IL-28B genetic variation, gender, age, jaundice, hepatitis C virus genotype, and hepatitis B virus and HIV co-infection in spontaneous clearance ...
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O RI G I NAL ART I C L E LIVER IL-28B genetic variation, gender, age, jaundice, hepatitis C virus genotype, and hepatitis B virus and HIV co-infection in spontaneous clearance of hepatitis C virus Sergii V. Fedorchenko , Anna Klimenko , Tetyana Martynovich , Olga Liashok , Vitaliy Yanchenko Department of Viral Hepatitis and AIDS, The L.V. Gromashevskyi Institute of Epidemiology and Infectious Disease, Kiev, Ukraine Cite this article as: Fedorchenko SV, Klimenko A, Martynovich T, Liashok O, Yanchenko V. IL-28B genetic variation, gender, age, jaundice, hepatitis C virus genotype, and hepatitis B virus and HIV co-infection in spontaneous clearance of hepatitis C virus. Turk J Gastroenterol 2019; DOI: 10.5152/tjg.2019.18328 ABSTRACT Background/Aims: Spontaneous viral clearance observed in some patients is one of the variants of the hepatitis C virus (HCV) infection natural history. We aimed to look at the complexity of factors affecting the spontaneous clearance of HCV (SC HCV). Materials and Methods: A total of 357 anti-HCV positive patients (309 with chronic hepatitis C and 48 patients with SC HCV) were included into the study. We studied the effects of the interleukin-28B (IL-28B) gene polymorphism, gender, age, the routes of virus transmission, past hepatitis C with jaundice, HCV genotype, and hepatitis B virus (HBV) and HIV co-infection on the outcome of HCV infection. Results: Based on the study results, the SC HCV was found in 48 individuals (13.4%). The most significant positive factors affecting the SC HCV included IL-28B single nucleotide polymorphism (SNP) rs12979860 (CC) and SNP rs8099917 (TT) (OR 4.03, p
Turk J G a st roe nt e ro l 20 19 Fe d o rche nko e t al . P re d i ct o rs o f spo nt ane o u s H CV c l ea ra nc e clearance of HCV, we do not know whether it has oc- negative verification tests (RIBA). In case of indetermi- curred during acute or chronic disease. Besides the nate RIBA results, the test was repeated in 4-6 months; above-mentioned factors, co-infection with other hep- repeated indeterminate or negative test result was in- atotropic viruses (hepatitis A virus, HBV, and hepatitis D terpreted as false positive. This group included 10 indi- virus), HIV co-infection, and intravenous drug use play viduals: 4 pregnant women, 2 patients with lymphocytic important role in patients with chronic disease. The НВV leukemia, 1 patient with myeloma, and 1 with the history superinfection in patients with chronic viral hepatitis of multiple hemotransfusions. C leads to the manifestation of clinical and laboratory symptoms of liver damage, but it often end with SC HCV Specimen collection (11). HIV co-infection in the setting of significant defi- Obtained serum samples were stored at -80˚C until anal- ciency of cell-mediated immunity in patients not receiv- ysis. For genetic testing, patients were recalled and, if ing highly active antiretroviral therapy (HAART) is a neg- they agreed, the ethylenediaminetetraacetic acid (EDTA) ative factor of virus clearance (4). Currently, there is no blood was drawn. The EDTA blood was centrifuged at agreement regarding the impact of intravenous