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      Diagnostic accuracy of the WHO clinical staging system for defining eligibility for ART in sub-Saharan Africa: a systematic review and meta-analysis

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          Abstract

          Introduction

          The World Health Organization (WHO) recommends that HIV-positive adults with CD4 count ≤500 cells/mm 3 initiate antiretroviral therapy (ART). In many countries of sub-Saharan Africa, CD4 count is not widely available or consistently used and instead the WHO clinical staging system is used to determine ART eligibility. However, concerns have been raised regarding its discriminatory ability to identify patients eligible to start ART. We therefore reviewed the accuracy of WHO stage 3 or 4 assessment in identifying ART eligibility according to CD4 count thresholds for ART initiation.

          Methods

          We systematically searched PubMed and Global Health databases and conference abstracts using a comprehensive strategy for studies that compared the results of WHO clinical staging with CD4 count thresholds. Studies performed in sub-Saharan Africa and published in English between 1998 and 2013 were eligible for inclusion according to our predefined study protocol. Two authors independently extracted data and assessed methodological quality and risk of bias using the Quality Assessment Tool for Diagnostic Accuracy Studies (QUADAS-2) tool. Summary estimates of sensitivity and specificity were derived for each CD4 count threshold and hierarchical summary receiver operator characteristic curves were plotted.

          Results

          Fifteen studies met the inclusion criteria, including 25,032 participants from 14 countries. Most studies assessed individuals attending ART clinics prior to treatment initiation. WHO clinical stage 3 or 4 disease had a sensitivity of 60% (95% CI: 45–73%, Q=914.26, p<0.001) and specificity of 73% (95% CI: 60–83%, Q=1439.43, p<0.001) for a CD4 threshold of ≤200 cells/mm 3 (11 studies); sensitivity and specificity for a threshold of CD4 count ≤350 cells/mm 3 were 45% (95% CI: 26–66%, Q=1607.31, p<0.001) and 85% (95% CI: 69–93%, Q=896.70, p<0.001), respectively (six studies). For the threshold of CD4 count ≤500 cells/mm 3 sensitivity was 14% (95% CI: 13–15%) and specificity was 95% (95% CI: 94–96%) (one study).

          Conclusions

          When used for individual treatment decisions, WHO clinical staging misses a high proportion of individuals who are ART eligible by CD4 count, with sensitivity falling as CD4 count criteria rises. Access to accurate, accessible, robust and affordable CD4 count testing methods will be a pressing need for as long as ART initiation decisions are based on criteria other than seropositivity.

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          Most cited references37

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          Effect of point-of-care CD4 cell count tests on retention of patients and rates of antiretroviral therapy initiation in primary health clinics: an observational cohort study.

          Loss to follow-up of HIV-positive patients before initiation of antiretroviral therapy can exceed 50% in low-income settings and is a challenge to the scale-up of treatment. We implemented point-of-care counting of CD4 cells in Mozambique and assessed the effect on loss to follow-up before immunological staging and treatment initiation. In this observational cohort study, data for enrolment into HIV management and initiation of antiretroviral therapy were extracted retrospectively from patients' records at four primary health clinics providing HIV treatment and point-of-care CD4 services. Loss to follow-up and the duration of each preparatory step before treatment initiation were measured and compared with baseline data from before the introduction of point-of-care CD4 testing. After the introduction of point-of-care CD4 the proportion of patients lost to follow-up before completion of CD4 staging dropped from 57% (278 of 492) to 21% (92 of 437) (adjusted odds ratio [OR] 0·2, 95% CI 0·15-0·27). Total loss to follow-up before initiation of antiretroviral treatment fell from 64% (314 of 492) to 33% (142 of 437) (OR 0·27, 95% CI 0·21-0·36) and the proportion of enrolled patients initiating antiretroviral therapy increased from 12% (57 of 492) to 22% (94 of 437) (OR 2·05, 95% CI 1·42-2·96). The median time from enrolment to antiretroviral therapy initiation reduced from 48 days to 20 days (p<0·0001), primarily because of a reduction in the median time taken to complete CD4 staging, which decreased from 32 days to 3 days (p<0·0001). Loss to follow-up between staging and antiretroviral therapy initiation did not change significantly (OR 0·84, 95% CI 0·49-1·45). Point-of-care CD4 testing enabled clinics to stage patients rapidly on-site after enrolment, which reduced opportunities for pretreatment loss to follow-up. As a result, more patients were identified as eligible for and initiated antiretroviral treatment. Point-of-care testing might therefore be an effective intervention to reduce pretreatment loss to follow-up. Absolute Return for Kids and UNITAID. Copyright © 2011 Elsevier Ltd. All rights reserved.
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            Expanding ART for Treatment and Prevention of HIV in South Africa: Estimated Cost and Cost-Effectiveness 2011-2050

