TB Modeling and Translational Epi Group

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- March 2019 -

Gonorrhoea and chlamydia diagnosis as an entry point for HIV pre-exposure prophylaxis: a modelling study. (2019). Kasaie P., Schumacher CM., Jennings JM., Berry SA., Tuddenham SA., Shah MS., Rosenberg ES., Hoover KW., Gift TL., Chesson H., German D., Dowdy DW, BMJ open, 9, e023453

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OBJECTIVES: Neisseria gonorrhoeae (NG) and Chlamydia trachomatis (CT) increase the risk of HIV transmission among men who have sex with men (MSM). Diagnosis of NG/CT may provide an efficient entry point for prevention of HIV through the delivery of pre-exposure prophylaxis (PrEP); however, the additional population-level impact of targeting PrEP to MSM diagnosed with NG/CT is unknown. DESIGN: An agent-based simulation model of NG/CT and HIV cocirculation among MSM calibrated against census data, disease surveillance reports and the US National HIV Behavioral Surveillance study. SETTING: Baltimore City, Maryland, USA. INTERVENTIONS: PrEP implementation was modelled under three alternative scenarios: (1) PrEP delivery at NG/CT diagnosis (targeted delivery), (2) PrEP evaluation at NG/CT screening/testing and (3) PrEP evaluation in the general community (untargeted). MAIN OUTCOME: The projected incidence of HIV after 20 years of PrEP delivery under two alternatives: when equal numbers of MSM are (1) screened for PrEP or (2) receive PrEP in each year. RESULTS: Assuming 60% uptake and 60% adherence, targeting PrEP to MSM diagnosed with NG/CT could reduce HIV incidence among MSM in Baltimore City by 12.4% (95% uncertainty range (UR) 10.3% to 14.4%) in 20 years, relative to no PrEP. Expanding the coverage of NG/CT screening (such that individuals experience a 50% annual probability of NG/CT screening and evaluation for PrEP on NG/CT diagnosis) can further increase the impact of targeted PrEP to generate a 22.0% (95% UR 20.1% to 23.9%) reduction in HIV incidence within 20 years. When compared with alternative implementation scenarios, PrEP evaluation at NG/CT diagnosis increased impact of PrEP on HIV incidence by 1.5(95% UR 1.1 to 1.9) times relative to a scenario in which PrEP evaluation happened at the time of NG/CT screening/testing and by 1.6 (95% UR 1.2 to 2.2) times relative to evaluating random MSM from the community. CONCLUSIONS: Targeting MSM infected with NG/CT increases the efficiency and effectiveness of PrEP delivery. If high levels of sexually transmitted infection screening can be achieved at the community level, NG/CT diagnosis may be a highly effective entry point for PrEP initialisation.

Screening for tuberculosis: time to move beyond symptoms. (2019). Yoon C., Dowdy DW., Esmail H., MacPherson P., Schumacher SG, The Lancet. Respiratory medicine, 7, 202-204

- January 2019 -

Xpert at 8 years: where are we now, and what should we do next? (2019). Dowdy DW, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 23, 3-4

Siyaphambili protocol: An evaluation of randomized, nurse-led adaptive HIV treatment interventions for cisgender female sex workers living with HIV in Durban, South Africa. (2019). Comins CA., Schwartz SR., Phetlhu DR., Guddera V., Young K., Farley JE., West N., Parmley L., Geng E., Beyrer C., Dowdy D., Mishra S., Hausler H., Baral S, Research in nursing & health, 42, 107-118

