TB Modeling and Translational Epi Group

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- September 2018 -

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.

Advancing global health and strengthening the HIV response in the era of the Sustainable Development Goals: the International AIDS Society-Lancet Commission. (2018). Bekker LG., Alleyne G., Baral S., Cepeda J., Daskalakis D., Dowdy D., Dybul M., Eholie S., Esom K., Garnett G., Grimsrud A., Hakim J., Havlir D., Isbell MT., Johnson L., Kamarulzaman A., Kasaie P., Kazatchkine M., Kilonzo N., Klag M., Klein M., Lewin SR., Luo C., Makofane K., Martin NK., Mayer K., Millett G., Ntusi N., Pace L., Pike C., Piot P., Pozniak A., Quinn TC., Rockstroh J., Ratevosian J., Ryan O., Sippel S., Spire B., Soucat A., Starrs A., Strathdee SA., Thomson N., Vella S., Schechter M., Vickerman P., Weir B., Beyrer C, Lancet (London, England), 392, 312-358

Incipient and Subclinical Tuberculosis: a Clinical Review of Early Stages and Progression of Infection. (2018). Drain PK., Bajema KL., Dowdy D., Dheda K., Naidoo K., Schumacher SG., Ma S., Meermeier E., Lewinsohn DM., Sherman DR, Clinical microbiology reviews, 31

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Tuberculosis (TB) is the leading infectious cause of mortality worldwide, due in part to a limited understanding of its clinical pathogenic spectrum of infection and disease. Historically, scientific research, diagnostic testing, and drug treatment have focused on addressing one of two disease states: latent TB infection or active TB disease. Recent research has clearly demonstrated that human TB infection, from latent infection to active disease, exists within a continuous spectrum of metabolic bacterial activity and antagonistic immunological responses. This revised understanding leads us to propose two additional clinical states: incipient and subclinical TB. The recognition of incipient and subclinical TB, which helps divide latent and active TB along the clinical disease spectrum, provides opportunities for the development of diagnostic and therapeutic interventions to prevent progression to active TB disease and transmission of TB bacilli. In this report, we review the current understanding of the pathogenesis, immunology, clinical epidemiology, diagnosis, treatment, and prevention of both incipient and subclinical TB, two emerging clinical states of an ancient bacterium.

Prevalence and Correlates of Snuff Use, and its Association With Tuberculosis, Among Women Living With HIV in South Africa. (2018). Elf JL., Variava E., Chon S., Lebina L., Motlhaoleng K., Gupte N., Niaura R., Abrams D., Martinson N., Golub JE, Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco

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Introduction: A higher proportion of people living with HIV (PLWH) smoke compared to the general population, but little information exists about the prevalence and correlates of smokeless tobacco use among PLWH. In South Africa, dry powdered tobacco is inhaled nasally as snuff. Methods: A cross-sectional survey among PLWH attending three HIV clinics was conducted. Snuff use was assessed via self-report and urine cotinine. Results: Given the low (3%) prevalence of snuff use among men, analysis was restricted to n = 606 nonsmoking women living with HIV. Half (n = 298, 49%) were snuff users, the majority of whom (n = 244, 84%) had a positive urine cotinine test. In adjusted analysis, snuff use was negatively associated with higher education (relative risk [RR] 0.55; 95% confidence interval [CI]: 0.39, 0.77) and mobile phone ownership (RR 0.83; 95% CI: 0.71, 0.98), and positively associated with ever having tuberculosis (TB) (RR 1.22; 95% CI: 1.03, 1.45). In adjusted analysis, with current TB as the outcome, snuff use was marginally statistically significantly associated with a twofold increase in odds of a current TB diagnosis (odds ratio [OR] 1.99; 95% CI: 0.98, 4.15). Discussion: A high proportion of nonsmoking South African women living with HIV use snuff, which was a risk factor for TB. Additional research is needed to understand the relationship between snuff, TB, and other potential health risks. Implications: PLWH have a higher prevalence of smoking than their seronegative peers, but there is a paucity of research on smokeless tobacco use in this population, especially in low-resource settings. TB is the leading cause of death among PLWH, and with improvements to HIV treatment and care, PLWH are at greater risk of tobacco-related diseases. We report an extremely high prevalence of snuff use among women living with HIV in South Africa. Further, in this population snuff use is positively associated with ever having a TB diagnosis, as well as currently having TB.

