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1.
N Engl J Med ; 388(10): 873-887, 2023 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-36808186

RESUMO

BACKGROUND: Tuberculosis is usually treated with a 6-month rifampin-based regimen. Whether a strategy involving shorter initial treatment may lead to similar outcomes is unclear. METHODS: In this adaptive, open-label, noninferiority trial, we randomly assigned participants with rifampin-susceptible pulmonary tuberculosis to undergo either standard treatment (rifampin and isoniazid for 24 weeks with pyrazinamide and ethambutol for the first 8 weeks) or a strategy involving initial treatment with an 8-week regimen, extended treatment for persistent clinical disease, monitoring after treatment, and retreatment for relapse. There were four strategy groups with different initial regimens; noninferiority was assessed in the two strategy groups with complete enrollment, which had initial regimens of high-dose rifampin-linezolid and bedaquiline-linezolid (each with isoniazid, pyrazinamide, and ethambutol). The primary outcome was a composite of death, ongoing treatment, or active disease at week 96. The noninferiority margin was 12 percentage points. RESULTS: Of the 674 participants in the intention-to-treat population, 4 (0.6%) withdrew consent or were lost to follow-up. A primary-outcome event occurred in 7 of the 181 participants (3.9%) in the standard-treatment group, as compared with 21 of the 184 participants (11.4%) in the strategy group with an initial rifampin-linezolid regimen (adjusted difference, 7.4 percentage points; 97.5% confidence interval [CI], 1.7 to 13.2; noninferiority not met) and 11 of the 189 participants (5.8%) in the strategy group with an initial bedaquiline-linezolid regimen (adjusted difference, 0.8 percentage points; 97.5% CI, -3.4 to 5.1; noninferiority met). The mean total duration of treatment was 180 days in the standard-treatment group, 106 days in the rifampin-linezolid strategy group, and 85 days in the bedaquiline-linezolid strategy group. The incidences of grade 3 or 4 adverse events and serious adverse events were similar in the three groups. CONCLUSIONS: A strategy involving initial treatment with an 8-week bedaquiline-linezolid regimen was noninferior to standard treatment for tuberculosis with respect to clinical outcomes. The strategy was associated with a shorter total duration of treatment and with no evident safety concerns. (Funded by the Singapore National Medical Research Council and others; TRUNCATE-TB ClinicalTrials.gov number, NCT03474198.).


Assuntos
Antituberculosos , Diarilquinolinas , Linezolida , Rifampina , Tuberculose Pulmonar , Humanos , Antituberculosos/efeitos adversos , Antituberculosos/uso terapêutico , Esquema de Medicação , Quimioterapia Combinada , Etambutol/efeitos adversos , Etambutol/uso terapêutico , Isoniazida/efeitos adversos , Isoniazida/uso terapêutico , Linezolida/efeitos adversos , Linezolida/uso terapêutico , Pirazinamida/efeitos adversos , Pirazinamida/uso terapêutico , Rifampina/efeitos adversos , Rifampina/uso terapêutico , Resultado do Tratamento , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/complicações , Diarilquinolinas/efeitos adversos , Diarilquinolinas/uso terapêutico
2.
J Infect Dis ; 229(4): 1229-1238, 2024 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-37788578

RESUMO

Positron emission tomography-computed tomography (PET-CT) has the potential to revolutionize research in infectious diseases, as it has done with cancer. There is growing interest in it as a biomarker in the setting of early-phase tuberculosis clinical trials, particularly given the limitations of current biomarkers as adequate predictors of sterilizing cure for tuberculosis. PET-CT is a real-time tool that provides a 3-dimensional view of the spatial distribution of tuberculosis within the lung parenchyma and the nature of lesions with uptake (ie, whether nodular, consolidative, or cavitary). Its ability to provide functional data on changes in metabolism, drug penetration, and immune control of tuberculous lesions has the potential to facilitate drug development and regimen selection for advancement to phase 3 trials in tuberculosis. In this narrative review, we discuss the role that PET-CT may have in evaluating responses to drug therapy in active tuberculosis treatment and the challenges in taking PET-CT forward as predictive biomarker of relapse-free cure in the setting of phase 2 clinical trials.


Assuntos
Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Tuberculose , Humanos , Tuberculose/diagnóstico por imagem , Tuberculose/tratamento farmacológico , Tuberculose/metabolismo , Pulmão/patologia , Recidiva , Biomarcadores , Fluordesoxiglucose F18/uso terapêutico , Tomografia por Emissão de Pósitrons , Ensaios Clínicos Fase II como Assunto
3.
J Infect Dis ; 2024 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-38527849

RESUMO

BACKGROUND: Interleukin-4 (IL-4), increased in tuberculosis infection, may impair bacterial killing. Blocking IL-4 confers benefit in animal models. We evaluated safety and efficacy of pascolizumab (humanised anti-IL-4 monoclonal antibody) as adjunctive tuberculosis treatment. METHODS: Participants with rifampicin-susceptible pulmonary tuberculosis received a single intravenous infusion of pascolizumab or placebo; and standard 6-month tuberculosis treatment. Pascolizumab dose increased in successive cohorts: [1] non-randomised 0.05 mg/kg (n = 4); [2] non-randomised 0.5 mg/kg (n = 4); [3] randomised 2.5 mg/kg (n = 9) or placebo (n = 3); [4] randomised 10 mg/kg (n = 9) or placebo (n = 3). Co-primary safety outcome was study-drug-related grade 4 or serious adverse event (G4/SAE); in all cohorts (1-4). Co-primary efficacy outcome was week-8 sputum culture time-to-positivity (TTP); in randomised cohorts (3-4) combined. RESULTS: Pascolizumab levels exceeded IL-4 50% neutralising dose for 8 weeks in 78-100% of participants in cohorts 3-4. There were no study-drug-related G4/SAEs. Median week-8 TTP was 42 days in pascolizumab and placebo groups (p = 0.185). Rate of TTP increase was greater with pascolizumab (difference from placebo 0.011 [95% Bayesian credible interval 0.006 to 0.015] log10TTP/day. CONCLUSIONS: There was no evidence to suggest blocking IL-4 was unsafe. Preliminary efficacy findings are consistent with animal models. This supports further investigation of adjunctive anti-IL-4 interventions for tuberculosis in larger phase 2 trials.