drug use 1500 g for 20 minutes at room temperature within 4 on SC. Several researchers observed high rates of the hours of venipuncture, and aliquots were frozen immedi- HCV clearance in active intravenous drug users (IDUs) ately after centrifugation at -80˚C until testing was per- (12,13), whereas others indicated poor likelihood of viral formed. elimination (14). Virologic testing The ultimate goal of the current study was to identify the The HCV RNA was tested with the qualitative CO- set of factors influencing the SC of HCV: the IL-28B gene BAS Amplicor HCV Test (Roche Molecular Systems, polymorphism, gender and age of HCV patients, the route Branchburg, NG; lower limit of detection, 50 IU/mL). of virus transmission, and HBV and HIV markers. The HCV genotype was determined using the VER- SANT HCV Genotype 2.0 Assay (LiPA; Siemens Med- MATERIALS AND METHODS ical Solutions Diagnostics, Tarrytown, NY). All assays The study was conducted between 2008 and 2014, and were performed according to the manufacturer’s in- it included 367 anti-HCV positive patients (309 with structions. chronic hepatitis C [CHC]; 48 with SC HCV; 10 with false positive anti-HCV result). Anti-HCV in serum samples HCV serotypes and serologic testing for HBV and HIV was studied with a third-generation microparticle en- Sera from patients with undetectable HCV RNA were zyme immunoassay (HCV version 3.0 Ax sym. Abbott tested for type-specific antibodies to HCV genotypes 1, Laboratories, Chicago, IL, USA; MonoLisa HCV Ag-Ab UL- 2, 3, 4, 5, and 6 using the MUREX HCV Serotyping 1-6 TRA, Bio-Rad, ETI-Ab-HCV K-3 ELISA, Sorin Bio Medica, Assay (Abbott, Wiesbaden, Germany). Italy). Antibodies directed against the HBV and HIV infection Diagnosis of chronic hepatitis C was based on positive status were carried out the Aksum system (Abbot. Lab- results for the presence of anti-HCV and HCV RNA (qual- oratories, Chicago, IL, USA) by determining anti-HBs itative test) in serum. The SC HCV was diagnosed when (AUSAB), anti-HBc (Core), and HBsAg (HBsAgV2). An- the serum contained anti-HCV and no HCV RNA. The ti-HIV were tested by Abbott PRISM (Abbott Laborato- patients were not receiving antiviral therapy. Antibody ries, Chicago, IL, USA). specificity was confirmed by a verification test (CHIRON RIBA HCV 3.0 SIA, Orto Diagnostic Systems Inc. Raritan Testing for interleukin-28B (IL-28В) NG, USA). To exclude patients with chronic hepatitis C Genomic DNA was isolated from peripheral blood ac- having a low-level viremia from this group (15), all the pa- cording to the QIAamp DNA Blood Mini Kit from Qiagen tients were tested two times within a 5-6 months inter- (Hilden, Germany). SNPs rs12979860 and rs8099917 in val for the presence of the HCV RNA in the serum (qual- the region of the IL28B gene were analyzed by the Ste- itative test) with a highly sensitive method of indication, pOnePlus Real-Time PCR System (Applied Biosystems, Real-Time HCV TM Abbott (Abbott Laboratories, Abbott Foster City, CA) with the help of a custom TaqMan SNP Park, Illinois, USA), having the lower threshold of sensi- Genotyping Assay developed together with Applied Bio- tivity 12 IU/mL. A false positive reaction to anti-HCV was systems. Amplicon sequencing was used to validate the determined based on positive test results (ELISA) and genotyping techniques.
