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Whole Genome Sequencing (WGS) is a promising tool in the global fight against tuberculosis (TB). The aim of this study was to evaluate the use of WGS in routine conditions for detection of drug resistance markers and transmission clusters in a multidrug-resistant TB hot-spot area in Peru. For this, 140 drug-resistant Mycobacterium tuberculosis strains from Lima and Callao were prospectively selected and processed through routine (GenoType MTBDRsl and BACTEC MGIT) and WGS workflows, simultaneously. Resistance was determined in accordance with the World Health Organization mutation catalogue. Agreements between WGS and BACTEC results were calculated for rifampicin, isoniazid, pyrazinamide, moxifloxacin, levofloxacin, amikacin and capreomycin. Transmission clusters were determined using different cut-off values of Single Nucleotide Polymorphism differences. 100% (140/140) of strains had valid WGS results for 13 anti-TB drugs. However, the availability of final, definitive phenotypic BACTEC MGIT results varied by drug with 10-17% of invalid results for the seven compared drugs. The median time to obtain results of WGS for the complete set of drugs was 11.5 days, compared to 28.6-52.6 days for the routine workflow. Overall categorical agreement by WGS and BACTEC MGIT for the compared drugs was 96.5%. Kappa index was good (0.65≤k≤1.00), except for moxifloxacin, but the sensitivity and specificity values were high for all cases. 97.9% (137/140) of strains were characterized with only one sublineage (134 belonging to "lineage 4" and 3 to "lineage 2"), and 2.1% (3/140) were mixed strains presenting two different sublineages. Clustering rates of 3.6% (5/140), 17.9% (25/140) and 22.1% (31/140) were obtained for 5, 10 and 12 SNP cut-off values, respectively. In conclusion, routine WGS has a high diagnostic accuracy to detect resistance against key current anti-TB drugs, allowing results to be obtained through a single analysis and helping to cut quickly the chain of transmission of drug-resistant TB in Peru.
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Antituberculosos , Mycobacterium tuberculosis , Tuberculose Resistente a Múltiplos Medicamentos , Sequenciamento Completo do Genoma , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/isolamento & purificação , Peru/epidemiologia , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia , Tuberculose Resistente a Múltiplos Medicamentos/epidemiologia , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Sequenciamento Completo do Genoma/métodos , Humanos , Antituberculosos/farmacologia , Antituberculosos/uso terapêutico , Polimorfismo de Nucleotídeo Único , Farmacorresistência Bacteriana Múltipla/genética , Testes de Sensibilidade Microbiana , Genoma Bacteriano , Masculino , FemininoRESUMO
Background: Emerging evidence suggests a link between infection with herpes viruses, particularly human cytomegalovirus (HCMV) and Epstein-Barr virus (EBV), and progression to tuberculosis disease. Methods: An unmatched case-control study was conducted among adolescents aged 10-19 years enrolled in an observational study (Teen TB) between November 2020 and November 2021, in Cape Town, South Africa. Fifty individuals with pulmonary tuberculosis and 51 healthy tuberculosis-exposed individuals without tuberculosis were included. Demographics and clinical data were obtained, and serum samples collected at enrolment were tested for HCMV immunoglobulin G (IgG) and EBV nuclear antigen (EBNA) IgG using 2 automated enzyme immunoassays. Odds ratios were estimated using unconditional logistic regression. Results: The median age of 101 participants was 15 years (interquartile range, 13-17 years); 55 (54%) were female. All participants were HCMV IgG seropositive, and 95% were EBNA IgG seropositive. Individuals with tuberculosis had higher HCMV IgG titers than healthy controls (P = .04). Individuals with upper-tertile HCMV IgG titers had 3.67 times greater odds of pulmonary tuberculosis than those with IgG titers in the lower tertile (95% confidence interval, 1.05-12.84; P = .04). There was a trend for increasing odds of pulmonary tuberculosis with increasing titers of HCMV IgG (P = .04). In contrast, there was no association between tuberculosis and higher EBNA IgG values. Conclusions: There is a high prevalence of sensitization to HCMV and EBV among adolescents in this high-tuberculosis-burden setting. Higher HCMV IgG titers were associated with pulmonary tuberculosis in adolescents.
