PHWR Public Health Weekly Report

Hepatitis C virus (HCV) is an RNA virus that belongs to the genus Hepacivirus (family, Flaviviridae). HCV is mainly transmitted via blood and body fluids and causes acute/chronic hepatitis. HCV is the second leading cause of chronic liver disease after hepatitis B virus, which is the primary cause of liver cirrhosis and hepatocellular carcinoma. According to the World Health Organization (WHO), globally, an estimated 50 million people have chronic HCV infection; approximately 1 million new infections and 400,000 deaths occur due to this virus each year [1,2]. In the Republic of Korea (ROK), HCV spreads as a blood-borne infection among intravenous drug abusers who share needles and is caused by the use of unsterilized medical devices, with an estimated 0.6–0.8% of the general public being infected with this virus [2,3].

Many genotypes and subtypes of HCV exist. As HCV can replicate very rapidly, this virus has a high mutation rate. Moreover, as genetically different variants of the virus may be present simultaneously within the same individual, the production of antibodies to defend against HCV is difficult. As a result, prophylactic vaccines against this condition have not yet been developed. With the development of a direct antiviral agent (DAA) as a therapeutic agent for HCV and its introduction in the ROK in 2016, a cure rate >95% has been achieved after 8–12 weeks of treatment.

Based on the development of such therapeutic and excellent treatment outcomes, the WHO declared its goal to eliminate viral hepatitis by diagnosing and treating more than 80% of affected individuals by 2030. Nonetheless, the need for HCV infection control in the ROK is still ongoing owing to an increase in the number of drug users (mostly minors), weak infection control in correctional facilities, and difficulties associated with its early detection due to HCV infection not being included in national screening programs [4].

To establish a cohort in the ROK [5], the Korea Disease Control and Prevention Agency (KDCA) assembled a multi-center prospective cohort of patients with HCV to identify the risk factors of HCV infection and disease progression factors in the ROK and clarify the basis of disease progression via studies on liver disease prevention, treatment, and long-term prognosis. In the present study, we aim to present the details and major achievements of the “Korea HCV cohort study,” a policy research project that has been ongoing since 2007.

1. Study Methods

1) Korea HCV cohort

Assembly of the HCV cohort began in 2007 with four institutions. Currently, the Korea HCV cohort spans 10 hospitals nationwide, where the clinical information of patients and test samples are collected. This HCV cohort comprises anti-HCV-positive or HCV RNA-positive patients aged ≥18 years. Of note, an annual enrollment of at least 1,500 patients is expected for this study. Briefly, a questionnaire survey related to risk factors has been used as the baseline survey; repeated surveys have been conducted every 6 months to track the clinical progress of the enrolled patients. In accordance with the Personal Information Protection Act, individuals are assigned a cohort management number to ensure that the cohort study does not contain personal identification and personally identifiable information, including resident registration number, name, and telephone number.

2) Establishment and operation of the Korea HCV cohort

The cohort has been established and surveys are being conducted in collaboration with 10 medical institutions across ROK (Seoul National University Bundang Hospital, Soonchunhyang University Bucheon Hospital, Inje University Busan Paik Hospital, Jeonbuk National University Hospital, Chonnam National University Hwasun Hospital, ASAN Medical Center, the Catholic University of Korea Seoul St. Mary’s Hospital, Chungnam National University Hospital, Ilsan Paik Hospital, and Keimyung University Daegu Dongsan Hospital). The epidemiology team of the National Cancer Center is responsible for data quality control (QC) and data cleansing, while the cohort study is being led by the Division of Clinical Research under the Korea National Institute of Health (KNIH) of the KDCA. Each participating hospital enrolls HCV-infected patients (anti-HCV antibody-positive patients) who have expressed their willingness to voluntarily participate in the cohort study by signing a “project participation consent form” and “consent form for donating human materials.” Subsequently, a standardized questionnaire survey is disseminated to the participants and health examinations are conducted to collect clinical and epidemiological data from them. Blood samples are collected according to the HCV cohort human material acquisition system and the blood samples are transported to contracted organizations for preparation as human materials [6]. The baseline and repeated (follow-up) survey data inputted by each participating hospital are managed through the integrated system (IS) of KDCA (http://is1.kdca.go.kr/). The central repository of the KNIH is contracted to store and manage the human materials. The epidemiology team is responsible for developing standardized questionnaires and guidelines, providing regular standardized training for participating researchers, and offering research support for data utilization, including data cleansing, epidemiological consulting, statistical analysis support, and provision of statistics. The KDCA KNIH assigns a cohort management number to each patient and manages the overall progress of the study. In particular, the KNIH manages the consent forms, data use, and human materials. Operating guidelines have been established to ensure efficient operation of the Korea HCV cohort study (2013). Of note, the survey tools and indicators are continuously being modified and updated.

