TB Modeling and Translational Epi Group

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- November 2019 -

Correction: Smoking, alcohol use disorder and tuberculosis treatment outcomes: A dual co-morbidity burden that cannot be ignored. (2019). Thomas BE., Thiruvengadam K., S R., Kadam D., Ovung S., Sivakumar S., Yogendra Shivakumar SVB., Paradkar M., Gupte N., Suryavanshi N., Dolla CK., Gupte AN., Kohli R., Pradhan N., Sivaramakrishnan GN., Gaikwad S., Kagal A., Dhanasekaran K., Deluca A., Golub JE., Mave V., Chandrasekaran P., Gupta A, PloS one, 14, e0224914

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[This corrects the article DOI: 10.1371/journal.pone.0220507.].

- October 2019 -

Incidence of tuberculosis in HIV-infected adults on first- and second-line antiretroviral therapy in India. (2019). Gupte AN., Kadam D., Sangle S., Rewari BB., Salvi S., Chavan A., Nimkar S., Golub J., Gupte N., Gupta A., Marbaniang I., Mave V, BMC infectious diseases, 19, 914

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BACKGROUND: Programmatic data on the baseline risk of tuberculosis in people living with HIV (PLHIV) are needed to evaluate long-term effectiveness of the ongoing isoniazid preventive therapy (IPT) roll-out in India. METHODS: We estimated the incidence rate and risk factors of tuberculosis disease in adult PLHIV initiating first- and second-line anti-retroviral therapy (ART) prior to widespread IPT in a public ART center in Pune, India. RESULTS: 4067 participants contributing 5205.7 person-years of follow-up on first-line ART and 871 participants contributing 1031.7 person-years of follow-up on second-line ART were included in the analysis. The incidence rate of tuberculosis was 4.39 cases (95%CI 3.86-5.00) per 100 person-years on first-line ART and 1.64 cases (95%CI 1.01-2.63) per 100 person-years on second-line ART (p < 0.001). After adjusting for competing risks, male sex (aSHR = 1.33, 95%CI 1.02-1.74, p = 0.03), urban residence (aSHR = 1.53, 95%CI 1.13-2.07, p = 0.006) and CD4+ counts < 350 cells/mm(3) (aSHR = 3.06 vs CD4 > 350 cells/mm(3), 95%CI 1.58-5.94, p < 0.001) at ART initiation were associated with higher risk of tuberculosis independent of ART regimen. CONCLUSION: Risk of tuberculosis was lower in PLHIV receiving second-line ART compared to first-line ART. Prioritizing IPT in PLHIV with low CD4+ counts, urban residence and in males may further mitigate the risk of tuberculosis during ART.

CD4 count stratification to guide tuberculosis preventive therapy for people living with HIV. (2019). Chaisson LH., Saraceni V., Cohn S., Seabrook D., Cavalcante S., Chaisson RE., Golub J., Durovni B, AIDS (London, England)

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OBJECTIVES: In 2018, Brazilian guidelines changed to recommend tuberculosis (TB) preventive therapy for all people with HIV and a CD4 350 cells/muL. We determined the potential effectiveness of CD4-based guidelines for TB testing and preventive therapy. DESIGN: Secondary analysis of the stepped-wedge, cluster-randomized THRio trial for isoniazid preventive therapy (IPT). METHODS: We analyzed data from 4,114 newly-registered patients with HIV in 29 clinics followed until TB diagnosis, death, or administrative censoring. We compared incidence rates of TB and TB/death between CD4, TST, IPT, and antiretroviral therapy (ART) categories. RESULTS: Initial CD4 count was 350 in 1,976 (48%) patients. TST was performed for 2,922 (71%), of whom 657 (16%) were TST-positive (278 [13%] CD4 350). A total of 619 (15%) received IPT and 2,806 (68%) received ART. For patients with CD4 350 who did not receive IPT, the incidence rates of TB and TB/death were 0.57/100pys and 1.49/100pys for TST-negatives, and 1.05/100pys and 1.64/100pys for TST-unknowns. CONCLUSIONS: TB incidence was high among all patients who did not receive IPT, including those with CD4> 350 and negative or unknown TST results. TB preventive therapy should be provided to all PLWH in medium burden settings, regardless of CD4 count and TST status.