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Background: Adults with HIV-associated cryptococcal meningitis have overlapping burdens of cytomegalovirus (CMV) and tuberculosis (TB) coinfections. CMV infection/reactivation is strongly associated with CMV-specific memory T-cell activation and upregulation of type 1 interferons, which may lead to increased risk of TB disease and poor outcomes. Methods: We conducted a cohort study of 2-week survivors of cryptococcal meningitis during 2010-2021 to determine TB incidence and all-cause mortality over time stratified by baseline CMV status. Results: We followed 497 Ugandans with HIV-associated cryptococcal meningitis for a median (interquartile range) of 4.6 (2.6-53.9) months. Overall, 42% (210/497) developed incident TB disease or died. One-fifth (98/497, 19.7%) developed incident TB disease, and 29% (142/497) of participants died during follow-up. Of 259 participants with CMV viral load measured at baseline, 37% (96/259) had concurrent CMV viremia (defined as anyone with detectable CMV DNA in plasma/serum by qualitative polymerase chain reaction [PCR] detection). Of 59 with measured CMV immunoglobulin G (IgG), 100% had positive CMV IgG antibody serology (≥10 enzyme-linked immunosorbent assay units/mL). CMV viremia was positively associated with higher HIV viral load (196 667 vs 73 295 copies/mL; P = .002) and higher cerebrospinal fluid fungal burden (68 500 vs 14 000â cfu/mL; P = .002) compared with those without. Participants with high-level CMV viremia (defined as CMV viral load ≥1000â IU/mL) had twice the risk of incident TB (subdistribution adjusted hazard ratio [aHR], 2.18; 95% CI, 1.11-4.27) and death (aHR, 1.99; 95% CI, 1.14-3.49) compared with participants with no or low-level CMV viremia. There was no association between the CMV IgG index and the incidence of TB/death (P = .75). Conclusions: CMV viremia >1000â IU/mL at meningitis diagnosis was associated with increased incident TB disease and mortality during long-term follow-up. Future studies to determine the causal relationship and potential for therapeutic intervention are warranted.
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BACKGROUND: The Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) pandemic has had an impact on the global tuberculosis (TB) epidemic but evidence on the possible interaction between SARS-CoV-2 and TB, especially in children and adolescents, remains limited. We aimed to evaluate the relationship between previous infection with SARS-CoV-2 and the risk of TB in children and adolescents. METHODS: An unmatched case-control study was conducted using SARS-CoV-2 unvaccinated children and adolescents recruited into two observational TB studies (Teen TB and Umoya), between November 2020 and November 2021, in Cape Town, South Africa. Sixty-four individuals with pulmonary TB (aged < 20 years) and 99 individuals without pulmonary TB (aged < 20 years) were included. Demographics and clinical data were obtained. Serum samples collected at enrolment underwent quantitative SARS-CoV-2 anti-spike immunoglobulin G (IgG) testing using the Abbott SARS-CoV-2 IgG II Quant assay. Odds ratios (ORs) for TB were estimated using unconditional logistic regression. RESULTS: There was no statistically significant difference in the odds of having pulmonary TB between those who were SARS-CoV-2 IgG seropositive and those who were seronegative (adjusted OR 0.51; 95% CI: 0.23-1.11; n = 163; p = 0.09). Of those with positive SARS-CoV-2 serology indicating prior infection, baseline IgG titres were higher in individuals with TB compared to those without TB (p = 0.04) and individuals with IgG titres in the highest tertile were more likely to have pulmonary TB compared to those with IgG levels in the lowest tertile (OR: 4.00; 95%CI: 1.13- 14.21; p = 0.03). CONCLUSIONS: Our study did not find convincing evidence that SARS-CoV-2 seropositivity was associated with subsequent pulmonary TB disease; however, the association between magnitude of SARS-CoV-2 IgG response and pulmonary TB warrants further investigation. Future prospective studies, evaluating the effects of sex, age and puberty on host immune responses to M. tuberculosis and SARS-CoV-2, will also provide more clarity on the interplay between these two infections.
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COVID-19 , Mycobacterium tuberculosis , Tuberculose Pulmonar , Adolescente , Criança , Humanos , SARS-CoV-2 , Estudos de Casos e Controles , Estudos Prospectivos , África do Sul/epidemiologia , Tuberculose Pulmonar/epidemiologia , Pandemias , Imunoglobulina GRESUMO
Historically SARS-CoV-2 secondary attack rates (SAR) have been based on PCR positivity on screening symptomatic contacts; this misses transmission events and identifies only symptomatic contacts who are PCR positive at the time of sampling. We used serology to detect the relative transmissibility of Alpha Variant of Concern (VOC) to non-VOC SARS-CoV-2 to calculate household secondary attack rates. We identified index patients diagnosed with Alpha and non-VOC SARS-CoV-2 across two London Hospitals between November 2020 and January 2021 during a prolonged and well adhered national lockdown. We completed a household seroprevalence survey and found that 61.8% of non-VOC exposed household contacts were seropositive compared to 82.1% of Alpha exposed household contacts. The odds of infection doubled with exposure to an index diagnosed with Alpha. There was evidence of transmission events in almost all households. Our data strongly support that estimates of SAR should include serological data to improve accuracy and understanding.
