Long-Term Outcomes of Children with Hepatitis C Virus Infection after Kidney Transplantation in Kazakhstan

( Marina Khvan ),( Nazym Nigmatullina ),( Saltanat Rakhimzhanova ),( Samat Issakov ),( Venera Altynova ) 대한간학회 2020 춘·추계 학술대회 (KASL) Vol.2020 No.1

Introduction: Hepatitis C virus (HCV) infection is an important co-morbidity in patients after kidney transplantation (KT) affecting patient and graft survival. In the era of Direct Acting Antiviral (DAA) drugs the current standards of management strongly suggest to treat HCV positive patient with end-stage renal disease (ESRD) before KT. However, in the conditions where this treatment is not available, KT remains the only lifesaving option for children with ESRD who is not able to sustain on dialysis any longer. Aim: Currently, there is limited data available about outcomes of pediatric patients with HCV after kidney transplantation. We studied the prevalence, clinical profile and outcome of HCV infection in KT pediatric recipients (KTPR) in Kazakhstan for the first time after the launching the National Pediatric KT Program in 2012. Methods: We studied pediatric patients who underwent KT from January 2012 to December 2018 at the Department of Nephrology, Dialysis and Transplantation, National Research Center of Mother and Child Health, University Medical Center, Nur-Sultan. HCV infection was defined as a positive anti-HCV antibody and/or HCV RNA PCR positivity. Control group included KTPRs with no evidence of HCV or hepatitis B virus (HBV) infection. Results: A total of 73 KTPRs were included. The mean age was 10.6 ± 4.5 years, male:female ratio was 1:1 and mean duration of post-transplant follow-up was 32 months. 9 patients (12%) had evidence of HCV infection. All HCV-positive patients underwent KT before DAAs were available in the country. Among them 4 patients were treated with interferon before KT, 4 patients had HCV infection by the time of KT and 1 patient developed de-novo HCV infection after KT. Although there was no statistical significant difference in patient survival (logrank P=0.82) and graft survival (log-rank P=0.416) between HCV-positive group and controls, the only death in HCV group was registered in the patient who had de-novo HCV infection after KT. 2 patients who were treated from HCV infection before KT lost their kidney grafts and returned on dialysis. Among 4 patients with persistent HCV infection by the time of KT, 2 were successfully treated with DAAs 5 years after KT without any side effects or worsening of graft function. 2 KTPRs still have chronic HCV infection Stage 0 - 1 with low viral load, normal liver function tests and normal kidney graft function over the 6 years after KT. Conclusions: In our cohort HCV-positive KTPRs did not have any difference in patient and graft survival comparing to KTPRs without HCV infection. The worst outcome had patient with de-novo developed HCV infection after KT. HCV treatment with DAA after KT was successful without deterioration of kidney graft function. Limitation: low number of HCV-positive KTPRs.