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In South Africa, 60% of female sex workers are estimated to be living with human immunodeficiency virus (HIV). Many of these women face structural and individual-level barriers to initiating, accessing, and adhering to antiretroviral therapy (ART). While data are limited, it is estimated that less than 40% of sex workers living with HIV achieve viral suppression, leading to suboptimal clinical outcomes and sustained risks of onward sexual and vertical HIV transmission. Siyaphambili, a NINR/NIH-funded study, focuses on studying optimal implementation strategies for meeting HIV treatment needs among cisgender female sex workers living with HIV who are not virally suppressed. Here, we present the study protocol of this sequential multiple assignment randomized trial. In total, 800 viremic female sex workers will be enrolled into an 18-month adaptive implementation study to 1) compare the effectiveness and durability of a nurse-led decentralized ART treatment program versus an individualized case management approach, in isolation or in combination to achieve viral suppression and 2) estimate incremental cost-effectiveness of interventions and combinations of interventions. The primary outcome is a combined intention-to-treat outcome of retention in ART care and viral suppression at 18 months with secondary implementation outcomes. Siyaphambili aims to inform the implementation of and scale-up of HIV treatment services for female sex workers by determining the minimal package of services needed to achieve viral suppression and by characterizing individuals in need of more intensive HIV treatment approaches.

Cost-effectiveness of universal isoniazid preventive therapy among HIV-infected pregnant women in South Africa. (2019). Kim HY., Hanrahan CF., Martinson N., Golub JE., Dowdy DW, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 22, 1435-1442

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OBJECTIVE: To estimate the incremental cost-effectiveness of universal vs. test-directed treatment of latent tuberculous infection (LTBI) among human immunodeficiency virus (HIV) positive pregnant women in South Africa. METHODS: We compared tuberculin skin test (TST) directed isoniazid preventive therapy (IPT) (TST placement with delivery of IPT to women with positive results) against QuantiFERON((R))-TB Gold In-Tube (QGIT) directed IPT and universal IPT using decision analysis. Costs were measured empirically in six primary care public health clinics in Matlosana, South Africa. The primary outcome was the incremental cost-effectiveness ratio, expressed in 2016 US$ per disability-adjusted life-year (DALY) averted. RESULTS: We estimated that 29.2 of every 1000 pregnant women would develop TB over the course of 1 year in the absence of IPT. TST-directed IPT reduced this number to 24.5 vs. 22.6 with QGIT-directed IPT and 21.0 with universal IPT. Universal IPT was estimated to cost $640/DALY averted (95% uncertainty range $44-$3146) relative to TST-directed IPT and was less costly and more effective (i.e., dominant) than QGIT-directed IPT. Cost-effectiveness was most sensitive to the probability of developing TB and LTBI prevalence. CONCLUSION: Providing IPT to all eligible women can be a cost-effective strategy to prevent TB among HIV-positive pregnant women in South Africa.

- December 2018 -

Spatially targeted screening to reduce tuberculosis transmission in high-incidence settings. (2018). Cudahy PGT., Andrews JR., Bilinski A., Dowdy DW., Mathema B., Menzies NA., Salomon JA., Shrestha S., Cohen T, The Lancet. Infectious diseases, 19, e89-e95

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As the leading infectious cause of death worldwide and the primary proximal cause of death in individuals living with HIV, tuberculosis remains a global concern. Existing tuberculosis control strategies that rely on passive case-finding appear insufficient to achieve targets for reductions in tuberculosis incidence and mortality. Active case-finding strategies aim to detect infectious individuals earlier in their infectious period to reduce onward transmission and improve treatment outcomes. Empirical studies of active case-finding have produced mixed results and determining how to direct active screening to those most at risk remains a topic of intense research. Our systematic review of literature evaluating the effects of geographically targeted tuberculosis screening interventions found three studies in low tuberculosis incidence settings, but none conducted in high tuberculosis incidence countries. We discuss open questions related to the use of spatially targeted approaches for active screening in countries where tuberculosis incidence is highest.

