Publications by authors named "Amita Gupta"

233 Publications

Stages of pregnancy and HIV affect diagnosis of tuberculosis infection and Mycobacterium tuberculosis (MTB)-induced immune response: Findings from PRACHITi, a cohort study in Pune, India.

Int J Infect Dis 2021 Sep 10. Epub 2021 Sep 10.

Byramjee Jeejeebhoy Government Medical College- Johns Hopkins University Clinical Trials Unit, 1st Floor, ENT department, Jai Prakash Narayan Rd. Pune, 411001, Maharashtra, India; Weill Cornell Medical College, 402 E. 67th Street, 2nd floor, New York, NY 10065, USA.

Background: Accurate tuberculosis infection (TBI) tests are critical for pregnant women, especially with HIV, who have a high risk of TB disease.

Methods: We enrolled interferon gamma release assay (IGRA)+ pregnant women with and without HIV in a longitudinal study, followed at delivery and 6 months postpartum. Tuberculin skin test (TST) and IGRA were compared by HIV status at each timepoint.

Results: Of 165 enrolled IGRA+ pregnant women: 35 (21%) had HIV and were on antiretroviral therapy with median CD4 of 476 (IQR 399-586). Compared to antepartum, significantly fewer women remained IGRA+ at delivery [HIV+ n=21/35 (62%, p=0.009); HIV- n=100/130 (77%, p=0.002)] and postpartum [HIV+ n=30/35 (87%, p=0.03); HIV- n=116/130 (89%, p=0.01)]. IGRA/TST discordance was high in pregnant women (HIV+: 51%; HIV-: 25%). Median IFN-γ was lowest for all women at delivery; significantly lower in women with HIV at all timepoints compared to women without HIV. TB incidence was 50/ 1000 person-years and 18/1000 person-years among women with and without HIV respectively.

Conclusions: Pregnancy affects TBI test results and reduces IFN-γ response to M. tuberculosis stimulation. Despite adequate CD4 counts, women with HIV express less IFN-γ than women without HIV , which may explain the high TB incidence in postpartum women with HIV.
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http://dx.doi.org/10.1016/j.ijid.2021.09.010DOI Listing
September 2021

Urine Lipoarabinomannan Testing in Adults With Advanced Human Immunodeficiency Virus in a Trial of Empiric Tuberculosis Therapy.

Clin Infect Dis 2021 08;73(4):e870-e877

Division of Infectious Diseases, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina,USA.

Background: The urine lipoarabinomannan (LAM) antigen test is a tuberculosis (TB) diagnostic test with highest sensitivity in individuals with advanced human immunodeficiency virus (HIV). Its role in TB diagnostic algorithms for HIV-positive outpatients remains unclear.

Methods: The AIDS Clinical Trials Group (ACTG) A5274 trial demonstrated that empiric TB therapy did not improve 24-week survival compared to isoniazid preventive therapy (IPT) in TB screen-negative HIV-positive adults initiating antiretroviral therapy with CD4 counts <50 cells/µL. Retrospective LAM testing was performed on stored urine obtained at baseline. We determined the proportion of LAM-positive participants and conducted modified intent-to-treat analysis excluding LAM-positive participants to determine the effect on 24-week survival, TB incidence, and time to TB using Kaplan-Meier method.

Results: A5274 enrolled 850 participants; 53% were male and the median CD4 count was 18 (interquartile range, 9-32) cells/µL. Of the 850, 566 (67%) had LAM testing (283 per arm); 28 (5%) were positive (21 [7%] and 7 [2%] in the empiric and IPT arms, respectively). Of those LAM-positive, 1 participant in each arm died and 5 of 21 and 0 of 7 in empiric and IPT arms, respectively, developed TB. After excluding these 28 cases, there were 19 and 21 deaths in the empiric and IPT arms, respectively (P = .88). TB incidence remained higher (4.6% vs 2%, P = .04) and time to TB remained faster in the empiric arm (P = .04).

Conclusions: Among outpatients with advanced HIV who screened negative for TB by clinical symptoms, microscopy, and Xpert testing, LAM testing identified an additional 5% of individuals with TB. Positive LAM results did not change mortality or TB incidence.
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http://dx.doi.org/10.1093/cid/ciab179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8366821PMC
August 2021

Host Lipidome and Tuberculosis Treatment Failure.

Eur Respir J 2021 Jun 17. Epub 2021 Jun 17.

National Institute for Research in Tuberculosis, Chennai, Tamil Nadu, India.

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 utilised 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 (CE) and oxylipin, and higher baseline levels of ceramides and triglycerides compared to controls. Two CE lipids combined in a unique classifier model provided an AUC of 0.79 (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. A lipid signature with prognostic accuracy for TB treatment failure was also identified. These lipids could be potential targets for risk-stratification, adjunct therapy and treatment monitoring.
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http://dx.doi.org/10.1183/13993003.04532-2020DOI Listing
June 2021

Pharmacokinetics and Safety of Three Months of Weekly Rifapentine and Isoniazid for Tuberculosis Prevention in Pregnant Women.

Clin Infect Dis 2021 Jul 29. Epub 2021 Jul 29.

Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Background: Pregnancy increases the risk of tuberculosis and its complications. A 3-month regimen of weekly isoniazid and rifapentine (3HP) is safe and effective for tuberculosis prevention in adults and children, including those with HIV, but 3HP has not been evaluated in pregnancy.

Methods: IMPAACT 2001 was a Phase I/II trial evaluating the pharmacokinetics and safety of 3HP among pregnant women with indications for tuberculosis preventative therapy in Haiti, Kenya, Malawi, Thailand, and Zimbabwe (NCT02651259). Isoniazid and rifapentine were provided at standard doses (900mg weekly). Pharmacokinetic sampling was performed with the first (2 nd/3 rd trimester) and twelfth (3 rd trimester/postpartum) doses. Non-linear mixed effects models were used to estimate drug population pharmacokinetics.

Results: Of 50 participants, 20 had HIV and were taking efavirenz-based antiretroviral therapy. Among women without HIV, clearance of rifapentine was 28% lower during pregnancy than postpartum (1.20 vs. 1.53 L/h, p<0.001), with area under the concentration-time curve (AUCSS) of 786 and 673 mg*hr/L, respectively. In pregnant women with HIV, clearance was 30% higher than women without HIV (p<0.001), resulting in a lower AUCss (522 mg*h/L); clearance did not change significantly between pregnancy and postpartum. Pregnancy did not impact isoniazid pharmacokinetics. There were no drug-related serious adverse events, treatment discontinuations, or TB cases in women or infants.

Conclusions: 3HP does not require dose adjustment in pregnancy. Rifapentine clearance is higher among women with HIV, but all women achieved exposures of rifapentine and isoniazid associated with successful tuberculosis prevention. The data support proceeding with larger safety-focused studies of 3HP in pregnancy.
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http://dx.doi.org/10.1093/cid/ciab665DOI Listing
July 2021

Utility of the Interferon-Gamma Release Assay for Latent Tuberculosis Infection Screening among Indian Health-Care Workers.

