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•Management of tuberculosis is complicated by high levels of drug resistance in some regions of the world.•Increasingly, molecular diagnostics are being used for resistance detection ...to certain first-line anti-TB drugs.•Genotype-phenotype relationships for resistance to other drugs are complex making DST by molecular methods challenging.•Individualized approaches to MDR-TB treatment management may help to minimize the development of further resistance.•Individualized approaches to MDR-TB treatment management may help to minimize the development of further resistance.
With an estimated incidence of 490000 cases in 2016, multidrug resistant tuberculosis (TB), against which key first-line anti-tuberculars are less efficacious, presents major challenges for global health. Poor treatment outcomes coupled with a yawning treatment gap between those in need of second-line therapy and those who receive it, underscore the urgent need for new approaches to tackle the scourge of drug-resistant TB. Against this background, significant progress has been made in understanding the complex biology of TB drug resistance and disease pathogenesis, and in establishing a pipeline for delivering new drugs and drug combinations. In this review, we highlight the challenges of drug-resistant TB and the ways in which new advances could be harnessed to improve treatment outcomes.
Xpert MTB/RIF is approved for use in tuberculosis (TB) and rifampicin-resistance diagnosis. However, data are limited on the impact of Xpert under routine conditions in settings with high TB burden.
...A pragmatic prospective cluster-randomised trial of Xpert for all individuals with presumptive (symptomatic) TB compared to the routine diagnostic algorithm of sputum microscopy and limited use of culture was conducted in a large TB/HIV primary care clinic. The primary outcome was the proportion of bacteriologically confirmed TB cases not initiating TB treatment by 3 mo after presentation. Secondary outcomes included time to TB treatment and mortality. Unblinded randomisation occurred on a weekly basis. Xpert and smear microscopy were performed on site. Analysis was both by intention to treat (ITT) and per protocol. Between 7 September 2010 and 28 October 2011, 1,985 participants were assigned to the Xpert (n = 982) and routine (n = 1,003) diagnostic algorithms (ITT analysis); 882 received Xpert and 1,063 routine (per protocol analysis). 13% (32/257) of individuals with bacteriologically confirmed TB (smear, culture, or Xpert) did not initiate treatment by 3 mo after presentation in the Xpert arm, compared to 25% (41/167) in the routine arm (ITT analysis, risk ratio 0.51, 95% CI 0.33-0.77, p = 0.0052). The yield of bacteriologically confirmed TB cases among patients with presumptive TB was 17% (167/1,003) with routine diagnosis and 26% (257/982) with Xpert diagnosis (ITT analysis, risk ratio 1.57, 95% CI 1.32-1.87, p<0.001). This difference in diagnosis rates resulted in a higher rate of treatment initiation in the Xpert arm: 23% (229/1,003) and 28% (277/982) in the routine and Xpert arms, respectively (ITT analysis, risk ratio 1.24, 95% CI 1.06-1.44, p = 0.013). Time to treatment initiation was improved overall (ITT analysis, hazard ratio 0.76, 95% CI 0.63-0.92, p = 0.005) and among HIV-infected participants (ITT analysis, hazard ratio 0.67, 95% CI 0.53-0.85, p = 0.001). There was no difference in 6-mo mortality with Xpert versus routine diagnosis. Study limitations included incorrect intervention allocation for a high proportion of participants and that the study was conducted in a single clinic.
These data suggest that in this routine primary care setting, use of Xpert to diagnose TB increased the number of individuals with bacteriologically confirmed TB who were treated by 3 mo and reduced time to treatment initiation, particularly among HIV-infected participants.
Pan African Clinical Trials Registry PACTR201010000255244. Please see later in the article for the Editors' Summary.
Highlights • Dietary nutrients and microbial metabolites can selectively activate different EECs. • L cell peptides, PYY and GLP-1 can be stored independently and released differentially. • Selective ...GPR119, FFA1-4 and MC4R agonism cause L cell peptide release but, there are some notable species and intestinal area differences. • Dual agonism amplifies incretin release and could be more physiologically relevant.
