[Show abstract][Hide abstract] ABSTRACT: Rationale: Rifapentine has potent activity in mouse models of tuberculosis chemotherapy but its optimal dose and exposure in humans are unknown. Objective: 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 eight weeks (intensive phase), with isoniazid, pyrazinamide, and ethambutol. The primary tolerability endpoint was treatment discontinuation. The primary efficacy endpoint was negative sputum cultures at completion of intensive phase. Measurements and Main Results: 334 participants were enrolled. Percentages of participants discontinuing assigned treatment were significantly below the pre-specified rate of 30% for each arm (rifampin 12.9%; rifapentine 10, 15, or 20 mg/kg 5.7%, 6.2%, and 11.1%, respectively). 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. 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 registration information available at www.clinicaltrials.gov, ID NCT00694629.
Preview · Article · Dec 2014 · American Journal of Respiratory and Critical Care Medicine
[Show abstract][Hide abstract] ABSTRACT: Quantifying anti-tuberculosis drug concentrations in multinational trials currently requires collection of modest blood volumes, centrifugation, aliquoting of plasma, freezing, and keeping samples frozen during shipping. We prospectively enrolled healthy individuals into Tuberculosis Trials Consortium Study 29B, a Phase I dose escalation study of rifapentine, a rifamycin under evaluation in tuberculosis treatment trials. We developed a liquid chromatographic-tandem mass spectrometric (LC-MS/MS) method for quantification of rifapentine in whole blood from dried blood spots (DBS) to facilitate pharmacokinetic/pharmacodynamic analyses in trials. Paired plasma and whole blood samples were collected by venipuncture; whole blood was spotted on Whatman 903® cards. Methods were optimized for plasma and then validated for DBS. The analytical measuring range was 50 to 80,000 ng/ml in whole blood DBS. Analytes were stable on cards for 11 weeks with desiccant at room temperature protected from light. Method concordance for paired plasma and whole blood DBS samples was determined after correcting for participant hematocrit or population-based estimates of bias from Bland-Altman plots. The application of either correction factor resulted in excellent correlation between plasma and whole blood DBS (Passing-Bablok regression corrected for hematocrit; y=0.98x+356). Concentrations of rifapentine may be determined from whole blood DBS collected via venipuncture after normalization to account for dilutional effects of red blood cells; additional studies are focused on the application of this methodology to capillary blood collected by finger stick. Simplicity of processing, storage, shipping and low blood volume makes whole blood DBS attractive for rifapentine pharmacokinetic evaluations, especially in international and pediatric trials.
[Show abstract][Hide abstract] ABSTRACT: Background:
In a phase 3, randomized clinical trial (PREVENT TB) of 8053 people with latent tuberculosis infection, 12 once-weekly doses of rifapentine and isoniazid had good efficacy and tolerability. Children received higher rifapentine milligram per kilogram doses than adults. In the present pharmacokinetic study (a component of the PREVENT TB trial), rifapentine exposure was compared between children and adults.
Rifapentine doses in children ranged from 300 to 900 mg, and adults received 900 mg. Children who could not swallow tablets received crushed tablets. Sparse pharmacokinetic sampling was performed with 1 rifapentine concentration at 24 hours after drug administration (C24). Rifapentine area under concentration-time curve (AUC) was estimated from a nonlinear, mixed effects regression model (NLME).
There were 80 children (age: median, 4.5 years; range, 2-11 years) and 77 adults (age: median, 40 years; all ≥18 years) in the study. The geometric mean rifapentine milligram per kilogram dose was greater in children than in adults (children, 23 mg/kg; adults, 11 mg/kg). Rifapentine geometric mean AUC and C24 were 1.3-fold greater in children (all children combined) than in adults. Children who swallowed whole tablets had 1.3-fold higher geometric mean AUC than children who received crushed tablets, and children who swallowed whole tablets had a 1.6-fold higher geometric mean AUC than adults. The higher rifapentine doses in children were well tolerated. To obtain rifapentine exposures comparable in children to adults, dosing algorithms modeled by NLME were developed.
