TB Modeling and Translational Epi Group

Group Publications

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- December 2015 -

Evaluating the cost of adult voluntary medical male circumcision in a mixed (surgical and PrePex) site compared to a hypothetical PrePex-only site in South Africa. (2015). Kim HY., Lebina L., Milovanovic M., Taruberekera N., Dowdy DW., Martinson NA, Global health action, 8, 29116

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BACKGROUND: Several circumcision devices have been evaluated for a safe and simplified male circumcision among adults. The PrePex device was prequalified for voluntary male medical circumcision (VMMC) in May 2013 by the World Health Organization and is expected to simplify the procedure safely while reducing cost. South Africa is scaling up VMMC. OBJECTIVE: To evaluate the overall unit cost of VMMC at a mixed site vs. a hypothetical PrePex-only site in South Africa. DESIGN: We evaluated the overall unit cost of VMMC at a mixed site where PrePex VMMC procedure was added to routine forceps-guided scalpel-based VMMC in Soweto, South Africa. We abstracted costs and then modeled these costs for a hypothetical PrePex-only site, at which 9,600 PrePex circumcisions per year could be done. We examined cost drivers and modeled costs, varying the price of the PrePex device. The healthcare system perspective was used. RESULTS: In both sites, the main contributors of cost were personnel and consumables. If 10% of all VMMC were by PrePex at the mixed site, the overall costs of the surgical method and PrePex were similar - US$59.62 and $59.53, respectively. At the hypothetical PrePex-only site, the unit cost was US$51.10 with PrePex circumcisions having markedly lower personnel and biohazardous waste management costs. In sensitivity analysis with the cost of PrePex kit reduced to US$10 and $2, the cost of VMMC was further reduced. CONCLUSIONS: Adding PrePex to an existing site did not necessarily reduce the overall costs of VMMC. However, starting a new PrePex-only site is feasible and may significantly reduce the overall cost by lowering both personnel and capital costs, thus being cost-effective in the long term. Achieving a lower cost for PrePex will be an important contributor to the scale-up of VMMC.

Sustainable HIV treatment in Africa through viral-load-informed differentiated care. (2015). Phillips A., Shroufi A., Vojnov L., Cohn J., Roberts T., Ellman T., Bonner K., Rousseau C., Garnett G., Cambiano V., Nakagawa F., Ford D., Bansi-Matharu L., Miners A., Lundgren JD., Eaton JW., Parkes-Ratanshi R., Katz Z., Maman D., Ford N., Vitoria M., Doherty M., Dowdy D., Nichols B., Murtagh M., Wareham M., Palamountain KM., Chakanyuka Musanhu C., Stevens W., Katzenstein D., Ciaranello A., Barnabas R., Braithwaite RS., Bendavid E., Nathoo KJ., van de Vijver D., Wilson DP., Holmes C., Bershteyn A., Walker S., Raizes E., Jani I., Nelson LJ., Peeling R., Terris-Prestholt F., Murungu J., Mutasa-Apollo T., Hallett TB., Revill P, Nature, 528, S68-76

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There are inefficiencies in current approaches to monitoring patients on antiretroviral therapy in sub-Saharan Africa. Patients typically attend clinics every 1 to 3 months for clinical assessment. The clinic costs are comparable with the costs of the drugs themselves and CD4 counts are measured every 6 months, but patients are rarely switched to second-line therapies. To ensure sustainability of treatment programmes, a transition to more cost-effective delivery of antiretroviral therapy is needed. In contrast to the CD4 count, measurement of the level of HIV RNA in plasma (the viral load) provides a direct measure of the current treatment effect. Viral-load-informed differentiated care is a means of tailoring care so that those with suppressed viral load visit the clinic less frequently and attention is focussed on those with unsuppressed viral load to promote adherence and timely switching to a second-line regimen. The most feasible approach to measuring viral load in many countries is to collect dried blood spot samples for testing in regional laboratories; however, there have been concerns over the sensitivity and specificity of this approach to define treatment failure and the delay in returning results to the clinic. We use modelling to synthesize evidence and evaluate the cost-effectiveness of viral-load-informed differentiated care, accounting for limitations of dried blood sample testing. We find that viral-load-informed differentiated care using dried blood sample testing is cost-effective and is a recommended strategy for patient monitoring, although further empirical evidence as the approach is rolled out would be of value. We also explore the potential benefits of point-of-care viral load tests that may become available in the future.

