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

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

Helminth Coinfection Alters Monocyte Activation, Polarization, and Function in Latent Mycobacterium tuberculosis Infection.

Helminth infections are known to influence T and B cell responses in latent tuberculosis infection (LTBI). Whether helminth infections also modulate monocyte responses in helminth-LTBI coinfection has not been fully explored. To this end, we examined the activation, polarization, and function of human monocytes isolated from individuals with LTBI with (n = 25) or without (n = 25) coincident Strongyloides stercoralis infection (S. stercoralis-positive and S. stercoralis-negative respectively). Our data reveal that the presence of S. stercoralis infection is associated with lower frequencies of monocytes expressing CD54, CD80, CD86 at baseline (absence of stimulation) and in response to mycobacterial-Ag stimulation than monocytes from S. stercoralis-negative individuals. In contrast, S. stercoralis infection was associated with higher frequencies of M2-like monocytes, as determined by expression of CD206 and CD163. Monocytes from S. stercoralis-positive individuals had a reduced capacity to phagocytose or exhibit respiratory burst activity following mycobacterial-Ag or LPS stimulation and were less capable of expression of IL-1ß, TNF-α, IL-6, and IL-12 at baseline and/or following Ag stimulation compared with those without S. stercoralis infection. In addition, definitive treatment of S. stercoralis infection resulted in a significant reversal of the altered monocyte function 6 mo after anthelmintic therapy. Finally, T cells from S. stercoralis-positive individuals exhibited significantly lower activation at baseline or following mycobacterial-Ag stimulation. Therefore, our data highlight the induction of dampened monocyte activation, enhanced M2 polarization, and impaired monocyte function in helminth-LTBI coinfection. Our data also reveal a different mechanism by which helminth infection modulates immune function in LTBI.

Diminished Circulating Levels of Angiogenic Factors and Rage Ligands in Helminth-Diabetes Comorbidity and Reversal Following Anthelmintic Treatment.

BACKGROUND: Various epidemiological and experimental studies propose that helminths could play a preventive role against the progression of type 2 diabetes mellitus (T2DM). T2DM induces microvascular and large vessel complications mediated by elevated levels of angiogenic factors and soluble receptor for advanced glycation end product (RAGE) ligands. However, the interactions between helminths and host angiogenic factors and RAGE ligands are unexplored. METHODS: To assess the relationship between a soil-transmitted helminth, Strongyloides stercoralis (Ss), and T2DM, we measured plasma levels of vascular endothelial growth factor (VEGF)-A, -C, and -D; angiopoietins 1 and 2 (Ang-1 and Ang-2); and their receptors VEGF-R1, -R2, and -R3 as well as soluble RAGE (sRAGE) and their ligands advanced glycation end products (AGEs), S100A12, and high mobility group box 1 (HMGB-1) in individuals with T2DM with or those without Ss infection. In Ss-infected individuals, we also measured the levels of aforementioned factors 6 months following anthelmintic therapy. RESULTS: Ss-infected individuals exhibited significantly decreased levels of VEGF-A, VEGF-C, VEGF-D, Ang-1, and Ang-2 and their soluble receptors VEGF-R1, -R2, and -R3, that increased following anthelmintic therapy. Likewise, Ss-infected individuals exhibited significantly decreased levels of AGEs and their ligands sRAGE, S100A12, and HMGB-1, which reversed following anthelmintic therapy. CONCLUSIONS: Our data suggest that Ss infection could play a beneficial role by limiting or delaying T2DM-related vascular complications.

Elevated levels of matrix metalloproteinases reflect severity and extent of disease in tuberculosis-diabetes co-morbidity and are predominantly reversed following standard anti-tuberculosis or metformin treatment.

