Background: Despite the outstanding results of direct-acting antiviral therapies (DAAs) of Hepatitis C infection (HCV), non-responders had to be more defined.

Aim: assess the outcome of DAAs in linkage with Interferon lambda 3 (IFNL3) in HCV patients.

Methods: This case-control-study was conducted on 495 chronic-HCV (genotype-4a), previously treated Egyptians by either DAAs (responders 195, 120 relapsers) or interferon/ribavirin (IFN/RBV) (140 responders, 60 relapsers), and 98 healthy controls. IFNL3 distribution, clinical and laboratory data were assessed.

Results: CT was the most predominant genotype in Egyptians (51%). All genotypes were sensitive to DAAs mainly CT genotype (60%), even TT genotype (resistant to IFN/RBV 40%) had 29.2% sensitivity. CT genotype was predominant in sofosbuvir/Daclatasvir responders (67.6%) (OR = 0.66), while non-CT prevailed in relapsers (56.7%). TT genotype may respond to SOF/Ledi better than other regimens (66.7%). In IFN/RBV relapsers; CT genotype was commoner (50%) than others, while CC genotype predominated in responders (54.3%). The c allele was the commonest in responders to IFN/RBV (71.4%), while the T allele was resistant to treatment (65% in relapsers). Addition of RBV to SOF/DCV reported higher resistance with CT genotype (42.2%-50%) and TT genotype (17.8%-27.8%).

Conclusion: This study recommended IFNL3 genotyping to be a prerequisite before stratifying treatment for HCV-4a Egyptians.

Keywords: Direct acting antiviral drugs; HCV; IFNL3; single nucleotide polymorphism; therapy response.

Type III interferon (IFNs) encoded by IFN lambda (IFNL) genes induce antiviral activity. The IFNL clusters include IFNL1/IL29, IFNL2/IL28A, IFNL3/IL28B and IFNL4 genes. The single nucleotide polymorphisms (SNPs, rs12979860 and rs8099917) associated with virological responses against hepatitis C virus (HCV) infections are recently mapped to IFNL4 gene. The IFNL gene polymorphisms also plays role in immune clearance, inflammation and risk of developing hepatocellular carcinoma. There is significant genetic heterogeneity of IFNL4 polymorphisms among ethnic populations that need to be regionally studied for viral infection, treatment response and relapse. The IFNL4 risk allele, genotype and haplotype frequencies across north Indian cohort were determined among chronic hepatitis C (CHC) cases (n = 141) and healthy controls (n = 111) by allele specific real-time PCR. Odds ratio was calculated for HCV exposure and treatment response using dominant and minor allele/genotype as reference. Non-random associations of these two SNP loci were evaluated by linkage disequilibrium plot. The minor allele (T) frequency of rs12979860C/T is 0.241 and 0.229; and minor allele (G) frequency for SNP rs8099917T/G is 0.174 and 0.171 among CHC cases and healthy control respectively. Coefficient of linkage disequilibrium (D') of these two SNPs is very high (D' = 0.98, r² > 0.6) in CHC group than in healthy control (D' = 0.76, r² = 0.39) which indicate that both SNPs are strongly linked in CHC population than healthy control. Favorable association of IFNL4 haplotype (C-T), genotype (CC for rs12979860 and TT for rs8099917) with anti HCV therapy were found significant (p = 0.009, 0.021 and 0.001) for SVR. Favorable genotypes are also found to be predominant across the Indian study population.

