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Hepatitis C Core Antigen Testing for Diagnosis of Hepatitis C Virus Infection: A Systematic Review and Meta-analysisHepatitis C Core Antigen Testing

J. Morgan Freiman, MD; Trang M. Tran, BA; Samuel G. Schumacher, MSc, PhD; Laura F. White, PhD; Stefano Ongarello, PhD; Jennifer Cohn, MD, MPH; Philippa J. Easterbrook, MD, MPH; Benjamin P. Linas, MD, MPH; and Claudia M. Denkinger, MD, PhD
[+] Article, Author, and Disclosure Information

This article was published at www.annals.org on 21 June 2016.


From Boston Medical Center, Boston University School of Public Health, and Beth Israel Deaconess Medical Center, Boston, Massachusetts; Médecins Sans Frontières Access Campaign, World Health Organization, and Foundation for Innovative New Diagnostics, Geneva, Switzerland; and University of Pennsylvania, Philadelphia, Pennsylvania.

Acknowledgment: The authors thank all of the study authors who provided additional data necessary to complete this review and the following persons: Jeanne Chauffor (Médecins Sans Frontières) and Audrey Albertini (Foundation for Innovative New Diagnostics [FIND]) for translation of studies in French, Kuniaki Arai (World Health Organization) for translation of studies in Japanese, Joseph Tucker (University of North Carolina) for translation of author communication in Mandarin Chinese, David Flynn (Boston University School of Medicine Alumni Medical Library) and Genevieve Gore (McGill University) for their help with search terms, and Ranald Sutherland and Martin Brusdeilins from FIND for their input on the technical aspects and commercial availability of HCVcAg tests.

Grant Support: By the National Institutes of Health (grants 5T32AI052074-10, 5R01DA031059-04, 1P30DA040500-01, and 5P30AI042853-18).

Disclosures: Dr. White reports grants from the National Institutes of Health during the conduct of the study. Dr. Ongarello reports personal fees from FIND (salaried employee) during the conduct of the study and outside the submitted work. Dr. Denkinger reports nonfinancial support and other from Cepheid and grants (to FIND) outside the submitted work. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M16-0065.

Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that she has no financial relationships or interests to disclose. Darren B. Taichman, MD, PhD, Executive Deputy Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Pfizer and Johnson & Johnson.

Reproducible Research Statement:Study protocol: See the Supplement. Statistical code: Available from Dr. Freiman (e-mail, J.Morgan.Freiman@bmc.org). Data set: Data from extracted studies available upon request (e-mail, J.Morgan.Freiman@bmc.org).

Requests for Single Reprints: J. Morgan Freiman, MD, One Boston Medical Center Place, Dowling 3 North, Boston, MA 02118; e-mail, j.morgan.freiman@bmc.org.

Current Author Addresses: Dr. Freiman: One Boston Medical Center Place, Dowling 3 North, Boston, MA 02118.

Dr. Cohn and Ms. Tran: Médecins Sans Frontières Access Campaign, Rue de Lausanne 78, PO Box 116, CH-1211 Geneva 21, Switzerland.

Drs. Schumacher, Ongarello, and Denkinger: Campus Biotech, Chemin des Mines 9, 1202 Geneva, Switzerland.

Dr. White: Department of Biostatistics, Boston University School of Public Health, Crosstown Building, 801 Massachusetts Avenue, 3rd Floor, Boston, MA 02118.

Dr. Easterbrook: HIV/AIDS Department, World Health Organization, Department 20, Avenue Appia, CH-1211 Geneva 27, Switzerland.

Dr. Linas: Section of Infectious Diseases, Boston University School of Medicine, Crosstown Building, 801 Massachusetts Avenue, 2nd Floor, Boston, MA 02118.

Author Contributions: Conception and design: J.M. Freiman, S.G. Schumacher, J. Cohn, P.J. Easterbrook, C.M. Denkinger.

Analysis and interpretation of the data: J.M. Freiman, S.G. Schumacher, S. Ongarello, J. Cohn, P.J. Easterbrook, C.M. Denkinger.

Drafting of the article: J.M. Freiman, T.M. Tran, S.G. Schumacher, C.M. Denkinger.

Critical revision of the article for important intellectual content: J.M. Freiman, T.M. Tran, S.G. Schumacher, S. Ongarello, J. Cohn, P.J. Easterbrook, C.M. Denkinger.

Final approval of the article: J.M. Freiman, T.M. Tran, S.G. Schumacher, S. Ongarello, J. Cohn, P.J. Easterbrook, C.M. Denkinger.