The melanocortin-4 receptor (MC4R) is expressed in the brainstem and vagal afferent nerves and regulates a number of aspects of gastrointestinal function. Here we show that the receptor is also ...diffusely expressed in cells of the gastrointestinal system, from stomach to descending colon. Furthermore, MC4R is the second most highly enriched GPCR in peptide YY (PYY) and glucagon-like peptide 1 (GLP-1) expressing enteroendocrine L cells. When vectorial ion transport is measured across mouse or human intestinal mucosa, administration of α-MSH induces a MC4R-specific PYY-dependent antisecretory response consistent with a role for the MC4R in paracrine inhibition of electrolyte secretion. Finally, MC4R-dependent acute PYY and GLP-1 release from L cells can be stimulated in vivo by intraperitoneal (i.p.) administration of melanocortin peptides to mice. This suggests physiological significance for MC4R in L cells and indicates a previously unrecognized peripheral role for the MC4R, complementing vagal and central receptor functions.
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•MC4R is diffusely expressed in cells of the GI system, from stomach to colon•MC4R is highly expressed in enteroendocrine L cells in the mouse•MC4R induces a PYY-dependent antisecretory response in mouse and human colon•MC4R agonist administration in the mouse rapidly elevates plasma PYY and GLP-1
The melanocortin-4 receptor (MC4R) is expressed in brainstem and vagal nerves and regulates energy homeostasis and gastrointestinal function. This study shows functional expression of the receptor in enteroendocrine L cells in mice and human. This demonstrates potential peripheral nonneuronal functions for the MC4R and suggests attendant therapeutic opportunities.
Multi-drug or rifamycin-resistant tuberculosis (MDR/RR-TB) is an important public health concern, including in settings with high HIV prevalence. TB drug resistance can be directly transmitted or ...arise through resistance acquisition during first-line TB treatment. Limited evidence suggests that people living with HIV (PLHIV) might have an increased risk of acquired rifamycin-resistance (ARR). To assess HIV as a risk factor for ARR during first-line TB treatment, a systematic review and meta-analysis was conducted. ARR was defined as rifamycin-susceptibility at treatment start with rifamycin-resistance diagnosed during or at the end of treatment, or at recurrence. PubMed/MEDLINE, CINAHL, Cochrane Library, and Google Scholar databases were searched from inception to 23 May 2024 for articles in English; conference abstracts were also searched from 2004 to 2021. The Mantel-Haenszel random-effects model was used to estimate the pooled odds ratio of any association between HIV and ARR among individuals receiving first-line TB treatment. Ten studies that included data collected between 1990 and 2014 were identified: five from the United States, two from South Africa and one each from Uganda, India and Moldova. A total of 97,564 individuals were included across all studies, with 13,359 (13.7%) PLHIV. Overall, 312 (0.32%) acquired rifamycin-resistance, among whom 115 (36.9%) were PLHIV. The weighted odds of ARR were 4.57 (95% CI, 2.01-10.42) times higher among PLHIV compared to HIV-negative individuals receiving first-line TB treatment. The available data, suggest that PLHIV have an increased ARR risk during first-line TB treatment. Further research is needed to clarify specific risk factors, including advanced HIV disease and TB disease severity. Given the introduction of shorter, 4-month rifamycin-based regimens, there is an urgent need for additional data on ARR, particularly for PLHIV. PROSPERO CRD42022327337.
Summary Background In South Africa, sputum smear microscopy has been replaced with Xpert MTB/RIF as the initial diagnostic test for tuberculosis. In a pragmatic parallel cluster-randomised trial, we ...evaluated the effect on patient and programme outcomes. Methods We randomly allocated 20 laboratories (clusters) in medium-burden districts of South Africa to either an Xpert (immediate Xpert) or microscopy (Xpert deferred) group (1:1), stratified by province. At two primary care clinics per laboratory, a systematic sample of adults giving sputum for tuberculosis investigation was assessed for eligibility. The primary outcome was mortality at 6 months from enrolment. Masking of participants' group allocation was not possible because of the pragmatic trial design. The trial is registered with the ISRCTN registry (ISRCTN68905568) and the South African Clinical Trial Register (DOH-27-1011-3849). Findings Between June and November, 2012, 4972 people were screened, and 4656 (93·6%) enrolled (median age 36 years; 2891 62% female; 2212 62% reported being HIV-positive). There was no difference between the Xpert and microscopy groups with respect to mortality at 6 months (91/2324 3·9% vs 116/2332 5·0%, respectively; adjusted risk ratio aRR 1·10, 95% CI 0·75–1·62). Interpretation Xpert did not reduce mortality at 6 months compared with sputum microscopy. Improving outcomes in drug-sensitive tuberculosis programmes might require not only better diagnostic tests but also better linkage to care. Funding Bill & Melinda Gates Foundation.