Many people living with hepatitis C virus (HCV) infection will continue to rely on interferon-based regimens until effective strategies to minimize the cost of directly acting antivirals (DAAs) and to improve treatment access are implemented. Host single-nucleotide polymorphisms related to IFNL3 and IFNL4 are associated with spontaneous clearance of HCV, and pegylated interferon- and DAA-based treatment outcomes. We describe a simple and rapid genotyping method for IFNL rs12979860, rs8099917, and rs368234815 using high-resolution melting analysis for DNA extracted from whole blood, buffy coat, plasma, serum, and dried blood spots. This assay successfully detected all three polymorphisms on DNA extracted by the automated platform easyMAG from all samples when compared to sequenced amplicons. Analysis of 126 participants with recent HCV infection from the Australian Trial in Acute Hepatitis C study demonstrated the prevalence of favorable single-nucleotide polymorphisms were 62%, 51%, and 45% for rs8099917 TT, rs12979860 CC, and rs368234815 TT/TT, respectively. The genotyping assay described here provides a rapid and affordable IFNL3 and IFNL4 genotyping method for a range of clinical sample types. Until global access to DAAs is achieved, IFNL3 and IFNL4 genotyping could identify those likely to clear naturally and in whom treatment could be delayed, or help prioritize DAA treatment to those less likely to respond to interferon-containing regimens.

The mode of action of ribavirin is not completely understood. Ribavirin monotherapy has a measurable antiviral effect, which shows great variability. It might lead to an earlier steady state of plasma concentration and therefore enhance the effect of following combination treatment. The aim of this study was to evaluate the antiviral effect of ribavirin priming and its influence on sustained virologic response after combination treatment in a group of patients with different hepatitis C virus (HCV) types with or without prior treatment experience. Retrospective analysis of 75 patients (37 treatment naïve, 20 prior relapse, 16 prior nonresponse, genotype 1 present in 60 patients) from five centres who received ribavirin priming as part of an individual strategy in order to improve treatment outcome. All patients received ribavirin monotherapy with a mean dose of 14.5 mg kg-1 body weight for a mean of 28 days. After ribavirin priming, dual combination treatment with pegylated interferon alfa and ribavirin was started. The mean HCV RNA decline after ribavirin priming was 0.6 log10 IU mL-1 (P<.001). The initial viral decline depended on HCV type and previous treatment status being highest among prior relapsers (0.8 log10 IU mL-1 ; P=.002) and HCV type 2/3 (1.2 log10 IU mL-1 ; P=.05) and lowest among those with prior nonresponse (0.3 log10 IU mL-1 , P=.01). IFNL4 (formerly IL28B) genotype for rs12979860 and IFNL3 genotype rs8099917 did not influence the initial viral decline. The study demonstrates a significant variability in the viral dynamics and antiviral efficacy of ribavirin monotherapy, which is mainly influenced by prior treatment status. The fact that the lowest response pattern was observed in prior nonresponder patients to pegylated interferon alfa plus ribavirin combination therapy can be taken as a hint that not only the individual interferon, but also the ribavirin sensitivity contributes significantly to the nonresponsive state.

The new direct-acting antivirals agents (DAAs) rapidly changed the treatment approach in chronic hepatitis C (CHC); however, the interferon (IFN)-free therapies availability is currently different in some countries, due to higher costs of these drugs. Naïve treated patients, who are not eligible for IFN-free therapies, could be selected for standard dual treatment with pegylated (PEG)-IFN and ribavirin (RBV), through IFN lambda 3 gene polymorphisms and fibrosis stage evaluation. Inclusion criteria were: naïve treated CHC patients with GT1 or GT4, without major contraindication to PEG-IFN or RBV, with fibrosis stage F0-F2 and IFNL3 rs8099917/rs12979860 TT/CC genotypes. 65 patients were included in the study. Overall SVR was observed in 50 patients (76.9%); SVR rates among different genotypes were as follows: 15 with GT1a (71.4%), 27 with GT1b (79.4%) and 8 for GT4 (80%). The RBV cutoff at 2weeks of 1800ng/mL, predictor of RVR, was determined (p=0.003; sensibility=60.4%, specificity=88.2%, positive predictive value=88.9%, negative predictive value=100%). In multivariate analysis, factors significantly associated with treatment failure were living alone condition (OR=4.302; 95%IC=1.254-16.257; p=0.034) and RBV plasma level <1800ng/mL at 2weeks (OR=4.970; 95%IC=1.405-17.565; p=0.009). Considering a pharmacogenetic-guided approach, dual therapy with PEG-IFN and RBV can be considered a reliable option for patients ineligible for IFN-free treatments, who are motivated and well informed about all the aspects related to PEG-IFN administration.

