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1.
medRxiv ; 2024 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-38712023

RESUMO

Although tuberculosis (TB) remains a major killer among infectious diseases and the leading cause of death for people with HIV, drivers of immunopathology, particularly at the site of infection in the lungs remain incompletely understood. To fill this gap, we compared cytokine profiles in paired plasma and sputum samples collected from adults with pulmonary TB with and without HIV. We found that people with pulmonary TB with HIV had significantly higher markers of inflammation in both plasma and sputum than those without HIV; these differences were present despite a similar extent of radiographic involvement. We also found that the strength and direction of correlations between biomarkers in the blood and lung compartments differed by HIV status and people with HIV had more positive correlations than those without HIV. Future studies can further explore these differences in inflammation by HIV status across the blood and lung compartments and seek to establish how these profiles may be associated with long-term outcomes and lung health after completion of TB treatment.

2.
Public Health Pract (Oxf) ; 7: 100483, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38449769

RESUMO

Objectives: In the United States, a federal emergency program has made SARS-CoV-2 self-test kits available at no cost. It is unclear how widely free tests are preferred. We conducted a survey to estimate the proportion of respondents who do not prefer a free test. We hypothesized that free tests would not be preferred universally, and that a preference for paying would be more common among those with conservative politics than with liberal politics, regardless of income. Design: Observational study design. Methods: A national sample of US adults completed an online survey. To reduce potential enrollment bias, the survey's focus was not specified beforehand. To prioritize a high-risk group, participation was limited to those who were unvaccinated or were incompletely vaccinated in the primary series against COVID-19. Participants reported their testing preferences and socio-demographic characteristics, including political affiliation. The main outcome assessed if a participant preferred to pay for a self-test or receive a free one (subsidized by the US government). Results: Among 1215 participants, (73%, n = 886) preferred free self-testing, while 27% (n = 329) preferred to pay for the same testing. After adjusting for income, the odds of preferring to pay for self-testing were 66% higher in "strong" Republicans compared to "strong" Democrats (odds ratio = 1.66, 95% confidence interval = 1.07-2.62). Conclusions: More than a quarter of individuals preferred paying for these tests. This preference was more likely among those with right-wing politics. Policy implications are discussed, along with future research directions.

3.
J Acquir Immune Defic Syndr ; 95(5): 494-504, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38346410

RESUMO

BACKGROUND: Food insecurity and undernutrition are related but distinct concepts contributing to poor HIV and tuberculosis outcomes. Pathways linking them with immunologic profile, which may relate to clinical outcomes, remain understudied. METHODS: We analyzed data from a cohort study of 165 antiretroviral therapy (ART)-naïve adults with advanced HIV and newly diagnosed tuberculosis in Botswana from 2009 to 2013. Twenty-nine plasma biomarkers were measured pre-ART and 4 weeks post-ART initiation. We used principal components analysis (PCA) and multivariable linear regression models to assess relationships between immunological profiles and food insecurity (based on the Household Food Insecurity Access Scale), undernutrition (body mass index <18.5 kg/m 2 ), and clinical outcomes. RESULTS: PCA identified 5 principal components with eigenvalues >1. After adjustment, food insecurity was associated with PC3 pre-ART (0.19 per increased category of severity, 95% CI: 0.02 to 0.36) and post-ART (0.24, 95% CI: 0.07 to 0.41). PC3 was driven by higher levels of IFN-α, IFN-γ, interleukin (IL)-12p40, vascular endothelial growth factor, IL-1α, and IL-8 and decreased concentrations of IL-3. Undernutrition was associated with PC5 post-ART (0.49, 95% CI: 0.16 to 0.82). PC5 was driven by higher levels of IL-8, MIP-1α, IL-6, and IL-10 and decreased concentrations in IP-10 and IFN-α. Post-ART PC3 (4.3 percentage point increased risk per increased score of 1, 95% CI: 0.3 to 8.9) and post-ART PC5 (4.8, 95% CI: 0.6 to 8.9) were associated with death in adjusted models. DISCUSSION: We identified 2 distinct immunologic profiles associated with food insecurity, undernutrition, and clinical outcomes in patients with advanced HIV and tuberculosis. Different pathophysiologic processes may link food insecurity and undernutrition with poor outcomes in this vulnerable patient population. Future studies should assess the impact of improving food access and intake on immune function and clinical outcomes.


