IFN-λ Research Articles

Impact of interleukin 28B rs12979860 C/T polymorphism on severity of disease and response to treatment in hepatitis delta.

Pegylated-interferon alpha (Peg-IFN α) is the therapy most commonly used to treat chronic hepatitis delta virus (HDV) infection. In the present study, we planned to investigate effect of IL28B polymorphism on response to Peg-IFN α therapy and disease progression in patients with chronic HDV. A total of 47 patients who received Peg-IFNα therapy for at least one year were investigated. The patients were divided into three groups based on their response to treatment: sustained viral response (SVR) (32%), unresponsive (53%), and relapse (15%). The groups were compared in terms of age, gender, blood biochemistry (albumin, total bilirubin, lactic acid dehydrogenase, ALT, AST, ALP, GGT), complete blood count, HBeAg, HBsAg, HBV-DNA, HDV-RNA, IL28B genotypes (CC, CT, TT), and results of liver biopsy. Regarding the investigation of IL28B genotype, the prevalence of CC, CT, and TT showed no difference among the three groups. In the SVR group, the prevalence of CC was 53%, CT was 47%, but there was no patient with TT. In the unresponsive group, prevalence of CC was 52%, CT was 32%, and TT was 16%. In the relapse group, prevalence of CC was 43%, CT was 57%, but there was no patient with TT genotype. No significant difference was found among the groups with sustained response, no response, and relapse in terms of CC and CT polymorphisms (p>0.05). No relationship was found between IL28B rs12979860 polymorphism and response to treatment and disease severity in patients with chronic HDV infection.

Downregulation of autophagy-related gene ATG5 and GABARAP expression by IFN-λ1 contributes to its anti-HCV activity in human hepatoma cells

Type-III interferon (IFN-λ), the most recently discovered family of IFNs, shares common features with type I IFNs, but also has many distinctive activities. It is not clear that whether IFN-λ has additional antiviral mechanisms. In this study, we investigated the effects of IFN-λ on autophagy, a cellular process closely related to hepatitis C virus (HCV) infection in human hepatoma Huh7 cells. Our results showed that IFN-λ1 treatment inhibit autophagic activity in Huh7 cells, as evidenced by the decreased expression of microtubule-associated protein 1 light chain 3B (LC3B)-II and conversion of LC3B-I to LC3B-II, decreased formation of GFP-LC3 puncta and accumulation of autophagosomes. IFN-λ1 could also inhibit HCV-induced or tunicamycin (a known inducer of autophagy with similar mechanism to HCV infection) -induced LC3B-II expression and autophagosome formation. Through PCR array, real time RT PCR, and western blot, two autophagy-related genes, ATG5 and GABARAP, were identified and verified to be down-regulated by IFN-λ1 treatment, either in HCV-uninfected Huh7 cells or in HCV JFH-1-infected cells. Overexpression of ATG5 and/or GABARAP could partly recover the IFN-λ1-inhibited HCV replication. Mechanism research demonstrated that IFN-λ1 could induce the expression of miR-181a and miR-214 (targeting ATG5 and GABARAP respectively), by which down-regulates ATG5 and GABARAP expression. Taken together, our results indicate that suppression of the autophagy response by IFN-λ1 contributes to IFN-λ1 anti-HCV activity. The results also provide a theoretical basis for improving the effectiveness of IFN treatment of HCV infection through inhibition of the HCV-induced autophagy response.

IFN-lambda preferably inhibits PEDV infection of porcine intestinal epithelial cells compared with IFN-alpha