C형 간염 바이러스 : 진단 및 유전적 변이성 Diagnosis and Genetic Variability

장숙진 대한화학요법학회 1999 대한화학요법학회지 Vol.17 No.1

C형 간염 바이러스는 만성 간염과 간경변증, 간세포암의 주요 원인균중 하나이다. HCV는 Flalviviridae과에 속하는 단일쇄의 positive-sense RNA 바이러스이다. HCV의 진단방법으로는 항체 검사를 위한 혈청학적 검사방법과 바이러스 RNA를 검출하는 분자생물학적 방법이 있다. 항-HCV항체를 점출하기 취한 혈청학적 검사법으로 ELISA 검사와 recombinant immunoblot assay(RIBA) 확진검사법이 사용되어져 왔으며 양자의 민감도는 비슷하다. 먼저 ELISA 검사로 검색한 후 그것에 비특이적인 반응을 보이는지 확인이 필요할 때 immunoblot법을 사용한다. RT-PCR로 혈청내 HCV RNA를 측정하는 방법은 C형간염 진단에 참조검사로 인정받고 있으며, HCV-RNA 혈중량이 인터페론 치료에 대한 반응을 평가할 수 있는 주요 예견자로 여겨짐에 따라 HCY-RNA 농도를 정량하는 시약들이 시판되고 있다. HCV의 유전형은 계층적으로 형, 아형, 분리주, quasispecies로 구성된 4단계로 나눌 수 있다. HCV의 분류에는 Simmonds 분류법이 널리 쓰이며 유전자형 la와 Ib, Ic, 2a, 2b, 2c, 3a, 3b, 4a, 5a, 6a형이 전세계적으로 분포되어 있다. 그중 1a형은 미국에 흔하고 1b형은 한국과 일본, 유럽에 흔하다. HCV quasispecies가 인터페론 치료에 대한 반응을 예측하거나 감염의 전파원을 찾는데 이용될 수 있어 활발히 연구되어 왔다. 그러나 HCV quasispecies에 대한 많은 연구들에서 핵산염기서열 분석자료들이 인위적으로 치환된 자료를 많이 포함하고 있어서 quasispecies의 출현빈도가 실제보다 과대평가되었을 가능성이 있으므로 향후 HCV 염기서열의 변이에 대해 연 구할 때는 인위적인 치환을 피할 수 있는 방법을 사용하도록 추천되고 있다. Hepatitis C virus(HCV) is the one of the major cause of chronic hepatitis, cirrhosis and hepatocellular carcinoma. HCV is a single-stranded positive sense RNA virus that has been classified in the Flaviviridae family. Diagnostic assays for HCV include serologic tests for antibody detection and molecular techniques for detection of viral RNA. Serologic tests such as enzyme-linked immunosorbent assay(EL1SA) and confimatory recombinant immunoblot assay(RU3A) have been used to detect anti-HCV antibodies. The sensitivity of ELISA is comparable to RIBA test. RIBA test has been used to check whether positive reaction on ELISA is nonspecific or not. Detection of HCV RNA in serum by RT-PCR used as a reference method for diagnosis of hepatitis C viral infection. The pretreatment level of HCV RNA appears to be a very important predictor of patient's response to interferon therapy. The assay kits for quantitation of HCV RNA are commercially available HCV genotype consist of 4 hierarchical strata: groups above subgroups above isolates above quasispecies. Simmon's classification is widely used for HCV classification. Genotypes la, lb, lc. 2a. 2b, 2c, 3a, 3b, 4a. 5a, and 6a are the most commonly encountered. The relative prevalence of HCV subtype l b is high m Korea, Japan and Europe but lower in the united states, where HCV subtype l a is more prevalent. HCV quasispecies have been studied actively because such informations are useful to predict patient response to interferon therapy and to detect transmission source of HCV infection in epidemiological studies It is possible to overestimate the frequency of quasispecies because some nucleotide sequence data obtained from studies of HCV quasispecies include a high frequency of artefactual substitutions. So it is recommended to use methods to avoid artefactual substitutions to study HCV sequence variation.

