TB Modeling and Translational Epi Group

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- November 2020 -

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.

Costing the implementation of public health interventions in resource-limited settings: a conceptual framework. (2020). Sohn H., Tucker A., Ferguson O., Gomes I., Dowdy D, Implementation science : IS, 15, 86

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BACKGROUND: Failing to account for the resources required to successfully implement public health interventions can lead to an underestimation of costs and budget impact, optimistic cost-effectiveness estimates, and ultimately a disconnect between published evidence and public health decision-making. METHODS: We developed a conceptual framework for assessing implementation costs. We illustrate the use of this framework with case studies involving interventions for tuberculosis and HIV/AIDS in resource-limited settings. RESULTS: Costs of implementing public health interventions may be conceptualized as occurring across three phases: design, initiation, and maintenance. In the design phase, activities include developing intervention components and establishing necessary infrastructure (e.g., technology, standard operating procedures). Initiation phase activities include training, initiation of supply chains and quality assurance procedures, and installation of equipment. Implementation costs in the maintenance phase include ongoing technical support, monitoring and evaluation, and troubleshooting unexpected obstacles. Within each phase, implementation costs can be incurred at the site of delivery ("site-specific" costs) or more centrally ("above-service" or "central" costs). For interventions evaluated in the context of research studies, implementation costs should be classified as programmatic, research-related, or shared research/program costs. Purely research-related costs are often excluded from analysis of programmatic implementation. CONCLUSIONS: In evaluating public health interventions in resource-limited settings, accounting for implementation costs enables more realistic estimates of budget impact and cost-effectiveness and provides important insights into program feasibility, scale-up, and sustainability. Assessment of implementation costs should be planned prospectively and performed in a standardized manner to ensure generalizability.

The Impact of Hypertension and Use of Calcium Channel Blockers on Tuberculosis Treatment Outcomes. (2020). Chidambaram V., Gupte A., Wang JY., Golub JE., Karakousis PC, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America

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BACKGROUND: Hypertension induces systemic inflammation, but its impact on the outcome of infectious diseases like tuberculosis (TB) is unknown. Calcium channel blockers (CCB) improve TB treatment outcomes in pre-clinical models, but their effect in patients with TB remain unclear. METHODS: This retrospective cohort study, including all patients > 18 years receiving treatment for culture-confirmed, drug-sensitive TB from 2000 to 2016 at the National Taiwan University Hospital, assessed the association of hypertension and CCB use with all-cause and infection-related mortality during the first 9 months of TB treatment, as well as sputum-smear microscopy and sputum-culture positivity at 2 and 6 months. RESULTS: 1052 of the 2894 patients (36.4%) had hypertension. Multivariable analysis revealed that hypertension was associated with increased mortality due to all causes (HR 1.57, 95% confidence interval[CI], 1.23-1.99) and infections (HR 1.87, 95%CI, 1.34-2.6), but there was no statistical difference in microbiological outcomes when stratified based on hypertensive group. Dihydropyridine-CCB (DHP-CCB) use was associated with reduced all-cause mortality (HR 0.67, 95%CI: 0.45-0.98) only by univariate Cox regression. There was no association between DHP-CCB use and infection-related mortality (HR 0.78, 95%CI: 0.46-1.34) or microbiological outcomes in univariate or multivariate regression analyses. CONCLUSIONS: Patients with hypertension have increased all-cause mortality and infection-related mortality during the 9 months following TB treatment initiation. DHP-CCB use may lower all-cause mortality in TB patients with hypertension. The presence of hypertension or the use of CCB did not result in a significant change in microbiological outcomes.

Effect of 2 Integrated Interventions on Alcohol Abstinence and Viral Suppression Among Vietnamese Adults With Hazardous Alcohol Use and HIV: A Randomized Clinical Trial. (2020). Go VF., Hutton HE., Ha TV., Chander G., Latkin CA., Mai NVT., Quynh BX., Nguyen V., Sripaipan T., Lancaster KE., Blackburn N., Hershow RB., Dowdy DW., Frangakis C, JAMA network open, 3, e2017115