Implementation of Xpert((R)) MTB/RIF: real challenges, real promise. (2019). Dowdy DW, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 23, 1123

Delays and barriers to early treatment initiation for childhood tuberculosis in India. (2019). Valvi C., Chandanwale A., Khadse S., Kulkarni R., Kadam D., Kinikar A., Joshi S., Lokhande R., Pardeshi G., Garg P., Gupte N., Jain D., Suryavanshi N., Golub JE., Shankar A., Gupta A., Dhumal G., Deluca A., Bollinger RC, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 23, 1090-1099

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BACKGROUND: India accounts for 27% of global childhood tuberculosis (TB) burden. Understanding barriers to early diagnosis and treatment in children may improve care and outcomes.METHODS: A cross-sectional study was performed among 89 children initiated on anti-TB treatment from a public hospital in Pune during 2016, using a structured questionnaire and hospital records. Health care providers (HCPs) were defined as medical personnel consulted about the child's TB symptoms. Time-to-treatment initiation (TTI) was defined as the number of days between onset of TB symptoms and anti-TB treatment initiation. Based on Revised National TB Control Programme recommendations, delayed TTI was defined as >28 days.RESULTS: Sixty-seven (75%) of 89 enrolled children had significant TTI delays (median 51 days, interquartile range [IQR] 27-86). Sixty-six (74%) children visited 1-8 HCPs in the private sector before approaching the public sector. The median HCP delay was 28 days (IQR 10-75). Bacille Calmette-Guerin vaccination (aOR 10.96, P = 0.04) and loss of appetite (aOR 4.44, P = 0.04) were associated with delayed TTI.CONCLUSION: The majority of the children had TTI delays due to delays by HCPs in the private sector. Strengthening HCP competency in TB symptom screening and encouraging early referrals are crucial for rapid scaling up of early treatment initiation in childhood TB.

Comparative Modelling of Tuberculosis Epidemiology and Policy Outcomes in California. (2019). Menzies NA., Parriott A., Shrestha S., Dowdy DW., Cohen T., Salomon JA., Marks SM., Hill AN., Winston CA., Asay G., Barry P., Readhead A., Flood J., Kahn JG., Shete PB, American journal of respiratory and critical care medicine

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Rationale Mathematical modelling is used to understand disease dynamics, forecast trends, and inform public health prioritization. We conducted a comparative analysis of tuberculosis (TB) epidemiology and potential intervention effects in California, using three previously developed epidemiologic models of TB. Measurements and Methods We compared model results between 2005 and 2050 under a base case scenario representing current TB services, and alternative scenarios including: (i) sustained interruption of Mycobacterium tuberculosis (Mtb) transmission, (ii) sustained resolution of latent TB infection (LTBI) and TB prior to entry of new residents, and (iii) one-time targeted testing and treatment of LTBI among 25% of non-US-born individuals residing in California. Results Model estimates of TB cases and deaths in California were in close agreement over the historical period but diverged for LTBI prevalence and new Mtb infections-outcomes for which definitive data are unavailable. Between 2018 and 2050, models projected average annual declines of 0.58-1.42% in TB cases, without additional interventions. A one-time LTBI testing and treatment intervention among non-US-born residents was projected to produce sustained reductions in TB incidence. Models found prevalent Mtb infection and migration to be more significant drivers of future TB incidence than local transmission. Conclusions All models projected a stagnation in the decline of TB incidence, highlighting the need for additional interventions including greater access to LTBI diagnosis and treatment for non-US-born individuals. Differences in model results reflect gaps in historical data and uncertainty in the trends of key parameters, demonstrating the need for high-quality, up-to-date TB determinant and outcome data.

Clinical Consequences of Using an Indeterminate Range for Early Infant Diagnosis of HIV: A Decision Model. (2019). Salvatore P., Johnson K., Vojnov L., Doherty M., Dowdy D, Journal of acquired immune deficiency syndromes (1999), 82, 287-296