3) Survey methods

An annual enrollment of at least 1,500 patients and an actual follow-up rate of ≥70% for at least 5 years are expected for this study. The surveys consist of baseline, repeat, and end-of-study (EOS) surveys. The baseline survey is conducted at the time of enrollment in the cohort and comprises basic items (sex, age, drinking status, disease history, etc.) and disease-related items (diagnosis, treatment history, serology, etc.). The repeated survey, which is carried out using a questionnaire designed to assess the items from the baseline survey that may change over time, is conducted during the follow-up visits held every 6 months from enrollment (Table 1). If a physician determines that follow-up can be performed after a longer period, such as that for patients with a previous infection or post-treatment follow-up, the follow-up period was set to every 12 months, and the visit date could be up to 3 months before or after the optimal visit date. The EOS survey is conducted when the participant is no longer participating in the study for various reasons, including death, transfer, withdrawal of consent, and dropout. Participants who do not visit the study site for 12 months after enrollment or cannot be contacted by telephone are considered non-participants. Accordingly, these cases are defined as “dropout” cases. Discontinued participation due to other reasons, such as death and withdrawal of consent, is recorded via the EOS survey (Table 1). The standardized questionnaire retains the IS input format established previously through the Korea HCV cohort study; however, if the input process requires improvement, the opinions of the database (DB) users are collected to enable continued updates. From August 2023 to present, Case Report Form version 4.1 has been used.

Table 1 Korea HCV cohort study questionnaires

Category	Variables (factors)
Self-administered
Sociodemographic status	Cohort ID, sex, date of birth, race (ethnicity), marital status, etc.
Health-related lifestyle	Smoking, drinking habits (smoking status, duration of smoking, drinking status, duration of drinking, etc.)
Past disease history	History of past diseases (hepatitis, HCC, gastrointestinal diseases, etc.)
Family history	Family history of diseases (hepatitis B, hepatitis C, cirrhosis, HCC)
Risk factors	HCV-related risk factors (blood transfusion, acupuncture, needles injury, etc.)
Investigator-administered
Diagnosis	Physical examination, diagnosis at registration, date of diagnosis, cohort registration status
Treatment	Treatment status, clinical progress report on treatment, medication adherence status, etc.
Physical and clinical examinations
Physical examination	Height (cm), weight (kg)
Serological examination	Anti-HCV, HCV RNA, HCV genotype, HAV IgG, HIV, HBsAg, anti-HBc, HBV DNA quantitative test, HBV DNA qualitative test, HBV antiretroviral treatment status
Blood chemistry	WBC, hemoglobin, platelet, ANC, cholesterol, GGT/upper normal limit, protein, TG, albumin, HDL cholesterol, globulin, LDL cholesterol, total bilirubin, FBS, ALP, BUN, AST, Cr, ALT, ALP/AST ratio, ALP/upper normal limit, ALP/ALT ratio, GGT, HbA1C, prothrombin time, AFP, PIVKA II, TSH, free T4
Cirrhosis severity assessment	Ascites, hepatic coma, Child–Pugh score, MELD score
Endoscope	Endoscope examination status, date of endoscope, gastroesophageal varices related bleeding
Imaging test	Imagine test status, type, date, diagnosis findings
Biopsy	Biopsy status, date, lobular activity, fibrosis stage, cirrhosis and HCC status, result
Fibroscan test	Fibroscan examination status, liver stiffness