Indian J Community Med 2021 Apr-Jun;46(2):281-284. Epub 2021 May 29.

Byramjee Jeejeebhoy Government Medical College-Johns Hopkins Clinical Trials Unit, Pune, Maharashtra, India.

Background: The utility of interferon-gamma release assays (IGRAs) for latent tuberculosis infection (LTBI) screening among health-care workers (HCWs) in low- and middle-income countries (LMICs) remains unclear.

Methods: This was a prospective cohort study among HCW trainees undergoing annual LTBI screening via tuberculin skin test (TST) and QuantiFERON TB Gold Test-in-tube (QFT-GIT) in Pune, India. TST induration ≥ 10 mm and QFT-GIT ≥ 0.35 IU/ml were considered positive. Test concordance was evaluated at entry among the entire cohort and at 1 year among baseline TST-negative participants with follow-up testing. Overall test agreement was evaluated at both timepoints using the kappa statistic: fair (k < 0.40), good (0.41 ≥ k ≤0.60), or strong (k > 0.60).

Results: Of 200 participants, prevalent LTBI was detected in 42 (21%) via TST and 45 (23%) via QFT-GIT; QFT-GIT was positive in 27/42 (64%) TST-positive and 18/158 (11%) TST-negative trainees. Annual TST conversion was 28% (40/142) and included 11 trainees with baseline TST-/IGRA+; QFT-GIT was positive in 17/40 (43%) TST-positive and 5/102 (5%) TST-negative trainees. Overall test concordance was 84% (k = 0.52; 95% confidence interval [CI]: 0.38-0.66) and 80% (k = 0.44; 95% CI: 0.29-0.59) at baseline and 12 months, respectively.

Conclusions: We observed good overall agreement between TST and QFT-GIT, and QFT-GIT detected additional LTBI cases among TST-negative trainees with possible early detection of LTBI conversion. Overall, our results support the use of IGRA for annual LTBI screening among HCWs in a high burden LMIC setting.
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http://dx.doi.org/10.4103/ijcm.IJCM_761_20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8281831PMC
May 2021

Technical Difficult Subarachnoid Block in a Morbidly Obese Patient: Ultrasound Guidance and Improvisation is the Key to Success.

J Coll Physicians Surg Pak 2021 Jul;30(7):873-874

Department of Anaesthesia, Pain Medicine and Critical Care, VMMC and Safdarjung Hospital, New Delhi, India.

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http://dx.doi.org/10.29271/jcpsp.2021.07.873DOI Listing
July 2021

Impact of HIV status on systemic inflammation during pregnancy.

AIDS 2021 Jul 8. Epub 2021 Jul 8.

Department of Epidemiology, Columbia University Mailman School of Public Health, New York, USA Department of Medicine, Weill Cornell Medical College, New York, USA Department of Biostatistics, Columbia University Mailman School of Public Health, New York, USA Department of Obstetrics and Gynecology, Byramjee Jeejeebhoy Government Medical College, Pune, India Byramjee-Jeejeebhoy Government Medical college-Johns Hopkins University Clinical Research Site, Pune, India Instituto Goncalo Moniz, Fundação Oswaldo Cruz, Salvador, Brazil Multinational Organization Network Sponsoring Translational and Epidemiological Research, (MONSTER) Initiative, Salvador, Brazil Faculdade de Medicina, Universidade Federal da Bahia, Salvador, Brazil Curso de Medicina, Faculdade de Tecnologia e Ciências, Salvador, Brazil Universidade Salvador (UNIFACS), Laureate Universities, Salvador, Brazil Escola Bahiana de Medicina e Saúde Pública (EBMSP), Salvador, Brazil National Institutes of Health, National Institute for Research in Tuberculosis, International Center for Excellence in Research, Chennai, India Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, USA.

Objective: There are limited studies on the association of HIV infection with systemic inflammation during pregnancy.

Design: A cohort study (N = 220) of pregnant women with HIV (N = 70) (all on antiretroviral therapy) and without HIV (N = 150) were enrolled from an antenatal clinic in Pune, India.

Methods: The following systemic inflammatory markers were measured in plasma samples using immunoassays: soluble CD163 (sCD163), soluble CD14 (sCD14), intestinal fatty acid-binding protein (I-FABP), C-reactive protein (CRP), alpha 1-acid glycoprotein (AGP), interferon-β (IFNβ), interferon-γ (IFNγ), interleukin (IL)-1β, IL-6, IL-13, IL-17A and tumor necrosis factor α (TNFα). Generalized estimating equation (GEE) and linear regression models were used to assess the association of HIV status with each inflammatory marker during pregnancy and by trimester, respectively.

Results: Pregnant women with HIV had higher levels of markers for gut barrier dysfunction (I-FABP), monocyte activation (sCD14) and markers of systemic inflammation (IL-6 and TNFα), but surprisingly lower levels of AGP, an acute phase protein, compared to pregnant women without HIV, with some trimester-specific differences.

Conclusions: Our data show that women with HIV had higher levels of markers of gut barrier dysfunction, monocyte activation and systemic inflammation. These markers, some of which are associated with preterm birth, might help explain the increase in adverse birth outcomes in women with HIV and could suggest targets for potential interventions.
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http://dx.doi.org/10.1097/QAD.0000000000003016DOI Listing
July 2021

Integrative Multi-Omics Reveals Serum Markers of Tuberculosis in Advanced HIV.

Front Immunol 2021 8;12:676980. Epub 2021 Jun 8.

Center for Clinical Global Health Education and Center for Tuberculosis Research, Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States.

Tuberculosis (TB) accounts for disproportionate morbidity and mortality among persons living with HIV (PLWH). Conventional methods of TB diagnosis, including smear microscopy and Xpert MTB/RIF, have lower sensitivity in PLWH. Novel high-throughput approaches, such as miRNAomics and metabolomics, may advance our ability to recognize subclinical and difficult-to-diagnose TB, especially in very advanced HIV. We conducted a case-control study leveraging REMEMBER, a multi-country, open-label randomized controlled trial comparing 4-drug empiric standard TB treatment with isoniazid preventive therapy in PLWH initiating antiretroviral therapy (ART) with CD4 cell counts <50 cells/μL. Twenty-three cases of incident TB were site-matched with 32 controls to identify microRNAs (miRNAs), metabolites, and cytokines/chemokines, associated with the development of newly diagnosed TB in PLWH. Differentially expressed miRNA analysis revealed 11 altered miRNAs with a fold change higher than 1.4 or lower than -1.4 in cases relative to controls (p<0.05). Our analysis revealed no differentially abundant metabolites between cases and controls. We found higher TNFα and IP-10/CXCL10 in cases (p=0.011, p=0.0005), and higher MDC/CCL22 in controls (p=0.0072). A decision-tree algorithm identified gamma-glutamylthreonine and hsa-miR-215-5p as the optimal variables to classify incident TB cases (AUC 0.965; 95% CI 0.925-1.000). hsa-miR-215-5p, which targets genes in the TGF-β signaling pathway, was downregulated in cases. Gamma-glutamylthreonine, a breakdown product of protein catabolism, was less abundant in cases. To our knowledge, this is one of the first uses of a multi-omics approach to identify incident TB in severely immunosuppressed PLWH.
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http://dx.doi.org/10.3389/fimmu.2021.676980DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217878PMC
June 2021

Diabetes Mellitus and Tuberculosis Treatment Outcomes in Pune, India.