Assuntos
Infecções por HIV , Desnutrição , Tuberculose , Adulto , Humanos , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Estudos de Coortes , Interleucina-8/uso terapêutico , Fator A de Crescimento do Endotélio Vascular/uso terapêutico , Desnutrição/complicações , Desnutrição/epidemiologia , Tuberculose/complicações , Insegurança Alimentar , Abastecimento de Alimentos
4.
J Infect Dis ; 229(3): 824-832, 2024 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-37386883

RESUMO

BACKGROUND: Identification of proinflammatory factors responding to Mycobacterium tuberculosis is important to reduce long-term sequelae of pulmonary tuberculosis (TB). METHODS: We examined the association between plasma biomarkers, the fraction of exhaled nitric oxide (FeNO), and lung function among a prospective cohort of 105 adults newly diagnosed with TB/human immunodeficiency virus (HIV) in South Africa. Participants were followed for 48 weeks from antiretroviral therapy (ART) initiation with serial assessments of plasma biomarkers, FeNO, lung function, and respiratory symptoms. Linear regression and generalized estimating equations were used to examine the associations at baseline and over the course of TB treatment, respectively. RESULTS: At baseline, higher FeNO levels were associated with preserved lung function, whereas greater respiratory symptoms and higher interleukin (IL)-6 plasma levels were associated with worse lung function. After ART and TB treatment initiation, improvements in lung function were associated with increases in FeNO (rate ratio [RR] = 86 mL, 95% confidence interval [CI] = 34-139) and decreases in IL-6 (RR = -118 mL, 95% CI = -193 to -43) and vascular endothelial growth factor ([VEGF] RR = -178 mL, 95% CI = -314 to -43). CONCLUSIONS: Circulating IL-6, VEGF, and FeNO are associated with lung function in adults being treated for TB/HIV. These biomarkers may help identify individuals at higher risk for post-TB lung disease and elucidate targetable pathways to modify the risk of chronic lung impairment among TB survivors.


Assuntos
Infecções por HIV , Tuberculose , Adulto , Humanos , Óxido Nítrico/metabolismo , Fator A de Crescimento do Endotélio Vascular , HIV , Interleucina-6 , Estudos Prospectivos , Tuberculose/tratamento farmacológico , Tuberculose/complicações , Biomarcadores/metabolismo , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Pulmão/metabolismo
5.
BMC Pulm Med ; 23(1): 53, 2023 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-36737697

RESUMO

BACKGROUND: Patients with tuberculosis (TB) and HIV often present with impairments in lung function and exercise capacity after treatment. We evaluated clinical and immunologic variables associated with a minimum clinically important difference (MCID) in the change in the 6 min walk test distance during the first 24 weeks of antiretroviral (ART) and anti-tubercular therapy. METHODS: Adults initiating ART and anti-TB treatment in the setting of newly-diagnosed HIV and pulmonary TB were enrolled in a prospective cohort study in South Africa. Patients underwent 6 min walk tests and spirometry at weeks 0, 4, 12, and 24 and biomarker level measurements early during treatment, at weeks 0, 4, and 12, when inflammation levels are typically elevated. Biomarkers included matrix metalloproteinases-1 (MMP-1), tissue inhibitor of MMP (TIMP)-1, collagen 1a, IL-6, IL-8, vascular cell adhesion molecule 1 (VCAM-1), C-X-C motif chemokine 10 (CXCL-10), CXCL-11, macrophage colony-stimulating factor (M-CSF), plasminogen activator, vascular endothelial growth factor, and chemokine (C-C) motif-2 (CCL-2). An MCID was derived statistically, and achievement of an MCID was modeled as the outcome using logistic regression model. RESULTS: Eighty-nine patients walked an average of 393 (± standard deviation = 69) meters at baseline, which increased by an average of 9% (430 ± 70 m) at week 24. The MCID for change in walk distance was estimated as 41 m. Patients experiencing an MCID on treatment had worse lung function, lower 6 min walk test distance, higher levels of proinflammatory biomarkers including TIMP-1 and M-CSF, and lower levels of collagen 1a at baseline. Experiencing an MCID during treatment was associated with increases in forced expiratory volume in 1-s [odds ratio (OR) = 1.17, 95% confidence interval (CI) = 1.05-1.33] and increases in blood collagen 1a levels (OR = 1.31, 95%CI 1.06-1.62). CONCLUSIONS: ART and TB treatment are associated with substantial improvements in 6 min walk test distance over time. Achievement of an MCID in the 6 min walk test in this study was associated with more severe disease at baseline and increases in collagen 1a levels and lung function during therapy.


Assuntos
Infecções por HIV , Tuberculose , Humanos , Adulto , Teste de Caminhada , Fator Estimulador de Colônias de Macrófagos/uso terapêutico , Estudos Prospectivos , Fator A de Crescimento do Endotélio Vascular/uso terapêutico , Tuberculose/complicações , Biomarcadores , Pulmão , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico
7.
Tuberculosis (Edinb) ; 137: 102271, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36375279

