Drug resistance and epidemiological success of modern Mycobacterium tuberculosis lineages in western India.

BACKGROUND: Transmission is contributing to the slow decline of tuberculosis (TB) incidence globally. Drivers of TB transmission in India, the country estimated to carry a quarter of the World's burden, are not well studied. We conducted a genomic epidemiology study to compare epidemiological success, host factors and drug resistance (DR) among the four major Mycobacterium tuberculosis (Mtb) lineages (L1-4) circulating in Pune, India. METHODS: We performed whole-genome sequencing (WGS) of Mtb sputum culture-positive isolates from participants in two prospective cohort studies and predicted genotypic susceptibility using a validated random forest model. We used maximum likelihood estimation to build phylogenies. We compared lineage specific phylogenetic and time-scaled metrics to assess epidemiological success. RESULTS: Of the 642 isolates that underwent WGS, 612 met sequence quality criteria. Most isolates belonged to L3 (44.6%). The majority (61.1%) of multidrug-resistant isolates belonged to L2 (P < 0.001). In molecular dating, L2 demonstrated a higher rate and more recent resistance acquisition. We measured higher clustering, and time-scaled haplotypic density (THD) for L4 and L2 compared to L3 and/or L1 suggesting higher epidemiological success. L4 demonstrated higher THD and clustering (OR 5.1 (95% CI 2.3-12.3) in multivariate models controlling for host factors and DR. CONCLUSION: L2 shows a higher frequency of DR and both L2 and L4 demonstrate evidence of higher epidemiological success than L3 or L1 in the study setting. Our findings highlight the need for contact tracing around TB cases, and heightened surveillance of TB DR in India.

Reducing HIV-associated post-hospital mortality through home-based care in South Africa: a randomized controlled trial.

BACKGROUND: Twenty-three percent of people with HIV (PWH) die within 6-months of hospital discharge. We tested the hypothesis whether a series of structured home visits could reduce mortality. METHODS: We designed a disease neutral home visit package with up to 6 home visits starting 1-week post-hospitalization and every 2 weeks thereafter. The home visit team used a structured assessment algorithm to evaluate and triage social and medical needs of the participant and provide nutritional support. We compared all-cause mortality 6-months following discharge for the intervention compared to usual care in a pilot randomized trial conducted in South Africa. To inform potential scale-up we also included and separately analyzed a group of people without HIV (PWOH). RESULTS: We enrolled 125 people with HIV and randomized them 1:1 to the home visit intervention or usual care. Fourteen were late exclusions because of death prior to discharge or delayed discharge leaving 111 for analysis. The median age was 39 years, 31% were men; and 70% had advanced HIV disease. At six months among PWH 4 (7.3%) in the home visit arm and 10 (17.9%) in the usual care arm (p = 0.09) had died. Among the 70 PWOH enrolled overall 6-month mortality was 10.1%. Of those in the home visit arm, 91% received at least one home visit. CONCLUSIONS: We demonstrated feasibility of delivering post-hospital home visits and demonstrated preliminary efficacy among PWH with a substantial, but not statistically significant, effect size (59% reduction in mortality). COVID-19 related challenges resulted in under-enrollment.

Tuberculosis Pathways to Care and Transmission of Multidrug Resistance in India.