What if They Don't Have Tuberculosis? The Consequences and Trade-offs Involved in False-positive Diagnoses of Tuberculosis. (2018). Houben RMGJ., Lalli M., Kranzer K., Menzies NA., Schumacher SG., Dowdy DW, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 68, 150-156

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To find the millions of missed tuberculosis (TB) cases, national TB programs are under pressure to expand TB disease screening and to target populations with lower disease prevalence. Together with imperfect performance and application of existing diagnostic tools, including empirical diagnosis, broader screening risks placing individuals without TB on prolonged treatment. These false-positive diagnoses have profound consequences for TB patients and prevention efforts, yet are usually overlooked in policy decision making. In this article we describe the pathways to a false-positive TB diagnosis, including trade-offs involved in the development and application of diagnostic algorithms. We then consider the wide range of potential consequences for individuals, households, health systems, and reliability of surveillance data. Finally, we suggest practical steps that the TB community can take to reduce the frequency and potential harms of false-positive TB diagnosis and to more explicitly assess the trade-offs involved in the screening and diagnostic process.

Yield of household contact tracing for tuberculosis in rural South Africa. (2018). Little KM., Msandiwa R., Martinson N., Golub J., Chaisson R., Dowdy D, BMC infectious diseases, 18, 299

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BACKGROUND: Efficient and effective strategies for identifying cases of active tuberculosis (TB) in rural sub-Saharan Africa are lacking. Household contact tracing offers a potential approach to diagnose more TB cases, and to do so earlier in the disease course. METHODS: Adults newly diagnosed with active TB were recruited from public clinics in Vhembe District, South Africa. Study staff visited index case households and collected sputum specimens for TB testing via smear microscopy and culture. We calculated the yield and the number of households needed to screen (NHNS) to find one additional case. Predictors of new TB among household contacts were evaluated using multilevel logistic regression. RESULTS: We recruited 130 index cases and 282 household contacts. We identified 11 previously undiagnosed cases of bacteriologically-confirmed TB, giving a prevalence of 3.9% (95% CI: 2.0-6.9%) among contacts, a yield of 8.5 per 100 (95% CI: 4.2-15.1) index cases traced, and NHNS of 12 (95% CI: 7-24). The majority of new TB cases (10/11, 90.9%) were smear negative, culture positive. The presence of TB symptoms was not associated with an increased odds of active TB (aOR: 0.3, 95% CI: 0.1-1.4). CONCLUSIONS: Household contacts of recently diagnosed TB patients in rural South Africa have high prevalence of TB and can be feasibly detected through contact tracing, but more sensitive tests than sputum smear are required. Symptom screening among household contacts had low sensitivity and specificity for active TB in this study.

Maternal priorities for preventive therapy among HIV-positive pregnant women before and after delivery in South Africa: a best-worst scaling survey. (2018). Kim HY., Dowdy DW., Martinson NA., E Golub J., Bridges JFP., Hanrahan CF, Journal of the International AIDS Society, 21, e25143

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INTRODUCTION: Pregnant women newly diagnosed with HIV during pregnancy are often lost to follow up and their adherence rates drop after delivery. We quantified changes in priorities related to isoniazid preventive therapy (IPT) and antiretroviral therapy (ART) among pregnant women living with HIV. METHODS: We enrolled pregnant women recently diagnosed with HIV from 14 primary health clinics during pregnancy and followed them after delivery in Matlosana, South Africa. Best-worst scaling (BWS) was used to determine the women's priorities out of 11 attributes related to preventive therapy in the ante- versus postpartum periods. Aggregate BWS scores were calculated based on the frequency with which participants selected each attribute as the best or worst among five options (across multiple choice sets). Individual BWS scores were also calculated and rescaled from 0 (always selected as worst) to 10 (always selected as best), and changes in BWS scores in the ante- versus postpartum periods were compared, using a paired t-test. Factors associated with the changes in BWS scores were examined in multiple linear regressions. Spearman's rho was used to compare the ranking of attributes. RESULTS: Out of a total of 204 participants, 154 (75.5%) completed the survey in the postpartum at the median 15 (IQR: 11 to 27) weeks after delivery. Trust in healthcare providers was most highly prioritized both in the ante- (individual BWS Score = 7.34, SE = 0.13) and postpartum periods (BWS = 7.21 +/- 0.11), followed by living a long life (BWS = 6.77 +/- 0.09 in the ante- vs. BWS = 6.86 +/- 0.10 in the postpartum). Prevention for infants' health was more prioritized in the post- (BWS = 6.54 +/- 0.09) versus antepartum periods (BWS = 6.11 +/- 0.10) (p = 0.05). This change was associated with IPT initiation at enrolment (regression coefficient = 0.78 +/- 0.33, p = 0.001). Difficulty in daily pill-uptake was significantly more prioritized in the postpartum (BWS = 5.03 +/- 0.11) than in the antepartum (BWS = 4.43 +/- 0.10) (p < 0.01). Transportation cost and worry about side effects of pills were least prioritized. Overall ranking of attributes was similar in both time periods (spearman's rho = 0.90). CONCLUSIONS: Comprehensive interventions to build trust in healthcare providers and support adherence may increase uptake of preventive therapy. Counselling needs to emphasize medication benefits for both maternal and infant health among HIV-positive pregnant women.

