Last data update: May 13, 2024. (Total: 46773 publications since 2009)
Records 1-29 (of 29 Records) |
Query Trace: Johnson JL[original query] |
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A standardized approach for collection of objective data to support outcome determination for late-phase TB trials
Kurbatova EV , Phillips PP , Dorman SE , Sizemore EE , Bryant KE , Purfield AE , Ricaldi J , Brown NE , Johnson JL , Wallis CL , Akol JP , Ocheretina O , Van Hung N , Mayanja-Kizza H , Lourens M , Dawson R , Nhung NV , Pierre S , Musodza Y , Shenje J , Badal-Faesen S , Vilbrun SC , Waja Z , Peddareddy L , Scott NA , Yuan Y , Vernon A , Goldberg SV , Swindells S , Chaisson RE , Nahid P . Am J Respir Crit Care Med 2023 207 (10) 1376-1382 INTRODUCTION: We developed a standardized method, "Possible poor treatment response" (PPTR), to help ascertain efficacy endpoints in Study S31/A5349 (NCT02410772), an open-label trial comparing two 4-month rifapentine-based regimens with a standard 6-month regimen for the treatment of pulmonary TB. We describe the use of the PPTR process and evaluate whether the goals of minimizing bias in efficacy endpoint assessment and attainment of relevant data to determine outcome for all participants were achieved. METHODS/DESIGN: A PPTR event was defined as the occurrence of one or more pre-specified triggers. Each PPTR required initiation of a standardized evaluation process that included obtaining multiple sputum samples for microbiology. RESULTS: Among 2,343 participants with culture-confirmed drug-susceptible TB, 454 individuals (19.4%) had a total of 534 individual PPTR events, of which 76.6% were microbiological (positive smear or culture at or after 17 weeks). At least one PPTR event was experienced by 92.4% (133 of 144) of participants with TB-related unfavorable outcome, and between 13.8 and 14.7% of participants with favorable and not assessable outcomes. 75% of participants with TB-related unfavorable outcomes had microbiological confirmation of failure to achieve disease-free cure. DISCUSSION: Standardized methodologies, such as our PPTR approach, could facilitate unbiased efficacy outcome determinations, improve discrimination between outcomes that are related and unrelated to regimen efficacy, and enhance the ability to conduct pooled analyses of contemporary trials. Clinical trial registration available at www. CLINICALTRIALS: gov, ID: NCT02410772. |
Rifapentine with and without moxifloxacin for pulmonary tuberculosis in people with HIV (S31/A5349)
Pettit AC , Phillips PP , Kurbatova E , Vernon A , Nahid P , Dawson R , Dooley KE , Sanne I , Waja Z , Mohapi L , Podany AT , Samaneka W , Savic RM , Johnson JL , Muzanyi G , Lalloo UG , Bryant K , Sizemore E , Scott N , Dorman SE , Chaisson RE , Swindells S . Clin Infect Dis 2022 76 (3) e580-e589 BACKGROUND: Tuberculosis (TB) Trials Consortium Study 31/AIDS Clinical Trials Group A5349, an international randomized open-label phase 3 non-inferiority trial showed that a 4-month daily regimen substituting rifapentine for rifampin and moxifloxacin for ethambutol had non-inferior 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 pre-specified subgroup of people with 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 post-randomization (efficacy) and ≥ grade 3 adverse events (AEs) on treatment (safety) were compared, using a 6.6% non-inferiority 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: 2,516 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 non-inferior to control (absolute difference in unfavorable outcomes -7.4% [95% CI -20.8% to +6.0%]); the rifapentine regimen was not non-inferior 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 non-inferior to the 6-month control regimen and was safe. |
Efavirenz pharmacokinetics and HIV-1 viral suppression among patients receiving TB treatment containing daily high-dose rifapentine
Podany AT , Pham M , Sizemore E , Martinson N , Samaneka W , Mohapi L , Badal-Faesen S , Dawson R , Johnson JL , Mayanja H , Lalloo U , Whitworth WC , Pettit A , Campbell K , Phillips P , Bryant K , Scott N , Vernon A , Kurbatova E , Chaisson RE , Dorman S , Nahid P , Swindells S , Dooley KE , Fletcher CV . Clin Infect Dis 2021 75 (4) 560-566 BACKGROUND: A four-month regimen containing rifapentine and moxifloxacin has non-inferior efficacy compared to the standard 6-month regimen for drug-sensitive tuberculosis. We evaluated the effect of regimens containing daily, high-dose rifapentine on efavirenz pharmacokinetics and viral suppression in patients with HIV-associated TB. METHODS: In the context of a Phase 3 randomized controlled trial, HIV-positive individuals already virally suppressed on efavirenz--containing ART (EFV1), or newly initiating efavirenz (EFV2) received TB treatment containing rifapentine (1200mg), isoniazid, pyrazinamide, and either ethambutol or moxifloxacin. Mid-interval efavirenz concentrations were measured (a) during ART and TB co-treatment (Weeks 4, 8, 12 and 17, different by EFV group) and (b) when ART was taken alone (pre- or post-TB treatment, Weeks 0 and 22). Apparent oral clearance (CL/F) was estimated and compared. Target mid-interval efavirenz concentrations were > 1 mg/L. Co-treatment was considered acceptable if >80% of participants had mid-interval efavirenz concentrations meeting this target. RESULTS: EFV1 and EFV2 included 70 and 41 evaluable participants, respectively. The geometric mean ratio comparing efavirenz CL/F with vs. without TB drugs was 0.79 [90% CI 0.72-0.85] in EFV1 and 0.84 [90% CI 0.69-0.97] in EFV2. The percent of participants with mid-interval efavirenz concentrations >1mg/L in EFV1 at Weeks 0, 4, 8, and 17 was 96%, 96%, 88%, and 89%, respectively. In EFV2, at approximately 4 and 8 weeks post efavirenz initiation, the value was 98%. CONCLUSIONS: TB treatment containing high-dose daily rifapentine modestly decreased (rather than increased) efavirenz clearance and therapeutic targets were met supporting the use of efavirenz with these regimens, without dose adjustment. |