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IMPORTANCE: Hazardous and heavy alcohol use is common among people living with HIV and may decrease antiretroviral therapy (ART) adherence, but limited data exist from randomized clinical trials about the effects of interventions on viral load. OBJECTIVE: To compare the efficacy of 2 scalable ART clinic-based interventions on alcohol use and viral suppression. DESIGN, SETTING, AND PARTICIPANTS: This 3-group randomized clinical trial was conducted among 440 adults with HIV who were being treated at 7 ART clinics in Thai Nguyen, Vietnam. Adults receiving ART with hazardous alcohol use (Alcohol Use Disorders Identification Test-Consumption score ≥4 for men or ≥3 for women) and no plans to leave Thai Nguyen were included. Data were collected from March 2016 to May 2018 and analyzed from June 2018 to February 2020. INTERVENTIONS: Participants were randomly assigned (1:1:1) to standard of care (SOC), a combined intervention of motivational enhancement therapy and cognitive behavioral therapy (6 in-person sessions of 1 hour each and 3 optional group sessions), or a brief intervention with similar components as the combined intervention but consisting of 2 shorter in-person sessions and 2 telephone sessions. MAIN OUTCOMES AND MEASURES: The primary study outcomes were percentage of days abstinent from alcohol, confirmed using the alcohol biomarker phosphatidylethanol, and viral suppression at 12 months after enrollment. RESULTS: A total of 440 eligible individuals (mean [SD] age, 40.2 [5.8] years; 426 [96.8%] men) were enrolled; 147 (33.4%) were assigned to the combined intervention, 147 (33.4%) to the brief intervention, and 146 (33.2%) to SOC. In the combined intervention group, 112 participants (76.2%) attended all 6 sessions, and in the brief intervention group, 124 (84.4%) attended all 4 sessions; in the whole sample, 390 (88.6%) completed 12 months of follow-up. At 12 months, the mean (SE) percentage of days abstinent was 65% (3.1%) among those in the combined intervention group, 65% (3.2%) among those in the brief intervention group, and 50% (3.4%) among those in the in the SOC group (Cohen d for combined intervention vs SOC and brief intervention vs SOC: 39%; 95% CI, 15% to 64%). Viral suppression (ie, <20 copies of HIV-1 RNA per milliliter) at 12 months was higher after the brief intervention than SOC (difference, 11%; 95% CI, 2% to 20%), but the difference between the combined intervention and SOC was not significantly different (difference, 5%; 95%, CI, -5% to 15%). CONCLUSIONS AND RELEVANCE: In this study, the brief intervention resulted in a significant increase in percentage of days abstinent from alcohol and a significant increase in viral suppression after 12 months. Future implementation science studies evaluating scale-up of the brief intervention are needed. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02720237.

Estimated Population-Level Impact of Using a Six-Week Regimen of Daily Rifapentine to Treat Latent Tuberculosis Infection in the United States. (2020). Shrestha S., Parriott A., Menzies NA., Shete PB., Hill AN., Marks SM., Dowdy DW, Annals of the American Thoracic Society, 17, 1639-1642

Implementation of two alcohol reduction interventions among persons with hazardous alcohol use who are living with HIV in Thai Nguyen, Vietnam: a micro-costing analysis. (2020). Blackburn NA., Go VF., Bui Q., Hutton H., Tampi RP., Sripaipan T., Ha TV., Latkin C., Golden S., Golin C., Chander G., Frangakis C., Gottfredson N., Dowdy DW, Global health action, 13, 1814035

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BACKGROUND: Hazardous alcohol use is detrimental to persons with HIV (PWH), impacting medication adherence and liver function, yet globally resources to target alcohol use behavior in this population are limited. Few studies have identified the costs of integrating alcohol reduction interventions into HIV care. OBJECTIVE: To estimate the costs of implementing and delivering two evidence-based behavioral counseling interventions targeting hazardous alcohol use among persons with HIV and to estimate the costs of scale-up in ART clinics in Thai Nguyen, Vietnam. METHODS: We undertook a micro-costing approach to determine the costs of delivering two adapted evidence-based interventions to reduce alcohol use: an intensive combined cognitive behavioral therapy and motivational enhancement therapy-informed intervention (CoI) and an abbreviated brief alcohol intervention (BI). A total of 294 participants with hazardous alcohol use were identified through a brief screening tool and received the CoI (n = 147) and the BI (n = 147) over 3 months. We estimated costs using time and motion studies, budget analysis, staff interviews, and participant questionnaires. Data were collected from 2016 to 2018 in VND and converted to USD. RESULTS: The total cost of implementation and administration of the intervention to 147 participants receiving the CoI was $13,900 ($95 per participant) and to 147 participants receiving the BI was $5700 ($39 per participant). Implementation and startup costs including training accounted for 27% of costs for the CoI and 28% for the BI. Counselor costs accounted for a large proportion of both the CoI (41%) and the BI (30%). CONCLUSIONS: Implementing and delivering alcohol reduction interventions to people with HIV in Vietnam with appropriate fidelity is costly. These costs may be reduced, particularly counselor labor costs, by using an evidence-based brief intervention format. Future research should explore the budgetary impact of brief and combined interventions to reduce hazardous alcohol use, particularly among vulnerable populations.

