TB Modeling and Translational Epi Group

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- March 2021 -

Evaluating the effects of two alcohol reduction counseling interventions on intimate partner violence perpetration: Secondary analysis of a three-arm randomized controlled trial among Vietnamese men with HIV. (2021). Hershow RB., Reyes HLMN., Ha TV., Chander G., Mai NVT., Sripaipan T., Dowdy DW., Latkin C., Hutton HE., Pettifor A., Maman S., Frangakis C., Go VF, Addiction (Abingdon, England)

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BACKGROUND AND AIMS: Evidence suggests that alcohol reduction interventions decrease intimate partner violence (IPV) perpetration, although this remains untested in low- and middle-income countries and among men with human immunodeficiency virus (HIV). This study evaluates the effectiveness of alcohol reduction counseling interventions on IPV perpetration among men on antiretroviral therapy (ART) and tests whether alcohol use explains the intervention effects. DESIGN: Secondary analysis of data from a three-arm randomized controlled trial among ART patients with hazardous alcohol use. Participants were recruited from March 2016 through May 2017. SETTING: Thai Nguyen, Vietnam. PARTICIPANTS: Male participants (n=426). INTERVENTIONS AND COMPARATORS: Participants received a two-session Brief Intervention (BI), a six-session Combined Intervention (CoI), or the standard of care (SOC) comprising alcohol treatment referrals. Alcohol reduction counseling interventions were guided by Cognitive Behavioral Therapy and Motivational Enhancement Therapy. They were delivered by psychosocial counselors over 3 months. MEASUREMENTS: IPV perpetration was measured using shortened Conflict Tactics Scale 2 and alcohol use was measured using Timeline Followback. FINDINGS: BI and CoI participants reported reduced IPV perpetration at 3 months compared with SOC participants (BI: adjusted odds ratio [aOR]=0.27, 95% Confidence Interval [CI] 0.11, 0.65; CoI: aOR=0.50, 95% CI 0.22, 1.13); the association was only significant for the BI group. Intervention effects were not sustained at 6 and 12 months. There was little evidence that alcohol use acted as a mediator (Indirect effect, BI: aOR=0.84, 95% CI 0.63, 1.04; Indirect effect, CoI: aOR=0.86, 95% CI 0.66, 1.03). CONCLUSIONS: Among Vietnamese men receiving antiretroviral therapy, alcohol reduction counseling interventions appeared to reduce intimate partner violence perpetration immediately post-intervention but reductions were not sustained at 6 and 12 months and were not explained by alcohol reduction.

Ethical Implications of eHealth Tools for Delivering STI/HIV Laboratory Results and Partner Notifications. (2021). Godongwana M., Chewparsad J., Lebina L., Golub J., Martinson N., Jarrett BA, Current HIV/AIDS reports

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PURPOSE OF REVIEW: eHealth tools are increasingly utilized for communication with patients. Although efficacious and cost-effective, these tools face several barriers that challenge their ethical use in sexual health. We reviewed literature from the past decade to pick illustrative studies of eHealth tools that deliver results of laboratory tests for sexually transmitted infections, including the human immunodeficiency virus, as well as partner notifications. We describe ethical implications for such technologies. RECENT FINDINGS: Our review found that despite widespread research on the use of eHealth tools in delivering laboratory results and partner notifications, these studies rarely measured or reported on the ethical implications. Such implications can be organized according to the four major principles in bioethics: beneficence, patient autonomy, non-maleficence, and justice. The beneficence of eHealth typically measures efficacy in comparison to existing standards of care. Patient autonomy includes the ability to opt in or out of eHealth tools, right-based principles of consent, and sovereignty over healthcare data. To adhere to the principle of non-maleficence, relevant harms must be identified and measured-such as unintentional disclosure of illness, sexual orientation, or sexual activity. Justice must also be considered to accommodate all users equally, irrespective of their literacy level, with easy-to-use platforms that provide clear messages. Based on case studies from this review, we developed a list of recommendations for the ethical development and evaluation of eHealth platforms to deliver STI/HIV results to patients and notifications to partners.

