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1.  Determine TB-LAM lateral flow urine antigen assay for HIV-associated tuberculosis: recommendations on the design and reporting of clinical studies 
BMC Infectious Diseases  2013;13:407.
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.
doi:10.1186/1471-2334-13-407
PMCID: PMC3846798  PMID: 24004840
Determine TB-LAM Ag; Lipoarabinomannan; Tuberculosis; Diagnosis; Diagnostic accuracy; Sensitivity; Specificity; Point-of-care
2.  The proportions of people living with HIV in low and middle-income countries who test tuberculin skin test positive using either a 5 mm or a 10 mm cut-off: a systematic review 
BMC Infectious Diseases  2013;13:307.
Background
A positive tuberculin skin test (TST) is often defined by skin induration of ≥10 mm 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 ≥5 mm 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 ≥5 mm and ≥10 mm 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 ≥5 mm was 26.8% (IQR, 19.8-46.1%; range, 2.5-81.0%). Using a cut-off of ≥10 mm, 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 ≥500 cells/μL, the proportion of positive tests defined by the ≥5 mm cut-off that were between 5.0 and 9.9 mm 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 ≥5 mm compared to ≥10 mm. This proportion was similar across the range of CD4+ cell strata, supporting the current standardization of this cut-off at all levels of immunodeficiency.
doi:10.1186/1471-2334-13-307
PMCID: PMC3716635  PMID: 23834892
HIV; Tuberculin skin test; TST; Tuberculosis; CD4
3.  Point-of-care detection of lipoarabinomannan (LAM) in urine for diagnosis of HIV-associated tuberculosis: a state of the art review 
BMC Infectious Diseases  2012;12:103.
Detection of Mycobacterium tuberculosis antigens in urine is attractive as a potential means of diagnosing tuberculosis (TB) regardless of the anatomical site of disease. The most promising candidate antigen is the cell wall lipopolysaccharide antigen lipoarabinomannan (LAM), which has been used to develop commercially available enzyme-linked immunosorbent assays. Although highly variable diagnostic accuracy has been observed in different clinical populations, it is now clear that this assay has useful sensitivity for diagnosis of HIV-associated TB in patients with advanced immunodeficiency and low CD4 cell counts. Thus, this assay is particularly useful when selectively used among patients enrolling in antiretroviral treatment services or in HIV-infected patients requiring admission to hospital medical wards. These are the very patients who have the highest mortality risk and who stand to gain the most from rapid diagnosis, permitting immediate initiation of TB treatment. A recently developed low-cost, lateral-flow (urine ‘dip-stick’) format of the assay provides a result within 30 minutes and is potentially a major step forward as it can be used at the point-of-care, making the possibility of immediate diagnosis and treatment a reality. This paper discusses the likely utility of this point-of-care assay and how it might best be used in combination with other diagnostic assays for TB. The many further research studies that are needed on this assay are described. Consideration is particularly given to potential reasons for the variable specificity observed in existing field evaluations of LAM ELISAs. Whether this might be related to the assay itself or to the challenges associated with study design is discussed.
doi:10.1186/1471-2334-12-103
PMCID: PMC3423001  PMID: 22536883
HIV; Tuberculosis; Screening; Diagnosis; Culture; Asymptomatic; Subclinical
4.  Lipoarabinomannan in urine during tuberculosis treatment: association with host and pathogen factors and mycobacteriuria 
Background
Detection of lipoarabinomannan (LAM), a Mycobacterium tuberculosis (Mtb) cell wall antigen, is a potentially attractive diagnostic. However, the LAM-ELISA assay has demonstrated variable sensitivity in diagnosing TB in diverse clinical populations. We therefore explored pathogen and host factors potentially impacting LAM detection.
Methods
LAM-ELISA assay testing, sputum smear and culture status, HIV status, CD4 cell count, proteinuria and TB outcomes were prospectively determined in adults diagnosed with TB and commencing TB treatment at a South African township TB clinic. Sputum TB isolates were characterised by IS61110-based restriction fragment length polymorphism (RFLP) and urines were tested for mycobacteriuria by Xpert® MTB/RIF assay.