In contrast to type I interferons that target various types of cells and organs, interferon lambda (IFN-L) primarily acts on mucosal epithelial cells and exhibits robust antiviral activity within the mucosal surface. Porcine epidemic diarrhea virus (PEDV), which causes high morbidity and mortality in piglets, is an enteropathogenic coronavirus with economic importance. Here, we demonstrated that both recombinant porcine IFN-L1 (rpIFN-L1) and rpIFN-L3 have powerful antiviral activity against PEDV infection of both Vero E6 cells and the intestinal porcine epithelial cell line J2 (IPEC-J2). Both forms of rpIFN-L inhibited two genotypes of PEDV (strain CV777 of genotype 1 and strain LNCT2 of genotype 2). rpIFN-L1 primarily controlled viral infection in the early stage and had less antiviral activity in IPEC-J2 than in rpIFN-L3 cells infected with PEDV. In addition, rpIFN-L1 exhibited greater antiviral activity against PEDV infection of IPEC-J2 cells than that of porcine IFN-alpha. Consistent with this finding, rpIFN-L1 triggered higher levels of certain antiviral IFN-stimulated genes (ISGs) (ISG15, OASL, and MxA) in IPEC-J2 cells than porcine IFN-alpha. Although IPEC-J2 cells responded to both IFN-alpha and lambda, transcriptional profiling of ISGs (specifically ISG15, OASL, MxA, and IFITMs) differed when induced by either IFN-alpha or rpIFN-L. Therefore, our data provide the experimental evidence that porcine IFN-L suppresses PEDV infection of IPEC-J2 cells, which may offer a promising therapeutic for combating PED in piglets.

The Role of Type III Interferons in Hepatitis C Virus Infection and Therapy.

The human interferon (IFN) response is a key innate immune mechanism to fight virus infection. IFNs are host-encoded secreted proteins, which induce IFN-stimulated genes (ISGs) with antiviral properties. Among the three classes of IFNs, type III IFNs, also called IFN lambdas (IFNLs), are an essential component of the innate immune response to hepatitis C virus (HCV). In particular, human polymorphisms in IFNL gene loci correlate with hepatitis C disease progression and with treatment response. To date, the underlying mechanisms remain mostly elusive; however it seems clear that viral infection of the liver induces IFNL responses. As IFNL receptors show a more restricted tissue expression than receptors for other classes of IFNs, IFNL treatment has reduced side effects compared to the classical type I IFN treatment. In HCV therapy, however, IFNL will likely not play an important role as highly effective direct acting antivirals (DAA) exist. Here, we will review our current knowledge on IFNL gene expression, protein properties, signaling, ISG induction, and its implications on HCV infection and treatment. Finally, we will discuss the lessons learnt from the HCV and IFNL field for virus infections beyond hepatitis C.

Association of IFNL3 Genotype with Hepatic Steatosis in Chronic Hepatitis C Patients Treated with Peginterferon and Ribavirin Combination Therapy.

Background: Genetic variation near the interferon lambda 3 (IFNL3) is known to be associated with response to pegylated interferon (pegIFN) and ribavirin combination therapy in patients with chronic hepatitis C virus (HCV) infection which is often accompanied by hepatic steatosis.Aims: We examined whether this genetic variation is associated with host lipids and treatment response.Methods: A total of 101 Japanese patients who had underwent liver biopsy before treatment with pegIFN and ribavirin for HCV genotype 1b infection were retrospectively analyzed for association between IFNL3 genotypes (rs8099917) and clinical factors including histopathological features of the liver. The presence of >5% steatosis in the liver specimen was defined as hepatic steatosis.Results: Forty patients (40%) had liver steatosis before therapy. Patients with IFNL3 minor genotype (non-TT) showed lower low-density lipoprotein cholesterol level (p=0.0045), higher γ-glutamyl transpeptidase level (p=0.0003) and higher prevalence of hepatic steatosis (p=0.0002). Advanced fibrosis [odds ratio (OR) 4.63, p=0.03] and IFNL3 major genotype (OR 0.13, p=0.001) were 2 independent factors for determining the presence of hepatic steatosis. Among the factors associated with sustained virological response, IFNL3 genotype was the most significant predictor, as per multivariate analysis.Conclusions: Our results confirmed that IFNL3 genotype is associated with hepatic steatosis as well as IFN response.

Efficacy and safety of telaprevir- and simeprevir-based triple therapies for older patients with chronic hepatitis C.

