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      Systematic review and individual-patient-data meta-analysis of non-invasive fibrosis markers for chronic hepatitis B in Africa

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          Abstract

          In sub-Saharan Africa, simple biomarkers of liver fibrosis are needed to scale-up hepatitis B treatment. We conducted an individual participant data meta-analysis of 3,548 chronic hepatitis B patients living in eight sub-Saharan African countries to assess the World Health Organization-recommended aspartate aminotransferase-to-platelet ratio index and two other fibrosis biomarkers using a Bayesian bivariate model. Transient elastography was used as a reference test with liver stiffness measurement thresholds at 7.9 and 12.2kPa indicating significant fibrosis and cirrhosis, respectively. At the World Health Organization-recommended cirrhosis threshold (>2.0), aspartate aminotransferase-to-platelet ratio index had sensitivity (95% credible interval) of only 16.5% (12.5–20.5). We identified an optimised aspartate aminotransferase-to-platelet ratio index rule-in threshold (>0.65) for liver stiffness measurement >12.2kPa with sensitivity and specificity of 56.2% (50.5–62.2) and 90.0% (89.0–91.0), and an optimised rule-out threshold (<0.36) with sensitivity and specificity of 80.6% (76.1–85.1) and 64.3% (62.8–65.8). Here we show that the World Health Organization-recommended aspartate aminotransferase-to-platelet ratio index threshold is inappropriately high in sub-Saharan Africa; improved rule-in and rule-out thresholds can optimise treatment recommendations in this setting.

          Abstract

          Authors carry out a systematic review and meta-analysis to evaluate the performance of fibrosis biomarkers for the diagnosis of fibrosis and cirrhosis in patients with chronic hepatitis B virus infection living in sub-Saharan Africa.

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          Most cited references59

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          QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies.

          In 2003, the QUADAS tool for systematic reviews of diagnostic accuracy studies was developed. Experience, anecdotal reports, and feedback suggested areas for improvement; therefore, QUADAS-2 was developed. This tool comprises 4 domains: patient selection, index test, reference standard, and flow and timing. Each domain is assessed in terms of risk of bias, and the first 3 domains are also assessed in terms of concerns regarding applicability. Signalling questions are included to help judge risk of bias. The QUADAS-2 tool is applied in 4 phases: summarize the review question, tailor the tool and produce review-specific guidance, construct a flow diagram for the primary study, and judge bias and applicability. This tool will allow for more transparent rating of bias and applicability of primary diagnostic accuracy studies.
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            EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection.

            Hepatitis B virus (HBV) infection remains a global public health problem with changing epidemiology due to several factors including vaccination policies and migration. This Clinical Practice Guideline presents updated recommendations for the optimal management of HBV infection. Chronic HBV infection can be classified into five phases: (I) HBeAg-positive chronic infection, (II) HBeAg-positive chronic hepatitis, (III) HBeAg-negative chronic infection, (IV) HBeAg-negative chronic hepatitis and (V) HBsAg-negative phase. All patients with chronic HBV infection are at increased risk of progression to cirrhosis and hepatocellular carcinoma (HCC), depending on host and viral factors. The main goal of therapy is to improve survival and quality of life by preventing disease progression, and consequently HCC development. The induction of long-term suppression of HBV replication represents the main endpoint of current treatment strategies, while HBsAg loss is an optimal endpoint. The typical indication for treatment requires HBV DNA >2,000IU/ml, elevated ALT and/or at least moderate histological lesions, while all cirrhotic patients with detectable HBV DNA should be treated. Additional indications include the prevention of mother to child transmission in pregnant women with high viremia and prevention of HBV reactivation in patients requiring immunosuppression or chemotherapy. The long-term administration of a potent nucleos(t)ide analogue with high barrier to resistance, i.e., entecavir, tenofovir disoproxil or tenofovir alafenamide, represents the treatment of choice. Pegylated interferon-alfa treatment can also be considered in mild to moderate chronic hepatitis B patients. Combination therapies are not generally recommended. All treated and untreated patients should be monitored for treatment response and adherence, and the risk of progression and development of complications. HCC remains the major concern for treated chronic hepatitis B patients. Several subgroups of patients with HBV infection require specific focus. Future treatment strategies to achieve 'cure' of disease and new biomarkers are discussed.
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              Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance.