NOTE: ARCHIVED ON 15 JULY 2020 BECAUSE SIMEPREVIR IS NO LONGER LICENSED FOR USE IN THE USA. THIS SUMMARY IS FOR HISTORIAL REFERENCE ONLY AND WILL NOT BE UPDATED. Simeprevir is a hepatitis C virus (HCV) protease inhibitor used in combination with other drugs to treat chronic hepatitis genotype 1 or 4 infection (1). Previously, the standard care of patients with HCV infection was peginterferon alfa and ribavirin, but ~40-50% of patients with HCV genotype 1 infection had a suboptimal sustained virological response (SVR) (2). A SVR is defined as undetectable HCV RNA by the end of treatment and at a specific number of weeks after the end of treatment. The addition of simeprevir increased the SVR in patients with HCV genotype 1 infection who were previously untreated. However, there were reports of treatment failure, most commonly in adults, who failed to respond to previous peginterferon and ribavirin treatment (3). The FDA-approved drug label for simeprevir contains information regarding a genetic variant near the IFNL3 gene (a C to T change;rs12979860), which is a strong predictor of response to peginterferon alfa and ribavirin treatment. The label states that in phase 3 clinical trials, SVR rates were lower in patients with CT and TT genotypes, compared to patients with the CC genotype. However, patients of all IFNL3 genotypes had highest SVR rates when being treated with regimens that included simeprevir. In addition, the label strongly recommends patients with HCV genotype 1a infection should be screened for the presence of virus with the S3 Q80K polymorphism. If Q80K is detected, the label strongly recommends that alternative therapy be considered (4).

Background: Dengue patients develop different disease severity ranging from mild (dengue fever [DF]) to severe forms (dengue hemorrhagic fever [DHF] and the fatal dengue shock syndrome [DSS]). Host genetics are considered to be one factor responsible for the severity of dengue outcomes. To identify genes associated with dengue severity that have not been studied yet, we performed genetic association analyses of interferon lambda 3 (IFNL3), CD27, and human leukocyte antigen-DPB1 (HLA-DPB1) genes in Thai dengue patients.

Methods: A case-control association study was performed in 877 children (age ≤ 15 years) with dengue infection (DF, n = 386; DHF, n = 416; DSS, n = 75). A candidate single nucleotide polymorphism of each of IFNL3, CD27, and HLA-DPB1 was selected to be analyzed. Genotyping was performed by TaqMan real-time PCR assay, and the association with dengue severity was examined.

Results: The rs9277534 variant of HLA-DPB1 was weakly associated with DHF. The genotype GG and G allele conferred protection against DHF (p = 0.04, odds ratio 0.74 for GG genotype, p = 0.03, odds ratio 0.79 for G allele). The association became borderline significant after adjusting for confounders (p = 0.05, odds ratio 0.82). No association was detected for IFNL3 or CD27.

Conclusions: The present study demonstrated the weak association of the rs9277534 variant of HLA-DPB1 with protection against DHF. This variant is in the 3' untranslated region and affects HLA-DPB1 surface protein expression. Our finding suggests that HLA-DPB1 may be involved in DHF pathogenesis.

Keywords: CD27; Dengue; Disease severity; Genetic association; HLA-DPB1; IFNL3.

OBJECTIVE

A recent meta-analysis revealed that the genotype PNPLA3 rs738409 GG is associated with a higher risk of hepatic steatosis (HS) in Caucasian patients with chronic hepatitis C (CHC). However, controversial results were found regarding Asian populations. Furthermore, previous studies have shown a negative association between interferon lambda 3 (IFNL3) rs12979860 CC and HS in Caucasian CHC patients, but there have been no reports indicating any such association in Asian populations. In this study, then, we investigated the association of PNPLA3 and IFNL3 polymorphisms with HS in Asian CHC patients.