AIMTo evaluate and compare the efficacy and safety of telaprevir (TVR)-and simeprevir (SMV)-based triple therapies in elderly patients, specifically patients aged 66 years or older.METHODSThe present study enrolled 112 and 76 Japanese patients with chronic hepatitis C virus genotype 1b infection who were treated with a 12-wk TVR-based or SMV-based triple therapy, respectively, followed by a dual therapy that included pegylated interferon α and ribavirin (RBV) for 12 wk. The patients were categorized into two groups according to age as follows: A younger group of patients aged ≤ 65 years old and an older group of patients aged > 65 years old. Among the patients treated with TVR-based triple therapy, 34 patients were included in the older group. The median ages were 56 years (range: 28-65 years) in the younger group and 69 years (range: 66-81 years) in the older group. Among the patients treated with SMV-based triple therapy, 39 patients were included in the older group. The median ages were 59 years (range: 36-65 years) in the younger group and 71 years (range: 66-86 years) in the older group. The clinical, biochemical and virological data were analyzed before and during treatment.RESULTSAmong the patients treated with the TVR-based triple therapy, no significant difference in the sustained virological response (SVR) was found between the younger (80.8%) and older (88.2%) groups. The SVR rates for patients with the interleukin 28B (IL28B) (rs8099917) TG/GG-genotypes (73.9% and 60.0% in the younger and older groups, respectively) were significantly lower than for patients with the IL28B TT-genotype (86.3% and 92.9%, respectively). The cumulative exposure to RBV for the entire 24-wk treatment period (as a percentage of the target dose) was significantly higher in the younger group than in the older group (91.7% vs 66.7%, respectively, P < 0.01), but the cumulative exposure to TVR was not significantly different between the younger and older groups (91.6% vs 81.9%, respectively). A multivariate analysis identified the TT-genotype of IL28B (OR = 8.160; 95%CI: 1.593-41.804, P = 0.012) and the adherence of RBV (> 60%) (OR = 11.052; 95%CI: 1.160-105.273, P = 0.037) as independent factors associated with the SVR. Adverse events resulted in discontinuation of the treatment in 11.3% and 14.7% of the younger and older groups, respectively. Among the patients treated with the SMV-based triple therapy, no significant difference in the SVR rare was found between the younger (81.1%) and older (82.1%) groups. The SVR rates for patients with the IL28B TG/GG-genotypes (77.8% and 64.7% in the younger and older groups, respectively) were significantly lower than for patients with the IL28B TT-genotype (88.2% and 100%, respectively). A multivariate analysis identified the TT-genotype of IL28B as an independent factor associated with the SVR (OR = 9.677; 95%CI: 1.114-84.087, P = 0.040). Adverse events resulted in discontinuation of the treatment in 7.0% and 14.3% of patients in the younger and older groups, respectively.CONCLUSIONBoth TVR- and SMV-based triple therapies can be successfully used to treat patients aged 66 years or older with genotype 1b chronic hepatitis C. Genotyping of the IL28B indicates a potential to achieve SVR in these difficult-to-treat elderly patients.

Interleukin-28B Polymorphism is a Pharmacogenetic Predictor during Sofosbuvir Plus Pegylated Interferon and Ribavirin Therapy for Chronic Hepatitis C Egyptian Patients

Background and Aim: Interleukin-28B (IL-28B) polymorphism is a predictor of sustained virologic response (SVR), spontaneous clearance and personalizing therapy of hepatitis C virus (HCV). This study aimed to determine IL28B rs12979860 polymorphism among chronic hepatitis C (CHC) Egyptian patients as a step in personalized HCV therapy and pharmacogenomics. Methods: CHC Egyptian patients were received sofosbuvir (SOF) plus pegylated interferon (PEG-IFN) and ribavirin (RBV) for 12 weeks. A total of 82 HCV infected Egyptian patients and 27 healthy individuals were included in the present study. CHC Patients were classified as achieving SVR if plasma HCV-RNA was undetectable (group A) and non-responders if plasma HCV-RNA was detectable (group B). IL28B genotypes were analyzed and their associations with SVR were selected. Results: The end of treatment response (ETR) rate was 100%. However, SVR12 was 76.8% (group A) and 23.2% relapsed (group B). Among studied CHC patients, 50% were IL-28B TT, 40.2% CT, and 9.8% CC. while the percentage of their frequencies in the healthy persons were 18.5%, 51.8%, and 29.6%, respectively. These results showed that the frequencies of TT genotypes were more prevalent in HCV patients. The genotype CC (n=8) achieved higher rates of SVR in group A (87.5%) than relapsed patients in group B (12.5%) and it had the least prevalence in group B compared with the frequencies of CT (21.2%) and TT (26.9%) genotypes. These results showed that CC genotype was associated with SVR. Conclusions: It can be concluded that the individuals with IL28B TT genotype are more susceptible to HCV infection in Egyptian patients and relapse. Moreover, IL-28B CC is useful for pretreatment prediction of the outcome of HCV treatment. Hence, IL28B polymorphism could be considered as a pharmacogenetic predictor in personalized HCV therapy and pharmacogenomics during SOF plus PEG-IFN and RBV therapy for chronic hepatitis C Egyptian patients.

