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Background: Simple methods for the accurate triaging and screening of HIV-associated tuberculosis (TB) are urgently needed. We hypothesized that combining serum antibody with urine lipoarabinomannan (U-LAM) detection can improve the detection of HIV-associated TB., Methods: We performed a case-control study with sampling from a prospective study of South African HIV-infected subjects who were screened for TB prior to initiating antiretroviral therapy. Sera from all available TB cases (n = 74) and randomly selected non-TB controls (n = 30), all tested for U-LAM, sputum microscopy, GeneXpert, and cultures, were evaluated for antibodies to LAM and arabinomannan (AM). Diagnostic logistic regression models for TB were developed based on the primary test results and the additive effect of antibodies with leave-one-out cross-validation., Results: Antibody responses to LAM and AM correlated strongly (p<0.0001), and IgG and IgM reactivities were significantly higher in TB than non-TB patients (p<0.0001). At 80% specificity, the target specificity for a non-sputum-based simple triage/screening test determined by major TB stakeholders, combining U-LAM with IgG detection significantly increased the sensitivity for HIV-associated TB to 92% compared to 30% for U-LAM alone (p<0.001). Sputum microscopy combined with IgG detection increased sensitivity to 88% compared to 31% for microscopy alone, and Xpert with IgG increased sensitivity to 96% and 99% compared to 57% for testing one, and 70% for testing two sputa with Xpert alone, respectively., Conclusion: Combining U-LAM with serum antibody detection could provide a simple low-cost method that meets the requirements for a non-sputum-based test for the screening of HIV-associated TB., Competing Interests: The authors have declared that no competing interests exist.

Background: Anaemia commonly complicates both human immunodeficiency virus (HIV) infection and tuberculosis (TB), contributing substantially to morbidity and mortality. The mechanisms underlying anaemia and corresponding treatments in co-infected patients are poorly defined., Objective: To determine the relative contributions of anaemia of chronic disease (ACD) and iron deficiency to anaemia in patients with HIV-associated TB., Design: Consecutively recruited hospitalised (n = 102) and matched ambulatory patients (n = 51) with microbiologically confirmed HIV-associated TB in Cape Town, South Africa, were included. Haemoglobin levels, iron status markers, hepcidin and pro-inflammatory cytokines in blood were measured. We determined the prevalence of ACD and iron-deficiency anaemia (IDA) using seven different published definitions of IDA., Results: More than 80% of enrolled HIV-associated TB patients were anaemic, and anaemia was more severe among in-patients. Over 95% of anaemic HIV-associated TB patients had ACD, whereas the proportion with IDA using a range of seven different definitions was low overall (median <3%, range 0-32.6) in both patient groups. The proportion with IDA and hepcidin concentration ⩿ 20.0 ng/ml (predictive of responsiveness to oral iron supplementation) was also very low (median <3%, range 0-15.1)., Conclusions: ACD was the predominant cause underlying anaemia in HIV-associated TB patients, and IDA was very uncommon in this setting. The majority of anaemic HIV-associated TB patients were unlikely to benefit from oral iron supplementation.

The role of Xpert(®) MTB/RIF for tuberculosis (TB) diagnosis remains to be clearly delineated in high-resource settings. At a London hospital, we evaluated a policy of selective assay use, with testing restricted to defined sub-groups of patients. Management was directly influenced in 30% of patients studied, including 'ruling-in' a TB diagnosis (leading to initiation of treatment for TB or for potential multidrug-resistant TB); negative assay results also helped support decisions for cessation of empirical anti-tuberculosis treatment or the safe initiation of other treatments such as immunosuppressant drugs. The benefits and pitfalls of this assay's use within high-resource settings are discussed.

