Abstract
Background and Aim
The World Health Organization has a goal to eliminate the hepatitis C virus (HCV) by 2030. To achieve this, effective screening for HCV is essential. We evaluated the utility of the ELECSYS® HCV Duo immunoassay (Duo assay) for HCV screening.
Materials and Methods
This single-center retrospective study included 184 HCV patients from 2014 to 2017. We measured HCV antibody (Duo/Ab) and HCV core antigen (Duo/cAg) using the Duo assay in HCV RNA-positive samples obtained before DAA therapy. We compared Duo/cAg positivity rates according to host and viral factors. We also performed logistic regression analysis and decision tree analysis to identify independent factors and profiles for Duo/cAg false-negative results, respectively.
Results
Duo/Ab positivity rates were 100%, and Duo/cAg positivity rates were 78% in all subjects. Duo/cAg positivity rates were 40.0%, 78.6%, and 92.9% at HCV RNA levels ≤4.9, 5.0–5.9, and ≥6.0 log IU/mL, respectively (p<0.0001). There were no significant differences in Duo/cAg positivity rates by gender, age, body mass index, ALT >30 U/L, and HCV genotype. In multivariate analysis, the HCV RNA level (Unit −1.0 log IU/mL, OR 5.49, CI 3.12–10.56, p<0.0001) was the only independent factor associated with Duo/cAg false-negative results. Decision tree analysis revealed that HCV RNA ≥5.7 log IU/mL was the profile associated with the lowest false-negative rate (7.4%). In contrast, HCV RNA <4.4 log IU/mL was the profile associated with the highest false-negative rate (100%).
Conclusion
The Duo assay identified approximately 80% of HCV carriers without HCV RNA measurement, regardless of patient background, providing substantial clinical, economic, and time-saving benefits. However, clinicians should be aware of limitations in patients with low HCV RNA levels.
Keywords: HCV, HCV antibody, HCV antigen, HCV duo
Highlights & Insights
Scientific Gap: Despite the goal of eliminating HCV by 2030, many HCV patients remain undiagnosed. The ELECSYS® HCV Duo immunoassay (Duo assay) detects both antibodies and core antigens, but its sensitivity and specificity in real-world practice are unclear.
Key Finding: The Duo assay identified 100% of HCV carriers via antibody detection and 78% via core antigen detection, with fewer false negatives in high viral load patients.
Clinical Impact: The Duo assay is a rapid, cost-effective screening tool for diagnosing HCV without RNA testing, aiding early diagnosis and treatment.
Introduction
Chronic hepatitis C virus (HCV) infection is a leading cause of liver cirrhosis, liver failure, and hepatocellular carcinoma (HCC).[1–3] Direct-acting antiviral agents (DAA) have contributed to high rates of sustained virological response (SVR) in patients with HCV-related chronic liver disease.[4,5] However, in Japan, it is estimated that 300,000–600,000 untreated patients with HCV remain, and the eradication of HCV has not yet been achieved.[6]
The World Health Organization (WHO) has set a goal of eliminating HCV by 2030 in World.[7] An obstacle to achieving this goal is that HCV RNA is not measured in a large number of individuals with positive HCV antibody tests.[8,9] Therefore, they have not been diagnosed as HCV carriers and are missing the opportunity to receive treatment. Thus, it is crucial to efficiently identify patients eligible for treatment among those who test positive for HCV antibodies.
The ELECSYS® HCV Duo immunoassay (Duo assay) was developed in 2022. The Duo assay is designed for the detection of HCV carriers through a simultaneous immunoassay for HCV antibodies (Duo/Ab) and HCV core antigens (Duo/cAg) within a single platform. This assay provides rapid results with a processing time of only 27 minutes. Notably, a positive Duo/cAg test result makes it possible for individuals to be diagnosed as HCV carriers on the same day their blood sample is collected.[10] Consequently, the Duo assay may reduce the need for additional HCV RNA measurement to identify infected individuals. Furthermore, the rapid identification of HCV-infected individuals is expected to improve medical consultation and increase the number of patients receiving antiviral therapy. However, there are still few reports on the diagnostic sensitivity and specificity of the Duo assay as applied to real-world clinical practice.[10–12]
The aim of this study was to evaluate the usefulness of the Duo assay in the diagnosis of HCV carriers. In addition, we also identified independent factors and profiles for Duo/cAg false-negative results.
Materials and Methods
Study Design and Ethics
This study is a single-center retrospective study. The study was performed in accordance with the ethical principles described in the Declaration of Helsinki. It was approved by the Clinical Research Ethics Committee of our hospital on November 11, 2024 (approval no. 24152). An opt-out approach was used to obtain informed consent from the patients, and personal information was protected during data collection.