RESUMO

OBJECTIVE AND METHODS: Our objective was to investigate the role of patient pharmacogenetic variability in determining site of action target attainment during tuberculous meningitis (TBM) treatment. Rifampin and isoniazid PBPK model that included SLCO1B1 and NAT2 effects on exposures respectively were obtained from literature, modified, and validated using available cerebrospinal-fluid (CSF) concentrations. Population simulations of isoniazid and rifampin concentrations in brain interstitial fluid and probability of target attainment according to genotypes and M. tuberculosis MIC levels, under standard and intensified dosing, were conducted. RESULTS: The rifampin and isoniazid model predicted steady-state drug concentration within brain interstitial fluid matched with the observed CSF concentrations. At MIC level of 0.25 mg/L, 57% and 23% of the patients with wild type and heterozygous SLCO1B1 genotype respectively attained the target in CNS with rifampin standard dosing, improving to 98% and 91% respectively with 35 mg/kg dosing. At MIC level of 0.25 mg/L, 33% of fast acetylators attained the target in CNS with isoniazid standard dosing, improving to 90% with 7.5 mg/kg dosing. CONCLUSION: In this study, the combined effects of pharmacogenetic and M. tuberculosis MIC variability were potent determinants of target attainment in CNS. The potential for genotype-guided dosing during TBM treatment should be further explored in prospective clinical studies.


Assuntos
Arilamina N-Acetiltransferase , Mycobacterium tuberculosis , Tuberculose Meníngea , Humanos , Tuberculose Meníngea/diagnóstico , Tuberculose Meníngea/tratamento farmacológico , Isoniazida/uso terapêutico , Rifampina/farmacologia , Antituberculosos/uso terapêutico , Farmacogenética , Estudos Prospectivos , Probabilidade , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Arilamina N-Acetiltransferase/genética
8.
Open Forum Infect Dis ; 9(7): ofac325, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35899273

RESUMO

Background: People with human immunodeficiency virus (HIV) and advanced immunosuppression initiating antiretroviral therapy (ART) remain vulnerable to tuberculosis (TB) and early mortality. To improve early survival, isoniazid preventive therapy (IPT) or empiric TB treatment have been evaluated; however, their benefit on longer-term outcomes warrants investigation. Methods: We present a 96-week preplanned secondary analysis among 850 ART-naive outpatients (≥13 years) enrolled in a multicountry, randomized trial of efavirenz-containing ART plus either 6-month IPT (n = 426) or empiric 4-drug TB treatment (n = 424). Inclusion criteria were CD4 count <50 cells/mm3 and no confirmed or probable TB. Death and incident TB were compared by strategy arm using the Kaplan-Meier method. The impact of self-reported adherence (calculated as the proportion of 100% adherence) was assessed using Cox-proportional hazards models. Results: By 96 weeks, 85 deaths and 63 TB events occurred. Kaplan-Meier estimated mortality (10.1% vs 10.5%; P = .86) and time-to-death (P = .77) did not differ by arm. Empiric had higher TB risk (6.1% vs 2.7%; risk difference, -3.4% [95% confidence interval, -6.2% to -0.6%]; P = .02) and shorter time to TB (P = .02) than IPT. Tuberculosis medication adherence lowered the hazards of death by ≥23% (P < .0001) in empiric and ≥20% (P < .035) in IPT and incident TB by ≥17% (P ≤ .0324) only in IPT. Conclusions: Empiric TB treatment offered no longer-term advantage over IPT in our population with advanced immunosuppression initiating ART. High IPT adherence significantly lowered death and TB incidence through 96 weeks, emphasizing the benefit of ART plus IPT initiation and completion, in persons with advanced HIV living in high TB-burden, resource-limited settings.

9.
Clin Infect Dis ; 73(4): e870-e877, 2021 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-34398958

RESUMO

BACKGROUND: The urine lipoarabinomannan (LAM) antigen test is a tuberculosis (TB) diagnostic test with highest sensitivity in individuals with advanced human immunodeficiency virus (HIV). Its role in TB diagnostic algorithms for HIV-positive outpatients remains unclear. METHODS: The AIDS Clinical Trials Group (ACTG) A5274 trial demonstrated that empiric TB therapy did not improve 24-week survival compared to isoniazid preventive therapy (IPT) in TB screen-negative HIV-positive adults initiating antiretroviral therapy with CD4 counts <50 cells/µL. Retrospective LAM testing was performed on stored urine obtained at baseline. We determined the proportion of LAM-positive participants and conducted modified intent-to-treat analysis excluding LAM-positive participants to determine the effect on 24-week survival, TB incidence, and time to TB using Kaplan-Meier method. RESULTS: A5274 enrolled 850 participants; 53% were male and the median CD4 count was 18 (interquartile range, 9-32) cells/µL. Of the 850, 566 (67%) had LAM testing (283 per arm); 28 (5%) were positive (21 [7%] and 7 [2%] in the empiric and IPT arms, respectively). Of those LAM-positive, 1 participant in each arm died and 5 of 21 and 0 of 7 in empiric and IPT arms, respectively, developed TB. After excluding these 28 cases, there were 19 and 21 deaths in the empiric and IPT arms, respectively (P = .88). TB incidence remained higher (4.6% vs 2%, P = .04) and time to TB remained faster in the empiric arm (P = .04). CONCLUSIONS: Among outpatients with advanced HIV who screened negative for TB by clinical symptoms, microscopy, and Xpert testing, LAM testing identified an additional 5% of individuals with TB. Positive LAM results did not change mortality or TB incidence.