Measuring health-care delays among privately insured patients with tuberculosis in the USA: an observational cohort study. (2021). El Halabi J., Palmer N., McDuffie M., Golub JJ., Fox K., Kohane I., Farhat MR, The Lancet. Infectious diseases

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BACKGROUND: A high index of suspicion is needed to initiate appropriate testing for tuberculosis due to its protean symptoms, yet health-care providers in low-incidence settings are becoming less familiar with the disease as rates decline. We aimed to estimate delays in tuberculosis diagnosis and treatment at the US national level between 2008 and 2016. METHODS: In this retrospective observational cohort study, we repurposed private insurance claims data provided by Aetna (Connecticut, USA), to measure health-care delays in tuberculosis diagnosis in the USA in 2008-16. Active tuberculosis was determined by diagnosis codes and the filling of anti-tuberculosis treatment prescriptions. Health-care delays were defined as the duration between the first health-care visit for a tuberculosis symptom and the initiation of anti-tuberculosis treatment. We assessed if delays varied over time, and by patient and system variables, using multivariable regression. We estimated household tuberculosis transmission and respiratory complications after treatment initiation. FINDINGS: We confirmed 738 active tuberculosis cases (incidence 1·45 per 100 000 person-years) with a median health-care delay of 24 days (IQR 10-45). Multivariable regression analysis showed that longer delays were associated with older age (8·4% per 10 year increase [95% CI 4·0 to 13·1]; p<0·0086) and non-HIV immunosuppression (19·2% [15·1 to 60·0]; p=0·0432). Presenting with three or more symptoms was associated with a shorter delay (-22·5% [-39·1 to -2·0]; p=0·0415), relative to presenting with one symptom, as did use of chest imaging (-24·9% [-37·9 to -8·9]; p<0·0098), tuberculosis nucleic acid amplification tests (-19·2% [-32·7 to -3·1]; p=0·0241), and care by a tuberculosis specialist provider (-17·2% [-33·1 to -22·3]; p<0·0087). Longer delays were associated with an increased rate of respiratory complications even after controlling for patient characteristics, and an increased rate of secondary tuberculosis among dependents. INTERPRETATION: In the USA, the median health-care delay for privately insured patients with tuberculosis exceeds WHO-recommended levels of 21 days (3 weeks). The results suggest the need for health-care provider education on best practices in tuberculosis diagnosis, including the use of molecular tests and the maintenance of a high index of suspicion for the disease. FUNDING: US National Institutes of Health.

Community-based active case-finding interventions for tuberculosis: a systematic review. (2021). Burke RM., Nliwasa M., Feasey HRA., Chaisson LH., Golub JE., Naufal F., Shapiro AE., Ruperez M., Telisinghe L., Ayles H., Corbett EL., MacPherson P, The Lancet. Public health

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BACKGROUND: Community-based active case-finding interventions might identify and treat more people with tuberculosis disease than standard case detection. We aimed to assess whether active case-finding interventions can affect tuberculosis epidemiology in the wider community. METHODS: We did a systematic review by searching PubMed, Embase, Scopus, and Cochrane Library for studies that compared tuberculosis case notification rates, tuberculosis disease prevalence, or tuberculosis infection prevalence or incidence in children, between populations exposed and unexposed to active case-finding interventions. We included studies published in English between Jan 1, 1980, and April 13, 2020. Studies of active case-finding in the general population, in populations perceived to be at high risk for tuberculosis, and in closed settings were included, whereas studies of tuberculosis screening at health-care facilities, among household contacts, or among children only, and studies that screened fewer than 1000 people were excluded. To estimate effectiveness, we extracted or calculated case notification rates, prevalence of tuberculosis disease, and incidence or prevalence of tuberculosis infection in children, and compared ratios of these outcomes between groups that were exposed or not exposed to active case-finding interventions. RESULTS: 27 883 abstracts were screened and 988 articles underwent full text review. 28 studies contributed data for analysis of tuberculosis case notifications, nine for prevalence of tuberculosis disease, and two for incidence or prevalence of tuberculosis infection in children. In one cluster-randomised trial in South Africa and Zambia, an active case-finding intervention based on community mobilisation and sputum drop-off did not affect tuberculosis prevalence, whereas, in a cluster-randomised trial in Vietnam, an active case-finding intervention based on sputum tuberculosis tests for everyone reduced tuberculosis prevalence in the community. We found inconsistent, low-quality evidence that active case-finding might increase the number of cases of tuberculosis notified in populations with structural risk factors for tuberculosis. INTERPRETATION: Community-based active case-finding for tuberculosis might be effective in changing tuberculosis epidemiology and thereby improving population health if delivered with high coverage and intensity. If possible, active case-finding projects should incorporate a well designed, robust evaluation to contribute to the evidence base and help elucidate which delivery methods and diagnostic strategies are most effective. FUNDING: WHO Global TB Programme.

