TB Modeling and Translational Epi Group

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- January 2021 -

Modeling the cost-effectiveness of point-of-care platforms for infant diagnosis of HIV in sub-Saharan African countries. (2021). Salvatore PP., de Broucker G., Vojnov L., Moss WJ., Dowdy DW., Sutcliffe CG, AIDS (London, England), 35, 287-297

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BACKGROUND: Early infant diagnosis of HIV (EID) improves child survival through earlier initiation of antiretroviral therapy (ART). In many settings, ART initiation is hindered by delays in testing performed in centralized labs. Point-of-care (PoC) platforms offer opportunities to improve the timeliness of ART initiation. METHODS: We used a mathematical model to estimate the costs and performance of on-site PoC testing using three platforms (m-PIMA, GeneXpert IV, and GeneXpert Edge) compared with the standard of care (SoC). Primary outcomes included ART initiation within 60 days of sample collection, HIV-related mortality before ART initiation, and incremental cost-effectiveness ratios (ICERs). RESULTS: PoC testing significantly increased ART initiation within 60 days (from 19% with SoC to 82-84% with PoC) and decreased HIV-related mortality (from 23% with SoC to 5% with PoC). ART initiation and mortality were similar across PoC platforms. When only used for EID and with high coverage of prevention of mother-to-child transmission (PMTCT) programs, ICERs for PoC testing compared with the SoC ranged from $430 to $1097 per additional infant on ART within 60 days and from $1527 to $3888 per death averted. PoC-based testing was more cost-effective in settings with lower PMTCT coverage, greater delays in the SoC, and when PoC instruments could be integrated with other disease programs. CONCLUSION: Our findings illustrate that PoC platforms can dramatically improve the timeliness of EID and linkage to HIV care. The cost-effectiveness of PoC platforms depends on the cost of PoC testing, existing access to diagnostic testing, and the ability to integrate PoC testing with non-EID programs.

The Cost-Effectiveness of Adapting and Implementing a Brief Intervention to Target Frequent Alcohol Use Among Persons with HIV in Vietnam. (2021). Blackburn NA., Go VF., Bui Q., Hutton H., Tampi RP., Sripaipan T., Ha TV., Latkin CA., Golden S., Golin C., Chander G., Frangakis C., Gottfredson N., Dowdy DW, AIDS and behavior, 25, 2108-2119

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Brief interventions to reduce frequent alcohol use among persons with HIV (PWH) are evidence-based, but resource-constrained settings must contend with competition for health resources. We evaluated the cost-effectiveness of two intervention arms compared to the standard of care (SOC) in a three-arm randomized control trial targeting frequent alcohol use in PWH through increasing the percent days abstinent from alcohol and viral suppression. We estimated incremental cost per quality-adjusted life year (QALY) gained from a modified societal perspective and a 1-year time horizon using a Markov model of health outcomes. The two-session brief intervention (BI), relative to the six-session combined intervention (CoI), was more effective and less costly; the estimated incremental cost-effectiveness of the BI relative to the SOC, was $525 per QALY gained. The BI may be cost-effective for the HIV treatment setting; the health utility gained from viral suppression requires further exploration.

Isoniazid preventive therapy plus antiretroviral therapy for the prevention of tuberculosis: a systematic review and meta-analysis of individual participant data. (2021). Ross JM., Badje A., Rangaka MX., Walker AS., Shapiro AE., Thomas KK., Anglaret X., Eholie S., Gabillard D., Boulle A., Maartens G., Wilkinson RJ., Ford N., Golub JE., Williams BG., Barnabas RV, The lancet. HIV, 8, e8-e15

