Last data update: Sep 23, 2024. (Total: 47723 publications since 2009)
Records 1-4 (of 4 Records) |
Query Trace: Velasquez GE [original query] |
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Pyrazinamide safety, efficacy, and dosing for treating drug-susceptible pulmonary tuberculosis: A phase 3, randomized, controlled clinical trial
Xu AY , Velásquez GE , Zhang N , Chang VK , Phillips PP , Nahid P , Dorman SE , Kurbatova EV , Whitworth WC , Sizemore E , Bryant K , Carr W , Brown NE , Engle ML , Nhung NV , Nsubuga P , Diacon A , Dooley KE , Chaisson RE , Swindells S , Savic RM . Am J Respir Crit Care Med 2024 RATIONALE: Optimizing pyrazinamide dosing is critical to improve treatment efficacy while minimizing toxicity during tuberculosis treatment. Study 31/ACTG A5349 represents the largest Phase 3 randomized controlled therapeutic trial to date for such investigation. OBJECTIVES: We sought to report pyrazinamide pharmacokinetic parameters, risk factors for lower pyrazinamide exposure, and relationships between pyrazinamide exposure with efficacy and safety outcomes. We aimed to determine pyrazinamide dosing strategies that optimize risks and benefits. METHODS: We analyzed pyrazinamide steady-state pharmacokinetic data using population nonlinear mixed-effects models. We evaluated the contribution of pyrazinamide exposure to long-term efficacy using parametric time-to-event models and safety outcomes using logistic regression. We evaluated optimal dosing with therapeutic windows targeting ≥95% durable cure and safety within the observed proportion of the primary safety outcome. MEASUREMENTS AND MAIN RESULTS: Among 2255 participants with 6978 plasma samples, pyrazinamide displayed 7-fold exposure variability (151-1053 mg·h/L). Body weight was not a clinically relevant predictor of drug clearance and thus did not justify the need for weight-banded dosing. Both clinical and safety outcomes were associated with pyrazinamide exposure, resulting in a therapeutic window of 231-355 mg·h/L for the control and 226-349 mg·h/L for the rifapentine-moxifloxacin regimen. Flat dosing of pyrazinamide at 1000 mg would have permitted an additional 13.1% (n=96) participants allocated to the control and 9.2% (n=70) to the rifapentine-moxifloxacin regimen dosed within the therapeutic window, compared to the current weight-banded dosing. CONCLUSIONS: Flat dosing of pyrazinamide at 1000 mg daily would be readily implementable and could optimize treatment outcomes in drug-susceptible tuberculosis. Clinical trial registration available at www. CLINICALTRIALS: gov, ID: NCT02410772. |
Pharmacokinetic-pharmacodynamic evidence from a phase 3 trial to support flat-dosing of rifampicin for tuberculosis
Ngo HX , Xu AY , Velásquez GE , Zhang N , Chang VK , Kurbatova EV , Whitworth WC , Sizemore E , Bryant K , Carr W , Weiner M , Dooley KE , Engle M , Dorman SE , Nahid P , Swindells S , Chaisson RE , Nsubuga P , Lourens M , Dawson R , Savic RM . Clin Infect Dis 2024 BACKGROUND: The optimal dosing strategy for rifampicin in treating drug-susceptible tuberculosis (TB) is still highly debated. In the Phase 3 clinical trial Study 31/ACTG 5349 (NCT02410772), all participants in the control regimen arm received 600 mg rifampicin daily as a flat dose. Here, we evaluated relationships between rifampicin exposure and efficacy and safety outcomes. METHODS: We analyzed rifampicin concentration time profiles using population nonlinear mixed-effects models. We compared simulated rifampicin exposure from flat- and weight-banded dosing. We evaluated the effect of rifampicin exposure on stable culture conversion at 6 months, TB-related unfavorable outcomes at 9, 12, and 18 months using Cox proportional hazard models, and all trial-defined safety outcomes using logistic regression. RESULTS: Our model derived rifampicin exposure ranged from 4.57 mg·h/L to 140.0 mg·h/L with a median of 41.8 mg·h/L. Pharmacokinetic simulations demonstrated that flat-dosed rifampicin provided exposure coverage similar to weight-banded dose. Exposure-efficacy analysis (N=680) showed that participants with rifampicin exposure