Open Forum Infect Dis 2021 Apr 4;8(4):ofab097. Epub 2021 Mar 4.

Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Background: Diabetes mellitus (DM) increases the risk of tuberculosis (TB) disease. Knowledge of the impact of DM on TB treatment outcomes is primarily based on retrospective studies.

Methods: We conducted a prospective cohort study of new pulmonary TB patients with and without DM (TB-DM and TB only) in India. The association of DM with a composite unfavorable TB treatment outcome (failure, recurrence, mortality) over 18 months was determined, and the effect of DM on all-cause mortality and early mortality (death during TB treatment) was assessed.

Results: Of 799 participants, 574 (72%) had TB only and 225 (28%) had TB-DM. The proportion of patients with DM who experienced the composite outcome was 20%, as compared with 21% for TB-only participants (adjusted hazard ratio [aHR], 1.13; 95% CI, 0.75-1.70). Mortality was higher in participants with DM (10% vs 7%), and early mortality was substantially higher among patients with DM (aHR, 4.36; 95% CI, 1.62-11.76).

Conclusions: DM was associated with early mortality in this prospective cohort study, but overall unfavorable outcomes were similar to participants without DM. Interventions to reduce mortality during TB treatment among people with TB-DM are needed.
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http://dx.doi.org/10.1093/ofid/ofab097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047862PMC
April 2021

Sex and gender differences in COVID testing, hospital admission, presentation, and drivers of severe outcomes in the DC/Maryland region.

medRxiv 2021 Apr 7. Epub 2021 Apr 7.

Background: Rates of severe illness and mortality from SARS-CoV-2 are greater for males, but the mechanisms for this difference are unclear. Understanding the differences in outcomes between males and females across the age spectrum will guide both public health and biomedical interventions.

Methods: Retrospective cohort analysis of SARS-CoV-2 testing and admission data in a health system. Patient-level data were assessed with descriptive statistics and logistic regression modeling was used to identify features associated with increased male risk of severe outcomes.

Results: In 213,175 SARS-CoV-2 tests, despite similar positivity rates (8.2%F vs 8.9%M), males were more frequently hospitalized (28%F vs 33%M). Of 2,626 hospitalized individuals, females had less severe presenting respiratory parameters and males had more fever. Comorbidity burden was similar, but with differences in specific conditions. Medications relevant for SARS-CoV-2 were used at similar frequency except tocilizumab (M>F). Males had higher inflammatory lab values. In a logistic regression model, male sex was associated with a higher risk of severe outcomes at 24 hours (odds ratio (OR) 3.01, 95%CI 1.75, 5.18) and at peak status (OR 2.58, 95%CI 1.78,3.74) among 18-49 year-olds. Block-wise addition of potential explanatory variables demonstrated that only the inflammatory labs substantially modified the OR associated with male sex across all ages.

Conclusion: Higher levels of clinical inflammatory labs are the only features that are associated with the heightened risk of severe outcomes and death for males in COVID-19.

Trial Registration: NA.

Funding: Hopkins inHealth; COVID-19 Administrative Supplement (HHS Region 3 Treatment Center), Office of the ASPR; NIH/NCI U54CA260492 (SK), NIH/NIA U54AG062333 (SK).
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http://dx.doi.org/10.1101/2021.04.05.21253827DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043487PMC
April 2021

Sex-biased clinical presentation and outcomes from COVID-19.

Clin Microbiol Infect 2021 08 1;27(8):1072-1073. Epub 2021 Apr 1.

W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, MD, USA. Electronic address:

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http://dx.doi.org/10.1016/j.cmi.2021.03.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8015344PMC
August 2021

Resistance to Mycobacterium tuberculosis Infection Among Household Contacts: A Multinational Study.

Clin Infect Dis 2021 Sep;73(6):1037-1045

Emory Rollins School of Public Health, Atlanta, Georgia, USA.

Background: Some contacts of patients with tuberculosis remain negative on tests for tuberculosis infection, despite prolonged exposure, suggesting they might be resistant to Mycobacterium tuberculosis infection. The objective of this multinational study was to estimate the proportion of household contacts resistant to M. tuberculosis (resisters).

Methods: We conducted a longitudinal study enrolling index patients enrolled in treatment for pulmonary multidrug- or rifampin-resistant tuberculosis and their household contacts. Contacts were tested for tuberculosis infection with a tuberculin skin test (TST) and interferon-gamma release assay (IGRA) at baseline and after 1 year. Exposure was quantified based on index patients' infectiousness, index patient and household contact interaction, and age. We explored multiple definitions of resistance to tuberculosis infection by varying TST negativity cutoffs (0 vs <5 mm), classification of missing test results, and exposure level.

Results: In total, 1016 contacts were evaluated from 284 households; 572 contacts aged ≥5 years had TST and longitudinal IGRA results available. And 77 (13%) or 71 (12%) contacts were classified as resisters with a <5 mm or 0 mm TST threshold, respectively. Among 263 highly exposed contacts, 29 (11%) or 26 (10%) were classified as resisters using TST cutoffs of <5 mm and 0 mm, respectively. The prevalence of resisters did not differ substantially by sex, age, human immunodeficiency virus (HIV) coinfection, or comorbid conditions.

Conclusions: At least 10% of household contacts can be classified as resistant to tuberculosis infection, depending on the definition used, including those with high exposure. Further studies to understand genetic or immunologic mechanisms underlying the resister phenotype may inform novel strategies for therapeutics and vaccines.
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http://dx.doi.org/10.1093/cid/ciab269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8442792PMC
September 2021

Comparison of Time to Clinical Improvement With vs Without Remdesivir Treatment in Hospitalized Patients With COVID-19.

JAMA Netw Open 2021 03 1;4(3):e213071. Epub 2021 Mar 1.

Department of Applied Mathematics and Statistics, Johns Hopkins University, Baltimore, Maryland.

Importance: Clinical effectiveness data on remdesivir are urgently needed, especially among diverse populations and in combination with other therapies.

Objective: To examine whether remdesivir administered with or without corticosteroids for treatment of coronavirus disease 2019 (COVID-19) is associated with more rapid clinical improvement in a racially/ethnically diverse population.

