Clin Gastroenterol Hepatol. 2020 Apr 29. pii: S1542-3565(20)30590-5. doi: 10.1016/j.cgh.2020.04.045. [Epub ahead of print]
Assay for Hepatitis B Core-related Antigen Identify Patients With High Viral Load: Systematic Review and Meta-analysis of Individual Participant Data.
Yoshida K1, Desbiolles A2, Feldman SF2, Ahn SH3, Alidjinou EK4, Atsukawa M5, Bocket L4, Brunetto MR6, Buti M7, Carey I8, Caviglia GP9, Chen EQ10, Cornberg M11, Enomoto M12, Honda M13, Zu Siederdissen CH11, Ishigami M14, Janssen H15, Maasoumy B11, Matsui T16, Matsumoto A17, Nishiguchi S18, Riveiro-Barciela M7, Takaki A19, Tangkijvanich P20, Toyoda H21, van Campenhout MJ22, Wang B8, Wei L23, Yang HI24, Yano Y25, Yatsuhashi H26, Yuen MF27, Tanaka E28, Lemoine M1, Tanaka Y29, Shimakawa Y30.
Author information
1
Department of Surgery and Cancer, Liver Unit, Imperial College London, Praed St, Paddington, London W2 1NY, UK.
2
Unité d'Épidémiologie des Maladies Émergentes, Institut Pasteur, 25-28 Rue du Dr Roux, 75015 Paris, France.
3
Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 120-752, Korea.
4
Laboratoire de Virologie, Centre de Biologie Pathologie, CHU de Lille, Boulevard du Professeur Jules Leclercq, 59037 Lille, France.
5
Division of Gastroenterology, Department of Internal Medicine, Nippon Medical School Chiba Hokusoh Hospital, 1715 Kamakari, Inzai, Chiba 270-1694, Japan.
6
Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, University Hospital of Pisa, Lungarno Antonio Pacinotti, 43, 56126 Pisa PI, Italy.
7
Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron and Universitat Autònoma de Barcelona, Passeig Vall Hebron, 119-129, 08035, Barcelona, Spain.
8
Institute of Liver Studies, King's College Hospital, Denmark Hill, Brixton, London SE5 9RS, UK.
9
Department of Medical Sciences, University of Turin, Corso Dogliotti 14, Turin 10126, Italy.
10
Center of Infectious Diseases, West China Hospital, Sichuan University, No. 37 Guo Xue Xiang, Wuhou District, Chengdu 610041, China.
11
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl-Neuberg Strasse 1, 30625 Hannover, Germany.
12
Department of Hepatology, Graduate School of Medicine, Osaka City University Medical School, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan.
13
Department of Gastroenterology, and Department of Advanced Medical Technology, Kanazawa University Graduate School of Health Medicine, 13-1 Takara-Machi, Kanazawa, Ishikawa 920-8641, Japan.
14
Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8550, Japan.
15
Toronto Centre for Liver Disease, Toronto General Hospital, University Of Toronto, 200 Elizabeth Street, Eaton Building 9th floor Room 234 (9EB234), Toronto, ON, Canada.
16
Center for Gastroenterology, Teine-Keijinkai Hospital, 12-1-40 Maeda-ichijo, Teine, Sapporo, Hokkaido 006-0811, Japan.
17
Department of Internal Medicine, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan.
18
Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawacho, Nishinomiya, Hyogo 663-8501, Japan.
19
Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama 700-8558, Japan.
20
Center of Excellence in Hepatitis and Liver cancer, Faculty of Medicine, Chulalongkorn University, 1873 Rama IV Rd, 10330, Bangkok, Thailand.
21
Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, 4-86 Minaminokawa, Ogaki, Gifu 503-8502, Japan.
22
Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Doctor Molewaterplein 40, 3015 GD Rotterdam, The Netherlands.
23
Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Peking University People's Hospital, No. 11 Xizhimen South Street, Beijing 100044, China.
24
Genomics Research Center, Academia Sinica, 128 Academia Road, Nankang, Taipei 11529, Taiwan.
25
Center for Infectious Diseases, Department of Gastroenterology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
26
Clinical Research Center, National Hospital Organization (NHO), Nagasaki Medical Center, 2-1001-1, Kubara, Omura, Nagasaki 856-8562, Japan.
