TB Modeling and Translational Epi Group

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- May 2019 -

Diabetes mellitus and tuberculosis in Korean adults: impact on tuberculosis incidence, recurrence and mortality. (2019). Golub JE., Mok Y., Hong S., Jung KJ., Jee SH., Samet JM, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 23, 507-513

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SETTING The prevalence of diabetes mellitus (DM) worldwide is increasing markedly, and many countries with rising rates also have a high incidence rate of tuberculosis (TB). OBJECTIVE To investigate the relationships of fasting serum glucose (FSG) and DM with TB incidence, recurrence and mortality risk in a prospective cohort study in South Korea. DESIGN Our study comprised 1 267 564 Koreans who received health insurance from the National Health Insurance System, had an initial medical evaluation between 1997 and 2000 and were prospectively followed biennially. RESULTS Participants with DM had a higher risk for incident TB (hazard ratio [HR] 1.81, 95%CI 1.71-1.91 in males, HR 1.33; 95%CI 1.20-1.47 in females) than those without DM. There was a strong positive trend for TB risk with rising FSG among males. The risk for recurrent TB among those with previous TB was significantly higher in males (HR 1.58, 95%CI 1.43-1.75) and in females with DM (HR 1.38, 95%CI 1.08-1.76). The increased risk of death from TB during follow-up was also significant in men (HR 1.91, 95%CI 1.87-1.95) and in women (HR 1.71, 95%CI 1.65-1.77). CONCLUSIONS A diagnosis of DM is a risk factor for TB, TB recurrence and death from TB. Screening for TB should be considered among people living with DM in Korea, particularly those with severe DM. .

Respiratory health status is associated with treatment outcomes in pulmonary tuberculosis. (2019). Gupte AN., Selvaraju S., Paradkar M., Danasekaran K., Shivakumar SVBY., Thiruvengadam K., Dolla C., Shivaramakrishnan G., Pradhan N., Kohli R., John S., Raskar S., Jain D., Momin A., Subramanian B., Gaikwad A., Lokhande R., Suryavanshi N., Gupte N., Salvi S., Murali L., Checkley W., Golub JE., Bollinger R., Chandrasekaran P., Mave V., Gupta A, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 23, 450-457

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BACKGROUND The association between respiratory impairment and tuberculosis (TB) treatment outcomes is not clear. METHODS We prospectively evaluated respiratory health status, measured using the Saint George's Respiratory Questionnaire (SGRQ), in a cohort of new adult pulmonary TB cases during and up to 18 months following treatment in India. Associations between total SGRQ scores and poor treatment outcomes of failure, recurrence and all-cause death were measured using multivariable Poisson regression. RESULTS We enrolled 455 participants contributing 619 person-years at risk; 39 failed treatment, 23 had recurrence and 16 died. The median age was 38 years (interquartile range 26-49); 147 (32%) ever smoked. SGRQ scores at treatment initiation were predictive of death during treatment (14% higher risk per 4-point increase in baseline SGRQ scores, 95%CI 2-28, P = 0.01). Improvement in SGRQ scores during treatment was associated with a lower risk of failure (1% lower risk for every per cent improvement during treatment, 95%CI 1-2, P = 0.05). Clinically relevant worsening in SGRQ scores following successful treatment was associated with a higher risk of recurrence (15% higher risk per 4-point increase scores, 95%CI 4-27, P = 0.004). CONCLUSION Impaired respiratory health status was associated with poor TB treatment outcomes. The SGRQ may be used to monitor treatment response and predict the risk of death in pulmonary TB. .

Contact tracing versus facility-based screening for active TB case finding in rural South Africa: A pragmatic cluster-randomized trial (Kharitode TB). (2019). Hanrahan CF., Nonyane BAS., Mmolawa L., West NS., Siwelana T., Lebina L., Martinson N., Dowdy DW, PLoS medicine, 16, e1002796

