The Phase 3 randomized controlled trial, TBTC Study 31/ACTG A5349 (NCT02410772) demonstrated that a 4-month rifapentine-moxifloxacin regimen for drug-susceptible pulmonary tuberculosis was safe and effective. The primary efficacy outcome was 12-month tuberculosis disease free survival, while the primary safety outcome was the proportion of grade 3 or higher adverse events during the treatment period. We conducted an analysis of demographic, clinical, microbiologic, radiographic, and pharmacokinetic data and identified risk factors for unfavorable outcomes and adverse events. Among participants receiving the rifapentine-moxifloxacin regimen, low rifapentine exposure is the strongest driver of tuberculosis-related unfavorable outcomes (HR 0.65 for every 100 µg∙h/mL increase, 95%CI 0.54-0.77). The only other risk factors identified are markers of higher baseline disease severity, namely Xpert MTB/RIF cycle threshold and extent of disease on baseline chest radiography (Xpert: HR 1.43 for every 3-cycle-threshold decrease, 95%CI 1.07-1.91; extensive disease: HR 2.02, 95%CI 1.07-3.82). From these risk factors, we developed a simple risk stratification to classify disease phenotypes as easier-, moderately-harder, or harder-to-treat TB. Notably, high rifapentine exposures are not associated with any predefined adverse safety outcomes. Our results suggest that the easier-to-treat subgroup may be eligible for further treatment shortening while the harder-to-treat subgroup may need higher doses or longer treatment.

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.

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.

Sierra Leone is vulnerable to a wide range of vector-borne diseases transmitted by mosquitoes, tsetse flies, black flies, and other vectors. Malaria, lymphatic filariasis, and onchocerciasis have posed the greatest threat and have received the most attention in terms of vector control and capacity for diagnosis. However, malaria infection rates remain high, and there is evidence of circulation of other vector-borne diseases, such as chikungunya and dengue, which may go undiagnosed and unreported. The limited understanding of the prevalence and transmission of these diseases restricts the capacity for predicting outbreaks, and impedes the planning of appropriate responses. We review the available literature and gather expert opinions from those working in the country to report on the status of vector-borne disease transmission and control in Sierra Leone, and present an assessment of the threats of these diseases. Our discussions highlight an absence of entomological testing for disease agents and the need for more investment in surveillance and capacity strengthening.

Results from sampling healthcare surfaces for pathogens are difficult to interpret without understanding the factors that influence pathogen detection. We investigated the recovery of four healthcare-associated pathogens from three common surface materials, and how a body fluid simulant (artificial test soil, ATS), deposition method, and contamination levels influence the percent of organisms recovered (%R). Known quantities of carbapenemase-producing KPC+ Klebsiella pneumoniae (KPC), Acinetobacter baumannii, vancomycin-resistant Enterococcus faecalis, and Clostridioides difficile spores (CD) were suspended in Butterfield's buffer or ATS, deposited on 323cm2 steel, plastic, and laminate surfaces, allowed to dry 1h, then sampled with a cellulose sponge wipe. Bacteria were eluted, cultured, CFU counted and %R determined relative to the inoculum. The %R varied by organism, from <1% (KPC) to almost 60% (CD) and was more dependent upon the organism's characteristics and presence of ATS than on surface type. KPC persistence as determined by culture also declined by >1 log10 within the 60 min drying time. For all organisms, the %R was significantly greater if suspended in ATS than if suspended in Butterfield's buffer (p<0.05), and for most organisms the %R was not significantly different when sampled from any of the three surfaces. Organisms deposited in multiple droplets were recovered at equal or higher %R than if spread evenly on the surface. This work assists in interpreting data collected while investigating a healthcare infection outbreak or while conducting infection intervention studies.

In August 2017, after Hurricane Harvey made landfall, almost 52 inches of rain fell during a three-day period along the Gulf Coast Region of Texas, including Harris County, where Houston is located. Harris County was heavily impacted with over 177,000 homes and buildings (approximately 12 percent of all buildings in the county) experiencing flooding. The objective of this study was to measure 13 heavy metals in soil in residential areas and to assess cancer and non-cancer risk for children and adults after floodwaters receded. Between September and November 2017, we collected 174 surface soil samples in 10 communities, which were classified as "High Environmental Impact" or "Low Environmental Impact" communities, based on a composite metric of six environmental parameters. A second campaign was conducted between May 2019 and July 2019 when additional 204 soil samples were collected. Concentrations of metals at both sampling campaigns were higher in High Environmental Impact communities than in Low Environmental Impact communities and there was little change in metal levels between the two sampling periods. The Pollution Indices of lead (Pb), zinc, copper, nickel, and manganese in High Environmental Impact communities were significantly higher than those in Low Environmental Impact communities. Further, cancer risk estimates in three communities for arsenic through soil ingestion were greater than 1 in 1,000,000. Although average soil Pb was lower than the benchmark of the United States Environmental Protection Agency, the hazard indices for non-cancer outcomes in three communities, mostly attributed to Pb, were greater than 1. Health risk estimates for children living in these communities were greater than those for adults.