HCC=hepatocellular carcinoma; HCV=hepatitis C virus; HAV IgG=hepatitis A virus immunoglobulin G; HBsAg=hepatitis B surface antigen; HBc=hepatitis B core antibody; HBV=hepatitis B virus; WBC=white blood cell; ANC=absolute neutrophil count; GGT=gamma glutamyl transferase; TG=triglyceride; HDL=high density lipoprotein; LDL=low density lipoprotein; FBS=fetal bovine serum; ALP=alanine aminotransferase; BUN=blood urea nitrogen; AST=aspartate aminotransferase; Cr=creatinine; ALT=alanine aminotransferase; HbA1C=hemoglobin A1c; AFP=alpha-fetoprotein; PIVKA II=protein induced by vitamine K antagonist-II; TSH=thyroid stimulating hormone; free T4=free thyroxine; MELD=end‐stage liver disease..

The collection of human materials (blood samples) is recommended during each visit, with the general rule of collecting two samples (8 ml each) in mononuclear cell preparation tube and serum separate tube. Each hospital is responsible for directly collecting the samples. The blood samples are used to prepare plasma, serum, and peripheral blood mononuclear cell (PBMC) samples. A total of 200 samples are collected each time, and sent to the central repository of KDCA KNIH to be deposited and processed. The transportation and preparation of the bioresource samples are performed by specialized service contractors in accordance with the Korea HCV cohort bioresource acquisition system (established in 2013).

1. Achievements from the Korea HCV Cohort

1) Data management and upgrade

To date, the data QC plan has been used by the epidemiology team to modify the survey contents and methods. Data QC strategies have been set and QC measures have been implemented through data cleansing. The data QC in the Korea HCV cohort study can be divided into three stages: Stage 1, QC for the per-collection stage, consisting of questionnaire development/revision/update, unification of code values (code book creation, revision, and update), and standardized survey guidelines and training; Stage 2, QC for the data collection stage, consisting of monitoring, management of survey rate, and management of DB logic; and Stage 3, QC for the post-collection stage, consisting of raw data cleansing, re-survey, standardization of narrative and other questions, and preparation of guidelines for using raw data. Integrated guidelines, code book, and guidelines for using raw data were also provided to enable the researchers to effectively use the cleansed data. The DB system was updated to reflect survey items that were continuously revised. Furthermore, raw data for external distribution were collected by developing standardized integrated guidelines (for distribution) for data regarding 3,710 patients, excluding those who did not satisfy the HCV cohort enrollment criteria among all patients enrolled in the cohort from 2007 to December 31, 2021.

2) Collection of clinical/epidemiological data and human materials

(1) Status of the Korea HCV cohort resources

From 2007 to October 31, 2023, the total cumulative number of enrolled patients was 4,015 and the number of retained patients was 2,141, with an arithmetic follow-up rate of 53.1% or an actual follow-up rate of 70.0%, after excluding deaths, termination of treatment, and transferred patients. The survey results collected up to October 31, 2023 (baseline, repeated, and EOS surveys) comprised a total of 37,310 cases. In 2023, data were collected from a total of 2,178 cases, including 136 cases from baseline surveys and 2,042 cases from repeated surveys. Within the same period, samples, such as human materials, were collected from 623 patients. During the approximately 10-year study period, starting from 2013, when the human material acquisition system for this cohort was established, to the reference date, 198,967 vials of plasma and 103,415 vials of PBMCs were collected. In addition, 4,045 vials of serum were collected starting from 2023. Consequently, a total of 306,427 vials of samples are actively being stored and managed.

(2) Individuals in the Korea HCV cohort

Considering the analysis period, data collected up to September 30, 2023 were organized (Table 2). From 2007 to the present, an average of 235 patients were enrolled per year. The study began with 198 patients in 2007 and as of 2023, a total of 3,946 patients have been enrolled. Thus, the Korea HCV cohort comprises 3,968 patients, including those who completed study participation. However, three patients who were younger than 18 years at the time of enrollment and one patient for whom there was an error in the date of birth entry were excluded. Therefore, a total of 3,964 patients were included in the analysis (Figures 1, 2).