Lack of Association Between Interleukin 28B Polymorphism and Vertical Transmission of Hepatitis C.

Single genetic nucleotide polymorphism (rs12979860) near the gene for interleukin 28B (IL28B) is known to be of importance for frequency of spontaneous clearance and treatment outcome in interferon-based therapies in patients with hepatitis C virus (HCV) infection. The aim of the present study was to investigate whether IL28B polymorphism in children and/or their mothers plays a role in vertical transmission of HCV (HCV-VT). Plasma samples from 59 infected women, 76 uninfected children born to infected mothers, and 47 children with known vertically transmitted HCV infection, were analysed for IL28B polymorphism and classified by the IL28B genotype (C/C, C/T, and T/T) and by viral genotype. The proportion of children with genotype C/C was the same in the vertically infected (36%, 17/47) and the exposed uninfected children (38%, 29/76). No difference was seen when stratifying for viral genotype. There was no association between mothers' IL28B genotype and the risk of vertical transmission. Regardless of viral genotype we found no association between IL28B genotype and the risk of HCV-VT. The IL28B genotype CC, which has been shown to be favourable in other settings, was not protective of HCV-VT. Thus, other factors possibly associated with the risk of HCV-VT need to be explored.

Association of Serum Interleukin-28B with Clinical Features, Laboratory Values and Radiographic Score in Rheumatoid Arthritis Patients.

Interleukin-28B (IL-28B) is a member of the interferon lambda family (also known as type III interferons), it has already been studied in many diseases, but it has almost never been studied in rheumatoid arthritis (RA). With this background, we determined the serum levels of IL-28B in RA patients and investigated its clinical significances. IL-28B levels were measured by enzyme-linked immunosorbent assay (ELISA) in 80 RA patients and 80 healthy controls. Radiographs were scored for total Sharp score (TSS). Serum IL-28B levels were significantly lower in the RA than in the control (p = 0.02). Anticyclic citrullinated peptide (anti-CCP) antibodies and rheumatoid factor (RF) were negatively correlated with serum IL-28B levels. There was no association between serum IL-28B levels and TSS at baseline, but there was a significant difference in change of IL-28B during 6 months follow up between progressors and non-progressors. The disease activity of RA patients decreased, but no difference was observed in serum IL-28B levels between before and after disease-modifying anti-rheumatic drugs (DMARDs) therapy. These findings indicated a role of IL-28B in RA and it may contribute to avoiding osteoclasia in RA patients.

THU-181 - Interferon lambda 4 CC host genetic variant is linked with spontaneous hepatitis C virus clearance for genotypes 1,2, and 3

THU-181 - Interferon lambda 4 CC host genetic variant is linked with spontaneous hepatitis C virus clearance for genotypes 1,2, and 3

The impact of the recipient and donor interferon lambda-3 polymorphism on the course of HCV infection following liver transplantation.

Aim of the studyAim of the study was to assess the impact of the recipient and donor interferon lambda-3 (IFNL3) single-nucleotide polymorphisms (SNPs) rs12979860 and rs8099917 on the course of hepatitis C virus (HCV) reinfection following liver transplantation.Material and methodsThe study involved 141 subjects after liver transplantation for HCV-induced cirrhosis, performed between 2000 and 2015. It assessed the impact of both SNPs on the outcomes of interferon/ribavirin (IFN/RBV) treatment following transplantation, HCV viral load, laboratory test results, histological lesions in the liver graft, the risk of acute rejection, and the development of hepatocellular carcinoma (HCC) in patient’s own liver.ResultsIn the case of rs12979860, SVR was achieved in 58.8% of recipients with the CC genotype, and only 12% of recipients with the TT genotype (p = 0.016). Recipients with the rs12979860 CC variant had lower viral load and lower alanine transaminase (ALT) activity than recipients with a non-CC variant. Opposite effects were demonstrated in the analysis of the donors’ genotype. Recipients with the unfavorable variants (rs12979860 TT and rs8099917 GG) had a lower risk of graft rejection and tended to have a higher risk of developing HCC in their own liver.ConclusionsThe IFNL3 rs12979860 polymorphism may be considered a predictor for IFN/RBV effectiveness following liver transplantation. The course of HCV reinfection following liver transplantation may be more aggressive if an unfavorable variant in the recipient coexists with a promising variant in the donor. Particularly careful monitoring for HCC in recipients with unfavorable IFNL3 variants is warranted.