Effectiveness of low-dose theophylline for the management of biomass-associated COPD (LODOT-BCOPD): study protocol for a randomized controlled trial. (2021). Siddharthan T., Pollard SL., Jackson P., Robertson NM., Wosu AC., Rahman N., Padalkar R., Sekitoleko I., Namazzi E., Alupo P., Hurst JR., Kalyesubula R., Dowdy D., Wise R., Barnes PJ., Checkley W., Kirenga B, Trials, 22, 213

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BACKGROUND: COPD is a leading cause of death globally, with the majority of morbidity and mortality occurring in low- and middle-income country (LMIC) settings. While tobacco-smoke exposure is the most important risk factor for COPD in high-income settings, household air pollution from biomass smoke combustion is a leading risk factor for COPD in LMICs. Despite the high burden of biomass smoke-related COPD, few studies have evaluated the efficacy of pharmacotherapy in this context. Currently recommended inhaler-based therapy for COPD is neither available nor affordable in most resource-limited settings. Low-dose theophylline is an oral, once-a-day therapy, long used in high-income countries (HICs), which has been proposed for the management of COPD in LMICs in the absence of inhaled steroids and/or bronchodilators. The Low-dose Theophylline for the Management of Biomass-Associated COPD (LODOT-BCOPD) trial investigates the clinical efficacy and cost-effectiveness of low-dose theophylline for the management of biomass-related COPD in a low-income setting. METHODS: LODOT-BCOPD is a randomized, double-blind, placebo-controlled trial to test the efficacy of low-dose theophylline in improving respiratory symptoms in 110 participants with moderate to severe COPD in Central Uganda. The inclusion criteria are as follows: (1) age 40 to 80 years, (2) full-time resident of the study area, (3) daily biomass exposure, (4) post-bronchodilator FEV(1)/FVC below the 5th percentile of the Global Lung Initiative mixed ethnic reference population, and (5) GOLD Grade B-D COPD. Participants will be randomly assigned to receive once daily low-dose theophylline (200 mg ER, Unicontin-E) or placebo for 52 weeks. All participants will receive education about self-management of COPD and rescue salbutamol inhalers. We will measure health status using the St. George's Respiratory Questionnaire (SGRQ) and quality of life using the EuroQol-5D (EQ-5D) at baseline and every 6 months. In addition, we will assess household air pollution levels, serum inflammatory biomarkers (fibrinogen, hs-CRP), and theophylline levels at baseline, 1 month, and 6 months. The primary outcome is change in SGRQ score at 12 months. Lastly, we will assess the cost-effectiveness of the intervention by calculating quality-adjusted life years (QALYs) from the EQ-5D. TRIAL REGISTRATION: ClinicalTrials.gov NCT03984188 . Registered on June 12, 2019 TRIAL ACRONYM: Low-dose Theophylline for the Management of Biomass-Associated COPD (LODOT-BCOPD).

Cost-effectiveness of universal HIV testing and treatment: where next? (2021). Nachega JB., Borre ED., Dowdy DW., Chanda-Kapata P., Cleary S., Geng EH, The Lancet. Global health

Reply to: Subclinical Tuberculosis: Some Flies in the Ointment. (2021). Kendall EA., Shrestha S., Dowdy DW, American journal of respiratory and critical care medicine

Infection status of contacts is not associated with severity of TB in the index case. (2021). Baik Y., Nalutaaya A., Kitonsa PJ., Dowdy DW., Katamba A., Kendall EA, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 25, 237-240

Unhealthy alcohol use independently associated with unfavorable TB treatment outcomes among Indian men. (2021). Cox SR., Gupte AN., Thomas B., Gaikwad S., Mave V., Padmapriyadarsini C., Sahasrabudhe TR., Kadam D., Gupte N., Hanna LE., Kagal A., Paradkar M., Thiruvengadam K., Jain D., Atre S., Sekar K., Raskar S., Shivakumar SVBY., Santhappan R., Deshmukh S., Pradhan N., Kulkarni V., Kakrani A., Barthwal MS., Sawant T., DeLuca A., Suryavanshi N., Chander G., Bollinger R., Golub JE., Gupta A, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 25, 182-190