Rationale: India is experiencing a regional increase in cases of multidrug-resistant tuberculosis (MDR-TB). Objectives: Given the complexity of MDR-TB diagnosis and care, we sought to address key knowledge gaps in MDR risk factors, care delays, and drivers of delay to help guide disease control. Methods: From January 2018 to September 2019, we conducted interviews with adults registered with the National TB Elimination Program for MDR (n = 128) and non-MDR-TB (n = 269) treatment to quantitatively and qualitatively study care pathways. We collected treatment records and GeneXpert-TB/RIF diagnostic reports. Measurements and Main Results: MDR-TB was associated with young age and crowded residence. GeneXpert rifampicin resistance diversity was measured at 72.5% Probe E. Median time from symptom onset to diagnosis of MDR was 90 days versus 60 days for non-MDR, Wilcoxon P < 0.01. Delay decreased by a median of 30 days among non-MDR patients with wider access to GeneXpert, Wilcoxon P = 0.02. Pathways to care were complex, with a median (interquartile range) of 4 (3-5) and 3 (2-4) encounters for MDR and non-MDR, respectively. Of patients with MDR-TB, 68% had their first encounter in the private sector, and this was associated with a larger number of subsequent healthcare encounters and catastrophic expenditure. Conclusions: The association of MDR with young age, crowding, and low genotypic diversity raises concerns of ongoing MDR transmission fueled by long delays in care. Delays are decreasing with GeneXpert use, suggesting the need for routine use in presumptive TB. Qualitatively, we identify the need to improve patient retention in the National TB Elimination Program and highlight patients' trust relationship with private providers.

Household Contact Tracing With Intensified Tuberculosis and Human Immunodeficiency Virus Screening in South Africa: A Cluster-Randomized Trial.

BACKGROUND: Household contact tracing for tuberculosis (TB) may facilitate diagnosis and access to TB preventive treatment (TPT). We investigated whether household contact tracing and intensive TB/human immunodeficiency virus (HIV) screening would improve TB-free survival. METHODS: Household contacts of index TB patients in 2 South African provinces were randomized to home tracing and intensive HIV/TB screening or standard of care (SOC; clinic referral letters). The primary outcome was incident TB or death at 15 months. Secondary outcomes included tuberculin skin test (TST) positivity in children ≤14 years and undiagnosed HIV. RESULTS: From December 2016 through March 2019, 1032 index patients (4459 contacts) and 1030 (4129 contacts) were randomized to the intervention and SOC arms. Of intervention arm contacts, 3.2% (69 of 2166) had prevalent microbiologically confirmed TB. At 15 months, the cumulative incidence of TB or death did not differ between the intensive screening (93 of 3230, 2.9%) and SOC (80 of 2600, 3.1%) arms (hazard ratio, 0.90; 95% confidence interval [CI], .66-1.24). TST positivity was higher in the intensive screening arm (38 of 845, 4.5%) compared with the SOC arm (15 of 800, 1.9%; odds ratio, 2.25; 95% CI, 1.07-4.72). Undiagnosed HIV was similar between arms (41 of 3185, 1.3% vs 32 of 2543, 1.3%; odds ratio, 1.02; 95% CI, .64-1.64). CONCLUSIONS: Household contact tracing with intensive screening and referral did not reduce incident TB or death. Providing referral letters to household contacts of index patients is an alternative strategy to home visits. CLINICAL TRIALS REGISTRATION: ISRCTN16006202.

Whole Genome Sequencing Assessing Impact of Diabetes Mellitus on Tuberculosis Mutations and Type of Recurrence in India.

BACKGROUND: Evidence describing the impact of diabetes mellitus (DM) on the recurrence and mutation rate of Mycobacterium tuberculosis (Mtb) is limited. METHODS: This study was nested in 3 cohort studies of tuberculosis (TB) patients with and without DM in India. Paired Mtb isolates recovered at baseline and treatment failure/recurrence underwent whole genome sequencing. We compared acquisition of single-nucleotide polymorphisms (SNPs), TB drug resistance mutations, and type of recurrence (endogenous reactivation [<8 SNPs] or exogenous reinfection [≥8 SNPs]) by DM status. RESULTS: Of 1633 enrolled in the 3 parent cohorts, 236 (14.5%) had microbiologically confirmed TB treatment failure/recurrence; 76 Mtb isolate pairs were available for sequencing (22 in TB-DM and 54 in TB-only). The SNP acquisition rate was overall was 0.43 (95% confidence interval [CI], .25-.64) per 1 person-year (PY); 0.77 (95% CI, .40-1.35) per 1 PY, and 0.44 (95% CI, .19-.86) per 1 PY at treatment failure and recurrence, respectively. Significant difference in SNP rates by DM status was seen at recurrence (0.21 [95% CI, .04-.61]) per 1 PY for TB-only vs 1.28 (95% CI, .41-2.98) per 1 PY for TB-DM; P = .02). No significant difference in SNP rates by DM status was observed at treatment failure. Acquired TB drug resistance was seen in 4 of 18 (22%) in TB-DM vs 4 of 45 (9%) in TB-only (P = .21). Thirteen (17%) participants had exogenous reinfection; the reinfection rate at recurrence was 25% (3/12) for TB-DM vs 17% (4/24) in TB-only (P = .66). CONCLUSIONS: Considerable intrahost Mtb mutation rates were present at recurrence among patients with DM in India. One-fourth of patients with DM had exogenous reinfection at recurrence.