Figure 1. Figure 1. Study population of Korea hepatitis C virus (HCV) cohort study
The number of newly diagnosed HCV infections represents as of September 30, 2023.

Table 2 Basic characteristics of patients who involved in the Korean hepatitis C virus cohort study

Basic characteristics	Number (%)
	Male	Female	Totala)
Age at baseline (yr)
18–29	34 (1.7)	32 (1.6)	66 (1.7)
30–39	108 (5.4)	125 (6.4)	233 (5.9)
40–49	372 (18.7)	248 (12.6)	620 (15.6)
50–59	566 (28.4)	591 (30.0)	1,157 (29.2)
60–69	525 (26.3)	535 (27.2)	1,060 (26.7)
70–79	332 (16.6)	352 (17.9)	684 (17.3)
≥80	58 (2.9)	86 (4.4)	144 (3.6)
Risk factorsb)
Blood transfusion	440 (22.1)	588 (29.9)	1,028 (25.9)
Needle stick injury	132 (6.6)	83 (4.2)	215 (5.4)
Acupuncture	1,536 (77.0)	1,691 (85.9)	3,227 (81.4)
Tattooing	297 (14.9)	1,219 (61.9)	1,516 (38.2)
Piercing	124 (6.2)	1,190 (60.4)	1,314 (33.2)
Inject drugs	164 (8.2)	34 (1.7)	198 (5.0)
Living in confinement facility	275 (13.8)	67 (3.4)	342 (8.6)
Diagnosis at baseline
Acute hepatitis C	57 (2.9)	65 (3.3)	122 (3.1)
Past infectionc)	37 (1.9)	46 (2.3)	83 (2.1)
Chronic hepatitis C	1,268 (63.6)	1,416 (71.9)	2,684 (67.7)
Compensated cirrhosis	279 (14.0)	267 (13.6)	546 (13.8)
Decompensated cirrhosis	52 (2.6)	59 (3.0)	111 (2.8)
Hepatocellular carcinoma	302 (15.1)	115 (5.8)	417 (10.5)
Liver transplant recipient	0 (0.0)	1 (0.1)	1 (0.0)
Antiviral therapy at baseline
Treatment termination	153 (7.7)	143 (7.3)	296 (7.5)
Undergoing treatment	444 (22.3)	471 (23.9)	915 (23.1)
Never treated	1,398 (70.1)	1,355 (68.8)	2,753 (69.5)

^a)Only subjects up to September 30, 2023 are included. ^b)Multiple responses possible. ^c)A patient diagnosed with hepatitis C in the past but not treated..

HCV genetic analysis found that type 1b and 2 genotypes were present in 35.4% (40/112) and 47.8% (54/112) of participants, respectively, indicating no significant difference compared with those found in previous years. Analysis of the demographic characteristics of the patients revealed a mean age of 58.4 years (males: 57.8 years [n=1,995, 50.3%], females: 59.1 years [n=1,969, 49.7%]). Among the male and female participants, the highest percentage of patients belonged to the 50–59 years age category, and regardless of sex, the number of patients included in the final analysis increased with an increase in age and decreased after 60–69 years.

Analysis of the risk factors revealed that 3,662 patients (92.4%) experienced at least one of the seven risk factors (blood transfusion, needlestick injury, acupuncture, tattoos, piercings, drug injection, and correctional facility). Of the seven risk factors, acupuncture had the highest frequency, followed by tattoos (e.g., eyebrow tattoo) and piercings (e.g., ear piercing). Among males, the risk factor with the highest frequency was acupuncture (n=1,536, 77.0%), followed by blood transfusion (n=440, 22.1%) and tattoos (n=297, 14.9%). Among females, acupuncture (n=1,691, 85.9%) had the highest frequency, followed by tattoos (n=1,219, 61.9%) and piercings (n=1,190, 60.4%). Of the risk factors, drug injection and correctional facilities were 4.8- and 4.1-fold higher, respectively, among males than among females.

Analysis of the anti-viral treatment at the time of enrollment revealed that the most common response was no treatment (69.5%) compared to treatment completion (7.5%) and treatment (23.1%).

