A single site study to investigate the current prevalence of anti‐hepatitis C virus antibody among substance use disorder patients in Hiroshima—Insufficient testing and diagnosis

Abstract

Aims

Hepatitis C virus (HCV) infection among drug users presents an important public health problem; however, little recognition and few approaches to address this issue in Japan. This study was conducted to investigate the current disease status by assessing anti‐HCV antibody (Ab) seroprevalence among people who inject drugs (PWIDs) and people who use drugs (PWUDs) in Hiroshima, Japan.

Methods

This study was a psychiatric single‐site chart review in patients with drug abuse problems in the Hiroshima region. The primary outcome was anti‐HCV Ab prevalence among PWIDs who underwent anti‐HCV Ab testing. The secondary outcomes included the prevalence of anti‐HCV Ab among PWUDs who underwent anti‐HCV Ab testing and the proportion of patients who underwent anti‐HCV Ab examination.

Results

A total of 222 PWUD patients were enrolled. Among these, 16 patients (7.2%) had records of injection drug use (PWIDs). Eleven (68.8%) of the 16 PWIDs received anti‐HCV Ab tests, and 4 (36.4%, 4/11) were anti‐HCV Ab‐positive. Among 222 PWUDs, 126 (56.8%) patients received anti‐HCV Ab tests, and 57 of these patients (45.2%, 57/126) were anti‐HCV Ab‐positive.

Conclusion

The prevalence of anti‐HCV Ab among PWIDs and PWUDs who visited the study site was higher than the general population, which was 2.2% among hospitalized patients between May 2018 and November 2019. Considering the World Health Organization's (WHO) elimination goal and recent advances in HCV treatment, patients with drug abuse experience should be encouraged to take HCV tests and consult hepatologists for further investigations and treatment if they are positive for anti‐HCV Ab.

INTRODUCTION

The World Health Organization (WHO) has called for the elimination of viral hepatitis by 2030.¹ In Japan, however, no official specified elimination goal has been established even though overall Japan is in alignment with the WHO objectives.

People who inject drugs (PWIDs) present a major problem in meeting the goal of elimination of viral hepatitis and PWIDs account for the majority of new HCV infection cases in high-income countries.² In the United States and European Union, PWIDs are recognized as key populations in which to prevent the spread of viral hepatitis.³ Medical associations and the Centers for Disease Control and Prevention (CDC) have taken initiatives to address this problem.^2–4 By contrast, little recognition and few approaches are available to address this issue in Japan.⁵

To date, general countermeasures against viral hepatitis have been highly appreciated in Japan.⁶ Soon after the discovery of HCV, screening of blood for transfusion and blood products was initiated. Nationwide measures to identify chronic HCV patients using a free-of-charge test were implemented in 2002. All residents aged 40 years and older were tested by the government screening program and as a result of this initiative, many people became aware that they were infected with HCV. In 2002, 1.9 million people underwent anti-HCV antibody (Ab) testing, and 31 000 people were found to be positive. The total prevalence of anti-HCV Ab was found to be approximately 1.6%.⁷

A medical expense subsidy to treat chronic HCV patients has been implemented and patients receive treatment at minimal financial cost. The number of chronic HCV patients has decreased, and the prevalence of anti-HCV Ab among the Japanese general population was estimated to be 0.28% in 2015,⁸ highlighting the success of this subsidy program.

It is believed that the number of HCV carriers is decreasing due to the improvement in HCV therapy using direct-acting antivirals (DAAs). The use of DAAs has changed the HCV treatment landscape since the late 2010s. The effectiveness of DAAs in treating naïve HCV patients in Japan is more than 96%.⁹ The high effectiveness and safety profile of DAAs have resulted in the majority of patients being cured after receiving treatment.¹⁰

In contrast, the seroprevalence of anti-HCV Ab was 36% among Japanese drug users (PWUDs) in 2017,¹¹ which was extremely high compared to that of the general Japanese population. The previous survey was conducted among drug users (61 patients in 2017; mean age, 43.4 years; number of males, 56 [91.8%]) who were admitted to or attended drug addiction rehabilitation centers. The primary drug of abuse was methamphetamine (54.1%) based on ICD-10 diagnosis.¹¹ According to the previously completed survey on drug use and infectious diseases, the prevalence of anti-HCV Ab among PWUDs (the primary drug of abuse was methamphetamine) between 1998 and 2017 was in the range of 23% to 53%.¹¹

Although the major risk factors for HCV transmission are considered to be injection drug use and tattooing,¹² there is no current data in Japan on the prevalence of anti-HCV Ab among PWUDs, and there are no data regarding how many PWUDs received confirmatory HCV RNA testing and subsequent treatment. Moreover, there is a lack of literature on the management of HCV testing and treatment among PWUDs, and there are only a few reports on HCV treatment among PWUDs and PWIDs in Japan.⁵

To achieve the WHO viral hepatitis elimination goal, it is critical to test for and treat chronic HCV in PWIDs/PWUDs, as they are a potential source of new infections. This study was, therefore, conducted to investigate the current disease status by assessing the seroprevalence of anti-HCV Ab among PWIDs and PWUDs in Japan. If the results show that the seroprevalence of anti-HCV Ab is high among PWIDs/PWUDs, then it will be essential to raise awareness of this fact and channel resources to identify and treat patients for HCV infection. The objective of this study was to estimate the seroprevalence of anti-HCV Ab among PWIDs and PWUDs between 2018 and 2021 in the Hiroshima region.