Patients
The subjects were 184 HCV patients who visited our hospital between January 2014 and December 2017. All patients were infected with HCV genotypes 1 or 2. HCV RNA-positive samples obtained before DAA treatment were used for analysis. According to the results of the Duo assay, all patients were classified into Duo/cAg-positive or false-negative groups. In this study, a “false-negative” result for Duo/cAg was defined as a negative Duo/cAg test in an HCV RNA-positive patient. We excluded patients who met any of the following criteria: HBV co-infection, HIV co-infection, or other liver diseases.
Laboratory Assessment
Measurement of Duo Assay
The Duo assay was measured using electrochemiluminescence immunoassay (ECLIA) for qualitative detection of HCV antibodies and HCV core antigens (ELECSYS® HCV Duo immunoassay; Roche Diagnostics GmbH, Mannheim, Germany). Stored serum samples were processed using the Cobas 8000 e801 machine following the manufacturer’s instructions (Roche Diagnostics GmbH). The results were reported as cutoff index (COI) values in three categories: the main result (Duo) and two modules consisting of Duo/Ab and Duo/cAg. The Duo result was automatically calculated from Duo/Ab and Duo/cAg values, with a COI of less than 1.0 indicating a non-reactive result and a COI of 1.0 or greater indicating reactivity. Similarly, for both Duo/Ab and Duo/cAg, COI values below 1.0 indicate non-reactive results, while values of 1.0 or higher indicate reactivity for Duo/Ab and Duo/cAg, respectively.
Measurement of HCV RNA
HCV RNA was measured using a quantitative real-time polymerase chain reaction (Cobas TaqMan HCV Test, version 3.0; Roche Diagnostics, Basel, Switzerland). The results of the HCV RNA test were based on the clinical data at the time of blood collection.
Data Collection
Information on gender, age, body mass index (BMI), obesity, and history of cirrhosis or interferon (IFN) therapy or HCC treatment was collected from medical records. We measured the following laboratory tests: aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (GGT), albumin, total bilirubin, prothrombin time, creatinine, white blood cell count, hemoglobin, platelet count, fibrosis-4 (FIB-4) index, alpha fetoprotein, and des-γ-carboxy prothrombin.
Statistical Analysis
Chi-square tests were used to analyze the association between categorical variables, and the Wilcoxon test was used for continuous variables. Factors associated with Duo/cAg false-negative results were statistically evaluated by univariate logistic regression models. Odds ratios and their 95% confidence intervals with corresponding P values are presented. All statistical analyses were performed using JMP® Pro version 16.0 (SAS Institute Inc., Cary, North Carolina, USA). Statistical significance was defined as p<0.05, as described previously.[13,14]
Comparison of Duo/cAg Positivity According to Host, Hepatic, and Viral Factors between the Duo/Cag-Positive and False-Negative Groups
We compared the Duo/cAg positivity rate according to host factors, including age, gender, and BMI. We also compared the Duo/cAg positivity rate according to hepatic and viral factors, including ALT >30 U/L, HCV genotype, and HCV RNA levels.
Independent Factors and Profiles of Duo/cAg False-Negative Results
A logistic regression model was used to identify independent variables associated with Duo/cAg false-negative results in multivariate analysis. Explanatory variables were selected based on age, sex, creatinine, and HCV RNA levels in a stepwise manner, minimizing the Bayesian information criterion as previously described.[15]
The stepwise selection procedure was chosen because it provides an objective and algorithmic method for selecting the most statistically significant set of variables.
Decision-Tree Algorithm
A decision-tree algorithm was constructed to reveal the profiles associated with Duo/cAg false-negative results, as previously described.[15,16] The initial classification was the most important factor associated with Duo/cAg false-negative results. The patients were classified according to the cutoff values indicated for each variable. The cutoff value was determined by decision tree analysis, which gave the best split of variables.[15] The following variables were used in the decision tree analysis: gender, age, BMI, AST, ALT, GGT, albumin, total bilirubin, prothrombin time, white blood cell count, hemoglobin, platelet count, FIB-4 index, alpha fetoprotein, des-gamma-carboxy prothrombin, HCV genotype, history of IFN therapy, history of HCC treatment, and HCV RNA.
Results
Usefulness of the Duo Assay to Identify Patients with HCV RNA Positive
Among the 184 HCV RNA-positive samples measured with the Duo assay, Duo/Ab positivity rates were 100% (184/184), and Duo/cAg positivity rates were 78% (143/184) (Fig. 1).
Figure 1.