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.

OBJECTIVES: In December 2020, CDC launched the Pharmacy Partnership for Long-Term Care Program to facilitate COVID-19 vaccination of residents and staff in long-term care facilities (LTCFs), including assisted living (AL) and other residential care (RC) communities. We aimed to assess vaccine uptake in these communities and identify characteristics that might impact uptake. DESIGN: Cross-sectional study. SETTING AND PARTICIPANTS: AL/RC communities in the Pharmacy Partnership for Long-Term Care Program that had ≥1 on-site vaccination clinic during December 18, 2020-April 21, 2021. METHODS: We estimated uptake by using the cumulative number of doses of COVID-19 vaccine administered and normalizing by the number of AL/RC community beds. We estimated the percentage of residents vaccinated in 3 states using AL census counts. We linked community vaccine administration data with county-level social vulnerability index (SVI) measures to calculate median vaccine uptake by SVI tertile. RESULTS: In AL communities, a median of 67 residents [interquartile range (IQR): 48-90] and 32 staff members (IQR: 15-60) per 100 beds received a first dose of COVID-19 vaccine at the first on-site clinic; in RC, a median of 8 residents (IQR: 5-10) and 5 staff members (IQR: 2-12) per 10 beds received a first dose. Among 3 states with available AL resident census data, median resident first-dose uptake at the first clinic was 93% (IQR: 85-108) in Connecticut, 85% in Georgia (IQR: 70-102), and 78% (IQR: 56-91) in Tennessee. Among both residents and staff, cumulative first-dose vaccine uptake increased with increasing social vulnerability related to housing type and transportation. CONCLUSIONS AND IMPLICATIONS: COVID-19 vaccination of residents and staff in LTCFs is a public health priority. On-site clinics may help to increase vaccine uptake, particularly when transportation may be a barrier. Ensuring steady access to COVID-19 vaccine in LTCFs following the conclusion of the Pharmacy Partnership is critical to maintaining high vaccination coverage among residents and staff.

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.

INTRODUCTION: With the growing use of online study management systems and rapid availability of data, timely data review and quality assessments are necessary to ensure proper clinical trial implementation. In this report we describe central monitoring used to ensure protocol compliance and accurate data reporting, implemented during a large phase 3 clinical trial. MATERIAL AND METHODS: The Tuberculosis Trials Consortium (TBTC) Study 31/AIDS Clinical Trials Group (ACTG) study A5349 (S31) is an international, multi-site, randomized, open-label, controlled, non-inferiority phase 3 clinical trial comparing two 4-month regimens to a standard 6 month regimen for treatment of drug-susceptible tuberculosis (TB) among adolescents and adults with a sample size of 2500 participants. RESULTS: Central monitoring utilized primary study data in a five-tiered approach, including (1) real-time data checks & topic-specific intervention reports, (2) missing forms reports, (3) quality assurance metrics, (4) critical data reports and (5) protocol deviation identification, aimed to detect and resolve quality challenges. Over the course of the study, 240 data checks and reports were programed across the five tiers used. DISCUSSION: This use of primary study data to identify issues rapidly allowed the study sponsor to focus quality assurance and data cleaning activities on prioritized data, related to protocol compliance and accurate reporting of study results. Our approach enabled us to become more efficient and effective as we informed sites about deviations, resolved missing or inconsistent data, provided targeted guidance, and gained a deeper understanding of challenges experienced at clinical trial sites. TRIAL REGISTRATION: This trial was registered with ClinicalTrials.gov (Identifier: NCT02410772) on April 8, 2015.

