|Year : 2017 | Volume
| Issue : 2 | Page : 262-268
The evaluation of interferon lambda 4 rs368234815 as a predictor factor in treated patients with chronic hepatitis C genotype 1a infection
Shahram Jalilian1, Seyed Mahmoud Latifi2, Manoochehr Makvandi1, Ali Teimoori1, Azarakhsh Azaran1, Mehdi Parsanahad1, Gholamabas Kayedani1
1 Infectious and Tropical Diseases Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
2 Diabetes Research Centre, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
|Date of Web Publication||5-Jul-2017|
Infectious and Tropical Diseases Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz
Source of Support: None, Conflict of Interest: None
Context: 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). Aims: 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). Subjects and 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.
Keywords: Chronic hepatitis C, interferon lambda 4, sustained virologic response
|How to cite this article:|
Jalilian S, Latifi SM, Makvandi M, Teimoori A, Azaran A, Parsanahad M, Kayedani G. The evaluation of interferon lambda 4 rs368234815 as a predictor factor in treated patients with chronic hepatitis C genotype 1a infection. Indian J Med Microbiol 2017;35:262-8
|How to cite this URL:|
Jalilian S, Latifi SM, Makvandi M, Teimoori A, Azaran A, Parsanahad M, Kayedani G. The evaluation of interferon lambda 4 rs368234815 as a predictor factor in treated patients with chronic hepatitis C genotype 1a infection. Indian J Med Microbiol [serial online] 2017 [cited 2017 Sep 26];35:262-8. Available from: http://www.ijmm.org/text.asp?2017/35/2/262/209583
| ~ Introduction|| |
Hepatitis C virus (HCV) belongs to the Flaviviridae family, a single-stranded RNA virus with molecular weight of about 9.6 kb and positive sense. It has been reported approximately 170 million of the world's population are chronically infected with HCV. According to the Iranian Ministry of Health and Medical Education, about 0.5% of the Iranian population are infected with HCV. In other words, amongst the 78 million Iranians, 390 thousand are HCV carriers.
At present, the Peg IFNα (Peg-IFNa; Pegasys ®, Roche, Switzerland) and Ribavirin (RBV; Copegus ®, RBV: Copegus, Roche, USA) are the standard dual HCV therapy. Based on the general protocol, the duration of treatment for HCV patients with genotype 1 and 4 is 48 weeks. Approximately 50% of patients with genotype 1 respond to the treatment.
The known side effects of IFN include myalgia, flu, hair loss, diarrhoea, renal disorders, thyroid dysfunction (mostly hypothyroidism), decreased white blood cells and mood changes, which are important challenges during treatment. If the patient has a history of psychiatric diseases such as unchecked epilepsy, psychosis or depression, uncontrolled diabetes or hyperglycaemia, the interferon therapy is not recommended. The most important effect of RBV is anaemia; thus, the prescription should be followed with great caution for individuals with thalassemia or unused.
Today a prophylactic vaccine is inaccessible, and current therapeutic regimen is suboptimal. Therefore, several predictors such as single nucleotide polymorphisms (SNPs) are necessary to predict drug treatment. Previous studies have revealed that prediction of response to HCV treatment is based on SNPs interferon lambda 3 (IFNL3 or interleukin 28b [IL28b]). More investigations have shown that mutations in SNPs rs12979860 and rs8099917 in the genomic region of IFNL3 play a significant role in predicting response or non-response to HCV treatment.,
Recently, IFNL4 rs368234815 was identified at chromosome 19:39248514-39248515 gene, harbours the dinucleotide variant (TT/ΔG) as high linkage disequilibrium (LD) with rs12979860 which found to be highly related to HCV clearing. The IFNL4 protein which can be generated only by carriers of rs368234815 (ΔG) allele is thought to reduce IFN responsiveness by inducing a weak expression of interferon-stimulated genes. Thus, based on the molecular approaches, the drug side effect is not only avoided but also the cost of treatment is prevented.
With regards to similar studies, moreover, SNPs, other factors including viral load, alanine aminotransferase (ALT), age, sex and body mass index (BMI) have been studied in the treatment response of chronic hepatitis C (CHC).,
Responses to antiviral therapy were defined as: (i) Rapid virologic response (RVR), decrease of more than 2log viral load serum HCV RNA titre or HCV RNA undetectable at 4 weeks after the initiation of antiviral therapy, and (ii) Sustained virologic response (SVR), undetectable serum HCV RNA titre at 24 weeks after the termination of antiviral therapy.