METHODS

We enrolled consecutive CHC patients who underwent liver biopsy prior to antiviral therapy. We excluded those patients with decompensated liver disease, any co-existing chronic liver disease, or HIV or HBV co-infection.

RESULTS

1080 CHC patients were enrolled, and HS was found in 453 (41.9%) patients. The frequency distribution of the G allele was significantly associated with HS (P<0.001), and this conferred a higher risk to G allele homozygotes (OR: 2.06, 95% CI: 1.46-2.88, P <0.001) than to G allele carriers (OR: 1.98, 95% CI: 1.52-2.58, P<0.001). There was a borderline significant difference in the prevalence of HS in rs12979860 CC versus non-CC (40.8% versus 49.3%, P = 0.059). After adjustment for age, sex, body mass index, diabetes, and excessive alcohol intake, the rs738409 G allele homozygote carriers still carried a higher risk for HS (OR: 1.93, 95% CI: 1.35-2.77, P = 0.003).

CONCLUSIONS

The PNPLA3 rs738409 GG genotype is positively associated with HS, while the IFNL3 rs 12979860 CC genotype may be negatively associated with HS, in Asian CHC patients.

HCV infection causes acute and chronic liver diseases including, cirrhosis and hepatocellular carcinoma. Following HCV infection, spontaneous clearance occurs in approximately 20 % of the population dependant upon HCV genotype. In this study, functional and non-functional variant analysis was executed for the classical and the latest HCV clearance candidate genes namely, KIR2DL3 and IFNL3. Initially, the functional effects of non-synonymous SNPs were assigned on exposing to homology based tools, SIFT, PolyPhen-2 and PROVEAN. Further, UTR and splice sites variants were scanned for the gene expression and regulation changes. Subsequently, the haplotype and CNV were also identified. The mutation H77Y of KIR2DL3 and R157Q, H156Y, S63L, R157W, F179V, H128R, T101M, R180C, and F176I of IFNL3 results in conservation, RMSD, total energy, stability, and secondary structures revealed a negative impact on the structural fitness. UTRscan and the splice site result indicate functional change, which may affect gene regulation and expression. The graphical display of selected population shows alleles like rs270779, rs2296370, rs10423751, rs12982559, rs9797797, and rs35987710 of KIR2DL3 and rs12972991, rs12980275, rs4803217, rs8109886, and rs8099917 of IFNL3 are in high LD with a measure of [Formula: see text] broadcasting its protective effect in HCV clearance. Similarly, CNV report suggests major DNA fragment loss that could have a profound impact on the gene expression affecting the overall phenotype. This roundup report specifies the effect of NK cell receptor, KIR2DL3 and IFNL3 variants that can have a better prospect in GWAS and immunogenetic studies leading to better understanding of HCV clearance and progression.

HCV has been associated with a pro-inflammatory state, which predisposes to hepatocellular carcinoma (HCC). However, the different molecular mechanisms underlying the effect of HCV infection on HCC progression remain unclear. Although HCV infection illustrates the potential role of host genetics in the outcome of infectious diseases, there is no clear overview of some single nucleotide polymorphisms (SNPs) influencing spontaneous or treatment-induced HCV eradication. We studied the possible role of HCV infection in the processes of HCC initiation and performed a systematic analysis using data mining approaches to identify host polymorphisms associated with treatment response and HCC development using topological analysis of protein-proteins interactions (PPI) networks. On the basis of our analysis performed, we identified key hub proteins related to HCV-treatment response infection and to HCC development. Host genetic polymorphisms, such as inosine triphosphatase (ITPA), interferon, lambda 3 (IFNL3), Q5 interferon, lambda 4 (IFNL4), toll-like receptors (TLRs) and interferon-stimulated gene 15 (ISG-15), were identified as key genes for treatment prediction and HCC evolution. By comparing unique genes for HCV-treatment response and genes particular to HCV-HCC development, we found a common PPI network that may participate in more extensive signalling processes during anti-HCV treatment, which can play important roles in modulating the immune response to the occurrence of HCC. Data mining is an effective tool for identifying potential regulatory pathways involved in treatment response and HCC development. Our study may contribute to a better understanding of HCV immunopathogenesis and highlights the complex role of host genetics in HCV clearance.

