Publications
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Coussens AK, Zaidi SMA, Allwood BW, et al., 2024, Classification of early tuberculosis states to guide research for improved care and prevention: an international Delphi consensus exercise., Lancet Respir Med
The current active-latent paradigm of tuberculosis largely neglects the documented spectrum of disease. Inconsistency with regard to definitions, terminology, and diagnostic criteria for different tuberculosis states has limited the progress in research and product development that are needed to achieve tuberculosis elimination. We aimed to develop a new framework of classification for tuberculosis that accommodates key disease states but is sufficiently simple to support pragmatic research and implementation. Through an international Delphi exercise that involved 71 participants representing a wide range of disciplines, sectors, income settings, and geographies, consensus was reached on a set of conceptual states, related terminology, and research gaps. The International Consensus for Early TB (ICE-TB) framework distinguishes disease from infection by the presence of macroscopic pathology and defines two subclinical and two clinical tuberculosis states on the basis of reported symptoms or signs of tuberculosis, further differentiated by likely infectiousness. The presence of viable Mycobacterium tuberculosis and an associated host response are prerequisites for all states of infection and disease. Our framework provides a clear direction for tuberculosis research, which will, in time, improve tuberculosis clinical care and elimination policies.
Verma R, Silva KED, Rockwood N, et al., 2024, A Nanopore Sequencing-based Pharmacogenomic Panel to Personalize Tuberculosis Drug Dosing, American Journal of Respiratory and Critical Care Medicine, ISSN: 1073-449X
Abdelgawad N, Chirehwa M, Schutz C, et al., 2024, Pharmacokinetics of antitubercular drugs in patients hospitalized with HIV-associated tuberculosis: a population modeling analysis, Wellcome Open Research, Vol: 7, Pages: 72-72
<ns3:p>Background Early mortality among hospitalized HIV-associated tuberculosis (TB/HIV) patients is high despite treatment. The pharmacokinetics of rifampicin, isoniazid, and pyrazinamide were investigated in hospitalized TB/HIV patients and a cohort of outpatients with TB (with or without HIV) to determine whether drug exposures differed between groups. Methods Standard first-line TB treatment was given daily as per national guidelines, which consisted of oral 4-drug fixed-dose combination tablets containing 150 mg rifampicin, 75 mg isoniazid, 400 mg pyrazinamide, and 275 mg ethambutol. Plasma samples were drawn on the 3rd day of treatment over eight hours post-dose. Rifampicin, isoniazid, and pyrazinamide in plasma were quantified and NONMEM® was used to analyze the data. Results Data from 60 hospitalized patients (11 of whom died within 12 weeks of starting treatment) and 48 outpatients were available. Median (range) weight and age were 56 (35 - 88) kg, and 37 (19 - 77) years, respectively. Bioavailability and clearance of the three drugs were similar between TB/HIV hospitalized and TB outpatients. However, rifampicin’s absorption was slower in hospitalized patients than in outpatients; mean absorption time was 49.9% and 154% more in hospitalized survivors and hospitalized deaths, respectively, than in outpatients. Higher levels of conjugated bilirubin correlated with lower rifampicin clearance. Isoniazid’s clearance estimates were 25.5 L/h for fast metabolizers and 9.76 L/h for slow metabolizers. Pyrazinamide’s clearance was more variable among hospitalized patients. The variability in clearance among patients was 1.70 and 3.56 times more for hospitalized survivors and hospitalized deaths, respectively, than outpatients. Conclusions We showed that the pharmacokinetics of first-line TB drugs are not substantially different between hospitalized TB/HIV patients and TB (with or without HIV) outpatients. Hospitalized patients do not seem
CRyPTIC Consortium, 2024, Quantitative measurement of antibiotic resistance in Mycobacterium tuberculosis reveals genetic determinants of resistance and susceptibility in a target gene approach, Nature Communications, Vol: 15, ISSN: 2041-1723
The World Health Organization has a goal of universal drug susceptibility testing for patients with tuberculosis. However, molecular diagnostics to date have focused largely on first-line drugs and predicting susceptibilities in a binary manner (classifying strains as either susceptible or resistant). Here, we used a multivariable linear mixed model alongside whole genome sequencing and a quantitative microtiter plate assay to relate genomic mutations to minimum inhibitory concentration (MIC) in 15,211 Mycobacterium tuberculosis clinical isolates from 23 countries across five continents. We identified 492 unique MIC-elevating variants across 13 drugs, as well as 91 mutations likely linked to hypersensitivity. Our results advance genetics-based diagnostics for tuberculosis and serve as a curated training/testing dataset for development of drug resistance prediction algorithms.