Positivity rate of Duo/Ab and Duo/cAg using Duo assay.
Comparison of the Patient Characteristics between Duo/cAg-Positive and False-negative Groups
Table 1 shows a comparison of the patient characteristics between the Duo/cAg-positive group (n=143) and the Duo/cAg false-negative group (n=41) in the Duo assay. No significant difference was observed in gender, age, and BMI between the two groups (Fig. 2).
Table 1.
Comparison of host, hepatic, and viral factors between the Duo/cAg positive and false negative groups
| Positive (HCV RNA+, Duo/cAg+) (n=143) | False-negative (HCV RNA+, Duo/cAg-) (n=41) | p | |||
|---|---|---|---|---|---|
| Median (IQR) | Range (min–max) | Median (IQR) | Range (min–max) | ||
| Gender (female/male) | 54.5%/45.5% (78/65) | N/A | 58.5%/41.5% (24/17) | N/A | 0.6504 |
| Age (years) | 67 (57–73) | 27–91 | 65 (57–73) | 32–82 | 0.3387 |
| Proportion of age ≥65 years old (%) | 59.4% (85/143) | N/A | 53.7% (22/41) | N/A | 0.5082 |
| Body mass index (kg/m2) | 23.0 (21.0–25.4) | 16.6–32.9 | 22.3 (20.3–24.3) | 16.8–28.7 | 0.0903 |
| Prevalence of obesity (BMI ≥25 kg/m2) | 25.9% (37/143) | N/A | 22.0% (9/41) | N/A | 0.6091 |
| AST (U/L) | 41 (29–59) | 9–213 | 39 (28–71) | 19–125 | 0.8593 |
| ALT (U/L) | 36 (26–54) | 6–427 | 30 (21–72) | 16–226 | 0.2984 |
| GGT (U/L) | 30 (20–43) | 10–323 | 30 (18–66) | 13–230 | 0.5287 |
| Albumin (g/dL) | 4.0 (3.7–4.3) | 2.4–4.9 | 4.0 (3.7–4.2) | 3.1–4.7 | 0.9536 |
| Total bilirubin (mg/dL) | 0.8 (0.6–1.0) | 0.3–3.8 | 0.7 (0.6–0.9) | 0.2–2.5 | 0.7658 |
| Prothrombin time (%) | 98 (86–108) | 34–140 | 100 (84–110) | 52-130 | 0.9104 |
| Creatinine (mg/dL) | 0.67 (0.56–0.79) | 0.41–8.34 | 0.58 (0.47–0.74) | 0.36–6.36 | 0.0067 |
| White blood cell count (/μL) | 4450 (3300–5600) | 1600–9500 | 5000 (3800–6000) | 1900–11200 | 0.1856 |
| Hemoglobin (g/dL) | 13.3 (12.2–14.4) | 8.6–18.2 | 13.8 (12.7–15.0) | 9.7-16.4 | 0.2001 |
| Platelet count (×104/µL) | 15.3 (10.3–19.6) | 2.0–34.8 | 16.1 (11.6–21.5) | 4.6–28.6 | 0.2427 |
| FIB-4 index | 3.06 (1.92–5.44) | 0.57–29.44 | 2.82 (1.71–4.55) | 0.63–13.94 | 0.3444 |
| Alpha fetoprotein (ng/mL) | 4.6 (2.8–11.3) | 1.0–157.5 | 4.4 (2.7–7.7) | 0.9-43.7 | 0.3636 |
| Des-gamma-carboxy prothrombin (mAU/mL) | 17 (14–22) | 4–195 | 17 (15–23) | 6-41 | 0.6964 |
| HCV RNA (log IU/mL) | 5.9 (5.5–6.5) | 4.4–7.3 | 5.1 (4.4–5.6) | 3.6-6.9 | <0.0001 |
| HCV genotype (1a+1b/2a+2b) | 103/40 | N/A | 27/14 | N/A | 0.4440 |
| Prevalence of pre-existing cirrhosis | 44.1% (63/143) | N/A | 34.1% (14/41) | N/A | 0.2568 |
| History of IFN therapy (%) (no/yes/unknown) | 14.7% (105/21/17) | N/A | 7.3% (36/3/2) | N/A | 0.1571 |
| History of HCC treatment | 16.8% (24/143) | N/A | 17.1% (7/41) | N/A | 0.9651 |
Data are expressed as median (interquartile range [IQR]), range, or number. N/A: Not applicable; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; GGT: Gamma-glutamyl transpeptidase; FIB-4: Fibrosis-4; HCV RNA: Hepatitis C virus ribonucleic acid; IFN: Interferon; HCC: Hepatocellular carcinoma.