Results
32/199 (16.1%) of patients tested LAM-ELISA positive. Median optical density and proportion testing LAM positive remained unchanged during 2 weeks of treatment and then declined over 24 weeks. LAM was associated with positive sputum smear and culture status, HIV infection and low CD4 cell counts but not proteinuria, RFLP strain or TB treatment outcome. The sensitivity of LAM for TB in HIV-infected patients with CD4 counts of ≥ 200, 100-199, 50-99, and < 50 cells/μl, was 15.2%, 32%, 42.9%, and 69.2% respectively. Mycobacteriuria was found in 15/32 (46.9%) of LAM positive patients and in none of the LAM negative controls.
Conclusions
Urinary LAM was related to host immune factors, was unrelated to Mtb strain and declined steadily after an initial 2 weeks of TB treatment. The strong association of urine LAM with mycobacteriuria is a new finding, indicating frequent TB involvement of the renal tract in advanced HIV infection.
doi:10.1186/1471-2334-12-47
PMCID: PMC3349560  PMID: 22369353
5.  Treatment outcomes in HIV-infected adolescents attending a community-based antiretroviral therapy clinic in South Africa 
Background
Very few data are available on treatment outcomes of adolescents living with HIV infection (whether perinatally acquired or sexually acquired) in sub-Saharan Africa. The present study therefore compared the treatment outcomes in adolescents with those of young adults at a public sector community-based ART programme in Cape Town, South Africa.
Methods
Treatment outcomes of adolescents (9-19 years) were compared with those of young adults (20-28 years), enrolled in a prospective cohort between September 2002 and June 2009. Kaplan-Meier estimates and Cox proportional hazard models were used to assess outcomes and determine associations with age, while adjusting for potential confounders. The treatment outcomes were mortality, loss to follow-up (LTFU), immunological response, virological suppression and virological failure.
Results
883 patients, including 65 adolescents (47 perinatally infected and 17 sexually infected) and 818 young adults, received ART. There was no difference in median baseline CD4 cell count between adolescents and young adults (133.5 vs 116 cells/μL; p = 0.31). Overall mortality rates in adolescents and young adults were 1.2 (0.3-4.8) and 3.1 (2.4-3.9) deaths per 100 person-years, respectively. Adolescents had lower rates of virological suppression (< 400 copies/mL) at 48 weeks (27.3% vs 63.1%; p < 0.001). Despite this, however, the median change in CD4 count from baseline at 48 weeks of ART was significantly greater for adolescents than young adults (373 vs 187 cells/μL; p = 0.0001). Treatment failure rates were 8.2 (4.6-14.4) and 5.0 (4.1-6.1) per 100 person-years in the two groups. In multivariate analyses, there was no significant difference in LTFU and mortality between age groups but increased risk in virological failure [AHR 2.06 (95% CI 1.11-3.81; p = 0.002)] in adolescents.
Conclusions
Despite lower virological suppression rates and higher rates of virological failure, immunological responses were nevertheless greater in adolescents than young adults whereas rates of mortality and LTFU were similar. Further studies to determine the reasons for poorer virological outcomes are needed.
doi:10.1186/1471-2334-12-21
PMCID: PMC3295677  PMID: 22273267
antiretroviral; adolescents; outcomes; mortality; virological failure; Africa
6.  Delays in starting antiretroviral therapy in patients with HIV-associated tuberculosis accessing non-integrated clinical services in a South African township 
BMC Infectious Diseases  2011;11:258.
Background
Delays in the initiation of antiretroviral therapy (ART) in patients with HIV-associated tuberculosis (TB) are associated with increased mortality risk. We examined the timing of ART among patients receiving care provided by non-integrated TB and ART services in Cape Town, South Africa.
Methods
In an observational cohort study, we determined the overall time delay between starting treatment for TB and starting ART in patients treated in Gugulethu township between 2002 and 2008. For patients referred from TB clinics to the separate ART clinic, we quantified and identified risk factors associated with the two component delays between starting TB treatment, enrolment in the ART clinic and subsequent initiation of ART.
Results
Among 893 TB patients studied (median CD4 count, 81 cells/μL), the delay between starting TB treatment and starting ART was prolonged (median, 95 days; IQR = 49-155). Delays were shorter in more recent calendar periods and among those with lower CD4 cell counts. However, the median delay was almost three-fold longer for patients referred from separate TB clinics compared to patients whose TB was diagnosed in the ART clinic (116 days versus 41 days, respectively; P < 0.001). In the most recent calendar period, the proportions of patients with CD4 cell counts < 50 cells/μL who started ART within 4 weeks of TB diagnosis were 11.1% for patients referred from TB clinics compared to 54.6% of patients with TB diagnosed in the ART service (P < 0.001).