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BACKGROUND: Isoniazid preventive therapy prevents active tuberculosis in people with HIV, but previous studies have found no evidence of benefit in people with HIV who had a negative tuberculin skin test, and a non-significant effect on mortality. We aimed to estimate the effect of isoniazid preventive therapy given with antiretroviral therapy (ART) for the prevention of tuberculosis and death among people with HIV across population subgroups. METHODS: We searched PubMed, Embase, the Cochrane database, and conference abstracts from database inception to Jan 15, 2019, to identify potentially eligible randomised trials. Eligible studies were trials that enrolled HIV-positive adults (age ≥15 years) taking ART who were randomly assigned to either daily isoniazid preventive therapy plus ART or ART alone and followed up longitudinally for outcomes of incident tuberculosis and mortality. We approached all authors of included trials and requested individual participant data: coprimary outcomes were relative risk of incident tuberculosis and all-cause mortality. We did a single-stage meta-analysis of individual participant data using stratified Cox-proportional hazards models. We did prespecified subgroup analyses by sex, CD4 cell count, and evidence of immune sensitisation to tuberculosis (indicated by tuberculin skin test or interferon-γ release assays [IGRAs]). We also assessed the relative risk of liver injury in an additional prespecified analysis. This study is registered with PROSPERO, CRD42019121400. FINDINGS: Of 838 records, we included three trials with data for 2611 participants and 8584·8 person-years of follow-up for the outcome of incident tuberculosis, and a subset of 2362 participants with 8631·6 person-years of follow-up for the coprimary outcome of all-cause mortality. Risk for tuberculosis was lower in participants given isoniazid preventive therapy and ART than participants given ART alone (hazard ratio [HR] 0·68, 95% CI 0·49-0·95, p=0·02). Risk of all-cause mortality was lower in participants given isoniazid preventive therapy and ART than participants given ART alone, but this difference was non-significant (HR 0·69, 95% CI 0·43-1·10, p=0·12). Participants with baseline CD4 counts of less than 500 cells per μL had increased risk of tuberculosis, but there was no significant difference in the benefit of isoniazid preventive therapy with ART by sex, baseline CD4 count, or results of tuberculin skin test or IGRAs. 65 (2·5%) of 2611 participants had raised alanine aminotransferase, but data were insufficient to calculate an HR. INTERPRETATION: Isoniazid preventive therapy with ART prevents tuberculosis across demographic and HIV-specific and tuberculosis-specific subgroups, which supports efforts to further increase use of isoniazid preventive therapy with ART broadly among people living with HIV. FUNDING: National Institutes of Health and National Institute of Allergy and Infectious Diseases.

Costs along the TB diagnostic pathway in Uganda. (2021). Tucker A., Oyuku D., Nalugwa T., Nantale M., Ferguson O., Farr K., Reza TF., Shete PB., Cattamanchi A., Dowdy DW., Sohn H., Katamba A, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 25, 61-63

- December 2020 -

Evaluation of underweight status may improve identification of the highest-risk patients during outpatient evaluation for pulmonary tuberculosis. (2020). Kitonsa PJ., Nalutaaya A., Mukiibi J., Nakasolya O., Isooba D., Kamoga C., Baik Y., Robsky K., Dowdy DW., Katamba A., Kendall EA, PloS one, 15, e0243542

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BACKGROUND: When evaluating symptomatic patients for tuberculosis (TB) without access to same-day diagnostic test results, clinicians often make empiric decisions about starting treatment. The number of TB symptoms and/or underweight status could help identify patients at highest risk for a positive result. We sought to evaluate the usefulness of BMI assessment and a count of characteristic TB symptoms for identifying patients at highest risk for TB. METHODS: We enrolled adult patients receiving pulmonary TB diagnoses and a representative sample with negative TB evaluations at four outpatient health facilities in Kampala, Uganda. We asked patients about symptoms of chronic cough, night sweats, chest pain, fever, hemoptysis, or weight loss; measured height and weight; and collected sputum for mycobacterial culture. We evaluated the diagnostic accuracy (for culture-positive TB) of two simple scoring systems: (a) number of TB symptoms, and (b) number of TB symptoms plus one or more additional points for underweight status (body mass index [BMI] ≤ 18.5 kg/m2). RESULTS: We included 121 patients with culture-positive TB and 370 patients with negative culture results (44 of whom had been recommended for TB treatment by evaluating clinicians). Of the six symptoms assessed, the median number of symptoms that patients reported was two (interquartile range [IQR]: 1, 3). The median BMI was 20.9 kg/m2 (IQR: 18.6, 24.0), and 118 (24%) patients were underweight. Counting the number of symptoms provided an area under the Receiver Operating Characteristic curve (c-statistic) of 0.77 (95% confidence interval, CI: 0.72, 0.81) for identifying culture-positive TB; adding two points for underweight status increased the c-statistic to 0.81 (95%CI: 0.76, 0.85). A cutoff of ≥3 symptoms had sensitivity and specificity of 65% and 74%, whereas a score of ≥4 on the combined score (≥2 symptoms if underweight, ≥4 symptoms if not underweight) gave higher sensitivity and specificity of 69% and 81% respectively. A sensitivity analysis defining TB by Xpert MTB/RIF status produced similar results. CONCLUSION: A count of patients' TB symptoms may be useful in clinical decision-making about TB diagnosis. Consideration of underweight status adds additional diagnostic value.