BACKGROUND: Matrix metalloproteinases (MMPs) are considered to be key mediators of tuberculosis (TB) pathology but their role in tuberculosis - diabetes comorbidity (TB-DM) is not well understood. METHODS: To study the association of MMP levels with severity and extent of disease as well as bacterial burden in TB-DM, we examined the systemic levels of MMP-1, - 2, - 3, - 7, - 8, - 9, - 10, - 12 and - 13 in individuals with TB-DM and compared them to those with TB alone (TB) or healthy controls (HC). RESULTS: Circulating levels of MMP-1, - 2, - 3, - 7, - 10 and - 12 were significantly higher in TB-DM compared to both TB and HC and MMP -13 levels were higher in comparison to HC alone. To understand the effect of standard anti-tuberculosis therapy (ATT) on these MMP levels in TB-DM, we measured the levels of MMPs at the end of treatment (post-treatment). Our findings indicate that ATT is associated with a significant reduction in the levels of MMP-1, - 2, - 3, - 8 and - 13 post-treatment. Moreover, the levels of MMP-1, - 2, - 3, - 9 and - 12 were significantly higher in TB-DM individuals with cavitary disease and/or bilateral disease at baseline but not post-treatment. Similarly, the levels of MMP -1, - 2, - 3 and - 8 exhibited a significant positive relationship with bacterial burden and HbA1c levels at baseline but not post-treatment. Within the TB-DM group, those known to be diabetic before incident TB (KDM) exhibited significantly higher levels of MMP-1, - 2, - 10 and - 12 at baseline and of MMP-1 and -3 post-treatment compared to those newly diagnosed with DM (NDM). Finally, KDM individuals on metformin treatment exhibited significantly lower levels of MMP-1, - 2, - 3, - 7, - 9 and - 12 at baseline and of MMP-7 post-treatment. CONCLUSIONS: Our data demonstrate that systemic MMP levels reflect baseline disease severity and extent in TB-DM, differentiate KDM from NDM and are modulated by ATT and metformin therapy.

Acquired rifampicin resistance in thrice-weekly antituberculosis therapy: impact of HIV and antiretroviral therapy.

BACKGROUND: Risk factors for acquired rifampicin resistance (ARR) in human immunodeficiency virus (HIV)/tuberculosis coinfection, in the highly active antiretroviral therapy (HAART) era, needs evaluation. We studied the impact of HIV and HAART on ARR among patients taking thrice-weekly antituberculosis therapy. METHODS: This cross-protocol analysis included patients with newly diagnosed, rifampicin-susceptible pulmonary tuberculosis, with and without HIV, enrolled in clinical trials (who took >80% of medication) at the National Institute for Research in Tuberculosis between 1999 and 2013. All patients received rifampicin and isoniazid for 6 months reinforced with pyrazinamide and ethambutol in the first 2 months, given thrice-weekly throughout the study along with HAART in one of the groups. Outcomes were categorized and multivariate logistic regression analysis performed to identify risk factors for ARR. RESULTS: The per-protocol results included patients with tuberculosis: 246 HIV-uninfected patients (HIV(-)TB(+)), 212 HIV patients not on HAART (non-HAART), and 116 HIV-infected patients on HAART. Median CD4 counts of the latter 2 groups were 150 and 93 cells/µL, respectively, and the median viral loads were 147 000 and 266 000 copies/mL, respectively. Compared with HIV(-)TB(+), the relative risks (RRs) for an unfavorable response in the coinfected, non-HAART and HAART groups were 2.1 (95% confidence interval [CI], 1.7-14.8; P<.0001) and 2.1 (95% CI, .9-5.2; P=.3), whereas for ARR, the RRs were 21.1 (95% CI, 2.6-184; P<.001) and 8.2 (95% CI, .6-104; P=.07), respectively. CONCLUSIONS: HIV-infected patients with tuberculosis treated with a thrice-weekly antituberculosis regimen are at a higher risk of ARR, compared with HIV-uninfected patients, in the presence of baseline isoniazid resistance. HAART reduces but does not eliminate the risk of ARR.

Relative contribution of biomedical, demographic, and socioeconomic factors to COVID-19 vaccine receipt in rural India.