METHODS

Study design and patients

This study was a retrospective cross-sectional study conducted at a psychiatric single-site, Senogawa Hospital, Hiroshima, Japan in patients with drug abuse problems. Hiroshima was chosen for conducting this study as this region has taken a leading initiative for HCV elimination in Japan.¹³

The study was conducted in accordance with the protocol and followed the ethical principles that have their origin in the Declaration of Helsinki (as revised in Fortaleza, Brazil, October 2013), as well as the “Ethical Guidelines for Medical and Health Research Involving Human Subjects” implemented by the Ministry of Health, Labour and Welfare (MHLW), Japan, in June 2021. The study protocol is in accordance with the Declaration of Helsinki (as revised in Fortaleza, Brazil, October 2013) and was approved by the Senogawa Medical Corporation Ethical Committee (ID: R03-14).

To obtain information from study participants we utilized the “opt-out” method, by posting a notice in accordance with the Senogawa Hospital “opt-out” policy.

The study population included patients that met all the following eligibility criteria. Patients aged 16 years or older at the time of conducting the study; patients that have experience using drugs and substance use disorders (PWUDs: had at least one diagnosis of ICD-10 F11-16, F18, F19); patients that had visited Senogawa Hospital from January 2018 through to September 2021; patients who had Japanese citizenship and patients who had long-term or permanent resident status (tourists and patients with short-term visas were not included).

Patients who explicitly declined the use of data for this study were excluded.

Outcomes

The primary outcome of this study was the prevalence of anti-HCV Ab among PWIDs who underwent anti-HCV Ab testing. In this study, PWIDs were defined as patients with a record of drug injection in their clinical charts and were included in PWUDs. The secondary outcomes included the following: the prevalence of anti-HCV Ab among PWUDs who underwent anti-HCV Ab testing; the proportion of patients who underwent anti-HCV Ab examination; the proportion of patients who underwent HCV RNA examination; the proportion of HCV RNA positivity among patients who underwent HCV RNA testing; the proportion of patients who received HCV treatment; seroprevalence of anti-HCV Ab by patient characteristics; HCV treatment details if the patient had received treatment; and the reasons for HCV non-treatment, non-referral to gastroenterologists, or lack of HCV RNA testing in cases where anti-HCV Ab test results were positive.

Procedures and data collection

The anonymized data and information in the patients' medical records (starting from January 2016) required for this study were transcribed into case report forms and were transported to and analyzed by a Contract Research Organization.

Demographic data were collected including sex, birth year, history of substance abuse including the record of injection drug use, history of methamphetamine use and ICD-10 diagnosis, hepatitis B virus (HBV) infection, type of medical insurance, incarceration history, and employment status.

Laboratory data were collected and included alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin, total bilirubin (T-Bil), platelet count, γ-glutamyl transpeptidase (γ-GTP), anti-HCV Ab testing (date and results), HCV RNA testing (date and results), HCV treatment details (regimen and results), and the reasons for HCV non-treatment, non-referral to gastroenterologists or lack of HCV RNA testing in cases where anti-HCV Ab test results were positive.

To predict the future risk of advanced liver diseases, we assessed the degree of liver fibrosis using the Fibrosis-4 Index (FIB-4 index), which was calculated using the following formula:¹⁴$\mathrm{FIB}-4\text{index}=\left[\mathrm{AST}\left(\mathrm{IU}/\mathrm{L}\right)\times \mathrm{age}\left(\text{years}\right)\right]/\left[\text{platelet count}\left({10}^9/\mathrm{L}\right)\times \mathrm{ALT}{\left(\mathrm{IU}/\mathrm{L}\right)}^{½}\right].$

Statistical methods

All statistical analysis procedures were described in detail in the Statistical Analysis Plan (SAP). Descriptive statistics were used to describe the demographic and other basic features of the data. Continuous variables were described by the number of valid cases and missing data, mean, standard deviation, median, minimum, and maximum. Categorical variables were described as the total number and percentage per category. Fisher's exact test was used to compare the laboratory data between anti-HCV Ab-positive patients and anti-HCV Ab-negative patients. In this study, p-values less than 0.05 were considered statistically significant. All statistical analyses were conducted using SAS version 9.4 (SAS Institute Inc., Cary, NC, USA).

