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Infant TB Infection Prevention Study (iTIPS): a randomised trial protocol evaluating isoniazid to prevent M. tuberculosis infection in HIV-exposed uninfected children.
LaCourse, SM, Richardson, BA, Kinuthia, J, Warr, AJ, Maleche-Obimbo, E, Matemo, D, Cranmer, LM, Escudero, JN, Hawn, TR, John-Stewart, GC
BMJ open. 2020;(1):e034308
Abstract
INTRODUCTION HIV-exposed uninfected (HEU) infants in tuberculosis (TB) endemic settings are at high risk of Mycobacterium tuberculosis (Mtb) infection and TB disease, even in the absence of known Mtb exposure. Because infancy is a time of rapid progression from primary infection to active TB disease, it is important to define when and how TB preventive interventions exert their effect in order to develop effective prevention strategies in this high-risk population. METHODS AND ANALYSIS We designed a non-blinded randomised controlled trial to determine efficacy of isoniazid (INH) to prevent primary Mtb infection among HEU children. Target sample size is 300 (150 infants in each arm). Children are enrolled at 6 weeks of age from maternal and child health clinics in Kenya and are randomised to receive 12 months of daily INH ~10 mg/kg plus pyridoxine or no INH. The primary endpoint is Mtb infection, assessed by interferon-gamma release assay QuantiFERON-TB Gold Plus (QFT-Plus) or tuberculin skin test after 12 months post-enrolment. Secondary outcomes include severe adverse events, expanded Mtb infection definition using additional QFT-Plus supernatant markers and determining correlates of Mtb infection. Exploratory analyses include a combined outcome of TB infection, disease and mortality, and sensitivity analyses excluding infants with baseline TB-specific responses on flow cytometry. ETHICS AND DISSEMINATION An external and independent Data and Safety Monitoring Board monitors adverse events. Results will be disseminated through peer-reviewed journals, presentations at local and international conferences to national and global policy-makers, the local community and participants. TRIAL REGISTRATION NUMBER NCT02613169; Pre-results.
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High prevalence of Mycobacterium tuberculosis bacteraemia among a cohort of HIV-infected patients with severe sepsis in Lusaka, Zambia.
Muchemwa, L, Shabir, L, Andrews, B, Bwalya, M
International journal of STD & AIDS. 2017;(6):584-593
Abstract
Tuberculosis is recognised as one of the leading causes of severe sepsis among HIV-infected patients. Most patients with Mycobacterium tuberculosis bacteraemia have advanced HIV disease with CD4 counts less than 100 cells/μl and its presentation is non-specific in most instances. This was a cross-sectional study which was done by analyzing data from 201 adult HIV-infected patients who met the inclusion criteria for severe sepsis. The prevalence of Mycobacterium tuberculosis bactraemia in the study population was 34.8%. Severe sepsis caused by other etiologies was observed in 33 (16.4%) of the participants. Concomitant infection of Mycobacterium tuberculosis bactraemia with other organisms is not uncommon in patients with severe sepsis. This cohort of HIV-infected patients had severe immunosuppression with a median CD4 count of 51 (20-136) cells/μl with moderate anaemia, mean haemoglobin 8.0 (3.0) g/dl, and were generally underweight with a mean mid upper arm circumference (MUAC) of 21.0 (3.4) cm. Mycobacterium tuberculosis bacteraemia is very common in HIV-infected patients with advanced HIV disease who present with severe sepsis. Mycobacterium tuberculosis bacteraemia co-infection with aerobic organisms is not uncommon. Factors that were independently associated with Mycobacterium tuberculosis bacteraemia in our study population were MUAC and sodium level.
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Adenovirus type 35-vectored tuberculosis vaccine has an acceptable safety and tolerability profile in healthy, BCG-vaccinated, QuantiFERON(®)-TB Gold (+) Kenyan adults without evidence of tuberculosis.