Middelkoop K, Micklesfield LK, Walker N, et al., 2024, Influence of vitamin D supplementation on bone mineral content, bone turnover markers and fracture risk in south African schoolchildren: multicentre double-blind randomised placebo-controlled trial (ViDiKids)., J Bone Miner Res
Randomised controlled trials (RCT) to determine the influence of vitamin D on bone mineral content (BMC) and fracture risk in children of Black African ancestry are lacking. We conducted a sub-study (n=450) nested within a Phase 3 RCT of weekly oral supplementation with 10,000 IU vitamin D3 vs. placebo for 3 years in HIV-uninfected Cape Town schoolchildren aged 6-11 years. Outcomes were BMC at the whole body less head (WBLH) and lumbar spine (LS) and serum 25-hydroxyvitamin D3 (25[OH]D3), parathyroid hormone (PTH), alkaline phosphatase, C-terminal telopeptide and procollagen type 1 N propeptide. Incidence of fractures was a secondary outcome of the main trial (n=1682). At baseline, mean serum 25(OH)D3 concentration was 70.0 nmol/L (s.d. 13.5), and 5.8% of participants had serum 25(OH)D3 concentrations <50 nmol/L. Among sub-study participants, end-trial serum 25(OH)D3 concentrations were higher for participants allocated to vitamin D vs. placebo (adjusted mean difference [aMD] 39.9 nmol/L, 95% CI 36.1 to 43.6) and serum PTH concentrations were lower (aMD -0.55 pmol/L, 95% CI -0.94 to -0.17). However, no interarm differences were seen for WBLH BMC (aMD -8.0 g, 95% CI -30.7 to 14.7) or LS BMC (aMD -0.3 g, 95% CI -1.3 to 0.8) or serum concentrations of bone turnover markers. Fractures were rare among participants in the main trial randomised to vitamin D vs. placebo (7/755 vs. 10/758 attending at least one follow-up; adjusted odds ratio 0.70, 95% CI 0.27 to 1.85). In conclusion, a 3-year course of weekly oral vitamin D supplementation elevated serum 25(OH)D3 concentrations and suppressed serum PTH concentrations in HIV-uninfected South African schoolchildren of Black African ancestry but did not influence BMC or serum concentrations of bone turnover markers. Fracture incidence was low, limiting power to detect an effect of vitamin D on this outcome.
Barnacle J, Davis A, Wilkinson R, 2024, Recent advances in understanding the human host immune response in tuberculous meningitis, Frontiers in Immunology, Vol: 14, ISSN: 1664-3224
Tuberculous meningitis (TBM), the most severe form of tuberculosis, causes death in approximately 25% cases despite antibiotic therapy, and half of survivors are left with neurological disability. Mortality and morbidity are contributed to by a dysregulated immune response, and adjunctive host-directed therapies are required to modulate this response and improve outcomes. Developing such therapies relies on improved understanding of the host immune response to TBM. The historical challenges in TBM research of limited in vivo and in vitro models have been partially overcome by recent developments in proteomics, transcriptomics, and metabolomics, and the use of these technologies in nested substudies of large clinical trials. We review the current understanding of the human immune response in TBM. We begin with M. tuberculosis entry into the central nervous system (CNS), microglial infection and blood-brain and other CNS barrier dysfunction. We then outline the innate response, including the early cytokine response, role of canonical and non-canonical inflammasomes, eicosanoids and specialised pro-resolving mediators. Next, we review the adaptive response including T cells, microRNAs and B cells, followed by the role of the glutamate-GABA neurotransmitter cycle and the tryptophan pathway. We discuss host genetic immune factors, differences between adults and children, paradoxical reaction, and the impact of HIV-1 co-infection including immune reconstitution inflammatory syndrome. Promising immunomodulatory therapies, research gaps, ongoing challenges and future paths are discussed.
Amaral EP, Namasivayam S, Queiroz ATL, et al., 2024, BACH1 promotes tissue necrosis and Mycobacterium tuberculosis susceptibility., Nat Microbiol, Vol: 9, Pages: 120-135
Oxidative stress triggers ferroptosis, a form of cellular necrosis characterized by iron-dependent lipid peroxidation, and has been implicated in Mycobacterium tuberculosis (Mtb) pathogenesis. We investigated whether Bach1, a transcription factor that represses multiple antioxidant genes, regulates host resistance to Mtb. We found that BACH1 expression is associated clinically with active pulmonary tuberculosis. Bach1 deletion in Mtb-infected mice increased glutathione levels and Gpx4 expression that inhibit lipid peroxidation. Bach1-/- macrophages exhibited increased resistance to Mtb-induced cell death, while Mtb-infected Bach1-deficient mice displayed reduced bacterial loads, pulmonary necrosis and lipid peroxidation concurrent with increased survival. Single-cell RNA-seq analysis of lungs from Mtb-infected Bach1-/- mice revealed an enrichment of genes associated with ferroptosis suppression. Bach1 depletion in Mtb-infected B6.Sst1S mice that display human-like necrotic lung pathology also markedly reduced necrosis and increased host resistance. These findings identify Bach1 as a key regulator of cellular and tissue necrosis and host resistance in Mtb infection.