한국 혈우병 환자에서 C형 간염 바이러스 유전자형(Genotype)의 분포 양상

김은준,이은희 大韓血液學會 1999 大韓血液學會誌 Vol.34 No.2

HCV感染과 ALT와의 關係에 對한 硏究

문희주 서울保健大學 1994 論文集 Vol.14 No.1

The species of virus caused by Hepatitis were known over 25 but there were examined A type(HAV), B type(HBV). C type (HCV), D type(HDV) and E type(HEV) in its essence. Recently the study is receving about F type. In all viruses, HCV was known lately, 47~68% of NANB type hepatitis were HCV antibody(+), 43~74% NANB type-hepatic cirrhosis were patients HCV antibody(+). It is suggested that HCV acts on a factor of various hepatopathy included hepatoma. But only HCV make dear caused by C type hepatitis. It was not examined its structure and attribute, but made dear small virus caused by C type hepatitis. So much is trouble in diagnosis for a small percentage of the blood circulation, a lower of immune reaction, non exploitation that raise antigen in peculiarity. The thesis was made of basal data for a diagnosis in effective and early. The object of this experiment is on 100,000 blood donor of KOREA RED-CROSS BLOOD BANK and the examinded was related among of the HCV antibody positive ratio, HCV and ALT. The results obtained were as follows : 1) The HCV antibody positive ratio is orderly 0.67% for male, 0.60% for female and 0.66% for mean, not significance between male and female. 2) According to age HCV antibody positive ratio is 2.82% over 50 ages group, 0.83% for 40~49 ages, 0.67% for 30~39 ages. 0.66% for 20~29 ages, 0.53% for 16~19 ages, therefore it is represents the highest in the prime of life for above 50 ages group. The correlation between the prime of life and young age represents significance(P<0.0l). 3) According to occupation HCV antibody positive ratio is orderly 1.57% for commerce, 0.88% for housekeeping, 0.70% for agriculture, 0.69% for businessman, 0.63% for soldier, 0.56% for public servant. 0.56% for student, therefore it is the highest engaged in commerce. When it is compared with another job series, it is significance(P<0.05). 4) The correlation between HCV infection and ALT value appeared positive ratio 0.6% in 0~19IU, 0.66% in 20~29IU. 0.57% in 30~39IU, 0.58% in 40~49IU, 0.71% m 50~59IU, 2.16% above 60IU for ALT value and the mean value of ALT is 39.86±3.54 for HCV antibody negative patients. Statistically significant difference existed between HCV infection and ALT value. 5) The correlation between RCV and HBsAg were 0.72% for HBsAg positive and 0.63% for HBsAg negative. It represented or so higher for HBsAg, no statistically significant difference existed between RCV and HBsAg.

HCV, Alcoholic : O-022 ; Hepatitis C virus infection enhances tumor necrosis factor-alpha-induced cell death via suppression of nuclear factor-kappaB

( Won Seok Kang ),( Jun Seong Park ),( Seung Wook Ryu ),( Woo Il Kim ),( Dong Yeop Chang ),( Dong Ho Lee ),( Do Youn Park ),( Youn Hee Choi ),( Kyung Sun Choi ),( Kwang Hyub Han ),( Chul Hee Choi ),( 대한간학회 2012 춘·추계 학술대회 (KASL) Vol.2012 No.-

Background: Hepatitis C virus (HCV) infection results in liver injury and long-term complications such as liver cirrhosis and hepatocellular carcinoma. Liver injury in HCV infection is believed to be caused by host immune responses, not by viral cytopathic effects. Tumor necrosis factor-α (TNF-α) plays a pivotal role in the inflammatory processes of hepatitis C. TNF-α induces cell death that can be ameliorated by nuclear factor kappaB (NF-κB) activation. We investigated the regulation of TNF-α signal transduction in HCV-infected cells and identified HCV proteins responsible for sensitization to TNF-α-induced cell death. Methods: We studied the effect of HCV infection on TNF-α signal transduction using an in vitro HCV infection model (JFH-1, genotype 2a) with Huh-7 and Huh-7.5 cells. Results: We found that TNF-α-induced cell death significantly increased in HCV-infected cells. HCV infection diminished TNF-α-induced phosphorylation of IKK and IκB, which are upstream regulators of NF-κB activation. HCV infection also inhibited nuclear translocation of NF-κB and expression of NF-κB-dependent anti-apoptotic proteins such as Bcl-xL, XIAP and c-FLIPL. Decreased levels of Bcl-xL, XIAP, and c-FLIP mRNA and protein were also observed in livers with chronic hepatitis C. Transfection with plasmids encoding each HCV protein revealed that core, NS4B, and NS5B attenuated TNF-α-induced NF-κB activation and enhanced TNF-α-induced cell death. Conclusions: HCV infection enhances TNF-α-induced cell death by suppressing NF-κB activation, through the action of core, NS4B, and NS5B. This mechanism may contribute to immune-mediated liver injury in HCV infection.

