Browsing by Author "Dowdy, David W."
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Item Challenges with scale-up of GeneXpert MTB/RIF® in Uganda: a health systems perspective(BMC health services research, 2020) Nalugwa, Talemwa; Shete, Priya B.; Nantale, Mariam; Farr, Katherine; Ojok, Christopher; Ochom, Emma; Mugabe, Frank; Joloba, Moses; Dowdy, David W.; Moore, David A. J.; Davis, J. Lucian; Cattamanchi, Adithya; Katamba, AchillesMany high burden countries are scaling-up GeneXpert® MTB/RIF (Xpert) testing for tuberculosis (TB) using a hub-and-spoke model. However, the effect of scale up on reducing TB has been limited. We sought to characterize variation in implementation of referral-based Xpert TB testing across Uganda, and to identify health system factors that may enhance or prevent high-quality implementation of Xpert testing services. Methods: We conducted a cross-sectional study triangulating quantitative and qualitative data sources at 23 community health centers linked to one of 15 Xpert testing sites between November 2016 and May 2017 to assess health systems infrastructure for hub-and-spoke Xpert testing. Data sources included a standardized site assessment survey, routine TB notification data, and field notes from site visits. Results: Challenges with Xpert implementation occurred at every step of the diagnostic evaluation process, leading to low overall uptake of testing. Of 2192 patients eligible for TB testing, only 574 (26%) who initiated testing were referred for Xpert testing. Of those, 54 (9.4%) were Xpert confirmed positive just under half initiated treatment within 14 days (n = 25, 46%). Gaps in required infrastructure at 23 community health centers to support the huband- spoke system included lack of refrigeration (n = 14, 61%) for sputum testing and lack of telephone/mobile communication (n = 21, 91%). Motorcycle riders responsible for transporting sputum to Xpert sites operated variable with trips once, twice, or three times a week at 10 (43%), nine (39%) and four (17%) health centers, respectively. Staff recorded Xpert results in the TB laboratory register at only one health center and called patients with positive results at only two health centers. Of the 15 Xpert testing sites, five (33%) had at least one non-functioning module. The median number of tests per day was 3.57 (IQR 2.06–4.54), and 10 (67%) sites had error/invalid rates > 5%. Conclusions: Although Xpert devices are now widely distributed throughout Uganda, health system factors across the continuum from test referral to results reporting and treatment initiation preclude effective implementation of Xpert testing for patients presenting to peripheral health centers. Support for scale up of innovative technologies should include support for communication, coordination and health systems integration.Item Characterization of geographic mobility among participants in facility- and community-based tuberculosis case finding in urban Uganda(PLoS ONE, 2021) Robsky, Katherine O.; Isooba, David; Nakasolya, Olga; Mukiibi, James; Nalutaaya, Annet; Kitonsa, Peter J.; Kamoga, Caleb; Baik, Yeonsoo; Kendall, Emily A.; Katamba, Achilles; Dowdy, David W.International and internal migration are recognized risk factors for tuberculosis (TB). Geographic mobility, including travel for work, education, or personal reasons, may also play a role in TB transmission, but this relationship is poorly defined. We aimed to define geographic mobility among participants in facility- and community-based TB case finding in Kampala, Uganda, and to assess associations between mobility, access to care, and TB disease. Methods We included consecutive individuals age �15 years diagnosed with TB disease through either routine health facility practices or community-based case finding (consisting of doorto- door testing, venue-based screening, and contact investigation). Each case was matched with one (for community-based enrollment) or two (health facility enrollment) TB-negative controls. We conducted a latent class analysis (LCA) of eight self-reported characteristics to identify and define mobility; we selected the best-fit model using Bayesian Information Criterion. We assessed associations between mobility and TB case status using multivariable conditional