Conclusions
Delays in starting ART were prolonged, especially for patients referred from separate TB clinics. Non-integration of TB and ART services is likely to be a substantial obstacle to timely initiation of ART.
doi:10.1186/1471-2334-11-258
PMCID: PMC3203070  PMID: 21957868
7.  Identification of losses to follow-up in a community-based antiretroviral therapy clinic in South Africa using a computerized pharmacy tracking system 
BMC Infectious Diseases  2010;10:329.
Background
High rates of loss to follow-up (LTFU) are undermining rapidly expanding antiretroviral treatment (ART) services in sub-Saharan Africa. The intelligent dispensing of ART (iDART) is an open-source electronic pharmacy system that provides an efficient means of generating lists of patients who have failed to pick-up medication. We determined the duration of pharmacy delay that optimally identified true LTFU.
Methods
We conducted a retrospective cross-sectional study of a community-based ART cohort in Cape Town, South Africa. We used iDART to identify groups of patients known to be still enrolled in the cohort on the 1st of April 2008 that had failed to pick-up medication for periods of ≥ 6, ≥ 12, ≥ 18 and ≥ 24 weeks. We defined true LTFU as confirmed failure to pick up medication for 3 months since last attendance. We then assessed short-term and long-term outcomes using a prospectively maintained database and patient records.
Results
On the date of the survey, 2548 patients were registered as receiving ART but of these 85 patients (3.3%) were found to be true LTFU. The numbers of individuals (proportion of the cohort) identified by iDART as having failed to collect medication for periods of ≥6, ≥12, ≥18 and ≥24 weeks were 560 (22%), 194 (8%), 117 (5%) and 80 (3%), respectively. The sensitivities of these pharmacy delays for detecting true LTFU were 100%, 100%, 62.4% and 47.1%, respectively. The corresponding specificities were 80.7%, 95.6%, 97.4% and 98.4%. Thus, the optimal delay was ≥12 weeks since last attendance at this clinic (equivalent to 8 weeks since medication ran out). Pharmacy delays were also found to be significantly associated with LTFU and death one year later.
Conclusions
The iDART electronic pharmacy system can be used to detect patients potentially LTFU and who require recall. Using a short a cut-off period was too non-specific for LTFU and would require the tracing of very large numbers of patients. Conversely prolonged delays were too insensitive. Of the periods assessed, a ≥12 weeks delay appeared optimal. This system requires prospective evaluation to further refine its utility.
doi:10.1186/1471-2334-10-329
PMCID: PMC3000400  PMID: 21078148
8.  Prevalence of HIV-associated ophthalmic disease among patients enrolling for antiretroviral treatment in India: A cross-sectional study 
Background
The ocular manifestations of HIV may lead to visual impairment or blindness. In India, patients typically initiate antiretroviral treatment (ART) with low CD4 cell counts when the risk of ocular complications may be high. The objective of this study was to determine the prevalence and types of HIV-associated ocular conditions in patients referred for ART in India.
Methods
This cross-sectional study was undertaken at a large public sector ART centre in Mumbai, India. Data collection including a standardised symptom screen, and an ophthalmic examination were performed on all consecutive patients satisfying the criteria for enrolment into the ART clinic irrespective of the presence or absence of ophthalmic/visual symptoms.
Results
Enrolled patients (n = 149) had a median CD4 cell count of 180 cell/μL (inter-quartile range [IQR], 106-253 cells/μL). The prevalence of HIV-associated ocular disease was 17.5% (95% CI, 11.2-23.6%) in all participants and 23.8% (95% CI: 14.5-33.1) in those with CD4 cell counts <200 cells/μL (n = 84). Only 7.7% of patients with HIV-associated ocular disease reported any eye symptoms in the standardised symptom screen. Objective visual impairment was detected in 20% of those with HIV-associated ocular disease compared to 6% in those without ocular manifestations (p = 0.02). Vitreoretinal disease was the most common manifestation, of which cytomegalovirus retinitis (CMVR) was the most frequent retinal infection (overall prevalence 8.7%, 95% CI: 4.1-13.3%). In a multivariable analysis, HIV-associated ocular disease was independently associated with a CD4 count <100 cells/μL (odds ratio [OR], 6.3, 95% CI: 1.5-25.9) and WHO clinical stages 3 and 4 (OR 9.4, 95% CI: 2.4-37.2). However, symptoms were not independently predictive of ocular disease. Sensitivity of ocular symptom screening was 7.7%, with a positive predictive value of 18% in this population.
