TY - JOUR
T1 - Deriving the optimal limit of detection for an HCV point-of-care test for viraemic infection
T2 - Analysis of a global dataset
AU - Freiman, J. Morgan
AU - Wang, Jianing
AU - Easterbrook, Philippa J.
AU - Horsburgh, C. Robert
AU - Marinucci, Francesco
AU - White, Laura F.
AU - Kamkamidze, George
AU - Krajden, Mel
AU - Loarec, Anne
AU - Njouom, Richard
AU - Nguyen, Kihn V.
AU - Shiha, Gamal
AU - Soliman, Reham
AU - Solomon, Sunil S.
AU - Tsertsvadze, Tengiz
AU - Denkinger, Claudia M.
AU - Linas, Benjamin
N1 - Funding Information:
The U.S. National Center for Advancing Translational Sciences (grant number 1KL2TR001411), and the National Institute on Drug Abuse (grant number P30DA040500) funded this project. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health. The WHO contribution was supported through a UNITAID enabling grant. The FIND contribution was also supported by UNITAID, grant 2016-04 FIND. The screening component for the Medecins Sans Frontières study in Mozambique was supported by UNITAID, grant N° SPHQ14-LOA-217. The screening component of the TREAT Asia study, a program of amfAR, The Foundation for AIDS Research was supported by the U.S. National Institutes of Health's National Institute of Allergy and Infectious Diseases, Eunice Kennedy Shriver National Institute of Child Health and Human Development, and National Cancer Institute, as part of the International Epidemiology Databases to Evaluate AIDS (IeDEA; U01AI069907), and amfAR. The Kirby Institute is funded by the Australian Government Department of Health and Ageing, and is affiliated with the Faculty of Medicine, UNSW Sydney. The British Columbia Centre for Disease Control is funded by the British Columbia Ministry of Health and is affiliated with the University of British Columbia Faculty of Medicine. We wish to acknowledge the following individuals for their contributions to this study: C. Fortas, Epicentre MSF, Paris, France; F Averhoff and M Nasrullah, Centers for Disease Control, Division of Viral Hepatitis, Atlanta, USA; E Yunihastuti, A Widhani, A Sanityoso, and J Kurniawan, Faculty of Medicine Universitas Indonesia – Dr. Cipto Mangunkusumo General Hospital, Jakarta, Indonesia; A Kamarulzaman, SF Syed Omar, V Pillai, and I Azwa, University Malaya Medical Centre, Kuala Lumpur, Malaysia; Kiat Ruxrungtham, A Avihingsanon, Salyavit Chittmittrapap, and P Phanuphak, HIV-NAT/Thai Red Cross AIDS Research Centre, Bangkok, Thailand; NV Trung, NTH Dung, BV Huy and Hoi LT, National Hospital for Tropical Diseases, Hanoi, Vietnam; AH Sohn, JL Ross, N Durier*, and B Petersen, TREAT Asia, amfAR – The Foundation for AIDS Research, Bangkok, Thailand; T Applegate, G Matthews, MG Law, and D Boettiger, The Kirby Institute, UNSW Sydney, Australia. *Current affiliation: Dreamlopments LTD, Bangkok, Thailand.
Funding Information:
The U.S. National Center for Advancing Translational Sciences (grant number 1KL2TR001411 ), and the National Institute on Drug Abuse (grant number P30DA040500 ) funded this project. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health. The WHO contribution was supported through a UNITAID enabling grant. The FIND contribution was also supported by UNITAID, grant 2016-04 FIND . The screening component for the Medecins Sans Frontières study in Mozambique was supported by UNITAID, grant N° SPHQ14-LOA-217. The screening component of the TREAT Asia study, a program of amfAR, The Foundation for AIDS Research was supported by the U.S. National Institutes of Health’s National Institute of Allergy and Infectious Diseases, Eunice Kennedy Shriver National Institute of Child Health and Human Development, and National Cancer Institute, as part of the International Epidemiology Databases to Evaluate AIDS (IeDEA; U01AI069907), and amfAR. The Kirby Institute is funded by the Australian Government Department of Health and Ageing, and is affiliated with the Faculty of Medicine, UNSW Sydney. The British Columbia Centre for Disease Control is funded by the British Columbia Ministry of Health and is affiliated with the University of British Columbia Faculty of Medicine.
Funding Information:
The U.S. National Center for Advancing Translational Sciences (grant number 1KL2TR001411), and the National Institute on Drug Abuse (grant number P30DA040500) funded this project. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health. The WHO contribution was supported through a UNITAID enabling grant. The FIND contribution was also supported by UNITAID, grant 2016-04 FIND. The screening component for the Medecins Sans Fronti?res study in Mozambique was supported by UNITAID, grant N? SPHQ14-LOA-217. The screening component of the TREAT Asia study, a program of amfAR, The Foundation for AIDS Research was supported by the U.S. National Institutes of Health's National Institute of Allergy and Infectious Diseases, Eunice Kennedy Shriver National Institute of Child Health and Human Development, and National Cancer Institute, as part of the International Epidemiology Databases to Evaluate AIDS (IeDEA; U01AI069907), and amfAR. The Kirby Institute is funded by the Australian Government Department of Health and Ageing, and is affiliated with the Faculty of Medicine, UNSW Sydney. The British Columbia Centre for Disease Control is funded by the British Columbia Ministry of Health and is affiliated with the University of British Columbia Faculty of Medicine.