- November 2018 -

Maternal Motivation to Take Preventive Therapy in Antepartum and Postpartum Among HIV-Positive Pregnant Women in South Africa: A Choice Experiment. (2018). Kim HY., Dowdy DW., Martinson NA., Kerrigan D., Tudor C., Golub J., Bridges JFP., Hanrahan CF, AIDS and behavior

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HIV-positive pregnant women who are initiated on lifelong antiretroviral therapy (ART) and isoniazid preventive therapy (IPT) have lower adherence rates after delivery. We quantified maternal motivation to take preventive therapy before and after delivery among pregnant women newly diagnosed with HIV. We enrolled pregnant women (>/= 18 years) with a recent HIV diagnosis (< 6 months) at 14 public primary health clinics in Matlosana, South Africa and followed them in the postpartum period. Participants received eight choice tasks comparing two mutually exclusive sub-sets of seven possible benefits related to preventive therapy identified through literature reviews and key informant interviews. Data was analyzed using conditional logit regression in the antepartum versus postpartum periods. Coefficients are reported with 95% confidence intervals (CI). Sixty-five women completed surveys both at enrollment and in the postpartum period. All women were already on ART, while 21 (32%) were receiving IPT at enrollment. The mean CD4 count was 436 (+/- 246) cells/mm(3). In the antepartum period, preventing HIV transmission to partners was the most important benefit (coefficients (ss) = 0.87, 95% CI 0.64, 1.11), followed by keeping healthy for family (ss = 0.75, 95% CI 0.52, 0.97). Such prioritization significantly decreased in the postpartum period (p < 0.001). Compared to other motivators, keeping a high CD4 count was least prioritized in the antepartum period (ss = 0.19, 95% CI - 0.04, 0.43) but was most prioritized in the postpartum period (ss = 0.39, 95% CI 0.21, 0.57). These results highlight that messages on family might be particularly salient in the antepartum period, and keeping CD4 count high in the postpartum period. Understanding maternal motivation may help to design targeted health promotion messages to HIV-positive women around the time of delivery.

Simple Inclusion of Complex Diagnostic Algorithms in Infectious Disease Models for Economic Evaluation. (2018). Dodd PJ., Pennington JJ., Bronner Murrison L., Dowdy DW, Medical decision making : an international journal of the Society for Medical Decision Making, 38, 930-941

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INTRODUCTION: Cost-effectiveness models for infectious disease interventions often require transmission models that capture the indirect benefits from averted subsequent infections. Compartmental models based on ordinary differential equations are commonly used in this context. Decision trees are frequently used in cost-effectiveness modeling and are well suited to describing diagnostic algorithms. However, complex decision trees are laborious to specify as compartmental models and cumbersome to adapt, limiting the detail of algorithms typically included in transmission models. METHODS: We consider an approximation replacing a decision tree with a single holding state for systems where the time scale of the diagnostic algorithm is shorter than time scales associated with disease progression or transmission. We describe recursive algorithms for calculating the outcomes and mean costs and delays associated with decision trees, as well as design strategies for computational implementation. We assess the performance of the approximation in a simple model of transmission/diagnosis and its role in simplifying a model of tuberculosis diagnostics. RESULTS: When diagnostic delays were short relative to recovery rates, our approximation provided a good account of infection dynamics and the cumulative costs of diagnosis and treatment. Proportional errors were below 5% so long as the longest delay in our 2-step algorithm was under 20% of the recovery time scale. Specifying new diagnostic algorithms in our tuberculosis model was reduced from several tens to just a few lines of code. DISCUSSION: For conditions characterized by a diagnostic process that is neither instantaneous nor protracted (relative to transmission dynamics), this novel approach retains the advantages of decision trees while embedding them in more complex models of disease transmission. Concise specification and code reuse increase transparency and reduce potential for error.

Economic and epidemiologic impact of guidelines for early ART initiation irrespective of CD4 count in Spain. (2018). Kasaie P., Radford M., Kapoor S., Jung Y., Hernandez Novoa B., Dowdy D., Shah M, PloS one, 13, e0206755