A Longitudinal Model-Based Biomarker Analysis of Exposure Response in Adults with Pulmonary Tuberculosis
Gewitz AD , Solans BP , Mac Kenzie WR , Heilig C , Whitworth WC , Johnson JL , Nsubuga P , Dorman S , Weiner M , Savic RM . Antimicrob Agents Chemother 2021 65 (10) Aac0179420 The identification of sensitive, specific and reliable biomarkers that can be quantified in the early phases of tuberculosis treatment and predictive of long-term outcome is key for the development of an effective short-course treatment regimen. Time-to-positivity (TTP), a biomarker of treatment outcome against Mycobacterium tuberculosis, measures longitudinal bacterial growth in Mycobacteria Growth Indicator Tube broth culture and may be predictive of standard time-to-stable-culture-conversion (TSCC). In two randomized phase 2b trials investigating dose-ranging rifapentine (Study 29 and 29x), 662 participants had sputum collected over six months where TTP, TSCC and time-to-culture-conversion were quantified. The goals of this post hoc study were to characterize longitudinal TTP profiles and to identify individual patient characteristics associated with delayed time to culture conversion. In order to do so, a nonlinear mixed-effects model describing longitudinal TTP was built. Independent variables associated with increased bacterial clearance (increased TTP), assessed by subject-specific and population-level trajectories, were higher rifapentine exposure, lower baseline grade of sputum acid-fast bacilli smear, absence of productive cough, and lower extent of lung infiltrates on radiographs. Importantly, sensitivity analysis revealed that major learning milestones in phase 2b trials, such as significant exposure-response and covariate relationships, could be detected using truncated TTP data as early as 6 weeks from start of treatment, suggesting alternative phase 2B study designs. The TTP model built depicts a novel phase 2B surrogate endpoint that can inform early assessment of experimental treatment efficacy and treatment failure or relapse in patients treated with shorter and novel TB treatment regimens, improving efficiency of phase 2 clinical trials. |
Four-Month Rifapentine Regimens with or without Moxifloxacin for Tuberculosis
Dorman SE , Nahid P , Kurbatova EV , Phillips PPJ , Bryant K , Dooley KE , Engle M , Goldberg SV , Phan HTT , Hakim J , Johnson JL , Lourens M , Martinson NA , Muzanyi G , Narunsky K , Nerette S , Nguyen NV , Pham TH , Pierre S , Purfield AE , Samaneka W , Savic RM , Sanne I , Scott NA , Shenje J , Sizemore E , Vernon A , Waja Z , Weiner M , Swindells S , Chaisson RE . N Engl J Med 2021 384 (18) 1705-1718 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.). |
Decreased plasma rifapentine concentrations associated with AADAC single nucleotide polymorphism in adults with tuberculosis.
Weiner M , Gelfond J , Johnson-Pais TL , Engle M , Johnson JL , Whitworth WC , Bliven-Sizemore E , Nsubuga P , Dorman SE , Savic R . J Antimicrob Chemother 2020 76 (3) 582-586 BACKGROUND: Rifapentine exposure is associated with bactericidal activity against Mycobacterium tuberculosis, but high interindividual variation in plasma concentrations is encountered. OBJECTIVES: To investigate a genomic association with interindividual variation of rifapentine exposure, SNPs of six human genes involving rifamycin metabolism (AADAC, CES2), drug transport (SLCO1B1, SLCO1B3) and gene regulation (HNF4A, PXR) were evaluated. METHODS: We characterized these genes in 173 adult participants in treatment trials of the Tuberculosis Trials Consortium. Participants were stratified by self-identified race (black or non-black), and rifapentine AUC from 0 to 24 h (AUC0-24) was adjusted by analysis of covariance for SNPs, rifapentine dose, sex, food and HIV coinfection. This study was registered at ClinicalTrials.gov under identifier NCT01043575. RESULTS: The effect on rifapentine least squares mean AUC0-24 in black participants overall decreased by -10.2% for AADAC rs1803155 G versus A allele (Wald test: P = 0.03; false discovery rate, 0.10). Black participants with one G allele in AADAC rs1803155 were three times as likely to have below target bactericidal rifapentine exposure than black participants with the A allele (OR, 2.97; 95% CI: 1.16, 7.58). With two G alleles, the OR was greater. In non-black participants, AADAC rs1803155 SNP was not associated with rifapentine exposure. In both black and non-black participants, other evaluated genes were not associated with rifapentine exposure (P > 0.05; false discovery rate > 0.10). CONCLUSIONS: Rifapentine exposure in black participants varied with AADAC rs1803155 genotype and the G allele was more likely to be associated with below bactericidal target rifapentine exposure. Further pharmacogenomic study is needed to characterize the association of the AADAC rs1803155 with inadequate rifapentine exposure in different patient groups. |