Distribution of HCV Genotypes in Chronic Korean HCV Patients

( Kyung Ok Lee ),( Su Jin Jeong ),( Ji Young Byun ),( Ae Sug Shim ),( Hye Soon Seong ),( Kyung Tae Kim ) 대한임상검사과학회 2007 대한임상검사과학회지(KJCLS) Vol.39 No.1

HCV는 single stranded RNA 바이러스로서 감염 시에는 만성간염 및 간경화 간암으로 진행될 수 있는 가능성이 높다. HCV는 6종의 주된 genotype과 그에 따른 많은 종류의 subtype이 보고되고 있으며, 세계 각 지역별로 그 분포는 매우 다양하다. 여러 가지 HCV genotype 중에서 1b 형에 감염되었을 경우 간경화나 간암으로 진행할 가능성이 높으며 치료효과도 떨어진다는 보고가 있어, 최근 HCV 환자의 치료에 있어서 HCV 바이러스 정량검사와 함께 HCV genotyping 검사의 임상적 활용이 높아지고 있다. 본 연구에서는 PCR-direct sequencing을 이용한 HCV genotyping 검사방법을 이용하여, 한국인 만성 HCV 간염환자에서 HCV genotype의 분포를 조사하였다. 검체로는 232명의 한국인 만성간염환자의 혈청을 사용하였으며, HCV 5``UTR 영역에서 선택한 2쌍의 primer로 nested PCR을 실시하였다. 증폭된 PCR산물 (215 bps)은 2% agrose gel로 전기영동을 하고 sequencing을 실시한 후 GeneBank의 BLAST 프로그램을 사용하여 HCV genotype을 분석하였다. HCV genotyping을 실시한 232명에서 5종류의 genotype, HCV 1b, 2a, 2b, 2c, 3a, 이 발견되었으며, HCV genotype 4, 5, 6 은 검출되지 않았다. 발견된 HCV genotype 중에서 HCV 1b의 검출률이 53.9%로 가장 높았고, 다음은 HCV 2a가 35.8%로 높게 나타나, 위 두 가지 HCV genotype을 합하면 거의 90%였다. 다음으로 HCV genotype 2b가 3.9%, 3a가 3.4% 그리고 2c가 3.0%의 순서로 검출되었다. 본 결과는 한국인 만성 HCV간염 환자의 치료 및 예후관리에 참고가 될 것으로 사료된다. 또한 PCR-direct sequencing을 이용한 HCV genotyping 검사는 간편하고 분명하게 결과를 판독할 수 있어 임상실험실에서 유용하게 사용될 수 있을 것으로 판단된다. HCV is a single-stranded RNA virus and more than 1 million new cases are reported annually worldwide. The six major HCV genotypes and numerous subtypes vary in their geographic distribution. It is thought that genetic heterogeneity of HCV may account for some of the differences in disease outcome and response to treatment observed in HCV infected persons. In this study, we determined HCV genotypes among chronic Korean HCV patients and evaluated direct sequence PCR protocols developed. For the study, 232 chronic HCV patient sera were used. HCV RNA was extracted and two pairs of consensus PCR primers were selected in 5’UTR region for amplification of HCV RNA. Amplification products obtained from the HCV positive cases were subjected to automatic sequencing. Sequences were compared with those in GenBank by using the BLAST program. From this study, five HCV genotypes, 1b, 2a, 2b, 2c and 3a were found. HCV genotypes 4, 5 and 6 were not determined. HCV genotype 1b (53.9%, 125/232) and 2a (35.8%, 83/232) were most frequently found. This group was followed by 2b (3.9%, 9/232), 3a (3.4%, 8/232) and 2c (3.0%, 7/232). The data presented here suggest a complex distribution of HCV types and they were well correlated with other reports on Koreans and will be helpful for type-specific follow-up of Korean HCV patients. This study showed that 5’UTR direct sequence analysis is a sensitive and rapid method to identify HCV genotypes.