- June 2018 -

A systematic review of the effectiveness of smoking cessation interventions among patients with tuberculosis. (2018). Whitehouse E., Lai J., Golub JE., Farley JE, Public health action, 8, 37-49

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Smoking is a significant risk factor for morbidity and mortality, particularly among patients with tuberculosis (TB). Although smoking cessation is recommended by the World Health Organization and the International Union Against Tuberculosis and Lung Disease, there has been no published evaluation of smoking cessation interventions among people with TB. The purpose of this review was to synthesize the evidence on interventions and suggest practice, research and policy implications. A systematic review of the literature identified 14 peer-reviewed studies describing 13 smoking cessation interventions between 2007 and 2017. There were five randomized controlled trials, three non-randomized interventions, and five prospective cohort studies. The primary types of interventions were brief advice (n = 9), behavioral counseling (n = 4), medication (n = 3), and community-based care (n = 3). A variety of health care workers (HCWs) implemented interventions, from physicians, nurses, clinic staff, community health workers (CHWs), as did family members. There was significant heterogeneity of design, definition of smoking and smoking abstinence, and implementation, making comparison across studies difficult. Although all smoking interventions increased smoking cessation between 15% and 82%, many studies had a high risk for bias, including six without a control group. The implementing personnel did not make a large difference in cessation results, suggesting that national TB programs may customize according to their needs and limitations. Family members may be important supporters/advocates for cessation. Future research should standardize definitions of smoking and cessation to allow comparisons across studies. Policy makers should encourage collaboration between tobacco and TB initiatives and develop smoking cessation measures to maximize results in low-resource settings.

Impact of Providing Preexposure Prophylaxis for Human Immunodeficiency Virus at Clinics for Sexually Transmitted Infections in Baltimore City: An Agent-based Model. (2018). Kasaie P., Berry SA., Shah MS., Rosenberg ES., Hoover KW., Gift TL., Chesson H., Pennington J., German D., Flynn CP., Beyrer C., Dowdy DW, Sexually transmitted diseases, 45, 791-797

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BACKGROUND: Preexposure prophylaxis (PrEP) greatly reduces the risk of human immunodeficiency virus (HIV) acquisition, but its optimal delivery strategy remains uncertain. Clinics for sexually transmitted infections (STIs) can provide an efficient venue for PrEP delivery. METHODS: To quantify the added value of STI clinic-based PrEP delivery, we used an agent-based simulation of HIV transmission among men who have sex with men (MSM). We simulated the impact of PrEP delivery through STI clinics compared with PrEP delivery in other community-based settings. Our primary outcome was the projected 20-year reduction in HIV incidence among MSM. RESULTS: Assuming PrEP uptake and adherence of 60% each, evaluating STI clinic attendees and delivering PrEP to eligible MSM reduced HIV incidence by 16% [95% uncertainty range, 14%-18%] over 20 years, an impact that was 1.8 (1.7-2.0) times as great as that achieved by evaluating an equal number of MSM recruited from the community. Comparing strategies where an equal number of MSM received PrEP in each strategy (ie, evaluating more individuals for PrEP in the community-based strategy, because MSM attending STI clinics are more likely to be PrEP eligible), the reduction in HIV incidence under the STI clinic-based strategy was 1.3 (1.3-1.4) times as great as that of community-based delivery. CONCLUSIONS: Delivering PrEP to MSM who attend STI clinics can improve efficiency and effectiveness. If high levels of adherence can be achieved in this population, STI clinics may be an important venue for PrEP implementation.