High-dose rifapentine with or without moxifloxacin for shortening treatment of pulmonary tuberculosis: Study protocol for TBTC study 31/ACTG A5349 phase 3 clinical trial
Dorman SE , Nahid P , Kurbatova EV , Goldberg SV , Bozeman L , Burman WJ , Chang KC , Chen M , Cotton M , Dooley KE , Engle M , Feng PJ , Fletcher CV , Ha P , Heilig CM , Johnson JL , Lessem E , Metchock B , Miro JM , Nhung NV , Pettit AC , Phillips PPJ , Podany AT , Purfield AE , Robergeau K , Samaneka W , Scott NA , Sizemore E , Vernon A , Weiner M , Swindells S , Chaisson RE . Contemp Clin Trials 2020 90 105938 INTRODUCTION: Phase 2 clinical trials of tuberculosis treatment have shown that once-daily regimens in which rifampin is replaced by high dose rifapentine have potent antimicrobial activity that may be sufficient to shorten overall treatment duration. Herein we describe the design of an ongoing phase 3 clinical trial testing the hypothesis that once-daily regimens containing high dose rifapentine in combination with other anti-tuberculosis drugs administered for four months can achieve cure rates not worse than the conventional six-month treatment regimen. METHODS/DESIGN: S31/A5349 is a multicenter randomized controlled phase 3 non-inferiority trial that compares two four-month regimens with the standard six-month regimen for treating drug-susceptible pulmonary tuberculosis in HIV-negative and HIV-positive patients. Both of the four-month regimens contain high-dose rifapentine instead of rifampin, with ethambutol replaced by moxifloxacin in one regimen. All drugs are administered seven days per week, and under direct observation at least five days per week. The primary outcome is tuberculosis disease-free survival at twelve months after study treatment assignment. A total of 2500 participants will be randomized; this gives 90% power to show non-inferiority with a 6.6% margin of non-inferiority. DISCUSSION: This phase 3 trial formally tests the hypothesis that augmentation of rifamycin exposures can shorten tuberculosis treatment to four months. Trial design and standardized implementation optimize the likelihood of obtaining valid results. Results of this trial may have important implications for clinical management of tuberculosis at both individual and programmatic levels. TRIAL REGISTRATION: NCT02410772. Registered 8 April 2015,https://www.clinicaltrials.gov/ct2/show/NCT02410772?term=02410772&rank=1. |
Bacterial factors that predict relapse after tuberculosis therapy
Colangeli R , Jedrey H , Kim S , Connell R , Ma S , Chippada Venkata UD , Chakravorty S , Gupta A , Sizemore EE , Diem L , Sherman DR , Okwera A , Dietze R , Boom WH , Johnson JL , Mac Kenzie WR , Alland D . N Engl J Med 2018 379 (9) 823-833 BACKGROUND: Approximately 5% of patients with drug-susceptible tuberculosis have a relapse after 6 months of first-line therapy, as do approximately 20% of patients after 4 months of short-course therapy. We postulated that by analyzing pretreatment isolates of Mycobacterium tuberculosis obtained from patients who subsequently had a relapse or were cured, we could determine any correlations between the minimum inhibitory concentration (MIC) of a drug below the standard resistance breakpoint and the relapse risk after treatment. METHODS: Using data from the Tuberculosis Trials Consortium Study 22 (development cohort), we assessed relapse and cure isolates to determine the MIC values of isoniazid and rifampin that were below the standard resistance breakpoint (0.1 mug per milliliter for isoniazid and 1.0 mug per milliliter for rifampin). We combined this analysis with clinical, radiologic, and laboratory data to generate predictive relapse models, which we validated by analyzing data from the DMID 01-009 study (validation cohort). RESULTS: In the development cohort, the mean (+/-SD) MIC of isoniazid below the breakpoint was 0.0334+/-0.0085 mug per milliliter in the relapse group and 0.0286+/-0.0092 mug per milliliter in the cure group, which represented a higher value in the relapse group by a factor of 1.17 (P=0.02). The corresponding MIC values of rifampin were 0.0695+/-0.0276 and 0.0453+/-0.0223 mug per milliliter, respectively, which represented a higher value in the relapse group by a factor of 1.53 (P<0.001). Higher MIC values remained associated with relapse in a multivariable analysis that included other significant between-group differences. In an analysis of receiver-operating-characteristic curves of relapse based on these MIC values, the area under the curve (AUC) was 0.779. In the development cohort, the AUC in a multivariable model that included MIC values was 0.875. In the validation cohort, the MIC values either alone or combined with other patient characteristics were also predictive of relapse, with AUC values of 0.964 and 0.929, respectively. The use of a model score for the MIC values of isoniazid and rifampin to achieve 75.0% sensitivity in cross-validation analysis predicted relapse with a specificity of 76.5% in the development cohort and a sensitivity of 70.0% and a specificity of 100% in the validation cohort. CONCLUSIONS: In pretreatment isolates of M. tuberculosis with decrements of MIC values of isoniazid or rifampin below standard resistance breakpoints, higher MIC values were associated with a greater risk of relapse than lower MIC values. (Funded by the National Institute of Allergy and Infectious Diseases.). |
Elevated Plasma Moxifloxacin Concentrations and SLCO1B1 g.-11187G>A Polymorphism in Adults with Pulmonary Tuberculosis.