            Background Antiretroviral Treatment (ART) significantly reduces HIV transmission. We conducted a cost-effectiveness analysis of the impact of expanded ART in South Africa. Methods We model a best case scenario of 90% annual HIV testing coverage in adults 15–49 years old and four ART eligibility scenarios: CD4 count <200 cells/mm3 (current practice), CD4 count <350, CD4 count <500, all CD4 levels. 2011–2050 outcomes include deaths, disability adjusted life years (DALYs), HIV infections, cost, and cost per DALY averted. Service and ART costs reflect South African data and international generic prices. ART reduces transmission by 92%. We conducted sensitivity analyses. Results Expanding ART to CD4 count <350 cells/mm3 prevents an estimated 265,000 (17%) and 1.3 million (15%) new HIV infections over 5 and 40 years, respectively. Cumulative deaths decline 15%, from 12.5 to 10.6 million; DALYs by 14% from 109 to 93 million over 40 years. Costs drop $504 million over 5 years and $3.9 billion over 40 years with breakeven by 2013. Compared with the current scenario, expanding to <500 prevents an additional 585,000 and 3 million new HIV infections over 5 and 40 years, respectively. Expanding to all CD4 levels decreases HIV infections by 3.3 million (45%) and costs by $10 billion over 40 years, with breakeven by 2023. By 2050, using higher ART and monitoring costs, all CD4 levels saves $0.6 billion versus current; other ART scenarios cost $9–194 per DALY averted. If ART reduces transmission by 99%, savings from all CD4 levels reach $17.5 billion. Sensitivity analyses suggest that poor retention and predominant acute phase transmission reduce DALYs averted by 26% and savings by 7%. Conclusion Increasing the provision of ART to <350 cells/mm3 may significantly reduce costs while reducing the HIV burden. Feasibility including HIV testing and ART uptake, retention, and adherence should be evaluated.
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              Immune reconstitution and "unmasking" of tuberculosis during antiretroviral therapy.

              Tuberculosis (TB) is the most common opportunistic disease in HIV-infected patients during the initial months of antiretroviral therapy (ART) and presents a great challenge to ART programs in resource-limited settings. The mechanisms underlying development of TB in this period are complex. Some cases may represent progression of undiagnosed subclinical disease present before starting ART, emphasizing the importance of careful screening strategies for TB. It has been suggested that progression in such cases is due to immune reconstitution disease-a phenomenon in which dysregulated restoration of pathogen-specific immune responses triggers the presentation of subclinical disease. However, whereas some cases have exaggerated or overtly inflammatory manifestations consistent with existing case definitions for IRD, many others do not. Moreover, since ART-induced immune recovery is a time-dependent process, active TB may develop as a consequence of persisting immunodeficiency. All these mechanisms are likely to be important, representing a spectrum of complex interactions between mycobacterial burden and changing host immune response. We propose that the potential range of effects of ART includes (1) shortening of the time for subclinical TB to become symptomatic (a phenomenon often referred to as "unmasking"), (2) increased rapidity of initial onset of TB symptoms, and (3) heightened intensity of clinical manifestations. We suggest that the term "ART-associated TB" be used to refer collectively to all cases of TB presenting during ART and that "immune reconstitution disease" be used to refer to the subset of ART-associated TB cases in which the effect on disease severity results in exaggerated and overtly inflammatory disease.
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                Author and article information

                Journal
                J Int AIDS Soc
                J Int AIDS Soc
                JIAS
                Journal of the International AIDS Society
                International AIDS Society
                1758-2652
                12 June 2014
                2014
                : 17
                : 1
                : 18932
                Affiliations
                [1 ]Department of International Public Health, Liverpool School of Tropical Medicine, Liverpool, UK
                [2 ]Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, UK
                [3 ]TB and HIV Group, Malawi–Liverpool–Wellcome Trust Clinical Research Programme, Blantyre, Malawi
                [4 ]Department of Clinical Research, London School of Hygiene and Tropical Medicine, London, UK
                [5 ]Department of HIV/AIDS, World Health Organization, Geneva, Switzerland
                Author notes
                [§ ] Corresponding author: Chigomezgo Munthali, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, UK. ( chigomw@ 123456yahoo.com )
                Article
                18932
                10.7448/IAS.17.1.18932
                4057784
                24929097
                f913ee73-27a6-4b99-90ad-9bdc6b9dec58
                © 2014 Munthali C et al; licensee International AIDS Society

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 28 October 2013
                : 27 April 2014
                : 01 May 2014
                Categories
                Research Article

                Infectious disease & Microbiology
                hiv,who clinical staging system,antiretroviral therapy,sub-saharan africa,systematic reviews,cd4 cell count

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