Design, Setting, And Participants: This retrospective comparative effectiveness research study was conducted from March 4 to August 29, 2020, in a 5-hospital health system in the Baltimore, Maryland, and Washington, DC, area. Of 2483 individuals with confirmed severe acute respiratory syndrome coronavirus 2 infection assessed by polymerase chain reaction, those who received remdesivir were matched to infected individuals who did not receive remdesivir using time-invariant covariates (age, sex, race/ethnicity, Charlson Comorbidity Index, body mass index, and do-not-resuscitate or do-not-intubate orders) and time-dependent covariates (ratio of peripheral blood oxygen saturation to fraction of inspired oxygen, blood pressure, pulse, temperature, respiratory rate, C-reactive protein level, complete white blood cell count, lymphocyte count, albumin level, alanine aminotransferase level, glomerular filtration rate, dimerized plasmin fragment D [D-dimer] level, and oxygen device). An individual in the remdesivir group with k days of treatment was matched to a control patient who stayed in the hospital at least k days (5 days maximum) beyond the matching day.

Exposures: Remdesivir treatment with or without corticosteroid administration.

Main Outcomes And Measures: The primary outcome was rate of clinical improvement (hospital discharge or decrease of 2 points on the World Health Organization severity score), and the secondary outcome, mortality at 28 days. An additional outcome was clinical improvement and time to death associated with combined remdesivir and corticosteroid treatment.

Results: Of 2483 consecutive admissions, 342 individuals received remdesivir, 184 of whom also received corticosteroids and 158 of whom received remdesivir alone. For these 342 patients, the median age was 60 years (interquartile range, 46-69 years), 189 (55.3%) were men, and 276 (80.7%) self-identified as non-White race/ethnicity. Remdesivir recipients had a shorter time to clinical improvement than matched controls without remdesivir treatment (median, 5.0 days [interquartile range, 4.0-8.0 days] vs 7.0 days [interquartile range, 4.0-10.0 days]; adjusted hazard ratio, 1.47 [95% CI, 1.22-1.79]). Remdesivir recipients had a 28-day mortality rate of 7.7% (22 deaths) compared with 14.0% (40 deaths) among matched controls, but this difference was not statistically significant in the time-to-death analysis (adjusted hazard ratio, 0.70; 95% CI, 0.38-1.28). The addition of corticosteroids to remdesivir was not associated with a reduced hazard of death at 28 days (adjusted hazard ratio, 1.94; 95% CI, 0.67-5.57).

Conclusions And Relevance: In this comparative effectiveness research study of adults hospitalized with COVID-19, receipt of remdesivir was associated with faster clinical improvement in a cohort of predominantly non-White patients. Remdesivir plus corticosteroid administration did not reduce the time to death compared with remdesivir administered alone.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.3071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7991975PMC
March 2021

A Two-Gene Signature for Tuberculosis Diagnosis in Persons With Advanced HIV.

Front Immunol 2021 22;12:631165. Epub 2021 Feb 22.

Byramjee-Jeejeebhoy Government Medical College-Johns Hopkins University Clinical Research Site (BJGMC-JHU CRS), Pune, India.

Transcriptomic signatures for tuberculosis (TB) have been proposed and represent a promising diagnostic tool. Data remain limited in persons with advanced HIV. We enrolled 30 patients with advanced HIV (CD4 <100 cells/mm) in India; 16 with active TB and 14 without. Whole-blood RNA sequencing was performed; these data were merged with a publicly available dataset from Uganda ( = 33; 18 with TB and 15 without). Transcriptomic profiling and machine learning algorithms identified an optimal gene signature for TB classification. Receiver operating characteristic analysis was used to assess performance. Among 565 differentially expressed genes identified for TB, 40 were shared across India and Uganda cohorts. Common upregulated pathways reflect Toll-like receptor cascades and neutrophil degranulation. The machine-learning decision-tree algorithm selected gene expression values from and as most informative for TB classification. The signature accurately classified TB in discovery cohorts (India AUC 0.95 and Uganda AUC 1.0; < 0.001); accuracy was fair in external validation cohorts. Expression values of and genes in peripheral blood compose a biosignature that accurately classified TB status among patients with advanced HIV in two geographically distinct cohorts. The functional analysis suggests pathways previously reported in TB pathogenesis.
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http://dx.doi.org/10.3389/fimmu.2021.631165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937880PMC
September 2021

Development of Severe COVID-19 Adaptive Risk Predictor (SCARP), a Calculator to Predict Severe Disease or Death in Hospitalized Patients With COVID-19.

Ann Intern Med 2021 06 2;174(6):777-785. Epub 2021 Mar 2.

Johns Hopkins University School of Medicine, Baltimore, Maryland (S.W., B.T.G., A.A.A., A.G., R.B., M.L.R.).

Background: Predicting the clinical trajectory of individual patients hospitalized with coronavirus disease 2019 (COVID-19) is challenging but necessary to inform clinical care. The majority of COVID-19 prognostic tools use only data present upon admission and do not incorporate changes occurring after admission.

Objective: To develop the Severe COVID-19 Adaptive Risk Predictor (SCARP) (https://rsconnect.biostat.jhsph.edu/covid_trajectory/), a novel tool that can provide dynamic risk predictions for progression from moderate disease to severe illness or death in patients with COVID-19 at any time within the first 14 days of their hospitalization.

Design: Retrospective observational cohort study.

Settings: Five hospitals in Maryland and Washington, D.C.

Patients: Patients who were hospitalized between 5 March and 4 December 2020 with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) confirmed by nucleic acid test and symptomatic disease.

Measurements: A clinical registry for patients hospitalized with COVID-19 was the primary data source; data included demographic characteristics, admission source, comorbid conditions, time-varying vital signs, laboratory measurements, and clinical severity. Random forest for survival, longitudinal, and multivariate (RF-SLAM) data analysis was applied to predict the 1-day and 7-day risks for progression to severe disease or death for any given day during the first 14 days of hospitalization.

Results: Among 3163 patients admitted with moderate COVID-19, 228 (7%) became severely ill or died in the next 24 hours; an additional 355 (11%) became severely ill or died in the next 7 days. The area under the receiver-operating characteristic curve (AUC) for 1-day risk predictions for progression to severe disease or death was 0.89 (95% CI, 0.88 to 0.90) and 0.89 (CI, 0.87 to 0.91) during the first and second weeks of hospitalization, respectively. The AUC for 7-day risk predictions for progression to severe disease or death was 0.83 (CI, 0.83 to 0.84) and 0.87 (CI, 0.86 to 0.89) during the first and second weeks of hospitalization, respectively.

Limitation: The SCARP tool was developed by using data from a single health system.

Conclusion: Using the predictive power of RF-SLAM and longitudinal data from more than 3000 patients hospitalized with COVID-19, an interactive tool was developed that rapidly and accurately provides the probability of an individual patient's progression to severe illness or death on the basis of readily available clinical information.

Primary Funding Source: Hopkins inHealth and COVID-19 Administrative Supplement for the HHS Region 3 Treatment Center from the Office of the Assistant Secretary for Preparedness and Response.
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http://dx.doi.org/10.7326/M20-6754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934337PMC
June 2021

Detection of genital tuberculosis among women with infertility using best clinical practices in India: An implementation study.

