RESUMO
BACKGROUND: Tuberculosis (TB) Trials Consortium Study 31/AIDS Clinical Trials Group A5349, an international randomized open-label phase 3 noninferiority trial showed that a 4-month daily regimen substituting rifapentine for rifampin and moxifloxacin for ethambutol had noninferior efficacy and was safe for the treatment of drug-susceptible pulmonary TB (DS-PTB) compared with the standard 6-month regimen. We explored results among the prespecified subgroup of people with human immunodeficiency virus (HIV) (PWH). METHODS: PWH and CD4+ counts ≥100 cells/µL were eligible if they were receiving or about to initiate efavirenz-based antiretroviral therapy (ART). Primary endpoints of TB disease-free survival 12 months after randomization (efficacy) and ≥ grade 3 adverse events (AEs) on treatment (safety) were compared, using a 6.6% noninferiority margin for efficacy. Randomization was stratified by site, pulmonary cavitation, and HIV status. PWH were enrolled in a staged fashion to support cautious evaluation of drug-drug interactions between rifapentine and efavirenz. RESULTS: A total of 2516 participants from 13 countries in sub-Saharan Africa, Asia, and the Americas were enrolled. Among 194 (8%) microbiologically eligible PWH, the median CD4+ count was 344 cells/µL (interquartile range: 223-455). The rifapentine-moxifloxacin regimen was noninferior to control (absolute difference in unfavorable outcomes -7.4%; 95% confidence interval [CI] -20.8% to 6.0%); the rifapentine regimen was not noninferior to control (+7.5% [95% CI, -7.3% to +22.4%]). Fewer AEs were reported in rifapentine-based regimens (15%) than the control regimen (21%). CONCLUSIONS: In people with HIV-associated DS-PTB with CD4+ counts ≥100 cells/µL on efavirenz-based ART, the 4-month daily rifapentine-moxifloxacin regimen was noninferior to the 6-month control regimen and was safe. CLINICAL TRIALS REGISTRATION: NCT02410772.
Assuntos
Infecções por HIV , Tuberculose Pulmonar , Tuberculose , Humanos , Rifampina/efeitos adversos , Moxifloxacina/efeitos adversos , Antituberculosos/efeitos adversos , HIV , Isoniazida/uso terapêutico , Quimioterapia Combinada , Tuberculose Pulmonar/complicações , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/microbiologia , Tuberculose/tratamento farmacológico , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológicoRESUMO
Background: The current six months regimen for drug-susceptible tuberculosis (TB) is long, complex, and requires adherence monitoring. TB hair drug level assay is one innovative approach to monitor TB treatment adherence however, its acceptability in the context of African multi-cultural settings is not known. Objective: To determine the acceptability of hair harvest and testing as a TB therapeutic drug monitoring method. Methods: The study explored perceptions, and lived experiences among TB patients with regard to using hair harvest and testing as a method of tuberculosis therapeutic drug monitoring in the context of their cultural beliefs, and faith. We used a descriptive phenomenological approach. Results: Four main themes emerged namely: participants' perceptions about the cultural meaning of their body parts; perceptions about hair having any medical value or meaning; perceptions about hospitals starting to use hair harvest and testing for routine hospital TB treatment adherence monitoring; and perceived advantages and disadvantages of using hair for treatment adherence monitoring. Overall, we found that using hair to monitor adherence was acceptable to TB patients provided the hair was harvested and tested by a medical worker. Conclusion: Hair harvest for medical testing is acceptable to TB patients on the condition that it is conducted by a medical worker.