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COVID-19 , SARS-CoV-2 , Humanos , Estudos Soroepidemiológicos , Estudos Transversais , Controle de Doenças TransmissíveisRESUMO
BACKGROUND: In patients with rifampin-resistant tuberculosis, all-oral treatment regimens that are more effective, shorter, and have a more acceptable side-effect profile than current regimens are needed. METHODS: We conducted an open-label, phase 2-3, multicenter, randomized, controlled, noninferiority trial to evaluate the efficacy and safety of three 24-week, all-oral regimens for the treatment of rifampin-resistant tuberculosis. Patients in Belarus, South Africa, and Uzbekistan who were 15 years of age or older and had rifampin-resistant pulmonary tuberculosis were enrolled. In stage 2 of the trial, a 24-week regimen of bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaLM) was compared with a 9-to-20-month standard-care regimen. The primary outcome was an unfavorable status (a composite of death, treatment failure, treatment discontinuation, loss to follow-up, or recurrence of tuberculosis) at 72 weeks after randomization. The noninferiority margin was 12 percentage points. RESULTS: Recruitment was terminated early. Of 301 patients in stage 2 of the trial, 145, 128, and 90 patients were evaluable in the intention-to-treat, modified intention-to-treat, and per-protocol populations, respectively. In the modified intention-to-treat analysis, 11% of the patients in the BPaLM group and 48% of those in the standard-care group had a primary-outcome event (risk difference, -37 percentage points; 96.6% confidence interval [CI], -53 to -22). In the per-protocol analysis, 4% of the patients in the BPaLM group and 12% of those in the standard-care group had a primary-outcome event (risk difference, -9 percentage points; 96.6% CI, -22 to 4). In the as-treated population, the incidence of adverse events of grade 3 or higher or serious adverse events was lower in the BPaLM group than in the standard-care group (19% vs. 59%). CONCLUSIONS: In patients with rifampin-resistant pulmonary tuberculosis, a 24-week, all-oral regimen was noninferior to the accepted standard-care treatment, and it had a better safety profile. (Funded by Médecins sans Frontières; TB-PRACTECAL ClinicalTrials.gov number, NCT02589782.).
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Antituberculosos , Tuberculose Resistente a Múltiplos Medicamentos , Tuberculose Pulmonar , Humanos , Antituberculosos/administração & dosagem , Antituberculosos/efeitos adversos , Antituberculosos/farmacologia , Antituberculosos/uso terapêutico , Quimioterapia Combinada , Moxifloxacina/administração & dosagem , Moxifloxacina/efeitos adversos , Moxifloxacina/uso terapêutico , Rifampina/efeitos adversos , Rifampina/farmacologia , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Pulmonar/tratamento farmacológico , Adolescente , Adulto Jovem , Adulto , Linezolida/administração & dosagem , Linezolida/efeitos adversos , Linezolida/uso terapêutico , Administração OralRESUMO
Chagas disease (CD) is caused by the parasite Trypanosoma cruzi, and it is endemic in Central, South America, Mexico and the South of the United States. It is an important cause of early mortality and morbidity, and it is associated with poverty and stigma. A third of the cases evolve into chronic cardiomyopathy and gastrointestinal disease. The infection is transmitted vertically and by blood/organ donation and can reactivate with immunosuppression. Case identification requires awareness and screening programmes targeting the population at risk (women in reproductive age, donors, immunocompromised patients). Treatment with benznidazole or nifurtimox is most effective in the acute phase and prevents progression to chronic phase when given to children. Treating women antenatally reduces but does not eliminate vertical transmission. Treatment is poorly tolerated, contraindicated during pregnancy, and has little effect modifying the disease in the chronic phase. Screening is easily performed with serology. Migration has brought the disease outside of the endemic countries, where the transmission continues vertically and via blood and tissue/organ donations. There are more than 32 million migrants from Latin America living in non-endemic countries. However, the infection is massively underdiagnosed in this setting due to the lack of awareness by patients, health authorities and professionals. Blood and tissue donation screening policies have significantly reduced transmission in endemic countries but are not universally established in the non-endemic setting. Antenatal screening is not commonly done. Other challenges include difficulties accessing and retaining patients in the healthcare system and lack of specific funding for the interventions. Any strategy must be accompanied by education and awareness campaigns directed to patients, professionals and policy makers. The involvement of patients and their communities is central and key for success and must be sought early and actively. This review proposes strategies to address challenges faced by non-endemic countries.