Host lipidome and tuberculosis treatment failure.

INTRODUCTION: Host lipids play important roles in tuberculosis (TB) pathogenesis. Whether host lipids at TB treatment initiation (baseline) affect subsequent treatment outcomes has not been well characterised. We used unbiased lipidomics to study the prospective association of host lipids with TB treatment failure. METHODS: A case-control study (n=192), nested within a prospective cohort study, was used to investigate the association of baseline plasma lipids with TB treatment failure among adults with pulmonary TB. Cases (n=46) were defined as TB treatment failure, while controls (n=146) were those without failure. Complex lipids and inflammatory lipid mediators were measured using liquid chromatography mass spectrometry techniques. Adjusted least-square regression was used to assess differences in groups. In addition, machine learning identified lipids with highest area under the curve (AUC) to classify cases and controls. RESULTS: Baseline levels of 32 lipids differed between controls and those with treatment failure after false discovery rate adjustment. Treatment failure was associated with lower baseline levels of cholesteryl esters and oxylipin, and higher baseline levels of ceramides and triglycerides compared to controls. Two cholesteryl ester lipids combined in a unique classifier model provided an AUC of 0.79 (95% CI 0.65-0.93) in the test dataset for prediction of TB treatment failure. CONCLUSIONS: We identified lipids, some with known roles in TB pathogenesis, associated with TB treatment failure. In addition, a lipid signature with prognostic accuracy for TB treatment failure was identified. These lipids could be potential targets for risk-stratification, adjunct therapy and treatment monitoring.

Baseline IL-6 is a biomarker for unfavourable tuberculosis treatment outcomes: a multisite discovery and validation study.

BACKGROUND: Biomarkers of unfavourable tuberculosis (TB) treatment outcomes are needed to accelerate new drug and regimen development. Whether plasma cytokine levels can predict unfavourable TB treatment outcomes is unclear. METHODS: We identified and internally validated the association between 20 a priori selected plasma inflammatory markers and unfavourable treatment outcomes of failure, recurrence and all-cause mortality among adults with drug-sensitive pulmonary TB in India. We externally validated these findings in two independent cohorts of predominantly diabetic and HIV co-infected TB patients in India and South Africa, respectively. RESULTS: Pre-treatment interferon-γ, interleukin (IL)-13 and IL-6 were associated with treatment failure in the discovery analysis. Internal validation confirmed higher pre-treatment IL-6 concentrations among failure cases compared with controls. External validation among predominantly diabetic TB patients found an association between pre-treatment IL-6 concentrations and subsequent recurrence and death. Similarly, external validation among predominantly HIV co-infected TB patients found an association between pre-treatment IL-6 concentrations and subsequent treatment failure and death. In a pooled analysis of 363 TB cases from the Indian and South African validation cohorts, high pre-treatment IL-6 concentrations were associated with higher risk of failure (adjusted OR (aOR) 2.16, 95% CI 1.08-4.33; p=0.02), recurrence (aOR 5.36, 95% CI 2.48-11.57; p<0.001) and death (aOR 4.62, 95% CI 1.95-10.95; p<0.001). Adding baseline IL-6 to a risk prediction model comprised of low body mass index, high smear grade and cavitation improved model performance by 15% (C-statistic 0.66 versus 0.76; p=0.02). CONCLUSIONS: Pre-treatment IL-6 is a biomarker for unfavourable TB treatment outcomes. Future studies should identify optimal IL-6 concentrations for point-of-care risk prediction.