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BACKGROUND: There is a dearth of comparative effectiveness research examining the implementation of different strategies for active tuberculosis (TB) case finding, particularly in rural settings, which represent 60% of the population of sub-Saharan Africa. METHODS AND FINDINGS: We conducted a pragmatic, cluster-randomized comparative effectiveness trial of two TB case finding strategies (facility-based screening and contact tracing) in 56 public primary care clinics in two largely rural districts of Limpopo Province, South Africa. In the facility-based screening arm, sputum Xpert MTB/RIF was performed on all patients presenting (for any reason) with TB symptoms to 28 study clinics, and no contact tracing was performed. In the contact-tracing arm, contacts of patients with active TB were identified (via household tracing in 14 clinics and using small monetary incentives in the other 14 clinics), screened for TB symptoms, and offered Xpert MTB/RIF testing. The primary outcome was the number of newly identified patients with TB started on treatment. The analysis used multivariable Poisson regression adjusted for historical clinic-level TB case volumes and district. The trial was registered with ClinicalTrials.gov (NCT02808507). From July 18, 2017, to January 17, 2019, a total of 3,755 individuals started TB treatment across 56 study clinics in the 18-month period. Clinic characteristics and clinic-level averages of patient characteristics were similar across the two arms: 40/56 (71%) clinics were in a rural location, 2,136/3,655 (58%) patients were male, and 2,243 (61%) were HIV positive. The treatment initiation ratio comparing the yield of TB patients started on treatment in the facility-based arm compared to that from the contact-tracing arm was 1.04 (95% confidence interval [CI] 0.83-1.30, p = 0. 73). In the contact-tracing arm, 1,677 contacts of 788 new TB index patients were screened, yielding 12 new patients with TB. Prespecified subgroup analyses resulted in similar results, with estimated treatment initiation ratios of 0.96 (95% CI 0.64-1.27; p = 0.78) and 1.23 (95% CI 0.87-1.59; p = 0.29) among historically smaller and historically larger clinics, respectively. This ratio was 1.02 (95% CI 0.66-1.37; p = 0.93) and 1.08 (95% CI 0.74-1.42; p = 0.68) in the Vhembe and Waterberg districts, respectively. The estimated treatment initiation ratio was unchanged in sensitivity analyses excluding 24 records whose TB registration numbers could not be verified (1.03, 95% CI 0.82-1.29; p = 0.78) and excluding transfers-in (1.02, 95% CI 0.80-1.29; p = 0.71). Study limitations include the possibility of imbalance on cluster size owing to changes in catchment population over time and the inability to distinguish the independent effects of the two contact investigation strategies. CONCLUSIONS: Contact tracing based on symptom screening and Xpert MTB/RIF testing did not increase the rate of treatment initiation for TB relative to the less resource-intensive approach of facility-based screening in this rural sub-Saharan setting. TRIAL REGISTRATION: ClinicalTrials.gov NCT02808507.

- April 2019 -

Differentiated care preferences of stable patients on ART in Zambia: A discrete choice experiment. (2019). Eshun-Wilson I., Mukumbwa-Mwenechanya M., Kim HY., Zannolini A., Mwamba CP., Dowdy D., Kalunkumya E., Lumpa M., Beres LK., Roy M., Sharma A., Topp SM., Glidden DV., Padian N., Ehrenkranz P., Sikazwe I., Holmes C., Bolton-Moore C., Geng EH, Journal of acquired immune deficiency syndromes (1999)

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BACKGROUND: Although differentiated service delivery (DSD) models for stable patients on antiretroviral therapy (ART) offer a range of health systems innovations, their comparative desirability to patients remains unknown. We conducted a discrete choice experiment to quantify service attributes most desired by patients to inform model prioritization METHODS:: Between July and December 2016 a sample of HIV-positive adults on ART at 12 clinics in Zambia were asked to choose between two hypothetical facilities which differed across six DSD attributes. We used mixed logit models to explore preferences, heterogeneity and trade-offs RESULTS:: Of 486 respondents, 59% were female and 85% resided in urban locations. Patients strongly preferred infrequent clinic visits (3 vs. 1-month visits: beta (i.e. relative utility) =2.84; p <0.001). Milder preferences were observed for: waiting time for ART pick-up (1 vs. 6 hrs.; beta=-0.67; p<0.001) or provider (1 vs. 3 hrs.; beta=-0.41; p=0.002); 'buddy' ART collection (beta=0.84; p <0.001); and ART pick-up location (clinic vs. community: beta=0.35; p=0.028). Urban patients demonstrated a preference for collecting ART at a clinic (beta=1.32, p<0.001), and although the majority of rural patients preferred community ART pick-up (beta=-0.74, p=0.049), 40% of rural patients still preferred facility ART collection. CONCLUSIONS: Stable patients on ART primarily want to attend clinic infrequently, supporting a focus in Zambia on optimizing multi-month prescribing over other DSD features - particularly in urban areas. Substantial preference heterogeneity highlights the need for DSD models to be flexible, and accommodate both setting features and patient choice in their design.This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Operational characteristics of antiretroviral therapy clinics in Zambia: a time and motion analysis. (2019). Tampi RP., Tembo T., Mukumba-Mwenechanya M., Sharma A., Dowdy DW., Holmes CB., Bolton-Moore C., Sikazwe I., Tucker A., Sohn H, BMC health services research, 19, 244