Thus, this study was to determine the frequency and association of IFNL4 rs368234815 with IFNL3 SNPs rs12979860, rs8099917 and other factors including cholesterol, ALT, fibrosis, viral load, age and BMI in treated CHC patients with genotype 1a, to achieve RVR and SVR.
| ~ Subjects And Methods|| |
The retrospective medical records of patients diagnosed with CHC genotype 1a were collected who referred to the city's health centres in Ahvaz, Iran, during May 2013–August 2015. All the patients underwent Peg-IFNa 2a and RBV (P/R) combination treatment for 48 weeks. Patients with co-infection of hepatitis B virus (HBV) or human immune-deficiency virus, autoimmune hepatitis, other related liver diseases and alcohol abusers were excluded from the study. Furthermore, pretermitted patients were withdrawn (unable to complete the course of treatment) due to adverse events or were lost during follow-up or on treatment. Finally, a total of 93 consecutive patients were considered, amongst which, 71 patients received successful treatment course. Their following data were analysed and followed up for at least 6 months after the completion of treatment.
The patient's profiles
- At baseline, HCV genotyping was identified by reverse transcriptase (RT) polymerase chain reaction (PCR) assay (AmpliSens HCV-genotype-EPh kit-Russia and Thermocycler peqLab Germany)
- HCV-RNA levels were determined by real-time-PCR (RT-PCR) using a commercial kit (Thermo Fisher-USA, ABI real-time PCR machine StepOnePlus) according to the manufacturer's instructions
- Serum glutamic pyruvic transaminase and cholesterol tests were done with Chemistry Analyser (Bionik kit, Germany-Roche Hitachi 704, Germany)
- Before treatment, liver biopsies of patients were performed by pathologist and fibrosis was graded according to the Metavir classification.
DNA extraction and single nucleotide polymorphism genotyping
The genomic DNA was extracted from peripheral blood samples using DNA Isolation Kit for Cells and Tissues (Roche, Germany). The rs12979860 and rs8099917 SNPs genotyping were determined by PCR method with Phusion ® high-fidelity DNA PCR kit (NEB, USA) and restriction fragment length polymorphism (RFLP). Briefly with limited modification in the PCR conditions, described by Hendy et al., PCR reaction mixture was subjected to thermocycler with following conditions: Initial denaturation at 95°C for 5 min, and 35 cycles of denaturation at 95°C for 1 min, annealing at 64°C for 30 s, extension at 72°C for 30 s and final extension at 72°C for 10 min. The PCR products for rs12979860 and rs8099917 were 403 bp and 401 bp, respectively. The RFLP assay was carried out in the same condition with 5U of BstU I restriction endonuclease (New England Biolabs, USA) and 1U of Mae III restriction endonuclease (Roche Molecular Systems, Branchburg, NJ, USA).
Genotyping for the interferon lambda 4 rs368348152 single-nucleotide polymorphism
For conforming rs368348152, the amplification-refractory mutation system (ARMS) PCR was used according to the method developed by Kucherenko et al. The PCR conditions for amplification were modified with the following programme: Initial denaturation at 95°C for 5 min, 35 cycles of 30 s at 95 °C, 30 s at 64°C and 30s at 72°C, final extension at 72°C for 5 min.
This project was approved by the Ethic Committee, Health Research Institute, Infectious and Tropical Diseases Research Centre, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran with ethical code: Ajums. REC.1393.236. All experiments were performed in compliance with relevant laws and institutional guidelines and in accordance with the ethical standards of the Declaration of Helsinki. Blood samples were collected only from those patients who were interested to donate their Blood voluntarily. The information of each patient under the study was preserved confidentially.