Provision of study materials or patients: C.M. Denkinger.

Statistical expertise: S.G. Schumacher, L.F. White, S. Ongarello, C.M. Denkinger.

Administrative, technical, or logistic support: T.M. Tran, C.M. Denkinger.

Collection and assembly of data: J.M. Freiman, T.M. Tran, P.J. Easterbrook, C.M. Denkinger.


Ann Intern Med. 2016;165(5):345-355. doi:10.7326/M16-0065
© 2016 American College of Physicians
Text Size: A A A

Background: Diagnosis of chronic hepatitis C virus (HCV) infection requires both a positive HCV antibody screen and confirmatory nucleic acid testing (NAT). Testing for hepatitis C virus core antigen (HCVcAg) is a potential alternative to NAT.

Purpose: To evaluate the accuracy of diagnosis of active HCV infection among adults and children for 5 HCVcAg tests compared with NAT.

Data Sources: EMBASE, PubMed, Web of Science, Scopus, and Cochrane Database of Systematic Reviews from 1990 through 31 March 2016.

Study Selection: Case–control, cross-sectional, cohort, or randomized trials that compared any of 5 HCVcAg tests with an NAT reference standard.

Data Extraction: 2 independent reviewers extracted data and assessed quality using an adapted QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies 2) tool.

Data Synthesis: 44 studies evaluated 5 index tests. Studies for the Abbott ARCHITECT HCV Ag assay had the highest quality, whereas those for the Ortho HCV Ag enzyme-linked immunosorbent assay (ELISA) had the lowest quality. From bivariate analyses, the sensitivity and specificity of the assays were as follows: Abbott ARCHITECT, 93.4% (95% CI, 90.1% to 96.4%) and 98.8% (CI, 97.4% to 99.5%); Ortho ELISA, 93.2% (CI, 81.6% to 97.7%) and 99.2% (CI, 87.9% to 100%); and Hunan Jynda Bioengineering Group HCV Ag ELISA, 59.5% (CI, 46.0% to 71.7%) and 82.9% (CI, 58.6% to 94.3%). Insufficient data were available for a meta-analysis about the Fujirebio Lumipulse Ortho HCV Ag and Eiken Lumispot HCV Ag assays. In 3 quantitative studies using Abbott ARCHITECT, HCVcAg correlated closely with HCV RNA levels greater than 3000 IU/mL.

Limitations: Insufficient data were available on covariates, such as HIV or hepatitis B virus status, for subgroup analyses. Few studies reported genotypes of isolates, and data for genotypes 4, 5, and 6 were scant. Most studies were conducted in high-resource settings and reference laboratories.

Conclusion: The HCVcAg assays with signal amplification have high sensitivity, high specificity, and good correlation with HCV RNA levels greater than 3000 IU/mL and have the potential to replace NAT in settings with high HCV prevalence.

Primary Funding Source: National Institutes of Health.

Figures

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Appendix Figure 1.

Flow diagram of included studies.

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Appendix Figure 2.

Risk of bias and applicability summary as judged by reviewers about each QUADAS-2 domain.

QUADAS-2 = Quality Assessment of Diagnostic Accuracy Studies 2.

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Appendix Figure 3.

Risk of bias and applicability summary as judged by reviewers about each QUADAS-2 domain, by individual study.

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Appendix Figure 3.

Continued

Green circles with a plus sign indicate low risk of bias. Yellow circles with a question mark indicate unclear risk of bias. Red circles with a minus sign indicate high risk of bias. Abbott ARCHITECT = Abbott ARCHITECT HCV Ag assay; Ag = antigen; Eiken Lumispot = Eiken Lumispot HCV Ag assay; HCV = hepatitis C virus; Hunan Jynda ELISA = Hunan Jynda Bioengineering Group HCV Ag ELISA; Ortho ELISA = Ortho HCV Ag ELISA; QUADAS-2 = Quality Assessment of Diagnostic Accuracy Studies 2.

* Same data for Fujirebio Lumipulse Ortho HCV Ag assay and Eiken Lumispot.

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Figure 1.

Forest plot of Abbott ARCHITECT's sensitivity and specificity for the diagnosis of active HCV infection compared with NAT for all samples, regardless of anti-HCV status.

Abbott ARCHITECT = Abbott ARCHITECT HCV Ag assay; Ag = antigen; anti-HCV = antibody to hepatitis C virus; HCV = hepatitis C virus; NAT = nucleic acid testing.

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Appendix Figure 4.