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BACKGROUND: The mass scale-up of antiretroviral therapy (ART) in Zambia has taken place in the context of limited infrastructure and human resources resulting in many operational side-effects. In this study, we aimed to empirically measure current workload of ART clinic staff and patient wait times and service utilization. METHODS: We conducted time and motion (TAM) studies from both the healthcare worker (HCW) and patient perspectives at 10 ART clinics throughout Zambia. Trained personnel recorded times for consecutive discrete activities based on direct observation of clinical and non-clinical activities performed by counselors, clinical officers, nurses, and pharmacy technicians. For patient TAM, we recruited consenting patients and recorded times of arrival and departure and major ART services utilized. Data from 10 clinics were pooled to evaluate median time per patient spent for each activity and patient duration of stay in the clinic. RESULTS: The percentage of observed clinical time for direct patient interaction (median time per patient encounter) was 43.1% for ART counselors (4 min, interquartile range [IQR] 2-7), 46.1% for nurses (3 min, IQR 2-4), 57.2% for pharmacy technicians (2 min, IQR 1-2), and 78.5% for clinical officers (3 min, IQR 2-5). Patient workloads for HCWs were heaviest between 8 AM and 12 PM with few clinical activities observed after 2 PM. The length of patient visits was inversely associated with arrival time - patients arriving prior to 8 AM spent 61% longer at the clinic than those arriving after 8 AM (277 vs. 171 min). Overall, patients spent 219 min on average for non-clinical visits, and 244 min for clinical visits, but this difference was not significant in rural clinics. In comparison, total time patients spent directly with clinic staff were 9 and 12 min on average for non-clinical and clinical visits. CONCLUSION: Current Zambian ART clinic operations include substantial inefficiencies for both patients and HCWs, with workloads heavily concentrated in the first few hours of clinic opening, limiting HCW and patient interaction time. Use of a differentiated care model may help to redistribute workloads during operational hours and prevent backlogs of patients waiting for hours before clinic opening, which may substantially improve ART delivery in the Zambian context.

Aminoglycoside-Induced Hearing Loss Among Patients Being Treated for Drug-Resistant Tuberculosis in South Africa: A Prediction Model. (2019). Hong H., Dowdy DW., Dooley KE., Francis HW., Budhathoki C., Han HR., Farley JE, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America

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BACKGROUND: Individuals treated for drug-resistant tuberculosis (DR-TB) with aminoglycosides (AGs) in resource-limited settings often experience permanent hearing loss, yet there is no practical method to identify those at higher risk. We sought to develop a clinical prediction model of AG-induced hearing loss among patients initiating DR-TB treatment in South Africa. METHODS: Using nested, prospective data from a cohort of 379 South African adults being treated for confirmed DR-TB with AG-based regimens we developed the prediction model using multiple logistic regression. Predictors were collected from clinical, audiological, and laboratory evaluations conducted at the initiation of DR-TB treatment. The outcome of AG-induced hearing loss was identified from audiometric and clinical evaluation by a worsened hearing threshold compared to baseline during the 6-month intensive phase. RESULTS: 63% of participants (n=238) developed any level of hearing loss. The model predicting hearing loss at frequencies from 250 to 8,000Hz included: weekly AG dose, HIV status with CD4 count, age, serum albumin, BMI, and pre-existing hearing loss. This model demonstrated reasonable discrimination (AUC=0.71) and calibration (chi2[8]=6.10, p=.636). Using a cutoff of 80% predicted probability of hearing loss, the positive predictive value of this model was 83% and negative predictive value was 40%. Model discrimination was similar for ultrahigh-frequency hearing loss (frequencies higher than 9,000Hz; AUC=0.81) but weaker for clinically determined hearing loss (AUC=0.60). CONCLUSIONS: This model may identify patients with DR-TB who are at the highest risk of developing AG-induced ototoxicity and may help prioritize patients for AG-sparing regimens in clinical settings where access is limited.