Statistical Packages for the Social Sciences (SPSS) version 19 (IBM ® SPSS ® Statistics, IBM Corp, New York, USA) were used for data analysis. Quantitative variables were summarised using frequency percentage and mean ± standard deviation. Chi-square tests were done for categorical variables. Correlation coefficients (r) were calculated using the Spearman's correlation analysis. The value of P< 0.05 level and finally regression binary logistics was conducted for independent predictors of SVR and RVR.
| ~ Results|| |
Initially, 93 patients with CHC genotype 1a were registered. Unfortunately, 22 of them were unable to receive the complete treatment course. Thus, 71 patients were followed up for further investigations. None of the patients had a previous history of HCV therapy. Of these individuals, 43/71 (60.6%) and 46/71 (64.8%), exhibited RVR and SVR, respectively, whereas the remaining individual shown relapses 11/71 (15.5%), nonresponders 9/71 (12.7%) and partial responders 5/71 (7.0%). The characteristics of patients at the baseline are summarised in [Table 1].
|Table 1: Baseline characteristics and treatment outcome with study population|
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Failure in therapy with interferon lambda 4 gene
The distribution of IFNL4 genotypes was evaluated amongst non-SVR patients. Non-SVR patients were classified into three subgroups: Non-responders, relapsers and partial-responders. The unfavourable genotypes (ΔG/ΔG and ΔG/TT) were found in all the relapsers, while the lower percentages of the mentioned unfavourable genotypes were observed in non-responders and partial responder patients (66.7/78 and 80%, respectively).
The patients mean age was 41.2 ± 8.3 years, of which 73.2% were male with mean BMI of 24.1 ± 3.3. Other criteria included, baseline viral load >400.000 IU/ML, 31/71 (43.7%); cholesterol below 175 mg/dl, 29/71 (40.8%); and ALT more than 1.5-fold, 33/71 (46.5%) were recorded. Liver biopsies were done for 59 patients, of which 30/59 (42%) showed advanced fibrosis (F3–F4).
The presence of C, T and TT alleles in rs12979860, rs8099917 and rs368234815 SNPs were observed in 58/71 (81.7%), 63/71 (88.7) and 57/71 (80.3%) cases, respectively. While in patients with the mentioned SNPs, alleles T, G and ΔG with frequency of 47/71 (66.2%), 37/71 (52.1%) and 47/71 (66.2%) were detected. Over 90% of those who achieved an SVR have at least one of the alleles belonging to the first category, whereas <7% of patients with SVR were homozygote for the allele's second category. The outcomes of results show the important role of alleles in achieving an SVR in CHC patients [Figure 1].
|Figure 1: Allele's frequency in the population of positive sustained virologic response.|
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The assessment of SVR in the subjects revealed that 20/24 (83.3%) of individuals had genotype TT/TT with the high association to reach an SVR. However, only 2/14 (14.2%) carriers of ΔG/ΔG alleles had an SVR.
As shown in [Table 2], multivariate logistic regression analysis showed that additional genotype TT/TT of IFNL4, cholesterol, HCV RNA and age, could be predicting factors for both SVR and RVR in the population.
Correlation coefficients between interleukin 28B and interferon lambda 4
Data analysis showed that rs368234815 has a strong correlation coefficient with rs12979860 (r = 0.788, P< 0.001). Hence that, 22/24 (91.7%) of patients with TT/TT genotype had CC allele. While the correlation coefficient between rs8099917 and rs368234815 was slightly significant (r = 0.299, P = 0.011). For example, only 16/71 (22.5%) of patients had both desirable alleles [Table 3]. Moreover, just 14/71 (19.7%) were homozygote for all favourable alleles.
| ~ Discussion|| |
Several studies have been conducted to achieve an SVR; the roles of SNPs were found prominent in about 80%–90% of treated patients with favourable IL28B genotype and 59%–73% of patients with other alleles of IL28B (18). In the current study, RVR and SVR rates were detected in 43/71 (60.6%) and 46/71 (64.8%) patients, respectively. The highest rate of SVR was observed in 20/24 (83.3%) patients with rs368234815 TT/TT genotype which shows a great predictive value of a positive response for HCV treatment.
The results of SVR in the Iranian patient's vary from 48% to 78.3%. Due to the wide difference in the outcomes of treatment, thus it will be controversial issues on the effect of P/R in Iranian patients. On the other hand, limited data are available regarding factors involved in RVR and SVR, amongst the CHC patients living in Ahvaz city.
The objective of this treatment is to reach an SVR (non-detectable virus by RT-PCR in the blood of patients 6 months after the end of treatment). Meanwhile, it has been shown that to achieve an SVR, racial diversity should be considered.