Weiner M , Gelfond J , Johnson-Pais TL , Engle M , Peloquin CA , Johnson JL , Sizemore EE , Mac Kenzie WR . Antimicrob Agents Chemother 2018 62 (5) Moxifloxacin exhibits concentration-dependent prolongation of human QTc intervals and bactericidal activity against Mycobacterium tuberculosis However, moxifloxacin plasma concentrations are variable between patients. We evaluated whether human gene polymorphisms affect moxifloxacin plasma concentrations in tuberculosis patients from two geographic regions. We enrolled a convenience sample of 49 adults with drug-sensitive pulmonary tuberculosis from Africa and the United State s enrolled in two treatment trials of moxifloxacin as part of multidrug therapy. Pharmacokinetic parameters were evaluated by noncompartmental techniques. Human single-nucleotide polymorphisms of transporter genes were evaluated with analysis of covariance on moxifloxacin exposure and peak concentration (Cmax). Moxifloxacin area under the concentration-time curve from 0 to 24 h (AUC0-24) and Cmax were significantly increased by drug mg/kg dosage and genotype of variant g.-11187G>A in the SLCO1B1 gene (rs4149015), but not by geographic region. Median moxifloxacin AUC0-24 was 46% higher and Cmax 30% higher in 4 (8% of) participants who had the SLCO1B1 g.-11187 AG genotype compared with 45 participants who had the wild type GG genotype (median from model, AUC0-24 34.4 vs. 23.6 mug*h/mL, P =.005; Cmax 3.5 vs. 2.7 mug/mL, P =.009, ANCOVA). Because moxifloxacin exhibits concentration-dependent prolongation of human QTc intervals, and prolonged QTc intervals are associated with cardiac arrhythmia, further study is needed to evaluate risk associated with the SLCO1B1 g.-11187G>A variant. |
Defining the optimal dose of rifapentine for pulmonary tuberculosis: Exposure-response relations from two phase 2 clinical trials
Savic RM , Weiner M , Mac Kenzie WR , Engle M , Whitworth WC , Johnson JL , Nsubuga P , Nahid P , Nguyen NV , Peloquin CA , Dooley KE , Dorman SE . Clin Pharmacol Ther 2017 102 (2) 321-331 Rifapentine is a highly active antituberculosis antibiotic with treatment-shortening potential; however, exposure-response relations and the dose needed for maximal bactericidal activity have not been established. We used pharmacokinetic/pharmacodynamic data from 657 adults with pulmonary tuberculosis participating in treatment trials to compare rifapentine (n = 405) with rifampin (n = 252) as part of intensive-phase therapy. Population pharmacokinetic/pharmacodynamic analyses were performed with nonlinear mixed-effects modeling. Time to stable culture conversion of sputum to negative was determined in cultures obtained over 4 months of therapy. Rifapentine exposures were lower in participants who were coinfected with human immunodeficiency virus, black, male, or fasting when taking drug. Rifapentine exposure, large lung cavity size, and geographic region were independently associated with time to culture conversion in liquid media. Maximal treatment efficacy is likely achieved with rifapentine at 1200 mg daily. Patients with large lung cavities appear less responsive to treatment, even at high rifapentine doses. |
Bodies don't sleep, neither do babies: experiences at the only maternity hospital isolation unit in Sierra Leone during the 2014 Ebola epidemic
Johnson JL . Am J Obstet Gynecol 2015 213 (5) 739-40 I arrived in Sierra Leone during the 2014 Ebola epidemic on Oct. 22, 2014, as part of a traveling group of 5 US Public Health responders working on behalf of the Centers for Disease Control and Prevention and joining a larger field team spread throughout the country. This was the first time I had been called to an outbreak, and I knew 2 things: I would be assigned to the infection prevention control team covering the maternity hospital isolation unit, and I should be ready for “rough conditions.” The short commute from the hotel took an hour during afternoon traffic. We pulled into the hospital gates to a courtyard crowded with people. Because we had not been screened on entry to the hospital grounds, I suspected they hadn’t been either. I stood the recommended arm and a half length away from people in the crowded hospital courtyard, knowing this would be the first of many long hours spent at the maternity hospital. My colleague gave me a tour of the facility: the isolation unit for women with suspected or confirmed Ebola virus disease (EVD), hospital wards, screening areas, morgue, laboratory, pharmacy, patient waiting areas, and the incinerator. Little did I know how accustomed I would grow to the smell, smoke, and eye-burning effects of the incinerator. I walked awkwardly behind her trying not to get too close to anything or anyone and followed her lead as we stood to the side while men in full personal protection equipment carried bodies on stretchers past us to the morgue. No one can quite prepare for these “rough conditions.” I was shocked at the large size of the hospital compound and the throngs of people who seemed unfazed to spend an afternoon in a hospital courtyard during an EVD epidemic. There were no weekends. Staff at the isolation unit worked nonstop, 7 days a week. The head nurse of the isolation unit would become a friend. During my 35-day tenure at the hospital, I would see her mood fluctuate from an ever-present exhaustion to hope and optimism with rare bouts of sadness and hopelessness. I wished I could give her the reprieve she undoubtedly needed and worried for her health and stamina. |
Serum biomarkers of treatment response within a randomized clinical trial for pulmonary tuberculosis