Conclusion
Over a fifth of unselected patients who are eligible for ART in this setting have HIV-related ocular disease of which CMVR is the most common form. Such patients may be at risk of developing ocular immune reconstitution phenomena during ART. Screening for ocular symptoms is not a reliable method to identify those with ocular morbidity and this highlights the need for routine ophthalmic screening prior to commencement of ART.
doi:10.1186/1471-2334-9-158
PMCID: PMC2759932  PMID: 19775470
9.  Utility of CD4 cell counts for early prediction of virological failure during antiretroviral therapy in a resource-limited setting 
Background
Viral load monitoring is not available for the vast majority of patients receiving antiretroviral therapy in resource-limited settings. However, the practical utility of CD4 cell count measurements as an alternative monitoring strategy has not been rigorously assessed.
Methods
In this study, we used a novel modelling approach that accounted for all CD4 cell count and VL values measured during follow-up from the first date that VL suppression was achieved. We determined the associations between CD4 counts (absolute values and changes during ART), VL measurements and risk of virological failure (VL > 1,000 copies/ml) following initial VL suppression in 330 patients in South Africa. CD4 count changes were modelled both as the difference from baseline (ΔCD4 count) and the difference between consecutive values (CD4 count slope) using all 3-monthly CD4 count measurements during follow-up.
Results
During 7093.2 patient-months of observation 3756 paired CD4 count and VL measurements were made. In patients who developed virological failure (n = 179), VL correlated significantly with absolute CD4 counts (r = - 0.08, P = 0.003), ΔCD4 counts (r = - 0.11, P < 0.01), and most strongly with CD4 count slopes (r = - 0.30, P < 0.001). However, the distributions of the absolute CD4 counts, ΔCD4 counts and CD4 count slopes at the time of virological failure did not differ significantly from the corresponding distributions in those without virological failure (P = 0.99, P = 0.92 and P = 0.75, respectively). Moreover, in a receiver operating characteristic (ROC) curve, the association between a negative CD4 count slope and virological failure was poor (area under the curve = 0.59; sensitivity = 53.0%; specificity = 63.6%; positive predictive value = 10.9%).
Conclusion
CD4 count changes correlated significantly with VL at group level but had very limited utility in identifying virological failure in individual patients. CD4 count is an inadequate alternative to VL measurement for early detection of virological failure.
doi:10.1186/1471-2334-8-89
PMCID: PMC2459184  PMID: 18601727
10.  Utility of interferon-γ ELISPOT assay responses in highly tuberculosis-exposed patients with advanced HIV infection in South Africa 
Background
Interferon-gamma (IFN-γ) ELISPOT assays incorporating Mycobacterium tuberculosis-specific antigens are useful in the diagnosis of tuberculosis (TB) or latent infection. However, their utility in patients with advanced HIV is unknown. We studied determinants of ELISPOT responses among patients with advanced HIV infection (but without active TB) living in a South African community with very high TB notification rates.
Methods
IFN-γ responses to ESAT-6 and CFP-10 in overnight ELISPOT assays and in 7-day whole blood assays (WBA) were compared in HIV-infected patients (HIV+, n = 40) and healthy HIV-negative controls (HIV-, n = 30) without active TB. Tuberculin skin tests (TSTs) were also done.
Results
ELISPOTs, WBAs and TSTs were each positive in >70% of HIV- controls, reflecting very high community exposure to M. tuberculosis. Among HIV+ patients, quantitative WBA responses and TSTs (but not the proportion of positive ELISPOT responses) were significantly impaired in those with CD4 cell counts <100 cells/μl compared to those with higher counts. In contrast, ELISPOT responses (but not WBA or TST) were strongly related to history of TB treatment; a much lower proportion of HIV+ patients who had recently completed treatment for TB (n = 19) had positive responses compared to those who had not been treated (11% versus 62%, respectively; P < 0.001). Multivariate analysis confirmed that ELISPOT responses had a strong inverse association with a history of recent TB treatment (adjusted OR = 0.06, 95%CI = 0.10–0.40, P < 0.01) and that they were independent of CD4 cell count and viral load. Among HIV+ individuals who had not received TB treatment both the magnitude and proportion of positive ELISPOT responses (but not TST or WBA) were similar to those of HIV-negative controls.