Lanni F, Antilus Sainte R, Hansen M, et al., 2023, A preclinical model of TB meningitis to determine drug penetration and activity at the sites of disease, Antimicrobial Agents and Chemotherapy, Vol: 67, ISSN: 0066-4804
Tuberculosis meningitis (TBM) is essentially treated with the first-line regimen used against pulmonary tuberculosis, with a prolonged continuation phase. However, clinical outcomes are poor in comparison, for reasons that are only partially understood, highlighting the need for improved preclinical tools to measure drug distribution and activity at the site of disease. A predictive animal model of TBM would also be of great value to prioritize promising drug regimens to be tested in clinical trials, given the healthy state of the development pipeline for the first time in decades. Here, we report the optimization of a rabbit model of TBM disease induced via inoculation of Mycobacterium tuberculosis into the cisterna magna, recapitulating features typical of clinical TBM: neurological deterioration within months post-infection, acid-fast bacilli in necrotic lesions in the brain and spinal cord, and elevated lactate levels in cerebrospinal fluid (CSF). None of the infected rabbits recovered or controlled the disease. We used young adult rabbits, the size of which allows for spatial drug quantitation in critical compartments of the central nervous system that cannot be collected in clinical studies. To illustrate the translational value of the model, we report the penetration of linezolid from plasma into the CSF, meninges, anatomically distinct brain areas, cervical spine, and lumbar spine. Across animals, we measured the bacterial burden concomitant with neurological deterioration, offering a useful readout for drug efficacy studies. The model thus forms the basis for building a preclinical platform to identify improved regimens and inform clinical trial design.
Booysen P, Wilkinson KA, Sheerin D, et al., 2023, Immune interaction between SARS-CoV-2 and Mycobacterium tuberculosis, Frontiers in Immunology, Vol: 14, ISSN: 1664-3224
SARS-CoV-2 and Mycobacterium tuberculosis (Mtb) are major infectious causes of death, with meta-analyses and population-based studies finding increased mortality in co-infected patients simultaneously diagnosed with COVID-19 and tuberculosis (TB). There is a need to understand the immune interaction between SARS-CoV-2 and Mtb which impacts poor outcomes for those co-infected. We performed a PubMed and preprint search using keywords [SARS-CoV-2] AND [tuberculosis] AND [Immune response], including publications after January 2020, excluding reviews or opinions. Abstracts were evaluated by authors for inclusion of data specifically investigating the innate and/or acquired immune responses to SARS-CoV-2 and Mtb in humans and animal models, immunopathological responses in co-infection and both trials and investigations of potential protection against SARS-CoV-2 by Bacille Calmette Guérin (BCG). Of the 248 articles identified, 39 were included. Incidence of co-infection is discussed, considering in areas with a high burden of TB, where reported co-infection is likely underestimated. We evaluated evidence of the clinical association between COVID-19 and TB, discuss differences and similarities in immune responses in humans and in murine studies, and the implications of co-infection. SARS-CoV-2 and Mtb have both been shown to modulate immune responses, particularly of monocytes, macrophages, neutrophils, and T cells. Co-infection may result in impaired immunity to SARS-CoV-2, with an exacerbated inflammatory response, while T cell responses to Mtb may be modulated by SARS-CoV-2. Furthermore, there has been no proven potential COVID-19 clinical benefit of BCG despite numerous large-scale clinical trials.