- March 2019 -

From Epidemiological Knowledge to Improved Health: A Vision for Translational Epidemiology. (2019). Windle M., Lee HD., Cherng ST., Lesko CR., Hanrahan C., Jackson JW., McAdams-DeMarco M., Ehrhardt S., Baral SD., D'Souza G., Dowdy DW, American journal of epidemiology

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Epidemiology should aim to improve population health; however, no consensus exists regarding the activities and skills that should be prioritized to achieve this goal. We performed a scoping review of articles addressing the translation of epidemiological knowledge into improved population health outcomes. We identified five themes in the translational epidemiology literature: foundations of epidemiological thinking, evidence-based public health or medicine, epidemiological education, implementation science, and community-engaged research (including literature on community-based participatory research). We then identified five priority areas for advancing translational epidemiology: (1) scientific engagement with public health; (2) public health communication; (3) epidemiological education; (4) epidemiology and implementation; and (5) community involvement. Using these priority areas as a starting point, we developed a conceptual framework of translational epidemiology that emphasizes interconnectedness and feedback between epidemiology, foundational science, and public health stakeholders. We also identified two to five representative principles in each priority area that could serve as the basis for advancing a vision of translational epidemiology. We believe that an emphasis on translational epidemiology can help the broader field to increase the efficiency of translating epidemiological knowledge into improved health outcomes and to achieve its goal of improving population health.

Gonorrhoea and chlamydia diagnosis as an entry point for HIV pre-exposure prophylaxis: a modelling study. (2019). Kasaie P., Schumacher CM., Jennings JM., Berry SA., Tuddenham SA., Shah MS., Rosenberg ES., Hoover KW., Gift TL., Chesson H., German D., Dowdy DW, BMJ open, 9, e023453

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OBJECTIVES: Neisseria gonorrhoeae (NG) and Chlamydia trachomatis (CT) increase the risk of HIV transmission among men who have sex with men (MSM). Diagnosis of NG/CT may provide an efficient entry point for prevention of HIV through the delivery of pre-exposure prophylaxis (PrEP); however, the additional population-level impact of targeting PrEP to MSM diagnosed with NG/CT is unknown. DESIGN: An agent-based simulation model of NG/CT and HIV cocirculation among MSM calibrated against census data, disease surveillance reports and the US National HIV Behavioral Surveillance study. SETTING: Baltimore City, Maryland, USA. INTERVENTIONS: PrEP implementation was modelled under three alternative scenarios: (1) PrEP delivery at NG/CT diagnosis (targeted delivery), (2) PrEP evaluation at NG/CT screening/testing and (3) PrEP evaluation in the general community (untargeted). MAIN OUTCOME: The projected incidence of HIV after 20 years of PrEP delivery under two alternatives: when equal numbers of MSM are (1) screened for PrEP or (2) receive PrEP in each year. RESULTS: Assuming 60% uptake and 60% adherence, targeting PrEP to MSM diagnosed with NG/CT could reduce HIV incidence among MSM in Baltimore City by 12.4% (95% uncertainty range (UR) 10.3% to 14.4%) in 20 years, relative to no PrEP. Expanding the coverage of NG/CT screening (such that individuals experience a 50% annual probability of NG/CT screening and evaluation for PrEP on NG/CT diagnosis) can further increase the impact of targeted PrEP to generate a 22.0% (95% UR 20.1% to 23.9%) reduction in HIV incidence within 20 years. When compared with alternative implementation scenarios, PrEP evaluation at NG/CT diagnosis increased impact of PrEP on HIV incidence by 1.5(95% UR 1.1 to 1.9) times relative to a scenario in which PrEP evaluation happened at the time of NG/CT screening/testing and by 1.6 (95% UR 1.2 to 2.2) times relative to evaluating random MSM from the community. CONCLUSIONS: Targeting MSM infected with NG/CT increases the efficiency and effectiveness of PrEP delivery. If high levels of sexually transmitted infection screening can be achieved at the community level, NG/CT diagnosis may be a highly effective entry point for PrEP initialisation.