4.
N Engl J Med ; 385(4): 330-341, 2021 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-34289276

RESUMO

BACKGROUND: The World Health Organization recommends dolutegravir with two nucleoside reverse-transcriptase inhibitors (NRTIs) for second-line treatment of human immunodeficiency virus type 1 (HIV-1) infection. Evidence is limited for the efficacy of this regimen when NRTIs are predicted to lack activity because of drug resistance, as well as for the recommended switch of an NRTI from tenofovir to zidovudine. METHODS: In a two-by-two factorial, open-label, noninferiority trial, we randomly assigned patients for whom first-line therapy was failing (HIV-1 viral load, ≥1000 copies per milliliter) to receive dolutegravir or ritonavir-boosted darunavir and to receive tenofovir or zidovudine; all patients received lamivudine. The primary outcome was a week 48 viral load of less than 400 copies per milliliter, assessed with the Food and Drug Administration snapshot algorithm (noninferiority margin for the between-group difference in the percentage of patients with the primary outcome, 12 percentage points). RESULTS: We enrolled 464 patients at seven sub-Saharan African sites. A week 48 viral load of less than 400 copies per milliliter was observed in 90.2% of the patients in the dolutegravir group (212 of 235) and in 91.7% of those in the darunavir group (210 of 229) (difference, -1.5 percentage points; 95% confidence interval [CI], -6.7 to 3.7; P = 0.58; indicating noninferiority of dolutegravir, without superiority) and in 92.3% of the patients in the tenofovir group (215 of 233) and in 89.6% of those in the zidovudine group (207 of 231) (difference, 2.7 percentage points; 95% CI, -2.6 to 7.9; P = 0.32; indicating noninferiority of tenofovir, without superiority). In the subgroup of patients with no NRTIs that were predicted to have activity, a viral load of less than 400 copies per milliliter was observed in more than 90% of the patients in the dolutegravir group and the darunavir group. The incidence of adverse events did not differ substantially between the groups in either factorial comparison. CONCLUSIONS: Dolutegravir in combination with NRTIs was effective in treating patients with HIV-1 infection, including those with extensive NRTI resistance in whom no NRTIs were predicted to have activity. Tenofovir was noninferior to zidovudine as second-line therapy. (Funded by Janssen; NADIA ClinicalTrials.gov number, NCT03988452.).


Assuntos
Fármacos Anti-HIV/administração & dosagem , Darunavir/administração & dosagem , Infecções por HIV/tratamento farmacológico , HIV-1 , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Oxazinas/administração & dosagem , Piperazinas/administração & dosagem , Piridonas/administração & dosagem , Inibidores da Transcriptase Reversa/administração & dosagem , Tenofovir/administração & dosagem , Zidovudina/administração & dosagem , Adolescente , Adulto , Fármacos Anti-HIV/efeitos adversos , Criança , Darunavir/efeitos adversos , Resistência a Medicamentos , Quimioterapia Combinada , Feminino , Infecções por HIV/virologia , HIV-1/isolamento & purificação , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Oxazinas/efeitos adversos , Piperazinas/efeitos adversos , Piridonas/efeitos adversos , Inibidores da Transcriptase Reversa/efeitos adversos , Carga Viral , Adulto Jovem
5.
Bull World Health Organ ; 102(8): 600-607, 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-39070602

RESUMO

Simpler, shorter, safer and more effective treatments for tuberculosis that are easily accessible to all people with tuberculosis are desperately needed. In 2016, the World Health Organization (WHO) developed target regimen profiles for the treatment of tuberculosis to make drug developers aware of both the important features of treatment regimens, and patient and programmatic needs at the country level. In view of recent ground-breaking advances in tuberculosis treatment, WHO has revised and updated these regimen profiles. We used a similar process as for the 2016 profiles, including a baseline treatment landscape analysis, an initial stakeholder survey, modelling studies estimating the impact and cost-effectiveness of novel tuberculosis treatment regimens, and an extensive stakeholder consultation. We developed target regimen profiles for the treatment of rifampicin-susceptible and rifampicin-resistant tuberculosis, as well as a pan-tuberculosis regimen that would be appropriate for patients with any type of tuberculosis. We describe the revised target regimen profile characteristics, with specific minimal and optimal targets to be met, rationale and justification, and aspects relevant to all target regimen profiles (drug susceptibility testing, adherence and forgiveness, treatment strategies, post-tuberculosis lung disease, and cost and access considerations). We discuss the trade-offs of proposed characteristics for decision-making at developmental or operational levels. We expect that, following these target regimen profile revisions, tuberculosis treatment developers will produce regimens that are quality-assured, affordable and widely available, and that meet the needs of affected populations.