Abdelgawad N, Wasserman S, Abdelwahab MT, et al., 2023, Linezolid population pharmacokinetic model in plasma and cerebrospinal fluid among patients with tuberculosis meningitis, Journal of Infectious Diseases, ISSN: 0022-1899
BACKGROUND: Linezolid is evaluated in novel treatment regimens for tuberculous meningitis (TBM). Linezolid pharmacokinetics have not been characterized in this population, particularly in cerebrospinal fluid (CSF) where exposures may be affected by changes in protein concentration. Linezolid co-administration with high-dose rifampicin, has also not been studied. We aimed to characterize linezolid plasma and CSF pharmacokinetics in adults with TBM. METHODS: In LASER-TBM pharmacokinetic-substudy, the intervention groups received high-dose rifampicin (35mg/kg) plus linezolid 1200mg/day for 28days, then reduced to 600mg/day. Plasma sampling was done on day 3 (intensive) and on day 28 (sparse). A lumbar CSF sample was obtained on both visits. RESULTS: 30-participants, median(min-max) age and weight of 40(27-56)years and 58(30-96)kg, contributed 247 plasma and 28 CSF observations. Plasma pharmacokinetics was described by one-compartment model with first-order absorption and saturable elimination. Maximal clearance was 7.25L/h, and Km was 27.2mg/L. Rifampicin co-treatment duration did not affect linezolid pharmacokinetics. CSF-Plasma partitioning correlated with CSF total-protein upto 1.2g/L where the partition-coefficient reached maximal value of 37%. Plasma-CSF equilibration half-life was ∼3.5hours. CONCLUSION: Linezolid was readily detected in CSF despite high-dose rifampicin co-administration. These findings support continued clinical evaluation of linezolid plus high-dose rifampicin for the treatment of TBM in adults.
Middelkoop K, Stewart J, Walker N, et al., 2023, Vitamin D supplementation to prevent tuberculosis infection in South African schoolchildren: multicenter phase 3 double-blind randomized placebo-controlled trial (ViDiKids), INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES, Vol: 134, Pages: 63-70, ISSN: 1201-9712
Riou C, du Bruyn E, Kim GHJ, et al., 2023, Derivation of a high-resolution CT-based, semi-automated radiographic score in tuberculosis and its relationship to bacillary load and antitubercular therapy, European Respiratory Journal, Vol: 62, ISSN: 0903-1936
Efforts to curb the tuberculosis (TB) pandemic remain hindered by a lack of objective measures to quantify disease severity and track treatment success that are valid in both HIV-1-infected and -uninfected TB patients. Ralph et al. [1] developed a promising radiographic scoring system, with baseline scores being predictive of sputum smear conversion at 2 months, but it is reliant on skilled readers and has not been systematically validated in predominantly HIV-infected study populations with varying CD4 counts. Superior to conventional chest radiography, high-resolution computed tomography (HRCT) is a highly sensitive tool to track endobronchial TB disease extent [2].
Wilkinson RJ, Donovan J, Thwaites GE, et al., 2023, Treatment of tuberculous meningitis: Overdue for concerted action, TUBERCULOSIS, Vol: 142, ISSN: 1472-9792
Proust A, Queval CJ, Harvey R, et al., 2023, Differential effects of SARS-CoV-2 variants on central nervous system cells and blood-brain barrier functions, Journal of Neuroinflammation, Vol: 20, Pages: 1-17, ISSN: 1742-2094
BACKGROUND: Although mainly causing a respiratory syndrome, numerous neurological symptoms have been identified following of SARS-CoV-2 infection. However, how the virus affects the brain and how the mutations carried by the different variants modulate those neurological symptoms remain unclear. METHODS: We used primary human pericytes, foetal astrocytes, endothelial cells and a microglial cell line to investigate the effect of several SARS-CoV-2 variants of concern or interest on their functional activities. Cells and a 3D blood-brain barrier model were infected with the wild-type form of SARS-CoV-2, Alpha, Beta, Delta, Eta, or Omicron (BA.1) variants at various MOI. Cells and supernatant were used to evaluate cell susceptibility to the virus using a microscopic assay as well as effects of infection on (i) cell metabolic activity using a colorimetric MTS assay; (ii) viral cytopathogenicity using the xCELLigence system; (iii) extracellular glutamate concentration by fluorometric assay; and (iv) modulation of blood-brain barrier permeability. RESULTS: We demonstrate that productive infection of brain cells is SARS-CoV-2 variant dependent and that all the variants induce stress to CNS cells. The wild-type virus was cytopathic to all cell types except astrocytes, whilst Alpha and Beta variants were only cytopathic for pericytes, and the Omicron variant cytopathic for endothelial cells and pericytes. Lastly wild-type virus increases blood-brain barrier permeability and all variants, except Beta, modulate extracellular glutamate concentration, which can lead to excitotoxicity or altered neurotransmission. CONCLUSIONS: These results suggest that SARS-CoV-2 is neurotropic, with deleterious consequences for the blood-brain barrier integrity and central nervous system cells, which could underlie neurological disorders following SARS-CoV-2 infection.