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BACKGROUND: To minimize false-positive diagnoses of HIV in exposed infants, the World Health Organization recommends confirmatory testing for all infants initiating antiretroviral therapy (ART). In settings where confirmatory testing is not feasible or intermittently performed, clinical decisions may be aided by semi-quantitative cycle thresholds (Cts) that identify positive results most likely to be false-positive. METHODS: We developed a decision analysis model of HIV-exposed infants in sub-Saharan Africa to estimate the clinical consequences of deferring ART for infants with weakly positive ("indeterminate") results. We assessed the degree to which "indeterminate" results may reduce the number of infants starting ART unnecessarily while missing a small number of HIV-infected infants. Our primary outcome was the ratio of averted unnecessary ART regimens to additional HIV-related deaths (due to false-negative diagnosis) at different Ct cutoffs. RESULTS: The clinical consequences of adopting an indeterminate range varied with the prevalence of HIV and Ct cutoff. Considering a Ct cutoff >/=33, adopting an indeterminate range could prevent a median of 1.4 infants from receiving ART unnecessarily (95% UR: 1.0-2.0) for each additional HIV-related death. This ratio could be improved by prioritizing infants with indeterminate results for confirmatory testing [median 8.8 (95% UR: 6.0-13.3)] and by adopting a higher cutoff [median 82.3 (95% UR: 49.0-155.8) with Ct >/=36]. CONCLUSIONS: When implemented in settings where confirmatory testing is not universal, the benefits of classifying weakly positive results as "indeterminate" may outweigh the risks. Accordingly, the World Health Organization has recommended Ct values >/=33 be considered indeterminate for infant HIV diagnosis.

Ending the HIV Epidemic: Towards an Evidence-Based Approach. (2019). Fojo AT., Dowdy DW, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America

Guidance for Studies Evaluating the Accuracy of Tuberculosis Triage Tests. (2019). Nathavitharana RR., Yoon C., Macpherson P., Dowdy DW., Cattamanchi A., Somoskovi A., Broger T., Ottenhoff THM., Arinaminpathy N., Lonnroth K., Reither K., Cobelens F., Gilpin C., Denkinger CM., Schumacher SG, The Journal of infectious diseases, 220, S116-S125

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Approximately 3.6 million cases of active tuberculosis (TB) go potentially undiagnosed annually, partly due to limited access to confirmatory diagnostic tests, such as molecular assays or mycobacterial culture, in community and primary healthcare settings. This article provides guidance for TB triage test evaluations. A TB triage test is designed for use in people with TB symptoms and/or significant risk factors for TB. Triage tests are simple and low-cost tests aiming to improve ease of access and implementation (compared with confirmatory tests) and decrease the proportion of patients requiring more expensive confirmatory testing. Evaluation of triage tests should occur in settings of intended use, such as community and primary healthcare centers. Important considerations for triage test evaluation include study design, population, sample type, test throughput, use of thresholds, reference standard (ideally culture), and specimen flow. The impact of a triage test will depend heavily on issues beyond accuracy, primarily centered on implementation.

Adherence to tuberculosis preventive therapy measured by urine metabolite testing among people with HIV. (2019). Kendall EA., Durovni B., Martinson NA., Cavalacante S., Masonoke K., Saraceni V., Lebina L., Efron A., Cohn S., Chon S., Chaisson RE., Dowdy DW., Golub JE, AIDS (London, England)

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OBJECTIVES: Tuberculosis preventive therapy for people living with HIV is effective, widely recommended, and increasingly prescribed, but completion rates are less than ideal, and adherence is not typically monitored. We sought to quantify adherence to isoniazid preventive therapy using a urine metabolite assay. DESIGN: Two cross-sectional surveys SETTING:: Rio de Janeiro, Brazil, 2008-2009; and Northwest Province, South Africa, 2018-2019 PARTICIPANTS:: 203 Brazilian and 93 South African patients attending HIV clinics with active prescriptions for isoniazid preventive therapy MAIN OUTCOME MEASURES:: Self-reported isoniazid adherence, paired with semiquantitative measurement of urine isoniazid metabolites. RESULTS: By self-report, 90% of patients (95% confidence interval [CI] 86-93%) reported having taken a dose of isoniazid on the day of enrollment or the preceding day, and 91% (95% CI 87-94%) reported missing an average of one dose or fewer per week. By urine testing, only 65% (95% CI 59-70%) of all patients, and 69% (95% CI 63-74%) of those who reported having taken isoniazid on the current or preceding day, had detectable urine metabolites (expected in 95% of patients at 24 hours). Longer time since starting preventive therapy was independently associated with a negative urine test for isoniazid metabolites (adjusted prevalence ratio 1.11 per month of isoniazid, 95% CI 1.05-1.18). CONCLUSIONS: Adherence to isoniazid preventive therapy among patients with HIV in Brazil and South Africa is inadequate, is overestimated by self-report, and declines with time on treatment. Shorter regimens for TB preventive therapy may improve adherence and completion, but adherence support for all patients may be necessary.