A 2-fold greater rifapentine dose for all children resulted in a 1.3-fold higher AUC compared to adults administered a standard dose. Use of higher weight-adjusted rifapentine doses for young children are warranted to achieve systemic exposures that are associated with successful treatment of latent tuberculosis infection in adults.
[Show abstract][Hide abstract] ABSTRACT: Rifapentine is highly protein bound in blood, but the free, unbound drug is the microbiologically active fraction. In this
exploratory study, we characterized the free plasma fraction of rifapentine in 41 patients with tuberculosis. We found a lower
total rifapentine concentration but significantly higher free rifapentine levels in African patients of black race compared
to non-Africans. These data support larger pharmacokinetic/pharmacodynamic studies to confirm these findings and assess free
rifapentine in relation to microbiological and clinical outcomes.
Full-text · Article · May 2014 · Antimicrobial Agents and Chemotherapy
[Show abstract][Hide abstract] ABSTRACT: Latent tuberculosis infection and tuberculosis disease are prevalent worldwide. However, antimycobacterial rifamycins have drug interactions with many antiretroviral drugs. We evaluated the effect of rifapentine on the pharmacokinetic properties of raltegravir.
In this open-label, fixed-sequence, three-period study, 21 healthy volunteers were given: raltegravir alone (400 mg every 12 h for 4 days) on days 1-4 of Period 1; rifapentine (900 mg once weekly for 3 weeks) on days 1, 8 and 15 of Period 2 and raltegravir (400 mg every 12 h for 4 days) on days 12-15 of Period 2; and rifapentine (600 mg once daily for 10 scheduled doses) on days 1, 4-8 and 11-14 of Period 3 and raltegravir (400 mg every 12 h for 4 days) on days 11-14 of Period 3. Plasma raltegravir concentrations were measured. ClinicalTrials.gov database: NCT00809718.
In 16 subjects who completed the study, coadministration of raltegravir with rifapentine (900 mg once weekly; Period 2) compared with raltegravir alone resulted in the geometric mean of the raltegravir AUC from 0 to 12 h (AUC0-12) being increased by 71%; the peak concentration increased by 89% and the trough concentration decreased by 12%. Coadministration of raltegravir with rifapentine in Period 3 did not change the geometric mean of the raltegravir AUC0-12 or the peak concentration, but it decreased the trough concentration by 41%. Raltegravir coadministered with rifapentine was generally well tolerated.
The increased raltegravir exposure observed with once-weekly rifapentine was safe and tolerable. Once-weekly rifapentine can be used with raltegravir to treat latent tuberculosis infection in patients who are infected with HIV.
No preview · Article · Dec 2013 · Journal of Antimicrobial Chemotherapy
[Show abstract][Hide abstract] ABSTRACT: A large randomized controlled trial recently showed that for treating latent tuberculous infection (LTBI) in persons at high risk of progression to tuberculosis (TB) disease, a 12-dose regimen of weekly rifapentine plus isoniazid (3HP) administered as directly observed treatment (DOT) can be as effective as 9 months of daily self-administered isoniazid (9H).
To assess the cost-effectiveness of 3HP compared to 9H.
A computational model was designed to simulate individuals with LTBI treated with 9H or 3HP. Costs and health outcomes were estimated to determine the incremental costs per active TB case prevented and per quality-adjusted life year (QALY) gained by 3HP compared to 9H.
Over a 20-year period, treatment of LTBI with 3HP rather than 9H resulted in 5.2 fewer cases of TB and 25 fewer lost QALYs per 1000 individuals treated. From the health system and societal perspectives, 3HP would cost respectively US21525 and 4294 more per TB case prevented, and respectively 4565 and 911 more per QALY gained.
3HP may be a cost-effective alternative to 9H, particularly if the cost of rifapentine decreases, the effectiveness of 3HP can be maintained without DOT, and 3HP treatment is limited to those with a high risk of progression to TB disease.