In the present study, the baseline predictors of RVR and SVR in patients infected with HCV genotype 1a were investigated. Based on the assessments on the multivariate logistic regression analysis between biological variables and the outcome of the treatment, it is shown that the CHC patients with rs368234815 genotype TT/TT, age below 40 years, high level of cholesterol and baseline viral load below 400000 IU/ML were favorably associated with RVR and SVR and could be independent predictors for the outcomes of treatment and shows a good predictive value of a positive response for HCV treatment.
In the present study, the majority of patients with high cholesterol showed better improvement following viral therapy than patients with low cholesterol (P = 0.001). Harrison et al. reported that the presence of high levels of low-density lipoprotein (LDL) and low levels of high-density lipoprotein (HDL) enhanced SVR response in CHC patients. The reason for this event is that HDL may modulate virus entry into cell and consequently, a low level of HDL reduces cell infection. The LDL receptor plays an important role in HCV entry. Thus, increasing LDL can reduce the entry of virus into liver cells.
Commonly, ALT levels are elevated in patients with CHC, but approximately half of the patients may have a normal ALT. In the latter category, a low degree of inflammation and hepatic fibrosis is frequently observed. Normal serum ALT levels were attributed to female gender, low HCV RNA copy number and decreased inflammation or fibrosis.
In the present study, the correlation between gender and the level of ALT and SVR was not found to be significant. Baseline, to measure the level of liver enzyme ALT, viral load (in all, 71 patients) and stage of fibrosis (59/71), revealed that 32/46 (69.6%) of patients with SVR had normal or slightly elevated ALT, whereas only 14 (30.4%) patients had an SVR with 1.5-fold ALT level (P < 0.001). Most of the mild fibrosis patients (F0–F2) with an SVR of 17/22 (77.3%) had normal or slightly elevated ALT level, whereas 17/19 (89.5%) of negative SVR patients with over 400,000 IU/ML viral load had 1.5-fold increase in ALT level.
In the current study, the presence of IFNL4 SNP in CHC genotype 1a was found better prediction value, in terms of treatment outcome when compared to IFNL3 SNPs. Besides the performance of diagnosis of genotyping IFNL3 and IFNL4 are the cost effective and can be performed in every laboratory, with minimum equipment.
The ARMS-PCR technique is the most appropriate cost-benefit test for the diagnosis of SNPs. The advantages of this approach are: Simple needs limited equipment and is a suitable test for the detection of SNPs, especially in developing countries. On the other hand, although RFLP is more costly than ARMS-PCR, its performance requires limited equipment. Performing and interpretation of both techniques are not so complicated and therefore, could be routinely utilised in small laboratories. It is noteworthy that the interpretations of results by both methods are the same (100%), when compared with results obtained with other molecular conventional methods such as qPCR and sequencing. Hence, the aforementioned SNPs can be diagnosed by the both techniques.
Stattermayer et al. showed that almost 20% of patients carrying the favourable genotypes in the IFNL3 CC and IFNL4 TT/TT failed to achieve an SVR. In our study, 4/22 (18.2%) patients with the mentioned genotypes did not access an SVR, and the reasons remain unknown.
In another survey, Bordi et al. revealed that overexpression of IFNAR-1 mRNA in patients with homozygote TT allele of IFNL4 were found to be 1.82-fold than ΔG allele which indicated that the association of favourable alleles of IFNL4 and IFNL3 increased IFNAR-1 mRNA by 2.6-fold. In the present study, 20/24 (83.3%) with rs368234815 TT/TT alleles achieved an SVR, but when rs368234815 TT/TT genotype was accompanied by rs12979860 CC genotype showed better SVR in which only one patient failed to respond to treatment.
The SNP rs12979860 is located within intron one and three kilobase (kb) upstream of rs368234815 with high LD. Although it was not unexpected, the close correlation of both genotypes showed the adjacent information. On the other hand, SNP rs8099917 is approximately 9 kb upstream of rs368234815 and moderately correlated with it. In the present study, the relationship between genotypes rs368234815 and rs8099917 was not found significant (r = 0. 299, P = 0. 011), but with slightly different is in accordance with the results reported by Stattermayer et al. The analysis of our data indicated that rs368234815 with rs12979860 (r = 0. 788, P< 0 001) are found to be favourable SNPs for predicting P/R therapy when compared with rs8099917 alleles (r = 0. 299, P = 0.011), thus the evaluation of these alleles at the baseline should be considered as a predicting SVR before treatment in CHC patients.