Understanding the incremental value of novel diagnostic tests for tuberculosis. (2015). Arinaminpathy N., Dowdy D, Nature, 528, S60-7

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Tuberculosis is a major source of global mortality caused by infection, partly because of a tremendous ongoing burden of undiagnosed disease. Improved diagnostic technology may play an increasingly crucial part in global efforts to end tuberculosis, but the ability of diagnostic tests to curb tuberculosis transmission is dependent on multiple factors, including the time taken by a patient to seek health care, the patient's symptoms, and the patterns of transmission before diagnosis. Novel diagnostic assays for tuberculosis have conventionally been evaluated on the basis of characteristics such as sensitivity and specificity, using assumptions that probably overestimate the impact of diagnostic tests on transmission. We argue for a shift in focus to the evaluation of such tests' incremental value, defining outcomes that reflect each test's purpose (for example, transmissions averted) and comparing systems with the test against those without, in terms of those outcomes. Incremental value can also be measured in units of outcome per incremental unit of resource (for example, money or human capacity). Using a novel, simplified model of tuberculosis transmission that addresses some of the limitations of earlier tuberculosis diagnostic models, we demonstrate that the incremental value of any novel test depends not just on its accuracy, but also on elements such as patient behaviour, tuberculosis natural history and health systems. By integrating these factors into a single unified framework, we advance an approach to the evaluation of new diagnostic tests for tuberculosis that considers the incremental value at the population level and demonstrates how additional data could inform more-effective implementation of tuberculosis diagnostic tests under various conditions.

- November 2015 -

Risk factors for transmission of tuberculosis among United States-born African Americans and Whites. (2015). Pagaoa MA., Royce RA., Chen MP., Golub JE., Davidow AL., Hirsch-Moverman Y., Marks SM., Teeter LD., Thickstun PM., Katz DJ, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 19, 1485-92

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SETTING: Tuberculosis (TB) patients and their contacts enrolled in nine states and the District of Columbia from 16 December 2009 to 31 March 2011. OBJECTIVE: To evaluate characteristics of TB patients that are predictive of tuberculous infection in their close contacts. DESIGN: The study population was enrolled from a list of eligible African-American and White TB patients from the TB registry at each site. Information about close contacts was abstracted from the standard reports of each site. RESULTS: Close contacts of African-American TB patients had twice the risk of infection of contacts of White patients (adjusted risk ratio [aRR] 2.1, 95%CI 1.3-3.4). Close contacts of patients whose sputum was positive for acid-fast bacilli on sputum smear microscopy had 1.6 times the risk of tuberculous infection compared to contacts of smear-negative patients (95%CI 1.1-2.3). TB patients with longer (>3 months) estimated times to diagnosis did not have higher proportions of infected contacts (aRR 1.2, 95%CI 0.9-1.6). CONCLUSION: African-American race and sputum smear positivity were predictive of tuberculous infection in close contacts. This study did not support previous findings that longer estimated time to diagnosis predicted tuberculous infection in contacts.

Burden of transmitted multidrug resistance in epidemics of tuberculosis: a transmission modelling analysis. (2015). Kendall EA., Fofana MO., Dowdy DW, The Lancet. Respiratory medicine, 3, 963-72