BACKGROUND: In the first year of roll-out, vaccination for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) prevented almost 20 million deaths from coronavirus disease 2019 (COVID-19). Yet, little is known about the factors influencing access to vaccination at the individual level within rural poor settings of low-income countries. The aim of this study was to examine determinants of vaccine receipt in rural India. METHODS: A census of a rural village in Tamil Nadu was undertaken from June 2021 to September 2022. We surveyed 775 participants from 262 households. Household-level data on socioeconomic status (SES), water, sanitation, and hygiene practices, and individual-level demographic information, travel history, and biomedical data, including anthropometry, vital signs, and comorbidities, were collected. Logistic regression models with 5-fold cross-validation were used to identify the biomedical, demographic, and socioeconomic determinants of vaccine receipt and the timing of receipt within the first 30 days of eligibility. Vaccine ineligible participants were excluded leaving 659 eligible participants. There were 650 eligible participants with complete biomedical, demographic, and socioeconomic data. RESULTS: There were 68.0% and 34.0% of individuals (N = 650) who had received one and two vaccine doses, respectively. Participants with household ownership of a permanent account number (PAN) or ration card were 2.15 (95% CI:1.32-3.52) or 3.02 (95% CI:1.72-5.29) times more likely to receive at least one vaccine dose compared to households with no ownership of such cards. Participants employed as housewives or self-employed non-agricultural workers were 65% (95% CI:0.19-0.67) or 59% (95% CI:0.22-0.76) less likely to receive at least one vaccine dose compared to salaried workers. Household PAN card ownership, occupation and age were linked to the timing of vaccine receipt. Participants aged ≤18 and 45-60 years were 17.74 (95% CI:5.07-62.03) and 5.51 (95% CI:2.74-11.10) times more likely to receive a vaccine within 30 days of eligibility compared to 19-44-year-olds. Biomedical factors including BMI, vital signs, comorbidities, and COVID-19 specific symptoms were not consistently associated with vaccine receipt or timing of receipt. No support was found that travel history, contact with COVID-19 cases, and hospital admissions influenced vaccine receipt or timing of receipt. CONCLUSION: Factors linked to SES were linked to vaccine receipt, more so than biomedical factors which were targeted by vaccine policies. Future research should explore if government interventions including vaccine mandates, barriers to vaccine access, or peer influence linked to workplace or targeted vaccine promotion campaigns underpin these findings.

Impact of Strongyloides stercoralis infection on complement activation in Type 2 diabetes mellitus: Insights from a clinical and anthelmintic intervention study.

BACKGROUND: Numerous studies indicate a potential protective role of helminths in diabetes mellitus (DM) progression. The complement system, vital for host defense, plays a crucial role in tissue homeostasis and immune surveillance. Dysregulated complement activation is implicated in diabetic complications. We aimed to investigate the influence of the helminth, Strongyloides stercoralis (Ss) on complement activation in individuals with type 2 DM (T2D). METHODOLOGY: We assessed circulating levels of complement proteins (C1q, C2, C3, C4, C4b, C5, C5a, and MBL (Lectin)) and their regulatory components (Factor B, Factor D, Factor H, and Factor I) in individuals with T2D with (n = 60) or without concomitant Ss infection (n = 58). Additionally, we evaluated the impact of anthelmintic therapy on these parameters after 6 months in Ss-infected individuals (n = 60). RESULTS: Ss+DM+ individuals demonstrated reduced levels of complement proteins (C1q, C4b, MBL (Lectin), C3, C5a, and C3b/iC3b) and complement regulatory proteins (Factor B and Factor D) compared to Ss-DM+ individuals. Following anthelmintic therapy, there was a partial reversal of these levels in Ss+DM+ individuals. CONCLUSION: Our findings indicate that Ss infection reduces complement activation, potentially mitigating inflammatory processes in individuals with T2D. The study underscores the complex interplay between helminth infections, complement regulation, and diabetes mellitus, offering insights into potential therapeutic avenues.

Hookworm infection induces glycometabolic modulation in South Indian individuals with type 2 diabetes.

Objectives: A number of epidemiological studies have demonstrated that there is an inverse relationship between helminth infections and diabetes mellitus, suggesting that helminth infection may have a positive effect on type 2 diabetes mellitus (T2DM). However, the association between hookworm infection and T2DM has barely been studied. Hence, we aimed to investigate and analyze the interaction and association between hookworm infection and T2DM. Methods: We examined the effect of hookworm infection on biochemical parameters, including plasma random blood glucose, glycated hemoglobin, and the plasma levels of pancreatic hormones, incretins, and adipokines in individuals with T2DM with (INF, n = 35) or without (UN, n = 35) hookworm infection. Moreover, we re-evaluated these analyte concentrations in a subset of INF individuals 6 months following anthelmintic therapy. Results: Compared to UN individuals, INF individuals had significantly lowered levels of random blood glucose and glycated hemoglobin. INF individuals also exhibited significantly diminished levels of adiponectin, adipsin, C-peptide, insulin, and glucagon compared to UN individuals. In contrast, INF individuals displayed substantially elevated levels of visfatin and incretins compared to UN individuals. Interestingly, this effect was not seen following anthelmintic treatment. Conclusion: Our study findings indicate that concomitant hookworm infection exerts a beneficial effect on glycometabolic parameters in T2DM.

Low body mass index is associated with diminished plasma cytokines and chemokines in both active and latent tuberculosis.