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BACKGROUND: Tuberculosis (TB) is a communicable, preventable and curable disease caused by the bacterium Mycobacterium tuberculosis (MTB). Peru is amongst the 30 countries with the highest burden of multidrug-resistant tuberculosis (MDR-TB) worldwide. In the fight against drug-resistant tuberculosis, the UKMYC6 microdilution plate was developed and validated by the CRyPTIC project. The objective of the study was to evaluate the use of the broth microdilution (BMD) plate methodology for susceptibility testing of drug-resistant MTB strains in Peru. METHODS: MTB strains isolated between 2015 and 2018 in Peru were used. 496 nationally-representative strains determined as drug-resistant by the routine 7H10 Agar Proportion Method (APM) were included in the present study. The Minimum Inhibitory Concentration (MIC) of 13 antituberculosis drugs were determined for each strain using the UKMYC6 microdilution plates. Diagnostic agreement between APM and BMD plate methodology was determined for rifampicin, isoniazid, ethambutol, ethionamide, kanamycin and levofloxacin. Phenotypes were set using binary (or ternary) classification based on Epidemiological cut-off values (ECOFF/ECV) proposed by the CRyPTIC project. Whole Genome Sequencing (WGS) was performed on strains with discrepant results between both methods. RESULTS: MIC distributions were determined for 13 first- and second-line anti-TB drugs, including new (bedaquiline, delamanid) and repurposed (clofazimine, linezolid) agents. MIC results were available for 80% (397/496) of the strains at 14 days and the remainder at 21 days. The comparative analysis determined a good agreement (0.64 ≤ k ≤ 0.79) for the drugs rifampicin, ethambutol, ethionamide and kanamycin, and the best agreement (k > 0.8) for isoniazid and levofloxacin. Overall, 12% of MIC values were above the UKMYC6 plate dilution ranges, most notably for the drugs rifampicin and rifabutin. No strain presented MICs higher than the ECOFF/ECV values for the new or repurposed drugs. Discrepant analysis using genotypic susceptibility testing by WGS supported half of the results obtained by APM (52%, 93/179) and half of those obtained by BMD plate methodology (48%, 86/179). CONCLUSIONS: The BMD methodology using the UKMYC6 plate allows the complete susceptibility characterization, through the determination of MICs, of drug-resistant MTB strains in Peru. This methodology shows good diagnostic performances for rifampicin, isoniazid, ethambutol, ethionamide, kanamycin and levofloxacin. It also allows for the characterization of MICs for other drugs used in previous years against tuberculosis, as well as for new and repurposed drugs recently introduced worldwide.
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Mycobacterium tuberculosis , Tuberculose dos Linfonodos , Tuberculose Resistente a Múltiplos Medicamentos , Antituberculosos/farmacologia , Etambutol/farmacologia , Etionamida , Humanos , Isoniazida , Canamicina , Levofloxacino , Testes de Sensibilidade Microbiana , Peru , Rifampina/farmacologia , Tuberculose Resistente a Múltiplos Medicamentos/microbiologiaRESUMO
BACKGROUND: Globally rifampicin-resistant tuberculosis disease affects around 460,000 people each year. Currently recommended regimens are 9-24 months duration, have poor efficacy and carry significant toxicity. A shorter, less toxic and more efficacious regimen would improve outcomes for people with rifampicin-resistant tuberculosis. METHODS: TB-PRACTECAL is an open-label, randomised, controlled, phase II/III non-inferiority trial evaluating the safety and efficacy of 24-week regimens containing bedaquiline and pretomanid to treat rifampicin-resistant tuberculosis. Conducted in Uzbekistan, South Africa and Belarus, patients aged 15 and above with rifampicin-resistant pulmonary tuberculosis and requiring a new course of therapy were eligible for inclusion irrespective of HIV status. In the first stage, equivalent to a phase IIB trial, patients were randomly assigned one of four regimens, stratified by site. Investigational regimens include oral bedaquiline, pretomanid and linezolid. Additionally, two of the regimens also included moxifloxacin (arm 1) and clofazimine (arm 2) respectively. Treatment was administered under direct observation for 24 weeks in investigational arms and 36 to 96 weeks in the standard of care arm. The second stage of the study was equivalent to a phase III trial, investigating the safety and efficacy of the most promising regimen/s. The primary outcome was the percentage of unfavourable outcomes at 72 weeks post-randomisation. This was a composite of early treatment discontinuation, treatment failure, recurrence, lost-to-follow-up and death. The study is being conducted in accordance with ICH-GCP and full ethical approval was obtained from Médecins sans Frontières ethical review board, London School of Hygiene and Tropical Medicine ethical review board as well as ERBs and regulatory authorities at each site. DISCUSSION: TB-PRACTECAL is an ambitious trial using adaptive design to accelerate regimen assessment and bring novel treatments that are effective and safe to patients quicker. The trial took a patient-centred approach, adapting to best practice guidelines throughout recruitment. The implementation faced significant challenges from the COVID-19 pandemic. The trial was terminated early for efficacy on the advice of the DSMB and will report on data collected up to the end of recruitment and, additionally, the planned final analysis at 72 weeks after the end of recruitment. TRIAL REGISTRATION: Clinicaltrials.gov NCT02589782. Registered on 28 October 2015.