- September 2019 -

Promoting Tuberculosis Preventive Therapy for People Living with HIV in South Africa: Interventions Hindered by Complicated Clinical Guidelines and Imbalanced Patient-Provider Dynamics. (2019). Jarrett BA., Woznica DM., Tilchin C., Mpungose N., Motlhaoleng K., Golub JE., Martinson NA., Hanrahan CF, AIDS and behavior

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Isoniazid preventive therapy (IPT) reduces the risk of active tuberculosis among people living with HIV, but implementation of IPT in South Africa and elsewhere remains slow. The objective of this study was to examine both nurse perceptions of clinical mentorship and patient perceptions of in-queue health education for promoting IPT uptake in Potchefstroom, South Africa. We measured adoption, fidelity, acceptability, and sustainability of the interventions using both quantitative and qualitative methods. Adoption, fidelity, and acceptability of the interventions were moderately high. However, nurses believed they could not sustain their increased prescriptions of IPT, and though many patients intended to ask nurses about IPT, few did. Most patients attributed their behavior to an imbalance of patient-provider power. National IPT guidelines should be unambiguous and easily implemented after minimal training on patient eligibility and appropriate medication durations, nurse-patient dynamics should empower the patient, and district-level support and monitoring should be implemented.

Estimating the impact of a novel drug regimen for treatment of tuberculosis: a modeling analysis of projected patient outcomes and epidemiological considerations. (2019). Kendall EA., Malhotra S., Cook-Scalise S., Denkinger CM., Dowdy DW, BMC infectious diseases, 19, 794

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BACKGROUND: Regimens that could treat both rifampin-resistant (RR) and rifampin-susceptible tuberculosis (TB) while shortening the treatment duration have reached late-stage clinical trials. Decisions about whether and how to implement such regimens will require an understanding of their likely clinical impact and how this impact depends on local epidemiology and implementation strategy. METHODS: A Markov state-transition model of 100,000 representative South African adults with TB was used to simulate implementation of the regimen BPaMZ (bedaquiline, pretomanid, moxifloxacin, and pyrazinamide), either for RR-TB only or universally for all patients. Patient outcomes, including cure rates, time with active TB, and time on treatment, were compared to outcomes under current care. Sensitivity analyses varied the drug-resistance epidemiology, rifampin susceptibility testing practices, and regimen efficacy. RESULTS: Using BPaMZ exclusively for RR-TB increased the proportion of all RR-TB that was cured by initial treatment from 60 +/- 1% to 67 +/- 1%. Expanding use of BPaMZ to all patients increased cure of RR-TB to 89 +/- 1% and cure of all TB from 87.3 +/- 0.1% to 89.5 +/- 0.1%, while shortening treatment by 1.9 months/person. In sensitivity analyses, reducing the coverage of rifampin susceptibility testing resulted in lower projected proportions of patients cured under all regimen scenarios (current care, RR-only BPaMZ, and universal BPaMZ), compared to the proportions projected using South Africa's high coverage; however, this reduced coverage resulted in greater expected incremental benefits of universal BPaMZ implementation, both when compared to RR-only BPaMZ implementation and when compared to to current care under the same low rifampin susceptibility testing coverage. In settings with higher RR-TB prevalence, the benefits of BPaMZ were magnified both for RR-specific and universal BPaMZ implementation. CONCLUSIONS: Novel regimens such as BPaMZ could improve RR-TB outcomes and shorten treatment for all patients, particularly with universal use. Decision-makers weighing early options for implementing such regimens at scale will want to consider the expected impact on patient outcomes and on the burden of treatment in their local context.

- August 2019 -

Tuberculosis fatality rates in the city of Campinas - Sao Paulo, Brazil, from 2001 to 2009. (2019). Oliveira HB., Marin-Leon L., Saita NM., Golub JE, Revista brasileira de epidemiologia = Brazilian journal of epidemiology, 22, e190043