Des traitements de la tuberculose plus simples, plus courts, plus sûrs et plus efficaces, facilement accessibles à toutes les personnes atteintes de tuberculose, font cruellement défaut. En 2016, l'Organisation mondiale de la santé (OMS) a élaboré des profils de schéma thérapeutique cible pour le traitement de la tuberculose, afin de sensibiliser les concepteurs de médicaments aux caractéristiques importantes des schémas thérapeutiques et aux besoins des patients et des programmes au niveau national. Compte tenu des avancées récentes dans le traitement de la tuberculose, l'OMS a révisé et mis à jour ces profils de schéma thérapeutique. Nous avons appliqué un processus similaire à celui des profils de 2016, y compris une analyse de base des différentes possibilités thérapeutiques, une enquête initiale auprès des parties prenantes, des études de modélisation estimant l'impact et le rapport coût-efficacité des nouveaux schémas thérapeutiques pour la tuberculose, ainsi qu'une vaste consultation des parties prenantes. Nous avons élaboré des profils de schéma thérapeutique cible pour le traitement de la tuberculose sensible à la rifampicine ou résistant à la rifampicine, ainsi qu'un schéma multiforme qui conviendrait aux patients atteints de n'importe quel type de tuberculose. Nous décrivons les caractéristiques du profil révisé de schéma thérapeutique cible, avec les objectifs minimaux et optimaux spécifiques à atteindre, le raisonnement et les aspects pertinents pour tous les profils de schéma thérapeutique cible (tests de sensibilité aux médicaments, observance thérapeutique et manque d'observance («forgiveness¼), stratégies de traitement, maladie pulmonaire post-tuberculeuse et considérations de coût et d'accès). Nous discutons des compromis des caractéristiques proposées pour la prise de décisions au niveau du développement ou au niveau opérationnel. Nous espérons qu'à la suite de ces révisions du profil de schéma thérapeutique cible, les concepteurs de traitements antituberculeux produiront des schémas dont la qualité est assurée, qui sont abordables et largement disponibles et qui répondent aux besoins des populations touchées.


Se necesitan con urgencia tratamientos más sencillos, breves, seguros y eficaces contra la tuberculosis que sean fácilmente accesibles para todas las personas con tuberculosis. En 2016, la Organización Mundial de la Salud (OMS) elaboró perfiles objetivo de esquemas terapéuticos para el tratamiento de la tuberculosis con el fin de que los fabricantes de medicamentos conocieran tanto las características importantes de estos esquemas como las necesidades programáticas y de los pacientes en cada país. Teniendo en cuenta los recientes avances pioneros en el tratamiento de la tuberculosis, la OMS ha revisado y actualizado estos perfiles de esquemas terapéuticos. Se ha seguido un proceso similar al de los perfiles de 2016, que incluye un análisis de referencia del panorama terapéutico, una encuesta inicial a las partes interesadas, estudios de modelización para estimar el impacto y la rentabilidad de los nuevos esquemas terapéuticos para el tratamiento de la tuberculosis, y una amplia consulta a las partes interesadas. Se desarrollaron perfiles objetivo de esquemas terapéuticos para el tratamiento de la tuberculosis sensibles a la rifampicina y resistente a la rifampicina, así como un esquema farmacológico capaz de tratar todas las formas de tuberculosis que sería apropiado para pacientes con cualquier tipo de tuberculosis. Se describieron las características revisadas de los perfiles objetivo de los esquemas terapéuticos, con los objetivos mínimos y óptimos específicos que deben alcanzarse, los fundamentos y la justificación, y los aspectos relevantes para todos los perfiles objetivo de los esquemas terapéuticos (pruebas de sensibilidad a los fármacos, adherencia y olvido, estrategias de tratamiento, enfermedad pulmonar postuberculosa, y consideraciones de coste y acceso). Se discutieron las ventajas y desventajas de las características propuestas para la toma de decisiones a nivel de desarrollo u operativo. Se espera que, tras estas revisiones de los perfiles objetivo de los esquemas terapéuticos, las personas encargadas del desarrollo de tratamientos para la tuberculosis elaboren esquemas terapéuticos de calidad garantizada, asequibles y ampliamente disponibles, y que respondan a las necesidades de las poblaciones afectadas.


Assuntos
Antituberculosos , Tuberculose , Organização Mundial da Saúde , Humanos , Antituberculosos/uso terapêutico , Tuberculose/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Rifampina/uso terapêutico , Análise Custo-Benefício , Adesão à Medicação
6.
Antimicrob Agents Chemother ; 66(2): e0169921, 2022 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-34871090

RESUMO

High-dose rifampicin improved bactericidal activity and culture conversion in early-phase tuberculosis (TB) trials, done mainly in Africa. We performed a whole-blood bactericidal activity (WBA) study to determine whether the effects of high-dose rifampicin differ across globally relevant TB strains and whether effects are similar in dormant bacilli that will be required for enhancing cure. Whole blood from healthy volunteers was spiked with rifampicin (range, 0.63 to 60 mg/L) and incubated with one of four Mycobacterium tuberculosis clinical strains (Haarlem, Latin American-Mediterranean [LAM], East African-Indian [EAI], and Beijing lineages) or a dormant strain (streptomycin-starved 18b [ss18b]). Change in bacterial CFU was estimated after inoculation of WBA cultures in MGIT. WBA increased with higher concentrations of rifampicin in all strains. At rifampicin concentrations up to 5 mg/L, the rates of increase in WBA per unit increase in rifampicin concentration were similar in all 4 clinical strains (P > 0.51). Above 5 mg/L, EAI (P < 0.001) and Beijing (P = 0.007) strains showed greater increases in WBA than did LAM; Haarlem was similar to LAM. The dormant strain showed a lower rate of increase in WBA than clinical strains at rifampicin concentrations up to 5 mg/L; above 5 mg/L, the rate of increase was similar to those in the LAM, Beijing, and Haarlem strains. Increasing rifampicin concentration enhanced WBA in all strains; the greatest effects were seen in strains common in Asia, suggesting that early-phase trial findings may be generalizable beyond Africa. Similar effects of high concentrations of rifampicin on the dormant strain support the concept that this intervention may enhance sterilizing activity.