Walsh, DS, Owira, V, Polhemus, M, Otieno, L, Andagalu, B, Ogutu, B, Waitumbi, J, Hawkridge, A, Shepherd, B, Pau, MG, et al
Vaccine. 2016;(21):2430-2436
Abstract
In a Phase 1 trial, we evaluated the safety of AERAS-402, an adenovirus 35-vectored TB vaccine candidate expressing 3 Mycobacterium tuberculosis (Mtb) immunodominant antigens, in subjects with and without latent Mtb infection. HIV-negative, BCG-vaccinated Kenyan adults without evidence of tuberculosis, 10 QuantiFERON(®)-TB Gold In-Tube test (QFT-G)(-) and 10 QFT-G(+), were randomized 4:1 to receive AERAS-402 or placebo as two doses, on Days 0 and 56, with follow up to Day 182. There were no deaths, serious adverse events or withdrawals. For 1 AERAS-402 QFT-G(-) and 1 AERAS-402 QFT-G(+) subject, there were 3 self-limiting severe AEs of injection site pain: 1 after the first vaccination and 1 after each vaccination, respectively. Two additional severe AEs considered vaccine-related were reported after the first vaccination in AERAS-402 QFT-G(+) subjects: elevated blood creatine phosphokinase and neutropenia, the latter slowly improving but remaining abnormal until study end. AERAS-402 was not detected in urine or throat cultures for any subject. In intracellular cytokine staining studies, curtailed by technical issues, we saw modest CD4+ and CD8+ T cell responses to Mtb Ag85A/b peptide pools among both QFT-G(-) and (+) subjects, with trends in the CD4+ T cells suggestive of boosting after the second vaccine dose, slightly more so in QFT-G(+) subjects. CD4+ and CD8+ responses to Mtb antigen TB10.4 were minimal. Increases in Adenovirus 35 neutralizing antibodies from screening to end of study, seen in 50% of AERAS-402 recipients, were mostly minimal. This small study confirms acceptable safety and tolerability profiles for AERAS-402, in line with other Phase 1 studies of AERAS-402, now to include QFT-G(+) subjects.
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Zinc and vitamin A supplementation fails to reduce sputum conversion time in severely malnourished pulmonary tuberculosis patients in Indonesia.
Pakasi, TA, Karyadi, E, Suratih, NM, Salean, M, Darmawidjaja, N, Bor, H, van der Velden, K, Dolmans, WM, van der Meer, JW
Nutrition journal. 2010;:41
Abstract
BACKGROUND A previous study showed that combination of zinc and vitamin A reduced sputum conversion time in pulmonary tuberculosis (TB) patients. OBJECTIVE We studied the efficacy of which single micronutrient contributed more to the sputum conversion time. METHODS In a double-blind randomized community trial, newly sputum smear positive pulmonary TB patients were assigned randomly to receive zinc, vitamin A, zinc + vitamin A or placebo on top of TB treatment. Patients were asked to deliver their sputum on weekly basis to measure positivity of the bacteria. Nutritional status, chest x-ray, hemoglobin, C-reactive protein (CRP), retinol and zinc level were examined prior to, after 2 and 6 months of treatment. RESULTS Initially, 300 patients were enrolled, and 255 finished the treatment. Most patients were severely malnourished (mean BMI 16.5 ± 2.2 Kg/m2). Patients in the zinc + vitamin A group showed earlier sputum conversion time (mean 1.9 weeks) compared with that in the other groups; however the difference was not significant. Also, no benefit could be demonstrated of any of the used supplementations on clinical, nutritional, chest x-ray, or laboratory findings. CONCLUSIONS This study among severely malnourished TB patients, did not confirm that single or combined supplementation of zinc and vitamin A significantly reduced sputum conversion time or had other significant benefit.
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Saline nebulization before gastric lavage in the diagnosis of pulmonary tuberculosis in children and adolescents.
Maciel, EL, Peres, RL, do Prado, TN, Macedo, CR, Palaci, M, Vinhas, SA, Dietze, R, Johnson, JL, Struchiner, CJ
Journal of tropical pediatrics. 2010;(6):458-9
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The main objective is to assess whether nebulization before gastric lavage (GL) improves its sensitivity for the diagnosis of childhood tuberculosis (TB). Children and adolescents suspected of pulmonary TB were randomly assigned (1 : 2) to nebulization with hypertonic saline 30 min before GL (Neb group; n = 36) or GL without prior nebulization (controls; n = 68). The proportion of positive GL smears was greater in Neb group than in the control group; however, no statistical significance was observed (36.3% vs. 22.2%; p = 0.4). Inhalation of nebulized hypertonic saline before GL did not improve TB diagnosis in this study. Nevertheless, the validation of our data will require large longitudinal studies.
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Shortening treatment in adults with noncavitary tuberculosis and 2-month culture conversion.