Figure 2.
Duo/cAg positivity rate by patient background (gender, age, and BMI).
No significant difference was also observed in ALT levels, albumin levels, bilirubin levels, prothrombin time, and FIB-4 index between the Duo/cAg-positive and false-negative groups (Fig. 3). There was no significant difference in HCV genotype between the Duo/cAg-positive and false-negative groups (Fig. 3). However, Duo/cAg positivity rates were lower according to the low HCV RNA viral load (p<0.0001) (Fig. 3).
Figure 3.
Duo/cAg positivity rate by patient background (ALT, HCV RNA, and HCV genotype).
Logistic Regression Analysis for Duo/cAg False Negative
There was a significant difference in serum creatinine and HCV RNA levels between the Duo/cAg-positive and false-negative groups in univariate analysis. However, only the HCV RNA level was identified as an independent factor (OR 5.49, CI 3.12–10.56, p<0.0001) related to Duo/cAg false-negative results in multivariate analysis (Table 2).
Table 2.
Independent factor for Duo/cAg false negative results
| Variable | Unit | OR | 95% CI | p |
|---|---|---|---|---|
| HCV RNA | -1.0 log IU/mL | 5.49 | 3.12–10.56 | <0.0001 |
| Creatinine | 1.0 mg/dL | 0.75 | 0.37–1.20 | 0.2567 |
OR: Odds ratios; CI: Confidence interval; HCV RNA: Hepatitis C virus ribonucleic acid.
Decision Tree Analysis for Duo/cAg False Negative
The most impacted factor for Duo/cAg false-negative results was HCV RNA. In patients with HCV RNA ≥5.7 log IU/mL, 7.4% had false-negative results. On the other hand, 43.4% had false-negative results in patients with HCV RNA <5.7 log IU/mL. Of these patients, the second impacted factor was also HCV RNA, and 100% had false-negative results in patients with HCV RNA <4.4 log IU/mL (Fig. 4).
Figure 4.
The profile of Duo/cAg false negative using decision tree analysis. The patients were classified according to the indicated cut-off values of the variables. The pie graphs indicate the percentage of patients with Duo/cAg positive (white)/patients with Duo/cAg false negative (black) in each group.
Discussion
The present study demonstrated that the Duo assay can identify 100% of HCV carriers by HCV antibody detection and approximately 80% of HCV carriers by HCV antigen detection without measuring HCV RNA. We also demonstrated that the HCV RNA level was the only independent factor and the most impacted factor influencing Duo/cAg false-negative results in the Duo assay.
In this study, we examined 184 cases of HCV-RNA-positive patients. Of these, HCV genotype 1 is the major genotype and accounts for 70.7% (130/184) of all subjects. Toyoda et al.[17] also reported that 72.1% (7,706/10,688) of the cases were genotype 1. Thus, our database appears to have the general characteristics of HCV carriers before DAA treatment in Japan. However, we have to be cautious that this is a single-center, retrospective study on a Japanese cohort with only HCV genotypes 1 and 2. Kanokudom et al.[11] reported that the detection rate of HCV antigen was lower in HCV genotype 3a. Accordingly, our results may differ from those of HCV genotype 3/4 and other genotypes.
We demonstrated that the Duo assay can identify 100% of HCV carriers by HCV antibody detection and approximately 80% of HCV carriers by HCV antigen detection without the need for HCV RNA measurement. HCV antibody detection using the Duo assay has been reported in some studies to identify 100% of HCV carriers.[11,12] This demonstrates its viability as a screening method equivalent to conventional approaches. On the other hand, Inoue et al.[12] reported that the Duo assay identified only 55% of patients who showed positive results of HCV core antigen. This lower identification rate may be due to the high proportion (36.7%) of cases with HCV RNA ≤4 log IU/mL. Their study demonstrated a detection rate of 87.5% (48/55) for HCV RNA ≥5.6 log IU/mL. Thus, our findings are in good agreement with the detection rates of Duo/Ab and Duo/cAg in previous studies.
We also demonstrated that the assay was effective at detecting HCV infection regardless of host factors such as gender, age, BMI, liver enzyme levels, and severity of liver disease. Unfortunately, we did not evaluate the impact of HIV co-infection on the detection rate of HCV antibody and antigen using the Duo assay. Juniastuti et al.[18] reported a high rate of seronegative HCV antibody in HIV-positive patients. On the other hand, Ananchuensook et al.[19] reported that the HCV Duo immunoassay effectively diagnosed HCV infection regardless of HIV status. These findings suggest that the HCV Duo is useful for the detection of HCV carriers in patients with HIV co-infection.