Assuntos
Mycobacterium tuberculosis , Tuberculose , Antituberculosos/farmacologia , Bioensaio , Atividade Bactericida do Sangue , Genótipo , Humanos , Rifampina/farmacologia , Tuberculose/tratamento farmacológico
8.
BMC Microbiol ; 20(1): 81, 2020 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-32264819

RESUMO

BACKGROUND: There is a need for better tools to evaluate new or repurposed TB drugs. The whole blood bactericidal activity (WBA) assay has been advocated for this purpose. We investigated whether transcriptional responses in the WBA assay resemble TB responses in vivo, and whether the approach might additionally reveal mechanisms of action. RESULTS: 1422 of 1798 (79%) of differentially expressed genes in WBA incubated with the standard combination of rifampicin, isoniazid, pyrazinamide and ethambutol were also expressed in sputum (P < 0.0001) obtained from patients taking the same combination of drugs; these comprised well-established treatment-response genes. Gene expression profiles in WBA incubated with the standard drugs individually, or with moxifloxacin or faropenem (with amoxicillin and clavulanic acid) clustered by individual drug exposure. Distinct pathways were detected for individual drugs, although only with isoniazid did these relate to known mechanisms of drug action. CONCLUSIONS: Substantial agreement between whole blood cultures and sputum and the ability to differentiate individual drugs suggest that transcriptomics may add value to the whole blood assay for evaluating new TB drugs.


Assuntos
Antituberculosos/farmacologia , Proteínas de Bactérias/genética , Sangue/microbiologia , Perfilação da Expressão Gênica/métodos , Mycobacterium tuberculosis/crescimento & desenvolvimento , Escarro/microbiologia , Combinação de Medicamentos , Reposicionamento de Medicamentos , Etambutol/farmacologia , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Humanos , Isoniazida/farmacologia , Modelos Biológicos , Mycobacterium tuberculosis/efeitos dos fármacos , Análise de Sequência com Séries de Oligonucleotídeos , Pirazinamida/farmacologia , Rifampina/farmacologia
9.
BMC Infect Dis ; 20(1): 403, 2020 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-32517725

RESUMO

BACKGROUND: Current tools for diagnosing latent TB infection (LTBI) detect immunological memory of past exposure but are unable to determine whether exposure is recent. We sought to identify a whole-blood transcriptome signature of recent TB exposure. METHODS: We studied household contacts of TB patients; healthy volunteers without recent history of TB exposure; and patients with active TB. We performed whole-blood RNA sequencing (in all), an interferon gamma release assay (IGRA; in contacts and healthy controls) and PET/MRI lung scans (in contacts only). We evaluated differentially-expressed genes in household contacts (log2 fold change ≥1 versus healthy controls; false-discovery rate < 0.05); compared these to differentially-expressed genes seen in the active TB group; and assessed the association of a composite gene expression score to independent exposure/treatment/immunological variables. RESULTS: There were 186 differentially-expressed genes in household contacts (n = 26, age 22-66, 46% male) compared with healthy controls (n = 5, age 29-38, 100% male). Of these genes, 141 (76%) were also differentially expressed in active TB (n = 14, age 27-69, 71% male). The exposure signature included genes from inflammatory response, type I interferon signalling and neutrophil-mediated immunity pathways; and genes such as BATF2 and SCARF1 known to be associated with incipient TB. The composite gene-expression score was higher in IGRA-positive contacts (P = 0.04) but not related to time from exposure, isoniazid prophylaxis, or abnormalities on PET/MRI (all P > 0.19). CONCLUSIONS: Transcriptomics can detect TB exposure and, with further development, may be an approach of value for epidemiological research and targeting public health interventions.


Assuntos
Tuberculose Latente/diagnóstico , RNA/sangue , Adulto , Idoso , Fatores de Transcrição de Zíper de Leucina Básica/genética , Estudos de Casos e Controles , Busca de Comunicante , Feminino , Humanos , Interferon Tipo I/metabolismo , Tuberculose Latente/microbiologia , Tuberculose Latente/transmissão , Masculino , Pessoa de Meia-Idade , Neutrófilos/imunologia , Neutrófilos/metabolismo , Mapas de Interação de Proteínas/genética , RNA/química , RNA/metabolismo , Receptores Depuradores Classe F/genética , Proteínas Supressoras de Tumor/genética , Adulto Jovem
10.
Clin Infect Dis ; 68(7): 1184-1192, 2019 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-30060027

RESUMO

BACKGROUND: Limited viral load (VL) testing in human immunodeficiency virus (HIV) treatment programs in low-income countries often delays detection of treatment failure. The impact of remaining on failing protease inhibitor (PI)-containing regimens is unclear. METHODS: We retrospectively tested VL in 2164 stored plasma samples from 386 patients randomized to receive lopinavir monotherapy (after initial raltegravir induction) in the Europe-Africa Research Network for Evaluation of Second-line Therapy (EARNEST) trial. Protease genotypic resistance testing was performed when VL >1000 copies/mL. We assessed evolution of PI resistance mutations from virological failure (confirmed VL >1000 copies/mL) until PI monotherapy discontinuation and examined associations using mixed-effects models. RESULTS: Median post-failure follow-up (in 118 patients) was 68 (interquartile range, 48-88) weeks. At failure, 20% had intermediate/high-level resistance to lopinavir. At 40-48 weeks post-failure, 68% and 51% had intermediate/high-level resistance to lopinavir and atazanavir; 17% had intermediate-level resistance (none high) to darunavir. Common PI mutations were M46I, I54V, and V82A. On average, 1.7 (95% confidence interval 1.5-2.0) PI mutations developed per year; increasing after the first mutation; decreasing with subsequent mutations (P < .0001). VL changes were modest, mainly driven by nonadherence (P = .006) and PI mutation development (P = .0002); I47A was associated with a larger increase in VL than other mutations (P = .05). CONCLUSIONS: Most patients develop intermediate/high-level lopinavir resistance within 1 year of ongoing viral replication on monotherapy but retain susceptibility to darunavir. Viral load increased slowly after failure, driven by non-adherence and PI mutation development. CLINICAL TRIALS REGISTRATION: NCT00988039.