Assuntos
Antituberculosos , Monitoramento de Medicamentos , Cabelo , Pesquisa Qualitativa , Tuberculose Pulmonar , Humanos , Feminino , Adulto , Masculino , Antituberculosos/uso terapêutico , Monitoramento de Medicamentos/métodos , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/psicologia , Cabelo/química , Pessoa de Meia-Idade , Adesão à Medicação/psicologia , Aceitação pelo Paciente de Cuidados de Saúde/psicologiaRESUMO
Background: Antiretroviral hair drug levels are currently being used to monitor adherence to HIV treatment. There is currently a dearth of literature on the preferred technique(s) of hair harvest for medical testing in the context of African multicultural settings. Objective: To explore the preferred techniques(s) of hair harvest for medical testing among TB patients. Methods: We used a descriptive phenomenological approach to conduct interviews for 15 TB patients from the 06th through the 24th of June 2022. Data was organized by N-VIVO version 10 and analysed step by step using a thematic analytical approach. Results: Participants aged <30 years were more knowledgeable, positively perceived, and experienced about the salon-based hair cutting technique compared to those aged≥30 years old. Participants aged ≥30 had experience, flexibility to use, and were knowledgeable in all three techniques, Overall, for all age categories (<30,30-40 and >40 years), majority of the respondents were knowledgeable, flexible and experienced in using all the three techniques. Conclusion: The majority of TB patients were knowledgeable, experienced and flexible about the hair cutting techniques however, efforts are needed to educate the youth that hair for medical testing can be cut by any of the three techniques without changing their cosmetic look.
Assuntos
Cabelo , Tuberculose Pulmonar , Humanos , Adulto , Masculino , Feminino , Cabelo/química , Tuberculose Pulmonar/diagnóstico , Tuberculose Pulmonar/tratamento farmacológico , Pessoa de Meia-Idade , Infecções por HIV/tratamento farmacológico , Conhecimentos, Atitudes e Prática em Saúde , Adulto Jovem , Remoção de Cabelo/métodosRESUMO
Background: Accumulation of chemicals including drugs in hair has been used in forensic investigations. Studies have reported isoniazid drug levels in the hair of TB patients. Objective: To review literature for evidence on isoniazid hair drug levels as a tool to monitor adherence, exposure, and TB treatment outcomes and the acceptability of using human hair for medical testing. Methods: We reviewed literature through Pubmed, Embase, Medline, google scholar, and google grey literature. The search terms focused on isoniazid/TB hair drug levels, adherence, treatment outcomes, and acceptability of using hair for medical testing. We kept refining our search terms at each step of our search. Results: The initial search yielded 186859 articles, which dropped to 88 after removing duplicates and irrelevant articles and eventually to 14 on further refining our search terms. On full review,2 out of 14 and 1 out of 14 articles touched the area of Isoniazid hair drug levels; adherence, exposure, TB treatment outcomes, and acceptability respectively. Further scrutiny showed that none of the articles had addressed our research question. Conclusion: Literature on Isoniazid hair drug levels among TB patients as a tool to monitor adherence, exposure, and TB treatment outcomes, and its acceptability is limited and more research is needed.