The Spectrum of Tuberculosis Disease in an Urban Ugandan Community and Its Health Facilities. (2020). Kendall EA., Kitonsa PJ., Nalutaaya A., Erisa KC., Mukiibi J., Nakasolya O., Isooba D., Baik Y., Robsky KO., Kato-Maeda M., Cattamanchi A., Katamba A., Dowdy DW, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 72, e1035-e1043

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BACKGROUND: New, sensitive diagnostic tests facilitate identification and investigation of milder forms of tuberculosis (TB) disease. We used community-based TB testing with the Xpert MTB/RIF Ultra assay ("Ultra") to characterize individuals with previously undiagnosed TB and compare them to those from the same community who were diagnosed with TB through routine care. METHODS: We offered community-based sputum Ultra testing to adult residents of a well-defined area (population 34 000 adults) in Kampala, Uganda, via door-to-door screening and venue-based testing, then used detailed interview and laboratory testing to characterize TB-positive individuals. We compared these individuals to residents diagnosed with pulmonary TB at local health facilities and a representative sample of residents without TB (controls). RESULTS: Of 12 032 residents with interpretable Ultra results, 113 (940 [95% confidence interval {CI}, 780-1130] per 100 000) tested positive, including 71 (63%) positive at the lowest (trace) level. A spectrum of TB disease was observed in terms of chronic cough (93% among health facility-diagnosed cases, 77% among residents with positive community-based Ultra results at levels above trace, 33% among trace-positive community participants, and 18% among TB-negative controls), TB symptom prevalence (99%, 87%, 60%, and 38%, respectively), and C-reactive protein (75th percentile: 101 mg/L, 28 mg/L, 6 mg/L, and 4 mg/L, respectively). Community-diagnosed cases were less likely than health facility-diagnosed cases to have human immunodeficiency virus coinfection or previous TB. The specificity of Ultra was 99.4% (95% CI, 99.2%-99.5%) relative to a single spot sputum culture. CONCLUSIONS: People with undiagnosed prevalent TB in the community have different characteristics than those diagnosed with pulmonary TB in health facilities. Newer diagnostic tests may identify a group of people with early or very mild disease.

- November 2020 -

Study protocol and implementation details for a pragmatic, stepped-wedge cluster randomised trial of a digital adherence technology to facilitate tuberculosis treatment completion. (2020). Crowder R., Kityamuwesi A., Kiwanuka N., Lamunu M., Namale C., Tinka LK., Nakate AS., Ggita J., Turimumahoro P., Babirye D., Oyuku D., Berger CA., Tucker A., Patel D., Sammann A., Dowdy D., Stavia T., Cattamanchi A., Katamba A, BMJ open, 10, e039895

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INTRODUCTION: Low-cost digital adherence technologies (DATs) such as 99DOTS have emerged as an alternative to directly observed therapy (DOT), the current standard for tuberculosis (TB) treatment supervision. However, there are limited data to support DAT scale-up. The 'DOT to DAT' trial aims to evaluate the effectiveness and implementation of a 99DOTS-based TB treatment supervision strategy. METHODS AND ANALYSIS: This is a pragmatic, stepped-wedge cluster randomised trial, with hybrid type 2 effectiveness-implementation design. The trial will include all adults (estimated N=1890) treated for drug-susceptible pulmonary TB over an 8-month period at 18 TB treatment units in Uganda. Three sites per month will switch from routine care (DOT) to the intervention (99DOTS-based treatment supervision) beginning in month 2, with the order determined randomly. 99DOTS enables patients to be monitored while self-administering TB medicines. Patients receive daily automated short message service (SMS) dosing reminders and confirm dosing by calling toll-free numbers. The primary effectiveness outcome is the proportion of patients completing TB treatment. With 18 clusters randomised into six steps and an average cluster size of 15 patients per month, the study will have 89% power to detect a 10% or greater increase in treatment completion between the routine care and intervention periods. Secondary outcomes include more proximal effectiveness measures as well as quantitative and qualitative assessments of the reach, adoption and implementation of the intervention. ETHICS AND DISSEMINATION: Ethics approval was granted by institutional review boards at Makerere University School of Public Health and the University of California San Francisco. Findings will be disseminated through peer-reviewed publications, presentations at scientific conferences and presentations to key stakeholders. TRIAL REGISTRATION NUMBER: PACTR201808609844917.

The Epidemiological Importance of Subclinical Tuberculosis. A Critical Reappraisal. (2020). Kendall EA., Shrestha S., Dowdy DW, American journal of respiratory and critical care medicine, 203, 168-174

Health-related quality of life of inpatients and outpatients with TB in rural Malawi. (2020). Jo Y., Gomes I., Shin H., Tucker A., Ngwira LG., Chaisson RE., Corbett EL., Dowdy DW, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 24, 1165-1171

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INTRODUCTION: Patients being treated for TB may suffer reductions in health-related quality of life (HRQoL). This study aims to assess the extent of such reductions and the trajectory of HRQoL over the course of treatment in rural Malawi.METHODS: We collected patient demographic and socioeconomic status, TB-related characteristics, and HRQoL data (i.e., EQ-5D and a visual analogue scale VAS) from adults (age ≥18 years) being treated for TB in 12 primary health centers and one hospital in rural Thyolo District, Malawi, from 2014 to 2016. Associations between HRQoL and patient characteristics were estimated using multivariable linear regression.RESULTS: Inpatients (n = 197) consistently showed lower median HRQoL scores and suffered more severe health impairments during hospitalization than outpatients (n = 156) (EQ5D and VAS: 0.79, 55 vs. 0.84, 70). Longer treatment duration was associated with higher HRQoL among outpatients (EQ5D: 0.034 increase per 2 months, 95%CI 0.012-0.057). We found no substantial associations between patients´ demographic and socioeconomic characteristics and HRQoL in this setting.CONCLUSION: HRQoL scores among patients receiving treatment for TB in rural Malawi differ by clinical setting and duration of treatment, with greater impairment among inpatients and those early in their treatment course.