The evaluation of SVR rate amongst the Iranian patients with CHC was also found higher when compared with SVR rate reported in China. In China, Wu et al. reported SVR rate of (47.7%) with a favourable allele of IFNL4, in CHC genotype 1b patients, which shows lower than our results (64.8%). It has been reported that genotype 1a is the most common genotype amongst patients with hepatitis C in Iran, and its treatment showed a better response than genotype 1b. The second reason is that each of the genotypes 1a, 1b, etc., has different subtypes with various responses to the therapy. The third reason for the high SVR rate is good tolerability to P/R were observed in Iranian patients.
Though for a long time, the Peg-IFN and RBV were the standard of care for patients with HCV infectious. However, some problems such as low SVR rate in patients with HCV genotype 1 after 48 weeks of treatment, severe adverse effects and subcutaneous injection, encouraged researchers to create more effective drugs. Recently, the first direct antiviral agent drugs (DAA), Telaprevir and Boceprevir, were generated to improve HCV treatment that should be used with P/R to prevent protease drug resistance (triple therapy). Fortunately, the new development in the treatment of HCV infection has broadly changed the landscape of achieved the SVR by using IFN-free DAA combinations. Consume as tablets with very few side-effects, reduced time treatment to 8–12 weeks and more than 90% curability are the most advantages of this therapy. The three main categories exist for current IFN-free DAA agents included: NS3/4A protease inhibitors, NS5B polymerase inhibitors and NS5A inhibitors. Amongst them, the combination of sofosbuvir (SOF) + ledipasvir (LDV) ± RBV, SOF + daclatasvir (DCV) ± RBV, SOF + simeprevir ± RBV, grazoprevir + elbasvir, have successfully used for the clinical treatment of HCV genotype 1a in developed countries of the world. Nevertheless, at present, the high cost of IFN-free DAA treatment is the most important obstacle which is unaffordable use of them for developing countries. As a result, P/R are still widely used in these areas. Even so, with the objective of eradication hepatitis C, in some of the newly industrialised countries such as India since 2015, with the cooperation of the Indian National Association for Study of the Liver (INASL), the worth programme is providing cheaper IFN-free DAA combinations for CHC treatment. In this therapeutic protocol, SOF, DCV and LDV with lower side effects, high efficacy, better tolerability, shorter duration of therapy and has simpler administration are available for HCV patients in India. Accordingly, INASL guidelines endorse HCV RNA monitoring only at baseline and 12 weeks after the completion of therapy for SVR. Taking into account the excellent response to the therapy with the new DAA combinations in patients across a wide range from F0 to F3 fibrosis, fibrosis evaluation may not be essential for every patient before therapy. In patients with no ultrasound evidence of cirrhosis, avoiding fibrosis appraisal by noninvasive means or liver biopsy would play a role in decreasing the cost of management of CHC.
Finally, this is the first report on predictor factors involved in CHC patients with genotype 1a in Ahvaz, Iran, however, still, comprehensive studies require to estimate the rate of SVR in different regions of Iran. In this study, the participants were Caucasian which were predominantly Arab and Bakhtiari euthenics and showed a good tolerability to P/R. However, further studies are required to evaluate amongst the other Iranian euthenics.
| ~ Conclusions|| |
The results of these findings emphasise that factors such as age, cholesterol, baseline viral load and IFNL4 rs368234815 are important predictive factors and at the baseline should be evaluated before CHC treatment.
Overall, The IFNL4 SNP rs368234815 allele has a significant advantage over the rs1279860 and rs8099917 alleles in achieving SVR as a prediction factor in treatment outcome.
According to the present results, factors including the side effects of medications amongst non-response patients, old age, high viral load, low cholesterol level and especially unfavourable alleles should be considered before initiation of anti-viral therapy.
This study was done as a research project with 92136 registration number in Health Research Institute, Infectious and Tropical Disease Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
Financial support and sponsorship
This study was supported by Health Research Institute, Infectious and Tropical disease Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3]