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Antituberculosos/uso terapêutico , Diarilquinolinas/uso terapêutico , Linezolida/uso terapêutico , Rifampina/uso terapêutico , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Adolescente , Adulto , Antibióticos Antituberculose/farmacologia , Antibióticos Antituberculose/uso terapêutico , Antituberculosos/farmacologia , Diarilquinolinas/farmacologia , Humanos , Linezolida/farmacologia , Pandemias , Rifampina/farmacologia , Resultado do Tratamento , Tuberculose Resistente a Múltiplos Medicamentos/diagnóstico , Adulto JovemRESUMO
Most culture-based methods for tuberculosis diagnosis remain low-cost options for low- and mid-income countries. The MODS culture is a rapid and low-cost assay to diagnose tuberculosis and determine drug susceptibility. However, its implementation is limited due to the low accessibility to supplies required for the enriched medium. In this study, we evaluate two alternative culture media: A powder-based mixed (PM) and a lyophilized media (LM). Catalase, PANTA, and gamma irradiation were evaluated as additions to PM and LM. The culture performance of the alternative media was compared with the standard MODS medium (MM) using Mycobacterium tuberculosis isolates and positive acid-fast smear sputum samples. Overall, no significant difference was observed in the bacterial growth between PM and LM with MM. However, PANTA and gamma irradiation combined reduced bacterial growth significantly in all media variants. A median positivity day of 6 ± 5 days was observed for sputum samples, regardless of the culture medium. The preliminary results show that the two variants culture media have a similar performance to the standard MODS medium. The powder-based media with PANTA (PM_P) showed a time-to-positivity and sensitivity similar to the standard MODS medium. It is the simplest to prepare and does not require any sterilization process.
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Mycobacterium tuberculosis , Tuberculose dos Linfonodos , Tuberculose Resistente a Múltiplos Medicamentos , Humanos , Antituberculosos/farmacologia , Antituberculosos/uso terapêutico , Análise Custo-Benefício , Meios de Cultura , Testes de Sensibilidade Microbiana , Microscopia/métodos , Pós/farmacologia , Sensibilidade e Especificidade , Escarro/microbiologia , Tuberculose dos Linfonodos/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/microbiologiaRESUMO
INTRODUCTION: A considerable burden of the tuberculosis (TB) epidemic is found in adolescents. The reasons for increased susceptibility to TB infection and higher incidence of TB disease in adolescence, compared with the 5-10 years old age group, are incompletely understood. Despite the pressing clinical and public health need to better understand and address adolescent TB, research in this field remains limited. METHODS AND ANALYSIS: Teen TB is an ongoing prospective observational cohort study that aims to better understand the biology, morbidity and social context of adolescent TB. The study plans to recruit 50 adolescents (10-19 years old) with newly diagnosed microbiologically confirmed pulmonary TB disease and 50 TB-exposed controls without evidence of TB disease in Cape Town, South Africa, which is highly endemic for TB. At baseline, cases and controls will undergo a detailed clinical evaluation, chest imaging, respiratory function assessments and blood collection for viral coinfections, inflammatory cytokines and pubertal hormone testing. At 2 weeks, 2 months and 12 months, TB disease cases will undergo further chest imaging and additional lung function testing to explore the patterns of respiratory abnormalities. At week 2, cases will complete a multicomponent quantitative questionnaire about psychological and social impacts on their experiences and longitudinal, in-depth qualitative data will be collected from a nested subsample of 20 cases and their families. ETHICS AND DISSEMINATION: The study protocol has received ethical approval from the Stellenbosch University Health Research Ethics Committee (N19/10/148). The study findings will be disseminated through peer-reviewed publications, academic conferences and formal presentations to health professionals. Results will also be made available to participants and caregivers.