RESULTS

Patient characteristics

A total of 224 cases were collected (Figure 1). Two patients that had medical records based on telephone consultations without visits were excluded from the study, and 222 patients who met all the selection criteria were enrolled in the study (PWUDs; study population). Among 222 patients, 16 (7.2%) patients had a record of drug injection (PWIDs; primary analysis population), 60 (27.0%) patients had no record of drug injection, and 146 (65.8%) patients had unknown experience of drug injection.

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Data were collected from 222 PWUDs (mean age, 49.3 years; number of males, 174 (78.4%), Table 1). A total of 92 (41.4%) patients were enrolled in national health insurance and 110 (49.5%) patients were on welfare. A total of 41 (18.5%) patients were employed, and 100 (45.0%) patients had a history of incarceration. Among 120 (54.1%) patients who underwent HBsAg testing, one (0.8%) patient was positive.

TABLE 1 Patient characteristics.

Characteristics	PWUDs (n = 222)	PWIDs (n = 16)
Age at diagnosis (years)
Mean (SD)	49.3 (14.0)	46.8 (14.0)
Median (min–max)	49.0 (20–90)	44.5 (23–74)
10–39	53 (23.9)	4 (25.0)
40–59	118 (53.2)	9 (56.3)
≥60	51 (23.0)	3 (18.8)
Sex
Male	174 (78.4)	12 (75.0)
Female	48 (21.6)	4 (25.0)
Type of health insurance
National	92 (41.4)	3 (18.8)
Welfare	110 (49.5)	12 (75.0)
Not applicable	20 (9.0)	1 (6.3)
Employment status
Yes	41 (18.5)	2 (12.5)
No	173 (77.9)	13 (81.3)
Unknown	8 (3.6)	1 (6.3)
Incarceration history
Yes	100 (45.0)	11 (68.8)
No	69 (31.1)	2 (12.5)
Unknown	53 (23.9)	3 (18.8)
Hospitalization in Senogawa Hospital
Yes	129 (58.1)	9 (56.3)
No	93 (41.9)	7 (43.8)
HBsAg test
Yes	120 (54.1)	11 (68.8)
No	102 (45.9)	5 (31.3)
HBsAg test
Positive	1 (0.8)	0 (0.0)
Negative	119 (99.2)	11 (100.0)

A total of 161 (72.5%) patients had experience with using methamphetamine, and 160 patients (72.1%) were diagnosed with ICD10 F15; other stimulant-related disorders including amphetamine-related disorders and caffeine (Table 2), consistent with the fact that methamphetamine/amphetamine is the most abused drug in Japan.¹⁵ A total of 47 patients (21.2%) were diagnosed with ICD10 F10; alcohol-related disorders at the same time as drug abuse (F11-16, F18, F19).

TABLE 2 Methamphetamine use and substance use disorders by ICD10 diagnosis.

	PWUDs (n = 222)	PWIDs (n = 16)
Methamphetamine use
Yes	161 (72.5)	15 (93.8)
No	61 (27.5)	1 (6.3)
Substance use disorders by ICD10
F10_Alcohol	47 (21.2)	3 (18.8)
F11_Opioids	2 (0.9)	0 (0.0)
F12_Cannabinoids	7 (3.2)	1 (6.3)
F13_Sedatives or hypnotics	54 (24.3)	4 (25.0)
F14_Cocaine	1 (0.5)	1 (6.3)
F15_Other stimulants incl. amphetamine-related disorders and caffeine	160 (72.1)	14 (87.5)
F16_Hallucinogens	0 (0.0)	0 (0.0)
F17_Tobacco	0 (0.0)	0 (0.0)
F18_Volatile solvents	16 (7.2)	0 (0.0)
F19_Multiple drug use and use of other psychoactive substances	6 (2.7)	0 (0.0)

Anti-HCV Ab testing and prevalence

Among 16 PWIDs, 11 (68.8%) patients received anti-HCV Ab examinations, and 4 (36.4%, 4/11) were anti-HCV Ab-positive (Figure 2A). Among 222 PWUDs, 126 (56.8%) patients received anti-HCV Ab tests, and 57 of these patients (45.2%, 57/126) were anti-HCV Ab-positive (Figure 2B).

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Among 161 patients with experience of methamphetamine use, 90 (55.9%) patients received anti-HCV Ab examinations, and 55 of these patients (61.6%, 55/90) were anti-HCV Ab-positive (Figure 2C).

The prevalence of anti-HCV Ab was higher among patients in their 40s and 50s (Table 3). The positivity of anti-HCV Ab was 50.6% in men and 32.4% in women. The positivity of anti-HCV Ab was significantly higher among patients who had experienced of methamphetamine use (61.1%) while 5.6% of patients without experience of methamphetamine use were anti-HCV Ab-positive. The prevalence of anti-HCV Ab was significantly higher among patients on welfare (55.1%) than patients enrolled in national health insurance (27.7%). The positivity of anti-HCV Ab was significantly higher among patients with a history of incarceration (62.3%). The positivity of anti-HCV Ab was higher among unemployed patients (49.5%), but the difference was not statistically significant.