logistic regression. Results We enrolled 267 cases and 432 controls. Cases were more likely than controls to have been born in Kampala (p<0.001); there was no difference between cases and controls for remaining mobility characteristics. We selected a two-class LCA model; the “mobile” class was perfectly correlated with a single variable: travel (>3 km) from residence 2 times per month. Mobility was associated with a 28% reduction in odds of being a TB case (adjusted matched odds ratio 0.72 [95% confidence interval 0.49, 1.06]). Conclusion Frequency of out-of-neighborhood travel is an easily measured variable that correlates closely with predicted mobility class membership. Mobility was associated with decreased risk of TB disease; this may be in part due to the higher socioeconomic status of mobile individuals in this population. However, more research is needed to improve assessment of mobility and understand how mobility affects disease risk and transmission.Item A clinical score for identifying active tuberculosis while awaiting microbiological results: Development and validation of a multivariable prediction model in sub- Saharan Africa(PLoS medicine, 2020) Baik, Yeonsoo; Rickman, Hannah M.; Hanrahan, Colleen F.; Mmolawa, Lesego; Kitonsa, Peter J.; Sewelana, Tsundzukana; Nalutaaya, Annet; Kendall, Emily A.; Lebina, Limakatso; Martinson, Neil; Katamba, Achilles; Dowdy, David W.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.Item Completion of isoniazid–rifapentine (3HP) for tuberculosis prevention among people living with HIV: Interim analysis of a hybrid type 3 effectiveness–implementation randomized trial(PLoS Med, 2021) Semitala, Fred C.; Kadota, Jillian L.; Musinguzi, Allan; Nabunje, Juliet; Welishe, Fred; Nakitende, Anne; Akello, Lydia; Kamya, Moses R.; Handley, Margaret A.; Katahoire, Anne; Berger, Christopher A.; Kiwanuka, Noah; Katamba, Achilles; Dowdy, David W.; Cattamanchi, AdithyaScaling up shorter regimens for tuberculosis (TB) prevention such as once weekly isoniazid–rifapentine (3HP) taken for 3 months is a key priority for achieving targets set forth in the World Health Organization’s (WHO) END TB Strategy. However, there are few data on 3HP patient acceptance and completion in the context of routine HIV care in sub-Saharan Africa. Methods and findings The 3HP Options Trial is a pragmatic, parallel type 3 effectiveness–implementation randomized trial comparing 3 optimized strategies for delivering 3HP—facilitated directly observed therapy (DOT), facilitated self-administered therapy (SAT), or informed choice between DOT and SAT using a shared decision-making aid—to people receiving care at a large urban HIV clinic in Kampala, Uganda. Participants and healthcare providers were not blinded to arm assignment due to the nature of the 3HP delivery strategies. We conducted an interim analysis of participants who were enrolled and exited the 3HP treatment period between July 13, 2020 and April 30, 2021. The primary outcome, which was aggregated across trial arms for this interim analysis, was the proportion who accepted and completed 3HP (�11 of 12 doses within 16 weeks of randomization). We used Bayesian inference analysis to estimate the posterior probability that this proportion would exceed 80% under at least 1 of the 3HP delivery strategies, a coprimary hypothesis of the trial. Through April 2021, 684 participants have been enrolled, and 479 (70%) have exited the treatment period. Of these 479 participants, 309 (65%) were women, mean age was 41.9 years (standard deviation (SD): 9.2), and mean time on antiretroviral therapy (ART) was 7.8 years (SD: 4.3). In total, 445 of them (92.9%, 95% confidence interval (CI): [90.2 to 94.9]) accepted and completed 3HP treatment. There were no differences in treatment acceptance and completion by sex, age, or time on ART. Treatment was discontinued due to a documented adverse event (AE) in 8 (1.7%) patients. The probability that treatment acceptance and completion exceeds 80% under at least 1 of the three 3HP delivery strategies was greater than 99%. The main limitations are that the trial was conducted at a single site, and the interim analysis focused on aggregate outcome data to maintain blinding of investigators to arm-specific outcomes. Conclusions 