Globally, over 4% of the world population is affected by hepatitis C virus (HCV) infection. The current standard of care for hepatitis C infection is combination therapy with pegylated interferon and ribavirin for 48 weeks, which yield a sustained virological response in only a little over half of the patients with genotype 1 HCV. We investigated the clinical importance of pharmacogenetics in treatment efficacy and prediction of hematotoxicity. A total of 148 patients infected with HCV were enrolled. All patients were treated for a period of 48 weeks or less with pegylated interferon and ribavirin. Four genotypes were investigated: inosine triphosphatase (ITPA) rs1127354, C20orf194 rs6051702, interferon lambda (IFNL)3 rs8099917, IFNL3÷4 rs12979860 in the population from southwestern Romania. Genetic variants for rs129798660 and rs6051702 proved once more to represent an indisputable clinical tool for predicting sustained virological response (SVR) (69.23%, chi-square p=0.007846, p<0.05 and 63.29%, chi-square p=0.007846, p<0.05, respectively). ITPA genetic variants protect against ribavirin-induced hemolytic anemia and C20orf194 also proved to be protective against thrombocytopenia. These clinical findings strengthen the belief that pharmacogenetics should play a constant role in treatment decisions for patients infected with hepatitis C virus.

Single nucleotide polymorphisms (SNPs) of the interleukin 28B (IL28B) gene has proven to be associated with the clinical outcome of patients with chronic hepatitis virus B or C (HBV or HCV) infections. However, whether IL28B SNPs have an influence on the risk of hepatocellular carcinoma (HCC) among patients with HBV or HCV infection remains controversial. Therefore, this study aims to determine the association between IL28B polymorphisms and the risk of HCC in individuals with HBV or HCV infection.PubMed, EMBASE, and Chinese National Knowledge Infrastructure (CNKI) databases were used to identify studies meeting the selection requirements using the terms "interleukin 28B", "IFN-lambda-3", "IFNL3", "single nucleotide polymorphisms", "SNPs", "hepatocellular carcinoma", "HCC", "liver cancer".A total of 24 eligible original studies (1 cohort study and 23 case-control studies) involved 20238 individuals (HCC group = 8725 vs control group = 11,513) were included. Both IL28B rs12979860 CC and rs8099917 TT genotypes were significantly associated with a decreased risk of HCC among patients with HBV or HCV infection (OR = 0.71, 95% CI = 0.57-0.88; OR = 0.82, 95% CI = 0.72-0.94, respectively). Egger test and Begg test revealed no' publication bias (P > .05). Sensitivity analyses suggested the robustness of the results in this meta-analysis.Both IL28B rs12979860 CC and rs8099917 TT genotypes are protective factors for the development of HCC among patients with HBV or HCV infection. Future prospective studies examining the impact of IL28B polymorphisms on the risk of HCC and investigating the underlying mechanism for the protective role of IL28B polymorphisms in HCC development are warranted.