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BACKGROUND: Approximately 10% of incident TB cases worldwide are attributable to alcohol. However, evidence associating alcohol with unfavorable TB treatment outcomes is weak.METHODS: We prospectively evaluated men (≥18 years) with pulmonary TB in India for up to 24 months to investigate the association between alcohol use and treatment outcomes. Unhealthy alcohol use was defined as a score of ≥4 on the Alcohol Use Disorders Identification Test-Concise (AUDIT-C) scale at entry. Unfavorable TB treatment outcomes included failure, recurrence, and all-cause mortality, analyzed as composite and independent endpoints.RESULTS: Among 751 men, we identified unhealthy alcohol use in 302 (40%). Median age was 39 years (IQR 28-50); 415 (55%) were underweight (defined as a body mass index [BMI] <18.5 kg/m²); and 198 (26%) experienced an unfavorable outcome. Unhealthy alcohol use was an independent risk factor for the composite unfavorable outcome (adjusted incidence rate ratio [aIRR] 1.47, 95% CI 1.05-2.06; P = 0.03) and death (aIRR 1.90, 95% CI 1.08-3.34; P = 0.03), specifically. We found significant interaction between AUDIT-C and BMI; underweight men with unhealthy alcohol use had increased risk of unfavorable outcomes (aIRR 2.22, 95% CI 1.44-3.44; P < 0.001) compared to men with BMI ≥18.5 kg/m² and AUDIT-C <4.CONCLUSION: Unhealthy alcohol use was independently associated with unfavorable TB treatment outcomes, highlighting the need for integrating effective alcohol interventions into TB care.

Determining the value of TB active case-finding: current evidence and methodological considerations. (2021). Sohn H., Sweeney S., Mudzengi D., Creswell J., Menzies NA., Fox GJ., MacPherson P., Dowdy DW, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 25, 171-181

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Active case-finding (ACF) is an important component of the End TB Strategy. However, ACF is resource-intensive, and the economics of ACF are not well-understood. Data on the costs of ACF are limited, with little consistency in the units and methods used to estimate and report costs. Mathematical models to forecast the long-term effects of ACF require empirical measurements of the yield, timing and costs of case detection. Pragmatic trials offer an opportunity to assess the cost-effectiveness of ACF interventions within a 'real-world´ context. However, such analyses generally require early introduction of economic evaluations to enable prospective data collection on resource requirements. Closing the global case-detection gap will require substantial additional resources, including continued investment in innovative technologies. Research is essential to the optimal implementation, cost-effectiveness, and affordability of ACF in high-burden settings. To assess the value of ACF, we must prioritize the collection of high-quality data regarding costs and effectiveness, and link those data to analytical models that are adapted to local settings.

Quantifying the potential value of antigen-detection rapid diagnostic tests for COVID-19: a modelling analysis. (2021). Ricks S., Kendall EA., Dowdy DW., Sacks JA., Schumacher SG., Arinaminpathy N, BMC medicine, 19, 75

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BACKGROUND: Testing plays a critical role in treatment and prevention responses to the COVID-19 pandemic. Compared to nucleic acid tests (NATs), antigen-detection rapid diagnostic tests (Ag-RDTs) can be more accessible, but typically have lower sensitivity and specificity. By quantifying these trade-offs, we aimed to inform decisions about when an Ag-RDT would offer greater public health value than reliance on NAT. METHODS: Following an expert consultation, we selected two use cases for analysis: rapid identification of people with COVID-19 amongst patients admitted with respiratory symptoms in a 'hospital' setting and early identification and isolation of people with mildly symptomatic COVID-19 in a 'community' setting. Using decision analysis, we evaluated the health system cost and health impact (deaths averted and infectious days isolated) of an Ag-RDT-led strategy, compared to a strategy based on NAT and clinical judgement. We adopted a broad range of values for 'contextual' parameters relevant to a range of settings, including the availability of NAT and the performance of clinical judgement. We performed a multivariate sensitivity analysis to all of these parameters. RESULTS: In a hospital setting, an Ag-RDT-led strategy would avert more deaths than a NAT-based strategy, and at lower cost per death averted, when the sensitivity of clinical judgement is less than 90%, and when NAT results are available in time to inform clinical decision-making for less than 85% of patients. The use of an Ag-RDT is robustly supported in community settings, where it would avert more transmission at lower cost than relying on NAT alone, under a wide range of assumptions. CONCLUSIONS: Despite their imperfect sensitivity and specificity, Ag-RDTs have the potential to be simultaneously more impactful, and have a lower cost per death and infectious person-days averted, than current approaches to COVID-19 diagnostic testing.