3HP was widely accepted by people living with HIV (PLHIV) in Uganda, and very high levels of treatment completion were achieved in a programmatic setting. These findings show that 3HP can enable effective scale-up of tuberculosis preventive therapy (TPT) in high-burden countries, particularly when delivery strategies are tailored to target known barriers to treatment completion.Item Design and execution of a public randomization ceremony to enhance stakeholder engagement within a cluster randomized trial to improve tuberculosis diagnosis in Uganda(Contemporary clinical trials communications, 2021) Reza, Tania F.; Nalugwa, Talemwa; Nantale, Mariam; Adams, Katherine; Fielding, Katherine; Nakaweesa, Annet; Oyuku, Denis; Nabwire, Sarah; Musinguzi, Johnson; Ojok, Christopher; Babirye, Diana; Ackerman, Sara L.; Handley, Margaret A.; Kityamuwesi, Alex; Dowdy, David W.; Moore, David A.J.; Davis, J. Lucian; Turyahabwe, Stavia; Katamba, Achilles; Cattamanch, AdithyaPublic randomization ceremonies have been proposed as a strategy to strengthen stakeholder engagement and address concerns and misconceptions associated with trial randomization. However, there are few published examples that describe how to conduct a public randomization ceremony with meaningful stakeholder engagement or how such ceremonies impact stakeholder perceptions about randomization and the randomization process. Cluster randomization for the GeneXpert Performance Evaluation for Linkage to Tuberculosis Care (XPEL-TB) trial was conducted at a public randomization ceremony attended by 70 stakeholders in Kampala, Uganda. Presentations given by the Acting Assistant Commissioner from the Uganda National Tuberculosis and Leprosy Programme and trial investigators emphasized how the trial aimed to further national TB goals, as well as how stakeholders contributed to the intervention design. The purpose and process of randomization were described using simple text and visuals. Randomization was an interactive activity that required participation of stakeholders from each trial site. A survey administered to stakeholders at the end of the ceremony suggested high comprehension of randomization (98%), trust in the randomization process (96%), and satisfaction with randomization outcomes (96%). Public randomization ceremonies should be considered more routinely to engage stakeholders in and address potential concerns about the fairness and impartiality of the randomization process for community-based trials.Item Empiric treatment of pulmonary TB in the Xpert era: Correspondence of sputum culture, Xpert MTB/RIF, and clinical diagnoses(PLoS ONE, 2019) Kendall, Emily A.; Kamoga, Caleb; Kitonsa, Peter J.; Nalutaaya, Annet; Salvatore, Phillip P.; Robsky, Katherine; Nakasolya, Olga; Mukiibi, James; Isooba, David; Cattamanchi, Adithya; Kato-Maeda, Midori; Katamba, Achilles; Dowdy, David W.Clinical tuberculosis diagnosis and empiric treatment have traditionally been common among patients with negative bacteriologic test results. Increasing availability of rapid molecular diagnostic tests, including Xpert MTB/RIF and the new Xpert Ultra cartridge, may alter the role of empiric treatment. Methods We prospectively enrolled outpatients age > = 15 who were evaluated for pulmonary tuberculosis at three health facilities in Kampala, Uganda. Using sputum mycobacterial culture, interviews, and clinical record abstraction, we estimated the accuracy of clinical diagnosis relative to Xpert and sputum culture and assessed the contribution of clinical diagnosis to case detection. Results Over a period of 9 months, 99 patients were diagnosed with pulmonary tuberculosis and subsequently completed sputum culture; they were matched to 196 patients receiving negative tuberculosis evaluations in the same facilities. Xpert was included in the evaluation of 291 (99%) patients. Compared to culture, Xpert had a sensitivity of 92% (95% confidence interval 83–97%) and specificity of 95% (92–98%). Twenty patients with negative Xpert were clinically diagnosed with tuberculosis and subsequently had their culture status determined; two (10%) were culture-positive. Considering all treated patients regardless of Xpert and culture data completeness, and considering treatment initiations before a positive