Direct-acting Antivirals Induce Lymphoproliferative Disease Response in HCV-infected Patients: A Prospective Case Series

Background Hepatitis C virus (HCV) infection is associated with the development of B-cell Non-Hodgkin lymphoma (NHL). Several studies report regression of indolent NHL in HCV-infected patients treated with interferon (IFN)-containing therapy without chemotherapy. We are describing, herein, the oncologic response of patients with such cancers treated with only direct antiviral agents (DAAs).Methods Patients with HCV-associated NHL seen at MD Anderson Cancer Center (6/2014 to 6/2017) and treated with DAAs were followed and those with indolent NHL treated with DAAs were further analyzed. DAA regimens were administered according to guidelines for HCV-infected patients without cancer. Efficacy was calculated on the basis of achieving sustained virologic response 12 weeks (SVR12) after end of treatment (EOT). NHL status was evaluated at the time of DAAs initiation and response was prospectively analyzed at 6 months after EOT using WHO criteria.ResultsSix patients received DAAs alone as first-line management of their NHL. Most patients 5/6 (83%) did respond to such treatment avoiding or delaying the use of chemotherapy (Table).Conclusion As described with IFN-containing therapy, the oncologic outcome of HCV-infected patients with indolent NHL could also improve by using only DAAs.Table: Characteristics of six patients with indolent NHL treated with DAAs.Number of patients (%) N = 6Median age (IQR), years60 (55- 65)Gender, male4 (67)NHL subtypeMarginal zone lymphomaa6 (100)HCV genotype13 (50)23 (50)rs12979860 genotypebCC2 (33)CT3 (50)TT1 (17)Cirrhosis0History of HCV treatment0DAA therapySofosbuvir + ribavirin2 (33)Sofosbuvir + simeprevir1 (17)Sofosbuvir + daclatasvir2 (33)Sofosbuvir + ledipasvir1 (17)DAA treatment duration of 12 weeks6 (100)NHL response after SVRComplete response2 (33)Partial response1 (17)Stable disease2 (33)Persistent disease1 (17)Chemotherapy needed after SVR3 (50)Abbreviations: IQR, interquartile range; NHL, Non-Hodgkin lymphoma; HCV, hepatitis C virus; DAA, direct acting agents; SVR, sustained virologic response. aNodal (n = 1), Extranodal (n = 2) splenic (n = 1), and mucosa-associated lymphoid tissue lymphomas (n = 2). bFormerly known as interleukin 28b genotype.Disclosures H. Torres, Gilead Sciences: Consultant and Grant Investigator, Consulting fee, Grant recipient and Research support. Merck & Co: Consultant and Grant Investigator, Consulting fee and Grant recipient. Janssen Pharmaceuticals, Inc.: Consultant, Consulting fee. Dynavax Technologies: Consultant, Consulting fee

Telaprevir combination therapy in patients infected with hepatitis C virus genotype 4

Background: The sustained virological response (SVR) rate for genotype 4 (G4) HCV-infected patients after pegylated interferon (PegIFN) and ribavirin (RBV) treatment is approximately 60%. We aimed to investigate the efficacy and safety of telaprevir (TVR) in combination with PegIFN and RBV in patients infected with G4 HCV who were previously treated with PegIFN/RBV and failed to achieve SVR. Material and Methods: The study included 10 patients: two prior relapsers, two prior partial responders, and six prior null responders to PegIFN/RBV treatment. The patients were given TVR/PegIFN/RBV for 12 weeks, followed by a 12-36 weeks PegIFN/RBV treatment. Rapid virological response (RVR), early virological response (EVR), extended rapid virological response (eRVR), SVR, and side effects of therapy were evaluated. Results: The mean age of the patients was 48.90±12.52 years and seven were female. All of HCV isolates were typed as 4d. Interleukin (IL) 28B genotype was found CT in seven patients and two patients had cirrhosis. Treatment was stopped within four weeks because of the side effects in two patients. Three of the remaining eight patients (37.5%) achived HVR, RVR, and eHVR. SVR was obtained in two of these patients, but one patient relapsed. SVR rates were 25% in all patients. Conclusion: TVR combination therapy had limited antiviral activity in this patient population. Further investigation of TVR combination therapy in patients with HCV G4 infection is warranted.