Assuntos
Infecções por HIV , Tuberculose , Adulto , Testes Diagnósticos de Rotina , HIV , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Humanos , Lipopolissacarídeos , Masculino , Sistemas Automatizados de Assistência Junto ao Leito , Estudos Retrospectivos , Sensibilidade e Especificidade , Tuberculose/diagnóstico , Tuberculose/tratamento farmacológico
10.
Front Immunol ; 12: 676980, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34168648

RESUMO

Tuberculosis (TB) accounts for disproportionate morbidity and mortality among persons living with HIV (PLWH). Conventional methods of TB diagnosis, including smear microscopy and Xpert MTB/RIF, have lower sensitivity in PLWH. Novel high-throughput approaches, such as miRNAomics and metabolomics, may advance our ability to recognize subclinical and difficult-to-diagnose TB, especially in very advanced HIV. We conducted a case-control study leveraging REMEMBER, a multi-country, open-label randomized controlled trial comparing 4-drug empiric standard TB treatment with isoniazid preventive therapy in PLWH initiating antiretroviral therapy (ART) with CD4 cell counts <50 cells/µL. Twenty-three cases of incident TB were site-matched with 32 controls to identify microRNAs (miRNAs), metabolites, and cytokines/chemokines, associated with the development of newly diagnosed TB in PLWH. Differentially expressed miRNA analysis revealed 11 altered miRNAs with a fold change higher than 1.4 or lower than -1.4 in cases relative to controls (p<0.05). Our analysis revealed no differentially abundant metabolites between cases and controls. We found higher TNFα and IP-10/CXCL10 in cases (p=0.011, p=0.0005), and higher MDC/CCL22 in controls (p=0.0072). A decision-tree algorithm identified gamma-glutamylthreonine and hsa-miR-215-5p as the optimal variables to classify incident TB cases (AUC 0.965; 95% CI 0.925-1.000). hsa-miR-215-5p, which targets genes in the TGF-ß signaling pathway, was downregulated in cases. Gamma-glutamylthreonine, a breakdown product of protein catabolism, was less abundant in cases. To our knowledge, this is one of the first uses of a multi-omics approach to identify incident TB in severely immunosuppressed PLWH.


Assuntos
Infecções Oportunistas Relacionadas com a AIDS/complicações , HIV , Mycobacterium tuberculosis/genética , Tuberculose Pulmonar/sangue , Tuberculose Pulmonar/complicações , Infecções Oportunistas Relacionadas com a AIDS/tratamento farmacológico , Infecções Oportunistas Relacionadas com a AIDS/virologia , Adulto , Antirretrovirais/uso terapêutico , Antituberculosos/uso terapêutico , Biomarcadores/sangue , Estudos de Casos e Controles , Quimiocinas/sangue , Quimioterapia Combinada , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Isoniazida/uso terapêutico , Masculino , Metaboloma , Metabolômica/métodos , MicroRNAs/sangue , MicroRNAs/genética , Mycobacterium tuberculosis/isolamento & purificação , Resultado do Tratamento , Tuberculose Pulmonar/diagnóstico , Tuberculose Pulmonar/tratamento farmacológico
11.
BMC Pulm Med ; 21(1): 19, 2021 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-33413293

RESUMO

BACKGROUND: While tuberculosis is considered a risk factor for chronic obstructive pulmonary disease, a restrictive pattern of pulmonary impairment may actually be more common among tuberculosis survivors. We aimed to determine the nature of pulmonary impairment before and after treatment among people with HIV and tuberculosis and identify risk factors for long-term impairment. METHODS: In this prospective cohort study conducted in South Africa, we enrolled adults newly diagnosed with HIV and tuberculosis who were initiating antiretroviral therapy and tuberculosis treatment. We measured lung function and symptoms at baseline, 6, and 12 months. We compared participants with and without pulmonary impairment and constructed logistic regression models to identify characteristics associated with pulmonary impairment. RESULTS: Among 134 participants with a median CD4 count of 110 cells/µl, 112 (83%) completed baseline spirometry at which time 32 (29%) had restriction, 13 (12%) had obstruction, and 9 (7%) had a mixed pattern. Lung function was dynamic over time and 30 (33%) participants had impaired lung function at 12 months. Baseline restriction was associated with greater symptoms and with long-term pulmonary impairment (adjusted odds ratio 5.44, 95% confidence interval 1.16-25.45), while baseline obstruction was not (adjusted odds ratio 1.95, 95% confidence interval 0.28-13.78). CONCLUSIONS: In this cohort of people with HIV and tuberculosis, restriction was the most common, symptomatic, and persistent pattern of pulmonary impairment. These data can help to raise awareness among clinicians about the heterogeneity of post-tuberculosis pulmonary impairment, and highlight the need for further research into mediators of lung injury in this vulnerable population.