Full-text · Article · Dec 2013 · The International Journal of Tuberculosis and Lung Disease
[Show abstract][Hide abstract] ABSTRACT: Although the tuberculin skin test (TST) is frequently used to aid in the diagnosis of tuberculosis (TB) disease and to identify persons with latent TB infection, it is an imperfect test and approximately 10-25% of persons with microbiologically confirmed TB disease have a negative TST. Previous studies have suggested that persons with a negative TST are more likely to present with severe TB disease and have an increased rate of TB-related death.
We analyzed culture-confirmed TB cases captured in US TB surveillance data from 1993 to 2008 and performed multivariate logistic regression analysis to determine the association between TST result and death.
Of 284,866 cases of TB reported in the US, 58,180 persons were eligible for inclusion in the analysis and 3,270 of those persons died after initiating TB treatment. Persons with a negative TST accounted for only 14% of the eligible cases but accounted for 42% of the deaths. Persons with a TST≥15 mm had 67% lower odds of death than persons with a negative TST (adjusted odds ratio 0.33, 95% confidence interval 0.30-0.36).
A negative TST is associated with an increased risk of death among persons with culture-confirmed TB disease, even after adjustment for HIV status, site of TB disease, sputum smear AFB status, drug susceptibility, age, sex, and origin of birth. In addition to indicating risk of developing disease, the TST may also be a marker for increased risk of death.
[Show abstract][Hide abstract] ABSTRACT: The tuberculin skin test (TST) is used to test for latent tuberculosis (TB) infection and support the diagnosis of active TB. However, little is known about the relationship between the TST result and the clinical presentation of TB disease.
We analyzed US TB surveillance data, 1993--2010, and used multinomial logistic regression to calculate the association between TST result (0--4 mm [negative], 5--9 mm, 10--14 mm, and >= 15 mm) and clinical presentation of disease (miliary, combined pulmonary and extrapulmonary, extrapulmonary only, non-cavitary pulmonary, and cavitary pulmonary). For persons with pulmonary disease, multivariate logistic regression was used to calculate the odds of having acid-fast bacilli (AFB) positive sputum.
There were 64,238 persons with culture-confirmed TB included in the analysis, which was stratified by HIV status and birthplace (US- vs. foreign-born). Persons with a TST >= 15 mm were less likely to have miliary or combined pulmonary and extrapulmonary disease, but more likely to have cavitary pulmonary disease than non-cavitary pulmonary disease. Persons with non-cavitary pulmonary disease with a negative TST were significantly more likely to have AFB positive sputum.
Clinical presentation of TB disease differed according to TST result and persons with a negative TST were more likely to have disseminated disease (i.e., miliary or combined pulmonary and extrapulmonary). Further study of the TST result may improve our understanding of the host-pathogen relationship in TB disease.
Full-text · Article · Oct 2013 · BMC Infectious Diseases
[Show abstract][Hide abstract] ABSTRACT: Mycobacterium tuberculosis comprises four principal genetic lineages: one evolutionarily ancestral (Indo-Oceanic) and three modern. Whether response to tuberculosis (TB) treatment differs among the lineages is unknown.
To examine the association between M. tuberculosis lineage and time to sputum culture conversion in response to standard first-line drug therapy.
We conducted an exploratory retrospective cohort analysis of time to sputum culture conversion among pulmonary tuberculosis (PTB) cases reported in the United States from 2004 to 2007.
The analysis included 13 170 PTB cases with no documented resistance to first-line drugs who received a standard four-drug treatment regimen. Among cases with baseline positive sputum smear results, relative to cases with Euro-American lineage, cases with Indo-Oceanic lineage had higher adjusted hazards of sputum culture conversion (aHR 1.32, 95%CI 1.20-1.45), whereas cases with East-African-Indian or East-Asian lineage did not differ (aHR 1.05, 95%CI 0.88-1.25 and aHR 0.99, 95%CI 0.91-1.07, respectively). Among cases with baseline negative sputum smear results, time to sputum culture conversion did not differ by lineage.
Although these results are exploratory, they suggest that the eradication of viable bacteria may occur sooner among cases with Indo-Oceanic lineage than among those with one of the three modern lineages. Prospective studies of time to sputum culture conversion by lineage are required.