Fed orchenko e t a l . P re di c to rs o f s p o n ta n e o u s H CV cl e arance Tu r k J G a st ro e nt ero l 2019 Statistical analysis subdivided into four main groups: IDUs, recipients of Database management and statistical analysis were per- donated blood and its derivatives, patients who un- formed using commercially available software systems derwent surgical and medical procedures, and patients (Microsoft Office Excel 2010, Microsoft Corp, Redmond, whose route of transmission remained unknown. The WA; SPSS 2006 for Windows version 16, SPSS Inc, Chica- IDU group comprised both active users at the time of go, IL; and MedCalc 220.127.116.11, Software bvba, Mariakerke, the study and former users. Hemotransfusions and Belgium). Data were analyzed using the Mann-Whitney U transfusions of blood components were considered the test, as well as the χ2 test, and the degree of association cause of infection if jaundice or laboratory-confirmed between independent variables of the SC HCV group and HCV infection (positive result for anti-HCV or anti-HCV CHC was determined calculating the corresponding odds seroconversion) had developed within 1 year after the ratio (OR) and its 95% confidence interval (95% CI) by transfusion. Surgical interventions and invasive medi- means of simple logistic regression. cal procedures were considered the main route of the HCV transmission in the group of patients with severe To determine whether variables were normally distribut- comorbidity requiring lengthy stay at the hospital, with ed or not, the Kolmogorov-Smirnov test was applied. All other routes of HCV transmission ruled out as much as P values were two tailed, and those less than 0.05 were possible. As follows from the data presented in Table 1, considered statistically significant. the patient’s gender had a significant effect on the out- comes of HCV infection. Informed consent Informed consent was obtained from each patient. In the group of patients with CHC, males prevailed: 198 (64.1 %) males vs. 111 (35.9 %) females. The opposite RESULTS pattern was observed in the SC group of patients, with females being prevalent: 29 (60.4 %) females vs. 19 (39.6 Effect of gender, age, history of jaundice, and routes of %) males. Female gender was strongly associated with HCV transmission on spontaneous virus clearance spontaneous viral eradication (OR, 2.72 [95% CI, 1.46- The SC was diagnosed in 48 individuals (13.4%) evaluat- 5.08]; р
Turk J G a st roe nt e ro l 20 19 Fe d o rche nko e t al . P re d i ct o rs o f spo nt ane o u s H CV c l ea ra nc e We were not able to confirm the impact of IDU on the IL-28B gene SNP rs12979860 and SNP rs8099917 dis- HCV infection outcomes. At the same time, hemotrans- tribution in the group of patients with SC HCV fusion-transmitted HCV infection is more often associat- A total of 48 persons (19 men [39.6%] and 29 women ed with the development of CHC. Thus, hemotransfusion [60.4%]) were included into the group of patients with or transfusion of blood products caused infection in 41 SC HCV. The evaluation of this group for the IL-28B gene (13.3%) patients with CHC, 2 (4.2 %) with spontaneous SNP rs12979860 by the CC, CT, and TT alleles produced recovery (OR, 0.28 [95 % CI, 0.06-1.21]; р
Fed orchenko e t a l . P re di c to rs o f s p o n ta n e o u s H CV cl e arance Tu r k J G a st ro e nt ero l 2019 Table 2. Effect of the IL-28B gene SNP rs12979860 and SNP rs8099917 polymorphism on SC HCV IL-28В gene SNP polymorphism SC НСV n=48 Chronic HCV n=309 p OR 95% CI rs12979860 СС 33 (68.8%) 109 (35.3%) 0.001 4.037 (2.100-7.759) rs12979860 СТ 11 (22.9%) 177 (57.2%) 0.001 0.222 (0.109-0.451) rs12979860 ТТ 4 (8.3%) 23 (7.5%) 0.85 1.130 (0.373-3.424) rs8099917 ТТ 39 (81.3%) 179 (57.9%) 0.002 3.147 (1.473-6.724) rs8099917 ТG 9 (18.7%) 120 (38.9%) 0.007 0.365 (0.170-0.777) rs8099917 GG 0 10 (3.2%) IL: interleukin; SNP: single nucleotide polymorphism; SC НСV: spontaneous clearance of HCV; OR: odds ratio; CI: confidential interval An analysis of results of the IL-28B SNP rs8099917 gen- CI, 1.89-6.63]; р