Bivariate analysis of Abbott ARCHITECT's sensitivity and specificity for diagnosis of active HCV infection compared with NAT.

This plot shows the pooled summary estimate (red square). The dotted orange line represents the 95% confidence region, and the dashed green line represents the 95% prediction region. The individual circles represent each study, and the size of the circle is proportional to the total sample size. Abbott ARCHITECT = Abbott ARCHITECT HCV Ag assay; Ag = antigen; HCV = hepatitis C virus; NAT = nucleic acid testing.

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Appendix Figure 5.

Univariate analysis of Abbott ARCHITECT's sensitivity for the diagnosis of active HCV infection compared with NAT for all studies with sensitivity data, regardless of anti-HCV status.

Abbott ARCHITECT = Abbott ARCHITECT HCV Ag assay; Ag = antigen; anti-HCV = antibody to hepatitis C virus; HCV = hepatitis C virus; NAT = nucleic acid testing.

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Appendix Figure 6.

Forest plot of Abbott ARCHITECT's sensitivity and specificity for the diagnosis of active HCV infection compared with NAT for samples that are positive for anti-HCV.

Abbott ARCHITECT = Abbott ARCHITECT HCV Ag assay; Ag = antigen; anti-HCV = antibody to hepatitis C virus; HCV = hepatitis C virus; NAT = nucleic acid testing.

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Appendix Figure 7.

Forest plot of Abbott ARCHITECT's sensitivity and specificity for the diagnosis of active HCV infection compared with NAT for samples that are negative for anti-HCV.

Abbott ARCHITECT = Abbott ARCHITECT HCV Ag assay; Ag = antigen; anti-HCV = antibody to hepatitis C virus; HCV = hepatitis C virus; NAT = nucleic acid testing.

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Appendix Figure 8.

Funnel plot of published studies that used Abbott ARCHITECT.

Abbott ARCHITECT = Abbott ARCHITECT HCV Ag assay; Ag = antigen; HCV = hepatitis C virus.

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Appendix Figure 9.

Forest plot of the Ortho ELISA's sensitivity and specificity for diagnosis of active HCV infection compared with NAT for all samples, regardless of anti-HCV status.

Ag = antigen; anti-HCV = antibody to hepatitis C virus; ELISA = enzyme-linked immunosorbent assay; HCV = hepatitis C virus; NAT = nucleic acid testing; Ortho ELISA = Ortho HCV Ag ELISA.

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Appendix Figure 10.

Bivariate analysis of the Ortho ELISA's sensitivity and specificity for diagnosis of active HCV infection compared with NAT.

This plot shows the pooled summary estimate (red square). The dotted orange line represents the 95% confidence region, and the dashed green line represents the 95% prediction region. The individual circles represent each study, and the size of the circle is proportional to the total sample size. Ag = antigen; ELISA = enzyme-linked immunosorbent assay; HCV = hepatitis C virus; NAT = nucleic acid testing; Ortho ELISA = Ortho HCV Ag ELISA.

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Appendix Figure 11.

Forest plot of the Hunan Jynda ELISA's sensitivity and specificity for diagnosis of active HCV infection compared with NAT for all samples, regardless of anti-HCV status.

Ag = antigen; anti-HCV = antibody to hepatitis C virus; ELISA = enzyme-linked immunosorbent assay; HCV = hepatitis C virus; Hunan Jynda ELISA = Hunan Jynda Bioengineering Group HCV Ag ELISA; NAT = nucleic acid testing.

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Appendix Figure 12.

Bivariate analysis of the Hunan Jynda ELISA's sensitivity and specificity for diagnosis of active HCV infection compared with NAT.

This plot shows the pooled summary estimate (red square). The dotted orange line represents the 95% confidence region, and the dashed green line represents the 95% prediction region. The individual circles represent each study, and the size of the circle is proportional to the total sample size. Ag = antigen; ELISA = enzyme-linked immunosorbent assay; HCV = hepatitis C virus; Hunan Jynda ELISA = Hunan Jynda Bioengineering Group HCV Ag ELISA; NAT = nucleic acid testing.

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Figure 2.

Nonparametric regression smoother of pooled quantitative data assessing the correlation between Abbott ARCHITECT and HCV RNA.

The dashed line indicates the positivity threshold of the HCVcAg index test, corresponding to 3 fmol/L. Abbott ARCHITECT = Abbott ARCHITECT HCV Ag assay; Ag = antigen; HCVcAg = hepatitis C virus core antigen; HCV = hepatitis C virus.

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