below the median experienced similar hazards of stable culture conversion and TB-related unfavorable outcomes compared to those with exposure above the median. Exposure-safety analysis (N=722) showed that increased rifampicin exposure was not associated with increased grade 3 or higher adverse events, or serious adverse events. CONCLUSIONS: Flat-dosing of rifampicin at 600 mg daily may be a reasonable alternative to the incumbent weight-banded dosing strategy for the standard of care 6-month regimen. Future research should assess the optimal dosing strategy for rifampicin, at doses higher than the current recommendation. |
Impact of HIV on mortality among patients treated for tuberculosis in Lima, Peru: a prospective cohort study
Velasquez GE , Cegielski JP , Murray MB , Yagui MJ , Asencios LL , Bayona JN , Bonilla CA , Jave HO , Yale G , Suarez CZ , Sanchez E , Rojas C , Atwood SS , Contreras CC , Cruz JS , Shin SS . BMC Infect Dis 2016 16 (1) 45 BACKGROUND: Human immunodeficiency virus (HIV)-associated tuberculosis deaths have decreased worldwide over the past decade. We sought to evaluate the effect of HIV status on tuberculosis mortality among patients undergoing treatment for tuberculosis in Lima, Peru, a low HIV prevalence setting. METHODS: We conducted a prospective cohort study of patients treated for tuberculosis between 2005 and 2008 in two adjacent health regions in Lima, Peru (Lima Ciudad and Lima Este). We constructed a multivariate Cox proportional hazards model to evaluate the effect of HIV status on mortality during tuberculosis treatment. RESULTS: Of 1701 participants treated for tuberculosis, 136 (8.0 %) died during tuberculosis treatment. HIV-positive patients constituted 11.0 % of the cohort and contributed to 34.6 % of all deaths. HIV-positive patients were significantly more likely to die (25.1 vs. 5.9 %, P < 0.001) and less likely to be cured (28.3 vs. 39.4 %, P = 0.003). On multivariate analysis, positive HIV status (hazard ratio [HR] = 6.06; 95 % confidence interval [CI], 3.96-9.27), unemployment (HR = 2.24; 95 % CI, 1.55-3.25), and sputum acid-fast bacilli smear positivity (HR = 1.91; 95 % CI, 1.10-3.31) were significantly associated with a higher hazard of death. CONCLUSIONS: We demonstrate that positive HIV status was a strong predictor of mortality among patients treated for tuberculosis in the early years after Peru started providing free antiretroviral therapy. As HIV diagnosis and antiretroviral therapy provision are more widely implemented for tuberculosis patients in Peru, future operational research should document the changing profile of HIV-associated tuberculosis mortality. |
Targeted drug-resistance testing strategy for multidrug-resistant tuberculosis detection, Lima, Peru, 2005-2008
Velasquez GE , Yagui M , Cegielski JP , Asencios L , Bayona J , Bonilla C , Jave HO , Yale G , Susrez C , Atwood S , Contreras CC , Shin SS . Emerg Infect Dis 2011 17 (3) 432-440 The Peruvian National Tuberculosis Control Program issued guidelines in 2006 specifying criteria for culture and drug-susceptibility testing (DST), including district-level rapid DST. All patients referred for culture and DST in 2 districts of Lima, Peru, during January 2005-November 2008 were monitored prospectively. Of 1,846 patients, 1,241 (67.2%) had complete DST results for isoniazid and rifampin; 419 (33.8%) patients had multidrug-resistant (MDR) TB at the time of referral. Among patients with new smear-positive TB, household contact and suspected category I failure were associated with MDR TB, compared with concurrent regional surveillance data. Among previously treated patients with smear-positive TB, adult household contact, suspected category II failure, early relapse after category I, and multiple previous TB treatments were associated with MDR TB, compared with concurrent regional surveillance data. The proportion of MDR TB detected by using guidelines was higher than that detected by a concurrent national drug-resistance survey, indicating that the strategy effectively identified patients for DST. |
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