Indian J Tuberc 2021 Jan 11;68(1):85-91. Epub 2020 Aug 11.

Byramjee Jeejeebhoy Government Medical College/Johns Hopkins Clinical Trials Unit, Pune, Maharashtra, India.

Background: Diagnosis of genital tuberculosis (TB) as a cause of infertility still remains a diagnostic dilemma for clinicians, as no standard guidelines exist. The recently proposed best practices for genital TB diagnosis have not been evaluated yet in India.

Objectives: To implement best practices to diagnose and treat likely genital TB as a cause of infertility.

Methods: Between April 2016 and June 2018, consenting women seen at a tertiary hospital infertility clinic were assessed by thorough TB related clinical history, ultrasonography, tuberculin skin test (TST), and ESR. Those with suspected genital TB underwent laparohysteroscopy. Clinical and laboratory characteristics were compared between likely (microbiologically confirmed or probable TB) and unlikely (possible and no genital TB) genital TB. Fertility outcome was assessed among women initiated on anti-TB treatment (ATT).

Results: Of 185 women seeking infertility care, likely genital TB was identified among 29 (15.7%) women, with 6 (21%) confirmed and 23 (79%) probable genital TB. Compared to unlikely genital TB cases, the likely genital TB group were found to have past history of TB (p < 0.001); positive TST (p = 0.002) and elevated ESR (p = 0.001). Among the likely genital TB group, all 6 confirmed genital TB were started on ATT and 2 (33.3%) conceived. Of 5 probable genital TB started on ATT, 3 (60%) conceived.

Conclusion: Approximately 1/6th of women seeking infertility care met the criteria for likely genital TB. Conception among over-half of treated probable genital TB cases provides preliminary evidence that best clinical practices can be utilized, but needs further confirmatory studies.
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http://dx.doi.org/10.1016/j.ijtb.2020.08.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921546PMC
January 2021

Urine LAM Testing in Advanced HIV Positive Adults in a Trial of Empiric TB Therapy.

Clin Infect Dis 2021 Feb 26. Epub 2021 Feb 26.

Division of Infectious Diseases, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Background: The urine lipoarabinomannan (LAM) antigen test is a TB diagnostic test with highest sensitivity in individuals with advanced HIV. Its role in TB diagnostic algorithms for HIV positive outpatients remains unclear.

Methods: ACTG A5274 trial demonstrated that empiric TB therapy did not improve 24-week survival compared to isoniazid preventive therapy (IPT) in TB screen negative HIV positive adults initiating ART with CD4 counts <50 cells/µL. Retrospective LAM testing was performed on stored urine obtained at baseline. We determined the proportion of LAM-positive participants and conducted modified intent-to-treat analysis excluding LAM-positive participants to determine the effect on 24-week survival, TB incidence and time to TB using Kaplan-Meier method.

Results: A5274 enrolled 850 participants, 53% were male and median CD4 count was 18 cells/µL (IQR: 9, 32). Of the 850, 566 (67%) had LAM testing (283 per arm); 28 (5%) were positive [21 (7%); 7 (2%) in empiric and IPT arms, respectively]. Of those LAM-positive, 1 participant in each arm died and 5 of 21 and 0 of 7 in empiric and IPT arms, respectively, developed TB. After excluding these 28 cases, there were 19 and 21 deaths in empiric and IPT arms, respectively (p=0.88). TB incidence remained higher (4.6% vs. 2%, p=0.04) and time to TB remained faster in the empiric arm (p=0.04).

Conclusions: Among outpatients with advanced HIV who screened negative for TB by clinical symptoms, microscopy and Xpert testing, LAM testing identified an additional 5% of individuals with TB. . Positive LAM results did not change mortality or TB incidence.
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http://dx.doi.org/10.1093/cid/ciab179DOI Listing
February 2021

Drug susceptibility patterns of Mycobacterium tuberculosis from adults with multidrug-resistant tuberculosis and implications for a household contact preventive therapy trial.

BMC Infect Dis 2021 Feb 24;21(1):205. Epub 2021 Feb 24.

Department of Internal Medicine, Section of Infectious Diseases, University of Nebraska Medical Center, Omaha, NE, 68198-8106, USA.

Background: Drug susceptibility testing (DST) patterns of Mycobacterium tuberculosis (MTB) from patients with rifampicin-resistant tuberculosis (RR-TB) or multidrug-resistant TB (MDR-TB; or resistant to rifampicin and isoniazid (INH)), are important to guide preventive therapy for their household contacts (HHCs).

Methods: As part of a feasibility study done in preparation for an MDR-TB preventive therapy trial in HHCs, smear, Xpert MTB/RIF, Hain MTBDRplus, culture and DST results of index MDR-TB patients were obtained from routine TB programs. A sputum sample was collected at study entry and evaluated by the same tests. Not all tests were performed on all specimens due to variations in test availability.

Results: Three hundred eight adults with reported RR/MDR-TB were enrolled from 16 participating sites in 8 countries. Their median age was 36 years, and 36% were HIV-infected. Routine testing on all 308 were confirmed as having RR-TB, but only 75% were documented as having MDR-TB. The majority of those not classified as having MDR-TB were because only rifampicin resistance was tested. At study entry (median 59 days after MDR-TB treatment initiation), 280 participants (91%) were able to produce sputum for the study, of whom 147 (53%) still had detectable MTB. All but 2 of these 147 had rifampicin DST done, with resistance detected in 89%. Almost half (47%) of the 147 specimens had INH DST done, with 83% resistance. Therefore, 20% of the 280 study specimens had MDR-TB confirmed. Overall, DST for second-line drugs were available in only 35% of the 308 routine specimens and 15% of 280 study specimens.

Conclusions: RR-TB was detected in all routine specimens but only 75% had documented MDR-TB, illustrating the need for expanded DST beyond Xpert MTB/RIF to target preventive therapy for HHC.
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http://dx.doi.org/10.1186/s12879-021-05884-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903693PMC
February 2021

Systemic Inflammation in Pregnant Women With Latent Tuberculosis Infection.

Front Immunol 2020 27;11:587617. Epub 2021 Jan 27.

Department of Epidemiology, Columbia University Mailman School of Public Health, New York, NY, United States.

Background: Recent studies in adults have characterized differences in systemic inflammation between adults with and without latent tuberculosis infection (LTBI+ . LTBI-). Potential differences in systemic inflammation by LTBI status has not been assess in pregnant women.

Methods: We conducted a cohort study of 155 LTBI+ and 65 LTBI- pregnant women, stratified by HIV status, attending an antenatal clinic in Pune, India. LTBI status was assessed by interferon gamma release assay. Plasma was used to measure systemic inflammation markers using immunoassays: IFN, CRP, AGP, I-FABP, IFN, IL-1, soluble CD14 (sCD14), sCD163, TNF, IL-6, IL-17a and IL-13. Linear regression models were fit to test the association of LTBI status with each inflammation marker. We also conducted an exploratory analysis using logistic regression to test the association of inflammatory markers with TB progression.

