TB Modeling and Translational Epi Group

Group Publications

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- December 2014 -

Risk factors for delirium: are systematic reviews enough?. (2014). Brown CH 4th., Dowdy D, Critical care medicine, 43, 232-3

- November 2014 -

Long-term protection from isoniazid preventive therapy for tuberculosis in HIV-infected patients in a medium-burden tuberculosis setting: the TB/HIV in Rio (THRio) study. (2014). Golub JE., Cohn S., Saraceni V., Cavalcante SC., Pacheco AG., Moulton LH., Durovni B., Chaisson RE, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 60, 639-45

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BACKGROUND: The duration of protection against tuberculosis provided by isoniazid preventive therapy is not known for human immunodeficiency virus (HIV)-infected individuals living in settings of medium tuberculosis incidence. METHODS: We conducted an individual-level analysis of participants in a cluster-randomized, phased-implementation trial of isoniazid preventive therapy. HIV-infected patients who had positive tuberculin skin tests (TSTs) were followed until tuberculosis diagnosis, death, or administrative censoring. Nelson-Aalen cumulative hazard plots were generated and hazards were compared using the log-rank test. Cox proportional hazards models were fitted to investigate factors associated with tuberculosis diagnosis. RESULTS: Between 2003 and 2009, 1954 patients with a positive TST were studied. Among these, 1601 (82%) initiated isoniazid. Overall tuberculosis incidence was 1.39 per 100 person-years (PY); 0.53 per 100 PY in those who initiated isoniazid and 6.52 per 100 PY for those who did not (adjusted hazard ratio [aHR], 0.17; 95% confidence interval [CI], .11-.25). Receiving antiretroviral therapy at time of a positive TST was associated with a reduced risk of tuberculosis (aHR, 0.69; 95% CI, .48-1.00). Nelson-Aalen plots of tuberculosis incidence showed a constant risk, with no acceleration in 7 years of follow-up for those initiating isoniazid preventive therapy. CONCLUSIONS: Isoniazid preventive therapy significantly reduced tuberculosis risk among HIV-infected patients with a positive TST. In a medium-prevalence setting, 6 months of isoniazid in HIV-infected patients with positive TST reduces tuberculosis risk over 7 years of follow-up, in contrast to results of studies in higher-burden settings in Africa.

How much is tuberculosis screening worth? Estimating the value of active case finding for tuberculosis in South Africa, China, and India. (2014). Azman AS., Golub JE., Dowdy DW, BMC medicine, 12, 216

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BACKGROUND: Current approaches are unlikely to achieve the aggressive global tuberculosis (TB) control targets set for 2035 and beyond. Active case finding (ACF) may be an important tool for augmenting existing strategies, but the cost-effectiveness of ACF remains uncertain. Program evaluators can often measure the cost of ACF per TB case detected, but how this accessible measure translates into traditional metrics of cost-effectiveness, such as the cost per disability-adjusted life year (DALY), remains unclear. METHODS: We constructed dynamic models of TB in India, China, and South Africa to explore the medium-term impact and cost-effectiveness of generic ACF activities, conceptualized separately as discrete (2-year) campaigns and as continuous activities integrated into ongoing TB control programs. Our primary outcome was the cost per DALY, measured in relationship to the cost per TB case actively detected and started on treatment. RESULTS: Discrete campaigns costing up to $1,200 (95% uncertainty range [UR] 850-2,043) per case actively detected and started on treatment in India, $3,800 (95% UR 2,706-6,392) in China, and $9,400 (95% UR 6,957-13,221) in South Africa were all highly cost-effective (cost per DALY averted less than per capita gross domestic product). Prolonged integration was even more effective and cost-effective. Short-term assessments of ACF dramatically underestimated potential longer term gains; for example, an assessment of an ACF program at 2 years might find a non-significant 11% reduction in prevalence, but a 10-year evaluation of that same intervention would show a 33% reduction. CONCLUSIONS: ACF can be a powerful and highly cost-effective tool in the fight against TB. Given that short-term assessments may dramatically underestimate medium-term effectiveness, current willingness to pay may be too low. ACF should receive strong consideration as a basic tool for TB control in most high-burden settings, even when it may cost over $1,000 to detect and initiate treatment for each extra case of active TB.

