TB Modeling and Translational Epi Group

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- July 2018 -

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)

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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).

Cost-effectiveness of Preventive Therapy for Tuberculosis With Isoniazid and Rifapentine Versus Isoniazid Alone in High-Burden Settings. (2018). Johnson KT., Churchyard GJ., Sohn H., Dowdy DW, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 67, 1072-1078

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Background: A short-course regimen of 3 months of weekly rifapentine and isoniazid (3HP) has recently been recommended by the World Health Organization as an alternative to at least 6 months of daily isoniazid (isoniazid preventive therapy [IPT]) for prevention of tuberculosis (TB). The contexts in which 3HP may be cost-effective compared to IPT among people living with human immunodeficiency virus are unknown. Methods: We used a Markov state transition model to estimate the incremental cost-effectiveness of 3HP relative to IPT in high-burden settings, using a cohort of 1000 patients in a Ugandan HIV clinic as an emblematic scenario. Cost-effectiveness was expressed as 2017 US dollars per disability-adjusted life year (DALY) averted from a healthcare perspective over a 20-year time horizon. We explored the conditions under which 3HP would be considered cost-effective relative to IPT. Results: Per 1000 individuals on antiretroviral therapy in the reference scenario, treatment with 3HP rather than IPT was estimated to avert 9 cases of TB and 1 death, costing $9402 per DALY averted relative to IPT. Cost-effectiveness depended strongly on the price of rifapentine, completion of 3HP, and prevalence of latent TB. At a willingness to pay of $1000 per DALY averted, 3HP is likely to be cost-effective relative to IPT only if the price of rifapentine can be greatly reduced (to approximately $20 per course) and high treatment completion (85%) can be achieved. Conclusions: 3HP may be a cost-effective alternative to IPT in high-burden settings, but cost-effectiveness depends on the price of rifapentine, achievable completion rates, and local willingness to pay.

- March 2018 -

The effect of partner HIV status on motivation to take antiretroviral and isoniazid preventive therapies: a conjoint analysis. (2018). Kim HY., Hanrahan CF., Dowdy DW., Martinson N., Golub J., Bridges JFP, AIDS care, 30, 1298-1305

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Antiretroviral therapy (ART) and isoniazid preventive therapy (IPT) are important to reduce morbidity and mortality among people newly diagnosed of HIV. The successful uptake of ART and IPT requires a comprehensive understanding of patients' motivation to take such therapies. Partners also play an important role in the decision to be initiated and retained in care. We quantified patients' motivation to take preventive therapies (ART and IPT) and compared by partner HIV status among people newly diagnosed of HIV. We enrolled and surveyed adults (>/=18 years) with a recent HIV diagnosis (<6 months) from 14 public primary care clinics in Matlosana, South Africa. Participants received eight forced-choice tasks comparing two mutually exclusive sub-sets of seven possible benefits related to preventive therapies. A linear probability model was fitted to estimate the probability of prioritizing each benefit. Tests of concordance were conducted across partner HIV status (no partner, HIV- or unknown, or HIV+). A total of 424 people completed surveys. At the time of interview, 272 (64%) were on ART and 334 (79%) had a partner or spouse. Keeping themselves healthy for their family was the most important motivator to take preventive therapies (p < 0.001). Preventing HIV transmission to partners was also highly prioritized among participants with current partners independent of partner's HIV status (p < 0.001), but it was least prioritized among those without current partners (p = 0.72). Keeping themselves healthy was less prioritized. We demonstrate that social responsibility such as supporting family and preventing HIV transmission to partners may pose greater motivation for ART and IPT initiation and adherence compared to individual health benefits. These messages should be emphasized to provide effective patient-centered care and counseling.

Predictors of isoniazid preventive therapy completion among adults newly diagnosed with HIV in rural Malawi. (2018). Little KM., Khundi M., Barnes GL., Ngwira LG., Nkhoma A., Makombe S., Corbett EL., Chaisson RE., Dowdy DW, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 22, 371-377

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SETTING: To reduce the risk of tuberculosis (TB) among individuals with human immunodeficiency virus (HIV) infection, the World Health Organization recommends at least 6 months of isoniazid preventive therapy (IPT). Completion of IPT remains a major challenge in resource-limited settings. OBJECTIVE: To evaluate predictors of IPT completion in individuals newly diagnosed with HIV. DESIGN: Predictors of IPT completion among adults newly diagnosed with HIV in rural Malawi were evaluated using a multilevel logistic regression model. RESULTS: Of 974 participants who screened negative for active TB and were started on IPT, 732 (75%) completed treatment. Only one IPT-eligible individual refused treatment. Participants who were aged <25 years (compared with those aged >/=45 years, adjusted OR [aOR] 0.33, 95%CI 0.18-0.60) and male (compared to non-pregnant females, aOR 0.57, 95%CI 0.37-0.88) had lower odds of IPT completion. CONCLUSION: IPT provision at the time of initial HIV diagnosis was highly acceptable in rural Malawi; three quarters of those who initiated IPT successfully completed therapy. We observed lower odds of completion among males and among female participants aged <25 years. Additional efforts may be needed to ensure IPT completion among males and young females who have recently been diagnosed with HIV.

Of Testing and Treatment: Implications of Implementing New Regimens for Multidrug-Resistant Tuberculosis. (2018). Dowdy DW., Theron G., Tornheim JA., Warren R., Kendall EA, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 65, 1206-1211

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A novel, shorter-course regimen for treating multidrug-resistant (MDR) tuberculosis was recently recommended by the World Health Organization. However, the most appropriate use of drug susceptibility testing (DST) to support this regimen is less clear. Implementing countries must therefore often choose between using a standardized regimen despite high levels of underlying drug resistance or require more stringent DST prior to treatment initiation. The former carries a high likelihood of exposing patients to de facto monotherapy with a critical drug class (fluoroquinolones), whereas the latter could exclude large groups of patients from their most effective treatment option. We discuss the implications of this dilemma and argue for an approach that will integrate DST into the delivery of any novel antimicrobial regimen, without excessively stringent requirements. Such guidance could make the novel MDR tuberculosis regimen available to most patients while reducing the risk of generating additional drug resistance.