Effect of baseline micronutrient and inflammation status on CD4 recovery post-cART initiation in the multinational PEARLS trial. (2018). Shivakoti R., Ewald ER., Gupte N., Yang WT., Kanyama C., Cardoso SW., Santos B., Supparatpinyo K., Badal-Faesen S., Lama JR., Lalloo U., Zulu F., Pawar JS., Riviere C., Kumarasamy N., Hakim J., Pollard R., Detrick B., Balagopal A., Asmuth DM., Semba RD., Campbell TB., Golub J., Gupta A, Clinical nutrition (Edinburgh, Scotland), 38, 1303-1309

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BACKGROUND & AIMS: Nutritional deficiency and inflammation may impact CD4+ T cell recovery during combination antiretroviral therapy (cART), particularly in resource-limited settings where malnutrition is prevalent. The aim of this study was to investigate the relationship of micronutrient and inflammation biomarkers to CD4 recovery after cART initiation. METHODS: We conducted a secondary analysis of a random sub-cohort sample (n = 270) from a multinational randomized trial of cART regimen efficacy among 1571 cART-naive adults. We measured pre-cART serum levels of micronutrients (Vitamin A, B6, B12, D, total carotenoids, selenium, and iron) and inflammation (C-reactive protein, soluble CD14 (sCD14), IFNgamma, TNFalpha, Interleukin-6, and C-X-C motif chemokine 10 (CXCL10/IP10), EndoCab (IgM)) biomarkers. Biomarker status (i.e. micronutrient deficiency vs. sufficiency and elevated vs. low inflammation) was defined using established cutoffs or quartiles. Mixed-effects linear regression models were used to determine the association of baseline (pre-cART) concentrations of individual biomarkers with CD4 recovery through 96 weeks post-cART initiation. RESULTS: In models adjusting for time-dependent viral load and baseline CD4 count, age, sex, body mass index, country, treatment regimen, anemia and hypoalbuminemia status, pre-cART vitamin D deficiency was associated with lower CD4 recovery (-14.9 cells/mm(3), 95% CI: -27.9, -1.8) compared to sufficiency. In contrast, baseline selenium deficiency (20.8 cells/mm(3), 95% CI: 3.3, 38.3), vitamin A deficiency (35.9 cells/mm(3), 95% CI: 17.6, 54.3) and high sCD14 (23.4 cells/mm(3), 95% CI: 8.9, 37.8) were associated with higher CD4 recovery compared to sufficient/low inflammation status. CONCLUSIONS: In summary, baseline vitamin D deficiency was associated with diminished CD4 recovery after cART initiation; impaired CD4 recovery may contribute to the poor clinical outcomes recently observed in individuals with vitamin D deficiency. Vitamin A, selenium and sCD14 were associated with CD4 recovery but future studies are needed to further explore these relationships.

Would pan-tuberculosis treatment regimens be cost-effective? (2018). Kendall EA., Brigden G., Lienhardt C., Dowdy DW, The Lancet. Respiratory medicine, 6, 486-488

- May 2018 -

Sources of household air pollution and their association with fine particulate matter in low-income urban homes in India. (2018). Elf JL., Kinikar A., Khadse S., Mave V., Suryavanshi N., Gupte N., Kulkarni V., Patekar S., Raichur P., Breysse PN., Gupta A., Golub JE, Journal of exposure science & environmental epidemiology, 28, 400-410