Pyrazinamide is a potent sterilising agent that shortens the treatment duration needed to cure tuberculosis. It is synergistic with novel and existing drugs for tuberculosis. The dose of pyrazinamide that optimises efficacy while remaining safe is uncertain, as is its potential role in shortening treatment duration further.Pharmacokinetic data, sputum culture, and safety laboratory results were compiled from TBTC Studies 27 and 28 and PanACEA MAMS-TB, multi-center Phase 2 trials in which participants received rifampicin (range 10-35 mg·kg(-1)), pyrazinamide (range 20-30 mg·kg(-1)), plus two companion drugs. Pyrazinamide pharmacokinetic-pharmacodynamic (PK/PD) and PK-toxicity analyses were performed.In TBTC studies (n=77), higher pyrazinamide maximum concentration (Cmax) was associated with shorter time to culture conversion (TTCC) and higher probability of two-month culture conversion (p-value<0.001). Parametric survival analyses showed that relationships varied geographically, with steeper PK-PD relationships seen among non-African than African participants. In PanACEA MAMS-TB (n=363), TTCC decreased as pyrazinamide Cmax increased and varied by rifampicin Cmax (p-value<0.01). Modeling and simulation suggested that very high doses of pyrazinamide (>4500 mg) or increasing both pyrazinamide and rifampicin would be required to reach targets associated with treatment shortening. Combining all trials, liver toxicity was rare (3.9% with Grade 3 or higher liver function tests, LFT), and no relationship was seen between pyrazinamide Cmax and LFT levels.Pyrazinamide's microbiologic efficacy increases with increasing drug concentrations. Optimising pyrazinamide alone, though, is unlikely to be sufficient to allow tuberculosis treatment shortening; rather, rifampicin dose would need to be increased in parallel.

Existing human papillomavirus (HPV) vaccines are highly effective for prevention of HPV infection, the leading cause of cervical cancer and a significant cause of many other oral and anogenital cancers [1]. World Health Organization (WHO) has recommended including HPV vaccination of girls in national immunization programs since 2009 [2] and, in 2018, WHO’s Strategic Advisory Group of Experts (SAGE) on Immunization agreed that vaccination is the most critical intervention for cervical cancer elimination [3]. As of May 2020, 41% of low-and-middle income countries and 81% of high-income countries had introduced HPV vaccination [4]. Whilst a number of barriers exist to HPV vaccination programs, the worldwide HPV vaccine shortage is a current obstacle due to increasing demand. Expanding production capacity will take several years [5].

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.

The coronavirus disease 2019 (COVID-19) pandemic has highlighted the vulnerability of residents and staff members in long-term care facilities (LTCFs) (1). Although skilled nursing facilities (SNFs) certified by the Centers for Medicare & Medicaid Services (CMS) have federal COVID-19 reporting requirements, national surveillance data are less readily available for other types of LTCFs, such as assisted living facilities (ALFs) and those providing similar residential care. However, many state and territorial health departments publicly report COVID-19 surveillance data across various types of LTCFs. These data were systematically retrieved from health department websites to characterize COVID-19 cases and deaths in ALF residents and staff members. Limited ALF COVID-19 data were available for 39 states, although reporting varied. By October 15, 2020, among 28,623 ALFs, 6,440 (22%) had at least one COVID-19 case among residents or staff members. Among the states with available data, the proportion of COVID-19 cases that were fatal was 21.2% for ALF residents, 0.3% for ALF staff members, and 2.5% overall for the general population of these states. To prevent the introduction and spread of SARS-CoV-2, the virus that causes COVID-19, in their facilities, ALFs should 1) identify a point of contact at the local health department; 2) educate residents, families, and staff members about COVID-19; 3) have a plan for visitor and staff member restrictions; 4) encourage social (physical) distancing and the use of masks, as appropriate; 5) implement recommended infection prevention and control practices and provide access to supplies; 6) rapidly identify and properly respond to suspected or confirmed COVID-19 cases in residents and staff members; and 7) conduct surveillance of COVID-19 cases and deaths, facility staffing, and supply information (2).