TABLE 3 Seroprevalence of anti-HCV Ab by patient characteristics.

Characteristics	Anti-HCV ab results
Positive (n = 57)	Negative (n = 69)
Age
10–39	4 (11.4)	31 (88.6)
40–59	37 (58.7)	26 (41.3)
≥60	16 (57.1)	12 (42.9)
p Value	<0.0001
Sex
Male	45 (50.6)	44 (49.4)
Female	12 (32.4)	25 (67.6)
p Value	0.0778
Methamphetamine use
Yes	55 (61.1)	35 (38.9)
No	2 (5.6)	34 (94.4)
p Value	<0.0001
Type of health insurance
National	13 (27.7)	34 (72.3)
Welfare	38 (55.1)	31 (44.9)
Not applicable	6 (60.0)	4 (40.0)
p Value	0.0087
Incarceration history
Yes	38 (62.3)	23 (37.7)
No	7 (17.1)	34 (82.9)
Unknown	12 (50.0)	12 (50.0)
p Value	<0.000
Employment status
Yes	5 (26.3)	14 (73.7)
No	51 (49.5)	52 (50.5)
Unknown	1 (25.0)	3 (75.0)
p Value	0.1338

Laboratory data by sub-groups

Regarding PWUDs, the median ALT level was 24.0, and 31 (18.2%) patients had elevated ALT levels (>44, Table 4). The median AST level was 24.0, and 41 (24.1%) patients had elevated AST levels (>38). Platelet count, Alb, T-Bil, γ-GTP, and were within the reference range for more than 50% of patients. Laboratory data by anti-HCV Ab-positive/negative are as follows: median platelet count (20.80/26.70) was found to be lower in the anti-HCV Ab-positive group, and 22.8% of patients had platelet counts lower than the reference range (<15.0 × 10⁴/μL) in the anti-HCV-positive group while 5.8% of patients had platelet counts within the reference range in the anti-HCV-negative group. Median ALT and AST were higher in the anti-HCV Ab-positive group. In the anti-HCV-positive group, 28.1% and 45.6% of patients had ALT and AST values higher than the reference range (>44 and >38, respectively), while 11.6% and 14.5% of patients had elevated ALT and AST values in the anti-HCV negative group. Median FIB-4 index values, which predict future risk of advanced liver diseases, were higher in the anti-HCV Ab-positive group, and 54.4% of patients had a FIB-4 index value above the proposed low cut-off point (>1.45) in the anti-HCV-positive group. Laboratory data and the FIB-4 index distribution with statistical significance tests by anti-HCV Ab-positive/negative status in the PWUD population are shown in Table S1.

TABLE 4 Laboratory data by sub-groups.

Characteristics	PWUDs (n = 222)	HCV
Positive (n = 57)	Negative (n = 69)
Platelets (×104/μL), n (%)	170 (76.6)	57 (100.0)	69 (100.0)
Mean (SD)	23.37 (7.35)	21.10 (7.11)	26.21 (7.14)
Median (min–max)	23.90 (4.6–47.3)	20.80 (4.6–35.0)	26.70 (10.3–47.3)
Missing	52 (23.4)	0 (0.0)	0 (0.0)
<10.0	3 (1.8)	1 (1.8)	0 (0.0)
≥10.0–<15.0	21 (12.4)	12 (21.1)	4 (5.8)
≥15.0	146 (85.9)	44 (77.2)	65 (94.2)
ALT (IU/L), n (%)	170 (76.6)	57 (100.0)	69 (100.0)
Mean (SD)	31.9 (25.1)	37.4 (28.8)	27.7 (22.4)
Median (min–max)	24.0 (5–152)	28.0 (10–152)	22.0 (5–125)
Missing	52 (23.4)	0 (0.0)	0 (0.0)
≤44	139 (81.8)	41 (71.9)	61 (88.4)
>44–132	30 (17.6)	15 (26.3)	8 (11.6)
>132	1 (0.6)	1 (1.8)	0 (0.0)
AST (IU/L), n (%)	170 (76.6)	57 (100.0)	69 (100.0)
Mean (SD)	35.3 (31.3)	41.9 (32.6)	31.3 (33.6)
Median (min–max)	24.0 (9–223)	32.0 (12–213)	21.0 (9–223)
Missing	52 (23.4)	0 (0.0)	0 (0.0)
≤38	129 (75.9)	31 (54.4)	59 (85.5)
>38–114	36 (21.2)	25 (43.9)	7 (10.1)
>114	5 (2.9)	1 (1.8)	3 (4.3)
Alb (g/dL), n (%)	169 (76.1)	57 (100.0)	69 (100.0)
Mean (SD)	3.90 (0.48)	3.86 (0.39)	3.97 (0.59)
Median (min–max)	3.90 (1.1–5.0)	3.90 (2.8–4.6)	4.10 (1.1–5.0)
Missing	53 (23.9)	0 (0.0)	0 (0.0)
<4.0	89 (52.7)	34 (59.6)	31 (44.9)
≥4.0	80 (47.3)	23 (40.4)	38 (55.1)
T-Bil (mg/dL), n (%)	168 (75.7)	57 (100.0)	69 (100.0)
Mean (SD)	0.61 (0.49)	0.61 (0.33)	0.56 (0.35)
Median (min–max)	0.50 (0.2–5.0)	0.50 (0.2–1.8)	0.50 (0.2–2.2)
Missing	54 (24.3)	0 (0.0)	0 (0.0)
≤1.2	157 (93.5)	53 (93.0)	65 (94.2)
>1.2–3.0	10 (6.0)	4 (7.0)	4 (5.8)
>3.0	1 (0.6)	0 (0.0)	0 (0.0)
γ-GTP (IU/L), n (%)	170 (76.6)	57 (100.0)	69 (100.0)
Mean (SD)	58.4 (99.0)	61.3 (92.7)	61.2 (120.0)
Median (min–max)	29.5 (8–834)	30.0 (8–528)	28.0 (8–834)
Missing	52 (23.4)	0 (0.0)	0 (0.0)
≤73	141 (82.9)	47 (82.5)	59 (85.5)
>73	29 (17.1)	10 (17.5)	10 (14.5)
FIB-4 index, n (%)	169 (76.1)	57 (100.0)	69 (100.0)
Mean (SD)	1.65 (1.55)	2.16 (1.78)	1.12 (1.05)
Median (min–max)	1.11 (0.10–9.56)	1.64 0.48–9.37	0.64 (0.10–5.54)
Missing	52 (23.4)	0 (0.0)	0 (0.0)
<1.45	97 (57.4)	26 (45.6)	52 (75.4)
≥1.45–3.25	54 (32.0)	20 (35.1)	13 (18.8)
>3.25	18 (10.7)	11 (19.3)	4 (5.8)