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INTRODUCTION: The mortality rate among tuberculosis patients (TB fatality) has been attributed to irregular chemotherapy, delay in diagnosis, multidrug resistance, and HIV coinfection. OBJECTIVE: To analyze TB fatality rates by sex, clinical presentation and HIV coinfection in Campinas, Sao Paulo, Brazil. METHODS: Cohorts of residents in the city of Campinas who either died during treatment for tuberculosis or had the disease confirmed after death were divided into three intervals: 2001-2003, 2004-2006, and 2007-2009. Data were obtained from the database of the Tuberculosis Surveillance System of the University of Campinas, and notifications were gathered through TB-WEB Health Sao Paulo Secretary. Statistical significance was determined using a chi-square test, considering p < 0.05. RESULTS: Between 2001 and 2009, 3,416 TB patients were diagnosed: 2,827 (82.8%) were new TB cases and 589 (17.2%) were retreatments. Between the first and second triennium, the number of new patients decreased by 18%, and 23% among retreatments. Between the second and third intervals, the reduction was 5% and 21%, respectively. General case fatality rate declined from 11.4% to 9.9% across intervals, and was most significant among patients that had previously abandoned treatment (17.3% to 5.1%). Fatality rates among patients coinfected with TB-AIDS were 2-3 times that of patients not infected with TB-AIDS throughout the intervals. Fatality between the first and third triennium among TB-AIDS co-infected patients declined (24.8% to 19.5%), while increasing slightly among non-AIDS TB patients (7.3% to 8%) during this period. CONCLUSION: Though mortality among TB-AIDS patients declined from 2001-2009, rates among non-AIDS TB remained stagnant. Improved TB diagnosis and treatment is needed to further decrease TB mortality in Campinas.

Mobile phone access and comfort: implications for HIV and tuberculosis care in India and South Africa. (2019). Cox SN., Elf JL., Lokhande R., Ogale YP., DiAndreth L., Dupuis E., Milovanovic M., Mpungose N., Mave V., Suryavanshi N., Gupta A., Martinson N., Golub JE., Mathad JS, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 23, 865-872

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SETTING: India and South Africa shoulder the greatest burden of tuberculosis (TB) and human immunodeficiency virus (HIV) infection respectively, but care retention is suboptimal.OBJECTIVE: We conducted a study in Pune, India, and Matlosana, South Africa, 1) to identify the factors associated with mobile phone access and comfort of use, 2) to assess access patterns.DESIGN: A cross-sectional study assessed mobile phone access, and comfort; a longitudinal study assessed access patterns.RESULTS: We enrolled 261 participants: 136 in India and 125 in South Africa. Between 1 week and 6 months, participant contact decreased from 90% (n = 122) to 57% (n = 75) in India and from 93% (n = 116) to 70% (n = 88) in South Africa. In the latter, a reason for a clinic visit for HIV management was associated with 63% lower odds of contact than other priorities (e.g., diabetes mellitus, maternal health, TB). In India, 57% (n = 78) reported discomfort with texting; discomfort was higher in the unemployed (adjusted OR [aOR] 4.97, 95%CI 1.12-22.09) and those aged >/=35 years (aOR 1.10, 95%CI 1.04-1.16) participants, but lower in those with higher education (aOR 0.04, 95% CI 0.01-1.14). In South Africa, 91% (n = 114) reported comfort with texting.CONCLUSION: Mobile phone contact was poor at 6 months. While mHealth could transform TB-HIV care, alternative approaches may be needed for certain subpopulations.

Informing decision-making for universal access to quality tuberculosis diagnosis in India: an economic-epidemiological model. (2019). Sohn H., Kasaie P., Kendall E., Gomez GB., Vassall A., Pai M., Dowdy D, BMC medicine, 17, 155

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BACKGROUND: India and many other high-burden countries have committed to providing universal access to high-quality diagnosis and drug susceptibility testing (DST) for tuberculosis (TB), but the most cost-effective approach to achieve this goal remains uncertain. Centralized testing at district-level hub facilities with a supporting sample transport network can generate economies of scale, but decentralization to the peripheral level may provide faster diagnosis and reduce losses to follow-up (LTFU). METHODS: We generated functions to evaluate the costs of centralized and decentralized molecular testing for tuberculosis with Xpert MTB/RIF (Xpert), a WHO-endorsed test which can be performed at centralized and decentralized levels. We merged the cost estimates with an agent-based simulation of TB transmission in a hypothetical representative region in India to assess the impact and cost-effectiveness of each strategy. RESULTS: Compared against centralized Xpert testing, decentralization was most favorable when testing volume at decentralized facilities and pre-treatment LTFU were high, and specimen transport network was exclusively established for TB. Assuming equal quality of centralized and decentralized testing, decentralization was cost-saving, saving a median $338,000 (interquartile simulation range [IQR] - $222,000; $889,000) per 20 million people over 10 years, in the most cost-favorable scenario. In the most cost-unfavorable scenario, decentralized testing would cost a median $3161 [IQR $2412; $4731] per disability-adjusted life year averted relative to centralized testing. CONCLUSIONS: Decentralization of Xpert testing is likely to be cost-saving or cost-effective in most settings to which these simulation results might generalize. More decentralized testing is more cost-effective in settings with moderate-to-high peripheral testing volumes, high existing clinical LTFU, inability to share specimen transport costs with other disease entities, and ability to ensure high-quality peripheral Xpert testing. Decision-makers should assess these factors when deciding whether to decentralize molecular testing for tuberculosis.