Introduction: Low body mass index (BMI) is a major risk factor for tuberculosis (PTB). Low BMI can impair the immune system and thus might affect TB incidence. Methods: We examined the plasma levels of Type 1, Type 17, pro-inflammatory, Type 2 and regulatory cytokines and CC and CXC chemokines in PTB and latent TB (LTB) individuals with low BMI (LBMI) or normal BMI (NBMI). Results: Our data show that PTB is associated with significantly lower levels of IFNγ, TNFα, IL-2, IL-17A, IL-6, IL-12, IL-4 and IL-5 cytokines but significantly higher levels of IL-10, TGFß and GM-CSF in LBMI compared to NBMI. Similarly, PTB is also associated with significantly lower levels of CCL2, CCL3, CCL11, CXCL1, CXCL9 and CXCL10 chemokines in LBMI compared to NBMI. Our data reveals that LTB is associated with significantly lower levels of IFNγ, TNFα, IL-2, IL1ß, IL-12, IL-13 cytokines but significantly higher levels of IL-10, TGFß, IL-4 and IL-22 in LBMI compared to NBMI. Similarly, LTB is also associated with significantly lower levels of CCL2, CXCL1, CXCL9 and CXCL10 and significantly higher levels of CCL1, CCL3, and CCL4 in LBMI compared to NBMI. Conclusion: Thus, LBMI has a major impact on the cytokine and chemokine milieu of both PTB and LTB and might predispose to the increased risk of tuberculosis by this immunomodulatory effect.

Prevalence and factors associated with tuberculosis infection in India.

BACKGROUND: The risk of tuberculosis (TB) disease is higher in individuals with TB infection. In a TB endemic country like India, it is essential to understand the current burden of TB infection at the population level. The objective of the present analysis is to estimate the prevalence of TB infection in India and to explore the factors associated with TB infection. METHODS: Individuals aged > 15 years in the recently completed National TB prevalence survey in India who were tested for TB infection by QuantiFERON-TB Gold Plus (QFT-Plus) assay were considered for this sub-analysis. TB infection was defined as positive by QFT-Plus (value >0.35 IU/ml). The estimates for prevalence, prevalence ratio (PR) and adjusted risk ratio (aRR) estimates with 95% confidence intervals (CIs) were calculated. RESULTS: Of the 16864 individuals analysed, the prevalence of TB infection was 22.6% (95% CI:19.4 -25.8). Factors more likely to be associated with TB infection include age > 30 years (aRR:1.49;95% CI:1.29-1.73), being male (aRR:1.26; 95%CI: 1.18-1.34), residing in urban location (aRR:1.58; 95%CI: 1.03-2.43) and past history of TB (aRR:1.49; 95%CI: 1.26-1.76). CONCLUSION: About one fourth (22.6%) of the individuals were infected with TB in India. Individuals aged > 30 years, males, residing in urban location, and those with past history of TB were more likely to have TB infection. Targeted interventions for prevention of TB and close monitoring are essential to reduce the burden of TB in India.

High Dimensionality Reduction and Immune Phenotyping of Natural Killer and Invariant Natural Killer Cells in Latent Tuberculosis-Diabetes Comorbidity.

Natural killer (NK) and invariant NKT (iNKT) cells are unique innate lymphocytes that coordinate diverse immune responses and display antimycobacterial potential. However, the role of NK and iNKT cells expressing cytokines, cytotoxic, and immune markers in latent tuberculosis (LTB), diabetes mellitus (DM), or preDM (PDM) and nonDM (NDM) comorbidities is not known. Thus, we have studied the unstimulated (UNS), Mycobacterium tuberculosis (Mtb [PPD, WCL]), and mitogen (P/I)-stimulated NK and iNKT cells expressing Type 1 (IFNγ, TNFα, and IL-2), Type 17 (IL-17A, IL-17F, and IL-22) cytokines, cytotoxic (perforin, granzyme B, and granulysin) and immune (GMCSF, PD-1, and CD69) markers in LTB comorbidities by dimensionality reduction and flow cytometry. Our results suggest that LTB DM and PDM individuals express diverse NK and iNKT cell immune clusters compared to LTB NDM individuals. In UNS condition, frequencies of NK and iNKT cells expressing markers are not significantly different. After Mtb antigen stimulation, NK cell expressing [Type 1 (IFNγ, TNFα, and IL-2), GMCSF in PPD and IFNγ in WCL), Type 17 [(IL-17A), PD-1 in PPD), (IL-17A, IL-17F, and IL-22), PD-1 in WCL], and cytotoxic (perforin, granzyme B in PPD, and WCL)] marker frequencies were significantly reduced in LTB DM and/or PDM individuals compared to LTB NDM individuals. Similarly, iNKT cells expressing [Type 1 (IFNγ, IL-2), GMCSF in PPD), TNFα, GMCSF in WCL), Type 17 (IL-17A), PD-1 in PPD, IL-17F in WCL) cytokines were increased and cytotoxic or immune (perforin, granzyme B, granulysin), CD69 in PPD, perforin and CD69 in WCL] marker frequencies were significantly diminished in LTB DM and/or PDM compared to LTB NDM individuals. Finally, NK and iNKT cell frequencies did not exhibit significant differences upon positive control antigen stimulation between the study population. Therefore, altered NK cell and iNKT cells expressing cytokines, cytotoxic, and immune markers are characteristic features in LTB PDM/DM comorbidities.