(3) Diagnosis and treatment of patients in the Korea HCV cohort

Among the 3,964 patients included in the final analysis, the most common diagnosis at the time of cohort enrollment was chronic HCV infection (67.7%), followed by compensated cirrhosis (13.8%) and hepatocellular carcinoma (10.5%). Analysis of viral infection treatment status revealed that 67.6% of the patients had used DAA between 2007 and September 30, 2023. When analyzed according to age and sex, it was observed that among the 1,664 patients who were DAA users, DAA was used most frequently by the subjects belonging to the 50–59 years age category, regardless of sex.

(4) Korea HCV cohort discontinuation

Of the 3,964 patients included in the final analysis, 1,835 discontinued their participation in the study (46.3%): 959 of 1,995 males (48.1%) and 876 of 1,969 females (44.5%). The reasons for discontinuation were dropout (28.2%), death (8.9%), and treatment refusal (4.3%). Of the 351 cases for whom death was listed as the reason for discontinuation, the cause of death was only specified for 337 cases. The progression of liver cancer (n=163, 48.7%) was the most common cause of death, followed by unknown causes (n=52, 15.4%) and others (n=51, 15.1%).

(5) Use of the Korea HCV cohort findings

The results of the present study were used in clinical practice guidelines for patients with HCV infection. However, our findings also highlight the need for early diagnosis and early treatment of infected patients. Notably, the findings were used as scientific evidence for policies, such as the implementation of HCV screening and national health examination in the ROK and the “First Basic Plan for the Management of Viral Hepatitis (types B and C) for 2023–2027” based on a cost-effectiveness study on HCV treatment, along with the identification of the major route of HCV transmission in the ROK.

With the recent increase in the number of injection drug users, the need for studies that can provide scientific evidence to establish policies regarding HCV prevention and management has also increased. Accordingly, a study on the development of HCV prevention and treatment strategies for injection drug users in the ROK is being conducted as a part of an academic research and development support program since 2022. By analyzing the prevalence of HCV-related infections among injection drug users and studying the clinical and epidemiological characteristics through a multi-center prospective follow-up survey, treatment linkage rates were monitored. As a result, measures for linking hepatitis control projects are being established, including HCV diagnosis, treatment linkage, and prevention education. Moreover, as the risk of liver cancer and liver disease-related deaths can be reduced by 59% and 74%, respectively, after HCV treatment, evidence was obtained to demonstrate that HCV treatment contributes to the improvement of public health. Based on the present study, other studies are being actively conducted to identify the route of hepatitis C infection in the ROK, examine patient prognosis according to the therapeutics used, and establish preventive measures and treatment strategies.

To the best of our knowledge, this study is the only HCV cohort study conducted at the national level that follows up the epidemiological and clinical data of patients with HCV infection over time. To promote HCV research using the clinical data and materials collected to date, we aim to deposit clinical information and human materials in the National Central Human Body Resource Bank and establish a system that would enable the efficient use of the collected resources. Despite the high cure rate resulting from the introduction of HCV-targeted therapeutics, many of the enrolled patients lacked treatment experience. Accordingly, the findings of our study are expected to serve as evidence for establishing effective policies for infected patients in the ROK, including efforts to include HCV testing as a part of the national health examination. To account for the epidemiological characteristics of new infection cases that have changed in recent years, the basis for long- and short-term clinical studies on HCV infection must be created. These studies can then be used as the basis for creating a public health safety net at the national level to effectively manage hepatitis C, which currently resides in a management blind spot. The findings of the Korea HCV cohort study can be used as highly representative national data for the early diagnosis and elimination of HCV infections in the ROK. Assessments will continue to be performed to survey and monitor changing risk groups and provide scientific evidence for policy proposals.

Ethics Statement: Not applicable.

Funding Source: This research was supported by the Korea National Institute of Health (KNIH) research project (#2023-E1901-01).

Acknowledgments: None.

Conflict of Interest: The authors have no conflicts of interest to declare.

Author Contributions: Conceptualization: OUJ, SMR, JGL, MJG. Supervision: MJG, JYK. Writing – original draft: OUJ, SMR. Writing – review & editing: OUJ, SMR, MJG, JYK.