Screening for tuberculosis: time to move beyond symptoms. (2019). Yoon C., Dowdy DW., Esmail H., MacPherson P., Schumacher SG, The Lancet. Respiratory medicine, 7, 202-204

- January 2019 -

Xpert at 8 years: where are we now, and what should we do next? (2019). Dowdy DW, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 23, 3-4

Siyaphambili protocol: An evaluation of randomized, nurse-led adaptive HIV treatment interventions for cisgender female sex workers living with HIV in Durban, South Africa. (2019). Comins CA., Schwartz SR., Phetlhu DR., Guddera V., Young K., Farley JE., West N., Parmley L., Geng E., Beyrer C., Dowdy D., Mishra S., Hausler H., Baral S, Research in nursing & health, 42, 107-118

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In South Africa, 60% of female sex workers are estimated to be living with human immunodeficiency virus (HIV). Many of these women face structural and individual-level barriers to initiating, accessing, and adhering to antiretroviral therapy (ART). While data are limited, it is estimated that less than 40% of sex workers living with HIV achieve viral suppression, leading to suboptimal clinical outcomes and sustained risks of onward sexual and vertical HIV transmission. Siyaphambili, a NINR/NIH-funded study, focuses on studying optimal implementation strategies for meeting HIV treatment needs among cisgender female sex workers living with HIV who are not virally suppressed. Here, we present the study protocol of this sequential multiple assignment randomized trial. In total, 800 viremic female sex workers will be enrolled into an 18-month adaptive implementation study to 1) compare the effectiveness and durability of a nurse-led decentralized ART treatment program versus an individualized case management approach, in isolation or in combination to achieve viral suppression and 2) estimate incremental cost-effectiveness of interventions and combinations of interventions. The primary outcome is a combined intention-to-treat outcome of retention in ART care and viral suppression at 18 months with secondary implementation outcomes. Siyaphambili aims to inform the implementation of and scale-up of HIV treatment services for female sex workers by determining the minimal package of services needed to achieve viral suppression and by characterizing individuals in need of more intensive HIV treatment approaches.

Cost-effectiveness of universal isoniazid preventive therapy among HIV-infected pregnant women in South Africa. (2019). Kim HY., Hanrahan CF., Martinson N., Golub JE., Dowdy DW, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 22, 1435-1442

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OBJECTIVE: To estimate the incremental cost-effectiveness of universal vs. test-directed treatment of latent tuberculous infection (LTBI) among human immunodeficiency virus (HIV) positive pregnant women in South Africa. METHODS: We compared tuberculin skin test (TST) directed isoniazid preventive therapy (IPT) (TST placement with delivery of IPT to women with positive results) against QuantiFERON((R))-TB Gold In-Tube (QGIT) directed IPT and universal IPT using decision analysis. Costs were measured empirically in six primary care public health clinics in Matlosana, South Africa. The primary outcome was the incremental cost-effectiveness ratio, expressed in 2016 US$ per disability-adjusted life-year (DALY) averted. RESULTS: We estimated that 29.2 of every 1000 pregnant women would develop TB over the course of 1 year in the absence of IPT. TST-directed IPT reduced this number to 24.5 vs. 22.6 with QGIT-directed IPT and 21.0 with universal IPT. Universal IPT was estimated to cost $640/DALY averted (95% uncertainty range $44-$3146) relative to TST-directed IPT and was less costly and more effective (i.e., dominant) than QGIT-directed IPT. Cost-effectiveness was most sensitive to the probability of developing TB and LTBI prevalence. CONCLUSION: Providing IPT to all eligible women can be a cost-effective strategy to prevent TB among HIV-positive pregnant women in South Africa.