Home-based tuberculosis contact investigation in Uganda: a household randomised trial. (2019). Davis JL., Turimumahoro P., Meyer AJ., Ayakaka I., Ochom E., Ggita J., Mark D., Babirye D., Okello DA., Mugabe F., Fair E., Vittinghoff E., Armstrong-Hough M., Dowdy D., Cattamanchi A., Haberer JE., Katamba A, ERJ open research, 5

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Introduction: The World Health Organization (WHO) recommends household tuberculosis (TB) contact investigation in low-income countries, but most contacts do not complete a full clinical and laboratory evaluation. Methods: We performed a randomised trial of home-based, SMS-facilitated, household TB contact investigation in Kampala, Uganda. Community health workers (CHWs) visited homes of index patients with pulmonary TB to screen household contacts for TB. Entire households were randomly allocated to clinic (standard-of-care) or home (intervention) evaluation. In the intervention arm, CHWs offered HIV testing to adults; collected sputum from symptomatic contacts and persons living with HIV (PLWHs) if >/=5 years; and transported sputum for microbiologic testing. CHWs referred PLWHs, children <5 years, and anyone unable to complete sputum testing to clinic. Sputum testing results and/or follow-up instructions were returned by automated SMS texts. The primary outcome was completion of a full TB evaluation within 14 days; secondary outcomes were TB and HIV diagnoses and treatments among screened contacts. Results: There were 471 contacts of 190 index patients allocated to the intervention and 448 contacts of 182 index patients allocated to the standard-of-care. CHWs identified 190/471 (40%) intervention and 213/448 (48%) standard-of-care contacts requiring TB evaluation. In the intervention arm, CHWs obtained sputum from 35/91 (39%) of sputum-eligible contacts and SMSs were sent to 95/190 (50%). Completion of TB evaluation in the intervention and standard-of-care arms at 14 days (14% versus 15%; difference -1%, 95% CI -9% to 7%, p=0.81) and yields of confirmed TB (1.5% versus 1.1%, p=0.62) and new HIV (2.0% versus 1.8%, p=0.90) diagnoses were similar. Conclusions: Home-based, SMS-facilitated evaluation did not improve completion or yield of household TB contact investigation, likely due to challenges delivering the intervention components.

Smoking, alcohol use disorder and tuberculosis treatment outcomes: A dual co-morbidity burden that cannot be ignored. (2019). Thomas BE., Thiruvengadam K., S R., Kadam D., Ovung S., Sivakumar S., Bala Yogendra Shivakumar SV., Paradkar M., Gupte N., Suryavanshi N., Dolla CK., Gupte AN., Kohli R., Pradhan N., Sivaramakrishnan GN., Gaikwad S., Kagal A., Dhanasekaran K., Deluca A., Golub JE., Mave V., Chandrasekaran P., Gupta A, PloS one, 14, e0220507