Conclusion
The proportion of positive ELISPOT responses in patients with advanced HIV infection was independent of CD4 cell count but had a strong inverse association with history of TB treatment. This concurs with the previously documented low TB risk among patients in this cohort with a history of recent treatment for TB. These data suggest ELISPOT assays may be useful for patient assessment and as an immuno-epidemiological research tool among patients with advanced HIV and warrant larger scale prospective evaluation.
doi:10.1186/1471-2334-7-99
PMCID: PMC2031899  PMID: 17725839
11.  Plasma levels of soluble urokinase-type plasminogen activator receptor (suPAR) and early mortality risk among patients enrolling for antiretroviral treatment in South Africa 
Background
Serum concentrations of soluble urokinase-type plasminogen activator receptor (suPAR) have a strong independent association with HIV-1-related mortality. The practical utility of plasma suPAR in assessing short-term all-cause mortality risk was evaluated in patients with advanced immunodeficiency enrolling in an antiretroviral treatment (ART) programme in South Africa.
Methods
An enzyme-linked immunosorbent assay (ELISA) was used to measure plasma concentrations of suPAR in patients at the time of enrolment to the ART programme. The association between plasma suPAR concentrations, baseline patient characteristics and cohort outcomes after 4 months of ART were determined.
Results
Patients (n = 293, 70% female) had a median age of 33 years and were followed up for a median of 5 months from enrolment. The median CD4 cell count was 47 cells/μl (IQR = 22–72) and 38% of patients had WHO stage 4 disease. 218 (74%) patients remained alive after 4 months of ART; 39 (13%) died and 36 (12%) were lost to the programme for other reasons. Patients who died had significantly higher plasma suPAR concentrations compared to those who either survived (P < 0.01) or left the programme for other reasons (P < 0.043). In multivariate analysis, higher log10 suPAR concentrations were significantly associated with lower CD4 cell counts, WHO clinical stage 4 disease and male sex. In multivariate analysis to identify factors associated with death, log10 suPAR concentration was the most strongly associated variable (P < 0.001). However, examination of sensitivity and specificity characteristics using receiver operating characteristic (ROC) analysis revealed that results from this assay did not have a discriminatory cut-point to provide clinically useful information.
Conclusion
Plasma suPAR concentration was the strongest independent predictor of short-term mortality risk among patients with advanced immunodeficiency enrolling in this ART programme. However, lack of a discriminatory threshold did not permit this marker to be used to triage patients according to short-term mortality risk.
doi:10.1186/1471-2334-7-41
PMCID: PMC1885800  PMID: 17509133
12.  CD4 cell count recovery among HIV-infected patients with very advanced immunodeficiency commencing antiretroviral treatment in sub-Saharan Africa 
Background
Patients accessing antiretroviral treatment (ART) programmes in sub-Saharan Africa frequently have very advanced immunodeficiency. Previous data suggest that such patients may have diminished capacity for CD4 cell count recovery.
Methods
Rates of CD4 cell increase were determined over 48 weeks among ART-naïve individuals (n = 596) commencing ART in a South African community-based ART programme.
Results
The CD4 cell count increased from a median of 97 cells/μl at baseline to 261 cells/μl at 48 weeks and the proportion of patients with a CD4 cell count <100 cells/μl decreased from 51% at baseline to just 4% at 48 weeks. A rapid first phase of recovery (0–16 weeks, median rate = 25.5 cells/μl/month) was followed by a slower second phase (16–48 weeks, median rate = 7.7 cells/μl/month). Compared to patients with higher baseline counts, multivariate analysis showed that those with baseline CD4 counts <50 cells/μl had similar rates of phase 1 CD4 cell recovery (P = 0.42), greater rates of phase 2 recovery (P = 0.007) and a lower risk of immunological non-response (P = 0.016). Among those that achieved a CD4 cell count >500 cells/μl at 48 weeks, 19% had baseline CD4 cell counts <50 cells/μl. However, the proportion of these patients that attained a CD4 count 200 cells/μl at 48 weeks was lower than those with higher baseline CD4 cell counts.
Conclusion
Patients in this cohort with baseline CD4 cell counts <50 cells/μl have equivalent or greater capacity for immunological recovery during 48 weeks of ART compared to those with higher baseline CD4 cell counts. However, their CD4 counts remain <200 cells/μl for a longer period, potentially increasing their risk of morbidity and mortality in the first year of ART.
doi:10.1186/1471-2334-6-59
PMCID: PMC1435908  PMID: 16551345

Results 1-12 (12)