Assuntos
Antituberculosos , Cabelo , Isoniazida , Tuberculose , Humanos , Isoniazida/uso terapêutico , Isoniazida/farmacocinética , Cabelo/química , Antituberculosos/uso terapêutico , Antituberculosos/farmacocinética , Tuberculose/tratamento farmacológico , Resultado do Tratamento , Adesão à Medicação/estatística & dados numéricosRESUMO
Background: The current six months regimen for drug-susceptible tuberculosis (TB) is long, complex, and requires adherence monitoring. TB hair drug level assay is one innovative approach to monitor TB treatment adherence however, its acceptability in the context of African multi-cultural settings is not known. Objective: To determine the acceptability of hair harvest and testing as a TB therapeutic drug monitoring method. Methods: The study explored perceptions, and lived experiences among TB patients with regard to using hair harvest and testing as a method of tuberculosis therapeutic drug monitoring in the context of their cultural beliefs, and faith. We used a descriptive phenomenological approach. Results: Four main themes emerged namely: participants' perceptions about the cultural meaning of their body parts; perceptions about hair having any medical value or meaning; perceptions about hospitals starting to use hair harvest and testing for routine hospital TB treatment adherence monitoring; and perceived advantages and disadvantages of using hair for treatment adherence monitoring. Overall, we found that using hair to monitor adherence was acceptable to TB patients provided the hair was harvested and tested by a medical worker. Conclusion: Hair harvest for medical testing is acceptable to TB patients on the condition that it is conducted by a medical worker
Assuntos
Tuberculose PulmonarRESUMO
Background: Antiretroviral hair drug levels are currently being used to monitor adherence to HIV treatment. There is currently a dearth of literature on the preferred technique(s) of hair harvest for medical testing in the context of African multicultural settings. Objective: To explore the preferred techniques(s) of hair harvest for medical testing among TB patients. Methods: We used a descriptive phenomenological approach to conduct interviews for 15 TB patients from the 06th through the 24th of June 2022. Data was organized by N-VIVO version 10 and analysed step by step using a thematic analytical approach. Results: Participants aged <30 years were more knowledgeable, positively perceived, and experienced about the salon-based hair cutting technique compared to those aged≥30 years old. Participants aged ≥30 had experience, flexibility to use, and were knowledgeable in all three techniques, Overall, for all age categories (<30,30-40 and >40 years), majority of the respondents were knowledgeable, flexible and experienced in using all the three techniques. Conclusion: The majority of TB patients were knowledgeable, experienced and flexible about the hair cutting techniques however, efforts are needed to educate the youth that hair for medical testing can be cut by any of the three techniques without changing their cosmetic look.
Assuntos
Humanos , Masculino , Feminino , Tuberculose Pulmonar , Infecções por HIV , Cabelo , Técnicas de Laboratório Clínico , DiagnósticoRESUMO
Background: Collaborative research between institutions may not yield results to transform communities. Many research collaborations come to the end of their life time without achieving their originally set goals and with a dearth of community transformation to show for it. Objective: To delineate and highlight the achievements of the Uganda (Makerere University)-Case Western Reserve University Research Collaboration. Methods: We retrospectively compiled and reviewed the data on research, training and policy impact achievements of the Uganda (Makerere University)-Case Western Reserve University Research Collaboration over a period of 30 years of its existence. Results: Over the last 35 years, the Uganda (Makerere University)-Case Western Reserve University Research Collaboration trained a total of 104 Ugandans with Masters, PhDs and other varied graduate training programs. More than 70 large tuberculosis/TB+HIV studies were conducted with more than 360 manuscripts published including landmark local and global TB/HIV policy impact publications. Conclusion: The Uganda (Makerere University)-Case Western Reserve University Research Collaboration has in the past 35 years built the capacity of Ugandan and international students through conducting landmark research, training and mentoring and contributed to TB HIV management policy changes in Uganda.
Assuntos
Infecções por HIV , Estudantes , Humanos , Universidades , Uganda , Estudos RetrospectivosRESUMO
Background: Collaborative research between institutions may not yield results to transform communities. Many research collaborations come to the end of their life time without achieving their originally set goals and with a dearth of community transformation to show for it. Objective: To delineate and highlight the achievements of the Uganda (Makerere University)-Case Western Reserve University Research Collaboration Methods: We retrospectively compiled and reviewed the data on research, training and policy impact achievements of the Uganda (Makerere University)-Case Western Reserve University Research Collaboration over a period of 30 years of its existence. Results: Over the last 35 years, the Uganda (Makerere University)-Case Western Reserve University Research Collaboration trained a total of 104 Ugandans with Masters, PhDs and other varied graduate training programs. More than 70 large tuberculosis/TB+HIV studies were conducted with more than 360 manuscripts published including landmark local and global TB/HIV policy impact publications. Conclusion: The Uganda (Makerere University)-Case Western Reserve University Research Collaboration has in the past 35 years built the capacity of Ugandan and international students through conducting landmark research, training and mentoring and contributed to TB HIV management policy changes in Uganda.