Occult HCV infection (OCI) is described as the presence of HCV RNA in the liver and peripheral blood mononuclear cells (PBMCs), with no HCV RNA in the serum. Single-nucleotide polymorphisms (SNPs) near interferon lambda 3/4 (IFNL3/4) gene are associated with spontaneous clearance and treatment response in patients with hepatitis C virus (HCV) infection. In this study, we evaluated the frequency of OCI in hemophilia patients and determined the association of three IFNL3 SNPs (rs12979860, rs12980275, and rs8099917) and IFNL4 ss469415590 with OCI positivity. A total of 450 hemophilia patients with HCV negative markers were included in this study. Positive- and negative-stranded HCV-RNA was determined in peripheral blood mononuclear cells (PBMCs) samples by reverse-transcription polymerase chain reaction (RT-PCR) method. The frequency of OCI was estimated at 10.2%. Among 46 OCI patients, 56.5%, 23.9%, and 19.6% were infected with HCV-1b, HCV-1a, and HCV-3a, respectively. Compared to patients without OCI, unfavorable IFNL3 rs12979860 TT, IFNL3 rs8099917 GG, IFNL3 rs12980275 GG, and IFNL4 ss469415590 ∆G/∆G genotypes were more frequently reported in OCI patients. The multivariate logistic regression analysis showed that alanine aminotransferase (ALT), cholesterol, triglyceride, IFNL3 rs12979860 (TT), IFNL3 rs8099917 (GG), IFNL3 rs12980275 (GG), and IFNL4 ss469415590 (∆G/∆G) were associated with OCI positivity. In conclusion, we studied the incidence of OCI in Iranian patients with hemophilia for the first time. Our results demonstrated that unfavorable genotypes of IFNL3 SNPs and IFNL4 ss469415590 have a strong relationship with OCI positivity. It seems that the host immune response plays a vital role in OCI positivity.

Background/aim: How hepatitis C virus (HCV) infection and mixed cryoglobulinemia interactively affect complement levels remains elusive, and we aimed to elucidate it.

Methods: A prospective cohort study of 678 consecutive chronic HCV-infected (CHC) patients was conducted. Of 678, 438 had completed a course of anti-HCV therapy and 362 had achieved a sustained virological response (SVR). The baseline and 24-week post-therapy variables including complement levels and mixed cryoglobulinemia status were surveyed.

Results: At baseline, lower complement component 3 (C3) and component 4 (C4) levels were noted in patients with than those without mixed cryoglobulinemia. The differences between pre-therapy (in 678 CHC patients) and 24-week post-therapy (in 362 SVR patients) factors associated with C3 levels were interferon λ3 (IFNL3) genotype, triglycerides, cirrhosis, and estimated glomerular filtration rate; the different associations with C4 levels were cirrhosis, sex and high sensitivity C-reactive protein. Compared with baseline, SVR patients without pre- and post-therapy mixed cryoglobulinemia had increased C3 levels, and SVR patients with pre-therapy mixed cryoglobulinemia had increased C4 levels. Lower C3 levels were noted in SVR patients with than those without post-therapy mixed cryoglobulinemia.

Conclusions: HCV might affect C3 levels through IFNL3 genotype, triglycerides, cirrhosis, and renal function; and affect C4 with a link to sex, inflammation, and cirrhosis. That C3 levels decreased in CHC patients without mixed cryoglobulinemia or in SVR patients with post-therapy mixed cryoglobulinemia, and C4 levels decreased in CHC patients with mixed cryoglobulinemia, suggested that mixed cryoglobulinemia and HCV infection antagonistically and synergistically decrease C3 and C4 levels, respectively.

Keywords: C3; C4; HCV; Mixed cryoglobulinemia.

Donor genotype for polymorphisms near IFNL3 influences hepatitis C virus (HCV) therapy responsiveness. This relationship has not been studied in a sample of HCV-infected living donor liver transplantation (LDLT) recipients in the United States (US). We investigated the association of donor and recipient genotypes near the IFNL3 gene at a large US liver transplant center. Recipient homozygosity for rs12979860 C was associated with increased sustained virologic response (SVR) in antiviral treatment-experienced patients pretransplant (P = 0.055). Consistently, donor homozygosity for rs12979860 C was also associated with increased SVR in patients who received post-transplant antiviral therapy (P = 0.048). Transplantation of an rs12979860 CC graft confers a favorable post-transplant antiviral response among HCV-positive recipients in an LDLT setting. Recipients with the favorable rs12979860 genotype receiving antiviral therapy before transplant are also more likely to achieve SVR. The effect of genotype status in the era of direct-acting antiviral agents will require future study.