Turk J G a st roe nt e ro l 20 19 Fe d o rche nko e t al . P re d i ct o rs o f spo nt ane o u s H CV c l ea ra nc e Table 3. Distribution of the HBV and HIV markers in the group of patients with SC HCV and patients with chronic HCV Markers SC НСV n=48 CHC n=309 p OR 95% CI HBsAg 4 (8.3%) 19 (6.1%) 0.56 1.388 (0.451-4.269) anti-НВс 25 (52.1%) 73 (23.6%) 0.001 3.514 (0.882-6.560) anti-НВs 9 (18.8%) 23 (7.4%) 0.01 2.87 (1.239-6.648) anti-НIV 0 28 (9.1%) SC НСV: spontaneous clearance of HCV; OR: odds ratio; CI: confidential interval An analysis of the obtained results allows us to conclude The patient’s gender plays an essential role in sponta- that the likelihood of SC HCV does not depend on the neous elimination of the virus. Thus, in our study, in case HCV genotype. of a favorable outcome, the female-to-male ratio was 1:0.66 and 1:1.78 in chronic disease (p=0.0013). These HBV and HIV markers in patients with SC HCV and pa- results are consistent with data obtained in Europe tients with CHC (16), Egypt (17), Australia (9), and China (18). One of the In the studied groups, the influence of the past HBV in- main hypotheses explaining the specifics of immune re- fection was assessed based on the testing of sera for sponse in women as compared with that of men con- anti-HBc and anti-HBs. The diagnosis of a chronic HBV siders the effect of sex hormones on the functional ac- infection was made based on the HBsAg detection. All tivity of lymphocytes, macrophages, dendritic cells, and positive HBsAg samples were tested for IgM anti-HBc to lymphoid tissue (19). An indirect effect of sex hormones rule out acute viral hepatitis B. Patients with negative re- via a specific receptor expressed on the immune com- sults were included into the study. An HIV infection was petent cell membranes ensures a better control over the diagnosed based on the presence of anti-HIV in the se- outcome of the HCV infection in female population, and rum. a direct effect of sex hormones on the HCV replication is also possible. Table 3 provides data of the HBV and HIV markers iden- tification in the group of patients with SC HCV and pa- The patient age had a significant influence on the out- tients with CHC. comes of the HCV infection. Spontaneous recovery oc- curred more often in younger age (from 18 to 35 years)-22 As follows from the data presented in Table 3, markers (45.8%) in HCV and 83 (26.9%) in CHC (р
Fed orchenko e t a l . P re di c to rs o f s p o n ta n e o u s H CV cl e arance Tu r k J G a st ro e nt ero l 2019 Marked necrotic and inflammatory processes in the liver regarding the role of the HCV genotype in the natural parenchyma with elevated serum enzymes and bilirubin history of the HCV infection. In the AHC development, are characteristic for the development of multispecif- patients infected with 1b HCV subtype had the highest ic strong cell-mediated and humoral immune response odds for the development of CHC as compared to those to viral-specific proteins, which often leads to spon- with genotypes 2 and 3 (10,30). At the same time, sever- taneous recovery (7,23). A strong specific immune re- al researchers have noted high likelihood of spontaneous sponse is determined by a number of genetic factors, recovery in patients with genotype 1 HCV from acute viral such as HLA-А, HLA-В, and IL-28B (24). In AHC, the hepatitis C (9). virus stimulates cell-mediated immune response and INF-α production. IL-28B would be induced by the vi- The evaluation of large cohorts of anti-HCV positive pa- ral infection itself and further enhanced by INF-α. The tients, including those from risk groups, did not allow an IL-28B responder genotypes in this context would allow unambiguous answer to the question about the role of for a stronger IL-28B induction and thereby increase the HCV genotype in spontaneous viral elimination in the ISG induction, with subsequently higher odds for chronic disease. Having monitored the natural course of spontaneous recovery. In the study conducted by Till- the HCV infection in children for 10 years, Bortolotti et mann et al. (25), it was found that patients with the SNP al. (22) noted that infection with the HCV genotype 3 is rs12979860 СС with AHC jaundice developed more of- an independent predictor of SC HCV. In evaluating 496 