Assuntos
Pesquisa , Infecções por HIV , Colaboração Intersetorial , Tutoria , LogroRESUMO
BACKGROUND: Tuberculosis (TB) sputum culture contaminants make it difficult to obtain pure TB isolates.We aimed to study and identify persistent TB sputum culture contaminants post the standard laboratory pre-culture sample decontamination techniques. METHODS: This was a longitudinal study of TB sputum culture contamination for a cohort of TB patients on standard treatment at: baseline, during TB treatment and post TB treatment. Sputum samples were decontaminated with 1.5%NaOH and neutralized using 6.8 Phosphate buffer solution.Sputum was then inoculated into MGIT (mycobactrial growth indicator tube) supplemented with 0.8ml PANTA. A drop of each positive MGIT culture was sub cultured onto blood agar and incubated for 48 hours at 35 -37OC.Any growth was identified using growth characteristics and colony morphology. RESULTS: From October 2017 through May 2019;we collected 8645 sputum samples of which 8624(99.8%) were eligible and inoculated into MGIT where 2444(28.3%)samples were TB culture positive and 255(10.4%)were positive for contaminants: 237 none-tuberculosis bacteria, 12 fungi and 6 mixed(none-tuberculous bacteria+fungi). There was no statistically significant difference between none tuberculosis bacteria and fungi in the treatment (OR=1.4,95%CI:0.26-7.47,p=0.690) and the post treatment TB phases(OR=2.02,95%CI:0.38-10.79,p=0.411)Vs baseline. CONCLUSION: None-tuberculous bacteria and fungi dominate the plethora of TB sputum culture contamination and persist beyond the standard laboratory pre-culture decontamination algorithm.
Assuntos
Antibacterianos/farmacologia , Técnicas Bacteriológicas/métodos , Escarro/microbiologia , Tuberculose/diagnóstico , Anfotericina B/farmacologia , Azlocilina/farmacologia , Bactérias/isolamento & purificação , Técnicas Bacteriológicas/normas , Fungos/isolamento & purificação , Humanos , Estudos Longitudinais , Mycobacterium tuberculosis/crescimento & desenvolvimento , Ácido Nalidíxico/farmacologia , Polimixina B/farmacologia , Trimetoprima/farmacologiaRESUMO
BACKGROUND: Rifapentine-based regimens have potent antimycobacterial activity that may allow for a shorter course in patients with drug-susceptible pulmonary tuberculosis. METHODS: In an open-label, phase 3, randomized, controlled trial involving persons with newly diagnosed pulmonary tuberculosis from 13 countries, we compared two 4-month rifapentine-based regimens with a standard 6-month regimen consisting of rifampin, isoniazid, pyrazinamide, and ethambutol (control) using a noninferiority margin of 6.6 percentage points. In one 4-month regimen, rifampin was replaced with rifapentine; in the other, rifampin was replaced with rifapentine and ethambutol with moxifloxacin. The primary efficacy outcome was survival free of tuberculosis at 12 months. RESULTS: Among 2516 participants who had undergone randomization, 2343 had a culture positive for Mycobacterium tuberculosis that was not resistant to isoniazid, rifampin, or fluoroquinolones (microbiologically eligible population; 768 in the control group, 791 in the rifapentine-moxifloxacin group, and 784 in the rifapentine group), of whom 194 were coinfected with human immunodeficiency virus and 1703 had cavitation on chest radiography. A total of 2234 participants could be assessed for the primary outcome (assessable population; 726 in the control group, 756 in the rifapentine-moxifloxacin group, and 752 in the rifapentine group). Rifapentine with moxifloxacin was noninferior to the control in the microbiologically eligible population (15.5% vs. 14.6% had an unfavorable outcome; difference, 1.0 percentage point; 95% confidence interval [CI], -2.6 to 4.5) and in the assessable population (11.6% vs. 9.6%; difference, 2.0 percentage points; 95% CI, -1.1 to 5.1). Noninferiority was shown in the secondary and sensitivity analyses. Rifapentine without moxifloxacin was not shown to be noninferior to the control in either population (17.7% vs. 14.6% with an unfavorable outcome in the microbiologically eligible population; difference, 3.0 percentage points [95% CI, -0.6 to 6.6]; and 14.2% vs. 9.6% in the assessable population; difference, 4.4 percentage points [95% CI, 1.2 to 7.7]). Adverse events of grade 3 or higher occurred during the on-treatment period in 19.3% of participants in the control group, 18.8% in the rifapentine-moxifloxacin group, and 14.3% in the rifapentine group. CONCLUSIONS: The efficacy of a 4-month rifapentine-based regimen containing moxifloxacin was noninferior to the standard 6-month regimen in the treatment of tuberculosis. (Funded by the Centers for Disease Control and Prevention and others; Study 31/A5349 ClinicalTrials.gov number, NCT02410772.).