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INTRODUCTION: Emerging data suggest that early antiretroviral therapy (ART) could reduce serious AIDS and non-AIDS events and deaths but could also increase costs. In January 2016, the Spanish guidelines were updated to recommend ART at any CD4 count. However, the epidemiologic and economic impacts of early ART initiation in Spain remain unclear. METHODS: The Johns Hopkins HIV Economic-Epidemiologic Mathematical Model (JHEEM) was utilized to estimate costs, transmissions, and outcomes in Spain over 20 years. We compared implementation of guidelines for early ART initiation to a counterfactual scenario deferring ART until CD4-counts fall below 350 cells/mm3. We additionally studied the impact of early ART initiation in combination with improvements to HIV screening, care linkage and engagement. RESULTS: Early ART initiation (irrespective of CD4-count) is expected to avert 20,100 [95% Uncertainty Range (UR) 11,100-83,000] new HIV cases over the next two decades compared to delayed ART (28% reduction), at an incremental health system cost of euro1.05 billion [euro0.66 - euro1.63] billion, and an incremental cost-effectiveness ratio (ICER) of euro29,700 [euro13,700 - euro41,200] per QALY gained. Projected ICERs declined further over longer time horizon; e.g., an ICER of euro12,691 over 30 years. Furthermore, the impact of early ART initiation was potentiated by improved HIV screening among high-risk individuals, averting an estimated 41,600 [23,200-172,200] HIV infections (a 58% decline) compared to delayed ART. CONCLUSIONS: Recommendations for ART initiation irrespective of CD4-counts are cost-effective and could avert > 30% of new cases in Spain. Improving HIV diagnosis can amplify this impact.

Tuberculosis Incidence Among Populations at High Risk in California, Florida, New York, and Texas, 2011-2015. (2018). Cherng ST., Shrestha S., Reynolds S., Hill AN., Marks SM., Kelly J., Dowdy DW, American journal of public health, 108, S311-S314

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OBJECTIVES: To illustrate the magnitude of between-state heterogeneities in tuberculosis (TB) incidence among US populations at high risk for TB that may help guide state-specific strategies for TB elimination. METHODS: We used data from the National Tuberculosis Surveillance System and other public sources from 2011 to 2015 to calculate TB incidence in every US state among people who were non-US-born, had diabetes, or were HIV-positive, homeless, or incarcerated. We then estimated the proportion of TB cases that reflected the difference between each state's reported risk factor-specific TB incidence and the lowest incidence achieved among 4 states (California, Florida, New York, Texas). We reported these differences for the 4 states and also calculated and aggregated across all 50 states to quantify the total percentage of TB cases nationally that reflected between-state differences in risk factor-specific TB incidence. RESULTS: On average, 24% of recent TB incidence among high-risk US populations reflected heterogeneity at the state level. The populations that accounted for the greatest percentage of heterogeneity-reflective cases were non-US-born individuals (51%) and patients with diabetes (24%). CONCLUSIONS: State-level differences in TB incidence among key populations provide clues for targeting state-level interventions.

The Importance of Heterogeneity to the Epidemiology of Tuberculosis. (2018). Trauer JM., Dodd PJ., Gomes MGM., Gomez GB., Houben RM., McBryde ES., Melsew YA., Menzies NA., Arinaminpathy N., Shrestha S., Dowdy DW, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America

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Although less well-recognised than for other infectious diseases, heterogeneity is a defining feature of TB epidemiology. To advance toward TB elimination, this heterogeneity must be better understood and addressed. Drivers of heterogeneity in TB epidemiology act at the level of the infectious host, organism, susceptible host, environment and distal determinants. These effects may be amplified by social mixing patterns, while the variable latent period between infection and disease may mask heterogeneity in transmission. Reliance on notified cases may lead to misidentification of the most affected groups, as case detection is often poorest where prevalence is highest. Assuming average rates apply across diverse groups and ignoring the effects of cohort selection may result in misunderstanding of the epidemic and the anticipated effects of control measures. Given this substantial heterogeneity, interventions targeting high-risk groups based on location, social determinants or comorbidities could improve efficiency, but raise ethical and equity considerations.