Significant adverse events (AE) have been reported in patients receiving medications for multidrug- and extensively-drug-resistant tuberculosis (MDR-TB & XDR-TB). However, there is little prospective ...data on AE in MDR- or XDR-TB/HIV co-infected patients on antituberculosis and antiretroviral therapy (ART) in programmatic settings.
Médecins Sans Frontières (MSF) is supporting a community-based treatment program for drug-resistant tuberculosis in HIV-infected patients in a slum setting in Mumbai, India since 2007. Patients are being treated for both diseases and the management of AE is done on an outpatient basis whenever possible. Prospective data were analysed to determine the occurrence and nature of AE.
Between May 2007 and September 2011, 67 HIV/MDR-TB co-infected patients were being treated with anti-TB treatment and ART; 43.3% were female, median age was 35.5 years (Interquartile Range: 30.5-42) and the median duration of anti-TB treatment was 10 months (range 0.5-30). Overall, AE were common in this cohort: 71%, 63% and 40% of patients experienced one or more mild, moderate or severe AE, respectively. However, they were rarely life-threatening or debilitating. AE occurring most frequently included gastrointestinal symptoms (45% of patients), peripheral neuropathy (38%), hypothyroidism (32%), psychiatric symptoms (29%) and hypokalaemia (23%). Eleven patients were hospitalized for AE and one or more suspect drugs had to be permanently discontinued in 27 (40%). No AE led to indefinite suspension of an entire MDR-TB or ART regimen.
AE occurred frequently in this Mumbai HIV/MDR-TB cohort but not more frequently than in non-HIV patients on similar anti-TB treatment. Most AE can be successfully managed on an outpatient basis through a community-based treatment program, even in a resource-limited setting. Concerns about severe AE in the management of co-infected patients are justified, however, they should not cause delays in the urgently needed rapid scale-up of antiretroviral therapy and second-line anti-TB treatment.
Background
The G protein‐coupled bile acid (BA) receptor, GPBA (previously named TGR5), mediates BA gastrointestinal (GI) activities. Our aim was to elucidate the mucosal and motility responses to ...selective GPBA agonists compared with conjugated BA (eg, taurodeoxycholate, TDCA) in mouse and human colon.
Methods
Ion transport responses to GPBA agonists or BAs were measured in mucosal preparations with intact submucous innervation, from C57Bl/6, PYY−/−, or GPBA−/− mice and compared with GPBA signaling in human colon. We also investigated the mechanisms underlying GPBA agonism in mucosae and on natural fecal pellet propulsion.
Key Results
GPBA agonist Merck V stimulated basolateral responses involving peptide YY (PYY), cholinergic, and 5‐HT mechanisms in colonic mucosa. The PYY‐mediated GPBA signal was glucose‐sensitive. Luminal TDCA crossed the epithelial lining via the apical sodium‐dependent BA transporter (ASBT) and its inhibitor, GSK2330672 significantly reduced luminal, but not basolateral TDCA activity. Merck V also slowed natural fecal pellet progression in wild‐type and PYY−/− colons but not in GPBA−/− colon, while TDCA increased motility in wild‐type colon. The antimotile GPBA effect was reversed by blockade of glucagon‐like peptide 1 (GLP‐1) receptors or nitric oxide synthase, indicating involvement of GLP‐1 and nitric oxide.