The Impact of Hypertension and Use of Calcium Channel Blockers on Tuberculosis Treatment Outcomes.

BACKGROUND: Hypertension induces systemic inflammation, but its impact on the outcome of infectious diseases like tuberculosis (TB) is unknown. Calcium channel blockers (CCB) improve TB treatment outcomes in preclinical models, but their effect in patients with TB remain unclear. METHODS: This retrospective cohort study, including all patients > 18 years receiving treatment for culture-confirmed, drug-sensitive TB from 2000 to 2016 at the National Taiwan University Hospital, assessed the association of hypertension and CCB use with all-cause and infection-related mortality during the first 9 months of TB treatment, as well as sputum smear microscopy and sputum culture positivity at 2 and 6 months. RESULTS: Of the 2894 patients, 1052 (36.4%) had hypertension. A multivariable analysis revealed that hypertension was associated with increased mortality due to all causes (hazard ratio [HR], 1.57; 95% confidence interval [CI], 1.23-1.99) and infections (HR, 1.87; 95% CI, 1.34-2.6), but there were no statistical differences in microbiological outcomes when stratified based on hypertensive group. Dihydropyridine-CCB (DHP-CCB) use was associated only with reduced all-cause mortality (HR, 0.67; 95% CI, .45-.98) by univariable Cox regression. There were no associations between DHP-CCB use and infection-related mortality (HR, 0.78; 95% CI, .46-1.34) or microbiological outcomes in univariable or multivariable regression analyses. CONCLUSIONS: Patients with hypertension have increased all-cause mortality and infection-related mortality during the 9 months following TB treatment initiation. DHP-CCB use may lower all-cause mortality in TB patients with hypertension. The presence of hypertension or the use of CCB did not result in a significant change in microbiological outcomes.

Ethical Implications of eHealth Tools for Delivering STI/HIV Laboratory Results and Partner Notifications.

PURPOSE OF REVIEW: eHealth tools are increasingly utilized for communication with patients. Although efficacious and cost-effective, these tools face several barriers that challenge their ethical use in sexual health. We reviewed literature from the past decade to pick illustrative studies of eHealth tools that deliver results of laboratory tests for sexually transmitted infections, including the human immunodeficiency virus, as well as partner notifications. We describe ethical implications for such technologies. RECENT FINDINGS: Our review found that despite widespread research on the use of eHealth tools in delivering laboratory results and partner notifications, these studies rarely measured or reported on the ethical implications. Such implications can be organized according to the four major principles in bioethics: beneficence, patient autonomy, non-maleficence, and justice. The beneficence of eHealth typically measures efficacy in comparison to existing standards of care. Patient autonomy includes the ability to opt in or out of eHealth tools, right-based principles of consent, and sovereignty over healthcare data. To adhere to the principle of non-maleficence, relevant harms must be identified and measured-such as unintentional disclosure of illness, sexual orientation, or sexual activity. Justice must also be considered to accommodate all users equally, irrespective of their literacy level, with easy-to-use platforms that provide clear messages. Based on case studies from this review, we developed a list of recommendations for the ethical development and evaluation of eHealth platforms to deliver STI/HIV results to patients and notifications to partners.

Subtherapeutic Rifampicin Concentration Is Associated With Unfavorable Tuberculosis Treatment Outcomes.