Full-text · Article · Jul 2013 · The International Journal of Tuberculosis and Lung Disease
[Show abstract][Hide abstract] ABSTRACT: The ultimate goal of evidence-based drug treatment is to produce a desired pharmacological response in a predictable manner and also to minimise adverse effects. This goal requires not only an increased awareness of the need to provide specific dosing recommendations aimed at specific patient groups, but also the implementation of a consistent integrative approach to recognise all factors contributing to the within- and between-subject variability in drug disposition and response. The assessment of new anti-tuberculosis agents and regimens in children requires a specific programme of investigation, and should be included early in human drug evaluation programmes. Appreciation of this principle is an important step forward towards the full integration of children into the tuberculosis research agenda and control programmes. The development of anti-tuberculosis drug formulations and regimens tailored to the requirements of children needs to consider physiological age-related differences for pharmacokinetics and toxicity between adults and children. Research based on these principles will create an evidence base that will inform the appropriate treatment of children with novel agents and regimens and will also inform future research, including the use of chemoprophylaxis and treatment-shortening strategies in children.
No preview · Article · Jun 2013 · The International Journal of Tuberculosis and Lung Disease
[Show abstract][Hide abstract] ABSTRACT: The treatment of multidrug-resistant tuberculosis (MDR-TB) is currently based upon expert opinion and findings from case series, rather than upon randomised clinical trials (RCTs).
To describe the challenges encountered during an RCT for the treatment of MDR-TB.
Tuberculosis Trials Consortium Study 30 was a pilot, Phase I/II, double-blind, placebo-controlled, RCT of the safety and tolerability of 16 weeks of daily, low-dose linezolid treatment for MDR-TB.
A total of 36 patients, 56% of the target of 64 patients, consented to participate, for an average of 0.69 enrolments per week. Of the 36 patients enrolled, only 25 (69%) completed at least 90 doses of study treatment. Among the 12 (33%) patients who did not complete all 112 doses of the study treatment, the median time to study withdrawal was 15 days (range 0-92). After the study, we discovered discordance between treatment assignment and study drug for at least 9 (25%) of the 36 patients.
Recruitment and retention in this MDR-TB clinical trial posed substantial challenges, suggesting the need for a large, multidisciplinary group of study staff to support the participants. Withdrawal tended to occur early in study treatment. The discrepancy in assigned study medication reflects the need for stronger administrative controls for study drugs.
Full-text · Article · Dec 2012 · The International Journal of Tuberculosis and Lung Disease
[Show abstract][Hide abstract] ABSTRACT: Despite the important role of fluoroquinolones and the predominant use of ofloxacin for treating multidrug-resistant tuberculosis in South Africa, there are limited data on ofloxacin pharmacokinetics in patients with multidrug-resistant tuberculosis, no ofloxacin pharmacokinetic data from South African patients, and no direct assessment of the relationship between ofloxacin pharmacokinetics and the MIC of ofloxacin of patient isolates. Our objectives are to describe ofloxacin pharmacokinetics in South African patients being treated for multidrug-resistant tuberculosis and assess the adequacy of ofloxacin drug exposure with respect to the probability of pharmacodynamic target attainment (area under the time curve/MIC ratio of at least 100). Sixty-five patients with multidrug-resistant tuberculosis were recruited from 2 hospitals in South Africa. We determined the ofloxacin MICs for the Mycobacterium tuberculosis isolates from baseline sputum specimens. Patients received daily doses of 800 mg ofloxacin, in addition to other antitubercular drugs. Patients underwent pharmacokinetic sampling at steady state. NONMEM was used for data analysis. The population pharmacokinetics of ofloxacin in this study has been adequately described. The probability of target attainment expectation in the study population was 0.45. Doubling the dose to 1,600 mg could increase this to only 0.77. The currently recommended ofloxacin dose appeared inadequate for the majority of this study population. Studies to assess the tolerability of higher doses are warranted. Alternatively, ofloxacin should be replaced with more potent fluoroquinolones.