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BACKGROUND: Multidrug-resistant (MDR) tuberculosis can be acquired through de-novo mutation during tuberculosis treatment or through transmission from other individuals with active MDR tuberculosis. Understanding the balance between these two mechanisms is essential when allocating resources for MDR tuberculosis. We aimed to create a dynamic transmission model of an MDR tuberculosis epidemic to estimate the contributions of treatment-related acquisition and person-to-person transmission of resistance to incident MDR tuberculosis cases. METHODS: In this modelling analysis, we constructed a dynamic transmission model of an MDR tuberculosis epidemic, allowing for both treatment-related acquisition and person-to-person transmission of resistance. We used national tuberculosis notification data to inform Bayesian estimates of the proportion of each country's 2013 MDR tuberculosis incidence that resulted from MDR transmission rather than treatment-related MDR acquisition. FINDINGS: Global estimates of 3.5% MDR tuberculosis prevalence among new tuberculosis notifications and 20.5% among re-treatment notifications translate into an estimate that resistance transmission rather than acquisition accounts for a median 95.9% (95% uncertainty range [UR] 68.0-99.6) of all incident MDR tuberculosis, and 61.3% (16.5-95.2) of incident MDR tuberculosis in previously treated individuals. The estimated proportion of MDR tuberculosis resulting from transmission varied substantially with different countries' notification data-ranging from 48% (95% UR 30-75) in Bangladesh to 99% (91-100) in Uzbekistan. Estimates were most sensitive to estimates of the transmissibility of MDR strains, the probability of acquiring MDR during tuberculosis treatment, and the responsiveness of MDR tuberculosis to first-line treatment. INTERPRETATION: Notifications of MDR prevalence from most high-burden settings are consistent with most incident MDR tuberculosis resulting from transmission rather than new treatment-related acquisition of resistance. Merely improving the treatment of drug-susceptible tuberculosis is unlikely to greatly reduce future MDR tuberculosis incidence. Improved diagnosis and treatment of MDR tuberculosis-including new tests and drug regimens-should be highly prioritised. FUNDING: National Institutes of Health and the Bill & Melinda Gates Foundation.

Mathematical Modelling and Tuberculosis: Advances in Diagnostics and Novel Therapies. (2015). Zwerling A., Shrestha S., Dowdy DW, Advances in medicine, 2015, 907267

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As novel diagnostics, therapies, and algorithms are developed to improve case finding, diagnosis, and clinical management of patients with TB, policymakers must make difficult decisions and choose among multiple new technologies while operating under heavy resource constrained settings. Mathematical modelling can provide helpful insight by describing the types of interventions likely to maximize impact on the population level and highlighting those gaps in our current knowledge that are most important for making such assessments. This review discusses the major contributions of TB transmission models in general, namely, the ability to improve our understanding of the epidemiology of TB. We focus particularly on those elements that are important to appropriately understand the role of TB diagnosis and treatment (i.e., what elements of better diagnosis or treatment are likely to have greatest population-level impact) and yet remain poorly understood at present. It is essential for modellers, decision-makers, and epidemiologists alike to recognize these outstanding gaps in knowledge and understand their potential influence on model projections that may guide critical policy choices (e.g., investment and scale-up decisions).

Bridging the gap between evidence and policy for infectious diseases: How models can aid public health decision-making. (2015). Knight GM., Dharan NJ., Fox GJ., Stennis N., Zwerling A., Khurana R., Dowdy DW, International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases, 42, 17-23

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The dominant approach to decision-making in public health policy for infectious diseases relies heavily on expert opinion, which often applies empirical evidence to policy questions in a manner that is neither systematic nor transparent. Although systematic reviews are frequently commissioned to inform specific components of policy (such as efficacy), the same process is rarely applied to the full decision-making process. Mathematical models provide a mechanism through which empirical evidence can be methodically and transparently integrated to address such questions. However, such models are often considered difficult to interpret. In addition, models provide estimates that need to be iteratively re-evaluated as new data or considerations arise. Using the case study of a novel diagnostic for tuberculosis, a framework for improved collaboration between public health decision-makers and mathematical modellers that could lead to more transparent and evidence-driven policy decisions for infectious diseases in the future is proposed. The framework proposes that policymakers should establish long-term collaborations with modellers to address key questions, and that modellers should strive to provide clear explanations of the uncertainty of model structure and outputs. Doing so will improve the applicability of models and clarify their limitations when used to inform real-world public health policy decisions.

