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.

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.

Virological failure among people living with HIV receiving second-line antiretroviral therapy in Pune, India.

BACKGROUND: The number of people receiving second-line antiretroviral therapy (ART) has increased as global access to ART has expanded. Data on the burden and factors associated with second-line ART virologic failure (VF) from India remain limited. METHODS: We conducted cross-sectional viral load (VL) testing among adults (≥ 18 years) who were registered at a publicly funded ART center in western India between 2014 and 2015 and had received second-line ART for at least 6 months. Sociodemographic and clinical characteristics were abstracted from routinely collected programmatic data. Logistic regression evaluated factors associated with VF (defined as VL > 1000 copies/mL). RESULTS: Among 400 participants, median age was 40 years (IQR 34-44), 71% (285/400) were male, and 15% (59/400) had VF. Relative to participants without VF, those with VF had lower median CD4 counts (230 vs 406 cells/mm3, p < 0.0001), lower weight at first-line failure (49 vs 52 kg, p = 0.003), were more likely to have an opportunistic infection (17% vs 3%, p < 0.0001) and less likely to have optimal ART adherence (71% vs 87%, p = 0.005). In multivariable analysis, VF was associated with opportunistic infection (aOR, 4.84; 95% CI, 1.77-13.24), lower CD4 count (aOR 4.15; 95% CI, 1.98-8.71) and lower weight at first-line failure (aOR, 2.67; 95% CI, 1.33-5.34). CONCLUSIONS: We found second-line VF in about a sixth of participants in our setting, which was associated with nearly fivefold increased odds in the context of opportunistic infection. Weight could be a useful clinical indicator for second-line VF.

Poor quality of life and incomplete self-reported adherence predict second-line ART virological failure in resource-limited settings.

We evaluated health-related quality of life (QoL) and self-reported incomplete adherence as predictors of early second-line antiretroviral (ART) virological failure (VF). ACTG A5273 study participants completed the ACTG SF-21 measure which has 8 QoL domains. We used exact logistic regression to assess the association of QoL at baseline and week 4 with early VF adjusted for self-reported adherence. Of 500 individuals (51% women, median age 39 years) in this analysis, 79% and 75% self-reported complete adherence (no missing doses in the past month) at weeks 4 and 24, respectively. Early VF was experienced by 7% and more common among those who self-reported incomplete adherence. Participants with low week 4 QoL scores had higher rates of early VF than participants with high scores. After adjusting for self-reported adherence at week 4, VL and CD4 at baseline, cognitive functioning, pain and mental health domains were significantly associated with subsequent early VF. In this post-hoc analysis, poorer QoL adds to self-reported incomplete adherence after 4 weeks of second-line ART in predicting VF at week 24. Evaluation is needed to assess whether individuals with poorer QoL might be targeted for greater support to reduce risk of VF.Trial registration: ClinicalTrials.gov identifier: NCT01352715.

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.

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.

Elevated highly sensitive C-reactive protein and d-dimer levels are associated with food insecurity among people living with HIV in Pune, India.

OBJECTIVE: To assess the prevalence and determinants of food insecurity among people living with HIV (PLWH) in Pune, India and its association with biomarkers known to confer increased risks of morbidity and mortality in this population. DESIGN: Cross-sectional analysis assessing food insecurity using the standardized Household Food Insecurity Access Scale. Participants were dichotomized into two groups: food insecure and food secure. Logistic regression models were used to assess associations between socio-economic, demographic, clinical, biochemical factors and food insecurity. SETTING: Antiretroviral therapy (ART) centre of Byramjee Jeejeebhoy Government Medical College and Sassoon General Hospitals (BJGMC-SGH), Pune, a large publicly funded tertiary and teaching hospital in western India.ParticpantsAdult (≥18 years) PLWH attending the ART centre between September 2015 and May 2016 who had received ART for either ≤7d (ART-naïve) or ≥1 year (ART-experienced). RESULTS: Food insecurity was reported by 40 % of 483 participants. Independent risk factors (adjusted OR; 95 % CI) included monthly family income <INR 5000 (~70 USD; 13·2; CI 5·4, 32·2) and consuming ≥4 non-vegetarian meals per week (4·7; 1·9, 11·9). High-sensitivity C-reactive protein (hs-CRP) ≥0·33 mg/dl (1·6; 1·04, 2·6) and d-dimer levels 0·19-0·31 µg/ml (1·6; 1·01, 2·6) and ≥0·32 µg/ml (1·9; 1·2, 3·2) were also associated with food insecurity. CONCLUSIONS: More than a third of the study participants were food insecure. Furthermore, higher hs-CRP and d-dimer levels were associated with food insecurity. Prospective studies are required to understand the relationship between food insecurity, hs-CRP and d-dimer better.