Publisher Copyright:
© 2019 European Association for the Study of the Liver
PY - 2019/7
Y1 - 2019/7
N2 - Background & Aims: Affordable point-of-care tests for hepatitis C (HCV) viraemia are needed to improve access to treatment in low- and middle-income countries. Our aims were to determine the target limit of detection (LOD) necessary to diagnose the majority of people with HCV eligible for treatment, and identify characteristics associated with low-level viraemia (LLV) (defined as the lowest 3% of the distribution of HCV RNA) to understand those at risk of being misdiagnosed. Methods: We established a multi-country cross-sectional dataset of first available quantitative HCV RNA measurements linked to demographic and clinical data. We excluded individuals on HCV treatment. We analysed the distribution of HCV RNA and determined critical thresholds for detection of HCV viraemia. We then performed logistic regression to evaluate factors associated with LLV, and derived relative sensitivities for significant covariates. Results: The dataset included 66,640 individuals with HCV viraemia from across the world. The LOD for the 95th and 99th percentiles were 3,311 IU/ml and 214 IU/ml. The LOD for the 97th percentile was 1,318 IU/ml (95% CI 1,298.4–1,322.3). Factors associated with LLV, defined as HCV RNA <1,318 IU/ml, were younger age 18–30 vs. 51–64 years (odds ratios [OR] 2.56; 95% CI 2.19–2.99), female vs. male sex (OR 1.32; 95% CI 1.18–1.49), and advanced fibrosis stage F4 vs. F0-1 (OR 1.44; 95% CI 1.21–1.69). Only the younger age group had a decreased relative sensitivity below 95%, at 93.3%. Conclusions: In this global dataset, a test with an LOD of 1,318 IU/ml would identify 97% of viraemic HCV infections among almost all populations. This LOD will help guide manufacturers in the development of affordable point-of-care diagnostics to expand HCV testing and linkage to care in low- and middle-income countries. Lay summary: We created and analysed a dataset from 12 countries with 66,640 participants with chronic hepatitis C virus infection. We determined that about 97% of those with viraemic infection had 1,300 IU/ml or more of circulating virus at the time of diagnosis. While current diagnostic tests can detect as little as 12 IU/ml of virus, our findings suggest that increasing the level of detection closer to 1,300 IU/ml would maintain good test accuracy and will likely enable development of more affordable portable tests for use in low- and middle-income countries.
AB - Background & Aims: Affordable point-of-care tests for hepatitis C (HCV) viraemia are needed to improve access to treatment in low- and middle-income countries. Our aims were to determine the target limit of detection (LOD) necessary to diagnose the majority of people with HCV eligible for treatment, and identify characteristics associated with low-level viraemia (LLV) (defined as the lowest 3% of the distribution of HCV RNA) to understand those at risk of being misdiagnosed. Methods: We established a multi-country cross-sectional dataset of first available quantitative HCV RNA measurements linked to demographic and clinical data. We excluded individuals on HCV treatment. We analysed the distribution of HCV RNA and determined critical thresholds for detection of HCV viraemia. We then performed logistic regression to evaluate factors associated with LLV, and derived relative sensitivities for significant covariates. Results: The dataset included 66,640 individuals with HCV viraemia from across the world. The LOD for the 95th and 99th percentiles were 3,311 IU/ml and 214 IU/ml. The LOD for the 97th percentile was 1,318 IU/ml (95% CI 1,298.4–1,322.3). Factors associated with LLV, defined as HCV RNA <1,318 IU/ml, were younger age 18–30 vs. 51–64 years (odds ratios [OR] 2.56; 95% CI 2.19–2.99), female vs. male sex (OR 1.32; 95% CI 1.18–1.49), and advanced fibrosis stage F4 vs. F0-1 (OR 1.44; 95% CI 1.21–1.69). Only the younger age group had a decreased relative sensitivity below 95%, at 93.3%. Conclusions: In this global dataset, a test with an LOD of 1,318 IU/ml would identify 97% of viraemic HCV infections among almost all populations. This LOD will help guide manufacturers in the development of affordable point-of-care diagnostics to expand HCV testing and linkage to care in low- and middle-income countries. Lay summary: We created and analysed a dataset from 12 countries with 66,640 participants with chronic hepatitis C virus infection. We determined that about 97% of those with viraemic infection had 1,300 IU/ml or more of circulating virus at the time of diagnosis. While current diagnostic tests can detect as little as 12 IU/ml of virus, our findings suggest that increasing the level of detection closer to 1,300 IU/ml would maintain good test accuracy and will likely enable development of more affordable portable tests for use in low- and middle-income countries.
KW - Diagnosis
KW - Hepatitis C virus
KW - Limit of detection
KW - Point-of-care
KW - Viraemia, Affordable
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U2 - 10.1016/j.jhep.2019.02.011
DO - 10.1016/j.jhep.2019.02.011
M3 - Article
C2 - 30797050
AN - SCOPUS:85064205863
SN - 0168-8278
VL - 71
SP - 62
EP - 70
JO - Journal of Hepatology
JF - Journal of Hepatology
IS - 1
ER -