- October 2015 -

Stopping the body count: a comprehensive approach to move towards zero tuberculosis deaths. (2015). Keshavjee S., Dowdy D., Swaminathan S, Lancet (London, England), 386, e46-7

Data for action: collection and use of local data to end tuberculosis. (2015). Theron G., Jenkins HE., Cobelens F., Abubakar I., Khan AJ., Cohen T., Dowdy DW, Lancet (London, England), 386, 2324-33

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Accelerating progress in the fight against tuberculosis will require a drastic shift from a strategy focused on control to one focused on elimination. Successful disease elimination campaigns are characterised by locally tailored responses that are informed by appropriate data. To develop such a response to tuberculosis, we suggest a three-step process that includes improved collection and use of existing programmatic data, collection of additional data (eg, geographic information, drug resistance, and risk factors) to inform tailored responses, and targeted collection of novel data (eg, sequencing data, targeted surveys, and contact investigations) to improve understanding of tuberculosis transmission dynamics. Development of a locally targeted response for tuberculosis will require substantial investment to reconfigure existing systems, coupled with additional empirical data to evaluate the effectiveness of specific approaches. Without adoption of an elimination strategy that uses local data to target hotspots of transmission, ambitious targets to end tuberculosis will almost certainly remain unmet.

Toward the optical "magic carpet": reducing the divergence of a light sheet below the diffraction limit. (2015). Golub I., Chebbi B., Golub J, Optics letters, 40, 5121-4

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In 3D, diffraction-free or Bessel beams are well known and have found applications in diverse fields. An analog in 2D, or pseudonondiffracting (PND) beams, is a nontrivial problem, and existing methods suffer from deficiencies. For example, Airy beams are not highly localized, some PND beams have significant side lobes, and a cosine beam has to be truncated by a very narrow aperture thus discarding most of the energy. We show, both theoretically and experimentally, that it is possible to generate a quasi-nondiffracting 2D light beam in a simple and efficient fashion. This is achieved by placing a mask consisting of a pair of double slits on a cylindrical lens. The applications include light sheet microscopy/optical sectioning and particle manipulation.

In reply. (2015). Johnston JC., Khan FA., Dowdy DW, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 19, 1264

Directly observed therapy of tuberculosis in Brazil: associated determinants and impact on treatment outcome. (2015). Reis-Santos B., Pellacani-Posses I., Macedo LR., Golub JE., Riley LW., Maciel EL, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 19, 1188-93

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SETTING: All Brazilian states. OBJECTIVES: To assess the determinants of tuberculosis (TB) in patients undergoing directly observed therapy (DOT) and the impact of DOT on treatment outcomes. DESIGN: This is a cross-sectional study among TB patients aged 18 years conducted in 2011. The primary outcome was the status of DOT received, while the secondary was the outcome of anti-tuberculosis treatment. RESULTS: In 2011, 35 775 (38.3%) subjects received DOT. The odds of receiving DOT were higher in patients with the following characteristics: brown/mestizo patients (OR 1.18, 95%CI 1.14-1.22) and those of other ethnic groups (OR 2.01, 95%CI 1.79-2.27) compared to Whites, alcohol users (OR 1.37, 95%CI 1.28-1.47) and those with mental disorders (OR 1.88, 95%CI 1.54-2.29). The odds of receiving DOT were lower in human immunodeficiency virus positive patients (OR 0.64, 95%CI 0.60-0.68). Patients who did not receive DOT were more likely to default from anti-tuberculosis treatment (OR 0.62, 95%CI 0.57-0.66), die due to TB (OR 0.68, 95%CI 0.61-0.77) and to have unknown treatment outcomes (OR 0.71, 95%CI 0.66-0.76). The adjusted preventable fraction of DOT in the reduction of unfavorable outcomes was 25%. CONCLUSION: Sociodemographic and clinical characteristics are determinants of anti-tuberculosis treatment outcomes in patients undergoing DOT; DOT use led to a 25% reduction in unfavorable outcomes.