Assuntos
Infecções por HIV/fisiopatologia , Pulmão/fisiopatologia , Tuberculose Pulmonar/fisiopatologia , Adulto , Fármacos Anti-HIV/uso terapêutico , Antituberculosos/uso terapêutico , Contagem de Linfócito CD4 , Estudos de Coortes , Feminino , Volume Expiratório Forçado/fisiologia , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Humanos , Pneumopatias Obstrutivas/fisiopatologia , Masculino , Estudos Prospectivos , África do Sul , Espirometria , Tuberculose Pulmonar/complicações , Tuberculose Pulmonar/tratamento farmacológico , Capacidade Vital/fisiologia
12.
Front Pharmacol ; 11: 1103, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32848735

RESUMO

BACKGROUND: The potential for hepatotoxicity during isoniazid-based tuberculosis (TB) treatment presents a major challenge for TB control programs worldwide. We sought to determine whether pharmacokinetic exposures of isoniazid and its metabolites were related to cellular oxidation/reduction status and downstream markers of oxidative DNA damage. METHODS: We performed intensive pharmacokinetic sampling among isoniazid-treated patients to determine the relative plasma exposures of isoniazid, acetylisoniazid, hydrazine, and acetylhydrazine. Physiologically-based pharmacokinetic modeling was used to estimate liver tissue exposures during a 24-h dosing interval for each compound. We experimentally treated HepG2 cells with isoniazid and metabolites at equimolar concentrations corresponding to these exposures for 7, 14, and 28-day periods, and performed assays related to redox imbalance and oxidative DNA damage at each timepoint. We related a urine marker of oxidative DNA damage to serum isoniazid pharmacokinetic exposures and pharmacogenetics in a clinical study. RESULTS: Among isoniazid-treated patients, serum concentrations of hydrazine and isoniazid concentrations were highly correlated. At equimolar concentrations that approximated hepatic tissue exposures during a 24-h dosing interval, hydrazine demonstrated the highest levels of redox imbalance, mitochondrial injury, and oxidative DNA damage over a 28-day treatment period. In a clinical validation study of isoniazid-treated TB patients, peak isoniazid serum concentrations were positively associated with a urine biomarker of oxidative DNA damage. CONCLUSIONS: Isoniazid and its metabolites share the potential for oxidative cellular damage, with the greatest effects observed for hydrazine. Future studies should investigate the clinical consequences of oxidative stress with regards to clinical episodes of drug induced liver injury during isoniazid treatment.

13.
Lancet ; 396(10248): 402-411, 2020 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-32771107

RESUMO

BACKGROUND: HIV-infection is associated with increased mortality during multidrug-resistant tuberculosis treatment, but the extent to which the use of antiretroviral therapy (ART) and anti-tuberculosis medications modify this risk are unclear. Our objective was to evaluate how use of these treatments altered mortality risk in HIV-positive adults with multidrug-resistant tuberculosis. METHODS: We did an individual patient data meta-analysis of adults 18 years or older with confirmed or presumed multidrug-resistant tuberculosis initiating tuberculosis treatment between 1993 and 2016. Data included ART use and anti-tuberculosis medications grouped according to WHO effectiveness categories. The primary analysis compared HIV-positive with HIV-negative patients in terms of death during multidrug-resistant tuberculosis treatment, excluding those lost to follow up, and was stratified by ART use. Analyses used logistic regression after exact matching on country World Bank income classification and drug resistance and propensity-score matching on age, sex, geographic site, year of multidrug-resistant tuberculosis treatment initiation, previous tuberculosis treatment, directly observed therapy, and acid-fast-bacilli smear-positivity to obtain adjusted odds ratios (aORs) and 95% CIs. Secondary analyses were conducted among those with HIV-infection. FINDINGS: We included 11 920 multidrug-resistant tuberculosis patients. 2997 (25%) were HIV-positive and on ART, 886 (7%) were HIV-positive and not on ART, and 1749 (15%) had extensively drug-resistant tuberculosis. By use of HIV-negative patients as reference, the aOR of death was 2·4 (95% CI 2·0-2·9) for all patients with HIV-infection, 1·8 (1·5-2·2) for HIV-positive patients on ART, and 4·2 (3·0-5·9) for HIV-positive patients with no or unknown ART. Among patients with HIV, use of at least one WHO Group A drug and specific use of moxifloxacin, levofloxacin, bedaquiline, or linezolid were associated with significantly decreased odds of death. INTERPRETATION: Use of ART and more effective anti-tuberculosis drugs is associated with lower odds of death among HIV-positive patients with multidrug-resistant tuberculosis. Access to these therapies should be urgently pursued. FUNDING: American Thoracic Society, Canadian Institutes of Health Research, US Centers for Disease Control and Prevention, European Respiratory Society, Infectious Diseases Society of America.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Antituberculosos/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/mortalidade , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/mortalidade , Adulto , Feminino , Infecções por HIV/complicações , Humanos , Masculino , Fatores de Risco , Tuberculose Resistente a Múltiplos Medicamentos/complicações
14.
Clin Infect Dis ; 70(8): 1750-1753, 2020 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-31552412