BACKGROUND: The relationships between first-line drug concentrations and clinically important outcomes among patients with tuberculosis (TB) remain poorly understood. METHODS: We enrolled a prospective cohort of patients with new pulmonary TB receiving thrice-weekly treatment in India. The maximum plasma concentration of each drug was determined at months 1 and 5 using blood samples drawn 2 hours postdose. Subtherapeutic cutoffs were: rifampicin <8 µg/mL, isoniazid <3 µg/mL, and pyrazinamide <20 µg/mL. Factors associated with lower log-transformed drug concentrations, unfavorable outcomes (composite of treatment failure, all-cause mortality, and recurrence), and individual outcomes were examined using Poisson regression models. RESULTS: Among 404 participants, rifampicin, isoniazid, and pyrazinamide concentrations were subtherapeutic in 85%, 29%, and 13%, respectively, at month 1 (with similar results for rifampicin and isoniazid at month 5). Rifampicin concentrations were lower with human immunodeficiency virus coinfection (median, 1.6 vs 4.6 µg/mL; P = .015). Unfavorable outcome was observed in 19%; a 1-µg/mL decrease in rifampicin concentration was independently associated with unfavorable outcome (adjusted incidence rate ratio [aIRR], 1.21 [95% confidence interval {CI}, 1.01-1.47]) and treatment failure (aIRR, 1.16 [95% CI, 1.05-1.28]). A 1-µg/mL decrease in pyrazinamide concentration was associated with recurrence (aIRR, 1.05 [95% CI, 1.01-1.11]). CONCLUSIONS: Rifampicin concentrations were subtherapeutic in most Indian patients taking a thrice-weekly TB regimen, and low rifampicin and pyrazinamide concentrations were associated with poor outcomes. Higher or more frequent dosing is needed to improve TB treatment outcomes in India.

Lipid mediators of inflammation and Resolution in individuals with tuberculosis and tuberculosis-Diabetes.

Individuals with concurrent tuberculosis (TB) and Type 2 diabetes (DM) have a higher risk of adverse outcomes. To better understand potential immunological differences, we utilized a comprehensive panel to characterize pro-inflammatory and pro-resolving (i.e., mediators involved in the resolution of inflammation) lipid mediators in individuals with TB and TB-DM. A nested cross-sectional study of 40 individuals (20 newly diagnosed DM and 20 without DM) was conducted within a cohort of individuals with active drug-susceptible treatment-naïve pulmonary TB. Lipid mediators were quantified in serum samples through lipid mediator profiling. We conducted correlation-based analysis of these mediators. Overall, the arachidonic acid-derived leukotriene and prostaglandin families were the most abundant pro-inflammatory lipid mediators, while lipoxins and maresins families were the most abundant pro-resolving lipid mediators in individuals with TB and TB-DM. Individuals with TB-DM had increased correlations and connectivity with both pro-inflammatory and pro-resolving lipid mediators compared to those with TB alone. We identified the most abundant lipid mediator metabolomes in circulation among individuals with TB and TB-DM; in addition, our data shows a substantial number of significant correlations between both pro-inflammatory and pro-resolving lipid mediators in individuals with TB-DM, delineating a molecular balance that potentially defines this comorbidity.

Promoting Tuberculosis Preventive Therapy for People Living with HIV in South Africa: Interventions Hindered by Complicated Clinical Guidelines and Imbalanced Patient-Provider Dynamics.

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

Secure Delivery of HIV-Related and Tuberculosis Laboratory Results to Patient Cell Phones: A Pilot Comparative Study.

South Africa processes 5.1 million HIV CD4, viral load (VL), and tuberculosis (TB) tests annually. This pilot non-randomized trial in South Africa explored an intervention ("MatlaMobile") to deliver laboratory results via mobile phone. Adults completing CD4, VL, and/or TB laboratory tests were enrolled-either receiving results by returning to clinic (control, n = 174) or mobile phone (intervention, n = 226). Study staff instructed control participants to return within 6 days (standard-of-care). MatlaMobile instructed intervention participants with clinically actionable results requiring intervention or treatment change (i.e., < 200 CD4 cells per milliliter, ≥ 400 viral copies per milliliter, or TB positive) to return immediately. A greater proportion of intervention participants than controls saw their results within 7 days of enrollment (73% vs. 8.6%, p < 0.001). Among participants instructed to return, more intervention participants (20%, n = 14/70) returned than controls (8.6%, n = 15/174, p = 0.02). MatlaMobile demonstrated that patients can quickly receive and respond appropriately to digital delivery of health information.

Formative research for an mHealth program to improve the HIV care continuum in South Africa.