Reasons for lack of follow-up testing and treatment

Among 222 PWUDs, eight patients (5, anti-HCV Ab-positive; 1, anti-HCV Ab negative; 2, unknown for anti-HCV Ab) underwent HCV RNA testing, and five of them (62.5%) were positive. Among 57 patients who were positive for anti-HCV Ab, only 5 (8.8%) received HCV RNA tests. The main reasons for the lack of HCV RNA testing were to prioritize psychiatric treatment (90.4%), and because no symptoms presented (9.6%, Figure 3A). Among 10 patients who received HCV treatment, 6 patients received interferon (IFN)-free DAA treatment (60.0%), 3 patients received IFN-based treatment (30.0%); 3 patients were cured (30.0%) while the outcome of the others was unknown. The main reasons for non-HCV treatment were to prioritize psychiatric treatment (87.5%), and because no symptoms presented (10.7%, Figure 3B). Among 222 PWUDs, 10 patients (4.5%) were referred to a gastroenterologist. The main reasons for not referring patients to a gastroenterologist were to prioritize psychiatric treatment (93.8%) and no request was made by patients (16.7%, Figure 3C).

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DISCUSSION

This study, using a medical chart review, is the first investigation to estimate the seroprevalence of anti-HCV Ab among PWIDs and PWUDs between 2018 and 2021 in the Hiroshima region in Japan.

Seroprevalence of anti-HCV Ab

The prevalence of anti-HCV Ab among PWIDs and PWUDs who visited the study site was 36.4% (95% CI: 10.9–69.2) and 45.2% (95% CI: 36.4–54.3), respectively. The prevalence of anti-HCV Ab observed in this study was similar to the previous survey.⁹ According to a research report by The Health and Labour Sciences Research Grants, the prevalence of anti-HCV Ab among hospitalized patients at a major medical institution was 2.2% between May 2018 and November 2019.¹⁶ These results imply that the prevalence of anti-HCV Ab among PWIDs and PWUDs was higher than that of the general population, and it was considered that there was no declining trend for the prevalence of anti-HCV Ab among PWIDs and PWUDs, despite the fact that anti-HCV Ab positivity is decreasing in the overall Japanese population.⁶

The positivity of anti-HCV Ab was significantly higher among patients who had experienced the use of methamphetamine, the most popular drug of abuse in Japan.¹⁵ According to the Japanese national survey on drug use and infectious diseases, more than 80% of patients with experience of methamphetamine use had experienced drug injection.¹¹ Although only 16 patients had records of drug injection in this study, it was considered that more patients with experience of methamphetamine use may have experienced drug injection, and this could be one of the possible reasons for the high prevalence of anti-HCV Ab.

Usually, the prevalence of anti-HCV Ab is considered to be higher in PWIDs than PWUDs, as PWUDs predominantly include drug users who use drugs by routes of administration other than injection (e.g., cannabis, over-the-counter drug). In this study, the prevalence of anti-HCV Ab was, however, higher in PWUDs than in PWIDs. It was considered that this might be attributed to limited information on the route of drug administration and that only 16 patients were included as PWIDs.