Xpert (N = 4) to be empiric, 26/101 (26%) tuberculosis treatment courses were started empirically. Compared to sputum smear- or Xpert-positive patients with positive cultures, empiricallytreated, Xpert-negative patients with negative cultures had higher prevalence of HIV (67% versus 37%), shorter duration of cough (median 4 versus 8 weeks), and lower inflammatory markers (median CRP 7 versus 101 mg/L). Conclusion Judged against sputum culture in a routine care setting of high HIV prevalence, the accuracy of Xpert was high. Clinical judgment identified a small number of additional culture-positive cases, but with poor specificity. Although clinicians should continue to prescribe tuberculosis treatment for Xpert-negative patients whose clinical presentations strongly suggest pulmonary tuberculosis, they should also carefully consider alternative diagnoses.Item Evaluation of underweight status may improve identification of the highest-risk patients during outpatient evaluation for pulmonary tuberculosis(PLoS ONE, 2020) Kitonsa, Peter J.; Nalutaaya, Annet; Mukiibi, James; Nakasolya, Olga; Isooba, David; Kamoga, Caleb; Baik, Yeonsoo; Robsky, Katherine; Dowdy, David W.; Katamba, Achilles; Kendall, Emily A.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 areaItem Is distance associated with tuberculosis treatment outcomes? A retrospective cohort study in Kampala, Uganda(BMC infectious diseases, 2020) Robsky, Katherine O.; Hughes, Seamus; Kityamuwesi, Alex; Kendall, Emily A.; Kitonsa, Peter James; Dowdy, David W.; Katamba, AchillesChallenges accessing nearby health facilities may be a barrier to initiating and completing tuberculosis (TB) treatment. We aimed to evaluate whether distance from residence to health facility chosen for treatment is associated with TB treatment outcomes. Methods: We conducted a retrospective cohort study of all patients initiating TB treatment at six health facilities in Kampala from 2014 to 2016. We investigated associations between distance to treating facility and unfavorable TB treatment outcomes (death, loss to follow up, or treatment failure) using multivariable Poisson regression. Results: Unfavorable treatment outcomes occurred in 20% (339/1691) of TB patients. The adjusted relative risk (aRR) for unfavorable treatment outcomes (compared to treatment success) was 0.87 (95% confidence interval [CI] 0.70, 1.07) for patients living ≥2 km from the facility compared to those living closer. When we separately compared each type of unfavorable treatment outcome to favorable outcomes, those living ≥2 km from the facility had increased risk of death (aRR 1.42 [95%CI 0.99, 2.03]) but decreased risk for loss to follow-up (aRR 0.57 [95%CI 0.41, 0.78]) than those living within 2 km. Conclusions: Distance from home residence to TB treatment facility is associated with increased risk of death but decreased risk of loss to follow up. Those who seek care further from home may have advanced disease, but once enrolled may be more likely to remain in treatment.Item Opportunities and Challenges for Cost-Efficient Implementation of New Point-of-Care Diagnostics for HIV and Tuberculosis(Journal of Infectious Diseases, 2012) Schito, Marco; Peter, Trevor F.; Cavanaugh, Sean; Piatek, Amy S.; Young, Gloria J.; Alexander, Heather; Coggin, William; Domingo, Gonzalo J.; Ellenberger, Dennis; Ermantraut, Eugen; Jani, Ilesh V.; Katamba, Achilles; Palamountain, Kara M.; Essajee, Shaffiq; Dowdy, David W.Stakeholders agree that supporting high-quality diagnostics is essential if we are to continue to make strides in the fight against human immunodeficiency virus (HIV) and tuberculosis. Despite the need to strengthen existing laboratory infrastructure, which includes expanding and developing new laboratories, there are clear diagnostic needs where conventional laboratory support is insufficient. Regarding HIV, rapid point-of-care (POC) testing for initial HIV diagnosis has been successful, but several needs remain. For tuberculosis, several new diagnostic tests have recently been endorsed by the World Health Organization, but a POC test remains elusive. Human immunodeficiency virus and tuberculosis are coendemic in many high prevalence locations, making parallel diagnosis of these conditions an important consideration. Despite