Assuntos
Farmacorresistência Viral , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Inibidores da Protease de HIV/farmacologia , Inibidores da Protease de HIV/uso terapêutico , HIV-1/efeitos dos fármacos , Adulto , África , Países em Desenvolvimento , Feminino , Técnicas de Genotipagem , HIV-1/genética , HIV-1/isolamento & purificação , Humanos , Lopinavir/farmacologia , Lopinavir/uso terapêutico , Masculino , Ensaios Clínicos Controlados Aleatórios como Assunto , Falha de Tratamento
11.
BMC Infect Dis ; 19(1): 83, 2019 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-30678651

RESUMO

BACKGROUND: The understanding of early events following TB exposure is limited by traditional tests that rely on detection of an immune response to infection, which is delayed, or on imaging tests with low sensitivity for early disease. We investigated for evidence of lung abnormalities in heavily exposed TB contacts using PET/MRI. METHODS: 30 household contacts of 20 index patients underwent clinical assessment, IGRA testing, chest x-ray and PET/MRI scan using 18-F-FDG. MRI images were examined by a radiology/nuclear medicine dual-qualified physician using a standardised report form, while PET/MRI images were examined independently by another radiology/nuclear medicine dual-qualified physician using a similar form. Standardised uptake value (SUV) was quantified for each abnormal lesion. RESULTS: IGRA was positive in 40%. PET/MRI scan was abnormal in 30%, predominantly FDG uptake in hilar or mediastinal lymph nodes and lung apices. We did not identify any relationship between PET/MRI findings and degree of exposure or IGRA status. CONCLUSION: PET-based imaging may provide important insights into the natural history following exposure to TB that may not be available from traditional tests of TB immune response or imaging. The clinical significance of the abnormalities is uncertain and merits further investigation in longitudinal studies.


Assuntos
Tuberculose Pulmonar/diagnóstico por imagem , Adulto , Idoso , Busca de Comunicante , Características da Família , Feminino , Fluordesoxiglucose F18/administração & dosagem , Humanos , Linfonodos/patologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/administração & dosagem , Tuberculose Pulmonar/diagnóstico , Tuberculose Pulmonar/transmissão , Adulto Jovem
12.
Health Qual Life Outcomes ; 17(1): 83, 2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-31077251

RESUMO

BACKGROUND: Mapping of health-related quality-of-life measures to health utility values can facilitate cost-utility evaluation. Regression-based methods tend to lead to shrinkage of variance. This study aims to map the Medical Outcomes Study HIV Health Survey (MOS-HIV) to EuroQoL 5 Dimensions (EQ-5D-3 L) utility index, and to characterize the performance of three mapping methods, including ordinary least squares (OLS), equi-percentile method (EPM), and a recently proposed method called Mean Rank Method (MRM). METHODS: This is a secondary analysis of data from a randomized HIV treatment trial. Baseline data from 421 participants were used to develop mapping functions. Follow-up data from 236 participants was used to validate the mapping functions. RESULTS: In the training dataset, MRM and OLS, but not EPM, reproduced the observed mean utility (0.731). MRM, OLS and EPM under-estimated the standard deviation by 0.3, 26.6 and 1.7%, respectively. MRM had the lowest mean absolute error (0.143) and highest intraclass correlation coefficient (0.723) with the observed utility values, whereas OLS had the lowest mean squared error (0.038) and highest R-squared (0.542). Regressing the MRM- and OLS-mapped utility values upon body mass index and log-viral load gave covariate associations comparable to those estimated from the observed utility data (all P > 0.10). EPM did not achieve this property. Findings from the validation data were similar. CONCLUSIONS: Functions are available for mapping the MOS-HIV to the EQ-5D-3 L utility values. MRM and OLS were comparable in terms of agreement with the observed utility values at the individual level. MRM had better performance at the group level in terms of describing the utility distribution. TRIAL REGISTRATION: NCT00988039 . Registered 30 September 2009.


Assuntos
Infecções por HIV/psicologia , Avaliação de Resultados em Cuidados de Saúde/métodos , Qualidade de Vida , Adulto , África Subsaariana , Feminino , Inquéritos Epidemiológicos/normas , Humanos , Análise dos Mínimos Quadrados , Masculino
13.
Clin Infect Dis ; 66(12): 1846-1857, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29272346

RESUMO

Background: In sub-Saharan Africa, 25.5 million people are living with human immunodeficiency virus (HIV), representing 70% of the global total. The need for second-line antiretroviral therapy (ART) is projected to increase in the next decade in keeping with the expansion of treatment provision. Outcome data are required to inform policy. Methods: We performed a systematic review and meta-analysis of studies reporting the virological outcomes of protease inhibitor (PI)-based second-line ART in sub-Saharan Africa. The primary outcome was virological suppression (HIV-1 RNA <400 copies/mL) after 48 and 96 weeks of treatment. The secondary outcome was the proportion of patients with PI resistance. Pooled aggregate data were analyzed using a DerSimonian-Laird random effects model. Results: By intention-to-treat analysis, virological suppression occurred in 69.3% (95% confidence interval [CI], 58.2%-79.3%) of patients at week 48 (4558 participants, 14 studies), and in 61.5% (95% CI, 47.2%-74.9%) at week 96 (2145 participants, 8 studies). Preexisting resistance to nucleos(t)ide reverse transcriptase inhibitors (NRTIs) increased the likelihood of virological suppression. Major protease resistance mutations occurred in a median of 17% (interquartile range, 0-25%) of the virological failure population and increased with duration of second-line ART. Conclusions: One-third of patients receiving PI-based second-line ART with continued NRTI use in sub-Saharan Africa did not achieve virological suppression, although among viremic patients, protease resistance was infrequent. Significant challenges remain in implementation of viral load monitoring. Optimizing definitions and strategies for management of second-line ART failure is a research priority. Prospero Registration: CRD42016048985.