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INTRODUCTION: Household air pollution (HAP) is poorly characterized in low-income urban Indian communities. MATERIALS AND METHODS: A questionnaire assessing sources of HAP and 24 h household concentrations of particulate matter less than 2.5 microns in diameter (PM2.5) were collected in a sample of low-income homes in Pune, India. RESULTS: In 166 homes, the median 24 h average concentration of PM2.5 was 167 mug/m(3) (IQR: 106-294). Although kerosene and wood use were highly prevalent (22% and 25% of homes, respectively), primarily as secondary fuel sources, high PM2.5 concentrations were also found in 95 (57%) homes reporting LPG use alone (mean 141 mug/m(3); IQR: 92-209). In adjusted linear regression, log PM2.5 concentration was positively associated with wood cooking fuel (GMR 1.5, 95% CI: 1.1-2.0), mosquito coils (GMR 1.5, 95% CI: 1.1-2.1), and winter season (GMR 1.7, 95% CI: 1.4-2.2). Households in the highest quartile of exposure were positively associated with wood cooking fuel (OR 1.3, 95% CI: 1.1-1.5), incense (OR 1.1, 95% CI: 1.0-1.3), mosquito coils (OR 1.3, 95% CI: 1.1-1.6), and winter season (OR 1.2, 95% CI: 1.1-1.4). DISCUSSION: We observed high concentrations of PM2.5 and identified associated determinants in urban Indian homes.

- April 2018 -

Transmission of Mycobacterium tuberculosis From Patients Who Are Nucleic Acid Amplification Test Negative. (2018). Xie YL., Cronin WA., Proschan M., Oatis R., Cohn S., Curry SR., Golub JE., Barry CE 3rd., Dorman SE, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 67, 1653-1659

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Background: Among adults with signs and symptoms of pulmonary tuberculosis (TB), recognition of transmissible TB has implications for airborne infection isolation and public health activities. Sputum smear-negative TB patients account for around one-fifth of tuberculosis transmission. The tuberculosis transmission risk of TB patients with negative results on nucleic acid amplification test (NAAT) of respiratory specimens has not been established. We sought to estimate the tuberculosis transmission risk of NAAT-negative TB patients. Methods: We retrospectively reviewed Maryland TB program data collected from 2004 to 2009, during which time NAAT using the Mycobacterium Tuberculosis Direct Test (MTD) was performed routinely. Patients with sputum Mycobacterium tuberculosis (M.tb) isolates having matching genotypes were assigned to clusters. Transmission sequence was approximated by collection order of individuals' first culture-positive specimens. Minimum transmission risks of NAAT (MTD)-negative TB patients and of smear-negative TB patients were estimated based on individuals' positions within clusters. Results: Among 809 patients with culture-confirmed TB, M.tb genotypes were available for 782 (96.7%). For NAA-negative TB patients, the minimum transmission risk estimate was 5.1% (95% CI 0-11.4). For smear-negative TB patients, the minimum transmission risk estimate was 11.2% (95% CI 7.2-15.3). Conclusions: Minimum transmission risk of NAAT-negative TB patients was lower than that of smear-negative TB patients. However, transmission risk of NAA-negative TB patients appears to not be negligible.

Relevance and acceptability of using the Quantiferon gold test (QGIT) to screen CD4 blood draws for latent TB infection among PLHIV in South Africa: formative qualitative research findings from the TEKO trial. (2018). Kerrigan D., Tudor C., Motlhaoleng K., Lebina L., Qomfu C., Variava E., Chon S., Martinson N., Golub JE, BMC health services research, 18, 288

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BACKGROUND: Tuberculosis (TB) is the leading cause of mortality among people living with HIV (PLHIV), despite the availability of effective preventive therapy. The TEKO trial is assessing the impact of using a blood test, Quantiferon-TB Gold In-Tube Test (QGIT), to screen for latent TB compared to the Tuberculin Screening Test (TST) among PLHIV in South Africa. METHODS: Fifty-six qualitative interviews were conducted with PLHIV and clinical providers participating in the TEKO trial. We explored TB screening, diagnosis, and treatment guidelines and processes and the use of the QGIT to screen for latent TB infection at the time of CD4 blood draw. Thematic content analysis was conducted. RESULTS: Considerable variability in TB screening procedures was documented due to lack of personnel and clarity regarding current national TB guidelines for PLHIV. Few clinics had started using the TST per national guidelines and many patients had never heard of isoniazid preventive therapy (IPT). Nearly all participants supported the idea of latent TB screening using routine blood drawn for CD4 counts. CONCLUSIONS: Findings indicate that screening for latent TB infection using QGIT from blood drawn for CD4 counts among PLHIV is an acceptable approach to increase latent TB detection given the challenges associated with ensuring systematic latent TB screening in overburdened public clinics. TRIAL REGISTRATION: The results presented here were from formative research related to the TEKO trial (Identifier NCT02119130 , registered 10 April 2014).

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