27
Department of Medicine, The University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong, China.
28
Department for the Promotion of Regional Medicine, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan.
29
Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho, Nagoya 467-8601, Japan.
30
Unité d'Épidémiologie des Maladies Émergentes, Institut Pasteur, 25-28 Rue du Dr Roux, 75015 Paris, France. Electronic address: [email protected].
Abstract
BACKGROUND & AIMS:
Scale-up of tests and treatments is needed to eliminate hepatitis B virus (HBV) infection from resource-limited countries. However, access to nucleic acid tests that quantify HBV DNA, to determine treatment eligibility, is severely limited. We performed a systematic review and meta-analysis to assess the performance of the hepatitis B core-related antigen (HBcrAg) immunoassay, a low-cost (less than $15/assay) alternative to the nucleic acid test, to identify highly viremic patients, infected with any HBV genotype.
METHODS:
We searched Medline, Embase, Scopus, and Web of Science through June 27, 2018 for studies that measured HBV DNA and HBcrAg in the same blood samples. We contacted study authors to obtain data from each study participant, and randomly assigned each participant to the derivation or validation cohorts. We applied optimal HBcrAg cut-off values derived from the derivation set to the validation set to estimate sensitivity and specificity of HBcrAg to indicate high viremia.
RESULTS:
Of 74 eligible studies found in the systematic review, we obtained individual participant data from 60 studies (81%). We performed a meta-analysis of individual participant data of 5591 HBV-infected patients who did not receive antiviral therapy and 4806 HBV-infected patients who received antiviral agents. In untreated patients, the pooled area under the receiver operating characteristic curve and the optimal cut-off value for the HBcrAg assay were 0.88 (95% CI, 0.83-0.94) and 3.6 log U/ml for identifying patients with a level of HBV DNA ≥2000 IU/ml, and 0.96 (95% CI, 0.94-0.98) and 5.3 log U/ml for identifying patients with a level of HBV DNA ≥200,000 IU/ml, respectively. In the validation set, the HBcrAg assay identified patients with ≥2000 IU/ml HBV DNA with 85.2% sensitivity and 84.7% specificity; the assay identified patients with ≥200,000 IU/ml HBV DNA with 91.8% sensitivity and 90.5% specificity. Performance did not vary among HBV genotypes. In patients receiving anti-HBV therapy, there was no correlation between levels of HBcrAg and HBV DNA.
CONCLUSIONS:
In a systematic review and meta-analysis of individual participant data, we found that the assay for HBcrAg identifies treatment-naïve patients with high levels of HBV DNA with high sensitivity and specificity, regardless of genotype. The HBcrAg assay is a good, low-cost alternative to the nucleic acid test to identify highly viremic patients infected with different genotypes.
我们在2018年6月27日之前搜索Medline，Embase，Scopus和Web of Science，以研究测量相同血液样本中HBV DNA和HBcrAg的研究。我们与研究作者联系以从每个研究参与者那里获取数据，并将每个参与者随机分配到派生或验证队列中。我们将源自派生集的最佳HBcrAg临界值应用于验证集，以估计HBcrAg的敏感性和特异性，以指示高病毒血症。
结果：
在系统评价中发现的74项合格研究中，我们从60项研究中获得了个体参与者数据（81％）。我们对5591例未接受抗病毒治疗的HBV感染患者和4806例接受抗病毒药物的HBV感染患者的个体参与者数据进行了荟萃分析。在未经治疗的患者中，接受者工作特征曲线下的合并面积和HBcrAg测定的最佳临界值为0.88（95％CI，0.83-0.94）和3.6 log U / ml，以鉴定具有HBV DNA水平的患者≥2000 IU / ml和0.96（95％CI，0.94-0.98）和5.3 log U / ml分别用于鉴定HBV DNA≥200,000 IU / ml的患者。在验证组中，HBcrAg分析确定了≥2000 IU / ml HBV DNA的患者，敏感性为85.2％，特异性为84.7％；该检测方法鉴定出≥200,000 IU / ml HBV DNA的患者，灵敏度为91.8％，特异性为90.5％。 HBV基因型之间的表现没有差异。在接受抗HBV治疗的患者中，HBcrAg水平和HBV DNA之间没有相关性。
结论：