Background: The impact of human immunodeficiency virus (HIV) infection and CD4 count on the diagnosis of tuberculosis (TB) at population level is incompletely defined., Objective: To determine how HIV infection and CD4 count affect disease site, sputum smear status and overall rate of laboratory confirmation (sputum smear microscopy or culture) of TB cases under routine programme conditions., Design: Retrospective analysis of the 2009 electronic TB register for Cape Town, South Africa., Results: Of 29,478 TB cases notified in 2009, HIV status was known for 25,744 (87.3%) cases, of whom 13,237 (51.4%) were HIV-positive. Of these, 61.2% had CD4 cell counts of <200 cells/μl and 82.7% had counts of <350 cells/μl. Laboratory confirmation of TB (by smear or culture) was obtained less frequently in HIV-infected than non-HIV-infected adult cases (53.9% vs. 74.3%, P< 0.001). HIV infection was associated with a higher proportion of sputum smear-negative and extra-pulmonary TB and lower grades of sputum smear positivity even among those with CD4 counts of ≥ 500 cells/μl. However, the relationship between the proportion of smear-positive cases and CD4 count was non-linear., Conclusion: Much TB is not laboratory-confirmed in this setting despite good laboratory services. HIV-associated TB is more difficult to diagnose even at high CD4 cell counts of >500 cells/μl, suggesting early impact after HIV seroconversion.

Tuberculosis is unique among the major infectious diseases in that it lacks accurate rapid point-of-care diagnostic tests. Failure to control the spread of tuberculosis is largely due to our inability to detect and treat all infectious cases of pulmonary tuberculosis in a timely fashion, allowing continued Mycobacterium tuberculosis transmission within communities. Currently recommended gold-standard diagnostic tests for tuberculosis are laboratory based, and multiple investigations may be necessary over a period of weeks or months before a diagnosis is made. Several new diagnostic tests have recently become available for detecting active tuberculosis disease, screening for latent M. tuberculosis infection, and identifying drug-resistant strains of M. tuberculosis. However, progress toward a robust point-of-care test has been limited, and novel biomarker discovery remains challenging. In the absence of effective prevention strategies, high rates of early case detection and subsequent cure are required for global tuberculosis control. Early case detection is dependent on test accuracy, accessibility, cost, and complexity, but also depends on the political will and funder investment to deliver optimal, sustainable care to those worst affected by the tuberculosis and human immunodeficiency virus epidemics. This review highlights unanswered questions, challenges, recent advances, unresolved operational and technical issues, needs, and opportunities related to tuberculosis diagnostics.

The human immunodeficiency virus (HIV) associated tuberculosis (TB) epidemic remains an enormous challenge to TB control in countries with a high prevalence of HIV. In their 1999 article entitled 'Will DOTS do it?', De Cock and Chaisson questioned whether the World Health Organization's DOTS Strategy could control this epidemic. Data over the past 10 years have clearly shown that DOTS is insufficient as a single TB control intervention in such settings because it does not address the fundamental epidemiological interactions between TB and HIV. Immunodeficiency is a principal driver of this epidemic, and the solution must therefore include immune recovery using antiretroviral therapy (ART). Thus, in the era of global ART scale-up, we now ask the question, 'Will ART do it?' ART reduces the risk of TB by 67% (95%CI 61-73), halves TB recurrence rates, reduces mortality risk by 64-95% in cohorts and prolongs survival in patients with HIV-associated drug-resistant TB. However, the cumulative lifetime risk of TB in HIV-infected individuals is a function of time spent at various CD4-defined levels of risk, both before and during ART. Current initiation of ART at low CD4 cell counts (by which time much HIV-associated TB has already occurred) and low effective coverage greatly undermine the potential impact of ART at a population level. Thus, while ART has proven a critical intervention for case management of HIV-associated TB, much of its preventive potential for TB control is currently being squandered. Much earlier ART initiation with high coverage is required if ART is to substantially influence the incidence of TB.