- October 2014 -

Modeling of novel diagnostic strategies for active tuberculosis - a systematic review: current practices and recommendations. (2014). Zwerling A., White RG., Vassall A., Cohen T., Dowdy DW., Houben RM, PloS one, 9, e110558

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INTRODUCTION: The field of diagnostics for active tuberculosis (TB) is rapidly developing. TB diagnostic modeling can help to inform policy makers and support complicated decisions on diagnostic strategy, with important budgetary implications. Demand for TB diagnostic modeling is likely to increase, and an evaluation of current practice is important. We aimed to systematically review all studies employing mathematical modeling to evaluate cost-effectiveness or epidemiological impact of novel diagnostic strategies for active TB. METHODS: Pubmed, personal libraries and reference lists were searched to identify eligible papers. We extracted data on a wide variety of model structure, parameter choices, sensitivity analyses and study conclusions, which were discussed during a meeting of content experts. RESULTS & DISCUSSION: From 5619 records a total of 36 papers were included in the analysis. Sixteen papers included population impact/transmission modeling, 5 were health systems models, and 24 included estimates of cost-effectiveness. Transmission and health systems models included specific structure to explore the importance of the diagnostic pathway (n = 4), key determinants of diagnostic delay (n = 5), operational context (n = 5), and the pre-diagnostic infectious period (n = 1). The majority of models implemented sensitivity analysis, although only 18 studies described multi-way sensitivity analysis of more than 2 parameters simultaneously. Among the models used to make cost-effectiveness estimates, most frequent diagnostic assays studied included Xpert MTB/RIF (n = 7), and alternative nucleic acid amplification tests (NAATs) (n = 4). Most (n = 16) of the cost-effectiveness models compared new assays to an existing baseline and generated an incremental cost-effectiveness ratio (ICER). CONCLUSION: Although models have addressed a small number of important issues, many decisions regarding implementation of TB diagnostics are being made without the full benefits of insight from mathematical models. Further models are needed that address a wider array of diagnostic and epidemiological settings, that explore the inherent uncertainty of models and that include additional epidemiological data on transmission implications of false-negative diagnosis and the pre-diagnostic period.

A piece of my mind. Healthy but harmed. (2014). Dowdy DW, JAMA, 312, 1399-400

Clinical effectiveness and cost-effectiveness of HIV pre-exposure prophylaxis in men who have sex with men: risk calculators for real-world decision-making. (2014). Chen A., Dowdy DW, PloS one, 9, e108742

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BACKGROUND: Oral pre-exposure prophylaxis (PrEP) can be clinically effective and cost-effective for HIV prevention in high-risk men who have sex with men (MSM). However, individual patients have different risk profiles, real-world populations vary, and no practical tools exist to guide clinical decisions or public health strategies. We introduce a practical model of HIV acquisition, including both a personalized risk calculator for clinical management and a cost-effectiveness calculator for population-level decisions. METHODS: We developed a decision-analytic model of PrEP for MSM. The primary clinical effectiveness and cost-effectiveness outcomes were the number needed to treat (NNT) to prevent one HIV infection, and the cost per quality-adjusted life-year (QALY) gained. We characterized patients according to risk factors including PrEP adherence, condom use, sexual frequency, background HIV prevalence and antiretroviral therapy use. RESULTS: With standard PrEP adherence and national epidemiologic parameters, the estimated NNT was 64 (95% uncertainty range: 26, 176) at a cost of $160,000 (cost saving, $740,000) per QALY--comparable to other published models. With high (35%) HIV prevalence, the NNT was 35 (21, 57), and cost per QALY was $27,000 (cost saving, $160,000), and with high PrEP adherence, the NNT was 30 (14, 69), and cost per QALY was $3,000 (cost saving, $200,000). In contrast, for monogamous, serodiscordant relationships with partner antiretroviral therapy use, the NNT was 90 (39, 157) and cost per QALY was $280,000 ($14,000, $670,000). CONCLUSIONS: PrEP results vary widely across individuals and populations. Risk calculators may aid in patient education, clinical decision-making, and cost-effectiveness evaluation.

