Browsing by Author "Kerkhoff, Andrew"

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    Open Access
    Determine TB-LAM lateral flow urine antigen assay for HIV-associated tuberculosis: recommendations on the design and reporting of clinical studies
    (BioMed Central Ltd, 2013) Lawn, Stephen; Dheda, Keertan; Kerkhoff, Andrew; Peter, Jonathan; Dorman, Susan; Boehme, Catharina; Nicol, Mark
    Detection of the Mycobacterium tuberculosis cell wall antigen lipoarabinomannan (LAM) in urine permits diagnoses of tuberculosis (TB) to be made in HIV-infected patients with advanced immunodeficiency. This can be achieved at the point-of-care within just 30 minutes using the Determine TB-LAM, which is a commercially available, lateral-flow urine 'strip test' assay. The assay has been shown to have useful diagnostic accuracy in patients enrolling in antiretroviral treatment services or in HIV-infected patients requiring admission to hospital medical wards in sub-Saharan Africa. Such patients have high mortality risk and have most to gain from rapid diagnosis of TB and immediate initiation of treatment. However, few studies using this assay have yet been reported and many questions remain concerning the correct use of the assay, interpretation of results, the role of the assay as an add-on test within existing diagnostic algorithms and the types of further studies needed. In this paper we address a series of questions with the aim of informing the design, conduct and interpretation of future studies. Specifically, we clarify which clinical populations are most likely to derive benefit from use of this assay and how patients enrolled in such studies might best be characterised. We describe the importance of employing a rigorous microbiological diagnostic reference standard in studies of diagnostic accuracy and discuss issues surrounding the specificity of the assay in different geographical areas and potential cross-reactivity with non-tuberculous mycobacteria and other organisms. We highlight the importance of careful procedures for urine collection and storage and the critical issue of how to read and interpret the test strips. Finally, we consider how the assay could be used in combination with other assays and outline the types of studies that are required to build the evidence base concerning its use.
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    HIV-associated tuberculosis: relationship between disease severity and the sensitivity of new sputum-based and urine-based diagnostic assays
    (BioMed Central Ltd, 2013) Lawn, Stephen; Kerkhoff, Andrew; Vogt, Monica; Wood, Robin
    BACKGROUND: Reducing mortality from HIV-associated tuberculosis (TB) requires diagnostic tools that are rapid and have high sensitivity among patients with poor prognosis. We determined the relationship between disease severity and the sensitivity of new sputum-based and urine-based diagnostic assays. METHODS: Consecutive ambulatory patients enrolling for antiretroviral treatment in South Africa were screened for TB regardless of symptoms using diagnostic assays prospectively applied to sputum (fluorescence smear microscopy, Xpert MTB/RIF and liquid culture (reference standard)) and retrospectively applied to stored urine samples (Determine TB-LAM and Xpert MTB/RIF). Assay sensitivities were calculated stratified according to pre-defined indices of disease severity: CD4 count, symptom intensity, serum C-reactive protein (CRP), hemoglobin concentration and vital status at 90 days. RESULTS: Sputum culture-positive TB was diagnosed in 15% (89/602) of patients screened and data from 86 patients were analyzed (median CD4 count, 131 cells/muL) including 6 (7%) who died. The sensitivity of sputum microscopy was 26.7% overall and varied relatively little with disease severity. In marked contrast, the sensitivities of urine-based and sputum-based diagnosis using Determine TB-LAM and Xpert MTB/RIF assays were substantially greater in sub-groups with poorer prognosis. Rapid diagnosis from sputum and/or urine samples was possible in >80% of patients in sub-groups with poor prognosis as defined by either CD4 counts <100 cells/muL, advanced symptoms, CRP concentrations >200 mg/L or hemoglobin <8.0 g/dl. Retrospective testing of urine samples with Determine TB-LAM correctly identified all those with TB who died. CONCLUSIONS: The sensitivities of Xpert MTB/RIF and Determine TB-LAM for HIV-associated TB were highest among HIV-infected patients with the most advanced disease and poorest prognostic characteristics. These data provide strong justification for large-scale intervention studies that assess the impact on survival of screening using these new sputum-based and urine-based diagnostic approaches.
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    The predictive value of current haemoglobin levels for incident tuberculosis and/or mortality during long-term antiretroviral therapy in South Africa: a cohort study
    (BioMed Central Ltd, 2015) Kerkhoff, Andrew; Wood, Robin; Cobelens, Frank; Gupta-Wright, Ankur; Bekker, Linda-Gail; Lawn, Stephen
    BACKGROUND: Low haemoglobin concentrations may be predictive of incident tuberculosis (TB) and death in HIV-infected patients receiving antiretroviral therapy (ART), but data are limited and inconsistent. We examined these relationships retrospectively in a long-term South African ART cohort with multiple time-updated haemoglobin measurements. METHODS: Prospectively collected clinical data on patients receiving ART for up to 8years in a community-based cohort were analysed. Time-updated haemoglobin concentrations, CD4 counts and HIV viral loads were recorded, and TB diagnoses and deaths from all causes were ascertained. Anaemia severity was classified using World Health Organization criteria. TB incidence and mortality rates were calculated and Poisson regression models were used to identify independent predictors of incident TB and mortality, respectively. RESULTS: During a median follow-up of 5.0years (IQR, 2.5-5.8) of 1,521 patients, 476 cases of incident TB and 192 deaths occurred during 6,459 person-years (PYs) of follow-up. TB incidence rates were strongly associated with time-updated anaemia severity; those without anaemia had a rate of 4.4 (95%CI, 3.8-5.1) cases/100 PYs compared to 10.0 (95%CI, 8.3-12.1), 26.6 (95%CI, 22.5-31.7) and 87.8 (95%CI, 57.0-138.2) cases/100 PYs in those with mild, moderate and severe anaemia, respectively. Similarly, mortality rates in those with no anaemia or mild, moderate and severe time-updated anaemia were 1.1 (95%CI, 0.8-1.5), 3.5 (95%CI, 2.7-4.8), 11.8 (95%CI, 9.5-14.8) and 28.2 (95%CI, 16.5-51.5) cases/100 PYs, respectively. Moderate and severe anaemia (time-updated) during ART were the strongest independent predictors for incident TB (adjusted IRR=3.8 [95%CI, 3.0-4.8] and 8.2 [95%CI, 5.3-12.7], respectively) and for mortality (adjusted IRR=6.0 [95%CI, 3.9-9.2] and adjusted IRR=8.0 [95%CI, 3.9-16.4], respectively). CONCLUSIONS: Increasing severity of anaemia was associated with exceptionally high rates of both incident TB and mortality during long-term ART. Patients receiving ART who have moderate or severe anaemia should be prioritized for TB screening using microbiological assays and may require adjunctive clinical interventions.