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                Author and article information

                Contributors
                uxasoh@siv.no
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                3 January 2023
                3 January 2023
                2023
                : 14
                : 45
                Affiliations
                [1 ]GRID grid.417292.b, ISNI 0000 0004 0627 3659, Department of Infectious Diseases, , Vestfold Hospital, ; Tønsberg, Norway
                [2 ]GRID grid.5510.1, ISNI 0000 0004 1936 8921, Institute of Clinical Medicine, , University of Oslo, ; Oslo, Norway
                [3 ]GRID grid.10025.36, ISNI 0000 0004 1936 8470, Department of Clinical Infection, Microbiology and Immunology, Institute of Infection, Veterinary and Ecological Sciences, , University of Liverpool, ; Liverpool, UK
                [4 ]GRID grid.419393.5, ISNI 0000 0004 8340 2442, Malawi-Liverpool-Wellcome Trust Clinical Research Programme, ; Blantyre, Malawi
                [5 ]GRID grid.48004.38, ISNI 0000 0004 1936 9764, Department of Clinical Sciences, , Liverpool School of Tropical Medicine, ; Liverpool, UK
                [6 ]GRID grid.412989.f, ISNI 0000 0000 8510 4538, Faculty of Medical Sciences, , University of Jos, ; Jos, Nigeria
                [7 ]GRID grid.414371.4, Service de Maladies Infectieuses et Tropicales, Centre Regional de Recherche et de Formation, , Centre Hospitalier National Universitaire de Fann, ; Dakar, Senegal
                [8 ]GRID grid.5734.5, ISNI 0000 0001 0726 5157, Institute of Social and Preventive Medicine, , University of Bern, ; Bern, Switzerland
                [9 ]GRID grid.7836.a, ISNI 0000 0004 1937 1151, Division of Hepatology, Department of Medicine, Faculty of Health Sciences, , University of Cape Town, ; Cape Town, South Africa
                [10 ]GRID grid.12984.36, ISNI 0000 0000 8914 5257, Department of Internal Medicine, , University of Zambia, ; Lusaka, Zambia
                [11 ]GRID grid.265892.2, ISNI 0000000106344187, University of Alabama at Birmingham, ; Birmingham, AL USA
                [12 ]GRID grid.460724.3, ISNI 0000 0004 5373 1026, Medical Department, , St. Paul’s Hospital Millennium Medical College, ; Addis Ababa, Ethiopia
                [13 ]GRID grid.414281.a, Department of Hepatology and Gastroenterology, , Hopital Principal de Dakar, ; Dakar, Senegal
                [14 ]GRID grid.11956.3a, ISNI 0000 0001 2214 904X, Division of Medical Virology, , Stellenbosch University Faculty of Medicine and Health Sciences, ; Cape Town, South Africa
                [15 ]GRID grid.417371.7, ISNI 0000 0004 0635 423X, Division of Infectious Diseases, Department of Medicine, , Tygerberg Hospital and Stellenbosch University, ; Cape Town, South Africa
                [16 ]GRID grid.4991.5, ISNI 0000 0004 1936 8948, Nuffield Department of Medicine, , University of Oxford, ; Oxford, UK
                [17 ]GRID grid.451388.3, ISNI 0000 0004 1795 1830, The Francis Crick Institute, ; London, UK
                [18 ]GRID grid.83440.3b, ISNI 0000000121901201, University College London, ; London, UK
                [19 ]GRID grid.503074.5, L’Institut de Recherche en Santé, , de Surveillance Épidémiologique et de Formations (IRESSEF), ; Dakar, Senegal
                [20 ]Yalgado Ouédraogo University Hospital Center, Ouagadougou, Burkina Faso
                [21 ]GRID grid.428999.7, ISNI 0000 0001 2353 6535, Unité d’Epidémiologie des Maladies Emergentes, Institut Pasteur, ; Paris, France
                [22 ]GRID grid.7445.2, ISNI 0000 0001 2113 8111, Department of Metabolism, Digestion and Reproduction, Division of Digestive Diseases, Hepatology section, , Imperial College London, ; London, UK
                Author information
                http://orcid.org/0000-0001-5966-7166
                http://orcid.org/0000-0002-5828-3328
                http://orcid.org/0000-0003-1242-839X
                http://orcid.org/0000-0003-3199-301X
                http://orcid.org/0000-0003-2042-5797
                http://orcid.org/0000-0002-6876-3712
                http://orcid.org/0000-0003-0619-1074
                http://orcid.org/0000-0002-4198-4785
                Article
                35729
                10.1038/s41467-022-35729-w
                9810658
                36596805
                615ec9d1-30c6-4497-a0ec-768bc7efaf37
                © The Author(s) 2023

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 30 July 2022
                : 20 December 2022
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                © The Author(s) 2023

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                hepatitis b,diagnostic markers
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                hepatitis b, diagnostic markers

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