- September 2014 -

Active case finding of tuberculosis (TB) in an emergency room in a region with high prevalence of TB in Brazil. (2014). Silva DR., Muller AM., Tomasini Kda S., Dalcin Pde T., Golub JE., Conde MB, PloS one, 9, e107576

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SETTING: Public hospital emergency room (ER) in Porto Alegre, Brazil, a setting with high prevalence of tuberculosis (TB) and human immunodeficiency virus (HIV) infection. OBJECTIVE: To determine the prevalence of PTB, using a symptom based active case finding (ACF) strategy in the ER of a public hospital in an area with high prevalence of TB and HIV, as well as variables associated with pulmonary TB diagnosis. METHODS: Cross sectional study. All patients >/= 18 years seeking care at the ER were screened for respiratory symptoms and those with cough >/= 2 weeks were invited to provide a chest radiograph and two unsupervised samples of sputum for acid-fast bacilli smear and culture. RESULTS: Among 31,267 admissions, 6,273 (20.1%) reported respiratory symptoms; 197 reported cough >/= 2 weeks, of which pulmonary TB was diagnosed in 30. In multivariate analysis, the variables associated with a pulmonary tuberculosis diagnosis were: age (OR 0.94, 95% CI: 0.92-0.97; p<0.0001), sputum production (OR 0.18, 95% CI 0.06-0.56; p = 0.003), and radiographic findings typical of TB (OR 12.11, 95% CI 4.45-32.93; p<0.0001). CONCLUSIONS: This study identified a high prevalence of pulmonary TB among patients who sought care at the emergency department of a tertiary hospital, emphasizing the importance of regular screening of all comers for active TB in this setting.

Bold thinking for bold results: modeling the elimination of tuberculosis. (2014). Azman AS., Dowdy DW, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 18, 883

Impact and cost-effectiveness of current and future tuberculosis diagnostics: the contribution of modelling. (2014). Dowdy DW., Houben R., Cohen T., Pai M., Cobelens F., Vassall A., Menzies NA., Gomez GB., Langley I., Squire SB., White R, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 18, 1012-8

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The landscape of diagnostic testing for tuberculosis (TB) is changing rapidly, and stakeholders need urgent guidance on how to develop, deploy and optimize TB diagnostics in a way that maximizes impact and makes best use of available resources. When decisions must be made with only incomplete or preliminary data available, modelling is a useful tool for providing such guidance. Following a meeting of modelers and other key stakeholders organized by the TB Modelling and Analysis Consortium, we propose a conceptual framework for positioning models of TB diagnostics. We use that framework to describe modelling priorities in four key areas: Xpert((R)) MTB/RIF scale-up, target product profiles for novel assays, drug susceptibility testing to support new drug regimens, and the improvement of future TB diagnostic models. If we are to maximize the impact and cost-effectiveness of TB diagnostics, these modelling priorities should figure prominently as targets for future research.

Reproducibility of interferon gamma (IFN-gamma) release Assays. A systematic review. (2014). Tagmouti S., Slater M., Benedetti A., Kik SV., Banaei N., Cattamanchi A., Metcalfe J., Dowdy D., van Zyl Smit R., Dendukuri N., Pai M., Denkinger C, Annals of the American Thoracic Society, 11, 1267-76

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RATIONALE: Interferon gamma (IFN-gamma) release assays for latent tuberculosis infection result in a larger-than-expected number of conversions and reversions in occupational screening programs, and reproducibility of test results is a concern. OBJECTIVES: Knowledge of the relative contribution and extent of the individual sources of variability (immunological, preanalytical, or analytical) could help optimize testing protocols. METHODS: We performed a systematic review of studies published by October 2013 on all potential sources of variability of commercial IFN-gamma release assays (QuantiFERON-TB Gold In-Tube and T-SPOT.TB). The included studies assessed test variability under identical conditions and under different conditions (the latter both overall and stratified by individual sources of variability). Linear mixed effects models were used to estimate within-subject SD. MEASUREMENTS AND MAIN RESULTS: We identified a total of 26 articles, including 7 studies analyzing variability under the same conditions, 10 studies analyzing variability with repeat testing over time under different conditions, and 19 studies reporting individual sources of variability. Most data were on QuantiFERON (only three studies on T-SPOT.TB). A considerable number of conversions and reversions were seen around the manufacturer-recommended cut-point. The estimated range of variability of IFN-gamma response in QuantiFERON under identical conditions was +/-0.47 IU/ml (coefficient of variation, 13%) and +/-0.26 IU/ml (30%) for individuals with an initial IFN-gamma response in the borderline range (0.25-0.80 IU/ml). The estimated range of variability in noncontrolled settings was substantially larger (+/-1.4 IU/ml; 60%). Blood volume inoculated into QuantiFERON tubes and preanalytic delay were identified as key sources of variability. CONCLUSIONS: This systematic review shows substantial variability with repeat IFN-gamma release assays testing even under identical conditions, suggesting that reversions and conversions around the existing cut-point should be interpreted with caution.