The infection of healthcare workers during the 2013 -2016 Ebola outbreak raised concerns about fomite transmission. In the wake of the Coronavirus Disease 2019 (COVID-19) pandemic, investigations are ongoing to determine the role of fomites in coronavirus transmission as well. The bacteriophage Phi 6 has a phospholipid envelope and is commonly used in environmental studies as a surrogate for human enveloped viruses. The persistence of Phi 6 was evaluated as a surrogate for EBOV and coronaviruses on porous and nonporous hospital surfaces. Phi 6 was suspended in a body fluid simulant and inoculated onto 1 cm(2) coupons of steel, plastic, and two fabric curtain types. The coupons were placed at two controlled absolute humidity (AH) levels; a low AH of 3.0 g/m(3) and a high AH of 14.4 g/m(3) Phi 6 declined at a slower rate on all materials under low AH conditions with a decay rate of 0.06 log10PFU/d to 0.11 log10PFU/d, as compared to the higher AH conditions with a decay rate of 0.65 log10PFU/h to 1.42 log10PFU/d. There was a significant difference in decay rates between porous and non-porous surfaces at both low AH (P < 0.0001) and high AH (P < 0.0001). Under these laboratory-simulated conditions, Phi 6 was found to be a conservative surrogate for EBOV under low AH conditions, in that it persisted longer than Ebola virus in similar AH conditions. Additionally, some coronaviruses persist longer than phi6 under similar conditions, therefore Phi6 may not be a suitable surrogate for coronaviruses.IMPORTANCE Understanding the persistence of enveloped viruses helps inform infection control practices and procedures in healthcare facilities and community settings. These data convey to public health investigators that enveloped viruses can persist and remain infective on surfaces, thus demonstrating a potential risk for transmission. Under these laboratory-simulated western indoor hospital conditions, Phi 6 was used to assess suitability as a surrogate for environmental persistence research related to enveloped viruses, including EBOV and coronaviruses.

More efficacious treatment regimens are needed for tuberculosis, however, drug development is impeded by a lack of reliable biomarkers of disease severity and of treatment effect. We conducted a directed screen of host biomarkers in participants enrolled in a tuberculosis clinical trial to address this need. Serum samples from 319 protocol-correct, culture-confirmed pulmonary tuberculosis patients treated under direct observation as part of an international, phase 2 trial were screened for 70 markers of infection, inflammation, and metabolism. Biomarker assays were specifically developed for this study and quantified using a novel, multiplexed electrochemiluminescence assay. We evaluated the association of biomarkers with baseline characteristics, as well as with detailed microbiologic data, using Bonferroni-adjusted, linear regression models. Across numerous analyses, seven proteins, SAA1, PCT, IL-1beta, IL-6, CRP, PTX-3 and MMP-8, showed recurring strong associations with markers of baseline disease severity, smear grade and cavitation; were strongly modulated by tuberculosis treatment; and had responses that were greater for patients who culture-converted at 8weeks. With treatment, all proteins decreased, except for osteocalcin, MCP-1 and MCP-4, which significantly increased. Several previously reported putative tuberculosis-associated biomarkers (HOMX1, neopterin, and cathelicidin) were not significantly associated with treatment response. In conclusion, across a geographically diverse and large population of tuberculosis patients enrolled in a clinical trial, several previously reported putative biomarkers were not significantly associated with treatment response, however, seven proteins had recurring strong associations with baseline radiographic and microbiologic measures of disease severity, as well as with early treatment response, deserving additional study.

Background: In Sierra Leone, over 4000 individuals survived Ebola since the outbreak began in 2014. Because Ebola survivorship was largely unprecedented prior to this outbreak, little is known about survivor experiences during and post illness. Methods To assess survivors' experiences and attitudes related to Ebola, 28 in-depth interviews and short quantitative surveys with survivors from all four geographic regions of Sierra Leone were conducted in May 2015. Results: Survivor experiences, emotions and attitudes changed over time as they moved from disease onset to treatment, discharge and life post-discharge. Survivors mentioned experiencing acute fear and depression when they fell ill. Only half reported positive experiences in holding centres but nearly all were positive about their treatment centre experiences. Survivor euphoria on discharge was followed by concerns about their financial situation and future. While all reported supportive attitudes from family members, about a third described discrimination and stigma from their communities. Over a third became unemployed, especially those previously engaged in petty trade. Survivor knowledge about sexual transmission risk reflected counselling messages. Many expressed altruistic motivations for abstinence or condom use. In addition, survivors were strongly motivated to help end Ebola and to improve the healthcare system. Key recommendations from survivors included improved counselling in holding centres and long-term government support for survivors, including opportunities for participation in Ebola response efforts. Conclusions: Survivors face myriad economic, social and health challenges. Addressing survivor concerns, including the discrimination they face, could facilitate their reintegration into communities and their contributions to future Ebola responses.