Prevalence of proximate risk factors of active tuberculosis in latent tuberculosis infection: A cross-sectional study from South India.

The prevalence of proximate risk factors for active tuberculosis (TB) in areas of high prevalence of latent tuberculosis infection (LTBI) is not clearly understood. We aimed at assessing the prevalence of non-communicable multi-morbidity focusing on diabetes mellitus (DM), malnutrition, and hypertension (HTN) as common risk factors of LTBI progressing to active TB. In a cross-sectional study, 2,351 adults (45% male and 55% female) from villages in the Kancheepuram district of South India were enrolled between 2013 and 2020. DM was defined as HbA1c >6.4%, undernutrition was defined as low body mass index (LBMI) <18.5 kg/m2, obesity was classified as BMI ≥25 kg/m2, HTN was reported as systolic pressure >130 mmHg, and LTBI was defined as positive (≥ 0.35 international units/ml) by QuantiFERON Gold In-Tube assay. A total of 1,226 individuals (52%) were positive for LTBI out of 2351 tested individuals. The prevalence of DM and pre-diabetes mellitus (PDM) was 21 and 35%, respectively, HTN was 15% in latent tuberculosis (LTB)-infected individuals. The association of DM [odds ratio (OR)]; adjusted odds ratio (aOR) (OR = 1.26, 95% CI: 1.13-1.65; aOR = 1.19, 95% CI: 1.10-1.58), PDM (OR = 1.11, 95% CI: 1.0-1.35), and HTN (OR = 1.28, 95% CI: 1.11-1.62; aOR = 1.18, 95% CI: 1.0-1.56) poses as risk factors of LTBI progression to active TB. The prevalence of LBMI 9% (OR = 1.07, 95% CI: 0.78-1.48) and obesity 42% (OR = 0.85, 95% CI: 0.70-1.03) did not show any statistically significant association with LTB-infected individuals. The present evidence of a high burden of multi-morbidity suggests that proximate risk factors of active TB in LTBI can be managed by nutrition and lifestyle modification.

Seroprevalence of Strongyloides stercoralis infection in a South Indian adult population.

BACKGROUND: The prevalence of Strongyloides stercoralis infection is estimated to be 30-100 million worldwide, although this an underestimate. Most cases remain undiagnosed due to the asymptomatic nature of the infection. We wanted to estimate the seroprevalence of S. stercoralis infection in a South Indian adult population. METHODS: To this end, we performed community-based screening of 2351 individuals (aged 18-65) in Kanchipuram District of Tamil Nadu between 2013 and 2020. Serological testing for S. stercoralis was performed using the NIE ELISA. RESULTS: Our data shows a seroprevalence of 33% (768/2351) for S. stercoralis infection which had a higher prevalence among males 36% (386/1069) than among females 29.8% (382/1282). Adults aged ≥55 (aOR = 1.65, 95% CI: 1.25-2.18) showed higher adjusted odds of association compared with other age groups. Eosinophil levels (39%) (aOR = 1.43, 95% CI: 1.19-1.74) and hemoglobin levels (24%) (aOR = 1.25, 95% CI: 1.11-1.53) were significantly associated with S. stercoralis infection. In contrast, low BMI (aOR = 1.15, 95% CI: 0.82-1.61) or the presence of diabetes mellitus (OR = 1.18, 95% CI: 0.83-1.69) was not associated with S. stercoralis seropositivity. CONCLUSIONS: Our study provides evidence for a very high baseline prevalence of S. stercoralis infection in South Indian communities and this information could provide realistic and concrete planning of control measures.

Dyslipidemia among HIV-infected Patients with tuberculosis taking once-daily nonnucleoside reverse-transcriptase inhibitor-based antiretroviral therapy in India.