Economic and epidemiological impact of early antiretroviral therapy initiation in India. (2015). Maddali MV., Dowdy DW., Gupta A., Shah M, Journal of the International AIDS Society, 18, 20217

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INTRODUCTION: Recent WHO guidance advocates for early antiretroviral therapy (ART) initiation at higher CD4 counts to improve survival and reduce HIV transmission. We sought to quantify how the cost-effectiveness and epidemiological impact of early ART strategies in India are affected by attrition throughout the HIV care continuum. METHODS: We constructed a dynamic compartmental model replicating HIV transmission, disease progression and health system engagement among Indian adults. Our model of the Indian HIV epidemic compared implementation of early ART initiation (i.e. initiation above CD4 >/=350 cells/mm(3)) with delayed initiation at CD4

- September 2015 -

The Distribution of Fitness Costs of Resistance-Conferring Mutations Is a Key Determinant for the Future Burden of Drug-Resistant Tuberculosis: A Model-Based Analysis. (2015). Knight GM., Colijn C., Shrestha S., Fofana M., Cobelens F., White RG., Dowdy DW., Cohen T, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 61Suppl 3, S147-54

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BACKGROUND: Drug resistance poses a serious challenge for the control of tuberculosis in many settings. It is well established that the expected future trend in resistance depends on the reproductive fitness of drug-resistant Mycobacterium tuberculosis. However, the variability in fitness between strains with different resistance-conferring mutations has been largely ignored when making these predictions. METHODS: We developed a novel approach for incorporating the variable fitness costs of drug resistance-conferring mutations and for tracking this distribution of fitness costs over time within a transmission model. We used this approach to describe the effects of realistic fitness cost distributions on the future prevalence of drug-resistant tuberculosis. RESULTS: The shape of the distribution of fitness costs was a strong predictor of the long-term prevalence of resistance. While, as expected, lower average fitness costs of drug resistance-conferring mutations were associated with more severe epidemics of drug-resistant tuberculosis, fitness distributions with greater variance also led to higher levels of drug resistance. For example, compared to simulations in which the fitness cost of resistance was fixed, introducing a realistic amount of variance resulted in a 40% increase in prevalence of drug-resistant tuberculosis after 20 years. CONCLUSIONS: The differences in the fitness costs associated with drug resistance-conferring mutations are a key determinant of the future burden of drug-resistant tuberculosis. Future studies that can better establish the range of fitness costs associated with drug resistance-conferring mutations will improve projections and thus facilitate better public health planning efforts.

The Epidemiologic and Economic Impact of Improving HIV Testing, Linkage, and Retention in Care in the United States. (2015). Shah M., Risher K., Berry SA., Dowdy DW, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 62, 220-229

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BACKGROUND: Recent guidelines advocate early antiretroviral therapy (ART) to decrease human immunodeficiency virus (HIV) morbidity and prevent transmission, but suboptimal engagement in care may compromise impact. We sought to determine the economic and epidemiologic impact of incomplete engagement in HIV care in the United States. METHODS: We constructed a dynamic transmission model of HIV among US adults (aged 15-65 years) and conducted a cost-effectiveness analysis of improvements along the HIV care continuum : We evaluated enhanced HIV testing (annual for high-risk groups), increased 3-month linkage to care (to 90%), and improved retention (50% relative reduction in yearly disengagement and 50% increase in reengagement). Our primary outcomes were HIV incidence, mortality, costs and quality-adjusted life-years (QALYs). RESULTS: Despite early ART initiation, a projected 1.39 million (95% uncertainty range [UR], 0.91-2.2 million) new HIV infections will occur at a (discounted) cost of $256 billion ($199-298 billion) over 2 decades at existing levels of HIV care engagement. Enhanced testing with increased linkage has modest epidemiologic benefits and could reduce incident HIV infections by 21% (95% UR, 13%-26%) at a cost of $65 700 per QALY gained ($44 500-111 000). By contrast, comprehensive improvements that couples enhanced testing and linkage with improved retention would reduce HIV incidence by 54% (95% UR, 37%-68%) and mortality rate by 64% (46%-78%), at a cost-effectiveness ratio of $45 300 per QALY gained ($27 800-72 300). CONCLUSIONS: Failure to improve engagement in HIV care in the United States leads to excess infections, treatment costs, and deaths. Interventions that improve not just HIV screening but also retention in care are needed to optimize epidemiologic impact and cost-effectiveness.