We identified that the HCV RNA level was the only independent factor influencing Duo/cAg false-negative results. In addition, decision tree analysis revealed that the Duo/cAg false-negative rate for cases with HCV RNA levels <4.4 log IU/mL was 100%. These findings are consistent with previous studies suggesting that the sensitivity of HCV Ag detection assays is highly dependent on viral load.[10] The reason why higher viral loads result in more positive Ag results is thought to be due to increased production and release of HCV core Ag into the systemic blood circulation. Some studies have reported that Abbott’s HCV Ag assay demonstrates a higher positivity rate even in patients with low viral load.[20,21] Therefore, further improvements are needed to reduce false negatives in the Duo assay.
HCV-PCR is the current standard for evaluating direct-acting antiviral (DAA) efficacy. However, if post-DAA initiation strategies using core antigen testing are validated,[22] the HCV Duo assay may offer significant medical-economic benefits. Simultaneous measurement of Duo/Ab and Duo/cAg incurs the same cost as conventional HCV Ab testing (USD 6.84 per test) and identifies approximately 80% of HCV carriers without requiring HCV RNA testing. Given the high sustained virologic response (SVR) rate among HCV Ab-positive individuals,[23] this approach could reduce the cost of HCV RNA measurement (USD 27.61 per test). Moreover, the Duo assay may be especially useful for non-hepatology specialists, who often do not order HCV RNA testing.[8] Core antigen testing also shows adequate sensitivity in high-risk populations, such as people living with HIV or those who inject drugs, particularly in resource-limited settings, as recognized by the WHO. In addition to economic advantages, the Duo assay is time-efficient, requiring only 27 minutes and allowing for same-day HCV Ab and Ag testing. This contrasts with RNA testing, which is typically ordered later. Thus, the Duo assay may promote earlier detection and increase referrals to hepatologists, offering an effective and practical tool for identifying HCV-infected individuals across diverse clinical settings.
This study has several limitations. First, it was a retrospective single-center design. Second, the study focused exclusively on a Japanese cohort with genotypes 1 and 2, limiting generalizability. Third, the use of stored serum samples may have impacted antigen stability and assay performance. HCV Ag degradation may occur, especially in cases with low viral load. Thus, an international prospective multi-center study with multi-genotypic HCV is required to confirm the broader applicability of the Duo assay. However, the strongest point of this study was that we assessed the usefulness in clinical practice and the characteristics of Duo/cAg false-negative results.
Conclusion
In conclusion, we demonstrated that Duo assay screening can identify approximately 80% of HCV carriers with no HCV RNA measurement. Additionally, the test offers significant medical economic and time-saving benefits by reducing HCV RNA measurement. Thus, the Duo assay may become an important screening test toward the elimination of HCV.
Footnotes
How to cite this article: Amano K, Sano T, Ide T, Nakano D, Bekki S, Arinaga-Hino T, et al. The usefulness of a simultaneous immunoassay for hepatitis C virus antigen-antibody using the ELECSYS HCV duo assay. Hepatology Forum 2026; 7(2):118–124.
Ethics Committee Approval
The study was performed in accordance with the ethical principles described in the Declaration of Helsinki. It was approved by the Kurume University Clinical Research Ethics Committee of our hospital on November 11, 2024 (approval no. 24152).
Informed Consent
An opt-out approach was used to obtain informed consent from the patients, and personal information was protected during data collection.
Conflicts of Interest
Takumi Kawaguchi has received lecture fees from ASKA Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Kowa Company, Ltd., AbbVie GK., Eisai Co., Ltd., EA Pharma Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Sumitomo Pharma Co., Ltd., Novo Nordisk Pharma Ltd., Otsuka Pharmaceutical Co., Ltd., Janssen Pharmaceutical K.K. Keisuke Amano, Tomoya Sano, Tatsuya Ide, Dan Nakano, Shigemune Bekki, and Teruko Arinaga-Hino have no conflicts of interest to declare.
Financial Disclosure
The authors declared that this study has received no financial support.
Use of AI for Writing Assistance
No artificial intelligence (AI)–assisted technologies (such as Large Language Models [LLMs], chatbots, or image creators) were used in the production of this manuscript.
Author Contributions
Concept: KA, DN; Design: KA, TI; Supervision: KA, SB; Funding: KA, SB, TK; Materials: KA, TS, TK; Data Collection and/or Processing: KA, TS, DN, TK; Analysis and/or Interpretation: KA, TS; Literature Search: KA, TI, TAH; Writing: KA, TI, TAH; Critical Reviews: KA, DN, TAH.
Peer-review
Externally peer-reviewed.
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