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    The proportions of people living with HIV in low and middle-income countries who test tuberculin skin test positive using either a 5mm or a 10mm cut-off: a systematic review
    (BioMed Central Ltd, 2013) Kerkhoff, Andrew; Gupta, Ankur; Samandari, Taraz; Lawn, Stephen
    BACKGROUND:A positive tuberculin skin test (TST) is often defined by skin induration of [greater than or equal to]10mm in people who are HIV-seronegative. However, to increase sensitivity for detection of Mycobacterium tuberculosis infection in the context of impaired immune function, a revised cut-off of [greater than or equal to]5mm is used for people living with HIV infection. The incremental proportion of patients who are included by this revised definition and the association between this proportion and CD4+ cell count are unknown. METHODS: The literature was systematically reviewed to determine the proportion of people living with HIV (PLWH) without evidence of active tuberculosis in low and middle-income countries who tested TST-positive using cut-offs of [greater than or equal to]5mm and [greater than or equal to]10mm of induration. The difference in the proportion testing TST-positive using the two cut-off sizes was calculated for all eligible studies and was stratified by geographical region and CD4+ cell count. RESULTS: A total of 32 studies identified meeting criteria were identified, providing data on 10,971 PLWH from sub-Saharan Africa, Asia and the Americas. The median proportion of PLWH testing TST-positive using a cut-off of [greater than or equal to]5mm was 26.8% (IQR, 19.8-46.1%; range, 2.5-81.0%). Using a cut-off of [greater than or equal to]10mm, the median proportion of PLWH testing TST-positive was 19.6% (IQR, 13.7-36.8%; range 0-52.1%). The median difference in the proportion of PLWH testing TST-positive using the two cut-offs was 6.0% (IQR, 3.4-10.1%; range, 0-37.6%). Among those with CD4+ cell counts of <200, 200-499 and [greater than or equal to]500 cells/muL, the proportion of positive tests defined by the [greater than or equal to]5mm cut-off that were between 5.0 and 9.9mm in diameter was similar (12.5%, 12.9% and 10.5%, respectively). CONCLUSIONS: There is a small incremental yield in the proportion of PLWH who test TST-positive when using an induration cut-off size of [greater than or equal to]5mm compared to [greater than or equal to]10mm. This proportion was similar across the range of CD4+ cell strata, supporting the current standardization of this cut-off at all levels of immunodeficiency.
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    Resolution of anaemia in a cohort of HIV-infected patients with a high prevalence and incidence of tuberculosis receiving antiretroviral therapy in South Africa
    (BioMed Central Ltd, 2014) Kerkhoff, Andrew; Wood, Robin; Cobelens, Frank; Gupta-Wright, Ankur; Bekker, Linda-Gail; Lawn, Stephen
    BACKGROUND: Anaemia is frequently associated with both HIV-infection and HIV-related tuberculosis (TB) in antiretroviral therapy (ART)-naive patients in sub-Saharan Africa and is strongly associated with poor prognosis. However, the effect of ART on the resolution of anaemia in patient cohorts with a high prevalence and incidence of tuberculosis is incompletely defined and the impact of TB episodes on haemoglobin recovery has not previously been reported. We therefore examined these issues using data from a well-characterised cohort of patients initiating ART in South Africa. METHODS: Prospectively collected clinical and haematological data were retrospectively analysed from patients receiving ART in a South African township ART service. TB diagnoses and time-updated haemoglobin concentrations, CD4 counts and HIV viral loads were recorded. Anaemia severity was classified according to WHO criteria. Multivariable logistic regression analysis was used to determine factors independently associated with anaemia after 12months of ART. RESULTS: Of 1,140 patients with baseline haemoglobin levels, 814 were alive in care and had repeat values available after 12months of ART. The majority of patients were female (73%), the median CD4 count was 104 cells/uL and 30.5% had a TB diagnosis in the first year of ART. At baseline, anaemia (any severity) was present in 574 (70.5%) patients and was moderate/severe in 346 (42.5%). After 12months of ART, 218 (26.8%) patients had anaemia of any severity and just 67 (8.2%) patients had moderate/severe anaemia. Independent predictors of anaemia after 12months of ART included greater severity of anaemia at baseline, time-updated erythrocyte microcytosis and receipt of an AZT-containing regimen. In contrast, prevalent and/or incident TB, gender and baseline and time-updated CD4 cell count and viral load measurements were not independent predictors. CONCLUSIONS: Although anaemia was very common among ART-naive patients, the anaemia resolved during the first year of ART in a large majority of patients regardless of TB status without routine use of additional interventions. However, approximately one-quarter of patients remained anaemic after one year of ART and may require additional investigations and/or interventions.