RESUMO

End-organ impairment has received relatively little research attention as a possible manifestation of tuberculosis immune reconstitution inflammatory syndrome (TB-IRIS). In this prospective cohort study, one-half of adults with human immunodeficiency virus and pulmonary tuberculosis experienced meaningful declines in lung function on antiretroviral therapy, suggesting a role for lung function in TB-IRIS definitions.


Assuntos
Infecções por HIV , Síndrome Inflamatória da Reconstituição Imune , Tuberculose , Adulto , HIV , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Humanos , Pulmão , Estudos Prospectivos
15.
Clin Infect Dis ; 70(9): 1845-1854, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-31242296

RESUMO

BACKGROUND: Immune restoration on antiretroviral therapy (ART) can drive inflammation in people living with human immunodeficiency virus (HIV) who have pulmonary tuberculosis (TB), but its effects on the lungs have not been assessed. We evaluated associations between pulmonary inflammation, recovery of pathogen-specific CD4 T-cell function, and lung injury prior to and after ART initiation in adults with HIV and pulmonary TB. METHODS: This was a prospective cohort study in South Africa, following adults with HIV and pulmonary TB prior to and up to 48 weeks after ART initiation. Pulmonary-specific inflammation was defined as total glycolytic activity (TGA) on [18]F-fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET-CT) at baseline and 4 weeks after ART initiation. Spirometry, respiratory symptom tests, and flow cytometry were performed at the same times to assess lung involvement and the frequency of mycobacteria-specific CD4 T-cells. In addition, we evaluated lung function longitudinally up to 48 weeks after ART initiation. RESULTS: Greater lung TGA on FDG PET-CT was associated with worse lung function and respiratory symptoms prior to ART initiation, and nearly half of subjects experienced worsening lung inflammation and lung function at Week 4 of ART. Worsening Week 4 lung inflammation and pulmonary function were both associated with greater increases in pathogen-specific functional CD4 T-cell responses on ART, and early decreases in lung function were independently associated with persistently lower lung function months after TB treatment completion. CONCLUSIONS: Increases in pulmonary inflammation and decreases in lung function are common on ART, relate to greater ART-mediated CD4 T-cell restoration, and are associated with the persistent impairment of lung function in individuals with HIV/TB.


Assuntos
Infecções por HIV , Lesão Pulmonar , Tuberculose , Adulto , Contagem de Linfócito CD4 , HIV , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Humanos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Estudos Prospectivos , África do Sul
16.
Clin Infect Dis ; 71(4): 924-932, 2020 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-31751447

RESUMO

BACKGROUND: Inflammasomes mediate inflammation in adults living with both human immunodeficiency virus (HIV) and tuberculosis (TB), but the relevance of inflammasome gene polymorphisms in TB-associated pulmonary damage is unknown. We hypothesized that functional single-nucleotide polymorphisms (SNPs) in inflammasome pathway genes modify systemic and pulmonary inflammation, contributing to respiratory impairment in adults living with HIV/pulmonary TB. METHODS: This was a prospective cohort study set in South Africa following individuals living with HIV/TB up to 48 weeks post-antiretroviral therapy (ART) initiation. Ten functional SNPs in 5 inflammasome pathway genes were related to circulating inflammatory biomarkers and lung function assessed by spirometry pre- and post-ART initiation. Analyses used 2-sided t tests, Wilcoxon rank sum tests, Spearman correlation coefficients, linear regression, and generalized estimating equation models. RESULTS: Among 102 patients with baseline samples, the minor allele (T) in NLRC4 rs385076 was independently associated with lower levels of interleukin (IL)-18 and IL-6 before and up to 12 weeks post-ART initiation (Benjamini-Hochberg corrected P values < .02). Patients with the CT/TT genotypes also had improved lung function vs CC patients up to 48 weeks post-ART initiation (forced vital capacity, 206 mL higher; 95% confidence interval [CI], 67-345 mL; P = .004 and forced expiratory volume in 1 second, 143 mL higher; 95% CI, 11-274 mL; P = .034). CONCLUSIONS: A common SNP in the NLRC4 inflammasome may modify TB-associated inflammation in clinically relevant ways. This SNP may identify high-risk groups for lung damage in TB. Inhibition of NLRC4 activity may be an important approach for TB host-directed therapy.