Antibiotic Utilization and the Role of Suspected and Diagnosed Mosquito-borne Illness Among Adults and Children With Acute Febrile Illness in Pune, India.

Background: Antibiotic resistance mechanisms originating in low- and middle- income countries are among the most common worldwide. Reducing unnecessary antibiotic use in India, the world's largest antibiotic consumer, is crucial to control antimicrobial resistance globally. Limited data describing factors influencing Indian clinicians to start or stop antibiotics are available. Methods: Febrile adults and children admitted to a public tertiary care hospital in Pune, India, were enrolled. Antibiotic usage and clinical history were recorded. Immunoassays for mosquito-borne disease and bacterial cultures were performed by protocol and clinician-directed testing. Clinical factors were assessed for association with empiric antibiotic initiation and discontinuation by day 5 using multivariable logistic regression and propensity score-matched Cox proportional hazard models. Results: Among 1486 participants, 683 (82%) adults and 614 (94%) children received empiric antibiotics. Participants suspected of having mosquito-borne disease were less likely to receive empiric antibiotics (adjusted odds ratio [AOR], 0.5; 95% confidence interval [CI], .4-.8). Empiric antibiotics were discontinued in 450 (35%) participants by day 5. Dengue or malaria testing performed before day 4 was positive in 162 (12%) participants, and was associated with antibiotic discontinuation (AOR, 1.7; 95% CI, 1.2-2.4). In a propensity score-matched model accounting for admission suspicion of mosquito-borne disease, positive dengue or malaria tests increased hazard of antibiotic discontinuation (hazard ratio, 1.6; 95% CI, 1.2-2.0). Conclusions: Most patients with acute febrile illness in an Indian public hospital setting receive empiric antibiotics. Mosquito-borne disease identification is associated with reduced empiric antibiotic use and faster antibiotic discontinuation.

Addressing knowledge gaps and prevention for tuberculosis-infected Indian adults: a vital part of elimination.

BACKGROUND: India plans to eliminate tuberculosis (TB) by 2025, and has identified screening and prevention as key activities. Household contacts (HHCs) of index TB cases are a high-risk population that would benefit from rapid implementation of these strategies. However, best practices for TB prevention and knowledge gaps among HHCs have not been studied. We evaluated TB knowledge and understanding of prevention among tuberculin skin-test (TST) positive HHCs. While extensive information is available in other high-burden settings regarding TB knowledge gaps, identifying how Indian adult contacts view their transmission risk and prevention options may inform novel screening algorithms and education efforts that will be part of the new elimination plan. METHODS: We approached adult HHC to administer a questionnaire on TB knowledge and understanding of infection. Over 1 year, 100 HHC were enrolled at a tertiary hospital in Pune, India. RESULTS: The study population was 61% (n = 61) female, with a mean age of 36.6 years (range 18-67, SD = 12). Education levels were high, with 78 (78%) having at least a high school education, and 23 (24%) had at least some college education. Four (4%) of our participants were HIV-infected. General TB knowledge among HHC was low, with a majority of participants believing that you can get TB from sharing dishes (70%) or touching something that has been coughed on (52%). Understanding of infection was also low, with 42% believing that being skin-test positive means you have disease. To assess readiness for preventive therapy, we asked participants whether they are at a higher risk of progressing to active disease because of their LTBI status. Fifty-four (55%) felt that they are at higher risk. Only 8% had heard of preventive therapy. CONCLUSION: Our TB knowledge survey among HHCs with evidence of recent exposure found that knowledge is poor and families are confused about transmission in the household. It is imperative that the Indian program develop tools and incentives that can be used to educate TB cases and their families on what infected HHCs can do to prevent disease, including preventive therapy.

