Accuracy of immunological criteria for identifying virological failure in children on antiretroviral therapy - The IeDEA Southern Africa Collaboration

School of Public Health and Family Medicine, University of Cape Town, Cape Town, South Africa.
Tropical Medicine & International Health (Impact Factor: 2.33). 08/2011; 16(11):1367-71. DOI: 10.1111/j.1365-3156.2011.02854.x
Source: PubMed


To determine the diagnostic accuracy of World Health Organization (WHO) 2010 and 2006 as well as United States Department of Health and Human Services (DHHS) 2008 definitions of immunological failure for identifying virological failure (VF) in children on antiretroviral therapy (ART).
Analysis of data from children (<16 years at ART initiation) at South African ART sites at which CD4 count/per cent and HIV-RNA monitoring are performed 6-monthly. Incomplete virological suppression (IVS) was defined as failure to achieve ≥1 HIV-RNA ≤400 copies/ml between 6 and 15 months on ART and viral rebound (VR) as confirmed HIV-RNA ≥5000 copies/ml in a child on ART for ≥18 months who had achieved suppression during the first year on treatment.
Among 3115 children [median (interquartile range) age 48 (20-84) months at ART initiation] on treatment for ≥1 year, sensitivity of immunological criteria for IVS was 10%, 6% and 26% for WHO 2006, WHO 2010 and DHHS 2008 criteria, respectively. The corresponding positive predictive values (PPV) were 31%, 20% and 20%. Diagnostic accuracy for VR was determined in 2513 children with ≥18 months of follow-up and virological suppression during the first year on ART with sensitivity of 5% (WHO 2006/2010) and 27% (DHHS 2008). PPV results were 42% (WHO 2010), 43% (WHO 2006) and 20% (DHHS 2008).
Current immunological criteria are unable to correctly identify children failing ART virologically. Improved access to viral load testing is needed to reliably identify VF in children.

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Available from: Karl-Günter Technau, Dec 20, 2013
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    • "In low- and middle-income countries (LMICs), there are added difficulties in identifying treatment failure early enough to prevent accumulation of drug resistance mutations [15]. Current World Health Organization (WHO) criteria to assess paediatric failure have been repeatedly shown to be inaccurate for predicting failure [16, 17]. The sensitivity of the 2006 and 2010 WHO immunologic failure guidelines was as low as 6% in a multicentre South African study [16] and 5% in a Cambodian study [17]. "
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    ABSTRACT: The global paediatric HIV epidemic is shifting into a new phase as children on antiretroviral therapy (ART) move into adolescence and adulthood, and face new challenges of living with HIV. UNAIDS reports that 3.4 million children aged below 15 years and 2 million adolescents aged between 10 and 19 years have HIV. Although the vast majority of children were perinatally infected, older children are combined with behaviourally infected adolescents and youth in global reporting, making it difficult to keep track of their outcomes. Perinatally HIV-infected adolescents (PHIVA) are a highly unique patient sub-population, having been infected before development of their immune systems, been subject to suboptimal ART options and formulations, and now face transition from complete dependence on adult caregivers to becoming their own caregivers. As we are unable to track long-term complications and survival of PHIVA through national and global reporting systems, local and regional cohorts are the main sources for surveillance and research among PHIVA. This global review will utilize those data to highlight the epidemiology of PHIVA infection, treatment challenges and chronic disease risks. Unless mechanisms are created to count and separate out PHIVA outcomes, we will have few opportunities to characterize the negative consequences of life-long HIV infection in order to find ways to prevent them.
    Full-text · Article · Jun 2013 · Journal of the International AIDS Society
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    • "WHO guidelines define immunological failure as a CD4 count falling to or below the baseline value, or a 50% fall from the on-treatment peak or persistent CD4 values below 100 cells/µl [16]. However, CD4 testing has a poor accuracy and low positive predictive value in both adults [10,18] and children [8] for diagnosing treatment failure. Thus, viral load remains the gold standard. "
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    ABSTRACT: Though the advantages of routine virological monitoring for patients on anti-retroviral therapy have been established, cost and complexity limit its full implementation. Monitoring is important for diagnosing virological failure early on, before the development of drug resistance mutations, and to trigger early adherence interventions. Simple and cost-effective viral load tests that facilitate simplification and decentralization of testing and strategies, such as the use of dried blood spots and pooled sample testing, which further aid simplification, are becoming available. In addition, replacing immunological monitoring with virological monitoring in non-viremic patients in a phased manner will reduce the costs associated with dual immuno-virological monitoring. Going forward, the simplification of testing paired with price reducing strategies that will allow for healthy competition between multiple manufacturers will enable the implementation of viral load testing in resource-poor settings. It is important that future HIV and AIDS treatment guidelines provide clear recommendations for routine virological monitoring and that governments and donors fund the implementation of accurate and operationally proven testing platforms in a comprehensive manner.
    Full-text · Article · Oct 2012 · Journal of the International AIDS Society
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    • "No definition of IF is provided for children <2 years of age (WHO 2010). We have previously shown that the sensitivity of the DHHS 2008 IF definition [27%; 95% confidence interval (CI): 19–35%] was greater than that of WHO 2010 definition (5%; 95% CI: 2–9%) for identifying children with confirmed virological rebound (Davies et al. 2011; Note: Confirmed virological rebound was defined as HIV-RNA >5000 copies ⁄ ml on two consecutive occasions <365 days apart in a child on ART for ‡18 months who achieved suppression during the first year on ART). However, PPV was low for both DHHS (20%; 95% CI: 13–26%) and WHO 2010 (42%; 95% CI: 22– 62%) criteria. "
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    ABSTRACT: Objectives: To determine the improvement in positive predictive value of immunological failure criteria for identifying virological failure in HIV-infected children on antiretroviral therapy (ART) when a single targeted viral load measurement is performed in children identified as having immunological failure. Methods: Analysis of data from children (<16 years at ART initiation) at South African ART sites at which CD4 count/per cent and HIV-RNA monitoring are performed 6-monthly. Immunological failure was defined according to both WHO 2010 and United States Department of Health and Human Services (DHHS) 2008 criteria. Confirmed virological failure was defined as HIV-RNA >5000 copies/ml on two consecutive occasions <365 days apart in a child on ART for ≥18 months. Results: Among 2798 children on ART for ≥18 months [median (IQR) age 50 (21-84) months at ART initiation], the cumulative probability of confirmed virological failure by 42 months on ART was 6.3%. Using targeted viral load after meeting DHHS immunological failure criteria rather than DHHS immunological failure criteria alone increased positive predictive value from 28% to 82%. Targeted viral load improved the positive predictive value of WHO 2010 criteria for identifying confirmed virological failure from 49% to 82%. Conclusion: The addition of a single viral load measurement in children identified as failing immunologically will prevent most switches to second-line treatment in virologically suppressed children.
    Full-text · Article · Sep 2012 · Tropical Medicine & International Health
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