The impact of novel tests for tuberculosis depends on the diagnostic cascade. (2014). Sun AY., Denkinger CM., Dowdy DW, The European respiratory journal, 44, 1366-9

Modeling the impact of novel diagnostic tests on pediatric and extrapulmonary tuberculosis. (2014). Denkinger CM., Kampmann B., Ahmed S., Dowdy DW, BMC infectious diseases, 14, 477

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BACKGROUND: Extrapulmonary tuberculosis (EPTB) and most pediatric TB cannot be diagnosed using sputum-based assays. The epidemiological impact of different strategies to diagnose EPTB and pediatric TB is unclear. METHODS: We developed a dynamic epidemic model of TB in a hypothetical population with epidemiological characteristics similar to India. We evaluated the impact of four alternative diagnostic test platforms on adult EPTB and pediatric TB mortality over 10 years: (1) Nucleic acid amplification test optimized for diagnosis of EPTB ("NAAT-EPTB"); (2) NAAT optimized for pediatric TB ("NAAT-Peds"); (3) more deployable NAAT for sputum-based diagnosis of adult pulmonary TB ("point-of-care (POC) sputum NAAT"); and (4) more deployable NAAT capable of diagnosing all forms of TB using non-invasive, non-sputum specimens ("POC non-sputum NAAT"). RESULTS: NAAT-EPTB lowered adult EPTB mortality by a projected 7.6% (95% uncertainty range [UR]: 6.5-8.8%). NAAT-Peds lowered pediatric TB mortality by 6.8% (UR: 4.9-8.4%). POC sputum NAAT, though only able to diagnose pulmonary TB, reduced projected pediatric TB deaths by 13.3% (UR: 4.6-15.7%) and adult EPTB deaths by 8.4% (UR 2.0-9.3%) simply by averting transmission of disease. POC non-sputum NAAT had the greatest effect, lowering pediatric TB mortality by 34.7% (UR: 26.8-38.7), and adult EPTB mortality by 38.5% (UR: 30.7-41.2). The relative impact of a POC sputum NAAT (i.e., enhanced deployability) versus NAAT-EPTB (i.e., enhanced ability to specifically diagnose TB-NSP) on adult EPTB mortality depends most strongly on factors that influence transmission, with settings of higher transmission (e.g., higher per-person transmission rate, lower diagnostic rate) favoring POC sputum NAAT. CONCLUSION: Although novel tests for pediatric TB and EPTB are likely to reduce TB mortality, major reductions in pediatric and EPTB incidence and mortality also require better diagnostic tests for adult pulmonary TB that reach a larger population.

- August 2014 -

Cost-effectiveness of novel algorithms for rapid diagnosis of tuberculosis in HIV-infected individuals in Uganda. (2014). Shah M., Dowdy D., Joloba M., Ssengooba W., Manabe YC., Ellner J., Dorman SE, AIDS (London, England), 27, 2883-92