- August 2015 -

Tobacco smoking and tuberculosis treatment outcomes: a prospective cohort study in Georgia. (2015). Gegia M., Magee MJ., Kempker RR., Kalandadze I., Chakhaia T., Golub JE., Blumberg HM, Bulletin of the World Health Organization, 93, 390-9

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OBJECTIVE: To assess the effect of tobacco smoking on the outcome of tuberculosis treatment in Tbilisi, Georgia. METHODS: We conducted a prospective cohort study of adults with laboratory-confirmed tuberculosis from May 2011 to November 2013. History of tobacco smoking was collected using a standardized questionnaire adapted from the global adult tobacco survey. We considered tuberculosis therapy to have a poor outcome if participants defaulted, failed treatment or died. We used multivariable regressions to estimate the risk of a poor treatment outcome. FINDINGS: Of the 591 tuberculosis patients enrolled, 188 (31.8%) were past smokers and 271 (45.9%) were current smokers. Ninety (33.2%) of the current smokers and 24 (18.2%) of the participants who had never smoked had previously been treated for tuberculosis (P < 0.01). Treatment outcome data were available for 524 of the participants, of whom 128 (24.4%) - including 80 (32.9%) of the 243 current smokers and 21 (17.2%) of the 122 individuals who had never smoked - had a poor treatment outcome. Compared with those who had never smoked, current smokers had an increased risk of poor treatment outcome (adjusted relative risk, aRR: 1.70; 95% confidence interval, CI: 1.00-2.90). Those who had ceased smoking more than two months before enrolment did not have such an increased risk (aRR: 1.01; 95% CI: 0.51-1.99). CONCLUSION: There is a high prevalence of smoking among patients with tuberculosis in Georgia and smoking increases the risk of a poor treatment outcome.

- July 2015 -

Pathways and costs of care for patients with tuberculosis symptoms in rural Uganda. (2015). Shete PB., Haguma P., Miller CR., Ochom E., Ayakaka I., Davis JL., Dowdy DW., Hopewell P., Katamba A., Cattamanchi A, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 19, 912-7

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SETTING: Six district-level government health centers in rural Uganda and the surrounding communities. OBJECTIVE: To determine pathways to care and associated costs for patients with chronic cough referred for tuberculosis (TB) evaluation in Uganda. DESIGN: We conducted a cross-sectional study, surveying 64 patients presenting with chronic cough and undergoing first-time sputum evaluation at government clinics. We also surveyed a random sample of 114 individuals with chronic cough in surrounding communities. We collected information on previous health visits for the cough as well as costs associated with the current visit. RESULTS: Eighty per cent of clinic patients had previously sought care for their cough, with a median of three previous visits (range 0-32, interquartile range [IQR] 2-5). Most (n = 203, 88%) visits were to a health facility that did not provide TB microscopy services, and the majority occurred in the private sector. The cost of seeking care for the current visit alone represented 28.8% (IQR 9.1-109.5) of the patients' median monthly household income. CONCLUSION: Most patients seek health care for chronic cough, but do so first in the private sector. Engagement of the private sector and streamlining TB diagnostic evaluation are critical for improving case detection and meeting global TB elimination targets.

Optimal Timing of Antiretroviral Therapy Initiation for HIV-Infected Adults With Newly Diagnosed Pulmonary Tuberculosis: A Systematic Review and Meta-analysis. (2015). Uthman OA., Okwundu C., Gbenga K., Volmink J., Dowdy D., Zumla A., Nachega JB, Annals of internal medicine, 163, 32-9