The proportion of patients who received HCV testing and treatment

Among 222 PWUDs, 126 patients (56.8%) underwent anti-HCV Ab testing. According to the questionnaire survey implemented by the MHLW in 2017, the general implementation rate of HCV tests among 8264 Japanese citizens (aged 20–89 years) was 60.9%.¹⁷ The implementation rate of anti-HCV Ab testing observed in this study was comparable to that of the previous survey conducted in 2017. However, considering the high positivity of anti-HCV Ab, more patients with experience of drug use should be encouraged to take HCV tests.

Among 57 patients who were positive for anti-HCV Ab, 5 (8.8%) received HCV RNA tests. Despite the high prevalence of anti-HCV Ab, only a few patients underwent HCV RNA testing and received treatment. HCV RNA testing is necessary to confirm and make a diagnosis of current HCV infection. Patients with HCV in their bloodstream that have not been diagnosed with HCV infection will not receive medical treatment and appropriate preventive services. It is, therefore, critical to conduct HCV RNA testing to identify current infections.

Additionally, while 17.2% of outpatients received an anti-HCV Ab test, 85.3% of hospitalized patients underwent anti-HCV Ab testing. This result may indicate that the main purpose of anti-HCV Ab testing may have been to prevent new HCV infections in the hospital.

These data imply that there is a certain number of HCV carriers who remain untested or untreated among people with experience of drug use.

Laboratory data and other results

The mean and median values of laboratory data (ALT, AST, FIB-4 index) were within the reference ranges; however, the mean and median value of ALT and AST were higher in the anti-HCV Ab-positive group than in other groups. Furthermore, the FIB-4 index, which shows the risk for the future development of hepatic disease, was also higher in the anti-HCV-positive group. Although the FIB-4 index tends to be higher in older populations, as its calculation formula contains “age”; 32.3% of PWUDs in the age range of 10–50 years had a Fib-4 index ≧1.45 (low cut-off point) in this study. The FIB-4 index distribution by age in the PWUD population is shown in Table S2. These data indicate that even younger PWUDs (10–50s) had a higher risk for hepatic diseases.

The main reasons for not undergoing HCV RNA testing and not receiving HCV treatment were to prioritize psychiatric treatment and because no symptoms were presented. Oral DAA treatment can, however, be administered concurrently with psychiatric treatment. Currently, therefore, HCV treatment has fewer barriers for PWIDs and PWUDs compared to previously, when only IFN treatment was available, which requires injection.

Considering the high prevalence of anti-HCV Ab among PWIDs and PWUDs, more anti-HCV Ab testing should be implemented for patients with drug use experience and patients should be encouraged to undergo HCV RNA testing in cases of positive results, regardless of laboratory data results.

Measures in the United States and challenges in linkage to care in Japan

The increase of HCV incidence due to increased numbers of PWIDs is considered an important public health problem in the United States. The CDC has begun surveillance, which includes systematic collection, analysis, evaluation, and interpretation of viral-hepatitis-related data to achieve the elimination goal; and this report is updated annually.⁴ More importantly HCV micro eliminations, a public health strategy that focuses on key populations (e.g., PWUDs, prisoners, etc.), have been implemented by integrating harm reduction, which is considered critical to reduce HCV infection.^18–20

In Japan, while collaborative efforts between gastroenterologists and addiction psychiatrists have reported on alcohol abuse treatment,²¹ HCV tests and treatments were rarely integrated with harm reduction in drug abuse treatment. This could also be the basis for the ongoing high prevalence of anti-HCV Ab, which will require a change to the status quo to lower the prevalence.

There may be discussions and arguments made on the appropriateness of promoting the testing and treatment for people who used illegal drugs, with a history of incarceration, on welfare, unemployed, and have a risk of reinfection. Treatment of advanced liver diseases (e.g., liver cirrhosis, hepatocellular carcinoma) incurs higher costs than conducting HCV testing and treatment,²² and promoting the increase of HCV testing in PWIDs and PWUDs is, therefore, beneficial from a health economics perspective. In a systematic review, the rate of HCV reinfection after successful DAA therapy among people with recent drug use was reported to be 5.9 per 100 person-years.²³ A recent study showed a reinfection rate of 1.7 per 100 person-years among people receiving opioid agonist therapy (OAT) for at least 3 months and who were at least 80% adherent to OAT appointments.²⁴ These data showed that the reinfection rate was lower if patients continue to engage in addiction treatment therapies. Furthermore, the cure for HCV infection should have a positive effect on PWIDs and PWUDs. The eradication of HCV results in clinical improvement, and the completion of HCV treatment might help these individuals to be comprehensively socially integrated by raising the self-esteem of patients.¹⁸

Study limitations

The results should be viewed with caution bearing the following limitations in mind.