Assuntos
Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Inibidores da Protease de HIV/uso terapêutico , Inibidores da Transcriptase Reversa/uso terapêutico , África Subsaariana/epidemiologia , Terapia Antirretroviral de Alta Atividade , Farmacorresistência Viral/genética , Feminino , HIV-1 , Humanos , Masculino , Mutação , Estudos Observacionais como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Resposta Viral Sustentada , Resultado do Tratamento , Carga Viral/efeitos dos fármacos , Viremia/tratamento farmacológico
14.
Artigo em Inglês | MEDLINE | ID: mdl-28739782

RESUMO

Coadministering pyrazinamide (PZA) with the xanthine oxidase inhibitor allopurinol increases systemic levels of the active metabolite, pyrazinoic acid (POA), but the effects on bactericidal activity against tuberculosis are unknown. We randomized healthy volunteers to take a single dose of PZA (either 10 or 25 mg/kg of body weight) at the first visit and the same dose 7 days later, coadministered with allopurinol (100 mg daily; 2 days before to 1 day after the PZA dose). Blood was drawn at intervals until 48 h after each PZA dose, and drug levels were measured using liquid chromatography-tandem mass spectrometry. Whole-blood bactericidal activity (WBA) was measured by inoculating blood samples with Mycobacterium tuberculosis and estimating the change in bacterial CFU after 72 h of incubation. Allopurinol increased the POA area under the concentration-time curve from 0 to 8 h (AUC0-8) (18.32 h · µg/ml versus 24.63 h · µg/ml for PZA alone versus PZA plus allopurinol) (P < 0.001) and its peak plasma concentration (Cmax) (2.81 µg/ml versus 4.00 µg/ml) (P < 0.001). There was no effect of allopurinol on mean cumulative WBA (0.01 ± 0.02 ΔlogCFU versus 0.00 ± 0.02 ΔlogCFU for PZA alone versus PZA plus allopurinol) (P = 0.49). Higher systemic POA levels were associated with greater WBA levels (P < 0.001), but the relationship was evident only at low POA concentrations. The lack of an effect of allopurinol on WBA despite a significant increase in blood POA levels suggests that host-generated POA may be less effective than POA generated inside bacteria. Coadministration of allopurinol does not appear to be a useful strategy for increasing the efficacy of PZA in clinical practice. (This study has been registered at ClinicalTrials.gov under registration no. NCT02700347.).


Assuntos
Alopurinol/sangue , Antituberculosos/sangue , Atividade Bactericida do Sangue/efeitos dos fármacos , Inibidores Enzimáticos/sangue , Mycobacterium tuberculosis/efeitos dos fármacos , Pirazinamida/sangue , Adulto , Idoso , Alopurinol/farmacologia , Antituberculosos/farmacologia , Quimioterapia Combinada , Inibidores Enzimáticos/farmacologia , Voluntários Saudáveis , Humanos , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Pirazinamida/farmacologia , Xantina Oxidase/antagonistas & inibidores , Adulto Jovem
15.
N Engl J Med ; 371(3): 234-47, 2014 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-25014688

RESUMO

BACKGROUND: The efficacy and toxic effects of nucleoside reverse-transcriptase inhibitors (NRTIs) are uncertain when these agents are used with a protease inhibitor in second-line therapy for human immunodeficiency virus (HIV) infection in resource-limited settings. Removing the NRTIs or replacing them with raltegravir may provide a benefit. METHODS: In this open-label trial in sub-Saharan Africa, we randomly assigned 1277 adults and adolescents with HIV infection and first-line treatment failure to receive a ritonavir-boosted protease inhibitor (lopinavir-ritonavir) plus clinician-selected NRTIs (NRTI group, 426 patients), a protease inhibitor plus raltegravir in a superiority comparison (raltegravir group, 433 patients), or protease-inhibitor monotherapy after 12 weeks of induction therapy with raltegravir in a noninferiority comparison (monotherapy group, 418 patients). The primary composite end point, good HIV disease control, was defined as survival with no new World Health Organization stage 4 events, a CD4+ count of more than 250 cells per cubic millimeter, and a viral load of less than 10,000 copies per milliliter or 10,000 copies or more with no protease resistance mutations at week 96 and was analyzed with the use of imputation of data (≤4%). RESULTS: Good HIV disease control was achieved in 60% of the patients (mean, 255 patients) in the NRTI group, 64% of the patients (mean, 277) in the raltegravir group (P=0.21 for the comparison with the NRTI group; superiority of raltegravir not shown), and 55% of the patients (mean, 232) in the monotherapy group (noninferiority of monotherapy not shown, based on a 10-percentage-point margin). There was no significant difference in rates of grade 3 or 4 adverse events among the three groups (P=0.82). The viral load was less than 400 copies per milliliter in 86% of patients in the NRTI group, 86% in the raltegravir group (P=0.97), and 61% in the monotherapy group (P<0.001). CONCLUSIONS: When given with a protease inhibitor in second-line therapy, NRTIs retained substantial virologic activity without evidence of increased toxicity, and there was no advantage to replacing them with raltegravir. Virologic control was inferior with protease-inhibitor monotherapy. (Funded by European and Developing Countries Clinical Trials Partnership and others; EARNEST Current Controlled Trials number, ISRCTN37737787, and ClinicalTrials.gov number, NCT00988039.).