Assuntos
Antibióticos Antituberculose/administração & dosagem , Antituberculosos/uso terapêutico , Moxifloxacina/administração & dosagem , Mycobacterium tuberculosis/isolamento & purificação , Rifampina/administração & dosagem , Tuberculose Pulmonar/tratamento farmacológico , Adolescente , Adulto , Antibióticos Antituberculose/efeitos adversos , Antituberculosos/efeitos adversos , Criança , Intervalos de Confiança , Esquema de Medicação , Quimioterapia Combinada , Feminino , Humanos , Masculino , Moxifloxacina/efeitos adversos , Rifampina/efeitos adversos , Adulto JovemRESUMO
BACKGROUND: Low education levels and language barriers present challenges in obtaining informed consent for clinical research. OBJECTIVE: To describe and correlate the association between the level of education and the participant's preferred language of consent. DESIGN: Descriptive-analytical cross-sectional study. PARTICIPANTS: Adults being consented for participation in tuberculosis(TB) research studies in an East African community with varying levels of education. PROCEDURES: We analyzed data on demographic and educational characteristics collected from adults being consented for participation in TB studies .Only participants who could understand and speak Luganda (the main local language) or English (the official language of Uganda) were included in this analysis. RESULTS: A total of 523 participants were consented between April 2015 and December 2017 and included in this analysis; 250 below Senior four (< 11yrs of education), 114 senior four (at 11yrs of education),73 senior five-senior six (12-13yrs of education) and 86 beyond senior six (> 13yrs of education). We noted that the preference for English rises with the rising levels of education and peaked at beyond senior six (83%Vs17%,OR=49,95%CI:22.8-106.3,p<0.001).Participants below senior four preferred Luganda Vs senior four and above(OR=16.9,95%CI:9.9-28.8,p<0.001). CONCLUSION: Rising education levels of participants were associated with preference for English language usage during initial consent for clinical research studies.
Assuntos
Participação da Comunidade , Compreensão , Escolaridade , Letramento em Saúde , Consentimento Livre e Esclarecido/estatística & dados numéricos , Idioma , Pesquisa/organização & administração , Adulto , Comunicação , Estudos Transversais , Feminino , Pesquisas sobre Atenção à Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Uganda , Adulto JovemRESUMO
OBJECTIVE: To explore simple inexpensive non-culture based predictors of recurrent pulmonary tuberculosis (PTB). SETTING AND STUDY POPULATION: HIV-infected and uninfected adults with the first episode of smear positive, culture-confirmed pulmonary tuberculosis in a high tuberculosis burden country. DESIGN: A nested prospective cohort study of participants with pulmonary tuberculosis (PTB) presenting to a hospital out-patient clinic. RESULTS: A total of 630 TB culture confirmed participants were followed up for eighteen months of which 57 (9%) developed recurrent recurrent TB. On univariate analysis,4.7% low grade(1+) pre-treatment sputum smear participants developed recurrent tuberculosis Vs 8.8% with high grade(3+) smears (OR=0.31,95%CI: 0.10-0.93, p=0.037).On multivariate analysis: participants with extensive fibro-cavitation had a high risk of recurrent TB Vs minimal end of treatment fibro-cavitation (18%Vs12%, OR=2.3,95%CI:1.09-4.68, p=0.03). Weight gain with HIV infection was assosciated with a high risk of recurrent TB Vs weight gain with no HIV infection(18%Vs 6%, OR=6.8,95%CI:165-27.83, p=0.008) where as weight gain with a low pre-treatment high bacillary burden was assosciated with a low risk of recurrent TB Vs weight gain with a high pre-treatmentbacillary burden(6.5%Vs7.9%, OR=0.2,95%CI:0.05-0.79, p=0.02). CONCLUSION: Extensive end of treatment pulmonary fibro-cavitation, high pre-treatment bacillary burden with no weight gain and HIV infection could be reliable predictors of recurrent tuberculosis.