Full-text · Article · May 2012 · Antimicrobial Agents and Chemotherapy
[Show abstract][Hide abstract] ABSTRACT: Although seasonal variation in tuberculosis incidence has been described in several recent studies, the mechanism underlying this seasonality remains unknown. Seasonality of tuberculosis disease may indicate the presence of season-specific risk factors that could potentially be controlled if they were better understood. We conducted this study to determine whether tuberculosis is seasonal in the United States and to describe patterns of seasonality in specific populations.
We performed a time series decomposition analysis of tuberculosis cases reported to the Centers for Disease Control and Prevention from 1993 through 2008. Seasonal amplitude of tuberculosis disease (the difference between the months with the highest and lowest mean case counts), was calculated for the population as a whole and for populations with select demographic, clinical, and epidemiologic characteristics.
A total of 243 432 laboratory-confirmed tuberculosis cases were reported over a period of 16 years. A mean of 21.4% more cases were diagnosed in March, the peak month, compared with November, the trough month. The magnitude of seasonality did not vary with latitude. The greatest seasonal amplitude was found among children aged <5 years and in cases associated with disease clusters.
Tuberculosis is a seasonal disease in the United States, with a peak in spring and trough in late fall. The latitude independence of seasonality suggests that reduced winter sunlight exposure may not be a strong contributor to tuberculosis risk. Increased seasonality among young children and clustered cases suggests that disease that is the result of recent transmission is more influenced by season than disease resulting from activation of latent infection.
[Show abstract][Hide abstract] ABSTRACT: Since 1953, through the cooperation of state and local health departments, the U.S. Centers for Disease Control and Prevention (CDC) has collected information on incident cases of tuberculosis (TB) disease in the United States. In 2009, TB case rates declined -11.4%, compared to an average annual -3.8% decline since 2000. The unexpectedly large decline raised concerns that TB cases may have gone unreported. To address the unexpected decline, we examined trends from multiple sources on TB treatment initiation, medication sales, and laboratory and genotyping data on culture-positive TB.
We analyzed 142,174 incident TB cases reported to the U. S. National Tuberculosis Surveillance System (NTSS) during January 1, 2000-December 31, 2009; TB control program data from 59 public health reporting areas; self-reported data from 50 CDC-funded public health laboratories; monthly electronic prescription claims for new TB therapy prescriptions; and complete genotyping results available for NTSS cases. Accounting for prior trends using regression and time-series analyses, we calculated the deviation between observed and expected TB cases in 2009 according to patient and clinical characteristics, and assessed at what point in time the deviation occurred.
The overall deviation in TB cases in 2009 was -7.9%, with -994 fewer cases reported than expected (P < .001). We ruled out evidence of surveillance underreporting since declines were seen in states that used new software for case reporting in 2009 as well as states that did not, and we found no cases unreported to CDC in our examination of over 5400 individual line-listed reports in 11 areas. TB cases decreased substantially among both foreign-born and U.S.-born persons. The unexpected decline began in late 2008 or early 2009, and may have begun to reverse in late 2009. The decline was greater in terms of case counts among foreign-born than U.S.-born persons; among the foreign-born, the declines were greatest in terms of percentage deviation from expected among persons who had been in the United States less than 2 years. Among U.S.-born persons, the declines in percentage deviation from expected were greatest among homeless persons and substance users. Independent information systems (NTSS, TB prescription claims, and public health laboratories) reported similar patterns of declines. Genotyping data did not suggest sudden decreases in recent transmission.
Our assessments show that the decline in reported TB was not an artifact of changes in surveillance methods; rather, similar declines were found through multiple data sources. While the steady decline of TB cases before 2009 suggests ongoing improvement in TB control, we were not able to identify any substantial change in TB control activities or TB transmission that would account for the abrupt decline in 2009. It is possible that other multiple causes coincident with economic recession in the United States, including decreased immigration and delayed access to medical care, could be related to TB declines. Our findings underscore important needs in addressing health disparities as we move towards TB elimination in the United States.
Full-text · Article · Nov 2011 · BMC Public Health
[Show abstract][Hide abstract] ABSTRACT: 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 ofa specimen repository to support biomarker testing. This article summarizes these recommendations and provides a roadmap for their implementation.
Full-text · Article · Jul 2011 · American Journal of Respiratory and Critical Care Medicine
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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.
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.