Assuntos
Infecções por HIV , Tuberculose , Adulto , Proteínas Adaptadoras de Sinalização CARD , Proteínas de Ligação ao Cálcio/genética , HIV , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Humanos , Inflamação/genética , Pulmão , Estudos Prospectivos , África do Sul , Tuberculose/genética
17.
Clin Infect Dis ; 71(10): 2645-2654, 2020 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31761933

RESUMO

BACKGROUND: People with advanced human immunodeficiency virus (HIV) (CD4 < 50) remain at high risk of tuberculosis (TB) or death despite the initiation of antiretroviral therapy (ART). We aimed to identify immunological profiles that were most predictive of incident TB disease and death. METHODS: The REMEMBER randomized clinical trial enrolled 850 participants with HIV (CD4 < 50 cells/µL) at ART initiation to receive either empiric TB treatment or isoniazid preventive therapy (IPT). A case-cohort study (n = 257) stratified by country and treatment arm was performed. Cases were defined as incident TB or all-cause death within 48 weeks after ART initiation. Using multiplexed immunoassay panels and ELISA, 26 biomarkers were assessed in plasma. RESULTS: In total, 52 (6.1%) of 850 participants developed TB; 47 (5.5%) died (13 of whom had antecedent TB). Biomarkers associated with incident TB overlapped with those associated with death (interleukin [IL]-1ß, IL-6). Biomarker levels declined over time in individuals with incident TB while remaining persistently elevated in those who died. Dividing the cohort into development and validation sets, the final model of 6 biomarkers (CXCL10, IL-1ß, IL-10, sCD14, tumor necrosis factor [TNF]-α, and TNF-ß) achieved a sensitivity of 0.90 (95% confidence interval [CI]: .87-.94) and a specificity of 0.71(95% CI: .68-.75) with an area under the curve (AUC) of 0.81 (95% CI: .78-.83) for incident TB. CONCLUSION: Among people with advanced HIV, a parsimonious inflammatory biomarker signature predicted those at highest risk for developing TB despite initiation of ART and TB preventive therapies. The signature may be a promising stratification tool to select patients who may benefit from increased monitoring and novel interventions. CLINICAL TRIALS REGISTRATION: NCT01380080.


Assuntos
Infecções por HIV , Tuberculose , Antituberculosos/uso terapêutico , Biomarcadores , Contagem de Linfócito CD4 , Estudos de Coortes , HIV , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Humanos , Tuberculose/diagnóstico , Tuberculose/tratamento farmacológico , Tuberculose/epidemiologia
18.
J Antimicrob Chemother ; 74(10): 2994-3002, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31273386

RESUMO

BACKGROUND: Reduced ethambutol serum concentrations are commonly observed among TB patients co-infected with HIV and may lead to treatment failure. OBJECTIVES: To perform a population pharmacokinetic study of ethambutol in HIV/TB patients, and to evaluate an intensified ethambutol weight-based dosing strategy to support pharmacokinetic target attainment. METHODS: We conducted a prospective study of ethambutol pharmacokinetics among HIV/TB patients administered first-line TB treatment in Botswana, with study visits before and after initiation of ART. Clinical and disease status markers, including HIV-associated systemic immune activation and gut dysfunction biomarkers, were evaluated as covariates of ethambutol pharmacokinetic parameters in non-linear mixed effects analysis. Monte Carlo simulations were performed to compare pharmacokinetic target attainment under standard and intensified weight-based ethambutol dosing strategies. RESULTS: We studied 40 HIV/TB patients prior to initiation of ART, of whom 24 returned for a second visit a median of 33 days following ART initiation. Ethambutol serum concentrations were best explained by a two-compartment model with first-order elimination, with a significant improvement in oral bioavailability following ART initiation. In Monte Carlo simulations, a supplementary ethambutol dose of 400 mg daily led to >2-fold improvements in pharmacokinetic target attainment probabilities in lung tissue, both before and after ART initiation. CONCLUSIONS: Low serum ethambutol concentrations were commonly observed among HIV/TB patients in Botswana, and the oral bioavailability of ethambutol increased following ART initiation. Supplementary ethambutol dosing among HIV/TB patients may provide a strategy to optimize anti-TB treatment regimens in this high-risk population.