Firstly, this is a psychiatric single-site study of patients with substance abuse problems and may not be generalizable to the nationwide population. The results and challenges reported in this study may, however, be applied not only to psychiatric hospitals but also to medical facilities in Japan, as challenges in insufficient HCV testing may be attributed to social issues and a conservative treatment strategy for drug users. It is believed that these individuals should first stop drug use, and after successful cessation would deserve access to social services, including medical treatment. This could also be one of the reasons that harm reduction is not fully incorporated into drug abuse treatment in Japan. While this was a single-site study, of note, the study was conducted at a psychiatric hospital designated as the central medical institute for addiction treatment in the Hiroshima region, and there are medical cooperation networks between the study site, several medical institutes, clinics, and the Hiroshima prefectural government. There are approximately 100 patients receiving treatment for drug abuse per year at the study site, and this hospital ranked high, seventh of 1217 institutes in 2020, for the number of patients with drug abuse problems, at a single medical institute in Japan.²⁵ Based on the above details, while the study results represent the actual conditions of PWUDs in the Hiroshima region, we believe that the results may broadly reflect the situation in Japan. To comprehensively understand the nationwide picture of drug abuse and HCV prevalence in Japan it is, however, necessary to conduct future nationwide studies to confirm the HCV testing and treatment status in Japan, and we hope that the results of this study will help generate interest in conducting such a nationwide study.

Secondly, there were only 16 patients in the primary analysis population due to inadequate procedures for recording the route of drug administration. Although more patients with experience of methamphetamine use were considered to have experienced drug injection, future prospective studies collecting the routes of drug administration are required to confirm the causal relationship between injection drug use and the high prevalence of anti-HCV Ab.

Thirdly, information on tattooing, one of the major risk factors for HCV transmission, is not available in this study, as the study population predominantly included tattooed patients, and as such no information on tattooing was collected in the medical records. Future prospective studies collecting information on tattooing are required to investigate the relationship between tattooing and the prevalence of anti-HCV Ab.

Fourthly, the FIB-4 index was higher in the anti-HCV-positive group; however, detailed information on alcohol consumption or other fibrosis markers was not obtained in this study. These data are required to evaluate the actual degree of liver fibrosis.

CONCLUSION

In this study, 36.4% of PWIDs and 45.2% of PWUDs were found to be anti-HCV Ab-positive and only a few patients received HCV RNA testing and treatment. More testing and treatment should be implemented for PWIDs and PWUDs to prevent new infections not only in hospital but also in the general public. The reinfection rate was lower if patients continue to engage in addiction treatment therapies. Promoting HCV testing in PWIDs and PWUDs is beneficial from a health economics perspective. Moreover, the life expectancy for people who respond well to HCV treatment is far higher than that for people with liver cirrhosis, hepatocellular carcinoma, etc. In consideration of the benefits listed above; the WHO elimination goal; the promotion of control measures for hepatitis by MHLW²⁶; and the significant improvement in HCV treatment, PWIDs and PWUDs should be encouraged to undergo HCV testing regardless of laboratory data results and to undergo treatment if they are infected.

AUTHOR CONTRIBUTIONS

All authors made substantial contributions to all of the following: (1) Substantial contributions to the conception or design of the work, or acquisition, analysis, or interpretation of data for the work; (2) drafting the work or revising it critically for important intellectual content; (3) final approval of the version to be published; (4) agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

ACKNOWLEDGMENTS

The authors extend their gratitude to the participants, their families, investigators, and site personnel who participated in this study. The authors wish to acknowledge Kazutake Yoshizawa, Luis Yamamoto, Masahiko Nakayama, Kazuo Morita, Hiroyuki Hozawa, Masao Urata, and Yukiko Okada of AbbVie GK for their contribution to this study. Medical writing support was provided by Robert Phillips and Kyoko Inuzuka at Clinical Study Support, Inc. (Nagoya, Japan) and was funded by AbbVie GK, Tokyo, Japan.

FUNDING INFORMATION

This study was funded by AbbVie GK, Tokyo, Japan. AbbVie contributed to the design; participated in the collection, analysis, and interpretation of data; in writing, reviewing, and approval of the final version of the manuscript.

CONFLICT OF INTEREST STATEMENT

In the previous 36 months, Ariyuki Kagaya has received research grants from AbbVie GK, Japan; Senogawa Hospital, Japan; and a Health Labour Sciences Research Grant (20GC1015); and is one of the directors of the “The Japanese Society of Alcohol-Related Problems”. Yuko Nagaoki declares no conflict of interest. Satomi Shimura is an employee of AbbVie GK, Tokyo, Japan, the company that funded this research. Katsuyoshi Kawana is an employee of AbbVie GK, Tokyo, Japan, the company that funded this research and holds stock or stock options in AbbVie Inc. In the previous 36 months, Kazuaki Chayama has received research grants from AbbVie GK, Japan; Eisai Co. Ltd., Japan; Otsuka Pharmaceutical Co. Ltd., Japan; and Chugai Pharmaceutical Co. Ltd., Japan; consulting fees from ASKA Pharmaceutical Co. Ltd., Japan; GlaxoSmithKline K.K., Japan; Eisai Co. Ltd., Japan; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AbbVie GK, Japan; MSD K.K., Japan; Bristol-Myers Squibb K.K., Japan; Abbott Japan LLC; and Gilead Sciences K.K., Japan.