Results: Study population was a median age of 23 (Interquartile range: 21-27), 28% undernourished (mid-upper arm circumference (MUAC) <23 cm), 12% were vegetarian, 10% with gestational diabetes and 32% with HIV. In multivariable models, LTBI+ women had significantly lower levels of third trimester AGP, IL1β, sCD163, IL-6 and IL-17a. Interestingly, in exploratory analysis, LTBI+ TB progressors had significantly higher levels of IL1, IL-6 and IL-13 in multivariable models compared to LTBI+ non-progressors.

Conclusions: Our data shows a distinct systemic immune profile in LTBI+ pregnant women compared to LTBI- women. Data from our exploratory analysis suggest that LTBI+ TB progressors do not have this immune profile, suggesting negative association of this profile with TB progression. If other studies confirm these differences by LTBI status and show a causal relationship with TB progression, this immune profile could identify subsets of LTBI+ pregnant women at high risk for TB progression and who can be targeted for preventative therapy.
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http://dx.doi.org/10.3389/fimmu.2020.587617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873478PMC
July 2021

Validation of New Interactive Nutrition Assistant - Diet in India Study of Health (NINA-DISH) FFQ with multiple 24-h dietary recalls among pregnant women in Pune, India.

Br J Nutr 2021 Oct 28;126(8):1247-1256. Epub 2020 Dec 28.

Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY10032, USA.

Adequate dietary intake is critical to prevent adverse pregnancy outcomes. India has a high burden of maternal and child morbidity and mortality, but there is a lack of adequate tools to assess dietary intake. We validate an FFQ, New Interactive Nutrition Assistant - Diet in India Study of Health (NINA-DISH), among pregnant women living with and without HIV in Pune, India. Women were selected from a cohort study investigating immune responses to HIV and latent tuberculosis during pregnancy. The FFQ was administered during the third trimester and validated against multiple 24-h dietary recalls (24-HDR) collected in second and third trimesters. Data for analysis were available from fifty-eight women out of seventy enrolled into this sub-study, after excluding those with incomplete data or implausible energy intake. The median (Q1, Q3) age of study participants was 23 (20, 25) years. Median (Q1, Q3) daily energy intakes were 10 552 (8000, 11 958) and 10 673 (8510, 13 962) kJ by 24-HDR and FFQ, respectively, with FFQ overestimating nutrient intake. Pearson correlations between log-transformed estimates from FFQ and 24-HDR for energy, protein, carbohydrate, fat, Fe and Zn were 0·47, 0·48, 0·45, 0·33, 0·4 and 0·54, respectively. Energy-adjusted and de-attenuated correlations ranged from 0·41 (saturated fat) to 0·73 (Na). The highest misclassification into extreme tertiles was observed for fat (22 %), saturated fat (21 %) and Na (21 %). Bias existed at higher intake levels as observed by Bland-Altman plots. In conclusion, NINA-DISH is a valid and feasible tool for estimating dietary intakes among urban pregnant women in Western India.
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http://dx.doi.org/10.1017/S0007114520005188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8236492PMC
October 2021

Association of Vegetable and Animal Flesh Intake with Inflammation in Pregnant Women from India.

Nutrients 2020 Dec 8;12(12). Epub 2020 Dec 8.

Department of Epidemiology, Columbia University Mailman School of Public Health, New York, NY 10032, USA.

In pregnant women, studies are lacking on the relationship of vegetable and animal flesh (poultry, red meat and seafood) intake with inflammation, especially in low- and middle-income countries. We conducted a cohort study of pregnant women receiving antenatal care at BJ Medical College in Pune, India. The dietary intake of pregnant women was queried in the third trimester using a validated food frequency questionnaire. Twelve inflammatory markers were measured in plasma samples using immunoassays. Only 12% of the study population were vegetarians, although animal flesh intake levels were lower compared to Western populations. In multivariable models, higher intakes of total vegetables were associated with lower levels of the T-helper (Th) 17 cytokine interleukin (IL)-17a ( = 0.03) and the monocyte/macrophage activation marker soluble CD163 (sCD163) ( = 0.02). Additionally, higher intakes of poultry were negatively associated with intestinal fatty-acid binding protein (I-FABP) levels ( = 0.01), a marker of intestinal barrier dysfunction and Th2 cytokine IL-13 ( = 0.03), and higher seafood was associated with lower IL-13 ( = 0.005). Our data from pregnant women in India suggest that a higher quality diet emphasizing vegetables and with some animal flesh is associated with lower inflammation. Future studies should confirm these findings and test if modulating vegetables and animal flesh intake could impact specific aspects of immunity and perinatal health.
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http://dx.doi.org/10.3390/nu12123767DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762525PMC
December 2020

Integration of metabolomics and transcriptomics reveals novel biomarkers in the blood for tuberculosis diagnosis in children.

Sci Rep 2020 11 11;10(1):19527. Epub 2020 Nov 11.

Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, 1551 East Jefferson Street, Room 110, Baltimore, MD, 21287, USA.

Pediatric tuberculosis (TB) remains a major global health problem. Improved pediatric diagnostics using readily available biosources are urgently needed. We used liquid chromatography-mass spectrometry to analyze plasma metabolite profiles of Indian children with active TB (n = 16) and age- and sex-matched, Mycobacterium tuberculosis-exposed but uninfected household contacts (n = 32). Metabolomic data were integrated with whole blood transcriptomic data for each participant at diagnosis and throughout treatment for drug-susceptible TB. A decision tree algorithm identified 3 metabolites that correctly identified TB status at distinct times during treatment. N-acetylneuraminate achieved an area under the receiver operating characteristic curve (AUC) of 0.66 at diagnosis. Quinolinate achieved an AUC of 0.77 after 1 month of treatment, and pyridoxate achieved an AUC of 0.87 after successful treatment completion. A set of 4 metabolites (gamma-glutamylalanine, gamma-glutamylglycine, glutamine, and pyridoxate) identified treatment response with an AUC of 0.86. Pathway enrichment analyses of these metabolites and corresponding transcriptional data correlated N-acetylneuraminate with immunoregulatory interactions between lymphoid and non-lymphoid cells, and correlated pyridoxate with p53-regulated metabolic genes and mitochondrial translation. Our findings shed new light on metabolic dysregulation in children with TB and pave the way for new diagnostic and treatment response markers in pediatric TB.
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http://dx.doi.org/10.1038/s41598-020-75513-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7658223PMC
November 2020

Using a Composite Maternal-Infant Outcome Measure in Tuberculosis-Prevention Studies Among Pregnant Women.

Clin Infect Dis 2021 08;73(3):e587-e593

Johns Hopkins University, Baltimore, Maryland, USA.

Background: Tuberculosis (TB-)-preventive therapy (TPT) among pregnant women reduces risk of TB in mothers and infants, but timing of initiation should consider potential adverse effects. We propose an analytical approach to evaluate the risk-benefit of interventions.