- August 2020 -

Protocol for the 3HP Options Trial: a hybrid type 3 implementation-effectiveness randomized trial of delivery strategies for short-course tuberculosis preventive therapy among people living with HIV in Uganda. (2020). Kadota JL., Musinguzi A., Nabunje J., Welishe F., Ssemata JL., Bishop O., Berger CA., Patel D., Sammann A., Katahoire A., Nahid P., Belknap R., Phillips PPJ., Namusobya J., Kamya M., Handley MA., Kiwanuka N., Katamba A., Dowdy D., Semitala FC., Cattamanchi A, Implementation science : IS, 15, 65

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BACKGROUND: Recently, a 3-month (12-dose) regimen of weekly isoniazid and rifapentine (3HP) was recommended by the World Health Organization for the prevention of tuberculosis (TB) among people living with HIV (PLHIV) on common antiretroviral therapy regimens. The best approach to delivering 3HP to PLHIV remains uncertain. METHODS: We developed a three-armed randomized trial assessing optimized strategies for delivering 3HP to PLHIV. The trial will be conducted at the Mulago Immune Suppression Syndrome (i.e., HIV/AIDS) clinic in Kampala, Uganda. We plan to recruit 1656 PLHIV, randomized 1:1 to each of the three arms (552 per arm). Using a hybrid type 3 effectiveness-implementation design, this pragmatic trial aims to (1) compare the acceptance and completion of 3HP among PLHIV under three delivery strategies: directly observed therapy (DOT), self-administered therapy (SAT), and informed patient choice of either DOT or SAT (with the assistance of a decision aid); (2) to identify processes and contextual factors that influence the acceptance and completion of 3HP under each delivery strategy; and (3) to estimate the costs and compare the cost-effectiveness of three strategies for delivering 3HP. The three delivery strategies were each optimized to address key barriers to 3HP completion using a theory-informed approach. We hypothesize that high levels of treatment acceptance and completion can be achieved among PLHIV in sub-Saharan Africa and that offering PLHIV an informed choice between the optimized DOT and SAT delivery strategies will result in greater acceptance and completion of 3HP. The design and planned evaluation of the delivery strategies were guided by the use of implementation science conceptual frameworks. DISCUSSION: 3HP-one of the most promising interventions for TB prevention-will not be scaled up unless it can be delivered in a patient-centered fashion. We highlight shared decision-making as a key element of our trial design and theorize that offering PLHIV an informed choice between optimized delivery strategies will facilitate the highest levels of treatment acceptance and completion. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03934931 ; Registered 2 May 2019.

Comparing a standard and tailored approach to scaling up an evidence-based intervention for antiretroviral therapy for people who inject drugs in Vietnam: study protocol for a cluster randomized hybrid type III trial. (2020). Nguyen MXB., Chu AV., Powell BJ., Tran HV., Nguyen LH., Dao ATM., Pham MD., Vo SH., Bui NH., Dowdy DW., Latkin CA., Lancaster KE., Pence BW., Sripaipan T., Hoffman I., Miller WC., Go VF, Implementation science : IS, 15, 64

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BACKGROUND: People who inject drugs (PWID) bear a disproportionate burden of HIV infection and experience poor outcomes. A randomized trial demonstrated the efficacy of an integrated System Navigation and Psychosocial Counseling (SNaP) intervention in improving HIV outcomes, including antiretroviral therapy (ART) and medications for opioid use disorder (MOUD) uptake, viral suppression, and mortality. There is limited evidence about how to effectively scale such intervention. This protocol presents a hybrid type III effectiveness-implementation trial comparing two approaches for scaling-up SNaP. We will evaluate the effectiveness of SNaP implementation approaches as well as cost and the characteristics of HIV testing sites achieving successful or unsuccessful implementation of SNaP in Vietnam. METHODS: Design: In this cluster randomized controlled trial, two approaches to scaling-up SNaP for PWID in Vietnam will be compared. HIV testing sites (n = 42) were randomized 1:1 to the standard approach or the tailored approach. Intervention mapping was used to develop implementation strategies for both arms. The standard arm will receive a uniform package of these strategies, while implementation strategies for the tailored arm will be designed to address site-specific needs. PARTICIPANTS: HIV-positive PWID participants (n = 6200) will be recruited for medical record assessment at baseline; of those, 1500 will be enrolled for detailed assessments at baseline, 12, and 24 months. Site directors and staff at each of the 42 HIV testing sites will complete surveys at baseline, 12, and 24 months. OUTCOMES: Implementation outcomes (fidelity, penetration, acceptability) and effectiveness outcomes (ART, MOUD uptake, viral suppression) will be compared between the arms. To measure incremental costs, we will conduct an empirical costing study of each arm and the actual process of implementation from a societal perspective. Qualitative and quantitative site-level data will be used to explore key characteristics of HIV testing sites that successfully or unsuccessfully implement the intervention for each arm. DISCUSSION: Scaling up evidence-based interventions poses substantial challenges. The proposed trial contributes to the field of implementation science by applying a systematic approach to designing and tailoring implementation strategies, conducting a rigorous comparison of two promising implementation approaches, and assessing their incremental costs. Our study will provide critical guidance to Ministries of Health worldwide regarding the most effective, cost-efficient approach to SNaP implementation. TRIAL REGISTRATION: NCT03952520 on Clinialtrials.gov. Registered 16 May 2019.

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