Kroon EE, Correa-Macedo W, Evans R, et al., 2023, Neutrophil extracellular trap formation and gene programs distinguish TST/IGRA sensitization outcomes among <i>Mycobacterium tuberculosis</i> exposed persons living with HIV, PLOS GENETICS, Vol: 19, ISSN: 1553-7404
Motta I, Boeree M, Chesov D, et al., 2023, Recent advances in the treatment of tuberculosis., Clin Microbiol Infect
BACKGROUND: Tuberculosis (TB) is a global health challenge and one of the leading causes of death worldwide. In the last decade, the TB treatment landscape has dramatically changed. After long years of stagnation, new compounds entered the market (bedaquiline, delamanid, and pretomanid) and phase III clinical trials have shown promising results towards shortening duration of treatment for both drug-susceptible (Study 31/A5349, TRUNCATE-TB, and SHINE) and drug-resistant TB (STREAM, NiX-TB, ZeNix, and TB-PRACTECAL). Dose optimization of rifamycins and repurposed drugs has also brought hopes of further development of safe and effective regimens. Consequently, international and WHO clinical guidelines have been updated multiple times in the last years to keep pace with these advances. OBJECTIVES: This narrative review aims to summarize the state-of-the-art on treatment of drug-susceptible and drug-resistant TB, as well as recent trial results and an overview of ongoing clinical trials. SOURCES: A non-systematic literature review was conducted in PubMed and MEDLINE, focusing on the treatment of TB. Ongoing clinical trials were listed according to the authors' knowledge and completed consulting clinicaltrials.gov and other publicly available websites (www.resisttb.org/clinical-trials-progress-report, www.newtbdrugs.org/pipeline/trials). CONTENT: This review summarizes the recent, major changes in the landscape for drug-susceptible and drug-resistant treatment, with a specific focus on their potential impact on patient outcomes and programmatic TB management. Moreover, insights in host-directed therapies, and advances in pharmacokinetics and pharmacogenomics are discussed. A thorough outline of ongoing therapeutic clinical trials is presented, highlighting different approaches and goals in current TB clinical research. IMPLICATIONS: Future research should be directed to individualize regimens and protect these recent breakthroughs by preventing and identifying the selectio
Esmail H, Coussens AK, Thienemann F, et al., 2023, High resolution imaging and five-year tuberculosis contact outcomes., medRxiv
BACKGROUND: The evolution of tuberculosis (TB) disease during the clinical latency period remains incompletely understood. METHODS: 250 HIV-uninfected, adult household contacts of rifampicin-resistant TB with a negative symptom screen underwent baseline 18F-Fluorodeoxyglucose positron emission and computed tomography (PET/CT), repeated in 112 after 5-15 months. Following South African and WHO guidelines, participants did not receive preventive therapy. All participants had intensive baseline screening with spontaneous, followed by induced, sputum sampling and were then observed for an average of 4.7 years for culture-positive disease. Baseline PET/CT abnormalities were evaluated in relation to culture-positive disease. RESULTS: At baseline, 59 (23.6%) participants had lung PET/CT findings consistent with TB of which 29 (11.6%) were defined as Subclinical TB, and 30 (12%) Subclinical TB-inactive. A further 83 (33.2%) had other lung parenchymal abnormalities and 108 (43.2%) had normal lungs. Over 1107-person years of follow-up 14 cases of culture-positive TB were diagnosed. Six cases were detected by intensive baseline screening, all would have been missed by the South African symptom-based screening strategy and only one detected by a WHO-recommended chest X-Ray screening strategy. Those with baseline Subclinical TB lesions on PET/CT were significantly more likely to be diagnosed with culture-positive TB over the study period, compared to those with normal lung parenchyma (10/29 [34.5%] vs 2/108 [1.9%], Hazard Ratio 22.37 [4.89-102.47, p<0.001]). CONCLUSIONS: These findings challenge the latent/active TB paradigm demonstrating that subclinical disease exists up to 4 years prior to microbiological detection and/or symptom onset. There are important implications for screening and management of TB.
Stek C, Shey M, Mnika K, et al., 2023, Relationship between lta4h promotor polymorphism and tuberculosis-associated immune reconstitution inflammatory syndrome and its prevention with prednisone, Open Forum Infectious Diseases, Vol: 10, Pages: 1-4, ISSN: 2328-8957
The development of paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) and its prevention using prednisone may potentially be mediated by the LTA4H genotype. We assessed this hypothesis in a clinical trial evaluating prednisone to prevent TB-IRIS. We did not find an association between LTA4H genotype and TB-IRIS incidence or prednisone efficacy.