Jayakumar A , Vittinghoff E , Segal MR , MacKenzie WR , Johnson JL , Gitta P , Saukkonen J , Anderson J , Weiner M , Engle M , Yoon C , Kato-Maeda M , Nahid P . Tuberculosis (Edinb) 2015 95 (4) 415-20 RATIONALE: Biomarkers for monitoring response to anti-tuberculosis treatment are needed. We explored immune markers previously published as having predictive capability for 8 week culture status in 39 adults enrolled in a clinical trial in Kampala, Uganda. METHODS: We consecutively selected 20 HIV-negative pulmonary TB subjects with positive cultures, and 19 subjects with negative cultures at the end of intensive phase therapy. At baseline and after 8 weeks, serum was assayed for nine cytokines and soluble cytokine receptors using multiplexed platforms or ELISA. We evaluated their association with week 8 culture status first using single-variable logistic models, then using cross-validated estimates of the C-statistic, a measure of discrimination, of candidate models including 2 or 3 analytes in addition to age. RESULTS: All but one analyte decreased from baseline to week 8 (all p < 0.01). Individual biomarkers were not associated with 8 week culture status. Logistic models including increasing age, higher baseline soluble tumor necrosis factor receptor alpha 1 (sTNF-R1), and higher week 8 C-reactive protein (CRP) concentration classified subjects by culture status with up to 85% accuracy and acceptable discrimination (cross-validated C-statistic 0.76) and calibration (Hosmer-Lemeshow P > 0.2). CONCLUSION: Exploratory post-hoc models including sTNF-R1, CRP, and age, classified 8 week culture status with promising accuracy. |
Daily rifapentine for treatment of pulmonary tuberculosis. A randomized, dose-ranging trial
Dorman SE , Savic RM , Goldberg S , Stout JE , Schluger N , Muzanyi G , Johnson JL , Nahid P , Hecker EJ , Heilig CM , Bozeman L , Feng PJ , Moro RN , MacKenzie W , Dooley KE , Nuermberger EL , Vernon A , Weiner M . Am J Respir Crit Care Med 2015 191 (3) 333-43 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). |
Trends in gestational weight gain: the Pregnancy Risk Assessment Monitoring System, 2000-2009
Johnson JL , Farr SL , Dietz PM , Sharma AJ , Barfield WD , Robbins CL . Am J Obstet Gynecol 2015 212 (6) 806 e1-8 OBJECTIVE: Achieving adequate gestational weight gain is important for optimal health of the infant and mother. We estimate current population-based trends of gestational weight gain. STUDY DESIGN: We analyzed data from the Pregnancy Risk Assessment Monitoring System for 124,348 women who delivered live infants in 14 states during 2000-2009. We examined prevalence and trends in gestational weight gain in pounds as a continuous variable, and within 1990 Institute of Medicine recommendations (yes/no) as a dichotomous variable. We examined adjusted trends in mean gestational weight gain using multivariable linear regression and gestational weight gain within recommendations using multivariable multinomial logistic regression. RESULTS: During 2000-2009, 35.8% of women gained within Institute of Medicine gestational weight gain recommendations, 44.4% gained above, and 19.8% gained below. From 2000-2009, there was a biennial 1.0 percentage point decrease in women gaining within Institute of Medicine gestational weight gain recommendations (P-trend <.01) and a biennial 0.8 percentage point increase in women gaining above Institute of Medicine recommendations (P-trend <.01). The percentage of women gaining weight below Institute of Medicine recommendations remained relatively constant from 2000-2009 (P-trend= .14). The adjusted odds of gaining within Institute of Medicine recommendations were lower in 2006-2007 (aOR= 0.90, 95% CI: 0.85-0.96) and 2008-2009 (aOR=0.90, 95% CI: 0.85-0.96) relative to 2000-2001. CONCLUSION: Overall, from 2000-2009 the percentage of women gaining within Institute of Medicine recommendations slightly decreased while mean gestational weight gain slightly increased. Efforts are needed to develop and implement strategies to ensure that women achieve gestational weight gain within recommendations. |
What is the most reliable solid culture medium for tuberculosis treatment trials?
Joloba ML , Johnson JL , Feng PJ , Bozeman L , Goldberg SV , Morgan K , Gitta P , Boom HW , Heilig CM , Mayanja-Kizza H , Eisenach KD . Tuberculosis (Edinb) 2014 94 (3) 311-6 We conducted a prospective study to determine which solid medium is the most reliable overall and after two months of therapy to detect Mycobacterium tuberculosis complex (MTB). MTB isolation and contamination rates on LJ and Middlebrook 7H10 and 7H11 agar with and without selective antibiotics were examined in a single laboratory and compared against a constructed reference standard and MGIT 960 results. Of 50 smear positive adults with pulmonary TB enrolled, 45 successfully completed standard treatment. Two spot sputum specimens were collected before treatment and at week 8 and one spot specimen each at weeks 2, 4, 6, and 12. The MTB recovery rate among all solid media for pre-treatment specimens was similar. After 8 weeks, selective (S) 7H11 had the highest positivity rate. Latent class analysis was used to construct the primary reference standard. The 98.7% sensitivity of 7H11S (95% Wilson confidence interval 96.4%-99.6%) was highest among the 5 solid media (P = 0.003 by bootstrap); the 82.6% specificity of 7H10S (95% CI 75.7%-87.8%) was highest (P = 0.098). Our results support 7H11S as the medium of choice. Further studies in different areas where recovery and contamination are likely to vary, are recommended. |
How we determined the most reliable solid medium for studying treatment of tuberculosis
Heilig CM , Feng PJ , Joloba ML , Johnson JL , Morgan K , Gitta P , Boom WH , Mayanja-Kizza H , Eisenach KD , Bozeman L , Goldberg SV . Tuberculosis (Edinb) 2014 94 (3) 317-22 Phase 2 clinical trials for tuberculosis (TB) treatment require reliable culture methods to determine presence or absence of Mycobacterium tuberculosis (Mtb) over the course of therapy, as these trials are based primarily on bacteriological endpoints. We evaluate which of 5 solid media is most reliable: Lowenstein-Jensen (LJ) egg-base medium and 4 Middlebrook agar media (nonselective 7H10 and 7H11 and selective 7H10 and 7H11). We analyze 393 specimens from 50 HIV-negative Ugandan adults with newly-diagnosed, pulmonary TB and high acid-fast bacillus smear grade. Specimens were collected every 2-4 weeks during the first 12 weeks of therapy. We compare the results for each culture to 2 composite reference standards-one that was deemed positive if any solid culture was positive for Mtb and another based on latent-class analysis. Both reference standards established that the 2 selective Middlebrook media most reliably determine the presence or absence of Mtb (P < 0.003), largely because of their lower contamination rates. We also showed that results on Middlebrook media were similar to each other, while LJ was most frequently discordant. Contaminated results appeared more likely to be truly negative than to harbor undetected Mtb. |
Aptamer-based proteomic signature of intensive phase treatment response in pulmonary tuberculosis