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BACKGROUND: More than 20% of tuberculosis (TB) disease worldwide may be attributable to smoking and alcohol abuse. India is the second largest consumer of tobacco products, a major consumer of alcohol particularly among males, and has the highest burden of TB globally. The impact of increasing tobacco dose, relevance of alcohol misuse and past versus current or never smoking status on TB treatment outcomes remain inadequately defined. METHODS: We conducted a multi-centric prospective cohort study of newly diagnosed adult pulmonary TB patients initiated on TB treatment and followed for a minimum of 6 months to assess the impact of smoking status with or without alcohol abuse on treatment outcomes. Smokers were defined as never smokers, past smokers or current smokers. Alcohol Use Disorder Identification Test (AUDIT) scores were used to assess alcohol misuse. The association between smoking status and treatment outcomes was assessed in univariate and multivariate random effects poisson regression models. RESULTS: Of 455 enrolled, 129 (28%) had a history of smoking with 94 (20%) current smokers and 35 (8%) past smokers. Unfavourable treatment outcomes were significantly higher among past and current smokers as compared to never smokers. Specifically, the risk of treatment failure was significantly higher among past smokers (aIRR = 2.66, 95% CI: 1.41-4.90, p = 0.002), recurrent TB among current smokers (aIRR = 2.94, 95% CI: 1.30-6.67, p = 0.010) and death among both past (2.63, 95% CI: 1.11-6.24, p = 0.028) and current (aIRR = 2.59, 95% CI: 1.29-5.18, p = 0.007) smokers. Furthermore, the combined effect of alcohol misuse and smoking on unfavorable treatment outcomes was significantly higher among past smokers (aIRR: 4.67, 95% CI: 2.17-10.02, p<0.001) and current smokers (aIRR: 3.58, 95% CI: 1.89-6.76, p<0.001). CONCLUSION: Past and current smoking along with alcohol misuse have combined effects on increasing the risk of unfavourable TB treatment outcomes. Innovative interventions that can readily address both co-morbidities are urgently needed.

70 years of TB Prevention: Efficacy, Effectiveness, Toxicity, Durability and Duration. (2019). Salazar-Austin N., Dowdy DW., Chaisson RE., Golub JE, American journal of epidemiology

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Tuberculosis (TB) has been a leading infectious cause of death worldwide for much of human history with 1.6 million deaths estimated in 2017. The Department of Epidemiology at the Johns Hopkins Bloomberg School of Public Health has played an important role in understanding and responding to TB, and has made particularly substantial contributions to prevention of TB with chemoprophylaxis. TB preventive therapy is highly efficacious in the prevention of TB disease, yet remains underutilized by TB programs worldwide despite strong evidence to support its use in high-risk groups including people living with HIV and household contacts, including those under 5 years of age. We review the evidence for TB preventive therapy and discuss the future of TB prevention.

- July 2019 -

Empiric treatment of pulmonary TB in the Xpert era: Correspondence of sputum culture, Xpert MTB/RIF, and clinical diagnoses. (2019). Kendall EA., Kamoga C., Kitonsa PJ., Nalutaaya A., Salvatore PP., Robsky K., Nakasolya O., Mukiibi J., Isooba D., Cattamanchi A., Kato-Maeda M., Katamba A., Dowdy DW, PloS one, 14, e0220251

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BACKGROUND: 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, empirically-treated, 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.

Infection free "resisters" among household contacts of adult pulmonary tuberculosis. (2019). Mave V., Chandrasekaran P., Chavan A., Shivakumar SVBY., Danasekaran K., Paradkar M., Thiruvengadam K., Kinikar A., Murali L., Gaikwad S., Hanna LE., Kulkarni V., Pattabiraman S., Suryavanshi N., Thomas B., Kohli R., Sivaramakrishnan GN., Pradhan N., Bhanu B., Kagal A., Golub J., Gandhi N., Gupte A., Gupte N., Swaminathan S., Gupta A, PloS one, 14, e0218034

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Despite substantial exposure to infectious pulmonary tuberculosis (TB) cases, some household contacts (HHC) never acquire latent TB infection (LTBI). Characterizing these "resisters" can inform who to study immunologically for the development of TB vaccines. We enrolled HHCs of culture-confirmed adult pulmonary TB in India who underwent LTBI testing using tuberculin skin test (TST) and QuantiFERON TB Gold Test-in-tube (QFT-GIT) at baseline and, if negative by both (<5mm TST and <0.35IU/mL QFT-GIT), underwent follow-up testing at 4-6 and/or 12 months. We defined persons with persistently negative LTBI tests at both baseline and followup as pLTBI- and resisters as those who had a high exposure to TB using a published score and remained pLTBI-. We calculated the proportion of resisters overall and resisters with complete absence of response to LTBI tests (0mm TST and/or QFT-GIT <0.01 IU/ml). Using random effects Poisson regression, we assessed factors associated with pLTBI-. Of 799 HHCs in 355 households, 67 (8%) were pLTBI- at 12 months; 52 (6.5%) pLTBI- in 39 households were resisters. Complete absence of response to LTBI tests was found in 27 (53%) resisters. No epidemiological characteristics were associated with the pLTBI- phenotype. LTBI free resisters among HHC exist but are uncommon and are without distinguishing epidemiologic characteristics. Assessing the genetic and immunologic features of such resister individuals is likely to elucidate mechanisms of protective immunity to TB.

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