- December 2018 -

Spatially targeted screening to reduce tuberculosis transmission in high-incidence settings. (2018). Cudahy PGT., Andrews JR., Bilinski A., Dowdy DW., Mathema B., Menzies NA., Salomon JA., Shrestha S., Cohen T, The Lancet. Infectious diseases, 19, e89-e95

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As the leading infectious cause of death worldwide and the primary proximal cause of death in individuals living with HIV, tuberculosis remains a global concern. Existing tuberculosis control strategies that rely on passive case-finding appear insufficient to achieve targets for reductions in tuberculosis incidence and mortality. Active case-finding strategies aim to detect infectious individuals earlier in their infectious period to reduce onward transmission and improve treatment outcomes. Empirical studies of active case-finding have produced mixed results and determining how to direct active screening to those most at risk remains a topic of intense research. Our systematic review of literature evaluating the effects of geographically targeted tuberculosis screening interventions found three studies in low tuberculosis incidence settings, but none conducted in high tuberculosis incidence countries. We discuss open questions related to the use of spatially targeted approaches for active screening in countries where tuberculosis incidence is highest.

- November 2018 -

Maternal Motivation to Take Preventive Therapy in Antepartum and Postpartum Among HIV-Positive Pregnant Women in South Africa: A Choice Experiment. (2018). Kim HY., Dowdy DW., Martinson NA., Kerrigan D., Tudor C., Golub J., Bridges JFP., Hanrahan CF, AIDS and behavior

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HIV-positive pregnant women who are initiated on lifelong antiretroviral therapy (ART) and isoniazid preventive therapy (IPT) have lower adherence rates after delivery. We quantified maternal motivation to take preventive therapy before and after delivery among pregnant women newly diagnosed with HIV. We enrolled pregnant women (>/= 18 years) with a recent HIV diagnosis (< 6 months) at 14 public primary health clinics in Matlosana, South Africa and followed them in the postpartum period. Participants received eight choice tasks comparing two mutually exclusive sub-sets of seven possible benefits related to preventive therapy identified through literature reviews and key informant interviews. Data was analyzed using conditional logit regression in the antepartum versus postpartum periods. Coefficients are reported with 95% confidence intervals (CI). Sixty-five women completed surveys both at enrollment and in the postpartum period. All women were already on ART, while 21 (32%) were receiving IPT at enrollment. The mean CD4 count was 436 (+/- 246) cells/mm(3). In the antepartum period, preventing HIV transmission to partners was the most important benefit (coefficients (ss) = 0.87, 95% CI 0.64, 1.11), followed by keeping healthy for family (ss = 0.75, 95% CI 0.52, 0.97). Such prioritization significantly decreased in the postpartum period (p < 0.001). Compared to other motivators, keeping a high CD4 count was least prioritized in the antepartum period (ss = 0.19, 95% CI - 0.04, 0.43) but was most prioritized in the postpartum period (ss = 0.39, 95% CI 0.21, 0.57). These results highlight that messages on family might be particularly salient in the antepartum period, and keeping CD4 count high in the postpartum period. Understanding maternal motivation may help to design targeted health promotion messages to HIV-positive women around the time of delivery.

Simple Inclusion of Complex Diagnostic Algorithms in Infectious Disease Models for Economic Evaluation. (2018). Dodd PJ., Pennington JJ., Bronner Murrison L., Dowdy DW, Medical decision making : an international journal of the Society for Medical Decision Making, 38, 930-941

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INTRODUCTION: Cost-effectiveness models for infectious disease interventions often require transmission models that capture the indirect benefits from averted subsequent infections. Compartmental models based on ordinary differential equations are commonly used in this context. Decision trees are frequently used in cost-effectiveness modeling and are well suited to describing diagnostic algorithms. However, complex decision trees are laborious to specify as compartmental models and cumbersome to adapt, limiting the detail of algorithms typically included in transmission models. METHODS: We consider an approximation replacing a decision tree with a single holding state for systems where the time scale of the diagnostic algorithm is shorter than time scales associated with disease progression or transmission. We describe recursive algorithms for calculating the outcomes and mean costs and delays associated with decision trees, as well as design strategies for computational implementation. We assess the performance of the approximation in a simple model of transmission/diagnosis and its role in simplifying a model of tuberculosis diagnostics. RESULTS: When diagnostic delays were short relative to recovery rates, our approximation provided a good account of infection dynamics and the cumulative costs of diagnosis and treatment. Proportional errors were below 5% so long as the longest delay in our 2-step algorithm was under 20% of the recovery time scale. Specifying new diagnostic algorithms in our tuberculosis model was reduced from several tens to just a few lines of code. DISCUSSION: For conditions characterized by a diagnostic process that is neither instantaneous nor protracted (relative to transmission dynamics), this novel approach retains the advantages of decision trees while embedding them in more complex models of disease transmission. Concise specification and code reuse increase transparency and reduce potential for error.