Drug-resistant Enterobacteriaceae colonization is associated with healthcare utilization and antimicrobial use among inpatients in Pune, India.

BACKGROUND: Healthcare exposure may increase drug-resistant Enterobacteriaceae colonization risk. Nascent antimicrobial stewardship efforts in low- and middle-income countries require setting-specific data. We aimed to evaluate risk factors for inpatient drug resistant Enterobacteriaceae colonization in a resource-limited setting in India. METHODS: Patients age ≥ 6 months admitted with ≥24 h of fever to a tertiary hospital in Pune, India were enrolled in a prospective cohort. Perirectal swabs, collected on admission and hospitalization day 3 or 4, were cultured in vancomycin- and ceftriaxone-impregnated media to assess for ceftriaxone-resistant Enterobacteriaceae (CTRE) and carbapenem-resistant Enterobacteriaceae (CPRE). Multivariable analyses assessed risk factors for drug-resistant Enterobacteriaceae colonization among participants without admission colonization. RESULTS: Admission perirectal swabs were collected on 897 participants; 87 (10%) had CTRE and 14 (1.6%) had CPRE colonization. Admission CTRE colonization was associated with recent healthcare contact (p < 0.01). Follow-up samples were collected from 620 participants, 67 (11%) had CTRE and 21 (3.4%) had CPRE colonization. Among 561 participants without enrollment CTRE colonization, 49 (9%) participants were colonized with CTRE at follow-up. Detection of CTRE colonization among participants not colonized with CTRE at admission was independently associated with empiric third generation cephalosporin treatment (adjusted odds ratio [OR] 2.9, 95% CI 1.5-5.8). Follow-up transition to CPRE colonization detection was associated with ICU admission (OR 3.0, 95% CI 1.0-8.5). CONCLUSIONS: Patients who receive empiric third generation cephalosporins and are admitted to the ICU rapidly develop detectable CTRE and CPRE colonization. Improved antimicrobial stewardship and infection control measures are urgently needed upon hospital admission.

High Burden of Antimicrobial Resistance and Mortality Among Adults and Children With Community-Onset Bacterial Infections in India.

Background: In India, antimicrobial consumption is high, yet systematically collected data on the epidemiology, risk factors, and outcomes of antimicrobial-resistant infections are limited. Methods: A prospective study of adults and children hospitalized for acute febrile illness was conducted between August 2013 and December 2015. In-hospital outcomes were recorded, and logistic regression was performed to identify independent predictors of community-onset antimicrobial-resistant infections. Results: Among 1524 patients hospitalized with acute febrile illness, 133 isolates were found among 115 patients with community-onset infections; 66 isolates (50.0%) were multidrug resistant and, of 33 isolates tested for carbapenem susceptibility, 12 (36%) were resistant. Multidrug-resistant infections were associated with recent antecedent antibiotic use (adjusted odds ratio [aOR], 4.17; 95% confidence interval [CI], 1.19-19.7) and were independently associated with mortality (aOR, 6.06; 95% CI, 1.2-55.7). Conclusion: We found a high burden of community-onset antimicrobial-resistant infection among patients with acute febrile illness in India. Multidrug-resistant infection was associated with prior antibiotic use and an increased risk of mortality.

Tuberculosis screening among persons with diabetes mellitus in Pune, India.