OBJECTIVE

Aim 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.

METHODS

The 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.

RESULTS

In 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.

CONCLUSIONS

The 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.

BACKGROUND

Host factors including single-nucleotide polymorphisms (SNPs) in or near interferon lambda (IFNL) gene are the important factors in predicting response to treatment of chronic hepatitis C (CHC).

OBJECTIVE

The aim of this study was to determine the frequency and association of IFNL4 rs368234815 with IFNL3 SNPs rs12979860, rs8099917 and other factors including cholesterol, alanine aminotransferase, fibrosis, viral load, age and body mass index in genotype 1a treated CHC patients, to achieve rapid virologic response (RVR) and sustained virologic response (SVR).

METHODS

A total of 71 hepatitis C virus genotype 1a patients were enrolled from 2013 to 2015. The genotypes of rs12979860, rs8099917 were identified by polymerase chain reaction (PCR) and restriction fragment length polymorphism while the genotype rs368234815 detected by amplification-refractory mutation system-PCR.

RESULTS

The rate of RVR and SVR were 43/71 (60.6%) and 46/71 (64.8%), respectively. To achieve an SVR in patients with rs368234815, TT/TT genotype 20/24 (83.3%) was found to be higher than other SNPs. The correlation coefficient of rs368234815 was strongly associated with rs12979860 (r = 0.788, P < 0.001). Multivariate logistic regression showed that the cholesterol (odds ratio [OR]: 0.205, confidence interval [CI] 95%: 0.047-0.891, P = 0.035), age (OR: 0.160, CI 95%: 0.035-0.730, P = 0.018), baseline viral load (OR: 0.167, CI 95%: 0.032-879, P < 0.035) and IFNL4 (OR: 5.453, CI 95%: 1.015-29.293, P < 0.048) could be independent predictors of SVR.

CONCLUSIONS

The results of these findings emphasise that factors such as age, cholesterol, baseline viral load and IFNL4 rs368234815 are better predictive factors and should be evaluated before CHC treatment.

OBJECTIVE

To assess the role of single nucleotide polymorphisms (SNPs) near the interferon lambda-3 (IFNλ3) (formal IL-28B) gene rs12979860 in predicting sustained virologic response (SVR) in hepatitis-C virus genotype-3 (HCV-3).

METHODS

Descriptive, analytical study.

METHODS

Department of Medicine, The Aga Khan University Hospital, Karachi, from July 2012 to June 2014.

METHODS

Patients with HCV-3 were classified as sustained virologic response (SVR), relapsers and non-responders. SNPrs12979860 was determined by PCR-RFLPprotocol. Differences between categorical variables were assessed by chi-square or Fisher's exact test, while those between continuous variables were evaluated using the Mann-Whitney U-test. Binary logistic regression analysis by forward conditional method was performed by using significant variables with p-values less than 0.05 as the criteria for model inclusion.

RESULTS

Out of 115 patients, rs12979860 genotype-CC, CT, TTwas found in 37 (32.2%), 70 (60.9%), and 8 (7%) patients. 72 patients were male with median age of 45 years. Cirrhosis was present in 32 patients. Patients with response failures (no response and relapse, n=36 and 29, respectively) had higher baseline gamma glutamyl transferase (GGT) level (p < 0.001), higher alanine aminotransferase (p=0.027) and cirrhosis (p=0.001) than patients with SVR. Genotype-CC was present in 16/65 in response failures compared to 21/50 who achieved SVR (p=0.048). Rapid virologic response (RVR) (p < 0.001), low GGT(p=0.001) and absence of cirrhosis (p=0.039) were the independent predictive factors for SVR. In patients who could not achieve RVR and in patients with cirrhosis, SVR was seen more in with genotype-CC (p=0.007 and 0.038).