Sonnenkalb L, Carter JJ, Spitaleri A, et al., 2023, Bedaquiline and clofazimine resistance in Mycobacterium tuberculosis: an in-vitro and in-silico data analysis, The Lancet Microbe, Vol: 4, Pages: e358-e368, ISSN: 2666-5247
BackgroundBedaquiline is a core drug for the treatment of multidrug-resistant tuberculosis; however, the understanding of resistance mechanisms is poor, which is hampering rapid molecular diagnostics. Some bedaquiline-resistant mutants are also cross-resistant to clofazimine. To decipher bedaquiline and clofazimine resistance determinants, we combined experimental evolution, protein modelling, genome sequencing, and phenotypic data.MethodsFor this in-vitro and in-silico data analysis, we used a novel in-vitro evolutionary model using subinhibitory drug concentrations to select bedaquiline-resistant and clofazimine-resistant mutants. We determined bedaquiline and clofazimine minimum inhibitory concentrations and did Illumina and PacBio sequencing to characterise selected mutants and establish a mutation catalogue. This catalogue also includes phenotypic and genotypic data of a global collection of more than 14 000 clinical Mycobacterium tuberculosis complex isolates, and publicly available data. We investigated variants implicated in bedaquiline resistance by protein modelling and dynamic simulations.FindingsWe discerned 265 genomic variants implicated in bedaquiline resistance, with 250 (94%) variants affecting the transcriptional repressor (Rv0678) of the MmpS5–MmpL5 efflux system. We identified 40 new variants in vitro, and a new bedaquiline resistance mechanism caused by a large-scale genomic rearrangement. Additionally, we identified in vitro 15 (7%) of 208 mutations found in clinical bedaquiline-resistant isolates. From our in-vitro work, we detected 14 (16%) of 88 mutations so far identified as being associated with clofazimine resistance and also seen in clinically resistant strains, and catalogued 35 new mutations. Structural modelling of Rv0678 showed four major mechanisms of bedaquiline resistance: impaired DNA binding, reduction in protein stability, disruption of protein dimerisation, and alteration in affinity for its fatty acid ligand.Inte
Ng K, Boumelha J, Enfield KSS, et al., 2023, Antibodies against endogenous retroviruses promote lung cancer immunotherapy, NATURE, Vol: 616, Pages: 563-+, ISSN: 0028-0836
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Davis AG, Wasserman S, Stek C, et al., 2023, A phase 2A trial of the safety and tolerability of increased dose rifampicin and adjunctive linezolid, with or without aspirin, for human immunodeficiency virus-associated tuberculous meningitis: the LASER-TBM trial, Clinical Infectious Diseases, Vol: 76, Pages: 1412-1422, ISSN: 1058-4838
Background:Drug regimens that include intensified antibiotics alongside effective anti-inflammatory therapies may improve outcomes in tuberculous meningitis (TBM). Safety data on their use in combination and in the context of human immunodeficiency virus (HIV) are needed to inform clinical trial design.Methods:We conducted a phase 2, open-label, parallel-design, randomized, controlled trial to assess the safety of high-dose rifampicin, linezolid, and high-dose aspirin in HIV-associated TBM. Participants were randomized (1.4:1:1) to 3 treatment arms (1, standard of care [SOC]; 2, SOC + additional rifampicin [up to 35 mg/kg/d] + linezolid 1200 mg/d reducing after 28 days to 600 mg/d; 3, as per arm 2 + aspirin 1000 mg/d) for 56 days, when the primary outcome of adverse events of special interest (AESI) or death was assessed.Results:A total of 52 participants with HIV-associated TBM were randomized; 59% had mild disease (British Medical Research Council (MRC) grade 1) vs 39% (grade 2) vs 2% (grade 3). AESI or death occurred in 10 of 16 (63%; arm 3) vs 4 of 14 (29%; arm 2) vs 6 of 20 (30%; arm 1; P = .083). The cumulative proportion of AESI or death (Kaplan–Meier) demonstrated worse outcomes in arm 3 vs arm 1 (P = .04); however, only 1 event in arm 3 was attributable to aspirin and was mild. There was no difference in efficacy (modified Rankin scale) between arms.Conclusions:High-dose rifampicin and adjunctive linezolid can safely be added to the standard of care in HIV-associated TBM. Larger studies are required to determine whether potential toxicity associated with these interventions, particularly high-dose aspirin, is outweighed by mortality or morbidity benefit.Clinical Trials Registration:NCT03927313.