수혈후 비 A 형 비 B 형 간염 환자혈청에서 분리한 C 형 간염 바이러스 유전자의 부분 염기서열분석

윤승규(Seung Kew Yoon),박영민(Young Min Park),정규원(Kyu Won Chung),김부성(Boo Sung Kim),김원용(Won Yong Kim),김철중(Chul Joong Kim) 대한내과학회 1994 대한내과학회지 Vol.46 No.1

N/A Objectives: Since hepatitis C virus (HCV) has been discovered, many strains of HCV have been isolated partially or completely and charaterized under molecular biologic level. Recently, several kinds of HCV typing method have been developed and the differences in the geographical distribution of each type were reported and the possibility that the viral pathogencecity and clinical significance according to HCV type may be different has been also suggested. Methods: To investigate the molecular biologic property of HCV isolated from two posttransfusion non A, non-B hepatitis (PT-NANRH) patients in Korea, we performed a molecular typing of HCV genome using reverse transcription-polymerase chain reaction (RT- PCR) with type specific primer sets deduced from NS5 region and a cloning-sequencing using the PCR products. Results: 1) In HCV typing by RT-nested PCR, one case showed a HCV-J type while the other case showed a HCV-J/K1 type. 2) At the nucletide level, the homologies between isolated 2 HCV genomes and HCV-J, -K1 type ranged from 93.0~93.5% to 91.5~93.5% respectively. 3) Deduced amino acid sequence homologies of 2cases ranged from 95.5~97.0% with HCV-J type and 92.4~95.5%. with HCV-K1 type. Conclusion: These results showed that HCU genome isolated from Korean patients were highty identical to HCV-J or HCV-K1 which were recognized as a major type in Japan, while it suggests that HCV type II corresponding to HCV-J or-K1 type may be the major type in Korea. To understand the pathogenesis of HCV and develope a diagnostic tool or vaccine for HCV compatible to Korean strains, more genetic information on the HCV genome isolated from Korean patients will be required.

만성 C형 간염바이러스 감염 환자에서 혈청 soluble Interleukin-2 receptor와 바이러스 RNA의 정량

양윤선,기창석,김종원 대한임상병리학회 1997 대한임상병리학회지 Vol.17 No.5

Distribution of HCV Genotypes in Chronic Korean HCV Patients

Lee, Kyung-Ok,Jeong, Su-Jin,Byun, Ji-Young,Shim, Ae-Sug,Seong, Hye-Soon,Kim, Kyung-Tae Korean Society for Clinical Laboratory Science 2007 대한임상검사과학회지(KJCLS) Vol.39 No.1