Assuntos
Escarro/microbiologia , Tuberculose Pulmonar/epidemiologia , Adulto , Feminino , Infecções por HIV/epidemiologia , Humanos , Masculino , Estudos Prospectivos , Recidiva , Fatores de Risco , Uganda/epidemiologiaRESUMO
RATIONALE: Rifapentine has potent activity in mouse models of tuberculosis chemotherapy but its optimal dose and exposure in humans are unknown. OBJECTIVES: We conducted a randomized, partially blinded dose-ranging study to determine tolerability, safety, and antimicrobial activity of daily rifapentine for pulmonary tuberculosis treatment. METHODS: Adults with sputum smear-positive pulmonary tuberculosis were assigned rifapentine 10, 15, or 20 mg/kg or rifampin 10 mg/kg daily for 8 weeks (intensive phase), with isoniazid, pyrazinamide, and ethambutol. The primary tolerability end point was treatment discontinuation. The primary efficacy end point was negative sputum cultures at completion of intensive phase. MEASUREMENTS AND MAIN RESULTS: A total of 334 participants were enrolled. At completion of intensive phase, cultures on solid media were negative in 81.3% of participants in the rifampin group versus 92.5% (P = 0.097), 89.4% (P = 0.29), and 94.7% (P = 0.049) in the rifapentine 10, 15, and 20 mg/kg groups. Liquid cultures were negative in 56.3% (rifampin group) versus 74.6% (P = 0.042), 69.7% (P = 0.16), and 82.5% (P = 0.004), respectively. Compared with the rifampin group, the proportion negative at the end of intensive phase was higher among rifapentine recipients who had high rifapentine areas under the concentration-time curve. Percentages of participants discontinuing assigned treatment for reasons other than microbiologic ineligibility were similar across groups (rifampin, 8.2%; rifapentine 10, 15, or 20 mg/kg, 3.4, 2.5, and 7.4%, respectively). CONCLUSIONS: Daily rifapentine was well-tolerated and safe. High rifapentine exposures were associated with high levels of sputum sterilization at completion of intensive phase. Further studies are warranted to determine if regimens that deliver high rifapentine exposures can shorten treatment duration to less than 6 months. Clinical trial registered with www.clinicaltrials.gov (NCT 00694629).