- February 2021 -

Cost-effectiveness of scaling up short course preventive therapy for tuberculosis among children across 12 countries. (2021). Jo Y., Gomes I., Flack J., Salazar-Austin N., Churchyard G., Chaisson RE., Dowdy DW, EClinicalMedicine, 31, 100707

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BACKGROUND: While household contact investigation is widely recommended as a means to reduce the burden of tuberculosis (TB) among children, only 27% of eligible pediatric household contacts globally received preventive treatment in 2018. We assessed the cost-effectiveness of household contact investigation for TB treatment and short-course preventive therapy provision for children under 15 years old across 12 high TB burden countries. METHODS: We used decision analysis to compare the costs and estimated effectiveness of three intervention scenarios: (a) status quo (existing levels of coverage with isoniazid preventive therapy), (b) contact investigation with treatment of active TB but no additional preventive therapy, and (c) contact investigation with TB treatment and provision of short-course preventive therapy. Using country-specific demographic, epidemiological and cost data from the literature, we estimated annual costs (in 2018 USD) and the number of TB cases and deaths averted across 12 countries. Incremental cost effectiveness ratios were assessed as cost per death and per disability-adjusted life year [DALY] averted. FINDINGS: Our model estimates that contact investigation with treatment of active TB and provision of preventive therapy could be highly cost-effective compared to the status quo (ranging from $100 per DALY averted in Malawi to $1,600 in Brazil; weighted average $383 per DALY averted [uncertainty range: $248 - $1,130]) and preferred to contact investigation without preventive therapy (weighted average $751 per DALY averted [uncertainty range: $250 - $1,306]). Key drivers of cost-effectiveness were TB prevalence, sensitivity of TB diagnosis, case fatality for untreated TB, and cost of household screening. INTERPRETATION: Based on this modeling analysis of available published data, household contact investigation with provision of short-course preventive therapy for TB has a value-for-money profile that compares favorably with other interventions. FUNDING: Unitaid (2017-20-IMPAACT4TB).

Patient choice improves self-efficacy and intention to complete tuberculosis preventive therapy in a routine HIV program setting in Uganda. (2021). Lim RK., Semitala FC., Atuhumuza E., Sabiti L., Namakula-Katende J., Muyindike WR., Kamya MR., Dowdy D., Cattamanchi A, PloS one, 16, e0246113

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A 12-dose weekly regimen of rifapentine plus isoniazid (3HP) is recommended for the prevention of active tuberculosis (TB); however, it is unclear whether 3HP should be provided by directly observed therapy (DOT) or self-administered therapy (SAT). In addition, the introduction of patient informed choice between delivery modalities may have a positive impact on factors leading to treatment completion. The authors randomized 252 participants with HIV to a hypothetical scenario of providing preventive therapy by either DOT or an informed choice between DOT and SAT. Out of 104 participants who were randomized to a choice between DOT and SAT, 103 chose therapy by SAT. Participants rated their level of confidence and intention to complete therapy. Compared to those assigned to the DOT scenario, patients assigned to the choice scenario expressed greater confidence and intention to complete preventive therapy. Convenience and travel required to complete 3HP therapy were important factors in deciding between delivery modalities. Those assigned to DOT identified more barriers to completing therapy than those given a choice. Empowering patients to make informed decisions about how they receive TB preventive therapy may improve completion rates.

- 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

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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., Kamoga CE., 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

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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 Xpert MTB/RIF Ultra ("Ultra") to characterize individuals with previously-undiagnosed TB and compare 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 per 100,000; 95% confidence interval 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, 18% among TB-negative controls), TB symptom prevalence (99%/87%/60%/38%), and C-reactive protein (75 th percentile 101/28/6/4 mg/L). Community-diagnosed cases were less likely than health-facility-diagnosed cases to have HIV coinfection or previous TB. The specificity of Ultra was 99.4% (99.2-99.5%) relative to a single spot sputum culture. CONCLUSIONS: People with undiagnosed prevalent TB in the community have different characteristics that 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.

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