Conclusions & Inferences
We conclude that several different targets within the lamina propria express GPBA, including L cells (that release PYY and GLP‐1), enterochromaffin cells and neurons (that release 5‐HT), and other enteric neurons. Furthermore, luminal‐conjugated BAs require transport across the epithelium via ASBT in order to activate basolateral GPBA.
Background
Propionate exhibits affinity for free fatty acid receptor 2 (FFA2, formerly GPR43) and FFA3 (GPR41). These two G protein‐coupled receptors (GPCRs) are expressed by enteroendocrine L cells ...that contain anorectic peptide YY (PYY) and glucagon‐like peptide 1 (GLP‐1), while FFA3 is also expressed by enteric neurons. Few studies have investigated the individual roles of FFA2 and FFA3 in propionate's gastrointestinal (GI) effects. Here, we compared FFA2, FFA3, and propionate mucosal responses utilizing selective ligands including an FFA3 antagonist, in mouse and human colonic mucosa.
Methods
Vectorial ion transport was measured in native colonic preparations from normal mouse and human colon with intact submucosal innervation. Endogenous fecal pellet propulsion was monitored in colons isolated from wild‐type (WT) and PYY−/− mice.
Key Results
FFA2 and FFA3 signaling differed significantly. FFA2 agonism involved endogenous L cell‐derived PYY and was glucose dependent, while FFA3 agonism was independent of PYY and glucose, but required submucosal enteric neurons for activity. Tonic FFA3 activity was observed in mouse and human colon mucosa. Apical propionate responses were a combination of FFA2‐PYY mediation and FFA3 neuronal GLP‐1‐ and CGRP‐dependent signaling in mouse ascending colon mucosa. Propionate also slowed WT and PYY−/− colonic transit, and this effect was blocked by a GLP‐1 receptor antagonist.
Conclusions & Inferences
We conclude that luminal propionate costimulates FFA2 and FFA3 pathways, reducing anion secretion and slowing colonic motility; FFA2 via PYY mediation and FFA3 signaling by activation of enteric sensory neurons.
FFA3 signaling involves enteric neurons and is glucose independent, whereas FFA2 signaling involves PYY and is mucosal derived. Luminal propionate costimulates FFA2 and FFA3 signaling and slows colonic transit by utilizing endogenous PYY and GLP‐1.
Mycobacterium tuberculosis complex (MTBC), the causative agent of tuberculosis (TB), is characterized by low sequence diversity making this bacterium one of the classical examples of a genetically ...monomorphic pathogen. Because of this limited DNA sequence variation, routine genotyping of clinical MTBC isolates for epidemiological purposes relies on highly discriminatory DNA fingerprinting methods based on mobile and repetitive genetic elements. According to the standard view, isolates exhibiting the same fingerprinting pattern are considered direct progeny of the same bacterial clone, and most likely reflect ongoing transmission or disease relapse within individual patients.
Here we further investigated this assumption and used massively parallel whole-genome sequencing to compare one drug-susceptible (K-1) and one multidrug resistant (MDR) isolate (K-2) of a rapidly spreading M. tuberculosis Beijing genotype clone from a high incidence region (Karakalpakstan, Uzbekistan). Both isolates shared the same IS6110 RFLP pattern and the same allele at 23 out of 24 MIRU-VNTR loci. We generated 23.9 million (K-1) and 33.0 million (K-2) paired 50 bp purity filtered reads corresponding to a mean coverage of 483.5 fold and 656.1 fold respectively. Compared with the laboratory strain H37Rv both Beijing isolates shared 1,209 SNPs. The two Beijing isolates differed by 130 SNPs and one large deletion. The susceptible isolate had 55 specific SNPs, while the MDR variant had 75 specific SNPs, including the five known resistance-conferring mutations.
Our results suggest that M. tuberculosis isolates exhibiting identical DNA fingerprinting patterns can harbour substantial genomic diversity. Because this heterogeneity is not captured by traditional genotyping of MTBC, some aspects of the transmission dynamics of tuberculosis could be missed or misinterpreted. Furthermore, a valid differentiation between disease relapse and exogenous reinfection might be impossible using standard genotyping tools if the overall diversity of circulating clones is limited. These findings have important implications for clinical trials of new anti-tuberculosis drugs.
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