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OBJECTIVE: Xpert MTB/RIF ('Xpert') and urinary lateral-flow lipoarabinomannan (LF-LAM) assays offer rapid tuberculosis (TB) diagnosis. This study evaluated the cost-effectiveness of novel diagnostic algorithms utilizing combinations of Xpert and LF-LAM for the detection of active TB among people living with HIV. DESIGN: Cost-effectiveness analysis using data from a comparative study of LF-LAM and Xpert, with a target population of HIV-infected individuals with signs/symptoms of TB in Uganda. METHODS: A decision-analysis model compared multiple strategies for rapid TB diagnosis:sputum smear-microscopy; sputum Xpert; smear-microscopy combined with LF-LAM; and Xpert combined with LF-LAM. Primary outcomes were the costs and DALY's averted for each algorithm. Cost-effectiveness was represented using incremental cost-effectiveness ratios (ICER). RESULTS: Compared with an algorithm of Xpert testing alone, the combination of Xpert with LF-LAM was considered highly cost-effective (ICER $57/DALY-averted) at a willingness to pay threshold of Ugandan GDP per capita. Addition of urine LF-LAM testing to smear-microscopy was a less effective strategy than Xpert replacement of smear-microscopy, but was less costly and also considered highly cost-effective (ICER $33 per DALY-averted) compared with continued usage of smear-microscopy alone. Cost-effectiveness of the Xpert plus LF-LAM algorithm was most influenced by HIV/ART costs and life-expectancy of patients after TB treatment. CONCLUSION: The addition of urinary LF-LAM to TB diagnostic algorithms for HIV-infected individuals is highly cost-effective compared with usage of either sputum smear-microscopy or Xpert alone.

Reply to "at the crossroads between early or delayed antiretroviral therapy initiation during TB/HIV coinfection". (2014). Saraceni V., Durovni B., Pacheco AG., Chaisson RE., Golub JE, The Brazilian journal of infectious diseases : an official publication of the Brazilian Society of Infectious Diseases, 18, 578-9

- July 2014 -

Factors associated with tuberculosis by HIV status in the Brazilian national surveillance system: a cross sectional study. (2014). do Prado TN., Miranda AE., de Souza FM., Dias Edos S., Sousa LK., Arakaki-Sanchez D., Sanchez MN., Golub JE., Maciel EL, BMC infectious diseases, 14, 415

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BACKGROUND: Over the last decade tuberculosis (TB) incidence and mortality in Brazil have been steadily declining. However, this downward trend has not been observed among HIV-infected patients. We describe the epidemiological and clinical profile of TB patients by HIV status using the Brazilian National Surveillance System. METHODS: All TB diagnoses with HIV status information between January 1, 2007 and December 31, 2011 were categorized as either HIV or non-HIV at time of TB diagnosis. Co-infected patients (TB-HIV) were compared to TB patients with no HIV-infection using a hierarchical logistic regression model using Stata 13.0. RESULTS: The prevalence of TB-HIV co-infection was 19% among adults >/= 15 years of age. We analyzed data from 243,676 individuals, of whom 46,466 were TB-HIV and 197,210 were only TB cases. The following factors increased risk of co-infection: male sex (OR: 1.06, 95% CI 1.03-1.10), 20 to 39 years of age (OR = 4.82, 95% CI 4.34-5.36), black (OR = 1.08, 95% CI 1.04-1.13), 4-7 years of education (OR = 1.13, 95% CI 1.19-1.28), diagnosed following default (OR = 2.65, 95% CI 1.13-6.25), presenting with pulmonary and extra-pulmonary forms of TB simultaneously (OR = 2.80, 95% CI 1.56-5.02), presenting with histopathologic examination suggestive of TB (OR = 2.15, 95% CI 1.13-4.07). Co-infected patients were less likely to live in rural areas (OR = 0.45, 95% CI 0.42-0.48), have diabetes (OR = 0.45, 95% CI 0.40-0.50) and be smear positive (OR = 0.55, 95% CI 0.32-0.95), and co-infected patients had higher risk of default (OR = 2.96, 95% CI 2.36-3.71) and death from TB (OR = 5.16, 95% CI 43.04-5.77). CONCLUSIONS: The prevalence of co-infection with HIV among TB patients is 19% in Brazil. By identifying predictors of co-infection targeted interventions can be developed to prevent both TB and HIV, and to diagnose each disease earlier and ultimately decrease poor treatment outcomes and death.