A clinical score for identifying active tuberculosis while awaiting microbiological results: Development and validation of a multivariable prediction model in sub-Saharan Africa. (2020). Baik Y., Rickman HM., Hanrahan CF., Mmolawa L., Kitonsa PJ., Sewelana T., Nalutaaya A., Kendall EA., Lebina L., Martinson N., Katamba A., Dowdy DW, PLoS medicine, 17, e1003420

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BACKGROUND: In highly resource-limited settings, many clinics lack same-day microbiological testing for active tuberculosis (TB). In these contexts, risk of pretreatment loss to follow-up is high, and a simple, easy-to-use clinical risk score could be useful. METHODS AND FINDINGS: We analyzed data from adults tested for TB with Xpert MTB/RIF across 28 primary health clinics in rural South Africa (between July 2016 and January 2018). We used least absolute shrinkage and selection operator regression to identify characteristics associated with Xpert-confirmed TB and converted coefficients into a simple score. We assessed discrimination using receiver operating characteristic (ROC) curves, calibration using Cox linear logistic regression, and clinical utility using decision curves. We validated the score externally in a population of adults tested for TB across 4 primary health clinics in urban Uganda (between May 2018 and December 2019). Model development was repeated de novo with the Ugandan population to compare clinical scores. The South African and Ugandan cohorts included 701 and 106 individuals who tested positive for TB, respectively, and 686 and 281 randomly selected individuals who tested negative. Compared to the Ugandan cohort, the South African cohort was older (41% versus 19% aged 45 years or older), had similar breakdown of biological sex (48% versus 50% female), and had higher HIV prevalence (45% versus 34%). The final prediction model, scored from 0 to 10, included 6 characteristics: age, sex, HIV (2 points), diabetes, number of classical TB symptoms (cough, fever, weight loss, and night sweats; 1 point each), and >14-day symptom duration. Discrimination was moderate in the derivation (c-statistic = 0.82, 95% CI = 0.81 to 0.82) and validation (c-statistic = 0.75, 95% CI = 0.69 to 0.80) populations. A patient with 10% pretest probability of TB would have a posttest probability of 4% with a score of 3/10 versus 43% with a score of 7/10. The de novo Ugandan model contained similar characteristics and performed equally well. Our study may be subject to spectrum bias as we only included a random sample of people without TB from each cohort. This score is only meant to guide management while awaiting microbiological results, not intended as a community-based triage test (i.e., to identify individuals who should receive further testing). CONCLUSIONS: In this study, we observed that a simple clinical risk score reasonably distinguished individuals with and without TB among those submitting sputum for diagnosis. Subject to prospective validation, this score might be useful in settings with constrained diagnostic resources where concern for pretreatment loss to follow-up is high.

Incorporating patient reporting patterns to evaluate spatially targeted TB interventions. (2020). Gomes I., Reja M., Shrestha S., Pennington J., Jo Y., Baik Y., Islam S., Khan AH., Faisel AJ., Cordon O., Roy T., Suarez P., Hussain H., Dowdy D, Annals of epidemiology, 54, 7-10

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PURPOSE: Tuberculosis (TB) is geographically heterogeneous, and geographic targeting can improve the impact of TB interventions. However, standard TB notification data may not sufficiently capture this heterogeneity. Better understanding of patient reporting patterns (discrepancies between residence and place of presentation) may improve our ability to use notifications to appropriately target interventions. METHODS: Using demographic data and TB reports from Dhaka North City Corporation and Dhaka South City Corporation, we identified wards of high TB incidence and developed a TB transmission model. We calibrated the model to patient-level data from selected wards under four different reporting pattern assumptions and estimated the relative impact of targeted versus untargeted active case finding. RESULTS: The impact of geographically targeted interventions varied substantially depending on reporting pattern assumptions. The relative reduction in TB incidence, comparing targeted with untargeted active case finding in Dhaka North City Corporation, was 1.20, assuming weak correlation between reporting and residence, versus 2.45, assuming perfect correlation. Similar patterns were observed in Dhaka South City Corporation (1.03 vs. 2.08). CONCLUSIONS: Movement of individuals seeking TB diagnoses may substantially affect ward-level TB transmission. Better understanding of patient reporting patterns can improve estimates of the impact of targeted interventions in reducing TB incidence. Incorporating high-quality patient-level data is critical to optimizing TB interventions.