Johnson, JL, Hadad, DJ, Dietze, R, Maciel, EL, Sewali, B, Gitta, P, Okwera, A, Mugerwa, RD, Alcaneses, MR, Quelapio, MI, et al
American journal of respiratory and critical care medicine. 2009;(6):558-63
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RATIONALE Cavitary disease and delayed culture conversion have been associated with relapse. Combining patient characteristics and measures of bacteriologic response might allow treatment shortening with current drugs in some patients. OBJECTIVES To assess whether treatment could be shortened from 6 to 4 months in patients with noncavitary tuberculosis whose sputum cultures converted to negative after 2 months. METHODS This study was a randomized, open-label equivalence trial. HIV-uninfected adults with noncavitary tuberculosis were treated daily with isoniazid, rifampin, pyrazinamide, and ethambutol for 2 months, followed by 2 months of isoniazid and rifampin. After 4 months, patients with drug-susceptible TB whose sputum cultures on solid media were negative after 8 weeks of treatment were randomly assigned to continue treatment for 2 more months or to stop treatment. Patients were followed for relapse for 30 months after beginning treatment. MEASUREMENTS AND MAIN RESULTS Enrollment was stopped by the safety monitoring committee after 394 patients were enrolled due to apparent increased risk for relapse in the 4-month arm. A total of 370 patients were eligible for per protocol analysis. Thirteen patients in the 4-month arm relapsed, compared with three subjects in the 6-month arm (7.0 vs. 1.6%; risk difference, 0.054; 95% confidence interval with Hauck-Anderson correction, 0.01-0.10). CONCLUSION Shortening treatment from 6 to 4 months in adults with noncavitary disease and culture conversion after 2 months using current drugs resulted in a greater relapse rate. The combination of noncavitary disease and 2-month culture conversion was insufficient to identify patients with decreased risk for relapse.
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Population pharmacokinetics of levofloxacin, gatifloxacin, and moxifloxacin in adults with pulmonary tuberculosis.
Peloquin, CA, Hadad, DJ, Molino, LP, Palaci, M, Boom, WH, Dietze, R, Johnson, JL
Antimicrobial agents and chemotherapy. 2008;(3):852-7
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The objective of this study was to determine the population pharmacokinetic parameters of levofloxacin, gatifloxacin, and moxifloxacin following multiple oral doses. Twenty-nine patients with tuberculosis at the University Hospital in Vitória, Brazil, participated. Subjects received multiple doses of one drug (levofloxacin, 1,000 mg daily, or gatifloxacin or moxifloxacin, 400 mg daily) as part of a 7-day study of early bactericidal activity. Serum samples were collected over 24 h after the fifth dose and assayed using validated high-performance liquid chromatography assays. Concentration-time data were analyzed using noncompartmental, compartmental, and population methods. The three drugs were well tolerated. Levofloxacin produced the highest maximum plasma concentrations (median, 15.55 microg/ml; gatifloxacin, 4.75 microg/ml; moxifloxacin, 6.13 microg/ml), largest volume of distribution (median, 81 liters; gatifloxacin, 79 liters; moxifloxacin, 63 liters), and longest elimination half-life (median, 7.4 h; gatifloxacin, 5.0 h; moxifloxacin, 6.5 h). A one-compartment model, with or without weight as a covariate, adequately described the data. Postmodeling simulations using median population parameter estimates closely approximated the median values from the original data. Area under the concentration-time curve/MIC ratios for free drug were high. All three quinolones showed favorable pharmacokinetic and pharmacodynamic indices, with the most favorable results in this population being seen with levofloxacin at the comparative doses used.
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Effect of high-dose vitamin A supplementation on the immune response to Bacille Calmette-Guerin vaccine.
Diness, BR, Fisker, AB, Roth, A, Yazdanbakhsh, M, Sartono, E, Whittle, H, Nante, JE, Lisse, IM, Ravn, H, Rodrigues, A, et al
The American journal of clinical nutrition. 2007;(4):1152-9
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BACKGROUND Vitamin A supplementation (VAS) at birth has been associated with decreased mortality in Asia. Bacille Calmette-Guérin (BCG) vaccine is given at birth in tuberculosis-endemic countries. Previous studies suggest that VAS may influence the immune response to vaccines. OBJECTIVE Our objective was to examine whether VAS influences the immune response to simultaneously administered BCG vaccine. DESIGN Within a randomized trial of 50,000 IU vitamin A or placebo given with BCG vaccine at birth in Guinea-Bissau, 2710 infants were examined for BCG scar formation and delayed-type hypersensitivity (DTH) to purified protein derivative of Mycobacterium tuberculosis (PPD) at 2 and 6 mo of age. The ex vivo cytokine response to PPD was measured in 607 infants. RESULTS At 2 mo of age, 39% (43% of the boys and 34% of the girls) responded to PPD. The prevalence ratio of a measurable PPD reaction for VAS compared with placebo recipients was 0.90 (95% CI: 0.80, 1.02) for all infants, 0.81 (95% CI: 0.69, 0.95) for boys, and 1.04 (95% CI: 0.86, 1.26) for girls. At 6 mo of age, 42% of the infants responded to PPD. No difference was observed between VAS and placebo recipients. The prevalence of BCG scar was not affected by VAS. The ex vivo interferon-gamma response to PPD was increased by VAS (means ratio: 1.40; 95% CI: 1.03, 1.91). CONCLUSIONS VAS with BCG vaccination does not appear to interfere with the long-term immune response to BCG. However, VAS temporarily altered the DTH reaction to PPD in boys at 2 mo of age, suggesting sex differences in the immunologic response to VAS given with BCG. This trial was registered at www.clinicaltrials.gov as #NCT00168597.