The importance of implementation strategy in scaling up Xpert MTB/RIF for diagnosis of tuberculosis in the Indian health-care system: a transmission model. (2014). Salje H., Andrews JR., Deo S., Satyanarayana S., Sun AY., Pai M., Dowdy DW, PLoS medicine, 11, e1001674

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BACKGROUND: India has announced a goal of universal access to quality tuberculosis (TB) diagnosis and treatment. A number of novel diagnostics could help meet this important goal. The rollout of one such diagnostic, Xpert MTB/RIF (Xpert) is being considered, but if Xpert is used mainly for people with HIV or high risk of multidrug-resistant TB (MDR-TB) in the public sector, population-level impact may be limited. METHODS AND FINDINGS: We developed a model of TB transmission, care-seeking behavior, and diagnostic/treatment practices in India and explored the impact of six different rollout strategies. Providing Xpert to 40% of public-sector patients with HIV or prior TB treatment (similar to current national strategy) reduced TB incidence by 0.2% (95% uncertainty range [UR]: -1.4%, 1.7%) and MDR-TB incidence by 2.4% (95% UR: -5.2%, 9.1%) relative to existing practice but required 2,500 additional MDR-TB treatments and 60 four-module GeneXpert systems at maximum capacity. Further including 20% of unselected symptomatic individuals in the public sector required 700 systems and reduced incidence by 2.1% (95% UR: 0.5%, 3.9%); a similar approach involving qualified private providers (providers who have received at least some training in allopathic or non-allopathic medicine) reduced incidence by 6.0% (95% UR: 3.9%, 7.9%) with similar resource outlay, but only if high treatment success was assured. Engaging 20% of all private-sector providers (qualified and informal [providers with no formal medical training]) had the greatest impact (14.1% reduction, 95% UR: 10.6%, 16.9%), but required >2,200 systems and reliable treatment referral. Improving referrals from informal providers for smear-based diagnosis in the public sector (without Xpert rollout) had substantially greater impact (6.3% reduction) than Xpert scale-up within the public sector. These findings are subject to substantial uncertainty regarding private-sector treatment patterns, patient care-seeking behavior, symptoms, and infectiousness over time; these uncertainties should be addressed by future research. CONCLUSIONS: The impact of new diagnostics for TB control in India depends on implementation within the complex, fragmented health-care system. Transformative strategies will require private/informal-sector engagement, adequate referral systems, improved treatment quality, and substantial resources. Please see later in the article for the Editors' Summary.

Transforming the fight against tuberculosis: targeting catalysts of transmission. (2014). Dowdy DW., Azman AS., Kendall EA., Mathema B, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 59, 1123-9

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The global tuberculosis control community has committed itself to ambitious 10-year targets. To meet these targets, biomedical advances alone will be insufficient; a more targeted public health tuberculosis strategy is also needed. We highlight the role of "tuberculosis transmission catalysts," defined as variabilities in human behavior, bacillary properties, and host physiology that fuel the propagation of active tuberculosis at the local level. These catalysts can be categorized as factors that increase contact rates, infectiousness, or host susceptibility. Different catalysts predominate in different epidemiological and sociopolitical settings, and public health approaches are likely to succeed only if they are tailored to target the major catalysts driving transmission in the corresponding community. We argue that global tuberculosis policy should move from a country-level focus to a strategy that prioritizes collection of data on key transmission catalysts at the local level followed by deployment of "catalyst-targeted" interventions, supported by strengthened health systems.

- June 2014 -

Prevalent tuberculosis at HIV diagnosis in Rio de Janeiro, Brazil: the TB/HIV in Rio (THRio) Cohort. (2014). Saraceni V., Cohn S., Cavalcante SC., Pacheco AG., Moulton LH., Chaisson RE., Durovni B., Golub JE, Journal of acquired immune deficiency syndromes (1999), 67, 98-101