Assuntos
Antibióticos Antituberculose/administração & dosagem , Rifampina/análogos & derivados , Tuberculose Pulmonar/tratamento farmacológico , Adolescente , Adulto , África , Idoso , Antituberculosos/administração & dosagem , Ásia , Esquema de Medicação , Quimioterapia Combinada , Europa (Continente) , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , América do Norte , Rifampina/administração & dosagem , Método Simples-Cego , América do Sul , Resultado do TratamentoRESUMO
BACKGROUND: New drug regimens of greater efficacy and shorter duration are needed for tuberculosis (TB) treatment. The identification of accurate, quantitative, non-culture based markers of treatment response would improve the efficiency of Phase 2 TB drug testing. METHODS: In an unbiased biomarker discovery approach, we applied a highly multiplexed, aptamer-based, proteomic technology to analyze serum samples collected at baseline and after 8 weeks of treatment from 39 patients with pulmonary TB from Kampala, Uganda enrolled in a Centers for Disease Control and Prevention (CDC) TB Trials Consortium Phase 2B treatment trial. RESULTS: We identified protein expression differences associated with 8-week culture status, including Coagulation Factor V, SAA, XPNPEP1, PSME1, IL-11 Rα, HSP70, Galectin-8, α2-Antiplasmin, ECM1, YES, IGFBP-1, CATZ, BGN, LYNB, and IL-7. Markers noted to have differential changes between responders and slow-responders included nectin-like protein 2, EphA1 (Ephrin type-A receptor 1), gp130, CNDP1, TGF-b RIII, MRC2, ADAM9, and CDON. A logistic regression model combining markers associated with 8-week culture status revealed an ROC curve with AUC = 0.96, sensitivity = 0.95 and specificity = 0.90. Additional markers showed differential changes between responders and slow-responders (nectin-like protein), or correlated with time-to-culture-conversion (KLRK1). CONCLUSIONS: Serum proteins involved in the coagulation cascade, neutrophil activity, immunity, inflammation, and tissue remodeling were found to be associated with TB treatment response. A quantitative, non-culture based, five-marker signature predictive of 8-week culture status was identified in this pilot study.
Assuntos
Antituberculosos/uso terapêutico , Proteínas de Bactérias/metabolismo , Tuberculose Pulmonar/tratamento farmacológico , Adulto , Biomarcadores/metabolismo , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Estudos Prospectivos , Proteômica/métodos , Técnica de Seleção de Aptâmeros/métodos , Resultado do Tratamento , Tuberculose Pulmonar/sangue , Adulto JovemRESUMO
In an unbiased approach to biomarker discovery, we applied a highly multiplexed proteomic technology (SOMAscan, SomaLogic, Inc, Boulder, CO) to understand changes in proteins from paired serum samples at enrollment and after 8 weeks of TB treatment from 39 patients with pulmonary TB from Kampala, Uganda enrolled in the Center for Disease Control and Prevention's Tuberculosis Trials Consortium (TBTC) Study 29. This work represents the first large-scale proteomic analysis employing modified DNA aptamers in a study of active tuberculosis (TB). We identified multiple proteins that exhibit significant expression differences during the intensive phase of TB therapy. There was enrichment for proteins in conserved networks of biological processes and function including antimicrobial defense, tissue healing and remodeling, acute phase response, pattern recognition, protease/anti-proteases, complement and coagulation cascade, apoptosis, immunity and inflammation pathways. Members of cytokine pathways such as interferon-gamma, while present, were not as highly represented as might have been predicted. The top proteins that changed between baseline and 8 weeks of therapy were TSP4, TIMP-2, SEPR, MRC-2, Antithrombin III, SAA, CRP, NPS-PLA2, LEAP-1, and LBP. The novel proteins elucidated in this work may provide new insights for understanding TB disease, its treatment and subsequent healing processes that occur in response to effective therapy.