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Tuberculose , Adolescente , Humanos , Pré-Escolar , Criança , Adulto Jovem , Adulto , Estudos Prospectivos , África do Sul/epidemiologia , Tuberculose/epidemiologia , Incidência , Meio Social , Biologia , Estudos Observacionais como AssuntoRESUMO
Recent advances in bacterial whole-genome sequencing have resulted in a comprehensive catalog of antibiotic resistance genomic signatures in Mycobacterium tuberculosis. With a view to pre-empt the emergence of resistance, we hypothesized that pre-existing polymorphisms in susceptible genotypes (pre-resistance mutations) could increase the risk of becoming resistant in the future. We sequenced whole genomes from 3135 isolates sampled over a 17-year period. After reconstructing ancestral genomes on time-calibrated phylogenetic trees, we developed and applied a genome-wide survival analysis to determine the hazard of resistance acquisition. We demonstrate that M. tuberculosis lineage 2 has a higher risk of acquiring resistance than lineage 4, and estimate a higher hazard of rifampicin resistance evolution following isoniazid mono-resistance. Furthermore, we describe loci and genomic polymorphisms associated with a higher risk of resistance acquisition. Identifying markers of future antibiotic resistance could enable targeted therapy to prevent resistance emergence in M. tuberculosis and other pathogens.
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Antituberculosos/farmacologia , Farmacorresistência Bacteriana Múltipla , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/genética , Tuberculose/microbiologia , Genoma Bacteriano , Genômica , Humanos , Isoniazida/farmacologia , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/isolamento & purificação , Filogenia , Rifampina/farmacologiaRESUMO
BACKGROUND: Effective strategies are needed to facilitate the prompt diagnosis and treatment of tuberculosis in countries with a high burden of the disease. METHODS: We conducted a cluster-randomized trial in which Ugandan community health centers were assigned to a multicomponent diagnostic strategy (on-site molecular testing for tuberculosis, guided restructuring of clinic workflows, and monthly feedback of quality metrics) or routine care (on-site sputum-smear microscopy and referral-based molecular testing). The primary outcome was the number of adults treated for confirmed tuberculosis within 14 days after presenting to the health center for evaluation during the 16-month intervention period. Secondary outcomes included completion of tuberculosis testing, same-day diagnosis, and same-day treatment. Outcomes were also assessed on the basis of proportions. RESULTS: A total of 20 health centers underwent randomization, with 10 assigned to each group. Of 10,644 eligible adults (median age, 40 years) whose data were evaluated, 60.1% were women and 43.8% had human immunodeficiency virus infection. The intervention strategy led to a greater number of patients being treated for confirmed tuberculosis within 14 days after presentation (342 patients across 10 intervention health centers vs. 220 across 10 control health centers; adjusted rate ratio, 1.56; 95% confidence interval [CI], 1.21 to 2.01). More patients at intervention centers than at control centers completed tuberculosis testing (adjusted rate ratio, 1.85; 95% CI, 1.21 to 2.82), received a same-day diagnosis (adjusted rate ratio, 1.89; 95% CI, 1.39 to 2.56), and received same-day treatment for confirmed tuberculosis (adjusted rate ratio, 2.38; 95% CI, 1.57 to 3.61). Among 706 patients with confirmed tuberculosis, a higher proportion in the intervention group than in the control group were treated on the same day (adjusted rate ratio, 2.29; 95% CI, 1.23 to 4.25) or within 14 days after presentation (adjusted rate ratio, 1.22; 95% CI, 1.06 to 1.40). CONCLUSIONS: A multicomponent diagnostic strategy that included on-site molecular testing plus implementation supports to address barriers to delivery of high-quality tuberculosis evaluation services led to greater numbers of patients being tested, receiving a diagnosis, and being treated for confirmed tuberculosis. (Funded by the National Heart, Lung, and Blood Institute; XPEL-TB ClinicalTrials.gov number, NCT03044158.).
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Centros Comunitários de Saúde/organização & administração , Técnicas de Diagnóstico Molecular , Testes Imediatos , Tuberculose/diagnóstico , Adulto , Feminino , Infecções por HIV/complicações , Infecções por HIV/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Técnicas de Amplificação de Ácido Nucleico , Tempo para o Tratamento , Tuberculose/complicações , Tuberculose/tratamento farmacológico , UgandaRESUMO
INTRODUCTION: Drug-resistant tuberculosis (TB) remains a global health threat, with little over 50% of patients successfully treated. Novel regimens like the ones being studied in the TB-PRACTECAL trial are urgently needed. Understanding anti-TB drug exposures could explain the success or failure of these trial regimens. We aim to study the relationship between the patients' exposure to anti-TB drugs in TB-PRACTECAL investigational regimens and their treatment outcomes. METHODS AND ANALYSIS: Adults with multidrug-resistant TB randomised to investigational regimens in TB-PRACTECAL will be recruited to a nested pharmacokinetic-pharmacodynamic (PKPD) study. Venous blood samples will be collected at 0, 2 and 23 hours postdose on day 1 and 0, 6.5 and 23 hours postdose during week 8 to quantify drug concentrations in plasma. Trough samples will be collected during week 12, 16, 20 and 24 visits. Opportunistic samples will be collected during weeks 32 and 72. Drug concentrations will be quantified using liquid chromatography-tandem mass spectrometry. Sputum samples will be collected at baseline, monthly to week 24 and then every 2 months to week 108 for MICs and bacillary load quantification. Full blood count, urea and electrolytes, liver function tests, lipase, ECGs and ophthalmology examinations will be conducted at least monthly during treatment.PK and PKPD models will be developed for each drug with nonlinear mixed effects methods. Optimal dosing will be investigated using Monte-Carlo simulations. ETHICS AND DISSEMINATION: The study has been approved by the Médecins sans Frontières (MSF) Ethics Review Board, the LSHTM Ethics Committee, the Belarus RSPCPT ethics committee and PharmaEthics and the University of Witwatersrand Human Research ethics committee in South Africa. Written informed consent will be obtained from all participants. The study results will be shared with public health authorities, presented at scientific conferences and published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT04081077; Pre-results.