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BACKGROUND: Although Brazil has model HIV care programs, many patients continue to present late to care. We studied the frequency of tuberculosis (TB) diagnosed at HIV diagnosis in Rio de Janeiro, Brazil, to quantify missed opportunities for TB prevention. METHODS: People living with HIV (PLHIV) and enrolled in the TB/HIV in Rio study between September 1, 2005, and August 31, 2009, were included. Prevalent TB was defined as TB diagnosed within 60 days of HIV diagnosis or HIV diagnosis during TB therapy. Survival was measured from HIV diagnosis. We conducted Kaplan-Meier survival plots and Cox regression analyses. RESULTS: Four thousand five hundred forty-eight newly diagnosed PLHIV were enrolled: 476 (10.5%) with prevalent TB. Individuals with prevalent TB were older, had lower CD4 counts, and higher viral loads than did those without TB. Median time to receiving highly active antiretroviral therapy (HAART) in those with prevalent TB was 99 days (interquartile range = 58-191) vs. 126 days (interquartile range = 63-301) in those without TB (P = 0.021). Among those with prevalent TB, 17% died during follow-up compared with 8% among those without TB (P < 0.001). After adjustment for sex, age, baseline CD4, and baseline viral load, the risk of occurrence of death remained significantly higher among those with prevalent TB [adjusted hazard ratio = 1.72 (confidence interval 95% 1.19 to 2.48)]. CONCLUSIONS: More than 10% of new PLHIV in our study presented to care with concurrent active TB disease and thus missed the opportunity for undergoing TB preventive therapy. Despite initiating HAART more quickly, these individuals were at a significantly greater risk of death. Earlier HIV diagnosis is necessary to provide earlier initiation of HAART and TB preventive therapy to reduce morbidity and mortality in PLHIV.

Cost-effectiveness of rapid susceptibility testing against second-line drugs for tuberculosis. (2014). Dowdy DW., van't Hoog A., Shah M., Cobelens F, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 18, 647-54

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BACKGROUND: Drug susceptibility testing (DST) against second-line tuberculosis drugs (SLDs) is essential for improving outcomes among multidrug-resistant (MDR-) and extensively drug-resistant tuberculosis (XDR-TB) cases. OBJECTIVE: To evaluate the potential cost-effectiveness of rapid DST for SLDs. DESIGN: We constructed a decision analysis model of Xpert MTB/RIF-based TB diagnosis in East and South-East Asia to compare culture-based DST vs. a hypothetical rapid SLD DST system for specimens resistant to rifampin. Our primary outcomes were the effectiveness and incremental cost-effectiveness of a rapid SLD DST assay relative to culture-based DST. RESULTS: For rapid SLD DST to be more effective than culture-based DST, treating individuals with pre-XDR/XDR-TB with a standardized MDR-TB regimen while awaiting culture-based DST must incur at least 30% excess XDR-TB mortality (100% = treatment with first-line drugs); rapid SLD DST should attain an aggregate sensitivity and specificity for all pre-XDR/XDR mutations of 88% and 96%, respectively. The unit cost of the rapid SLD DST assay must approach that of culture to achieve common thresholds for cost-effectiveness in low-income countries. CONCLUSION: Rapid SLD DST has the potential to be cost-effective, but must meet stringent criteria for accuracy and costs, and requires that standardized second-line treatment for pre-XDR/XDR-TB incur substantial excess mortality before the return of culture results.

Body mass index predictive of sputum culture conversion among MDR-TB patients in Indonesia. (2014). Putri FA., Burhan E., Nawas A., Soepandi PZ., Sutoyo DK., Agustin H., Isbaniah F., Dowdy DW, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 18, 564-70

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SETTING: Programmatic management of drug-resistant tuberculosis at Persahabatan Hospital, Jakarta, Indonesia. OBJECTIVE: To evaluate the association between body mass index (BMI) and sputum culture conversion during treatment for multidrug-resistant tuberculosis (MDR-TB). DESIGN: We conducted a retrospective cohort study of 212 MDR-TB patients. MDR-TB was confirmed using culture in liquid medium and line-probe assay. Patients were treated with a standardised regimen unless they were resistant to any of the drugs tested. Study outcomes were time to culture conversion (primary) and probability of conversion within 4 months (secondary). Data were analysed using Kaplan-Meier curves, discrete time-survival analysis and Poisson regression. RESULTS: Compared to patients with normal weight (BMI >/=18.5 kg/m(2)), severely underweight patients (BMI <16 kg/m(2)) had longer time to initial conversion (adjusted hazard ratio [aHR] 0.55, 95%CI 0.37-0.84) and a lower probability of sputum culture conversion within 4 months (adjusted relative risk 0.67, 95%CI 0.54-0.83). Other predictors for longer sputum culture conversion were female sex (aHR 0.55, 95%CI 0.39-0.78), resistance to injectables (aHR 0.59, 95%CI 0.42-0.83) and high baseline smear grade (aHR 0.33, 95%CI 0.18-0.60). CONCLUSION: Severe underweight was associated with longer time to initial sputum culture conversion among MDR-TB patients.

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