BACKGROUND: Our aim was to study the incidence and pattern of dyslipidemia among human immunodeficiency virus (HIV)-infected patients with tuberculosis (TB) who received once-daily antiretroviral therapy (ART). METHODS: Antiretroviral-naive HIV-infected patients with TB were recruited to a trial of once-daily nonnucleoside reverse-transcriptase inhibitor (NNRTI)-based ART and treated with rifampicin-based thrice-weekly antituberculosis treatment (ATT); participants were randomized to receive didanosine (250/400 mg) and lamivudine (300 mg) with either efavirenz (600 mg) or nevirapine (400 mg) once-daily after an intensive phase of ATT. Fasting triglyceride (TG) level, total cholesterol (TC) level, low-density cholesterol (LDL-c) level and high-density cholesterol (HDL-c) level were measured at baseline and at 6 and 12 months. Lipid levels at 6 and 12 months were compared with baseline values with use of repeated measures analyses. McNemar test was used to compare the proportion of patients with lipid abnormality at baseline versus at 12 months, and χ² test was used to compare between the 2 groups. RESULTS: Of 168 patients (79% men; mean age, 36 years; mean weight, 42 kg; median CD4+ cell count, 93 cells/mm³), 104 received efavirenz-based ART, and 64 received nevirapine-based ART. After 6 months, TC levels increased by 49 mg/dL, LDL-c levels by 30 mg/dL, and HDL-c levels increased by 18 mg/dL (P < .001 for all). At baseline and at 12 months, TC was >200 mg/dL for 1% and 26% of patients, respectively; LDL-c level was >130 mg/dL for 3% and 23%, respectively; HDL-c level was <40 mg/dL for 91% and 23%, respectively; and blood glucose level was >110 mg/dL for 14% and 13%, respectively. TC level >200 mg/dL was more common among patients who received efavirenz than among those who received nevirapine (32% vs 16%; P = .04). CONCLUSIONS: HIV-infected patients with TB who initiate NNRTI-based ART undergo complex changes in lipid profile, highlighting the importance of screening and treating other cardiovascular disease risk factors in this population.

Efficacy and safety of once-daily nevirapine- or efavirenz-based antiretroviral therapy in HIV-associated tuberculosis: a randomized clinical trial.

BACKGROUND: Nevirapine (NVP) can be safely and effectively administered once-daily but has not been assessed in human immunodeficiency virus (HIV)-infected patients with tuberculosis (TB). We studied the safety and efficacy of once-daily NVP, compared with efavirenz (EFV; standard therapy); both drugs were administered in combination with 2 nucleoside reverse-transcriptase inhibitors. METHODS: An open-label, noninferiority, randomized controlled clinical trial was conducted at 3 sites in southern India. HIV-infected patients with TB were treated with a standard short-course anti-TB regimen (2EHRZ(3)/4RH(3); [2 months of Ethambutol, Isoniazid, Rifampicin, Pyrazinamide / 4 months of Isoniazid and Rifampicin] thrice weekly) and randomized to receive once-daily EFV at a dose of 600 mg or NVP at a dose of 400 mg (after 14 days of 200 mg administered once daily) with didanosine 250/400 mg and lamivudine 300 mg after 2 months. Sputum smears and mycobacterial cultures were performed every month. CD4+ cell count, viral load, and liver function test results were monitored periodically. Primary outcome was a composite of death, virological failure, default, or serious adverse event (SAE) at 24 weeks. Both intent-to-treat and per protocol analyses were done, and planned interim analyses were performed. RESULTS: A total of 116 patients (75% [87 patients] of whom had pulmonary TB), with a mean age of 36 years, a median CD4+ cell count of 84 cells/mm(3), and a median viral load of 310 000 copies/mL, were randomized. At 24 weeks, 50 of 59 patients in the EFV group and 37 of 57 patients in the NVP group had virological suppression (P = .024). There were no deaths, 1 SAE, and 5 treatment failures in the EFV arm, compared with 5 deaths, 2 SAEs, and 10 treatment failures in the NVP arm. The trial was halted by the data and safety monitoring board at the second interim analysis. Favorable TB treatment outcomes were observed in 93% of the patients in the EFV arm and 84% of the patients in the NVP arm (P = .058). CONCLUSIONS: Compared with a regimen of didanosine, lamivudine, and EFV, a regimen of once-daily didanosine, lamivudine, and NVP was inferior and was associated with more frequent virologic failure and death. Clinical Trials Registration. NCT00332306.