Nahid P , Bliven-Sizemore E , Jarlsberg LG , De Groote MA , Johnson JL , Muzanyi G , Engle M , Weiner M , Janjic N , Sterling DG , Ochsner UA . Tuberculosis (Edinb) 2014 94 (3) 187-96 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 Ralpha, HSP70, Galectin-8, alpha2-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. |
Mycobacterium tuberculosis specific CD8(+) T cells rapidly decline with antituberculosis treatment
Nyendak MR , Park B , Null MD , Baseke J , Swarbrick G , Mayanja-Kizza H , Nsereko M , Johnson DF , Gitta P , Okwera A , Goldberg S , Bozeman L , Johnson JL , Boom WH , Lewinsohn DA , Lewinsohn DM . PLoS One 2013 8 (12) e81564 RATIONALE: Biomarkers associated with response to therapy in tuberculosis could have broad clinical utility. We postulated that the frequency of Mycobacterium tuberculosis (Mtb) specific CD8(+) T cells, by virtue of detecting intracellular infection, could be a surrogate marker of response to therapy and would decrease during effective antituberculosis treatment. OBJECTIVES: We sought to determine the relationship of Mtb specific CD4(+) T cells and CD8(+) T cells with duration of antituberculosis treatment. MATERIALS AND METHODS: We performed a prospective cohort study, enrolling between June 2008 and August 2010, of HIV-uninfected Ugandan adults (n = 50) with acid-fast bacillus smear-positive, culture confirmed pulmonary TB at the onset of antituberculosis treatment and the Mtb specific CD4(+) and CD8(+) T cell responses to ESAT-6 and CFP-10 were measured by IFN-gamma ELISPOT at enrollment, week 8 and 24. RESULTS: There was a significant difference in the Mtb specific CD8(+) T response, but not the CD4(+) T cell response, over 24 weeks of antituberculosis treatment (p<0.0001), with an early difference observed at 8 weeks of therapy (p = 0.023). At 24 weeks, the estimated Mtb specific CD8(+) T cell response decreased by 58%. In contrast, there was no significant difference in the Mtb specific CD4(+) T cell during the treatment. The Mtb specific CD4(+) T cell response, but not the CD8(+) response, was negatively impacted by the body mass index. CONCLUSIONS: Our data provide evidence that the Mtb specific CD8(+) T cell response declines with antituberculosis treatment and could be a surrogate marker of response to therapy. Additional research is needed to determine if the Mtb specific CD8(+) T cell response can detect early treatment failure, relapse, or to predict disease progression. |
The association between symptoms and microbiologically defined response to tuberculosis treatment
Hales CM , Heilig CM , Chaisson R , Leung CC , Chang KC , Goldberg SV , Gordin F , Johnson JL , Muzanyi G , Saukkonen J , Vernon A , Villarino ME , Burman WJ . Ann Am Thorac Soc 2013 10 (1) 18-25 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. |
Anti-tuberculosis treatment outcomes in HIV-infected adults exposed to isoniazid preventive therapy in Botswana
Sibanda T , Tedla Z , Nyirenda S , Agizew T , Marape M , Miranda AG , Reuter H , Johnson JL , Samandari T . Int J Tuberc Lung Dis 2013 17 (2) 178-85 SETTING: Eight public health clinics in Gaborone and Francistown, Botswana. OBJECTIVES: To describe the characteristics and outcomes of incident tuberculosis (TB) cases in human immunodeficiency virus (HIV) infected adults exposed to isoniazid preventive therapy (IPT) with access to antiretroviral and anti-tuberculosis treatment. DESIGN: In 1995 HIV-infected adults, TB disease was excluded before commencing IPT. During and after receipt of 6 or 36 months of IPT, symptomatic participants were evaluated using chest radiographs, sputum microscopy, cultures and drug susceptibility testing (DST). Incident TB cases received ≥6 months of anti-tuberculosis treatment. RESULTS: Seventy-five incident TB cases were identified among 619 symptomatic participants. The median duration of IPT in these cases was 6 months (range 1-35), and the median time to initiation of anti-tuberculosis treatment was 12 months after IPT cessation. Antiretroviral therapy (ART) was initiated before anti-tuberculosis treatment in 37 cases. Culture was positive in 43/58 (74%) TB cultures. DST was available for 38 cases, of which six (16%) were resistant to isoniazid (INH); 67/75 (89%) cases, including four with INH-monoresistant TB, completed anti-tuberculosis treatment or were cured. CONCLUSIONS: With prompt initiation of anti-tuberculosis treatment and access to ART, excellent outcomes were achieved in a public health setting in HIV-infected adults who developed TB disease. |
Substitution of rifapentine for rifampin during intensive phase treatment of pulmonary tuberculosis: study 29 of the Tuberculosis Trials Consortium
Dorman SE , Goldberg S , Stout JE , Muzanyi G , Johnson JL , Weiner M , Bozeman L , Heilig CM , Feng PJ , Moro R , Narita M , Nahid P , Ray S , Bates E , Haile B , Nuermberger EL , Vernon A , Schluger NW . J Infect Dis 2012 206 (7) 1030-1040 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. |
Effect of HIV infection on tolerability and bacteriologic outcomes of tuberculosis treatment
Bliven-Sizemore EE , Johnson JL , Goldberg S , Burman WJ , Villarino ME , Chaisson RE , Tuberculosis Clinical Trials Consortium . Int J Tuberc Lung Dis 2012 16 (4) 473-9 SETTING: Two international, multicenter Phase 2 clinical trials examining fluoroquinolone-containing regimens in adults with smear-positive pulmonary tuberculosis (TB), conducted from July 2003 to March 2007. Both trials enrolled human immunodeficiency virus (HIV) infected participants who were not receiving antiretroviral therapy (ART) at TB treatment initiation. OBJECTIVE: To assess the impact of HIV infection on TB treatment outcomes in Phase 2 clinical trials. DESIGN: Cross-protocol analysis comparing the safety, tolerability and outcomes of anti-tuberculosis treatment by HIV status. RESULTS: Of 750 participants who received at least one dose of study treatment, 123 (16%) were HIV-infected. Treatment completion rates were similar by HIV status (81% infected vs. 85% non-infected), as were rates of week 8 culture conversion (66% infected vs. 63% non-infected), and treatment failure (5% infected vs. 3% non-infected). Among HIV-infected participants, treatment failure detected using liquid media was more frequent in those treated thrice weekly (14% thrice weekly vs. 2% daily, P = 0.03). HIV-infected participants more frequently experienced an adverse event during the intensive phase treatment than non-HIV-infected participants (30% vs. 15%, P < 0.01). CONCLUSION: HIV-infected persons not receiving ART had more adverse events during the intensive phase of anti-tuberculosis treatment, but tolerated treatment well. Failure rates were higher among HIV-infected persons treated with thrice-weekly intensive phase therapy. |