- October 2018 -

Projected population-wide impact of antiretroviral therapy-linked isoniazid preventive therapy in a high-burden setting. (2018). Kendall EA., Azman AS., Maartens G., Boulle A., Wilkinson RJ., Dowdy DW., Rangaka MX, AIDS (London, England), 33, 525-536

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OBJECTIVE: Both isoniazid preventive therapy (IPT) and antiretroviral therapy (ART) reduce tuberculosis risk in individuals living with HIV. We sought to estimate the broader, population-wide impact of providing a pragmatically implemented 12-month IPT regimen to ART recipients in a high-burden community. DESIGN: Dynamic transmission model of a tuberculosis (TB)-HIV epidemic, calibrated to site-specific, historical epidemiologic and clinical trial data from Khayelitsha, South Africa. METHODS: We projected the 5-year impact of delivering a 12-month IPT regimen community-wide to 85% of new ART initiators and 15%/year of those already on ART, accounting for IPT-attributable reductions in TB infection, progression, and transmission. We also evaluated scenarios of continuously-delivered IPT, ongoing ART scale-up, and lower tuberculosis incidence. RESULTS: Under historical (early 2010) ART coverage, this ART-linked IPT intervention prevented one tuberculosis case per 18 [95% credible interval (CrI) 11-29] people treated. It lowered TB incidence by a projected 23% (95% CrI 14-30%) among people receiving ART, and by 5.2% (95% CrI 2.9-8.7%) in the total population. Continuous IPT reduced the number needed to treat to prevent one case of TB to 10 (95% CrI 7-16), though it required 74% more person-years of therapy (95% CrI 64-94%) to prevent one TB case, relative to 12-month therapy. Under expanding ART coverage, the tuberculosis incidence reduction achieved by 12-month IPT grew to 7.6% (95% CrI 4.3-12.6%). Effect sizes were similar in a simulated setting of lower TB incidence. CONCLUSIONS: IPT in conjunction with ART reduces tuberculosis incidence among those who receive therapy and has additional impact on tuberculosis transmission in the population.

- September 2018 -

The association of household fine particulate matter and kerosene with tuberculosis in women and children in Pune, India. (2018). Elf JL., Kinikar A., Khadse S., Mave V., Suryavanshi N., Gupte N., Kulkarni V., Patekar S., Raichur P., Paradkar M., Kulkarni V., Pradhan N., Breysse PN., Gupta A., Golub JE, Occupational and environmental medicine, 76, 40-47

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OBJECTIVES: Household air pollution (HAP) is a risk factor for respiratory disease, however has yet to be definitively associated with tuberculosis (TB). We aimed to assess the association between HAP and TB. METHODS: A matched case-control study was conducted among adult women and children patients with TB and healthy controls matched on geography, age and sex. HAP was assessed using questionnaires for pollution sources and 24-hour household concentrations of particulate matter <2.5 mum in diameter (PM2.5). RESULTS: In total, 192 individuals in 96 matched pairs were included. The median 24-hour time-weighted average PM2.5 was nearly seven times higher than the WHO's recommendation of 25 microg/m(3), and did not vary between controls (179 microg/m(3); IQR: 113-292) and cases (median 157 microg/m(3); 95% CI 93 to 279; p=0.57). Reported use of wood fuel was not associated with TB (OR 2.32; 95% CI 0.65 to 24.20) and kerosene was significantly associated with TB (OR 5.49, 95% CI 1.24 to 24.20) in adjusted analysis. Household PM2.5 was not associated with TB in univariate or adjusted analysis. Controlling for PM2.5 concentration, kerosene was not significantly associated with TB, but effect sizes ranged from OR 4.30 (95% CI 0.78 to 30.86; p=0.09) to OR 5.49 (0.82 to 36.75; p=0.08). CONCLUSIONS: Use of kerosene cooking fuel is positively associated with TB in analysis using reported sources of exposure. Ubiquitously high levels of particulates limited detection of a difference in household PM2.5 between cases and controls.