PECULIARITIES OF THE III TYPE INTERFERON GENES’ POLYMORPHISM IN HCV PATIENTS ON THE CROSS-BORDER REGIONS OF RUSSIA AND MONGOLIA

Aims: determine the structure of IFNL3/IFNL4 interferon genes’ polymorphism in healthy people and in HCV patients and the frequency of spontaneous viral clearance in ethnic groups of Caucasians and Mongolians, living in the Asian part of Russia (Irkutsk Region) and in Mongolia. Materials and methods: population genetic studies were conducted at 669 patients with hepatitis C, including 567 representatives Caucasian and 102 Mongoloid races. The control group consisted of 1520 healthy individuals, blood donors (800 Caucasians and 720 Mongoloids). Results: it was found that in Caucasians patients with chronic hepatitis C were significantly less common CC genotype rs12979860, TT genotype rs8099917 and TT/TT genotype rs368234815, than in the general population. However, in patients with chronic hepatitis C, the representatives of the Mongoloid race, compared with healthy individuals, significant differences were found only in relation to the TT genotype rs8099917 IFNL3 gene. Spontaneous clearance of the virus was significantly more common in the Mongoloid race than in Caucasians. Conclusions: the spontaneous viral clearance after clinical evidence or latent suffering hepatitis C was significantly more common in the Mongoloid race than in Caucasians that genetically determined high rate of prevalence in the popu lation of the Mongols CC genotype rs12979860, TT genotype rs8099917 and TT/TT genotype rs368234815 polymorphisms of interferon type III genes.

POLYMORPHIC VARIANTS OF THE GENE OF INTERFERON LAMBDA 3 AND FEATURES OF IMMUNE RESPONSE IN CHILDREN WITH CHRONIC VIRAL HEPATITIS C

To study the immune manifestations of the interferon-lambda 3 genepolymorphism in chronic viral hepatitis C, 110 Russian children (54 girls and 56 boys) with chronic HCV infection aged from 3 to 17 years were examined. All children were on combined therapy (pegylated interferon + ribavirin). It was found that among the studied polymorphic variants of the IFN-λ 3 gene in children with chronic HCV infection, T allele of the marker rs12979860 is associated with infection and chronization of HCV. The T/T rs12979860 genotype of the IFN-λ3 gene is unfavorable for the course of chronic HCV infection due to low levels of activated T-lymphocytes, intactness of the proinflammatory cytokines TNF-α, IL-6, IL-1α, and interferon-γ inducible protein IP-10. The revealed relation of the polymorphic variants of C/C + C/T locus rs12979860 of INF-λ3 gene with the expression of activated T-lymphocytes discloses the protective nature of these genotypes to the development of chronic HCV infection in children.

Circulating Interferon-λ3, Responsiveness to HBV Vaccination, and HBV/HCV Infections in Haemodialysis Patients

The IFN-λ3 gene (IFNL3) plays a role in HCV clearance. We investigated circulating IFN-λ3 and IFNL3 SNPs in haemodialysis patients who differed in their response to HBV vaccination and their HBV/HCV infection status. In 201 patients, plasma IFN-λ3 was determined using ELISA. IFNL3 SNPs (rs12979860, rs8099917) were genotyped using HRM analysis. Differences in IFN-λ3 levels were shown between responders and nonresponders to HBV vaccination and between HBsAg-positive patients and those who developed anti-HBs after infection and became HBsAg negative. HBV vaccine responders without HCV resolution revealed lower IFN-λ3 than noninfected responders. HBsAg/HCV RNA-positive subjects showed lower IFN-λ3 than patients positive only for HCV RNA or subjects who resolved both infections. Circulating IFN-λ3 correlated positively with anti-HBs and negatively with positive HCV RNA testing in the adjusted regression analyses. HBV vaccine nonresponders, HBsAg-positive patients, and subjects with replicating HCV composed a group with unfavourable outcomes. Responders to HBV vaccination, subjects who became HBsAg negative, and those who cleared HCV were analysed as having favourable outcomes. The latter showed higher IFN-λ3 but did not differ in distribution of IFNL3 SNPs compared with subjects with unfavourable outcomes. Higher IFN-λ3 concentrations are associated with response to HBV vaccination, self-limited HBV infection, and HCV resolution.