The Relationship of COVID-19 Severity with Cardiovascular Disease and Its Traditional Risk Factors: A Systematic Review and Meta-Analysis. (2020). Matsushita K., Ding N., Kou M., Hu X., Chen M., Gao Y., Honda Y., Zhao D., Dowdy D., Mok Y., Ishigami J., Appel LJ, Global heart, 15, 64

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BACKGROUND: Whether cardiovascular disease (CVD) and its traditional risk factors predict severe coronavirus disease 2019 (COVID-19) is uncertain, in part, because of potential confounding by age and sex. METHODS: We performed a systematic review of studies that explored pre-existing CVD and its traditional risk factors as risk factors of severe COVID-19 (defined as death, acute respiratory distress syndrome, mechanical ventilation, or intensive care unit admission). We searched PubMed and Embase for papers in English with original data (≥10 cases of severe COVID-19). Using random-effects models, we pooled relative risk (RR) estimates and conducted meta-regression analyses. RESULTS: Of the 661 publications identified in our search, 25 papers met our inclusion criteria, with 76,638 COVID-19 patients including 11,766 severe cases. Older age was consistently associated with severe COVID-19 in all eight eligible studies, with RR >~5 in >60-65 versus <50 years. Three studies showed no change in the RR of age after adjusting for covariate(s). In univariate analyses, factors robustly associated with severe COVID-19 were male sex (10 studies; pooled RR = 1.73, [95% CI 1.50-2.01]), hypertension (8 studies; 2.87 [2.09-3.93]), diabetes (9 studies; 3.20 [2.26-4.53]), and CVD (10 studies; 4.97 [3.76-6.58]). RR for male sex was likely to be independent of age. For the other three factors, meta-regression analyses suggested confounding by age. Only four studies reported multivariable analysis, but most of them showed adjusted RR ~2 for hypertension, diabetes, and CVD. No study explored renin-angiotensin system inhibitors as a risk factor for severe COVID-19. CONCLUSIONS: Despite the potential for confounding, these results suggest that hypertension, diabetes, and CVD are independently associated with severe COVID-19 and, together with age and male sex, can be informative for predicting the risk of severe COVID-19.

Modeling Mitigation Strategies to Reduce Opioid-Related Morbidity and Mortality in the US. (2020). Ballreich J., Mansour O., Hu E., Chingcuanco F., Pollack HA., Dowdy DW., Alexander GC, JAMA network open, 3, e2023677

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IMPORTANCE: The US opioid epidemic is complex and dynamic, yet relatively little is known regarding its likely future impact and the potential mitigating impact of interventions to address it. OBJECTIVE: To estimate the future burden of the opioid epidemic and the potential of interventions to address the burden. DESIGN, SETTING, AND PARTICIPANTS: A decision analytic dynamic Markov model was calibrated using 2010-2018 data from the National Survey on Drug Use and Health, Centers for Disease Control and Prevention, National Health and Nutrition Examination Survey, the US Census, and National Epidemiologic Survey on Alcohol and Related Conditions-III. Data on individuals 12 years or older from the US general population or with prescription opioid medical use; prescription opioid nonmedical use; heroin use; prescription, heroin, or combined prescription and heroin opioid use disorder (OUD); 1 of 7 treatment categories; or nonfatal or fatal overdose were examined. The model was designed to project fatal opioid overdoses between 2020 and 2029. EXPOSURES: The model projected prescribing reductions (5% annually), naloxone distribution (assumed 5% reduction in case-fatality), and treatment expansion (assumed 35% increase in uptake annually for 4 years and 50% relapse reduction), with each compared vs status quo. MAIN OUTCOMES AND MEASURES: Projected 10-year overdose deaths and prevalence of OUD. RESULTS: Under status quo, 484 429 (95% confidence band, 390 543-576 631) individuals were projected to experience fatal opioid overdose between 2020 and 2029. Projected decreases in deaths were 0.3% with prescribing reductions, 15.4% with naloxone distribution, and 25.3% with treatment expansion; when combined, these interventions were associated with 179 151 fewer overdose deaths (37.0%) over 10 years. Interventions had a smaller association with the prevalence of OUD; for example, the combined intervention was estimated to reduce OUD prevalence by 27.5%, from 2.47 million in 2019 to 1.79 million in 2029. Model projections were most sensitive to assumptions regarding future rates of fatal and nonfatal overdose. CONCLUSIONS AND RELEVANCE: The findings of this study suggest that the opioid epidemic is likely to continue to cause tens of thousands of deaths annually over the next decade. Aggressive deployment of evidence-based interventions may reduce deaths by at least a third but will likely have less impact for the number of people with OUD.