Yield and Efficiency of Novel Intensified Tuberculosis Case-Finding Algorithms for People Living with HIV. (2018). Yoon C., Semitala FC., Asege L., Katende J., Mwebe S., Andama AO., Atuhumuza E., Nakaye M., Armstrong DT., Dowdy DW., McCulloch CE., Kamya M., Cattamanchi A, American journal of respiratory and critical care medicine, 199, 643-650

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RATIONALE: The recommended tuberculosis (TB) intensified case finding (ICF) algorithm for people living with HIV (symptom-based screening followed by Xpert MTB/RIF [Xpert] testing) is insufficiently sensitive and results in unnecessary Xpert testing. OBJECTIVES: To evaluate whether novel ICF algorithms combining C-reactive protein (CRP)-based screening with urine Determine TB-LAM (TB-LAM), sputum Xpert, and/or sputum culture could improve ICF yield and efficiency. METHODS: We compared the yield and efficiency of novel ICF algorithms inclusive of point-of-care CRP-based TB screening and confirmatory testing with urine TB-LAM (if CD4 count

COach2Quit: a pilot randomized controlled trial of a personal carbon monoxide monitor for smoking cessation. (2018). Krishnan N., Elf JL., Chon S., Golub JE, Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco

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Introduction: Mobile phone messaging support and biomarker feedback independently show evidence of increasing an individual's likelihood of quitting smoking. However, the combination of these two strategies to facilitate smoking cessation has not been adequately explored. Methods: We conducted a randomized controlled trial in Baltimore, Maryland to assess the efficacy of COach2Quit, a smartphone application that provides exhaled carbon monoxide readings with message support. The primary outcome was self-reported and biochemically verified smoking cessation at 30-day follow-up. Secondary outcomes were smoking reduction, motivation to quit, use of, and satisfaction with COach2Quit. An intent to treat analysis was conducted. Results: Adult smokers were randomized 1:1 to receive brief advice and COach2Quit (intervention, n=50) or brief advice only (control, n=52). Thirteen participants were lost to follow-up. At 30-day follow-up, one participant in each arm quit smoking. Median change in CO levels (parts per million, ppm) (intervention: -3.0 IQR -12.0, 2.0) (control: -2.5 IQR -9.0, 2.0) and median change in number of cigarettes smoked/day (intervention: -5.5 IQR -14.0, -1.0) (control: -6.0 IQR -10.0, -2.0) was similar between study arms. There was no significant difference in mean percent change in the reasons for quitting (RFQ) scale score (intervention: 6.3 95% CI -2.2, 14.8) (control: -3.6 95% CI -9.2, 2.1). A majority (n=32, 91%) of participants liked having COach2Quit to help them quit smoking. Conclusions: There were no significant differences in smoking cessation, smoking reduction and motivation to quit between study arms. However, high satisfaction with the COach2Quit application indicates its feasibility and acceptability as a smoking cessation tool. Implications: Smoking is the leading preventable cause of morbidity and mortality in the United States. Although counseling and pharmacotherapy are efficacious for smoking cessation, they are not easily accessible or desirable to all smokers, highlighting the need for identifying other interventions. There is evidence for the efficacy of mobile phone based messaging support for smoking cessation. However, there is limited research on the efficacy of biomarker feedback, much less interventions that combine these two approaches. This research contributes to filling this gap and identifying novel interventions to facilitate smoking cessation.

- August 2018 -

Chest X-ray for tuberculosis preventive therapy: use caution. (2018). Hanrahan C., Dowdy D, The lancet. HIV, 5, e478-e479

Inequalities in HAART uptake and differential survival according to exposure category in Rio de Janeiro, Brazil. (2018). Lima TA., Beyrer C., Golub JE., Mota JCD., Malta MS., Silva CMFPD., Bastos FI, Cadernos de saude publica, 34, e00009617