Assuntos
Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/uso terapêutico , Inibidores da Transcriptase Reversa/uso terapêutico , Adolescente , Adulto , África Subsaariana , Idoso , Contagem de Linfócito CD4 , Criança , Farmacorresistência Viral/genética , Quimioterapia Combinada , Feminino , HIV/imunologia , Inibidores da Protease de HIV/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Pirrolidinonas/uso terapêutico , Raltegravir Potássico , Inibidores da Transcriptase Reversa/efeitos adversos , Carga Viral/efeitos dos fármacos , Adulto Jovem
16.
J Antimicrob Chemother ; 72(7): 2012-2019, 2017 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-28333342

RESUMO

Background: Faropenem has in vitro activity against Mycobacterium tuberculosis (Mtb) and shows synergy with rifampicin. We tested this in a whole-blood bactericidal activity (WBA) trial. Methods: We randomized healthy volunteers to receive a single oral dose of faropenem (600 mg) with amoxicillin/clavulanic acid (500/125 mg) ( n = 8), rifampicin (10 mg/kg) ( n = 14) or the combination rifampicin + faropenem + amoxicillin/clavulanic acid ( n = 14). Blood was drawn at intervals to 8 h post-dose. Drug levels were measured using LC-tandem MS. WBA was measured by inoculating blood samples with Mtb and estimating the change in bacterial cfu after 72 h. Trial registration: ClinicalTrials.gov (NCT02393586). Results: There was no activity in the faropenem + amoxicillin/clavulanic acid group (cumulative WBA 0.02 Δlog cfu; P = 0.99 versus zero change). There was a suggestion of a trend favouring the rifampicin + faropenem + amoxicillin/clavulanic acid group at 8 h (cumulative WBA -0.19 ±âŸ0.03 and -0.26 ±âŸ0.03 Δlog cfu in the rifampicin and rifampicin + faropenem + amoxicillin/clavulanic acid groups, respectively; P = 0.180), which was significant in the first hour post-dose ( P = 0.032). Faropenem C max and AUC were 5.4 mg/L and 16.2 mg·h/L, respectively, and MIC for Mtb H37Rv was 5-10 mg/L. Conclusions: Faropenem is not active when used alone, possibly due to inadequate plasma levels relative to MIC. However, there was a suggestion of modest synergy with rifampicin that may merit further testing in clinical trials.


Assuntos
Antibacterianos/administração & dosagem , Mycobacterium tuberculosis/efeitos dos fármacos , Rifampina/administração & dosagem , Teste Bactericida do Soro , beta-Lactamas/administração & dosagem , beta-Lactamas/farmacologia , Adulto , Combinação Amoxicilina e Clavulanato de Potássio/administração & dosagem , Combinação Amoxicilina e Clavulanato de Potássio/farmacologia , Antibacterianos/sangue , Antibacterianos/farmacocinética , Combinação de Medicamentos , Sinergismo Farmacológico , Feminino , Voluntários Saudáveis , Humanos , Masculino , Rifampina/sangue , Rifampina/farmacocinética , Rifampina/farmacologia , Adulto Jovem , beta-Lactamas/sangue , beta-Lactamas/farmacocinética
17.
Clin Infect Dis ; 63(2): 257-64, 2016 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-27143662

RESUMO

BACKGROUND: To determine whether treatment with ritonavir-boosted protease inhibitor (PI) monotherapy is associated with detrimental effects on neurocognitive function or brain imaging markers compared to standard antiretroviral therapy (ART). METHODS: Neuropsychological assessment and brain magnetic resonance imaging were performed at the last study visit in a subset of participants randomized to PI monotherapy (PI-mono group) or ongoing triple ART (OT group) in the PIVOT trial. We calculated a global z-score (NPZ-7) from the average of the individual test z-scores and the proportion of participants with symptomatic neurocognitive impairment (score >1 standard deviation below normative means in ≥2 cognitive domains and neurocognitive symptoms). In a subgroup, white matter hyperintensities, bicaudate index, global cortical (GCA) and medial temporal lobe atrophy scores and single voxel (basal ganglia) N-acetylaspartate (NAA)/Choline, NAA/Creatine and myo-inositol/Creatine ratios were measured. RESULTS: 146 participants (75 PI-mono) had neurocognitive testing (median time after randomization 3.8 years), of whom 78 were imaged. We found no difference between arms in NPZ-7 score (median -0.4 (interquartile range [IQR] = -0.7; 0.1) vs -0.3 (IQR = -0.7; 0.3) for the PI-mono and OT groups respectively, P = .28), the proportion with symptomatic neurocognitive impairment (13% and 18% in the PI-mono and OT groups respectively; P = .41), or any of the neuroimaging variables (P > .05). Symptomatic neurocognitive impairment was associated with higher GCA score (OR = 6.2 per additional score; 95% confidence interval, 1.7-22.3 P = .005) but no other imaging variables. CONCLUSIONS: Based on a comprehensive neuropsychological assessment and brain imaging, PI monotherapy does not increase the risk of neurocognitive impairment in stable human immunodeficiency virus-positive patients.


Assuntos
Terapia Antirretroviral de Alta Atividade , Inibidores da Protease de HIV/uso terapêutico , Soropositividade para HIV/tratamento farmacológico , Soropositividade para HIV/fisiopatologia , Transtornos Neurocognitivos/virologia , Ritonavir/uso terapêutico , Terapia Antirretroviral de Alta Atividade/efeitos adversos , Encéfalo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Estudos Transversais , Feminino , Inibidores da Protease de HIV/administração & dosagem , Inibidores da Protease de HIV/efeitos adversos , Soropositividade para HIV/virologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Transtornos Neurocognitivos/induzido quimicamente , Neuroimagem , Testes Neuropsicológicos , Ritonavir/administração & dosagem , Ritonavir/efeitos adversos , Carga Viral/efeitos dos fármacos
18.
Radiology ; 278(3): 881-7, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26402398