The current treatment used for tuberculosis (TB) is lengthy and needs to be shortened and improved. Pyrazinamide (PZA) has potent sterilizing activity and has the potential to shorten TB treatment duration, if optimized. The goals of this study were (a) to develop a population pharmacokinetic (PK) model for PZA among patients enrolled in PK sub-studies of Tuberculosis Trial Consortium (TBTC) trials 27 and 28, and (b) to determine covariates that affect PZA PK. We also (c) performed simulations and target attainment analysis using the proposed targets of Cmax >35 mcg/ml or AUC >363 mcg*hr/ml to see if higher weight-based dosing could improve PZA efficacy. Seventy-two patients participated in the sub-studies. The mean (standard deviation, SD) maximum plasma concentration (Cmax) was 30.8 (7.4) mcg/ml, and the area under the concentration-versus-time curve (AUC0-24) was 307 mcg*hr/ml (83). A one-compartment open model best described PZA PK. Only body weight was a significant covariate for PZA clearance. Women had a lower V/F compared to men, and both Cl/F and V/F increased with body weight. Our simulations show that higher doses for PZA (>50mg/kg) are needed to achieve the therapeutic target of AUC/MIC >11.3 in >80% of patients, while doses >80mg/kg are needed for 90% target attainment, given specific assumptions about MIC determinations. For the therapeutic targets of Cmax >35 mcg/ml and/or AUC >363 mcg*hr/ml, doses in the range of 30-40 mg/kg are needed to achieve the therapeutic target in >90 % of the patients. Further clinical trials are needed to evaluate the safety and efficacy of higher doses for PZA.Reference in this manuscript to any specific commercial product, process, service, manufacturer, or company does not constitute endorsement or recommendation by the U.S. Government or CDC. The findings and conclusions are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention.

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.

The Xpert(R) MTB/RIF assay is both sensitive and specific as a diagnostic test. Xpert also reports quantitative output in cycle thresholds (Ct), which may provide a dynamic measure of sputum bacillary burden when used longitudinally. We evaluated the relationship between Xpert Ct trajectory and drug exposure during TB treatment to evaluate the potential utility of Xpert Ct for treatment monitoring. We obtained serial sputum samples from patients with smear-positive pulmonary TB consecutively enrolled at ten international clinical trial sites participating in Study 29X, a CDC-sponsored TB Trials Consortium study evaluating the tolerability, safety, and antimicrobial activity of rifapentine at daily doses up to 20 mg/kg. Xpert was performed at weeks 0, 2, 4, 6, 8, and 12. Longitudinal Ct data were modeled using a nonlinear mixed effects model, in relation to rifapentine exposure (area under the concentration-time curve [AUC]). The rate of change of Ct was higher in subjects receiving rifapentine compared to that in subjects receiving standard dose rifampin. Moreover, rifapentine exposure, but not assigned dose, was significantly associated with rate of change in Ct (p = 0.02). The estimated increase in Ct slope for every additional 100 mcg*h/mL of rifapentine drug exposure (as measured by AUC) was 0.11 Ct/week (95% CI 0.05 - 0.17). Increasing rifapentine exposure is associated with faster rate of change of Xpert Ct, indicating faster clearance of MTB DNA. These data suggest that the quantitative outputs of the Xpert MTB/RIF assay may be useful as a dynamic measure of TB treatment response.

SETTING: Two-month solid medium culture conversion is a commonly used, if suboptimal, endpoint for phase 2 anti-tuberculosis treatment trials. OBJECTIVE AND DESIGN: To model the effect of the performance characteristics (sensitivity and contamination rate) of solid medium on required sample size for a two-arm clinical trial with 85% true (gold standard) culture conversion in the control and 95% in the experimental arm. RESULTS: Increasing sensitivity and decreasing contamination reduced the sample size from 239 subjects/arm (60% sensitivity, 30% contamination) to 138 subjects/arm (95% sensitivity, 1% contamination). CONCLUSION: Optimizing solid medium has significant potential to reduce sample size and increase the efficiency of tuberculosis clinical trials.

