (PEG-IFN) or nucleos(t)ide analogues (NAs). The major advantages of NAs are good tolerance and potent antiviral activity associated with high rates of on-treatment response to therapy. The advantages of PEG-IFN include a finite course of treatment, the absence of drug resistance, and an opportunity to obtain a durable post-treatment response to therapy. The use of these two antiviral agents with different mechanisms of action in combination is theoretically an attractive approach for treatment. Although several studies have confirmed certain virological advantages of combination therapies, pivotal prospective studies demonstrating long-term clinical benefit to patients are still missing and monotherapy with PEG_IFN or NAs remains the therapy of choice. Furthermore, with the current treatment approaches, only a limited number of patients reach the aim HBsAg loss, which is closest to clinical cure. The limited efficacy of current approved therapeutic regimens demands the development of more efficient therapeutic approaches enabling not only suppression of viral replication, but resolution of HBV infection. The unique replication strategy employed by HBV enables its persistence within the infected hepatocytes. As a consequence, relapse of viral activity is commonly observed after cessation of treatment. Both the persistence of the HBV genome, which forms a stable minichromosome, the covalently closed circular DNA (cccDNA) in the nucleus of infected hepatocytes, as well as the inability of the immune system to resolve chronic HBV infection are believed to be key mechanisms of HBV chronicity. The recent development and availability of innovative in vitro and in vivo systems and sensitive molecular techniques have opened new possibilities to study the complex network of interactions that HBV establishes with the host in the course of infection and to define new targets for antiviral strategies. Several new antiviral or immunomodulatory compounds have reached preclinical or clinical testing with the aim of a clinical cure of chronic HBV with the loss of HBsAg. This review summarizes the most recent therapeutic strategies designed to directly target the virus or to improve immune responses during chronic HBV infection.