Abdelgawad N, Wasserman S, Abdelwahab MT, et al., 2023, Linezolid population pharmacokinetic model in plasma and cerebrospinal fluid among patients with tuberculosis meningitis., medRxiv
BACKGROUND: Linezolid is being evaluated in novel treatment regimens for tuberculous meningitis (TBM). The pharmacokinetics of linezolid have not been characterized in this population, particularly in cerebrospinal fluid (CSF) where exposures may be affected by changes in protein concentration and rifampicin co-administration. METHODS: This was a sub-study of a phase 2 clinical trial of intensified antibiotic therapy for adults with HIV-associated TBM. Participants in the intervention groups received high-dose rifampicin (35 mg/kg) plus linezolid 1200 mg daily for 28 days followed by 600 mg daily until day 56. Plasma was intensively sampled, and lumbar CSF was collected at a single timepoint in a randomly allocated sampling window, within 3 days after enrolment. Sparse plasma and CSF samples were also obtained on day 28. Linezolid concentrations were analyzed using non-linear mixed effects modelling. RESULTS: 30 participants contributed 247 plasma and 28 CSF linezolid observations. Plasma PK was best described by a one-compartment model with first-order absorption and saturable elimination. The typical value of maximal clearance was 7.25 L/h. Duration of rifampicin co-treatment (compared on day 3 versus day 28) did not affect linezolid pharmacokinetics. Partitioning between plasma and CSF correlated with CSF total protein concentration up to 1.2 g/L where the partition coefficient reached a maximal value of 37%. The equilibration half-life between plasma and CSF was estimated at ∼3.5 hours. CONCLUSION: Linezolid was readily detected in CSF despite co-administration of the potent inducer rifampicin at high doses. These findings support continued clinical evaluation of linezolid plus high-dose rifampicin for the treatment of TBM in adults.
Zwyer M, Rutaihwa L, Windels E, et al., 2023, Back-to-Africa introductions of <i>Mycobacterium tuberculosis</i> as the main cause of tuberculosis in Dar es Salaam, Tanzania, PLOS PATHOGENS, Vol: 19, ISSN: 1553-7366
Gonzalez-Rodriguez E, Zol-Hanlon M, Bineva-Todd G, et al., 2023, O-linked sialoglycans modulate the proteolysis of SARS-CoV-2 spike and likely contribute to the mutational trajectory in variants of concern., ACS Central Science, Vol: 9, Pages: 393-404, ISSN: 2374-7951
The emergence of a polybasic cleavage motif for the protease furin in SARS-CoV-2 spike has been established as a major factor for human viral transmission. The region N-terminal to that motif is extensively mutated in variants of concern (VOCs). Besides furin, spikes from these variants appear to rely on other proteases for maturation, including TMPRSS2. Glycans near the cleavage site have raised questions about proteolytic processing and the consequences of variant-borne mutations. Here, we identify that sialic acid-containing O-linked glycans on Thr678 of SARS-CoV-2 spike influence furin and TMPRSS2 cleavage and posit O-linked glycosylation as a likely driving force for the emergence of VOC mutations. We provide direct evidence that the glycosyltransferase GalNAc-T1 primes glycosylation at Thr678 in the living cell, an event that is suppressed by mutations in the VOCs Alpha, Delta, and Omicron. We found that the sole incorporation of N-acetylgalactosamine did not impact furin activity in synthetic O-glycopeptides, but the presence of sialic acid reduced the furin rate by up to 65%. Similarly, O-glycosylation with a sialylated trisaccharide had a negative impact on TMPRSS2 cleavage. With a chemistry-centered approach, we substantiate O-glycosylation as a major determinant of spike maturation and propose disruption of O-glycosylation as a substantial driving force for VOC evolution.
Morfill C, Pankratova S, Machado P, et al., 2023, Addition to "Nanostars carrying multifunctional neurotrophic dendrimers protect neurons in preclinical in vitro models of neurodegenerative disorders"., ACS Applied Materials and Interfaces, Vol: 15, Pages: 13824-13824, ISSN: 1944-8244
In the original version of this article (p. 47457), some acknowledgments were not included. In the revised Acknowledgments section provided below, we additionally provide The REC reference for the ethical approval of the human astrocyte isolation, an acknowledgment to Dr. Alize Proust at the Francis Crick Institute for establishing the triple coculture BBB model used in this study, and the reference and the grant number for the source of the human fetal material. This does not affect the results or conclusions of our work.