CONCLUSIONS

In patients infected with HCV-3, IFNλ3 rs12979860, SNPhas less impact on SVR.

Pattern recognition receptors recognize RNA viruses and trigger type I and III interferon (IFN) production and apoptosis to limit viral replication and spread. Some innate immune cells produce oxidants in response to viral infection to protect against invasion. Recent studies have demonstrated the virucidal activity of hypothiocyanous acid (HOSCN), an oxidant generated by the peroxidase-catalyzed reaction of thiocyanate with hydrogen peroxide. However, the effects of HOSCN on host antiviral responses are still unknown. In this study, we aimed to clarify the role of HOSCN in host antiviral responses against RNA viruses in airway epithelial cells using polyinosinic-polycytidylic acid (polyI:C), a mimic of viral RNA. Our results show that HOSCN repressed antiviral responses in NCI-H292 human airway epithelial cells. HOSCN decreased polyI:C-induced apoptosis and the expression levels of IFNB1, IFNL1, IFNL2 and IFNL3 mRNAs. In addition, the induction of other interferon regulatory factor 3 (IRF3)-dependent genes was also suppressed by HOSCN. Further analyses focused on IRF3 revealed that HOSCN inhibited the phosphorylation of IRF3 at Ser386 and Ser396 as well as its dimerization and nuclear translocation by inhibiting the phosphorylation of TANK-binding kinase 1 (TBK1). Furthermore, HOSCN led to the phosphorylation of IRF3 at residues other than Ser386 and Ser396, implying that HOSCN may cause a conformational change in IRF3 to impair its function. Collectively, these results suggest that HOSCN plays a novel signaling role in the antiviral response, acting as a negative regulator of apoptotic and TBK1-IRF3 signaling pathways and limiting IRF3-dependent gene expression.

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.

Sustained virologic response (SVR) in chronic hepatitis C (CHC) treatment denotes that the host genetics controls the immune response and unequivocally contribute to viral clearance or disease severity. In this context, single nucleotide polymorphisms (SNPs) in the locus of interferon lambda 3 and 4 genes (IFNL3/4) have been important genetic markers of responsiveness to CHC as prognostic markers for the pegylated-Interferon-alpha/ribavirin (Peg-IFN-α/RBV). Here, we analyzed 12 SNPs at the IFNL3/4 region in 740 treatment-naïve patients with CHC infected with hepatitis C virus (HCV) genotypes 1, 2, or 3 treated with Peg-IFN-α/RBV. Individually, rs12979860-CC, rs8109886-CC, or rs8099917-TT were predictive markers of SVR, while rs12979860-CC demonstrated the stronger effect. Besides, the genotypic combination of these three predictors' genotypes, CC/CC/TT, increased the rate of SVR. Serum levels of cytokines and gene expression analysis on the genes IFNL3, IFNL4, IFNA1, and some of the IFN-stimulated genes (ISGs) were measured in a subgroup of 24 treated patients and 24 healthy volunteers. An antagonist effect was highlighted between the expression of IFNL3/4 and IFNA1 mRNA among patients. Besides, a prominent production of the pro-inflammatory chemokines CCL4 and CXCL10 was observed at a 12-week treatment follow-up. Lower serum levels of these chemokines were detected in patients with an rs12979860-CC genotype associated with the better treatment outcome. Also, lower expression levels of the IFI6, IFI16, IRF9 genes were observed among rs12979860-CC individuals. In conclusion, a combination of the genotypes at the IFNL3/4 locus can act as a better marker for the prognosis for virological responses in an admixed Brazilian population presenting the modulating effect over innate immunity and inflammation that are controlling the outcome of the viral infection, but also other infectious diseases. This study is registered on the ClinicalTrials.gov platform (accession number NCT01889849 and NCT01623336).

Keywords: Interferon lambda 3 e 4; hepatitis C; immune response; pegylated interferon; sustained virologic response.