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available in the manuscript and supplementary material of this article.

ETHICS STATEMENT

Approval of the Research Protocol by an Institutional Reviewer Board: The study protocol was approved by the Senogawa Medical Corporation Ethical Committee (ID: R03-14).

Informed Consent: Informed consent was conducted using the “opt-out” method in which a notice was posted in accordance with the Senogawa Hospital “opt-out” policy.

Registry and the Registration No. of the study/trial: The Registration No. of the study is ID: R03-14.

Animal Studies: Not applicable.

References

World Health Organization [Internet]. Final global health sector strategies on respectively, HIV, viral hepatitis and sexually transmitted infections, 2022–2030. [cited 2022 Oct 20]. Available from: https://www.who.int/teams/global‐hiv‐hepatitis‐and‐stis‐programmes/strategies/global‐health‐sector‐strategies/developing‐ghss‐2022‐2030

European Association for Study of the Liver [Internet]. Policy statement on drug use and the global hepatitis C elimination goal. [cited 2022 Oct 20]. Available from: https://easl.eu/publication/policy‐statement‐drug‐use‐hepc/

American Association for the Study of Liver Diseases Infectious Diseases Society of America [Internet]. HCV guidance: Recommendations for testing, managing, and treating hepatitis C. [cited 2022 Oct 20]. Available from: https://www.hcvguidelines.org/unique‐populations/key

Centers for Disease Control and Prevention [Internet]. Viral hepatitis. [cited 2022 Oct 20]. Available from: https://www.cdc.gov/hepatitis/index.htm

Tamori A, Uchida‐Kobayashi S, Kozuka R, Motoyama H, Yoshida K, Odagiri N, et al. High dropout rate from aftercare program of antihepatitis C therapy for patients with history of injection drug use. JGH Open. 2020;4(5):964–9.

Tanaka J, Akita T, Ko K, Miura Y, Satake M. Countermeasures against viral hepatitis B and C in Japan: an epidemiological point of view. Hepatol Res. 2019;49(9):990–1002.

Ministry of Health Labour and Welfare [Internet]. The results of viral hepatitis testing from 2002 to 2006. (in Japanese). [cited 2022 Oct 20]. Available from: https://www.mhlw.go.jp/houdou/2007/10/h1003‐1.html

Ministry of Health Labour and Welfare [Internet]. The 24th council for promotion of measures against hepatitis (in Japanese). [cited 2022 Oct 20]. Available from: https://www.mhlw.go.jp/stf/newpage_08387.html

Toyoda H, Atsukawa M, Uojima H, Nozaki A, Tamai H, Takaguchi K, et al. Trends and efficacy of interferon‐free anti‐hepatitis C virus therapy in the region of high prevalence of elderly patients, cirrhosis, and hepatocellular carcinoma: a real‐world, nationwide, multicenter study of 10 688 patients in Japan. Open Forum Infect Dis. 2019;6(5): [eLocator: ofz185].

Nozaki A, Atsukawa M, Kondo C, Toyoda H, Chuma M, Nakamuta M, et al. The effectiveness and safety of glecaprevir/pibrentasvir in chronic hepatitis C patients with refractory factors in the real world: a comprehensive analysis of a prospective multicenter study. Hepatol Int. 2020;14(2):225–38.

Wada K. “Research project on HIV infection and behavior monitoring among drug abusers and addicts”, Research program for counter measures of AIDS, Health and labor sciences research grant. (in Japanese). 2017.

Jafari S, Copes R, Baharlou S, Etminan M, Buxton J. Tattooing and the risk of transmission of hepatitis C: a systematic review and meta‐analysis. Int J Infect Dis. 2010;14(11):e928–40.

Hiroshima Prefecture [Internet]. Press release about an agreement for promoting countermeasures against viral hepatitis between Hiroshima prefecture, Hiroshima University, and AbbVie. (in Japanese). [cited 2022 Oct 20]. Available from: https://www.pref.hiroshima.lg.jp/site/kanenshinsei/hepacontract.html

Toyoda H, Atsukawa M, Watanabe T, Nakamuta M, Uojima H, Nozaki A, et al. Marked heterogeneity in the diagnosis of compensated cirrhosis of patients with chronic hepatitis C virus infection in a real‐world setting: a large, multicenter study from Japan. J Gastroenterol Hepatol. 2020;35(8):1420–5.

Yamamoto T, Kimura T, Tamakoshi A, Matsumoto T. Biennial changes in the characteristics of patients with methamphetamine use disorder in Japan from 2000 to 2020. J Psychoactive Drugs. 2022;1–9. doi: [DOI: https://dx.doi.org/10.1080/02791072.2022.2105181]