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A cholesterol-rich diet accelerates bacteriologic sterilization in pulmonary tuberculosis.
Pérez-Guzmán, C, Vargas, MH, Quiñonez, F, Bazavilvazo, N, Aguilar, A
Chest. 2005;(2):643-51
Abstract
BACKGROUND Hypocholesterolemia is common among tuberculous patients and is associated with mortality in miliary cases. Some in vitro studies have shown that cholesterol is necessary for the good functioning of macrophages and lymphocytes. STUDY OBJECTIVES To determine whether a cholesterol-rich diet could accelerate sputum sterilization in patients with pulmonary tuberculosis. DESIGN An 8-week follow-up, randomized, controlled trial carried out from March 2001 to January 2002. SETTING A third-level hospital for respiratory diseases in Mexico City. PATIENTS AND INTERVENTIONS Adult patients with newly diagnosed pulmonary tuberculosis were hospitalized for 8 weeks and randomly assigned to receive a cholesterol-rich diet (800 mg/d cholesterol [experimental group]) or a normal diet (250 mg/d cholesterol [control group]). All patients received the same four-drug antitubercular regimen (ie, isoniazid, rifampin, pyrazinamide, and ethambutol). MEASUREMENTS AND RESULTS Every week, a quantitative sputum culture and laboratory tests were done and respiratory symptoms were recorded. Patients in the experimental group (10 patients) and the control group (11 subjects) were HIV-negative and harbored Mycobacterium tuberculosis that was fully sensitive to antitubercular drugs. Sterilization of the sputum culture was achieved faster in the experimental group, as demonstrated either by the percentage of negative culture findings in week 2 (80%; control group, 9%; p = 0.0019) or by the Gehan-Breslow test for Kaplan-Meier curves (p = 0.0037). Likewise, the bacillary population decreased faster (p = 0.0002) in the experimental group. Respiratory symptoms improved in both groups, but sputum production decreased faster in the experimental group (p < 0.05). Laboratory test results did not differ between the groups. CONCLUSIONS A cholesterol-rich diet accelerated the sterilization rate of sputum cultures in pulmonary tuberculosis patients, suggesting that cholesterol should be used as a complementary measure in antitubercular treatment.
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A randomised controlled trial of oral zinc on the immune response to tuberculosis in HIV-infected patients.
Green, JA, Lewin, SR, Wightman, F, Lee, M, Ravindran, TS, Paton, NI
The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease. 2005;(12):1378-84
Abstract
SETTING The National HIV Unit, Singapore. OBJECTIVE To test whether zinc supplementation improves the immune response to tuberculosis in HIV-positive patients. DESIGN A double-blind, randomised, placebo-controlled trial of 28 days of oral zinc sulphate (50 mg of elemental zinc) or placebo in stable adult HIV-positive patients receiving antiretroviral therapy with a CD4 count <200 cells/microl. METHODS IFN-gamma response to mycobacterial antigen stimulation, CD4/8 cell count, lymphocyte subsets, T-cell receptor excision circle (TREC) levels and viral load were measured at baseline and day 28. RESULTS Thirty-two patients received zinc and 34 placebo. There was no significant change in the IFN-gamma response to human PPD stimulation in the zinc or placebo groups (placebo baseline: 0.42 +/- 1.03, day 28: 0.84 +/- 1.21 IU/ml, zinc baseline: 1.26 +/- 2.41, day 28: 1.39 +/- 1.88 IU/ml, P = 0.31 between groups), nor any of the other mycobacterial antigens tested. There were no changes in absolute CD4/8 cell levels or other lymphocyte subsets, TREC or viral load. Baseline zinc levels were normal in 62/66 (93.9%) patients. CONCLUSIONS We found no evidence for recommending pharmacological supplementation with oral zinc in HIV-positive patients without zinc deficiency.