The potential impact of the COVID-19 pandemic on the tuberculosis epidemic a modelling analysis. (2020). Cilloni L., Fu H., Vesga JF., Dowdy D., Pretorius C., Ahmedov S., Nair SA., Mosneaga A., Masini E., Sahu S., Arinaminpathy N, EClinicalMedicine, 28, 100603

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BACKGROUND: Routine services for tuberculosis (TB) are being disrupted by stringent lockdowns against the novel SARS-CoV-2 virus. We sought to estimate the potential long-term epidemiological impact of such disruptions on TB burden in high-burden countries, and how this negative impact could be mitigated. METHODS: We adapted mathematical models of TB transmission in three high-burden countries (India, Kenya and Ukraine) to incorporate lockdown-associated disruptions in the TB care cascade. The anticipated level of disruption reflected consensus from a rapid expert consultation. We modelled the impact of these disruptions on TB incidence and mortality over the next five years, and also considered potential interventions to curtail this impact. FINDINGS: Even temporary disruptions can cause long-term increases in TB incidence and mortality. If lockdown-related disruptions cause a temporary 50% reduction in TB transmission, we estimated that a 3-month suspension of TB services, followed by 10 months to restore to normal, would cause, over the next 5 years, an additional 1⋅19 million TB cases (Crl 1⋅06-1⋅33) and 361,000 TB deaths (CrI 333-394 thousand) in India, 24,700 (16,100-44,700) TB cases and 12,500 deaths (8.8-17.8 thousand) in Kenya, and 4,350 (826-6,540) cases and 1,340 deaths (815-1,980) in Ukraine. The principal driver of these adverse impacts is the accumulation of undetected TB during a lockdown. We demonstrate how long term increases in TB burden could be averted in the short term through supplementary "catch-up" TB case detection and treatment, once restrictions are eased. INTERPRETATION: Lockdown-related disruptions can cause long-lasting increases in TB burden, but these negative effects can be mitigated with rapid restoration of TB services, and targeted interventions that are implemented as soon as restrictions are lifted. FUNDING: USAID and Stop TB Partnership.

Choice architecture-based prescribing tool for TB preventive therapy: a pilot study in South Africa. (2020). Caturegli G., Materi J., Lombardo A., Milovanovic M., Yende N., Variava E., Golub JE., Martinson NA., Hoffmann CJ, Public health action, 10, 118-123

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BACKGROUND: All people with HIV who screen negative for active tuberculosis (TB) should receive isoniazid preventive therapy (IPT). IPT implementation remains substantially below the 90% WHO target. This study sought to further understanding of IPT prescription by piloting a simplified prescribing approach. SETTING: Primary care clinics in Matlosana, South Africa. DESIGN: This was a mixed-methods implementation study. METHODS: Nine providers were recruited and underwent training on 2018 WHO guidelines. A simplified prescribing tool containing antiretroviral therapy (ART) and IPT prescriptions was introduced into the workflow for 2 weeks. Prescription data were collected from file review. Interviews were conducted with prescribers. RESULTS: During the study period, 41 patients were evaluated for ART initiation; 34 (83%) files used the simplified prescribing tool. Thirty-seven (90%) patients were eligible for same-day ART and IPT initiation, of whom 36 (97%) received IPT prescription. Qualitative interviews identified the following barriers to IPT prescription: cognitive burden, extensive documentation, limited management support, paucity of training, stock-outs, and patient-related factors. Provider acceptability of the tool was favorable, with unanimous recommendation to colleagues on the basis of streamlining documentation and reminding to prescribe. CONCLUSIONS: This simplified prescribing device for IPT was feasible to implement. Streamlining documentation and reminding providers to prescribe can reduce work-flow barriers to IPT provision.

- October 2020 -

Cost-effectiveness of a 12 country-intervention to scale up short course TB preventive therapy among people living with HIV. (2020). Shin H., Jo Y., Chaisson RE., Turner K., Churchyard G., Dowdy DW, Journal of the International AIDS Society, 23, e25629

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INTRODUCTION: In 2017, the Aurum Institute, with support from Unitaid, launched an initiative to expand short-course therapy for the prevention of tuberculosis (TB) in 12 high-burden countries. This study aimed to investigate the importance of "catalytic" effects beyond the original project timeframe when estimating cost-effectiveness of such large investments. METHODS: We estimated the cost-effectiveness of the IMPAACT4TB (I4TB) initiative from a health system perspective, using a 10-year time horizon. We first conservatively estimated costs using a "top-down" approach considering only the direct health benefits of providing TB preventive therapy to people initiating antiretroviral therapy (ART) through I4TB activities. We then re-estimated the incremental cost-effectiveness of I4TB incorporating the costs and health benefits of potential catalytic effects beyond the program itself. RESULTS: We estimated that TB preventive therapy through the I4TB initiative alone would prevent 14 201 cases of active TB and 1562 TB deaths over 10 years with an up-front investment of $52.5 million; the estimated incremental cost-effectiveness was $1580 per disability-adjusted life year (DALY) averted. If this initiative could achieve its desired catalytic effects, an additional 375 648 cases and 41 321 deaths could be averted, at an incremental cost of $546 million and cost-effectiveness of $713 per DALY averted. CONCLUSIONS: Our findings provide donors with reasonable evidence of value for money to support investment in short-course TB preventive therapy for people initiating ART in high-burden settings. Our study also illustrates the importance of considering long-term secondary ("catalytic") effects when evaluating the cost-effectiveness of large-scale initiatives designed to change a global policy landscape.