Polymorphism of IL28B gene and response to pegylated interferon α2a in chronic hepatitis B

&lt;b&gt;Introduction: &lt;/b&gt;Because of its worldwide prevalence, chronic hepatitis B constitutes a significant global health issue. Chronic hepatitis B virus (HBV) infection affects about 350 million people, with 1 million deaths annually due to its sequelae. The unique way of replication makes HBV difficult to eradicate with the available treatment. Interferon is currently the only option offering a “curative treatment strategy”. Predictors of a sustained response to interferon are desired. The aim of this study was to assess the efficacy of chronic hepatitis B treatment with pegylated interferon 2a in relation to the polymorphisms of the interleukin 28B gene.&lt;br /&gt; &lt;b&gt;Material and methods&lt;/b&gt;: Eighty-six patients were included in the study. They were treated with PegIFN2a in the dose of 180 µg weekly for 48 weeks and were followed up for at least 1 year after the end of therapy (EOT). Treatment efficacy was defined as HBsAg clearance or HBV viral load ≤ 2000 IU/ml at the end of therapy and at the end of 12 consecutive months. Two polymorphisms of IL28B at loci rs12979860 and rs809997 were examined in every patient.&lt;br /&gt; &lt;b&gt;Results&lt;/b&gt;: No associations between any of the IL28B polymorphisms and HBsAg elimination were found. However, a weak but statistically significant association between persistent HBV-DNA decrease and a TT variant (C/T) of IL28B was found (Spearman’s correlation coefficient 0.236, p &lt; 0.001). Patients having this polymorphism also had significantly lower HBV-DNA loads after EOT (Spearman’s correlation coefficient 0.27, p = 0.02). The weak associations and small number of patients do not allow us to draw firm conclusions. &lt;br /&gt; &lt;b&gt;Conclusions&lt;/b&gt;: We discovered no associations between any of the IL28B polymorphisms and HBsAg loss, IL28B polymorphisms do not seem to play an important role as predictors of treatment efficacy in the treatment of chronic B hepatitis with pegylated interferon.

Epigenetic analysis of the IFNλ3 gene identifies a novel marker for response to therapy in HCV-infected subjects.

Chronic hepatitis C virus (HCV) infection is characterized by high interindividual variability in response to pegylated interferon and ribavirin. A genetic polymorphism on chromosome 19 (rs12979860) upstream of interferon-λ3 (IFNλ3) is associated with a twofold change in sustained virologic response rate after 48weeks of treatment with pegylated interferon/ribavirin in HCV genotype 1 (GT1) treatment-naïve patients. We conducted epigenetic analysis on the IFNλ3 promoter to investigate whether DNA methylation is associated with response to HCV therapy. DNA samples from HCV GT1-infected subjects receiving an interferon-free paritaprevir-containing combination regimen (N=540) and from HCV-uninfected, healthy controls (N=124) were analysed for IFNλ3 methylation levels. Methylation was strongly associated with rs12979860 allele status whether adjusting for HCV status (r=65.0%, 95% CI: [60.2%, 69.5%]), or not (r=64.4%), both with P<2.2×10-16 . In HCV GT1-infected subjects, C/C genotypes had significantly lower methylation levels relative to C/T or T/T genotypes (P<1×10-14 ), with each T allele resulting in a nine-unit increase in mean methylation level. Methylation levels did not correlate with response in subjects treated for 12 or 24 weeks. However, non-C/C subjects with higher methylation levels were more likely to relapse when treatment duration was 8weeks. This analysis suggests that methylation status of the IFNλ3 promoter region may be a useful parameter that identifies patients more likely to relapse following HCV therapy; however, continuing therapy for a sufficient duration can overcome this difference. These findings may provide mechanistic insight into the role of IFNλ3 genetic variants in HCV treatment response.