BACKGROUND: Diabetes mellitus (DM) increases tuberculosis (TB) risk, and there is increasing concern over the public health implications of the convergence of these two epidemics. Screening for TB among people with DM is now recommended in India. METHODS: People with DM seeking care at a large public sector tertiary care hospital clinic in Pune, India, were screened for TB from June 2015 to May 2016. All consenting people with DM were screened for TB at each clinic visit using a five-item, WHO-recommended questionnaire and those with TB symptoms and/or risk factors were tested for active TB using sputum smear microscopty, Xpert® MTB/RIF and TB culture. Categorical data and continuous variables were summarized using descriptive statistics. The x 2 test or Wilcoxon rank-sum test was used to ascertain significant associations between categorical and continuous variables, respectively. RESULTS: Among 630 adults approached for screening, median age was 60 (interquartile range (IQR), 57-64) years and 350 (56%) were females. Median hemoglobin A1c (HbA1c) was 8.7% (IQR, 6.7-9.9) and 444 (70.5%) were poorly controlled DM (HbA1c > 7). Forty-four (7%) had prior history of TB but the proportion with TB risk factors at screening was low (<5%). While 18% of participants reported any TB symptoms, none of these patients were diagnosed with culture confirmed TB. CONCLUSIONS: Our study failed to yield any active TB cases using a WHO-recommended questionnaire among people with DM. High TB risk populations among people with DM must be identified if TB screening is to be feasible in settings such as India where the DM epidemic continues to rise.

Tuberculosis Risk among Medical Trainees, Pune, India.

During 2012-2013, at a public hospital in Pune, India, 26 (3.9%) cases of tuberculosis were reported among 662 medical trainees, representing an estimated incidence of 3,279 cases/100,000 person-years. Three of these infections were isoniazid-resistant, 1 was multidrug-resistant, and 1 occurred in a trainee who had fulminant hepatitis after starting treatment for TB.

Glycated Hemoglobin Trajectories and Their Association With Treatment Outcomes Among Patients With Pulmonary TB in India: A Prospective Cohort Study.

BACKGROUND: Transient hyperglycemia is seen commonly during TB treatment, yet its association with unfavorable treatment outcomes is unclear. RESEARCH QUESTION: Does an association exist between glycated hemoglobin (HbA1c) trajectories and TB treatment outcomes? STUDY DESIGN AND METHODS: Adults with pulmonary TB were evaluated prospectively for 18 months after the second HbA1c measurement. HbA1c trajectories during the initial 3 months of treatment were defined as follows: persistent euglycemia, HbA1c < 6.5% at baseline and 3-month follow-up; persistent hyperglycemia, HbA1c ≥ 6.5% at baseline and 3-month follow-up; transient hyperglycemia, HbA1c ≥ 6.5% at baseline and < 6.5% at 3-month follow-up; incident hyperglycemia, HbA1c < 6.5% at baseline and ≥ 6.5% at 3-month follow-up. Multivariable Poisson regression was used to measure the association between HbA1c trajectories and unfavorable treatment outcomes of failure, recurrence, and all-cause mortality. RESULTS: Of the 587 participants, 443 participants (76%) had persistent euglycemia, 118 participants (20%) had persistent hyperglycemia, and 26 participants (4%) had transient hyperglycemia. One participant had incident hyperglycemia and was excluded. Compared with participants with persistent euglycemia, those with transient hyperglycemia showed a twofold higher risk of experiencing an unfavorable treatment outcome (adjusted incidence rate ratio [aIRR], 2.07; 95% CI, 1.04-4.15) after adjusting for confounders including diabetes treatment, and BMI; we did not find a significant association with persistent hyperglycemia (aIRR, 1.64; 95% CI, 0.71-3.79). Diabetes treatment was associated with a significantly lower risk of unfavorable treatment outcomes (aIRR, 0.38; 95% CI, 0.15-0.95). INTERPRETATION: Transient hyperglycemia and lack of diabetes treatment was associated with a higher risk of unfavorable treatment outcomes in adults with pulmonary TB.

Use of first line antiretroviral therapy from a free ART programme clinic in Pune, India - a preliminary report.