Economic and epidemiologic impact of guidelines for early ART initiation irrespective of CD4 count in Spain. (2018). Kasaie P., Radford M., Kapoor S., Jung Y., Hernandez Novoa B., Dowdy D., Shah M, PloS one, 13, e0206755

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INTRODUCTION: Emerging data suggest that early antiretroviral therapy (ART) could reduce serious AIDS and non-AIDS events and deaths but could also increase costs. In January 2016, the Spanish guidelines were updated to recommend ART at any CD4 count. However, the epidemiologic and economic impacts of early ART initiation in Spain remain unclear. METHODS: The Johns Hopkins HIV Economic-Epidemiologic Mathematical Model (JHEEM) was utilized to estimate costs, transmissions, and outcomes in Spain over 20 years. We compared implementation of guidelines for early ART initiation to a counterfactual scenario deferring ART until CD4-counts fall below 350 cells/mm3. We additionally studied the impact of early ART initiation in combination with improvements to HIV screening, care linkage and engagement. RESULTS: Early ART initiation (irrespective of CD4-count) is expected to avert 20,100 [95% Uncertainty Range (UR) 11,100-83,000] new HIV cases over the next two decades compared to delayed ART (28% reduction), at an incremental health system cost of euro1.05 billion [euro0.66 - euro1.63] billion, and an incremental cost-effectiveness ratio (ICER) of euro29,700 [euro13,700 - euro41,200] per QALY gained. Projected ICERs declined further over longer time horizon; e.g., an ICER of euro12,691 over 30 years. Furthermore, the impact of early ART initiation was potentiated by improved HIV screening among high-risk individuals, averting an estimated 41,600 [23,200-172,200] HIV infections (a 58% decline) compared to delayed ART. CONCLUSIONS: Recommendations for ART initiation irrespective of CD4-counts are cost-effective and could avert > 30% of new cases in Spain. Improving HIV diagnosis can amplify this impact.

Tuberculosis Incidence Among Populations at High Risk in California, Florida, New York, and Texas, 2011-2015. (2018). Cherng ST., Shrestha S., Reynolds S., Hill AN., Marks SM., Kelly J., Dowdy DW, American journal of public health, 108, S311-S314

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OBJECTIVES: To illustrate the magnitude of between-state heterogeneities in tuberculosis (TB) incidence among US populations at high risk for TB that may help guide state-specific strategies for TB elimination. METHODS: We used data from the National Tuberculosis Surveillance System and other public sources from 2011 to 2015 to calculate TB incidence in every US state among people who were non-US-born, had diabetes, or were HIV-positive, homeless, or incarcerated. We then estimated the proportion of TB cases that reflected the difference between each state's reported risk factor-specific TB incidence and the lowest incidence achieved among 4 states (California, Florida, New York, Texas). We reported these differences for the 4 states and also calculated and aggregated across all 50 states to quantify the total percentage of TB cases nationally that reflected between-state differences in risk factor-specific TB incidence. RESULTS: On average, 24% of recent TB incidence among high-risk US populations reflected heterogeneity at the state level. The populations that accounted for the greatest percentage of heterogeneity-reflective cases were non-US-born individuals (51%) and patients with diabetes (24%). CONCLUSIONS: State-level differences in TB incidence among key populations provide clues for targeting state-level interventions.

The Importance of Heterogeneity to the Epidemiology of Tuberculosis. (2018). Trauer JM., Dodd PJ., Gomes MGM., Gomez GB., Houben RM., McBryde ES., Melsew YA., Menzies NA., Arinaminpathy N., Shrestha S., Dowdy DW, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America

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Although less well-recognised than for other infectious diseases, heterogeneity is a defining feature of TB epidemiology. To advance toward TB elimination, this heterogeneity must be better understood and addressed. Drivers of heterogeneity in TB epidemiology act at the level of the infectious host, organism, susceptible host, environment and distal determinants. These effects may be amplified by social mixing patterns, while the variable latent period between infection and disease may mask heterogeneity in transmission. Reliance on notified cases may lead to misidentification of the most affected groups, as case detection is often poorest where prevalence is highest. Assuming average rates apply across diverse groups and ignoring the effects of cohort selection may result in misunderstanding of the epidemic and the anticipated effects of control measures. Given this substantial heterogeneity, interventions targeting high-risk groups based on location, social determinants or comorbidities could improve efficiency, but raise ethical and equity considerations.