Genetic Variation in Interleukin-28B and Response to Peg-IFNα-2a/RBV Combination Therapy in Patients with Hepatitis C Virus Infection

Background: The hepatitis C virus (HCV) infection is one of the major causes of progressive liver diseases worldwide. Despite the new treatments for HCV infection, antiviral therapy with a combination of pegylated interferon-α 2a plus ribavirin (Peg-IFNα-2a/RBV) is still used in developing countries. Objectives: The aim of the current study was to determine the relationship between rs12979860 polymorphism in the interleukin 28B gene (IL28B) and response to Peg-IFNα-2a/RBV combination therapy in Azerbaijani patients with chronic HCV infection. Methods: A total of 72 Azerbaijani patients with established chronic HCV-1b took part in this cross-sectional study between January 2010 and September 2015. Genomic DNA was extracted from peripheral blood mononuclear cells (PBMCs) of the patients and the rs12979860 single nucleotide polymorphism was diagnosed by polymerase chain reaction-restriction fragment length polymorphism assay (PCR-RFLP). Results: The mean age of the patients was 36.9 ± 12.4 (range of 27 - 57 years) and 42 (58.3%) out of 72 were male. Concerning the IL28B polymorphism in rs12979860, the results indicated the presence of CC, CT, and TT genotypes in 24 (33.3%), 42 (58.3%), and 6 (8.3%) patients, respectively. There was a significant association between IL28B genotypes and response to HCV combination therapy with peg-IFNα-2a/RBV (P = 0.001). Conclusions: The results of this study indicate that the rs12979860 CC genotype of IL28B was associated with a response to Peg-IFNα-2a/RBV combination therapy in Azerbaijani patients with HCV-1b infection. Therefore, host genetics may be useful in predicting the response to hepatitis C treatment.

HLA-B*57 and IFNL4-related polymorphisms are associated with protection against HIV-1 disease progression in controllers.

HIV-1-controllers maintain HIV-1 viremia at low levels (normally <2000 HIV-RNA copies/mL) without antiretroviral treatment. However, some HIV-1-controllers have evidence of immunologic progression with marked CD4+T-cell decline. We investigated host genetic factors associated with protection against CD4+T-cell loss in HIV-1-controllers. We analysed the association of interferon lambda 4 (IFNL4)-related polymorphisms and HLA-B haplotypes within Long Term Non-Progressor HIV-1-controllers ((LTNP-C), defined by maintaining CD4+T-cells counts >500 cells/mm3 for more than 7 years after HIV-1 diagnosis) versus non-LTNP-C, who developed CD4+T-cells counts <500 cells/mm3 Both a Spanish study cohort (n=140) and an international validation cohort (n=914) were examined. Additionally, in a subgroup of individuals HIV-1-specific T-cell responses and soluble cytokines were analysed RESULTS: HLA-B*57 was independently associated with the LTNP-C phenotype (OR=3.056 (1.029-9.069) p=0.044 and OR=1.924 (1.252-2.957) p=0.003) while IFNL4 genotypes represented independent factors for becoming non-LTNP-C (TT/TT, ss469415590, OR=0.401 (0.171-0.942) p=0.036 or A/A, rs12980275, OR=0.637 (0.434-0.934) p=0.021) in the Spanish and validation cohort, respectively, after adjusting for sex, age at HIV-1 diagnosis, IFNL4-related polymorphisms and different HLA-B haplotypes. LTNP-C showed lower plasma IP-10 (p=0.019) and higher IFN-γ (p=0.02) levels than the HIV-1-controllers with diminished CD4+T-cell numbers. Moreover, LTNP-C exhibited higher quantities of IL2+CD57- and IFN-γ+CD57- HIV-1-specific CD8+T-cells (p=0.002 and 0.041, respectively) than non-LTNP-C. We have defined genetic markers able to segregate stable HIV-1-controllers from those who experience CD4+T-cell decline. These findings allow for identification of HIV-1-controllers at risk for immunologic progression, and provide avenues for personalized therapeutic interventions and precision medicine for optimizing clinical care of these individuals.