BACKGROUND & OBJECTIVES: The treatment outcomes under national antiretroviral therapy (ART) programme are being evaluated in some ART centres in the country. We carried out this study to analyze the impact of first line antiretroviral therapy in HIV infected patients attending a free ART roll out national programme clinic in Pune, India. METHODS: Antiretroviral naive HIV infected patients attending the clinic between December 2005 and April 2008 and followed up till March 31, 2011 were included in the analysis. The enrolment and follow up of these patients were done as per the national guidelines. Viral load estimations were done in a subset of patients. results: One hundred and forty two patients with median CD4 count of 109 cells/µl (IQR: 60-160) were initiated on treatment. The median follow up was 44 months (IQR: 37-53.3 months). Survival analysis showed that the probability of being alive at the end of 5 years was 85 per cent. Overall increase in the median CD4 count was statistically significant (P<0.001). It was significant in patients with >95 per cent adherence (P<0.001). In 14 per cent patients, the absolute CD4 count did not increase by 100 or more cells/µl at the end of 12 months. Viral load estimation in a subset of 68 patients showed undetectable levels in 61 (89.7%) patients after a median duration of 46 months (IQR: 38.3-54.8). INTERPRETATION & CONCLUSIONS: The first line treatment was effective in patients attending the programme clinic. The adherence level influenced immunological and virological outcomes of patients.

Evaluation of a multimodal, distance learning HIV management course for clinical care providers in India.

Distance learning is an important tool for training HIV health workers. However, there is limited evidence on design and evaluation of distance learning HIV curricula and tools. We therefore designed, implemented, and evaluated a distance learning course on HIV management for clinical care providers in India. After course completion, participant scores rose significantly from a pretest (78.4% mean correct) compared with the posttest (87.5%, P < .001). After course completion, participants were more likely to be confident in starting an initial antiretroviral (ARV) regimen, understanding ARV toxicities, encouraging patient adherence, diagnosing immune reconstitution syndrome, and monitoring patients on ARV medications (P ≤ .05). All participants (100%) strongly agreed/agreed that they would recommend this course to others, and most of them (96%) strongly agreed/agreed that they would take a course in this format again. A pragmatic approach to HIV curriculum development and evaluation resulted in reliable learning outcomes, as well as learner satisfaction and improvement in knowledge.

Clinical and Immunological Markers of Pulmonary Impairment Among People With HIV in India.

Background: Despite antiretroviral therapy, chronic lung diseases remain an important source of morbidity and mortality in people with HIV (PWH). We sought to identify clinical and immunological markers of pulmonary impairment among PWH in India. Methods: Two hundred ten adult PWH receiving antiretroviral therapy (ART) were prospectively evaluated for 3 years. Plasma concentrations of interleukin (IL)-6, IL-10, tumor necrosis factor alpha, D-dimer, C-reactive protein, soluble (s)CD14, and sCD163 were measured at enrollment. We used multivariable linear and logistic regression to measure the association of baseline and time-varying clinical and immunological variables with spirometry-defined chronic obstructive pulmonary disease (COPD), restrictive spirometry pattern (RSP), preserved ratio impaired spirometry (PRISm), forced expiratory volume in 1 second (FEV1), and forced vital capacity (FVC) during the third year of follow-up. Results: After adjusting confounders, females were 7 times more likely to have RSP (95% CI, 2.81 to 17.62; P < .001) and 22 times more likely to have PRISm (95% CI, 7.42 to 69.92; P < .001) compared with men. Higher IL-6 concentrations were associated with lower FEV1 z-scores (ß, -0.14 per log-higher; 95% CI, -0.29 to 0.008; P = .06) and higher odds of COPD (adjusted odds ratio [aOR], 2.66 per log-higher; 95% CI, 1.16 to 6.09; P = .02). Higher D-dimer concentrations were associated with lower FVC z-scores (ß, -0.40 per log-higher; 95% CI, -0.78 to -0.01; P = .04). Conversely, higher IL-10 concentrations were associated with lower odds of PRISm (aOR, 0.76 per log-higher; 95% CI, 0.59 to 0.99; P = .04). Conclusions: Female sex, higher concentrations of IL-6 and D-dimer, and lower concentrations of IL-10 were associated with pulmonary impairment in adult PWH receiving ART in India.

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

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.

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

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.