Methods: A novel outcome measure that prioritizes maternal and infant events was developed with a 2-stage Delphi survey, where a panel of stakeholders assigned scores from 0 (best) to 100 (worst) based on perceived desirability. Using data from TB APPRISE, a trial among pregnant women living with human immunodeficiency virus (WLWH) that randomized the timing of initiation of isoniazid, antepartum versus postpartum, was evaluated.

Results: The composite outcome scoring/ranking system categorized mother-infant paired outcomes into 8 groups assigned identical median scores by stakeholders. Maternal/infant TB and nonsevere adverse pregnancy outcomes were assigned similar scores. Mean (SD) composite outcome scores were 43.7 (33.0) and 41.2 (33.7) in the antepartum and postpartum TPT initiation arms, respectively. However, a modifying effect of baseline antiretroviral regimen was detected (P = .049). When women received nevirapine, composite scores were higher (worse outcomes) in the antepartum versus postpartum arms (adjusted difference, 14.3; 95% confidence interval [CI], 2.4-26.2; P = .02), whereas when women received efavirenz there was no difference by timing of TPT (adjusted difference, .62; 95% CI, -3.2-6.2; P = .53).

Conclusions: For TPT, when used by otherwise healthy persons, preventing adverse events is paramount from the perspective of stakeholders. Among pregnant WLWH in high-TB-burden regions, it is important to consider the antepartum antiretroviral regimen taken when deciding when to initiate TPT. Clinical Trials Registration. NCT01494038 (IMPAACT P1078).
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http://dx.doi.org/10.1093/cid/ciaa1674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8326545PMC
August 2021

The burden of anxiety among people living with HIV during the COVID-19 pandemic in Pune, India.

BMC Public Health 2020 Oct 23;20(1):1598. Epub 2020 Oct 23.

Byramjee Jeejeebhoy Government Medical College - Johns Hopkins University Clinical Research Site, Jai Prakash Narayan Road, Maharashtra, 411001, Pune, India.

Introduction: Globally, India has the third largest population of people living with HIV (PLHIV) and the second highest number of COVID-19 cases. Anxiety is associated with antiretroviral therapy (ART) nonadherence. It is crucial to understand the burden of anxiety and its sources among Asian Indian PLHIV during the COVID pandemic, but data are limited.

Methods: During the first month of government mandated lockdown, we administered an anxiety assessment via telephone among PLHIV registered for care at a publicly funded antiretroviral therapy (ART) center in Pune, India. Generalized anxiety was defined as GAD-7 score ≥ 10. Sociodemographic and clinical variables were compared by anxiety status (GAD-7 score ≥ 10 vs GAD-7 score < 10). Qualitative responses to an open-ended question about causes of concern were evaluated using thematic analysis.

Results: Among 167 PLHIV, median age was 44 years (IQR 40-50); the majority were cisgender women (60%) and had a monthly family income < 200 USD (81%). Prior history of tuberculosis and other comorbidities were observed in 38 and 27%, respectively. Overall, prevalence of generalized anxiety was 25% (n = 41). PLHIV with GAD-7 score ≥ 10 had fewer remaining doses of ART than those with lower GAD-7 scores (p = 0.05). Thematic analysis indicated that concerns were both health related and unrelated, and stated temporally. Present concerns were often also projected as future concerns.

Conclusions: The burden of anxiety was high during COVID lockdown in our population of socioeconomically disadvantaged PLHIV in Pune and appeared to be influenced by concerns about ART availability. The burden of anxiety among PLHIV will likely increase with the worsening pandemic in India, as sources of anxiety are expected to persist. We recommend the regular use of short screening tools for anxiety to monitor and triage patients as an extension of current HIV services.
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http://dx.doi.org/10.1186/s12889-020-09656-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582417PMC
October 2020

Individual and Composite Adverse Pregnancy Outcomes in a Randomized Trial on Isoniazid Preventative Therapy Among Women Living With Human Immunodeficiency Virus.

Clin Infect Dis 2021 06;72(11):e784-e790

Center for Clinical Global Health Education, Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Background: International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) P1078, a randomized noninferiority study designed to compare the safety of starting isoniazid preventive therapy (IPT) in women living with human immunodeficiency virus (HIV) either during pregnancy or after delivery, showed that IPT during pregnancy increased the risk of composite adverse pregnancy outcomes, but not individual outcomes. Many known factors are associated with adverse pregnancy outcomes: these factors' associations and effect modifications with IPT and pregnancy outcomes were examined.

Methods: Pregnant women living with HIV from 8 countries with tuberculosis incidences >60/100 000 were randomly assigned to initiate 28 weeks of IPT either during pregnancy or at 12 weeks after delivery. Using univariable and multivariable logistic regression and adjusting for factors associated with pregnancy outcomes, composite and individual adverse pregnancy outcome measures were analyzed.

Results: This secondary analysis included 925 mother-infant pairs. All mothers were receiving antiretrovirals. The adjusted odds of fetal demise, preterm delivery (PTD), low birth weight (LBW), or a congenital anomaly (composite outcome 1) were 1.63 times higher among women on immediate compared to deferred IPT (95% confidence interval [CI], 1.15-2.31). The odds of fetal demise, PTD, LBW, or neonatal death within 28 days (composite outcome 2) were 1.62 times higher among women on immediate IPT (95% CI, 1.14-2.30). The odds of early neonatal death within 7 days, fetal demise, PTD, or LBW (composite outcome 3) were 1.74 times higher among women on immediate IPT (95% CI, 1.22-2.49).

Conclusions: We confirmed higher risks of adverse pregnancy outcomes associated with the initiation of IPT during pregnancy, after adjusting for known risk factors for adverse pregnancy outcomes.
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http://dx.doi.org/10.1093/cid/ciaa1482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8315231PMC
June 2021

Patient Trajectories Among Persons Hospitalized for COVID-19 : A Cohort Study.

Ann Intern Med 2021 01 22;174(1):33-41. Epub 2020 Sep 22.

Johns Hopkins University School of Medicine, Baltimore, Maryland (B.T.G., M.L.R., P.N., J.H.G., H.M., T.M.N., B.S.K., P.M.H., R.B., D.R.T., M.G.B., A.R., A.G.).

Background: Risk factors for progression of coronavirus disease 2019 (COVID-19) to severe disease or death are underexplored in U.S. cohorts.

Objective: To determine the factors on hospital admission that are predictive of severe disease or death from COVID-19.

Design: Retrospective cohort analysis.

Setting: Five hospitals in the Maryland and Washington, DC, area.

Patients: 832 consecutive COVID-19 admissions from 4 March to 24 April 2020, with follow-up through 27 June 2020.

Measurements: Patient trajectories and outcomes, categorized by using the World Health Organization COVID-19 disease severity scale. Primary outcomes were death and a composite of severe disease or death.