Efficacy of a 6-month versus 9-month intermittent treatment regimen in HIV-infected patients with tuberculosis: a randomized clinical trial.

RATIONALE: The outcome of fully intermittent thrice-weekly antituberculosis treatment of various durations in HIV-associated tuberculosis is unclear. OBJECTIVES: To compare the efficacy of an intermittent 6-month regimen (Reg6M: 2EHRZ(3)/4HR(3) [ethambutol, 1,200 mg; isoniazid, 600 mg; rifampicin, 450 or 600 mg depending on body weight <60 or > or =60 kg; and pyrazinamide, 1,500 mg for 2 mo; followed by 4 mo of isoniazid and rifampicin at the same doses]) versus a 9-month regimen (Reg9M: 2EHRZ(3)/7HR(3)) in HIV/tuberculosis (TB). METHODS: HIV-infected patients with newly diagnosed pulmonary or extrapulmonary TB were randomly assigned to Reg6M (n = 167) or Reg9M (n = 160) and monitored by determination of clinical, immunological, and bacteriological parameters for 36 months. Primary outcomes included favorable responses at the end of treatment and recurrences during follow-up, whereas the secondary outcome was death. Intent-to-treat and on-treatment analyses were performed. All patients were antiretroviral treatment-naive during treatment. MEASUREMENTS AND MAIN RESULTS: Of the patients, 70% had culture-positive pulmonary TB; the median viral load was 155,000 copies/ml and the CD4(+) cell count was 160 cells/mm(3). Favorable response to antituberculosis treatment was similar by intent to treat (Reg6M, 83% and Reg9M, 76%; P = not significant). Bacteriological recurrences occurred significantly more often in Reg6M than in Reg9M (15 vs. 7%; P < 0.05) although overall recurrences were not significantly different (Reg6M, 19% vs. Reg9M, 13%). By 36 months, 36% of patients undergoing Reg6M and 35% undergoing Reg9M had died, with no significant difference between regimens. All 19 patients who failed treatment developed acquired rifamycin resistance (ARR), the main risk factor being baseline isoniazid resistance. CONCLUSIONS: Among antiretroviral treatment-naive HIV-infected patients with TB, a 9-month regimen resulted in a similar outcome at the end of treatment but a significantly lower bacteriological recurrence rate compared with a 6-month thrice-weekly regimen. ARR was high with these intermittent regimens and neither mortality nor ARR was altered by lengthening TB treatment. Clinical Trials Registry Information: ID# NCT00376012 registered at www.clinicaltrials.gov.

Decreased Frequencies of Gamma/Delta T Cells Expressing Th1/Th17 Cytokine, Cytotoxic, and Immune Markers in Latent Tuberculosis-Diabetes/Pre-Diabetes Comorbidity.

Antigen-specific gamma-delta (γδ) T cells are important in exhibiting anti-mycobacterial immunity, but their role in latent tuberculosis (LTB) with diabetes mellitus (DM) or pre-DM (PDM) and non-DM comorbidities have not been studied. Thus, we have studied the baseline, mycobacterial (PPD, WCL), and positive control antigen-stimulated γδ T cells expressing Th1 (IFNγ, TNFα, IL-2) and Th17 (IL-17A, IL-17F, IL-22) cytokine as well as cytotoxic (perforin [PFN], granzyme [GZE B], granulysin [GNLSN]) and immune (GMCSF, PD-1, CD69) markers in LTB (DM, PDM, NDM) comorbidities by flow cytometry. In the unstimulated (UNS) condition, we did not observe any significant difference in the frequencies of γδ T cells expressing Th1 and Th17 cytokine, cytotoxic, and immune markers. In contrast, upon PPD antigen stimulation, the frequencies of γδ T cells expressing Th1 (IFNγ, TNFα) and Th17 (IL-17F, IL-22) cytokine, cytotoxic (PFN, GZE B, GNLSN), and immune (CD69) markers were significantly diminished in LTB DM and/or PDM individuals compared to LTB NDM individuals. Similarly, upon WCL antigen stimulation, the frequencies of γδ T cells expressing Th1 (TNFα) and Th17 (IL-17A, IL-22) cytokine, cytotoxic (PFN), and immune (PD-1, CD69) markers were significantly diminished in LTB DM and/or PDM individuals compared to LTB NDM individuals. Finally, upon P/I stimulation we did not observe any significant difference in the γδ T cell frequencies expressing cytokine, cytotoxic, and immune markers between the study populations. The culture supernatant levels of IFNγ, TNFα, and IL-17A cytokines were significantly increased in LTB DM and PDM after stimulation with Mtb antigens compared to LTB NDM individuals. Therefore, diminished γδ T cells expressing cytokine, cytotoxic, and other immune markers and elevated levels of cytokines in the supernatants is a characteristic feature of LTB PDM/DM co-morbidities.