HCV is a single-stranded RNA virus and more than 1 million new cases are reported annually worldwide. The six major HCV genotypes and numerous subtypes vary in their geographic distribution. It is thought that genetic heterogeneity of HCV may account for some of the differences in disease outcome and response to treatment observed in HCV infected persons. In this study, we determined HCV genotypes among chronic Korean HCV patients and evaluated direct sequence PCR protocols developed. For the study, 232 chronic HCV patient sera were used. HCV RNA was extracted and two pairs of consensus PCR primers were selected in 5'UTR region for amplification of HCV RNA. Amplification products obtained from the HCV positive cases were subjected to automatic sequencing. Sequences were compared with those in GenBank by using the BLAST program. From this study, five HCV genotypes, 1b, 2a, 2b, 2c and 3a were found. HCV genotypes 4, 5 and 6 were not determined. HCV genotype 1b (53.9%, 125/232) and 2a (35.8%, 83/232) were most frequently found. This group was followed by 2b (3.9%, 9/232), 3a (3.4%, 8/232) and 2c (3.0%, 7/232). The data presented here suggest a complex distribution of HCV types and they were well correlated with other reports on Koreans and will be helpful for type-specific follow-up of Korean HCV patients. This study showed that 5'UTR direct sequence analysis is a sensitive and rapid method to identify HCV genotypes. HCV는 single stranded RNA 바이러스로서 감염 시에는 만성간염 및 간경화 간암으로 진행될 수 있는 가능성이 높다. HCV는 6종의 주된 genotype과 그에 따른 많은 종류의 subtype이 보고되고 있으며, 세계 각 지역별로 그 분포는 매우 다양하다. 여러 가지 HCV genotype 중에서 1b 형에 감염되었을 경우 간경화나 간암으로 진행할 가능성이 높으며 치료효과도 떨어진다는 보고가 있어, 최근 HCV 환자의 치료에 있어서 HCV 바이러스 정량검사와 함께 HCV genotyping 검사의 임상적 활용이 높아지고 있다. 본 연구에서는 PCR-direct sequencing을 이용한 HCV genotyping 검사방법을 이용하여, 한국인 만성 HCV 간염환자에서 HCV genotype의 분포를 조사하였다. 검체로는 232명의 한국인 만성간염환자의 혈청을 사용하였으며, HCV 5'UTR 영역에서 선택한 2쌍의 primer로 nested PCR을 실시하였다. 증폭된 PCR산물 (215 bps)은 2% agrose gel로 전기영동을 하고 sequencing을 실시한 후 GeneBank의 BLAST 프로그램을 사용하여 HCV genotype을 분석하였다. HCV genotyping을 실시한 232명에서 5종류의 genotype, HCV 1b, 2a, 2b, 2c, 3a, 이 발견되었으며, HCV genotype 4, 5, 6 은 검출되지 않았다. 발견된 HCV genotype 중에서 HCV 1b의 검출률이 53.9%로 가장 높았고, 다음은 HCV 2a가 35.8%로 높게 나타나, 위 두 가지 HCV genotype을 합하면 거의 90%였다. 다음으로 HCV genotype 2b가 3.9%, 3a가 3.4% 그리고 2c가 3.0%의 순서로 검출되었다. 본 결과는 한국인 만성 HCV간염 환자의 치료 및 예후관리에 참고가 될 것으로 사료된다. 또한 PCR-direct sequencing을 이용한 HCV genotyping 검사는 간편하고 분명하게 결과를 판독할 수 있어 임상실험실에서 유용하게 사용될 수 있을 것으로 판단된다.

HCV의 가족내 감염양상 : HBV의 가족내 감염양상과 비교

이헌주 영남대학교 의과대학 1992 Yeungnam University Journal of Medicine Vol.9 No.2

Anti-HCV 양성인 만성간질환 환자 80명의 가족중 3가족에 걸쳐 3명이 anti-HCV 양성이었고 양성율 3.5%로서 HBsAg양성 만성간질환 환자 60명의 가족 중 40가족에서 HBsAg 양성자가 나타난 결과가 양성율 66.7%보다 월등히 낮은 수치를 보였다. 이 결과를 볼때 HCV는 HBV와는 다른 정도의 감염력을 가지거나 또는 다른 형태의 개체면역반응을 유도하여 항체 형성이 낮은 것이 아닌지 고려해 보아야겠다. 가족 중 배우자나 자녀에 있어서의 감염율은 HBV와 비교될 정도는 아니었으나 anti-HCV 양성인 사람이 배우자나 자녀였으므로 향후 성적접촉이나 수직감염에 의한 감염 가능성에 관해 더욱 조사가 필요할 것으로 사료된다. 그러나 아직 HCV RNA를 직접 검사하는 PCR검사가 보편화되어 있지 못하며 HCV 감염의 진단을 위한 검사법이 여러가지 난무하는 이유로 이후 정밀도가 높으며 쉽게 이용될 수 있는 HCV 감염진단을 위한 검사법이 확립되어 정확한 HCV 환자의 파악이 먼저 되어야 HCV 감염의 역학적 조사가 정확히 이루어지며 HCV 감염관리에 도움이 될 것으로 생각된다. Among 85 patients with anti-HCV positive chronic liver disease, only 21.2% have past history of blood transfusion and over half the cases, they do not have any suspicious risk factors for HCV infection. 3 of 85 families show anti-HCV positive family members. On the other hand, 40 of 60 patients with HBsAg positive chronic liver disease show HBsAg positive family members. In Korea, HBV is transmitted mainly through vertical and intrafamilial infection but HCV disease might be rather horizontal and sporadic than vertical. To define the evident source of infection in sporadic hepatitis C, first of all, simple test with high sensitivity and specificity for diagnosis of HCV infection would be needed.