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Despite substantial improvement in prognosis and quality of life among people living with HIV/AIDS (PLWHA) in Brazil, inequalities in access to treatment remain. We assessed the impact of these inequalities on survival in Rio de Janeiro over a 12-year period (2000/11). Data were merged from four databases that comprise the national AIDS monitoring system: SINAN-AIDS (Brazilian Information System for Notificable Diseases; AIDS cases), SISCEL (laboratory tests), SICLOM (electronic dispensing system), and SIM (Brazilian Mortality Information System), using probabilistic linkage. Cox regressions were fitted to assess the impact of HAART (highly active antiretroviral therapy) on AIDS-related mortality among men who have sex with men (MSM), people who inject drugs (PWID), and heterosexuals diagnosed with AIDS, between 2000 and 2011, in the city of Rio de Janeiro, RJ, Brazil. Among 15,420 cases, 60.7% were heterosexuals, 36.1% MSM and 3.2% PWID. There were 2,807 (18.2%) deaths and the median survival time was 6.29. HAART and CD4+ > 200 at baseline were associated with important protective effects. Non-whites had a 33% higher risk of dying in consequence of AIDS than whites. PWID had a 56% higher risk and MSM a 11% lower risk of dying of AIDS than heterosexuals. Non-white individuals, those with less than eight years of formal education, and PWID, were more likely to die of AIDS and less likely to receive HAART. Important inequalities persist in access to treatment, resulting in disparate impacts on mortality among exposure categories. Despite these persistent disparities, mortality decreased significantly during the period for all categories under analysis, and the overall positive impact of HAART on survival has been dramatic.

Effect of Diabetes Mellitus on the Pharmacokinetics and Pharmacodynamics of Tuberculosis Treatment. (2018). Alfarisi O., Mave V., Gaikwad S., Sahasrabudhe T., Ramachandran G., Kumar H., Gupte N., Kulkarni V., Deshmukh S., Atre S., Raskar S., Lokhande R., Barthwal M., Kakrani A., Chon S., Gupta A., Golub JE., Dooley KE, Antimicrobial agents and chemotherapy, 62

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Diabetes mellitus (DM) and tuberculosis (TB) are two common diseases with increasing geographic overlap and clinical interactions. The effect of DM and hemoglobin A1c (HbA1c) values on the pharmacokinetics (PK) and pharmacodynamics (PD) of anti-TB drugs remains poorly characterized. Newly diagnosed TB patients with and without DM starting fixed-dose, thrice-weekly treatment underwent sampling for PK assessments (predose and 0.5, 2, and 6 h postdose) during the intensive and continuation phases of treatment. The effect of DM and HbA1c values on the maximum concentration (C max) of rifampin, isoniazid, and pyrazinamide and the association between drug concentrations and microbiologic and clinical outcomes were assessed. Of 243 patients, 101 had DM. Univariate analysis showed significant reductions in the C max of pyrazinamide and isoniazid (but not rifampin) with DM or increasing HbA1c values. After adjusting for age, sex, and weight, DM was associated only with reduced pyrazinamide concentrations (adjusted geometric mean ratio = 0.74, P = 0.03). In adjusted Cox models, female gender (adjusted hazards ratio [aHR] = 1.75, P = 0.001), a lower smear grade with the Xpert assay (aHR = 1.40, P < 0.001), and the pyrazinamide C max (aHR = 0.99, P = 0.006) were independent predictors of sputum culture conversion to negative. Higher isoniazid or rifampin concentrations were associated with a faster time to culture conversion in patients with DM only. A pyrazinamide C max above the therapeutic target was associated with higher unfavorable outcomes (treatment failure, relapse, death) (odds ratio = 1.92, P = 0.04). DM and higher HbA1c values increased the risk of not achieving therapeutic targets for pyrazinamide (but not rifampin or isoniazid). Higher pyrazinamide concentrations, though, were associated with worse microbiologic and clinical outcomes. DM status also appeared to influence PK-PD relationships for isoniazid and rifampin.