Assuntos
Antituberculosos/administração & dosagem , Antituberculosos/farmacocinética , Coinfecção/tratamento farmacológico , Etambutol/administração & dosagem , Etambutol/farmacocinética , Infecções por HIV/tratamento farmacológico , Tuberculose Pulmonar/tratamento farmacológico , Adulto , Disponibilidade Biológica , Botsuana , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
19.
Eur J Drug Metab Pharmacokinet ; 44(2): 179-187, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30168000

RESUMO

BACKGROUND AND OBJECTIVE: Efavirenz is commonly used in Africa and is frequently associated with neurocognitive toxicity, which may compromise clinical outcomes. Older individuals are at increased risk for drug toxicity and clinical outcomes may be worse in older age, particularly among those individuals with cytochrome P450 (CYP) 2B6 polymorphisms associated with slower efavirenz metabolism. The aim of this study was to determine if the CYP2B6 polymorphisms differentially impacts loss to care in older people. METHODS: We conducted a prospective cohort study of 914 treatment-naïve HIV+ adults initiating efavirenz-based antiretroviral treatment at public HIV clinics in Gaborone, Botswana between 2009 and 2013. Older age, defined as age ≥ 50 years, was the primary exposure and loss to care at 6 months was the primary outcome. Interaction between age and CYP2B6 516G>T and 983T>C polymorphisms, defined as extensive, intermediate, and slow metabolism, was assessed. Neurocognitive toxicity was measured using a symptom questionnaire. Age-stratified logistic regression was performed to identify factors associated with loss to care. RESULTS: Older age was associated with loss to care (OR 1.95, 95% CI 1.30-2.92). Age modified the effect of CYP2B6 genotype on loss to care with older, slow metabolizers at over four-fold higher risk when compared to older, intermediate metabolizers (OR 4.06 95% CI 1.38-11.89); neurocognitive toxicity did not mediate this risk. CYP2B6 metabolism genotype did not increase risk of loss to care in younger participants. CONCLUSION: Older age was associated with loss to care, especially among those with slow efavirenz metabolism. Understanding the relationship between older age and CYP2B6 genotype will be important to improving outcomes in an aging population initiating efavirenz-based ART in similar settings.


Assuntos
Fármacos Anti-HIV/metabolismo , Benzoxazinas/metabolismo , População Negra , Infecções por HIV/tratamento farmacológico , Infecções por HIV/metabolismo , Inibidores da Transcriptase Reversa/metabolismo , Adulto , Fatores Etários , Alcinos , Fármacos Anti-HIV/uso terapêutico , Benzoxazinas/uso terapêutico , População Negra/genética , Botsuana/epidemiologia , Estudos de Coortes , Ciclopropanos , Citocromo P-450 CYP2B6/genética , Feminino , Infecções por HIV/genética , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Inibidores da Transcriptase Reversa/uso terapêutico , Resultado do Tratamento , Adulto Jovem
20.
Clin Infect Dis ; 68(3): 393-401, 2019 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-29945252

RESUMO

Background: We performed a phase 2 noninferiority trial examining the early fungicidal activity (EFA) of 3 short-course, high-dose liposomal amphotericin B (L-AmB) regimens for cryptococcal meningitis (CM) in Tanzania and Botswana. Methods: Human immunodeficiency virus (HIV)-infected adults with CM were randomized to (i) L-AmB 10 mg/kg on day 1 (single dose); (ii) L-AmB 10 mg/kg on day 1 and 5 mg/kg on day 3 (2 doses); (iii) L-AmB 10 mg/kg on day 1 and 5 mg/kg on days 3 and 7 (3 doses); or (iv) L-AmB 3 mg/kg/day for 14 days (control). All patients also received oral fluconazole 1200 mg/day for 14 days. Primary endpoint was mean rate of clearance of cerebrospinal fluid cryptococcal infection (EFA). Noninferiority was defined as an upper limit of the 2-sided 95% confidence interval (CI) of difference in EFA between intervention and control <0.2 log10 colony-forming units (CFU)/mL/day. Results: Eighty participants were enrolled. EFA for daily L-AmB was -0.41 log10 CFU/mL/day (standard deviation, 0.11; n = 17). Difference in mean EFA from control was -0.11 (95% CI, -.29 to .07) log10 CFU/mL/day faster with single dose (n = 16); -0.05 (95% CI, -.20 to .10) log10 CFU/mL/day faster with 2 doses (n = 18); and -0.13 (95% CI, -.35 to .09) log10 CFU/mL/day faster with 3 doses (n = 18). EFA in all short-course arms was noninferior to control. Ten-week mortality was 29% (n = 23) with no statistical difference between arms. All arms were well tolerated. Conclusions: Single-dose 10 mg/kg L-AmB was well tolerated and led to noninferior EFA compared to 14 days of 3 mg/kg/day L-AmB in HIV-associated CM. Induction based on a single 10 mg/kg L-AmB dose is being taken forward to a phase 3 clinical endpoint trial. Clinical Trials Registration: ISRCTN 10248064.


Assuntos
Anfotericina B/administração & dosagem , Antifúngicos/administração & dosagem , Infecções por HIV/complicações , Meningite Criptocócica/tratamento farmacológico , Adulto , Botsuana , Líquido Cefalorraquidiano/microbiologia , Cryptococcus neoformans/isolamento & purificação , Feminino , Humanos , Masculino , Tanzânia , Resultado do Tratamento
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