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Drogas em Investigação , Tuberculose Resistente a Múltiplos Medicamentos , Adulto , Antituberculosos/uso terapêutico , Humanos , Testes de Sensibilidade Microbiana , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológicoRESUMO
This study aimed to validate an ODK digital mobile application (ODK-DMA) in contacts exposed to multidrug-resistant tuberculosis (MDR-TB) in Lima, Peru. Using a questionnaire in an application on a mobile device, we registered 129 household contacts of 29 index cases of MDR-TB under treatment in 10 health facilities in South Lima in August 2018. The mean time of registration per contact was found to be 4 minutes. The prevalence of active TB symptoms among MDR-TB contacts was 3.1%. An acceptability questionnaire was completed by 31 respondents; all reported feeling comfortable or very comfortable with recording their data in the ODK-DMA, although 10% expressed concerns about confidentiality. We concluded that the ODK-DMA was a feasible and acceptable tool for registering household contacts exposed to cases with MDR-TB. Future studies should consider the use of mobile platforms for the monitoring of MDR-TB contacts.
El presente estudio tuvo como objetivo realizar una validación de un aplicativo móvil Open Data Kit (AM-ODK) en contactos expuestos a tuberculosis multidrogorresistente (TB-MDR) en Lima. Utilizando un cuestionario en una aplicación en un dispositivo móvil Android, se registraron 129 contactos intradomiciliarios de 29 casos índice de TB-MDR en tratamiento, en diez establecimientos de salud de Lima Sur en agosto de 2018. Se encontró un tiempo medio de registro por contacto de cuatro minutos. La frecuencia de síntomas de TB activa entre los contactos de TB-MDR fue 3,1%. Treinta y un encuestados completaron un cuestionario de aceptabilidad; todos manifestaron sentirse cómodos o muy cómodos con el registro de sus datos en AM-ODK, aunque 10% expresó inquietudes sobre la confidencialidad. Se concluye que el AM-ODK fue una herramienta viable y aceptable para registrar contactos intradomiciliarios expuestos a casos con TB-MDR. Estudios futuros deberían considerar el uso de plataformas móviles para el monitoreo de contactos de TB-MDR.
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Aplicativos Móveis , Tuberculose Resistente a Múltiplos Medicamentos , Busca de Comunicante , Características da Família , Estudos de Viabilidade , Humanos , Peru , Tuberculose Resistente a Múltiplos Medicamentos/diagnóstico , Tuberculose Resistente a Múltiplos Medicamentos/epidemiologiaRESUMO
INTRODUCTION: Catastrophic costs incurred by tuberculosis (TB) patients have received considerable attention, however little is known about costs and pathways to care after a negative TB evaluation. MATERIALS AND METHODS: We conducted a cross-sectional study of 70 patients with a negative TB evaluation at four community health centres in rural and peri-urban Uganda. Patients were traced 9 months post-evaluation using contact information from TB registers. We collected information on healthcare visits and implemented locally-validated costing questionnaires to assess the financial impact of their symptoms post-evaluation. RESULTS: Of 70 participants, 57 (81%) were traced and 53 completed the survey. 31/53 (58%) surveyed participants returned to healthcare facilities post-evaluation, making a median of 2 visits each (interquartile range [IQR] 1-3). 11.3% (95%CI 4.3-23.0%) of surveyed patients and 16.1% (95%CI 5.5-33.7%) of those returning to healthcare facilities incurred catastrophic costs (i.e., spent >20% annual household income). Indirect costs related to lost work represented 80% (IQR 32-100%) of total participant costs. CONCLUSIONS: Patients with TB symptoms who experience financial catastrophe after negative TB evaluation may represent a larger absolute number of patients than those suffering from costs due to TB. They may not be captured by existing definitions of non-TB catastrophic health expenditure.