Cost-effectiveness of one month of daily isoniazid and rifapentine versus three months of weekly isoniazid and rifapentine for prevention of tuberculosis among people receiving antiretroviral therapy in Uganda. (2020). Ferguson O., Jo Y., Pennington J., Johnson K., Chaisson RE., Churchyard G., Dowdy D, Journal of the International AIDS Society, 23, e25623

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INTRODUCTION: Preventive therapy is essential for reducing tuberculosis (TB) burden among people living with HIV (PLWH) in high-burden settings. Short-course preventive therapy regimens, such as three-month weekly rifapentine and isoniazid (3HP) and one-month daily rifapentine and isoniazid (1HP), may help facilitate uptake of preventive therapy for latently infected patients, but the comparative cost-effectiveness of these regimens under different conditions is uncertain. METHODS: We used a Markov state-transition model to estimate the incremental costs and effectiveness of 1HP versus 3HP in a simulated cohort of patients attending an HIV clinic in Uganda, as an example of a low-income, high-burden setting in which TB preventive therapy might be prescribed to PLWH. Our primary outcome was the incremental cost-effectiveness ratio, expressed as 2019 US dollars per disability-adjusted life year (DALY) averted. We estimated cost-effectiveness under different conditions of treatment completion and efficacy of 1HP versus 3HP, latent TB prevalence and rifapentine price. RESULTS: Assuming equivalent clinical outcomes using 1HP and 3HP and a rifapentine price of $0.21 per 150 mg, 1HP would cost an additional $4.66 per patient treated. Assuming equivalent efficacy but 20% higher completion with 1HP versus 3HP, 1HP would cost $1,221 per DALY averted relative to 3HP. This could be reduced to $18 per DALY averted if 1HP had 5% greater efficacy than 3HP and the price of rifapentine were 50% lower. At a rifapentine price of $0.06 per 150 mg, 1HP would become cost-neutral relative to 3HP. CONCLUSIONS: 1HP has the potential to be cost-effective under many realistic circumstances. Cost-effectiveness depends on rifapentine price, relative completion and efficacy, prevalence of latent TB and local willingness-to-pay.

Alcohol use, depressive symptoms, and intimate partner violence perpetration: A longitudinal analysis among men with HIV in northern Vietnam. (2020). Hershow RB., Reyes HLM., Ha TV., Chander G., Mai NVT., Sripaipan T., Frangakis C., Dowdy DW., Latkin C., Hutton HE., Pettifor A., Maman S., Go VF, PloS one, 15, e0240674

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BACKGROUND: While the link between alcohol use and male-perpetrated intimate partner violence (IPV) has been well-established, research is needed to test whether psychosocial factors interact with alcohol use to exacerbate IPV perpetration. We tested whether depressive symptoms influenced the strength and/or direction of the alcohol-IPV relationship among men with HIV in Vietnam. METHODS: This study is a secondary analysis using data from a randomized controlled trial conducted in Thai Nguyen, Vietnam. Participants were clinic patients with HIV and hazardous alcohol use. Questionnaires were administered at baseline, three, six, and 12 months. Alcohol use was assessed as proportion of days alcohol abstinent. Analyses were restricted to males who reported being married/cohabitating at baseline (N = 313). Multilevel growth models were used to test whether time-varying depressive symptoms modified the time-varying effect of alcohol use on IPV perpetration. RESULTS: Time-varying depressive symptoms modified the effect of proportion of days alcohol abstinent on IPV perpetration. However, the pattern of effect modification was not as expected, as reporting depressive symptoms weakened the alcohol-IPV relationship. At times when participants screened negative for depressive symptoms, those who reported higher proportion of days alcohol abstinent than usual had significantly lower odds of IPV perpetration (Odds Ratio [OR] = 0.17, 95% Confidence Interval 0.06, 0.45, p = 0.0004). At times when participants screened positive for depressive symptoms, there was no observed effect of alcohol use on IPV perpetration (OR = 4.28, 95% CI 0.80, 22.78, p = 0.09). CONCLUSION: The findings highlight the complex nature of the alcohol-IPV relationship and the need to investigate the intersection between hazardous drinking, mental health, and IPV. Men who concurrently report depressive symptoms and heightened alcohol use may be socially isolated from an intimate partner or experiencing fatigue, leading to less alcohol-related IPV perpetration. Mental health interventions addressing depression and alcohol misuse integrated into HIV services may reduce IPV perpetration.