Reasons for non-participation in an international multicenter trial of a new drug for tuberculosis treatment
Lamunu D , Chapman KN , Nsubuga P , Muzanyi G , Mulumba Y , Mugerwa MA , Goldberg S , Bozeman L , Engle M , Saukkonen J , Mastranunzio S , Mayanja-Kizza H , Johnson JL . Int J Tuberc Lung Dis 2012 16 (4) 480-485 SETTING: Clinical trials can provide a high standard of patient care and contribute to scientific knowledge; however, only a fraction of the patients screened participate and receive treatment as part of a trial. OBJECTIVE: To explore reasons why patients were not enrolled in an international tuberculosis (TB) treatment trial and to compare experiences among study sites. DESIGN: An analysis of reasons why patients were not enrolled was conducted among patients screened for a TB clinical trial at 26 sites in North and South America, Africa, and Europe. RESULTS: Staff at study sites screened 1119 potential candidates for the trial: 61% (n = 686) were not enrolled due to 1) failure to meet eligibility criteria (n = 405, 59%), 2) site's decision (n = 168, 24%), or 3) candidate's choice (n = 113, 16%). Study staff recorded a total of 144 reasons for why they believed patients chose not to participate, including concerns over research (28%), conflicts with work or school (21%), and life-style and family issues (20%). Socio-demographic and geographic factors also influenced participation. CONCLUSION: Increased evaluation of screening outcomes and of specific interventions, such as improved education and communication about trial procedures, may increase the efficiency of screening and enrollment in clinical trials. (2012 The Union.) |
Tuberculosis biomarker and surrogate endpoint research roadmap
Nahid P , Saukkonen J , Mac Kenzie WR , Johnson JL , Phillips PPJ , Andersen J , Bliven-Sizemore E , Belisle JT , Boom WH , Luetkemeyer A , Campbell TB , Eisenach KD , Hafner R , Lennox JL , Makhene M , Swindells S , Villarino ME , Weiner M , Benson C , Burman W . Am J Respir Crit Care Med 2011 184 (8) 972-979 The Centers for Disease Control and Prevention and National Institutes of Health convened a multidisciplinary meeting to discuss surrogate markers of treatment response in tuberculosis. The goals were to assess recent surrogate marker research and to provide specific recommendations for (1) the qualification and validation of biomarkers of treatment outcome; (2) the standardization of specimen and data collection for future clinical trials, including a minimum set of samples and collection time points; and (3) the creation of a specimen repository to support biomarker testing. This article summarizes these recommendations and provides a roadmap for their implementation. |
Geographic differences in time to culture conversion in liquid media: tuberculosis trials consortium study 28. Culture conversion is delayed in Africa
Mac Kenzie WR , Heilig CM , Bozeman L , Johnson JL , Muzanye G , Dunbar D , Jost KC Jr , Diem L , Metchock B , Eisenach K , Dorman S , Goldberg S . PLoS One 2011 6 (4) e18358 BACKGROUND: Tuberculosis Trials Consortium Study 28, was a double blind, randomized, placebo-controlled, phase 2 clinical trial examining smear positive pulmonary Mycobacterium tuberculosis. Over the course of intensive phase therapy, patients from African sites had substantially delayed and lower rates of culture conversion to negative in liquid media compared to non-African patients. We explored potential explanations of this finding. METHODS: In TBTC Study 28, protocol-correct patients (n = 328) provided spot sputum specimens for M. tuberculosis culture in liquid media, at baseline and weeks 2, 4, 6 and 8 of study therapy. We compared sputum culture conversion for African and non-African patients stratified by four baseline measures of disease severity: AFB smear quantification, extent of disease on chest radiograph, cavity size and the number of days to detection of M. tuberculosis in liquid media using the Kaplan-Meier product-limit method. We evaluated specimen processing and culture procedures used at 29 study laboratories serving 27 sites. RESULTS: African TB patients had more extensive disease at enrollment than non-African patients. However, African patients with the least disease by the 4 measures of disease severity had conversion rates on liquid media that were substantially lower than conversion rates in non-African patients with the greatest extent of disease. HIV infection, smoking and diabetes did not explain delayed conversion in Africa. Some inter-site variation in laboratory processing and culture procedures within accepted practice for clinical diagnostic laboratories was found. CONCLUSIONS: Compared with patients from non-African sites, African patients being treated for TB had delayed sputum culture conversion and lower sputum conversion rates in liquid media that were not explained by baseline severity of disease, HIV status, age, smoking, diabetes or race. Further investigation is warranted into whether modest variation in laboratory processes substantially influences the efficacy outcomes of phase 2 TB treatment trials or if other factors (e.g., nutrition, host response) are involved. TRIAL REGISTRATION: ClinicalTrials.gov NCT00144417. |
Evaluation of time to detection of Mycobacterium tuberculosis in broth culture as a determinant for end points in treatment trials
Weiner M , Prihoda TJ , Burman W , Johnson JL , Goldberg S , Padayatchi N , Duran P , Engle M , Muzanye G , Mugerwa RD , Sturm AW . J Clin Microbiol 2010 48 (12) 4370-6 Time to detection of Mycobacterium tuberculosis in broth culture was examined for utility as a treatment efficacy end point. Of 146 patients in a phase IIB trial, a decreased mean time to detection was found in 5 with treatment failure. Time to detection in an analysis-of-covariance model was associated with lung cavities, less intensive treatment, and differences in the bactericidal effects of treatment regimens. |