OBJECTIVE: Use of tuberculin skin tests (TSTs) and interferon gamma release assays (IGRAs) as part of tuberculosis (TB) screening among immigrants from high TB-burden countries has not been fully evaluated. METHODS: Prevalence of Mycobacterium tuberculosis infection (MTBI) based on TST, or the QuantiFERON-TB Gold test (QFT-G), was determined among immigrant applicants in Vietnam bound for the United States (US); factors associated with test results and discordance were assessed; predictive values of TST and QFT-G for identifying chest radiographs (CXRs) consistent with TB were calculated. RESULTS: Of 1,246 immigrant visa applicants studied, 57.9% were TST positive, 28.3% were QFT-G positive, and test agreement was 59.4%. Increasing age was associated with positive TST results, positive QFT-G results, TST-positive but QFT-G-negative discordance, and abnormal CXRs consistent with TB. Positive predictive values of TST and QFT-G for an abnormal CXR were 25.9% and 25.6%, respectively. CONCLUSION: The estimated prevalence of MTBI among US-bound visa applicants in Vietnam based on TST was twice that based on QFT-G, and 14 times higher than a TST-based estimate of MTBI prevalence reported for the general US population in 2000. QFT-G was not better than TST at predicting abnormal CXRs consistent with TB.

BACKGROUND: The QuantiFERON(R)-TB Gold In-Tube test (QFT-GIT) detects Mycobacterium tuberculosis (Mtb) infection by measuring release of interferon gamma (IFN-gamma) when T-cells (in heparinized whole blood) are stimulated with specific Mtb antigens. The amount of IFN-gamma is determined by enzyme-linked immunosorbent assay (ELISA). Automation of the ELISA method may reduce variability. To assess the impact of ELISA automation, we compared QFT-GIT results and variability when ELISAs were performed manually and with automation. METHODS: Blood was collected into two sets of QFT-GIT tubes and processed at the same time. For each set, IFN-gamma was measured in automated and manual ELISAs. Variability in interpretations and IFN-gamma measurements was assessed between automated (A1 vs. A2) and manual (M1 vs. M2) ELISAs. Variability in IFN-gamma measurements was also assessed on separate groups stratified by the mean of the four ELISAs. RESULTS: Subjects (N = 146) had two automated and two manual ELISAs completed. Overall, interpretations were discordant for 16 (11%) subjects. Excluding one subject with indeterminate results, 7 (4.8%) subjects had discordant automated interpretations and 10 (6.9%) subjects had discordant manual interpretations (p = 0.17). Quantitative variability was not uniform; within-subject variability was greater with higher IFN-gamma measurements and with manual ELISAs. For subjects with mean TB Responses +/-0.25 IU/mL of the 0.35 IU/mL cutoff, the within-subject standard deviation for two manual tests was 0.27 (CI95 = 0.22-0.37) IU/mL vs. 0.09 (CI95 = 0.07-0.12) IU/mL for two automated tests. CONCLUSION: QFT-GIT ELISA automation may reduce variability near the test cutoff. Methodological differences should be considered when interpreting and using IFN-gamma release assays (IGRAs).

BACKGROUND: The QuantiFERON(R)-TB Gold In-Tube test (QFT-GIT) is a viable alternative to the tuberculin skin test (TST) for detecting Mycobacterium tuberculosis infection. However, within-subject variability may limit test utility. To assess variability, we compared results from the same subjects when QFT-GIT enzyme-linked immunosorbent assays (ELISAs) were performed in different laboratories. METHODS: Subjects were recruited at two sites and blood was tested in three labs. Two labs used the same type of automated ELISA workstation, 8-point calibration curves, and electronic data transfer. The third lab used a different automated ELISA workstation, 4-point calibration curves, and manual data entry. Variability was assessed by interpretation agreement and comparison of interferon-gamma (IFN-gamma) measurements. Data for subjects with discordant interpretations or discrepancies in TB Response >0.05 IU/mL were verified or corrected, and variability was reassessed using a reconciled dataset. RESULTS: Ninety-seven subjects had results from three labs. Eleven (11.3%) had discordant interpretations and 72 (74.2%) had discrepancies >0.05 IU/mL using unreconciled results. After correction of manual data entry errors for 9 subjects, and exclusion of 6 subjects due to methodological errors, 7 (7.7%) subjects were discordant. Of these, 6 (85.7%) had all TB Responses within 0.25 IU/mL of the manufacturer's recommended cutoff. Non-uniform error of measurement was observed, with greater variation in higher IFN-gamma measurements. Within-subject standard deviation for TB Response was as high as 0.16 IU/mL, and limits of agreement ranged from -0.46 to 0.43 IU/mL for subjects with mean TB Response within 0.25 IU/mL of the cutoff. CONCLUSION: Greater interlaboratory variability was associated with manual data entry and higher IFN-gamma measurements. Manual data entry should be avoided. Because variability in measuring TB Response may affect interpretation, especially near the cutoff, consideration should be given to developing a range of values near the cutoff to be interpreted as "borderline," rather than negative or positive.