Brief Report: Proportion and Predictors of Adult TB Contacts Accepting HIV Testing During an Active TB Case Finding Intervention in South Africa. (2020). Albaugh NW., Nonyane BAS., Mmolawa L., Siwelana T., Lebina L., Dowdy DW., Martinson N., Hanrahan CF, Journal of acquired immune deficiency syndromes (1999), 85, 525-529

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BACKGROUND: Many individuals at risk for HIV may be reached through active TB case finding interventions in areas with highly prevalent co-epidemics of TB/HIV. METHODS: We analyzed data from a cluster-randomized trial of 2 TB case finding strategies: facility-based screening and contact investigation of newly identified TB cases. In both arms, on-site rapid HIV testing was offered to all contacts older than 18 months who did not self-report HIV-positive status. Those who were HIV infected were referred appropriately. All contacts 15 years and older were included in this analysis. RESULTS: Among 2179 contacts identified, 50% (1092) accepted HIV testing and counselling, of whom 6.3% (68) tested HIV-positive. Contacts who were unemployed [adjusted prevalence ratio (aPR) 1.14, 95% confidence interval (CI): 1.04 to 1.25], had not been to a clinic (aPR 1.09, 95% CI: 1.02 to 1.18) or HIV tested (aPR 1.25, 95% CI: 1.14 to 1.39) 6 months before, and those reporting gastrointestinal symptoms (aPR 1.22, 95% CI: 0.98 to 1.52) and genitourinary symptoms (aPR 1.30, 95% CI: 1.17 to 1.45) were significantly associated with accepting HIV testing. Women [adjusted odds ratio (aOR) 2.19, 95% CI: 1.26 to 3.81], individuals with a past history of tuberculosis (aOR 1.96, 95% CI: 0.93 to 4.14), and those not HIV tested 6 months before (aOR 2.20, 95% CI: 1.28 to 3.79) were significantly associated with testing HIV-positive. CONCLUSION: Offering HIV testing in the context of active tuberculosis case finding represents an opportunity to identify a large proportion of previously undiagnosed individuals with HIV in a population that might otherwise not seek testing.

- September 2020 -

Alcohol abstinence stigma and alcohol use among HIV patients in Thai Nguyen, Vietnam. (2020). Lancaster KE., Hetrick A., Sripaipan T., Ha TV., Hutton HE., Chander G., Latkin CA., Dowdy D., Frangakis C., Quynh BX., Go VF, PloS one, 15, e0239330

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BACKGROUND: Hazardous alcohol use is prevalent among people living with HIV (PWH), leading to sub-optimal HIV treatment outcomes. In Vietnam, alcohol use is highly normative making it socially challenging for PWH to reduce or abstain. We used mixed methods to develop a quantitative scale to assess alcohol abstinence stigma and examined the association between alcohol abstinence stigma with alcohol use among PWH in Vietnam. METHODS: We conducted qualitative interviews with 30 PWH with hazardous alcohol use from an antiretroviral therapy (ART) clinic in the Thai Nguyen to inform item development. Alcohol use was assessed using the Alcohol Use Disorders Identification Test. We tested items in a survey of 1,559 ART clinic patients to assess internal consistency and structural validity. We used log binomial modeling to estimate associations between any reported alcohol abstinence stigma and alcohol use. RESULTS: Using the results from the qualitative interview data, we developed the alcohol abstinence stigma scale with seven final items with scores ranging from 0 (no stigma) to 28 (high stigma). The scale had good internal consistency (α = 0.75). Exploratory factor analysis suggested the presence of three factors: internalized, experienced, and anticipated stigma that explained 56.9% of the total variance. The mean score was 2.74, (SD = 4.28) and 46% reported any alcohol abstinence stigma. We observed a dose-response relationship between alcohol abstinence stigma and alcohol use. PWH who reported any alcohol abstinence stigma had greater hazardous alcohol use (aPR = 1.32, 95% CI: 1.12, 1.56), harmful alcohol use (aPR = 2.26, 95% CI: 1.37, 3.72), and dependence symptoms (aPR = 3.81, 95% CI: 2.19, 6.64). CONCLUSION: Alcohol abstinence stigma is associated with increased alcohol levels of alcohol use among PWH in Vietnam, signaling challenges for alcohol reduction. Consideration of alcohol abstinence stigma will be essential for the design of effective alcohol reduction interventions and policy efforts to prevent adverse health consequences of alcohol use among PWH.

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