The human immunodeficiency virus (HIV) and HIV-associated tuberculosis (TB-HIV) epidemics remain uncontrolled in many resource-limited regions, especially in sub-Saharan Africa. The scale of these epidemics requires the consideration of innovative bold interventions and 'out-of-the-box' thinking. To this end, a symposium entitled 'Controversies in HIV' was held at the 40th Union World Conference on Lung Health in Cancun, Mexico, in December 2009. The first topic debated, entitled 'Annual HIV testing and immediate start of antiretroviral therapy for all HIV-infected persons', received much attention at international conferences and in the literature in 2009. The second topic forms the subject of this article. The rationale for the use of empirical TB treatment is premised on the hypothesis that in settings worst affected by the TB-HIV epidemic, a subset of HIV-infected patients have such a high risk of undiagnosed TB and of associated mortality that their prognosis may be improved by immediate initiation of empirical TB treatment used in conjunction with antiretroviral therapy. In addition to morbidity and mortality reduction, additional benefits may include prevention of nosocomial TB transmission and TB preventive effect. Potential adverse consequences, however, may include failure to consider other non-TB diagnoses, drug co-toxicity, compromised treatment adherence, and logistical and resource challenges. There may also be general reluctance among national TB programmes to endorse such a strategy. Following fruitful debate, the conclusion that this strategy should be carefully evaluated in randomised controlled trials was strongly supported. This paper provides an in-depth consideration of this proposed intervention.

Tuberculosis (TB) remains a major challenge to global public health in the 21st century. In 2007, there were an estimated 9.27 million new cases and 1.3 million deaths among HIV-negative patients with TB. The HIV-associated TB epidemic, drug-resistant disease, the need for better diagnostic assays and the limited efficacy of Bacille Calmette-Guerin vaccination are four important obstacles to further progress in global TB control. In this brief review, we provide a focused update on these four key areas of TB research.

Human immunodeficiency virus/acquired immune-deficiency syndrome (HIV/AIDS) and tuberculosis (TB) are overlapping epidemics that cause an immense burden of disease in sub-Saharan Africa. This region is home to the majority of the world's co-infected patents, who have higher TB case fatality and recurrence rates than patients with TB alone. A World Health Organization interim policy has been developed to reduce the joint burden of TB-HIV disease, an important component of which is provision of HIV care to co-infected patients. This review focuses on HIV testing of TB patients and, for those who are HIV-positive, the administration of adjunctive cotrimoxazole preventive treatment (CPT) and antiretroviral treatment (ART). HIV testing has moved from a voluntary, client-initiated intervention to one that is provider-initiated and a routine part of the diagnostic work-up. The efficacy and safety of CPT in HIV-infected patients is now well established, and this is an essential part of the package of HIV care. ART scale-up in Africa can substantially improve outcomes in co-infected patients. However, the clinical and programmatic challenges of combining ART with anti-tuberculosis treatment need to be resolved to realise the full potential of this benefit. These include the optimal time to start ART, how best to combine rifampicin-containing regimens with first-line and second-line ART regimens, management of immune reconstitution disease, the role of isoniazid preventive treatment with ART after TB treatment completion, and where and how to provide combined treatment to best suit the patient. Clinical and operational studies in the next few years should help to resolve some of these issues.

Since expression of both interleukin-2 (IL-2) and IL-2-receptor-alpha (IL-2R-alpha) by lymphocytes is inhibited by human immunodeficiency virus (HIV) in vitro, we hypothesized that HIV-co-infection among persons with tuberculosis (TB) might impair T-lymphocyte responses to TB via this mechanism. We measured soluble IL-2R-alpha (sIL-2R-alpha), a surrogate marker of T-lymphocyte activation and proliferation, and soluble tumour necrosis factor receptor I (sTNF-RI) in sera from West African patients categorized into 4 groups: those with TB alone (TB+ HIV-, n = 55), CD4-matched groups with TB and HIV co-infection (TB+ HIV+, n = 50) or HIV infection alone (TB- HIV+, n = 35), and patients with neither disease (TB- HIV-, n = 35). The median level of sIL-2R-alpha was markedly greater in the TB+ HIV- group (1580 U/mL) compared to the TB- HIV- (670 U/mL; P < 0.001) and TB- HIV+ (880 U/mL; P < 0.01) groups. More importantly, the median concentration of sIL-2R-alpha was much lower in the TB+ HIV+ group (855 U/mL) compared to the TB+ HIV- group (1580 U/mL; P < 0.01) despite similar levels of sTNF-RI. These results suggest that T-lymphocyte activation in TB patients is impaired by HIV co-infection and, furthermore, this suppressive effect was independent of numerical depletion of CD4 lymphocytes. Impairment to IL-2-signalling might contribute to the profound impact that HIV has had on both the incidence and the clinicopathological manifestations of TB.