- October 2018 -

Projected population-wide impact of antiretroviral therapy-linked isoniazid preventive therapy in a high-burden setting. (2018). Kendall EA., Azman AS., Maartens G., Boulle A., Wilkinson RJ., Dowdy DW., Rangaka MX, AIDS (London, England), 33, 525-536

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OBJECTIVE: Both isoniazid preventive therapy (IPT) and antiretroviral therapy (ART) reduce tuberculosis risk in individuals living with HIV. We sought to estimate the broader, population-wide impact of providing a pragmatically implemented 12-month IPT regimen to ART recipients in a high-burden community. DESIGN: Dynamic transmission model of a tuberculosis (TB)-HIV epidemic, calibrated to site-specific, historical epidemiologic and clinical trial data from Khayelitsha, South Africa. METHODS: We projected the 5-year impact of delivering a 12-month IPT regimen community-wide to 85% of new ART initiators and 15%/year of those already on ART, accounting for IPT-attributable reductions in TB infection, progression, and transmission. We also evaluated scenarios of continuously-delivered IPT, ongoing ART scale-up, and lower tuberculosis incidence. RESULTS: Under historical (early 2010) ART coverage, this ART-linked IPT intervention prevented one tuberculosis case per 18 [95% credible interval (CrI) 11-29] people treated. It lowered TB incidence by a projected 23% (95% CrI 14-30%) among people receiving ART, and by 5.2% (95% CrI 2.9-8.7%) in the total population. Continuous IPT reduced the number needed to treat to prevent one case of TB to 10 (95% CrI 7-16), though it required 74% more person-years of therapy (95% CrI 64-94%) to prevent one TB case, relative to 12-month therapy. Under expanding ART coverage, the tuberculosis incidence reduction achieved by 12-month IPT grew to 7.6% (95% CrI 4.3-12.6%). Effect sizes were similar in a simulated setting of lower TB incidence. CONCLUSIONS: IPT in conjunction with ART reduces tuberculosis incidence among those who receive therapy and has additional impact on tuberculosis transmission in the population.

- September 2018 -

The association of household fine particulate matter and kerosene with tuberculosis in women and children in Pune, India. (2018). Elf JL., Kinikar A., Khadse S., Mave V., Suryavanshi N., Gupte N., Kulkarni V., Patekar S., Raichur P., Paradkar M., Kulkarni V., Pradhan N., Breysse PN., Gupta A., Golub JE, Occupational and environmental medicine, 76, 40-47

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OBJECTIVES: Household air pollution (HAP) is a risk factor for respiratory disease, however has yet to be definitively associated with tuberculosis (TB). We aimed to assess the association between HAP and TB. METHODS: A matched case-control study was conducted among adult women and children patients with TB and healthy controls matched on geography, age and sex. HAP was assessed using questionnaires for pollution sources and 24-hour household concentrations of particulate matter <2.5 mum in diameter (PM2.5). RESULTS: In total, 192 individuals in 96 matched pairs were included. The median 24-hour time-weighted average PM2.5 was nearly seven times higher than the WHO's recommendation of 25 microg/m(3), and did not vary between controls (179 microg/m(3); IQR: 113-292) and cases (median 157 microg/m(3); 95% CI 93 to 279; p=0.57). Reported use of wood fuel was not associated with TB (OR 2.32; 95% CI 0.65 to 24.20) and kerosene was significantly associated with TB (OR 5.49, 95% CI 1.24 to 24.20) in adjusted analysis. Household PM2.5 was not associated with TB in univariate or adjusted analysis. Controlling for PM2.5 concentration, kerosene was not significantly associated with TB, but effect sizes ranged from OR 4.30 (95% CI 0.78 to 30.86; p=0.09) to OR 5.49 (0.82 to 36.75; p=0.08). CONCLUSIONS: Use of kerosene cooking fuel is positively associated with TB in analysis using reported sources of exposure. Ubiquitously high levels of particulates limited detection of a difference in household PM2.5 between cases and controls.

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