its clear advantages, POC testing has important limitations, and laboratory-based testing will continue to be an important component of future diagnostic networks. Ideally, a strategic deployment plan should be used to define where and how POC technologies can be most efficiently and cost effectively integrated into diagnostic algorithms and existing test networks prior to widespread scale-up. In this fashion, the global community can best harness the tremendous capacity of novel diagnostics in fighting these 2 scourges.Item Quality of care for patients evaluated for tuberculosis in the context of Xpert MTB/RIF scale-up(Journal of clinical tuberculosis and other mycobacterial diseases, 2019) Farra, Katherine; Nalugwa, Talemwa; Ojok, Christopher; Nantale, Mariam; Nabwire, Sarah; Oyuku, Denis; Shete, Priya B.; Han, Alvina H.; Fielding, Katherine; Joloba, Moses; Mugabe, Frank; Dowdy, David W.; Mooreh, DAJ; Davis, Lucian; Katamba, Achilles; Cattamanchi, AdithyaMany high-burden countries are scaling-up Xpert MTB/RIF using a hub-and-spoke model. We evaluated the quality of care for patients undergoing TB evaluation at microscopy centers (spokes) linked to Xpert testing sites (hubs) in Uganda. Objectives: To characterize the extent to which patients were receiving care in accordance with international and national guidelines. Methods: We conducted a prospective cohort study of all adults with presumptive pulmonary TB at 24 health centers linked to Xpert testing sites. Health center staff photographed TB registers, and uploaded photos to a secure server bi-weekly. We assessed the proportion of patients (1) initiating testing; (2) completing testing; and (3) treated for confirmed TB within 14 days. Measurements and Main Results: Between January to December 2017, 6744 patients underwent evaluation for pulmonary TB. Only 1316 patients had sputum referred for Xpert testing, including 1075/3229 (33.3%) people living with HIV and 241/3515 (6.9%) without HIV. Of 119 patients confirmed to have TB by Xpert testing, 44 (36%) did not initiate treatment. There were significant losses along the entire diagnostic cascade of care, with only 5330/6744 (79.0%) patients having samples referred for sputum-based testing, 2978/5330 (55.9%) patients completing recommended testing if referred, and 313/418 (74.9%) patients initiating treatment within 14 days if confirmed to have TB. Conclusions: Although coverage of Xpert testing services across Uganda is high, the quality of care delivered to patients undergoing TB evaluation remains poor. Further research is needed to identify health system interventions to facilitate uptake of Xpert testing and high-quality care.Item The Spectrum of Tuberculosis Disease in an Urban Ugandan Community and Its Health Facilities(Clinical Infectious Diseases, 2021) Kendall, Emily A.; Kitonsa, Peter J.; Nalutaaya, Annet; Erisa, Caleb; Mukiibi, James; Nakasolya, Olga; Isooba, David; Baik, Yeonsoo; Robsky, Katherine O.; Kato-Maeda, Midori; Cattamanchi, Adithya; Katamba, Achilles; Dowdy, David W.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. Keywords. active case-finding; Xpert MTB/RIF Ultra; subclinical tuberculosis; prevalent tuberculosis.Item Test and Treat: A New Standard for Smear-Positive Tuberculosis(Journal of acquired immune deficiency syndromes, 2012) Davis, J. Lucian; Dowdy, David W.; Boon, Saskia den; Walter, Nicholas D.; Katamba, Achilles; Cattamanchi, AdithyaOptimizing sputum smear microscopy, the principal method of tuberculosis (TB) diagnosis in high-burden settings around the world, is a critical priority for global TB control. To improve rates of testing, completion, and reporting, the World Health Organization (WHO) recently endorsed a policy of same-day diagnosis of TB by microscopy. Unfortunately, the implementation of this policy has emphasized same-day sputum collection alone, with patients required to return on a subsequent day to collect results. We use a simple decision analysis to demonstrate that the timing of results reporting has a greater impact on treatment initiation for smear-positive TB cases than the timing of specimen collection. Same-day diagnosis of smear-positive TB, including sputum collection and reporting of smear results, should be the new global standard.