The effects of tuberculosis, race and human gene SLCO1B1 polymorphisms on rifampin concentrations
Weiner M , Peloquin C , Burman W , Luo CC , Engle M , Prihoda TJ , MacKenzie WR , Bliven-Sizemore E , Johnson JL , Vernon A . Antimicrob Agents Chemother 2010 54 (10) 4192-200 BACKGROUND: Rifampin has concentration-dependent activity against Mycobacterium tuberculosis. However marked inter-subject variation of rifampin concentrations occur. In this study, we evaluated rifampin pharmacokinetics in relation to tuberculosis, geographic region, race, and single nucleotide polymorphisms of human transporter genes SLCO1B1, SLCO1B3 and MDR1. MATERIALS & METHODS: Seventy-two adults with pulmonary tuberculosis from Africa, North America and Spain were evaluated during multi-drug intensive-phase therapy, and compared to 16 healthy controls from North America. RESULTS: Rifampin pharmacokinetics values were similar between tuberculosis patients versus controls (geometric mean [GM] area under the concentration-time curve (AUC0-24) 40.2 vs. 40.9 mcg*h/ml, P=.9). However in multivariable analyses, rifampin AUC0-24 was significantly affected by rifampin dosage (mg/kg), polymorphisms in the SLCO1B1 gene, and presence of tuberculosis by geographic region. Adjusted rifampin AUC0-24 was lowest in patients with tuberculosis from Africa compared to non-African patients or control subjects. Adjusted rifampin AUC0-24 was also 36% lower among participants with SLCO1B1 c.463CA versus c.463CC genotype (adjusted GM 29.8 vs. 46.7 mcg*h/ml, P=.001). Polymorphisms in the SLCO1B1 gene associated with lower rifampin exposure were more frequent among subjects of Black race. CONCLUSIONS: Marked inter-subject variation of rifampin AUC0-24 was observed, but means of AUC0-24 did not significantly vary between patients with tuberculosis and healthy controls. Lower rifampin exposure was associated with the polymorphism of the SLCO1B1 c.463C>A gene. When adjusted for patient mg/kg dosage and transporter gene polymorphisms, rifampin exposure was lower in patients with tuberculosis which suggests that additional absorption or metabolic processes affect rifampin exposure with tuberculosis disease. |
Effect of improving the quality of radiographic interpretation on the ability to predict pulmonary tuberculosis relapse
Stout JE , Kosinski AS , Hamilton CD , Goodman PC , Mosher A , Menzies D , Schluger N , Khan A , Johnson JL . Acad Radiol 2010 17 (2) 157-62 RATIONALE AND OBJECTIVES: Chest radiographic findings are important for diagnosis and management of tuberculosis. The reliability of these findings is therefore of interest. We sought to describe interobserver reliability of chest radiographic findings in pulmonary tuberculosis, and to understand how the reliability of these findings might affect the utility of radiographic findings in predicting tuberculosis relapse. MATERIALS AND METHODS: Three blinded readers independently reviewed chest radiographs from a randomly selected group of 10% of HIV-seronegative subjects participating in a tuberculosis treatment trial. The three readers then arrived at a fourth, consensus radiographic interpretation. RESULTS: A total of 241 films obtained from 99 patients were reviewed. Agreement among the independent readers was very good for the findings of bilateral disease (kappa = 0.71-0.86 among readers) and cavitation (kappa = 0.66-0.73). The original interpretation was reasonably sensitive and specific (compared to the consensus interpretation) for bilateral disease, but the sensitivity for cavity decreased from 81% for the 2-month film to 47% at end of treatment (P = 0.013). Substituting the consensus interpretation for the original interpretation increased the odds ratio for the association between cavitation on early chest radiograph and subsequent tuberculosis relapse from 4.97 to 8.97. CONCLUSION: Radiographic findings were reasonably reliable between independent reviewers and the original interpretations. The original investigators, who knew the patient's clinical course, were less likely to identify cavitation on the end of treatment chest radiograph. Improving the reliability of these findings could improve the utility of chest radiographs for predicting tuberculosis relapse. |
Substitution of moxifloxacin for isoniazid during intensive phase treatment of pulmonary tuberculosis
Dorman SE , Johnson JL , Goldberg S , Muzanye G , Padayatchi N , Bozeman L , Heilig CM , Bernardo J , Choudhri S , Grosset JH , Guy E , Guyadeen P , Leus MC , Maltas G , Menzies D , Nuermberger EL , Villarino M , Vernon A , Chaisson RE , Tuberculosis Trials Consortium . Am J Respir Crit Care Med 2009 180 (3) 273-80 RATIONALE: Moxifloxacin has potent activity against Mycobacterium tuberculosis in vitro and in a mouse model of antituberculosis (TB) chemotherapy, but data regarding its activity in humans are limited. OBJECTIVES: Our objective was to compare the antimicrobial activity and safety of moxifloxacin versus isoniazid during the first 8 weeks of combination therapy for pulmonary TB. METHODS: Adults with sputum smear-positive pulmonary TB were randomly assigned to receive either moxifloxacin 400 mg plus isoniazid placebo, or isoniazid 300 mg plus moxifloxacin placebo, administered 5 days/week for 8 weeks, in addition to rifampin, pyrazinamide, and ethambutol. All doses were directly observed. Sputum was collected for culture every 2 weeks. The primary outcome was negative sputum culture at completion of 8 weeks of treatment. MEASUREMENTS AND MAIN RESULTS: Of 433 participants enrolled, 328 were eligible for the primary efficacy analysis. Of these, 35 (11%) were HIV positive, 248 (76%) had cavitation on baseline chest radiograph, and 213 (65%) were enrolled at African sites. Negative cultures at Week 8 were observed in 90/164 (54.9%) participants in the isoniazid arm, and 99/164 (60.4%) in the moxifloxacin arm (P = 0.37). In multivariate analysis, cavitation and enrollment at an African site were associated with lower likelihood of Week-8 culture negativity. The proportion of participants who discontinued assigned treatment was 31/214 (14.5%) for the moxifloxacin group versus 22/205 (10.7%) for the isoniazid group (RR, 1.35; 95% CI, 0.81, 2.25). CONCLUSIONS: Substitution of moxifloxacin for isoniazid resulted in a small but statistically nonsignificant increase in Week-8 culture negativity. |
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