BACKGROUND: Mycobacterium tuberculosis (Mtb) infection may cause overt disease or remain latent. Interferon gamma release assays (IGRAs) detect Mtb infection, both latent infection and infection manifesting as overt disease, by measuring whole-blood interferon gamma (IFN-gamma) responses to Mtb antigens such as early secreted antigenic target-6 (ESAT-6), culture filtrate protein 10 (CFP-10), and TB7.7. Due to a lack of adequate diagnostic standards for confirming latent Mtb infection, IGRA sensitivity for detecting Mtb infection has been estimated using patients with culture-confirmed tuberculosis (CCTB) for whom recovery of Mtb confirms the infection. In this study, cytokines in addition to IFN-gamma were assessed for potential to provide robust measures of Mtb infection. METHODS: Cytokine responses to ESAT-6, CFP-10, TB7.7, or combinations of these Mtb antigens, for patients with CCTB were compared with responses for subjects at low risk for Mtb infection (controls). Three different multiplexed immunoassays were used to measure concentrations of 9 to 20 different cytokines. Responses were calculated by subtracting background cytokine concentrations from cytokine concentrations in plasma from blood stimulated with Mtb antigens. RESULTS: Two assays demonstrated that ESAT-6, CFP-10, ESAT-6+CFP-10, and ESAT-6+CFP-10+TB7.7 stimulated the release of significantly greater amounts of IFN-gamma, IL-2, IL-8, MCP-1 and MIP-1beta for CCTB patients than for controls. Responses to combination antigens were, or tended to be, greater than responses to individual antigens. A third assay, using whole blood stimulation with ESAT-6+CFP-10+TB7.7, revealed significantly greater IFN-gamma, IL-2, IL-6, IL-8, IP-10, MCP-1, MIP-1beta, and TNF-alpha responses among patients compared with controls. One CCTB patient with a falsely negative IFN-gamma response had elevated responses with other cytokines. CONCLUSIONS: Multiple cytokines are released when whole blood from patients with CCTB is stimulated with Mtb antigens. Measurement of multiple cytokine responses may improve diagnostic sensitivity for Mtb infection compared with assessment of IFN-gamma alone.

INTRODUCTION: Interferon gamma (IFN-gamma) release assays, such as QuantiFERON(R)-TB Gold test (QFT-G) and QuantiFERON(R)-TB Gold In-Tube test (QFT-GIT) are designed to detect M. tuberculosis (Mtb) infection. Recognition of unusual IFN-gamma measurements may help indicate inaccurate results. METHODS: We examined QFT-G and QFT-GIT results from subjects who had two or more tests completed. We classified unusual IFN-gamma measurements as: 1) High Nil Concentration (HNC) when IFN-gamma concentration in plasma from unstimulated blood exceeded 0.7 IU/mL; 2) Low Mitogen Response (LMR) when Mitogen Response was <0.5 IU/mL; 3) Very Low Mitogen Response (VLMR) when Mitogen Response was ≤-0.5 IU/mL; and 4) Very Low Antigen Response (VLAR) when the response to a Mtb antigen was ≤-0.35 IU/mL and ≤-0.5 times the IFN-gamma concentration in plasma from unstimulated blood. RESULTS: Among 5,309 results from 1,728 subjects, HNC occurred in 234 (4.4%) tests for 162 subjects, LMR in 108 (2.0%) tests for 85 subjects, VLMR in 22 (0.4%) tests for 21 subjects, and VLAR in 41 (0.8%) tests for 39 subjects. QFT-GIT had fewer HNC, VLMR, and VLAR (p = 0.042, 0.004, and 0.067 respectively); QFT-G had fewer LMR (p = 0.005). Twenty-four (51.6%) of 47 subjects with positive results and HNC were negative or indeterminate by all other tests. Thirteen (61.9%) of 21 subjects with positive results and LMR were negative or indeterminate by all other tests. CONCLUSION: Unusual IFN-gamma measurements including HNC, LMR, VLMR, and VLAR were encountered in small numbers, and in most instances were not seen on simultaneously or subsequently performed tests. To avoid erroneous diagnosis of Mtb infection, IGRAs with unusual IFN-gamma measurements should be repeated with another blood sample and interpreted with caution if they recur.