Human immunodeficiency virus type 1 (HIV-1) bearing HLA-DR in its envelope was detected in plasma from all patients with chronic HIV-1 infection (n = 16) and was present at higher levels in patients with active tuberculosis coinfection (n = 6). Intriguingly, however, HLA-DR was not detectable in HIV-1 from patients during primary viremia (n = 6), suggesting the possibility of virus replication in less-activated cells.

The aim of this study was to identify immune markers that are independently associated with HIV infection or TB in vivo. Using commercially available assays, we measured concentrations of five immune markers in sera from 175 out-patients attending medical clinics in Cote D'Ivoire and Ghana, West Africa. Patients were categorized into groups with TB only (TB+HIV-, n = 55), TB and HIV co-infection (TB+HIV+, n = 50), HIV infection only (TB-HIV+, n = 35), or neither infection (TB-HIV-, n = 35). TB+HIV+ and TB-HIV+ groups were matched for blood CD4+ lymphocyte count. Mean +/- s.d. concentrations of beta2-microglobulin were similarly increased in both the TB-HIV+ (5.3+/-2.1 microg/ml, P<0.0001) and the TB+HIV+ (5.0+/-1.5 microg/ml, P<0.0001) groups compared with the TB-HIV- group (2.2+/-1.8 microg/ml), but were only slightly increased in the TB+HIV- group (3.2+/-1.8 microg/ml, P = 0.01). In contrast, mean serum concentrations of soluble tumour necrosis factor receptor type I (sTNF-RI) were similarly elevated in the TB+HIV- (1873+/-799 pg/ml, P<0.0001) and TB+HIV+ (1797+/-571 pg/ml, P<0.0001) groups compared with uninfected subjects (906+/-613 pg/ml), but there was only a small increase in sTNF-RI in the TB-HIV+ group (1231+/-165 pg/ml, P = 0.03). Both TB and HIV infection were associated with substantial elevation of serum concentrations of soluble CD8, soluble CD54, and sTNF-R type II. Analysis of additional samples from groups of TB+HIV- and TB+HIV+ patients receiving anti-TB treatment showed significant and equal reductions in mean serum sTNF-RI concentrations, but no significant change in mean beta2-microglobulin. Thus, serum beta2-microglobulin and sTNF-RI serve as relatively independent markers of HIV infection and TB, respectively, in studies of co-infected persons.

Data are limited regarding serum concentrations of soluble CD14 (sCD14), a marker of macrophage activation, in patients with active tuberculosis (TB) and during drug treatment. In this study, concentrations of sCD14 were measured in serum samples obtained from 105 African subjects who were categorized into one of four groups: persons with pulmonary TB alone (TB+HIV-, n = 30), pulmonary TB and HIV co-infection (TB+HIV+, n = 20), or HIV infection alone (TB-HIV+, n = 25), and healthy controls (TB-HIV-, n = 30). Mean total sCD14 was significantly increased in serum of patients with newly diagnosed pulmonary TB (mean = 6.6 g/ml, s.d. = 1.6 g/ml) compared with healthy controls (mean = 3.1 g/ml, s.d. = 0.6 g/ml; P < 0.0001), and this elevation comprised proportionate increases in the alpha (2.1-fold greater, P < 0.0001) and beta (2.0-fold greater, P < 0. 0001) forms of sCD14. Total sCD14 was also increased in serum of HIV-infected patients (mean = 4.1 g/ml, s.d. = 1.9 g/ml; P < 0.01), but the highest concentrations were observed in patients with pulmonary TB and HIV co-infection (mean = 8.7 g/ml, s.d. = 3.1 g/ml; P < 0.0001). Analysis of serum samples prospectively collected from TB+HIV-patients during the first 3 months of successful anti-TB treatment demonstrated steep reductions in mean concentrations of the acute-phase protein, C-reactive protein, and the soluble lymphocyte activation marker, sCD25. In contrast, levels of sCD14 increased during the first month of treatment and slowly declined thereafter. These data indicate that the serum concentration of sCD14 is not a sensitive index of response to anti-TB treatment and suggest that cellular activation resolves more slowly in the macrophage pool compared with the lymphocyte pool during anti-TB treatment.