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BACKGROUND: Initiation of antiretroviral therapy (ART) during tuberculosis (TB) treatment remains challenging. PURPOSE: To assess evidence from randomized, controlled trials of the timing of ART initiation in HIV-infected adults with newly diagnosed pulmonary TB. DATA SOURCES: PubMed, EMBASE, Cochrane Central Register of Controlled Trials, conference abstracts, and ClinicalTrials.gov (from January 1980 to May 2015). STUDY SELECTION: Randomized, controlled trials evaluating early versus delayed ART initiation (1 to 4 weeks vs. 8 to 12 weeks after initiation of TB treatment) or deferred ART initiation (after the end of TB treatment). DATA EXTRACTION: Three reviewers independently extracted data and assessed risk of bias. The main outcome measures were all-cause mortality and the TB-associated immune reconstitution inflammatory syndrome (TB-IRIS). DATA SYNTHESIS: The 8 included trials (n = 4568) were conducted in Africa, Asia, and the United States and were generally at low risk of bias for the assessed domains. Overall, early ART reduced mortality compared with delayed ART (relative risk [RR], 0.81 [95% CI, 0.66 to 0.99]; I2 = 0%). In a prespecified subgroup analysis, early ART reduced mortality compared with delayed ART among patients with baseline CD4+ T-cell counts less than 0.050 x 109 cells/L (RR, 0.71 [CI, 0.54 to 0.93]; I2 = 0%). However, a mortality benefit from early ART was not found among those with CD4+ T-cell counts greater than 0.050 x 109 cells/L (RR, 1.05 [CI, 0.68 to 1.61]; I2 = 56%). Early ART was associated with a higher incidence of TB-IRIS than delayed ART (RR, 2.31 [CI, 1.87 to 2.86]; I2 = 19%). LIMITATION: Few trials provided sufficient data for subgroup analysis. CONCLUSION: Early ART in HIV-infected adults with newly diagnosed TB improves survival in those with CD4+ T-cell counts less than 0.050 x 109 cells/L, although this is associated with a 2-fold higher frequency of TB-IRIS. In patients with CD4+ T-cell counts greater than 0.050 x 109 cells/L, evidence is insufficient to support or refute a survival benefit conferred by early versus delayed ART initiation. PRIMARY FUNDING SOURCE: None. (PROSPERO registration: CRD42012001884).

- June 2015 -

Screening for Tuberculosis Among Adults Newly Diagnosed With HIV in Sub-Saharan Africa: A Cost-Effectiveness Analysis. (2015). Zwerling AA., Sahu M., Ngwira LG., Khundi M., Harawa T., Corbett EL., Chaisson RE., Dowdy DW, Journal of acquired immune deficiency syndromes (1999), 70, 83-90

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OBJECTIVE: New tools, including light-emitting diode (LED) fluorescence microscopy and the molecular assay Xpert MTB/RIF, offer increased sensitivity for tuberculosis (TB) in persons with HIV but come with higher costs. Using operational data from rural Malawi, we explored the potential cost-effectiveness of on-demand screening for TB in low-income countries of Sub-Saharan Africa. DESIGN AND METHODS: Costs were empirically collected in 4 clinics and in 1 hospital using a microcosting approach, through direct interview and observation from the national TB program perspective. Using decision analysis, newly diagnosed persons with HIV were modeled as being screened by 1 of the 3 strategies: Xpert, LED, or standard of care (ie, at the discretion of the treating physician). RESULTS: Cost-effectiveness of TB screening among persons newly diagnosed with HIV was largely determined by 2 factors: prevalence of active TB among patients newly diagnosed with HIV and volume of testing. In facilities screening at least 50 people with a 6.5% prevalence of TB, or at least 500 people with a 2.5% TB prevalence, Xpert is likely to be cost-effective. At lower prevalence-including that observed in Malawi-LED microscopy may be the preferred strategy, whereas in settings of lower TB prevalence or small numbers of eligible patients, no screening may be reasonable (such that resources can be deployed elsewhere). CONCLUSIONS: TB screening at the point of HIV diagnosis may be cost-effective in low-income countries of Sub-Saharan Africa, but only if a relatively large population with high prevalence of TB can be identified for screening.

- May 2015 -

Reducing relapse in tuberculosis treatment: is it time to reassess WHO treatment guidelines? (2015). Johnston JC., Khan FA., Dowdy DW, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 19, 624

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