Mutavhatsindi H, Du Bruyn E, Ruzive S, et al., 2023, Blood and Site of Disease Inflammatory Profiles Differ in Patients With Pericardial Tuberculosis and Human Immunodeficiency Virus Type 1, OPEN FORUM INFECTIOUS DISEASES, Vol: 10, ISSN: 2328-8957
Davis AG, Dreyer AJ, Albertyn C, et al., 2023, Cognitive impairment in tuberculous meningitis, Clinical Infectious Diseases, Vol: 76, Pages: 842-849, ISSN: 1058-4838
BACKGROUND: Cognitive impairment is reported as a common complication in adult tuberculous meningitis (TBM), yet few studies have systematically assessed the frequency and nature of impairment. Moreover, the impact of impairment on functioning and medication adherence is not described. METHODS: A cognitive test battery (10 measures assessing 7 cognitive domains) was administered to 34 participants with HIV-associated TBM 6 months post-diagnosis. Cognitive performance was compared to a comparator group of 66 people living with HIV (PLWH) without a history of TB. A secondary comparison was made between TBM cases and 26 participants with HIV 6-months post diagnosis of TB outside the central nervous system (CNS). Impact on functioning was evaluated, including through assessment of medication adherence. RESULTS: In TBM, 16/34 (47%) of participants had low performance on cognitive testing. Cognition was impaired across all domains. Global cognitive performance was significantly lower in TBM cases compared to PLWH (mean T-score 41 vs 48, p < 0.001). TBM cases also had lower global cognition compared to those with non-CNS TB (mean global T score 41 vs 46, p = 0.016). Functional outcomes did not significantly correlate with cognitive performance in the sub-group of participants where this was assessed (n = 19). CONCLUSIONS: Low cognitive performance following HIV-associated TBM is common. This effect is independent of, and additional to, effects of HIV and non-CNS TB disease. Further studies are needed to understand longer term outcomes, clarify the association with treatment adherence, a key predictor of outcome in TBM, and develop context-specific tools to identify individuals with cognitive difficulties to improve outcomes in TBM.
Gollnick H, Barber J, Wilkinson RJ, et al., 2023, IL-27 inhibits anti- <i>Mycobacterium tuberculosis</i> innate immune activity of primary human macrophages, TUBERCULOSIS, Vol: 139, ISSN: 1472-9792
Lesmes-Rodríguez LC, Lambarey H, Chetram A, et al., 2023, Previous exposure to common coronavirus HCoV-NL63 is associated with reduced COVID-19 severity in patients from Cape Town, South Africa, Frontiers in Virology, Vol: 3
<jats:sec><jats:title>Background</jats:title><jats:p>Globally, the most significant risk factors for adverse COVID-19 outcome are increasing age and cardiometabolic comorbidities. However, underlying coinfections may modulate COVID-19 morbidity and mortality, particularly in regions with high prevalence of infectious diseases.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We retrospectively analyzed serum samples for IgG antibodies against the common circulating coronaviruses HCoV-NL63, HCoV-229E, HCoV-OC43 and HCoV-HKU1 from non-hospitalized and hospitalized confirmed COVID-19 patients recruited during the first (June-August 2020) and second (October 2020-June 2021) COVID-19 wave in Cape Town, South Africa. Patients were grouped according to COVID-19 disease severity: Group 1: previously SARS-CoV-2 infected with positive serology and no symptoms (n=94); Group 2: acutely SARS-CoV-2 infected, hospitalized for COVID-19 and severe symptoms (n=92).</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>The overall anti-HCoV IgG seroprevalence in the entire patient cohort was 60.8% (95% CI: 53.7 – 67.8), with 37.1% HCoV-NL63 (95% CI: 30 – 44), 30.6% HCoV-229E (95% CI: 24 – 37.3), 22.6% HCoV-HKU1 (95% CI: 16.6 – 28.6), and 21.0% HCoV-OC43 (95% CI: 15.1 – 26.8). We observed a significantly higher overall HCoV presence (72.3% versus 48.9%) and coinfection frequency (43.6% versus 19.6%) in group 1 compared to group 2 patients with significantly higher presentation of HCoV-NL63 (67.0% versus 6.6%) and HCoV-HKU1 (31.1% versus 14.1%). However, only antibody titers for HCoV-NL63 were significantly higher in group 1 compared to group 2 patients (p&lt; 0.0001, 1.90 [95% CI: 0.62 – 2.45] versus 1.32 [95% CI: 0.30 – 2.01]) which was independent of the participants’ HIV status. Logistic regression
Du Bruyn E, Ruzive S, Howlett P, et al., 2023, Comparison of the frequency and phenotypic profile of Mycobacterium tuberculosis-specific CD4 T cells between the site of disease and blood in pericardial tuberculosis (vol 13, 1009016, 2022), FRONTIERS IN IMMUNOLOGY, Vol: 14, ISSN: 1664-3224
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