Objective: To determine the impact of treatment of tuberculosis on plasma HIV-1 load in African subjects and to correlate viral load with response to treatment and changes in immune activation., Design: Clinical and microbiological responses, immune activation parameters and plasma HIV-1 load were determined in 20 patients with pulmonary tuberculosis and HIV-1 coinfection in Ghana, West Africa during the first 3 months of anti-tuberculosis treatment., Methods: Plasma HIV-1 load and markers of immune activation were determined by commercially available assays. Human leukocyte antigen (HLA)-DR incorporation into the HIV-1 envelope was measured by using an immunomagnetic capture technique., Results: Treatment of tuberculosis resulted in significant improvements in weight and haemoglobin, a high sputum smear conversion rate and marked reductions in mean plasma tumour necrosis factor (TNF) receptor-1, interleukin-6 and C-reactive protein. Furthermore, incorporation of host HLA-DR into the HIV-1 envelope decreased; this also suggested a reduction in immune activation of the cells supporting viral replication. However, of importance with regard to AIDS pathogenesis, neither mean plasma TNF-alpha nor HIV-1 load decreased significantly., Conclusions: The failure of HIV-1 plasma load to decline significantly during the initial months of anti-tuberculosis treatment is associated with high, sustained systemic levels of TNF-alpha. The dissociation between the sustained levels of plasma TNF-alpha and the major reductions in other, diverse immune activation parameters may represent dysregulation of cytokine production in these African patients.

Objectives: Molecular epidemiological studies of Mycobacterium tuberculosis in high prevalence areas in sub-Saharan Africa are hampered by the difficulty of culturing organisms from clinical samples. This study aimed to evaluate for application in a developing country, a modification of a novel polymerase chain reaction (PCR) based molecular epidemiological typing method, termed spoligotyping., Methods: DNA extraction from sputum was followed by PCR amplification of spacers between direct repeats in the M. tuberculosis genome, and hybridization to a range of the 53 known spacer sequences., Results: Sputum from 175 patients in the Ashanti region of Ghana were collected, and satisfactory spoligotyping results were obtained in 159. A total of 100 different spoligotype patterns were observed with 84 patients having unique patterns and the remainder falling into 16 clusters. A number of epidemiologically linked cases were shown to be unrelated on the basis of different spoligotype patterns, but epidemiological links were not found to explain clusters. Comparison of spoligotyping of DNA extracted from sputum with restriction fragment length polymorphism (RFLP) from mycobacterial culture in a subset of 25 patients, indicated that spoligotyping was less discriminatory than RFLP, Sixteen spoligotype patterns were shown to comprise 2 3 different RFLP patterns., Conclusions: This study suggests that the PCR based technique of spoligotyping can be applied successfully to DNA extracted from sputum collected in the setting of a developing country, but that this is less discriminatory than RFLP. Spoligotyping is particularly useful when used to support conventional epidemiology since a proportion of false epidemiological associations can be identified.