Assuntos
Efeitos Psicossociais da Doença , Equidade em Saúde/economia , Tuberculose/economia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Visita a Consultório Médico/estatística & dados numéricos , Tuberculose/epidemiologia , UgandaRESUMO
INTRODUCTION: A highly sensitive triage test that captures most symptomatic patients at increased likelihood of having pulmonary tuberculosis (PTB) would 'rule-out' lower-risk patients from expensive confirmatory testing. Although studies have assessed the diagnostic accuracy of a C-reactive protein (CRP) triage test for PTB in HIV+ patients, limited data are available from HIV- cohorts. MATERIALS AND METHODS: In this retrospective case-control study, 765 serum samples were selected from FIND's biobank. Each sample had been collected from an adult presenting with respiratory symptomatology to district hospitals in South Africa and referral hospitals in Cambodia, Peru, Georgia and Vietnam between 2007-2017. Serum CRP measurements were obtained using a laboratory-based assay. CRP cutoff-points of ≥8mg/L and ≥10mg/L were predefined as a positive triage test result. The PTB reference standard was two contemporaneously collected sputum liquid culture results. RESULTS: CRP demonstrated an overall sensitivity for PTB of 79.8% (95%CI 75.5-83.5) and 77.7% (95%CI 73.4-81.6) for cutoff-points of 8mg/L and 10mg/L respectively. Specificity was 62.8% (95%CI 57.8-67.6%) and 66.6% (95%CI 61.1-70.7) respectively. Area-under-the-curve using Receiver Operating Characteristic analysis was 0.77 (95%CI 0.74-0.81). Threshold analysis showed optimal CRP cutoff-points were higher in HIV+ than HIV- participants. An algorithm in which CRP triage was followed by confirmatory Xpert MTB/Rif testing achieved a sensitivity of 75.1% (95%CI 69.0-80.4%) whilst decreasing Xpert usage by 40.6%. DISCUSSION: CRP may not meet the challenge of a catch-all TB triage test. However, it shows promise in HIV+ individuals. Further research is required in a prospective study using point-of-care platforms to further evaluate its capabilities.
Assuntos
Proteína C-Reativa/metabolismo , Técnicas de Laboratório Clínico , Triagem , Tuberculose Pulmonar/diagnóstico , Adulto , Algoritmos , Feminino , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Curva ROC , Sensibilidade e Especificidade , Adulto JovemRESUMO
Public randomization ceremonies have been proposed as a strategy to strengthen stakeholder engagement and address concerns and misconceptions associated with trial randomization. However, there are few published examples that describe how to conduct a public randomization ceremony with meaningful stakeholder engagement or how such ceremonies impact stakeholder perceptions about randomization and the randomization process. Cluster randomization for the GeneXpert Performance Evaluation for Linkage to Tuberculosis Care (XPEL-TB) trial was conducted at a public randomization ceremony attended by 70 stakeholders in Kampala, Uganda. Presentations given by the Acting Assistant Commissioner from the Uganda National Tuberculosis and Leprosy Programme and trial investigators emphasized how the trial aimed to further national TB goals, as well as how stakeholders contributed to the intervention design. The purpose and process of randomization were described using simple text and visuals. Randomization was an interactive activity that required participation of stakeholders from each trial site. A survey administered to stakeholders at the end of the ceremony suggested high comprehension of randomization (98%), trust in the randomization process (96%), and satisfaction with randomization outcomes (96%). Public randomization ceremonies should be considered more routinely to engage stakeholders in and address potential concerns about the fairness and impartiality of the randomization process for community-based trials.
RESUMO
Host immune responses at the site of Mycobacterium tuberculosis infection can mediate pathogenesis of tuberculosis (TB) and onward transmission of infection. We hypothesized that pathological immune responses would be enriched at the site of host-pathogen interactions modeled by a standardized tuberculin skin test (TST) challenge in patients with active TB compared to those without disease, and interrogated immune responses by genome-wide transcriptional profiling. We show exaggerated interleukin-17A (IL-17A) and T helper 17 (TH17) responses among 48 individuals with active TB compared to 191 with latent TB infection, associated with increased neutrophil recruitment and matrix metalloproteinase-1 expression, both involved in TB pathogenesis. Curative antimicrobial treatment reversed these observed changes. Increased IL-1ß and IL-6 responses to mycobacterial stimulation were evident both in circulating monocytes and in molecular changes at the site of TST in individuals with active TB, supporting a model in which monocyte-derived IL-1ß and IL-6 promote TH17 differentiation within tissues. Modulation of these cytokine pathways may provide a rational strategy for host-directed therapy in active TB.