Tuberculosis Mortality in the United States: Epidemiology and Prevention Opportunities. (2018). Beavers SF., Pascopella L., Davidow AL., Mangan JM., Hirsch-Moverman YR., Golub JE., Blumberg HM., Webb RM., Royce RA., Buskin SE., Leonard MK., Weinfurter PC., Belknap RW., Hughes SE., Warkentin JV., Welbel SF., Miller TL., Kundipati SR., Lauzardo M., Barry PM., Katz DJ., Garrett DO., Graviss EA., Flood JM, Annals of the American Thoracic Society

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RATIONALE: More information on risk factors for death from tuberculosis in the United States could help reduce the tuberculosis mortality rate, which has remained steady for over a decade. Objective(s) To identify risk factors for tuberculosis-related death in adults. METHODS: We performed a retrospective study of 1,304 adults with tuberculosis who died before treatment completion and 1,039 frequency-matched controls who completed tuberculosis treatment in 2005-2006 in thirteen states reporting 65% of U.S. tuberculosis cases. We used in-depth record abstractions and a standard algorithm to classify deaths in persons with tuberculosis as tuberculosis-related or not. We then compared these classifications to causes of death as coded in death certificates. We used multivariable logistic regression to calculate adjusted odds ratios (aOR) for predictors of tuberculosis-related death among adults compared with those who completed tuberculosis treatment. RESULTS: Of 1,304 adult deaths, 942 (72%) were tuberculosis-related, 272 (21%) were not, and 90 (7%) couldn't be classified. Of 847 tuberculosis-related deaths with death certificates available, 378 (45%) did not list tuberculosis as a cause of death. Adjusting for known risks, we identified new risks for tuberculosis-related death during treatment: absence of pyrazinamide in the initial regimen (aOR=3.4, 95% CI=1.9-6.0); immunosuppressive medications (aOR=2.5, 95% CI=1.1-5.6); incomplete TB diagnostic evaluation (aOR=2.2, 95% CI=1.5-3.3), and an alternative non-TB diagnosis prior to TB diagnosis (aOR=1.6, 95% CI=1.2-2.2). Conclusions Most persons who died with tuberculosis had a tuberculosis-related death. Intensive record review revealed tuberculosis as a cause of death more often than did death certificate diagnoses. New tools, such as a TB mortality risk score based on our study findings, may identify TB patients for in-hospital interventions to prevent death.

- February 2018 -

Delay in seeking care for tuberculosis symptoms among adults newly diagnosed with HIV in rural Malawi. (2018). Ngwira LG., Dowdy DW., Khundi M., Barnes GL., Nkhoma A., Choko AT., Murowa M., Chaisson RE., Corbett EL., Fielding K, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 22, 280-286

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SETTING: Ten primary health clinics in rural Thyolo District, Malawi. OBJECTIVE: Tuberculosis (TB) is a common initial presentation of human immunodeficiency virus (HIV) infection. We investigated the time from TB symptom onset to HIV diagnosis to describe TB health-seeking behaviour in adults newly diagnosed with HIV. DESIGN: We asked adults (>/=18 years) about the presence and duration of TB symptoms at the time of receiving a new HIV diagnosis. Associations with delayed health seeking (defined as >30 and >90 days from the onset of TB symptoms) were evaluated using multivariable logistic regression. RESULTS: TB symptoms were reported by 416 of 1265 participants (33%), of whom 36% (150/416) had been symptomatic for >30 days before HIV testing. Most participants (260/416, 63%) were below the poverty line (US$0.41 per household member per day). Patients who first sought care from informal providers had an increased odds of delay of >30 days (adjusted odds ratio [aOR] 1.6, 95%CI 0.9-2.8) or 90 days (aOR 2.0, 95%CI 1.1-3.8). CONCLUSIONS: Delayed health seeking for TB-related symptoms was common. Poverty was ubiquitous, but had no clear relationship to diagnostic delay. HIV-positive individuals who first sought care from informal providers were more likely to experience diagnostic delays for TB symptoms.

What Will It Take to Reduce HIV Incidence in the United States: A Mathematical Modeling Analysis. (2018). Perry A., Kasaie P., Dowdy DW., Shah M, Open forum infectious diseases, 5, ofy008

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Background: The National HIV/AIDS Strategy has set ambitious goals to improve the epidemic in the United States. However, there is a paucity of usable program-level benchmarks tied to population-level epidemiologic goals. Our objective was to define tangible benchmarks for annual rates along the care continuum that are likely to translate to meaningful reductions in incidence. Methods: We used a validated mathematical model of HIV transmission and care engagement to characterize care continuum parameters that would translate into 50% reductions in incidence by 2025, compared with a base case scenario of the current US care continuum. We generated a large pool of simulations in which rates of screening, linkage, and retention in care were varied across wide ranges to evaluate permutations that halved incidence by 2025. Results: Among all simulations, 7% achieved a halving of incidence. It was impossible for our simulations to achieve this target if the annual rate of disengagement from care exceeded 20% per year, even at high rates of care reengagement. When retention in care was 95% per year and people living with HIV (PLWH) out of care reengaged within 1.5 years (on average), the probability of halving incidence by 2025 was approximately 90%. Conclusions: HIV programs should aim to retain at least 95% of PLWH in care annually and reengage people living with HIV into care within an average of 1.5 years to achieve the goal of halving HIV incidence by 2025.

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