The aim of this study was to identify immune markers that are independently associated with HIV infection or TB in vivo. Using commercially available assays, we measured concentrations of five immune markers in sera from 175 out-patients attending medical clinics in Cote D'Ivoire and Ghana, West Africa. Patients were categorized into groups with TB only (TB+HIV-, n = 55), TB and HIV co-infection (TB+HIV+, n = 50), HIV infection only (TB-HIV+, n = 35), or neither infection (TB-HIV-, n = 35). TB+HIV+ and TB-HIV+ groups were matched for blood CD4+ lymphocyte count. Mean ± s.d. concentrations of β2-microglobulin were similarly increased in both the TB-HIV+ (5·3 ± 2·1 μg/ml, P < 0·0001) and the TB+HIV+ (5·0 ± 1·5 μg/ml, P < 0·0001) groups compared with the TB-HIV- group (2·2 ± 1·8 μg/ml), but were only slightly increased in the TB+HIV- group (3·2 ± 1·8 μg/ml, P = 0·01). In contrast, mean serum concentrations of soluble tumour necrosis factor receptor type I (sTNF-RI) were similarly elevated in the TB+HIV- (1873 ± 799 pg/ml, P < 0·0001) and TB+HIV+ (1797 ± 571 pg/ml, P < 0·0001) groups compared with uninfected subjects (906 ± 613 pg/ml), but there was only a small increase in sTNF-RI in the TB-HIV+ group (1231 ± 165 pg/ml, P = 0·03). Both TB and HIV infection were associated with substantial elevation of serum concentrations of soluble CD8, soluble CD54, and sTNF-R type II. Analysis of additional samples from groups of TB+HIV- and TB+HIV+ patients receiving anti-TB treatment... [ABSTRACT FROM AUTHOR]

Abstract 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.

BACKGROUND In regions with high burdens of tuberculosis and human immunodeficiency virus (HIV), many HIV-infected adults begin antiretroviral therapy (ART) when they are already severely immunocompromised. Mortality after ART initiation is high in these patients, and tuberculosis and invasive bacterial diseases are common causes of death. METHODS We conducted a 48-week trial of empirical treatment for tuberculosis as compared with treatment guided by testing in HIV-infected adults who had not previously received ART and had CD4+ T-cell counts below 100 cells per cubic millimeter. Patients recruited in Ivory Coast, Uganda, Cambodia, and Vietnam were randomly assigned in a 1:1 ratio to undergo screening (Xpert MTB/RIF test, urinary lipoarabinomannan test, and chest radiography) to determine whether treatment for tuberculosis should be started or to receive systematic empirical treatment with rifampin, isoniazid, ethambutol, and pyrazinamide daily for 2 months, followed by rifampin and isoniazid daily for 4 months. The primary end point was a composite of death from any cause or invasive bacterial disease within 24 weeks (primary analysis) or within 48 weeks after randomization. RESULTS A total of 522 patients in the systematic-treatment group and 525 in the guidedtreatment group were included in the analyses. At week 24, the rate of death from any cause or invasive bacterial disease (calculated as the number of first events per 100 patient-years) was 19.4 with systematic treatment and 20.3 with guided treatment (adjusted hazard ratio, 0.95; 95% confidence interval [Cl], 0.63 to 1.44). At week 48, the corresponding rates were 12.8 and 13.3 (adjusted hazard ratio, 0.97 [95% Cl, 0.67 to 1.40]). At week 24, the probability of tuberculosis was lower with systematic treatment than with guided treatment (3.0% vs. 17.9%; adjusted hazard ratio, 0.15; 95% Cl, 0.09 to 0.26), but the probability of grade 3 or 4 drug-related adverse events was higher with systematic treatment (17.4% vs. 7.2%; adjusted hazard ratio 2.57; 95% Cl, 1.75 to 3.78). Serious adverse events were more common with systematic treatment. CONCLUSIONS Among severely immunosuppressed adults with HIV infection who had not previously received ART, systematic treatment for tuberculosis was not superior to test-guided treatment in reducing the rate of death or invasive bacterial disease over 24 or 48 weeks and was associated with more grade 3 or 4 adverse events. [ABSTRACT FROM AUTHOR]