In South Africa, high attrition rates throughout the care continuum present major barriers to controlling the HIV epidemic. Mobile health (mHealth) interventions may provide innovative opportunities for efficient healthcare delivery and improving retention in care. In this formative research, we interviewed 11 patients and 28 healthcare providers in North West Province, South Africa, to identify perceived benefits, concerns and suggestions for a future mHealth program to deliver HIV Viral Load and CD4 Count test results directly to patients via mobile phone. Thematic analysis found that reduced workload for providers, reduced wait times for patients, potential expanded uses and patient empowerment were the main perceived benefits of an mHealth program. Perceived concerns included privacy, disseminating distressing results through text messages and patients' inability to interpret results. Participants felt that an mHealth program should complement face-to-face interactions and educational information to interpret results is needed. Providers identified logistical considerations and suggested protocols be developed. An mHealth program to deliver HIV test results directly to patients could mitigate multiple barriers to care but needs to be tested for efficacy. Concerns identified by patients and providers must be addressed in designing the program to successfully integrate with health facility workflow and ensure its sustainability.

Seventy Years of Tuberculosis Prevention: Efficacy, Effectiveness, Toxicity, Durability, and Duration.

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

Maternal Motivation to Take Preventive Therapy in Antepartum and Postpartum Among HIV-Positive Pregnant Women in South Africa: A Choice Experiment.

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/mm3. 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.

Incidence of tuberculosis in HIV-infected adults on first- and second-line antiretroviral therapy in India.

BACKGROUND: Programmatic data on the baseline risk of tuberculosis in people living with HIV (PLHIV) are needed to evaluate long-term effectiveness of the ongoing isoniazid preventive therapy (IPT) roll-out in India. METHODS: We estimated the incidence rate and risk factors of tuberculosis disease in adult PLHIV initiating first- and second-line anti-retroviral therapy (ART) prior to widespread IPT in a public ART center in Pune, India. RESULTS: 4067 participants contributing 5205.7 person-years of follow-up on first-line ART and 871 participants contributing 1031.7 person-years of follow-up on second-line ART were included in the analysis. The incidence rate of tuberculosis was 4.39 cases (95%CI 3.86-5.00) per 100 person-years on first-line ART and 1.64 cases (95%CI 1.01-2.63) per 100 person-years on second-line ART (p < 0.001). After adjusting for competing risks, male sex (aSHR = 1.33, 95%CI 1.02-1.74, p = 0.03), urban residence (aSHR = 1.53, 95%CI 1.13-2.07, p = 0.006) and CD4+ counts < 350 cells/mm3 (aSHR = 3.06 vs CD4 > 350 cells/mm3, 95%CI 1.58-5.94, p < 0.001) at ART initiation were associated with higher risk of tuberculosis independent of ART regimen. CONCLUSION: Risk of tuberculosis was lower in PLHIV receiving second-line ART compared to first-line ART. Prioritizing IPT in PLHIV with low CD4+ counts, urban residence and in males may further mitigate the risk of tuberculosis during ART.

COach2Quit: A Pilot Randomized Controlled Trial of a Personal Carbon Monoxide Monitor for Smoking Cessation.

INTRODUCTION: Mobile phone-based 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 reduction in smoking, motivation to quit, and engagement and satisfaction with COach2Quit. An intention-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 carbon monoxide levels (in parts per million (ppm)) (intervention: -3.0 [interquartile range (IQR) -12.0, 2.0]; control: -2.5 [IQR -9.0, 2.0]) and median change in number of cigarettes smoked per 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 scale score (intervention: 6.3 [95% confidence interval = -2.2% to 14.8%]; control: -3.6 [95% confidence interval = -9.2% to 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.

Prevalence and Correlates of Snuff Use, and its Association With Tuberculosis, Among Women Living With HIV in South Africa.

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.

The association of household fine particulate matter and kerosene with tuberculosis in women and children in Pune, India.

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 µm 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 µg/m3, and did not vary between controls (179 µg/m3; IQR: 113-292) and cases (median 157 µg/m3; 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.