- July 2018 -

Screening for tuberculosis with Xpert MTB/RIF versus fluorescent microscopy among adults newly diagnosed with HIV in rural Malawi: a cluster randomized trial (CHEPETSA). (2018). Ngwira LG., Corbett EL., Khundi M., Barnes GL., Nkhoma A., Murowa M., Cohn S., Moulton LH., Chaisson RE., Dowdy DW, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America

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Background: Tuberculosis (TB) remains the leading cause of death among HIV-positive individuals globally. Screening for TB at the point of HIV diagnosis with a high-sensitivity assay presents an opportunity to reduce mortality. Methods: We performed a cluster randomized trial of TB screening among adults newly diagnosed with HIV in 12 primary health clinics in rural Thyolo, Malawi (clinicaltrials.gov NCT01450085). Clinics were allocated in a 1:1 ratio to perform either point-of-care Xpert MTB/RIF (Xpert) or point-of-care light-emitting diode fluorescence microscopy (LED FM) for individuals screening positive for TB symptoms. Asymptomatic participants were offered isoniazid preventive therapy in both arms. Investigators, but not clinic staff or participants, were masked to allocation. Our primary outcome was the incidence rate ratio (RR) of all-cause mortality within 12 months of HIV diagnosis. Results: Prevalent TB was diagnosed in 24 (2.4%) of 1001 individuals enrolled in clinics randomized to Xpert, versus 10 (1.2%) of 841 in clinics randomized to LED FM. All-cause mortality was 22% lower in the Xpert arm than in the LED FM arm (6.7 versus 8.6 per 100 person-years, RR 0.78; 95% confidence interval [CI]: 0.58-1.06). A planned subgroup analysis suggested that participants with more advanced HIV (World Health Organization clinical stage III or IV) disease had lower mortality in clinics randomized to Xpert than to LED FM (RR 0.43, 95%CI: 0.22-0.87). Conclusion: In rural Malawi, using point-of-care Xpert MTB/RIF to test symptomatic patients for TB at the time of HIV diagnosis reduced all-cause 12-month mortality among individuals with advanced HIV.

Trends in HbA1c levels and implications for diabetes screening in tuberculosis cases undergoing treatment in India. (2018). Gupte AN., Mave V., Meshram S., Lokhande R., Kadam D., Dharmshale S., Bharadwaj R., Kagal A., Pradhan N., Deshmukh S., Atre S., Sahasrabudhe T., Barthwal M., Meshram S., Kakrani A., Kulkarni V., Raskar S., Suryavanshi N., Shivakoti R., Chon S., Selvin E., Gupte N., Gupta A., Golub JE, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 22, 800-806

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SETTING: The optimal timing of screening for diabetes mellitus (DM) among tuberculosis (TB) cases is unclear due to the possibility of stress hyperglycemia. DESIGN: We evaluated adult (>/=18 years) pulmonary TB cases at treatment initiation as well as at 3 months, 6 months and 12 months. DM was identified by self-report (known DM) or glycated hemoglobin (HbA1c) >/= 6.5% (new DM). Trends in HbA1c levels during treatment were assessed using non-parametric tests. RESULTS: Of the 392 participants enrolled, 75 (19%) had DM, 30 (40%) of whom had new DM. Of the 45 participants with known DM, respectively 37 (82%) and 40 (89%) received medication to lower glucose levels at treatment initiation and completion; one participant with new DM initiated glucose-lowering medication during follow-up. The median HbA1c level in participants with known, new and no DM was respectively 10.1% (interquartile range [IQR] 8.3-11.6), 8.5% (IQR 6.7-11.5) and 5.6% (IQR 5.3-5.9) at treatment initiation, and 8.7% (IQR 6.8-11.3), 7.1% (IQR 5.8-9.5) and 5.3% (IQR 5.1-5.6) at treatment completion (P < 0.001). Overall, 5 (12%) with known and 13 (43%) with new DM at treatment initiation had reverted to HbA1c < 6.5% by treatment completion (P = 0.003); the majority of reversions occurred during the first 3 months, with no significant reversions beyond 6 months. CONCLUSION: HbA1c levels declined with anti-tuberculosis treatment. Repeat HbA1c testing at treatment completion could reduce the risk of misdiagnosis of DM.

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