RESUMO

PURPOSE: To investigate the feasibility of using a modified portable isolation chamber, which conforms to Centers for Disease Control and Prevention (CDC) isolation requirements, in the imaging of infectious patients. MATERIALS AND METHODS: This study was approved by the ethics committee, and all participants gave written informed consent. In this prospective study, the isolation chamber was assessed for computed tomographic (CT), magnetic resonance (MR), and positron emission tomographic (PET) image uniformity and noise by using uniform phantoms. For each modality, equivalent phantom examinations were performed without the isolation chamber. Paired analyses of the differences from these baseline values were conducted by finding the mean difference in the matched sections for each image quality parameter. A potential increase in CT patient dose was assessed, and MR radiofrequency (RF) interference was monitored. Eight participants with active pulmonary tuberculosis (mean age, 48.1 years; age range, 26-88 years; five men, three women) were then examined within a hybrid PET/MR imager. The 95% confidence intervals for the difference in the two matched population means were determined by using the two-sided t distribution for each of the phantom study imaging modalities. RESULTS: Phantom images were evaluated for image uniformity and noise. Increased image noise can affect low contrast resolution, which has the potential to mimic or mask abnormalities when the differences between healthy and diseased tissues are small; clinically, CT image noise is maintained at a constant level with dose modulation. Increased attenuation of annihilation photons, when not corrected for, could lead to photopenic areas on the PET image; PET image nonuniformity complied with guidelines. Artifacts on the MR image due to RF noise spikes could mask abnormalities; paired analysis of variations in MR imaging mean signal-to-noise ratio and uniformity from baseline were within 5% for both gradient-echo and spin-echo sequences. In the eight participants who underwent imaging, the increased radiation dose for the attenuation of the isolation chamber would have resulted in a mean increase in patient size-specific dose estimate of 0.32 mGy ± 0.04 (standard deviation). The RF noise assessment revealed no prominent increase at any frequency band. The eight participants were examined within the isolation chamber without incident. CONCLUSION A modified portable isolation chamber, which conforms to CDC infection control guidelines, was found to be feasible within the confines of CT, MR imaging, and PET environments.


Assuntos
Microbiologia do Ar , Infecção Hospitalar/prevenção & controle , Controle de Infecções/normas , Imageamento por Ressonância Magnética , Isolamento de Pacientes/instrumentação , Tomografia por Emissão de Pósitrons , Tomografia Computadorizada por Raios X , Adulto , Idoso , Idoso de 80 Anos ou mais , Artefatos , Desenho de Equipamento , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Imagens de Fantasmas
19.
J Neurovirol ; 22(1): 104-13, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26323809

RESUMO

Sensory peripheral neuropathy (PN) remains a common complication in HIV-positive patients despite effective combination anti-retroviral therapy (ART). Data on PN on second-line ART is scarce. We assessed PN using a standard tool in patients failing first-line ART and for 96 weeks following a switch to PI-based second-line ART in a large Randomised Clinical Trial in Sub-Saharan Africa. Factors associated with PN were investigated using logistic regression. Symptomatic PN (SPN) prevalence was 22% at entry (N = 1,251) and was associated (p < 0.05) with older age (OR = 1.04 per year), female gender (OR = 1.64), Tuberculosis (TB; OR = 1.86), smoking (OR = 1.60), higher plasma creatinine (OR = 1.09 per 0.1 mg/dl increase), CD4 count (OR = 0.83 per doubling) and not consuming alcohol (OR = 0.55). SPN prevalence decreased to 17% by week 96 (p = 0.0002) following similar trends in all study groups (p = 0.30). Asymptomatic PN (APN) increased over the same period from 21 to 29% (p = 0.0002). Signs suggestive of PN (regardless of symptoms) returned to baseline levels by week 96. At weeks 48 and 96, after adjusting for time-updated associations above and baseline CD4 count and viral load, SPN was strongly associated with TB (p < 0.0001). In summary, SPN prevalence was significantly reduced with PI-based second-line therapy across all treatment groups, but we did not find any advantage to the NRTI-free regimens. The increase of APN and stability of PN-signs regardless of symptoms suggest an underlying trend of neuropathy progression that may be masked by reduction of symptoms accompanying general health improvement induced by second-line ART. SPN was strongly associated with isoniazid given for TB treatment.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Lopinavir/uso terapêutico , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , RNA Viral/sangue , Raltegravir Potássico/uso terapêutico , Ritonavir/uso terapêutico , Adulto , África Subsaariana , Abstinência de Álcool , Terapia Antirretroviral de Alta Atividade , Antituberculosos/uso terapêutico , Contagem de Linfócito CD4 , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD4-Positivos/virologia , Combinação de Medicamentos , Feminino , Infecções por HIV/complicações , Infecções por HIV/fisiopatologia , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/crescimento & desenvolvimento , Humanos , Isoniazida/uso terapêutico , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Doenças do Sistema Nervoso Periférico/complicações , Doenças do Sistema Nervoso Periférico/fisiopatologia , Doenças do Sistema Nervoso Periférico/virologia , RNA Viral/antagonistas & inibidores , Fumar/fisiopatologia , Tuberculose Pulmonar/tratamento farmacológico , Carga Viral/efeitos dos fármacos
20.
J Biopharm Stat ; 25(1): 124-36, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-24835750

RESUMO

Clinical trials often use a binary "fold increase" endpoint defined according to the ratio of interval-censored measurement at end-of-study to that at baseline. We propose a simple yet principled analytic approach based on the linear mixed-effects model for interval-censored data for the analysis of such paired measurements. Having estimated the model parameters, the risk ratio can be estimated by explicit composite estimand and the variance is estimated using the delta method. The estimation can be implemented using the existing procedures in popular statistical software. We use antibody data from the Chloroquine for Influenza Prevention Trial for illustration.


Assuntos
Ensaios Clínicos como Assunto/estatística & dados numéricos , Modelos Estatísticos , Testes Sorológicos/estatística & dados numéricos , Anticorpos Antivirais/sangue , Antivirais/uso terapêutico , Biomarcadores/sangue , Cloroquina/uso terapêutico , Simulação por Computador , Humanos , Vírus da Influenza A Subtipo H1N1/imunologia , Influenza Humana/sangue , Influenza Humana/imunologia , Influenza Humana/prevenção & controle , Influenza Humana/transmissão , Influenza Humana/virologia , Modelos Lineares , Método de Monte Carlo , Razão de Chances , Valor Preditivo dos Testes , Software , Resultado do Tratamento
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