Prevalence of bacteriologically confirmed pulmonary tuberculosis and associated risk factors: A community survey in Thirvallur District, south India.

BACKGROUND: Tuberculosis (TB) prevalence surveys add to the active case detection in the community level burden of TB both national and regional levels. The aim of this study was to assess the prevalence of bacteriologically confirmed pulmonary tuberculosis (PTB) in the community. METHODS: Household community-based tuberculosis disease survey was conducted targeting 69054 population from 43 villages of 5 blocks in Tiruvallure district adopting cluster sampling methodology of ≥15 years old adult rural population of South India during 2015-2018. All eligible individuals with suspected symptoms of PTB were screened with chest X-ray. Two sputum specimens (one spot and the other early morning sample) were collected for M.tb smear and culture examination. Conversely demographical, smoking and alcohol drinking habits information were also collected to explore the risk factor. Stepwise logistic regression was employed to associate risk factors for PTB. RESULTS: A total of 62494 were screened among 69054 eligible population, of whom 6340 were eligible for sputum specimen collection. Sputum for M.tb smear and culture examination were collected in 93% of participants. The derived prevalence of PTB was 307/100000 population (smear-positive 130; culture positive 277). As expected that PTB has decreased substantially compared to preceding surveys and it showed that older age, male, low BMI, diabetes, earlier history of TB and alcohol users were significantly associated (p < .0001) with an increased risk of developing PTB. CONCLUSION: Upshot of the active survey has established a reduction in the prevalence of PTB in the rural area which can be accredited to better programmatic implementation and success of the National TB Control Programme in this district. It also has highlighted the need for risk reduction interventions accelerate faster elimination of TB.

Morphologic and body composition changes are different in men and women on generic combination antiretroviral therapy--an observational study.

BACKGROUND: Increasingly effective therapies for HIV infection, combination antiretroviral therapy, are now widely available in developing countries. A range of metabolic complications presenting as abnormalities of body-fat mass distribution in association with dyslipidemia and glucose homeostasis dysregulation, have been recognized as important toxicities in patients treated with these drugs. With increasing use of antiretroviral therapy in India, we examined the association between gender and body shape and composition, one year after initiating combination antiretroviral therapy and attempted to identify simple clinical markers to detect and monitor these changes. METHODS: Patients on combination antiretroviral therapy (2 NRTIs + 1 NNRTI), attending a HIV clinic between July 2005 and December 2006 had anthropometry clinical examination and bioelectric impedance analysis (BIA) performed along with blood tests at baseline and after 1 year. RESULTS: Of the 34 patients on combination antiretroviral therapy, 5 males and 12 females had noticeable changes in their body shape. Significant decrease in triceps skin fold thickness, an increase in waist circumference and waist: hip ratio was observed in females. BIA did not show any change in total body fat in either sex. CONCLUSIONS: Since the presence and severity of fat redistribution could affect adherence as well as the success of antiretroviral therapy, close monitoring is required to detect and prevent this complication early.

Helminth Mediated Attenuation of Systemic Inflammation and Microbial Translocation in Helminth-Diabetes Comorbidity.

Type 2 diabetes mellitus (T2DM) is characterized by heightened systemic inflammation and microbial translocation. Whether concomitant helminth infections can modulate this systemic response is unclear. We examined the presence of markers of systemic inflammation (levels of acute phase proteins) and of microbial translocation [levels of lipopolysaccharide (LPS) and its associated products] in T2DM individuals with (Ss+) or without (Ss-) Strongyloides stercoralis (Ss) infection. We also analyzed these parameters at 6 months following anthelmintic treatment in Ss+ individuals. Ss+ individuals exhibited significantly diminished levels of alpha-2 macroglobulin, C-reactive protein, haptoglobin and serum amyloid protein A1 compared to Ss- individuals and these levels increased significantly following therapy. Similarly, Ss+ individuals exhibited significantly diminished levels of LPS, sCD14, intestinal fatty acid binding protein, LPS binding protein and endotoxin IgG antibody and most of these levels increased significantly following therapy. Thus, helminth infection is associated with attenuation of systemic inflammation and microbial translocation in T2DM and its reversal following anthelmintic therapy.