Results: Median patient age was 64 years (range, 1 to 108 years); 47% were women, 40% were Black, 16% were Latinx, and 21% were nursing home residents. Among all patients, 131 (16%) died and 694 (83%) were discharged (523 [63%] had mild to moderate disease and 171 [20%] had severe disease). Of deaths, 66 (50%) were nursing home residents. Of 787 patients admitted with mild to moderate disease, 302 (38%) progressed to severe disease or death: 181 (60%) by day 2 and 238 (79%) by day 4. Patients had markedly different probabilities of disease progression on the basis of age, nursing home residence, comorbid conditions, obesity, respiratory symptoms, respiratory rate, fever, absolute lymphocyte count, hypoalbuminemia, troponin level, and C-reactive protein level and the interactions among these factors. Using only factors present on admission, a model to predict in-hospital disease progression had an area under the curve of 0.85, 0.79, and 0.79 at days 2, 4, and 7, respectively.

Limitation: The study was done in a single health care system.

Conclusion: A combination of demographic and clinical variables is strongly associated with severe COVID-19 disease or death and their early onset. The COVID-19 Inpatient Risk Calculator (CIRC), using factors present on admission, can inform clinical and resource allocation decisions.

Primary Funding Source: Hopkins inHealth and COVID-19 Administrative Supplement for the HHS Region 3 Treatment Center from the Office of the Assistant Secretary for Preparedness and Response.
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http://dx.doi.org/10.7326/M20-3905DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530643PMC
January 2021

Mental health and quality of life among healthcare professionals during the COVID-19 pandemic in India.

Brain Behav 2020 11 11;10(11):e01837. Epub 2020 Sep 11.

Lakshya, Society for Public Health Education and Research, Pune, India.

Background: The COVID-19 pandemic has placed healthcare professionals (HCP) in stressful circumstances with increased patient loads and a high risk of exposure. We sought to assess the mental health and quality of life (QoL) of Indian HCPs, the fourth highest-burden country for COVID-19.

Method: Using snowball sampling, we conducted an online survey in May 2020 among HCPs. Data were collected on demographics, depression, and anxiety using validated tools, quality of life, and perceived stressors. Multivariable logistic regression and principal component analysis were performed to assess risk factors associated with mental health symptoms.

Findings: Of 197 HCPs assessed, 157 (80%) were from Maharashtra, 130 (66%) from public hospitals, 47 (24%) nurses, 66 (34%) physicians, 101 (52%) females, and 81 (41%) ≤30 years. Eighty-seven percent provided direct COVID-19 care with 43% caring for >10 patients/day. A large proportion reported symptoms of depression (92, 47%), anxiety (98, 50%), and low QoL (89, 45%). Odds of combined depression and anxiety were 2.37 times higher among single HCPs compared to married (95% CI: 1.03-4.96). Work environment stressors were associated with 46% increased risk of combined depression and anxiety (95% CI: 1.15-1.85). Moderate to severe depression and anxiety were independently associated with increased risk of low QoL [OR: 3.19 (95% CI: 1.30-7.84), OR: 2.84 (95% CI: 1.29-6.29)].

Conclusion: Our study demonstrated a high prevalence of symptoms of depression and anxiety and low QoL among Indian HCPs during the COVID-19 pandemic. There is an urgent need to prevent and treat mental health symptoms among frontline HCPs.
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http://dx.doi.org/10.1002/brb3.1837DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667343PMC
November 2020

Pharmacokinetics and Drug-Drug Interactions of Isoniazid and Efavirenz in Pregnant Women Living With HIV in High TB Incidence Settings: Importance of Genotyping.

Clin Pharmacol Ther 2021 04 16;109(4):1034-1044. Epub 2020 Oct 16.

Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.

The World Health Organization guidelines recommend that individuals living with HIV receive ≥ 6 months of isoniazid preventive therapy, including pregnant women. Yet, plasma isoniazid exposure during pregnancy, in the antiretroviral therapy era, has not been well-described. We investigated pregnancy-induced and pharmacogenetic-associated pharmacokinetic changes and drug-drug interactions between isoniazid and efavirenz in pregnant women. Eight hundred forty-seven women received isoniazid for 28 weeks, either during pregnancy or at 12 weeks postpartum, and 786 women received efavirenz. After adjusting for NAT2 and CYP2B6 genotype and weight, pregnancy increased isoniazid and efavirenz clearance by 26% and 15%, respectively. Isoniazid decreased efavirenz clearance by 7% in CYP2B6 normal metabolizers and 13% in slow and intermediate metabolizers. Overall, both isoniazid and efavirenz exposures were reduced during pregnancy, but the main determinants of drug concentration were NAT2 and CYP2B6 genotypes, which resulted in a five-fold difference for both drugs between rapid and slow metabolizers.
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http://dx.doi.org/10.1002/cpt.2044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048881PMC
April 2021

The Burden of Anxiety During the COVID-19 Pandemic Among People Living with HIV (PLHIV) in Pune, India.

Res Sq 2020 Aug 13. Epub 2020 Aug 13.

Byramjee Jeejeebhoy Government Medical College - Johns Hopkins University Clinical Research Site.

: There is a dearth of data on anxiety related to the COVID-19 pandemic from people living with HIV (PLHIV). This is a cause of concern as anxiety is associated with antiretroviral therapy (ART) nonadherence. Globally, India has the third largest population of PLHIV and third highest number of COVID-19 cases which are rapidly increasing. Therefore, it is crucial to understand the burden of anxiety and its sources among Asian Indian PLHIV during this pandemic. We used data from a telephonically delivered assessment among PLHIV engaged in care at a tertiary healthcare associated antiretroviral therapy (ART) center in Pune, India. Assessments were conducted between April 21 and May 28, 2020, one month into the government mandated lockdown. GAD-7 was used to assess for anxiety over two-preceding weeks. Significant sociodemographic and clinical differences between groups (GAD-7<10 and GAD-7≥10) were assessed using Fisher's exact and Wilcoxson rank sum tests, for categorical and continuous variables, respectively. Thematic analysis was employed to analyze an open-ended question that asked about the most pressing cause(s) of concern. : Of 167 PLHIV contacted, median age was 44 years (IQR:40 - 50), 60% (n=100) were cisgender women and 81% (n=135) had a monthly family income<200 USD. Thirty-eight percent (n=64) had prior history of tuberculosis and 27% (n=45) were living with another comorbidity. A fourth (25%, n=41) had GAD-7 scores indicative of generalized anxiety. PLHIV who had fewer remaining doses of ART had significantly higher GAD-7 scores compared to those that had more doses (p=0.05). Thematic analysis indicated that concerns were both health related and unrelated, and stated temporally. Present concerns were often also projected as future concerns. : In a group of socioeconomically disadvantaged PLHIV, a fourth were found to have anxiety, that appeared to be influenced by concerns about ART availability. Furthermore, the persistence of sources of anxiety and therefore an increase in anxiety for these PLHIV is anticipated as the pandemic worsens in India. We recommend the regular utilization of short screening tools for anxiety to monitor and triage PLHIV as an extension of current HIV-services.
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http://dx.doi.org/10.21203/rs.3.rs-45412/v1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430601PMC
August 2020
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