ten than in non-CC. In carriers of the CC allele, jaundice anti-HCV positive and HBsAg negative IDUs, SC HCV was was not associated with SC HCV, and at the same time, diagnosed in 38%, with no effect of the HCV genotype in patients with the non-CC genotype, jaundice was the on disease outcomes noted (31). In two other extensive criterion of SC HCV. studies conducted in Great Britain, serological and mo- lecular-virological evaluation of 749 and 321 anti-HCV At present, conclusive data about the effect of IL-28B patients revealed association between the SC HCV and gene polymorphism on natural course of the HCV infec- the HCV genotype 1 (8,20). tion and response to interferon-containing treatment regimens were obtained. The SNP rs8099917 ТТ was An HBV superinfection significantly affects the natural shown to be closely associated with SC HCV (26,27), as course and outcomes of HCV. Two- to six-years-long well as with the likelihood of sustainable viral response to monitoring of 24 patients with a chronic HCV infection Peg INF+ ribavirin therapy in patients with the HCV gen- at the time of acute viral hepatitis B development allowed otype 1 and 4 infection, but not with the HCV genotypes to state the undetectable HCV RNA level at the end of 2 and 3 (28). the first year of the follow up in 7 (29.2 %), after 2 years in 14 (58.3%), and after 3 to 6 years in 18 (75%) patients. In our study, the rate of SNP rs12979860 genotype CC In six patients, the SC HCV was stated (18). Majority of occurrence in the group of patients with SC HCV was 1.9 works have indicated that markers of an active or past times higher than in the group with chronic HCV; and of HBV infection are more often found in patients with SC patients with the SNP rs8099917 genotype TT, it was 1.4 HCV (12). According to our data, an HIV co-infection is a times higher. negative factor in spontaneous recovery. Other authors also indicate a low likelihood of HCV clearance in the co- The distribution of favorable genotypes in groups did not hort of patients with an HCV/HIV co-infection not receiv- depend on gender. In studies by van den Berg et al. (16), ing HAART (32). The HAART initiation with the restitution women with unfavorable IL-28B gene polymorphism of cell-mediated immunity allows expecting the SC HCV rs12979860 СТ/ТG and SNP rs8099917 ТG/GG had sim- later, as well as an increased likelihood of patients with an ilar odds for SC HCV to those of men with favorable or HCV/HIV co-infection achieving SVR on antiviral therapy unfavorable genotype. Women with favorable IL-28B (32). polymorphism had the highest odds of SC HCV. According our results, the SC HCV was diagnosed in In the presented study, based on evaluation of 357 an- 48 patients (13.4%). The most significant positive fac- ti-HCV positive patients, the SC HCV was diagnosed in tors affecting the SC HCV include the IL-28B gene SNP 48 persons (13.4%). This is significantly lower than re- rs12979860 (CC) and SNP rs8099917 (TT), female gen- ported in other works conducted in European population der, young age, and a past history of jaundice, but not the (26,29). So, far there is no single answer to the question viral genotype.
Turk J G a st roe nt e ro l 20 19 Fe d o rche nko e t al . P re d i ct o rs o f spo nt ane o u s H CV c l ea ra nc e Ethics Committee Approval: Ethics committee approval was C infection. Clinical and Molecular Hepatology 2014; 20: 368-75. received for this study from the Ethics Committee of the L.V. [CrossRef] Gromashevsky Institute of Epidemiology and Infectious Diseas- 11. Sagnelli E, Coppola N, Pisaturu M, et al. HBV superinfection in es of the NAMS of Ukraine. HCV chronic carriers: a disease that is frequently severe but asso- ciated with the eradication of HCV. Hepatology 2009; 49: 1090-7. [CrossRef] Informed Consent: Written informed consent was obtained 12. Grebely J, Conway B, Raffa JD, et al. Hepatitis C virus rein- from the patients who participated in this study. fection in of injection drug users. Hepatology 2006; 44: 1139-45. [CrossRef] Peer-review: Externally peer-reviewed. 13. Kaber M, Hammarberg A, Weiland O. 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