Assuntos
Biomarcadores/sangue , Tuberculose Pulmonar/terapia , Adulto , Proteína C-Reativa/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fosfolipases A2/sangue , Proteômica , Proteína Amiloide A Sérica/metabolismoRESUMO
RATIONALE: The lack of consistent associations between clinical outcomes and microbiological responses to therapy for some infectious diseases has raised questions about the adequacy of microbiological endpoints for tuberculosis treatment trials. OBJECTIVES: To evaluate the association between symptoms and microbiological response to tuberculosis treatment. METHODS: We performed a retrospective analysis of four clinical trials in which participants had culture-positive tuberculosis, standardized symptom assessment, and follow-up mycobacterial cultures. Two trials (studies 22 and 23) followed participants to identify recurrent tuberculosis; participants in studies 27 and 28 were only followed to treatment completion. MEASUREMENTS AND MAIN RESULTS: This analysis included 1,978 participants; 39 (2.0%) had culture-confirmed treatment failure, and 75 (3.9%) had culture-confirmed recurrence. Productive cough was associated with indices of increased mycobacterial burden at diagnosis (acid-fast smear grade, severity of radiographic abnormalities). Fever and sweats improved rapidly with treatment, whereas productive cough decreased more slowly and was present in 20% of visits after treatment completion. During treatment, study participants with productive cough more often had concurrent culture positivity compared with those without productive cough (studies 22 and 23: adjusted odds ratio, 1.80; 95% confidence interval [CI], 1.33-2.44). Finally, symptoms during the latter part of treatment and follow-up were associated with culture-confirmed treatment failure and recurrence in studies 22 and 23 (for cough: adjusted hazard ratio, 2.07; 95% CI, 1.23-3.49; for fever: adjusted hazard ratio, 5.05; 95% CI, 2.76-9.19). CONCLUSIONS: There are consistent relationships between symptoms and microbiological indices of tuberculosis, including measures of mycobacterial burden at baseline, culture positivity during treatment, and time to culture-confirmed treatment failure and recurrence.
Assuntos
Antituberculosos , Tosse , Infecções por HIV/epidemiologia , Mycobacterium tuberculosis , Avaliação de Sintomas , Tuberculose , Adulto , Antituberculosos/administração & dosagem , Antituberculosos/farmacocinética , Disponibilidade Biológica , Ensaios Clínicos como Assunto/métodos , Ensaios Clínicos como Assunto/estatística & dados numéricos , Coinfecção , Tosse/tratamento farmacológico , Tosse/microbiologia , Feminino , Humanos , Masculino , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/isolamento & purificação , Avaliação de Processos e Resultados em Cuidados de Saúde/métodos , Modelos de Riscos Proporcionais , Radiografia , Recidiva , Estudos Retrospectivos , Índice de Gravidade de Doença , Avaliação de Sintomas/métodos , Avaliação de Sintomas/normas , Avaliação de Sintomas/estatística & dados numéricos , Falha de Tratamento , Tuberculose/diagnóstico por imagem , Tuberculose/tratamento farmacológico , Tuberculose/epidemiologia , Tuberculose/microbiologia , Tuberculose/fisiopatologia , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: Rifapentine administered 5 days per week has potent activity in mouse models of antituberculosis chemotherapy, but efficacy and safety data are limited in humans. We compared the antimicrobial activity and safety of rifapentine vs rifampin during the first 8 weeks of pulmonary tuberculosis treatment. METHODS: In total, 531 adults with sputum smear-positive pulmonary tuberculosis were randomized to rifapentine 10 mg/kg/dose or rifampin 10 mg/kg/dose, administered 5 days per week for 8 weeks (intensive phase), with isoniazid, pyrazinamide, and ethambutol. Coprimary outcomes were negative sputum culture on liquid and on solid media at completion of intensive phase. RESULTS: Negative cultures on solid media occurred in 145 of 174 participants (83.3%) in the rifampin group and 171 of 198 participants (86.4%) in the rifapentine group (difference, 3.0%; 95% confidence interval [CI]: -4.3, 10.5); negative cultures in liquid media occurred in 110 of 169 (65.1%) in the rifampin group and 133 of 196 (67.9%) in the rifapentine group (difference, 2.8%; 95% CI: -6.9, 12.4). Among 529 participants who received study therapy, 40 of 254 participants (15.7%) in the rifampin group and 40 of 275 participants (14.5%) in the rifapentine group prematurely discontinued treatment (P=.79). CONCLUSIONS: The rifapentine regimen was safe but not significantly more active than a standard rifampin regimen, by the surrogate endpoint of culture status at completion of intensive phase. Assessment of higher exposures to rifapentine for tuberculosis treatment is warranted. CLINICAL TRIALS REGISTRATION: NCT00694629.