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.

The US President's Emergency Plan for AIDS Relief (PEPFAR) supports molecular HIV and tuberculosis diagnostic networks and information management systems in low- and middle-income countries. We describe how national programs leveraged these PEPFAR-supported laboratory resources for SARS-CoV-2 testing during the COVID-19 pandemic. We sent a spreadsheet template consisting of 46 indicators for assessing the use of PEPFAR-supported diagnostic networks for COVID-19 pandemic response activities during April 1, 2020, to March 31, 2021, to 27 PEPFAR-supported countries or regions. A total of 109 PEPFAR-supported centralized HIV viral load and early infant diagnosis laboratories and 138 decentralized HIV and TB sites reported performing SARS-CoV-2 testing in 16 countries. Together, these sites contributed to >3.4 million SARS-CoV-2 tests during the 1-year period. Our findings illustrate that PEPFAR-supported diagnostic networks provided a wide range of resources to respond to emergency COVID-19 diagnostic testing in 16 low- and middle-income countries.

The CDC is unwavering in our commitment to provide the highest quality laboratory diagnostic services for parasitic diseases. We clearly hear, understand, and concur with the concerns expressed in the accompanying editorial and appreciate the challenges the pause in testing for parasitic diseases presents for health-care providers, particularly those treating people at elevated risk for parasitic diseases. | | We also recognize the crucial role that our agency plays in ensuring those at risk receive equitable services for infections, including those that are generally known to all Americans as well as neglected diseases that are unfamiliar to most Americans. More broadly, the CDC works to protect the global community from parasitic diseases through three main priorities: reducing parasitic disease-related death, illness, and disability in the United States; reducing the global burden of malaria; and eliminating targeted neglected tropical diseases. Our Parasitic Diseases Laboratory is, in many ways, the foundation of this work and serves as a critical resource and often a laboratory of last resort for challenging diagnoses of unfamiliar pathogens when state and private laboratories do not have the relevant testing capacity. Our laboratory experts develop and improve tools and approaches to detect, prevent, and control disease; provide diagnostic assistance and expertise to public health laboratories; and conduct diagnostic tests for parasitic diseases.

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.).

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.

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.

BACKGROUND: Cryptococcal meningitis is common and associated with high mortality among HIV infected persons. The World Health Organization recommends that routine Cryptococcal antigen (CrAg) screening in ART-naive adults with a CD4+ count <100 cells/muL followed by pre-emptive antifungal therapy for CrAg-positive patients be considered where CrAg prevalence is ≥3%. The prevalence of CrAg among HIV adults in Namibia is unknown. We estimated CrAg prevalence among HIV-infected adults receiving care in Namibia for the purpose of informing routine screening strategies. METHODS: The study design was cross-sectional. De-identified plasma specimens collected for routine CD4+ testing from HIV-infected adults enrolled in HIV care at 181 public health facilities from November 2013 to January 2014 were identified at the national reference laboratory. Remnant plasma from specimens with CD4+ counts <200 cells/muL were sampled and tested for CrAg using the IMMY(R) Lateral Flow Assay. CrAg prevalence was estimated and assessed for associations with age, sex, and CD4+ count. RESULTS: A total of 825 specimens were tested for CrAg. The median (IQR) age of patients from whom specimens were collected was 38 (32-46) years, 45.9% were female and 62.9% of the specimens had CD4 <100 cells/muL. CrAg prevalence was 3.3% overall and 3.9% and 2.3% among samples with CD4+ counts of CD4+<100 cells/muL and 100-200 cells/muL, respectively. CrAg positivity was significantly higher among patients with CD4+ cells/muL < 50 (7.2%, P = 0.001) relative to those with CD4 cells/muL 50-200 (2.2%). CONCLUSION: This is the first study to estimate CrAg prevalence among HIV-infected patients in Namibia. CrAg prevalence of ≥3.0% among patients with CD4+<100 cells/muL justifies routine CrAg screening and preemptive treatment among HIV-infected in Namibia in line with WHO recommendations. Patients with CD4+<100 cells/muL have a significantly greater risk for CrAg positivity. Revised guidelines for ART in Namibia now recommend routine screening for CrAg.

Coccidioidomycosis (Valley fever) is a major cause of illness in inmates in some California prisons. This article discusses an investigation conducted at two prisons to describe potential environmental exposures. The study did not identify modifiable risk factors; limiting the type or duration of outdoor activity in these prisons may not decrease coccidioidomycosis morbidity.

Since the start of the Ebola virus disease (Ebola) outbreak in West Africa, Sierra Leone has reported 8,706 confirmed Ebola cases and 3,956 deaths (1). During September 15-16, 2015, heavy rains flooded the capital, Freetown, resulting in eight deaths, home and property destruction, and thousands of persons in need of assistance (2). By September 27, approximately 13,000 flood-affected persons registered for flood relief services from the government (3). On September 17, two stadiums in Freetown were opened to provide shelter and assistance to flood-affected residents; a total of approximately 3,000 persons stayed overnight in both stadiums (Sierra Leone Ministry of Health and Sanitation, personal communication, September 2015). On the same day the stadiums were opened to flood-affected persons, the Ministry of Health and Sanitation (MoHS) and Western Area Ebola Response Center (WAERC) staff members from CDC, the World Health Organization (WHO), and the African Union evaluated the layout, logistics, and services at both stadiums and identified an immediate need to establish Ebola response activities. The patient in the last Ebola case in the Western Area, which includes Freetown, had died 37 days earlier, on August 11; however, transmission elsewhere in Sierra Leone was ongoing, and movement of persons throughout the country was common (4,5).

Bipolaris mould surgical site infections (SSIs) are exceedingly rare. We describe 21 cases of Bipolaris SSIs in pediatric and adult cardiothoracic surgery patients at ten hospitals in Texas, Arkansas, and Florida during 2008-2013. Median case-patient age was 55 years (range: 3 days-82 years), and 19 (90%) were male. Ten (48%) had coronary artery bypass or valve surgery, and seven (33%) had heart transplantation. Fifteen (71%) had more than one cardiothoracic procedure (median: 3, range: 1-11). Thirteen (62%) case-patients (all 5 pediatric patients, and 8 (50%) of 16 adult patients) had delayed sternal closure (chest closed >1 day [median = 8 days; range: 2-22] following the initial cardiothoracic procedure). Thirteen (62%) had mediastinitis. Median time from initial surgery to positive Bipolaris culture was 20 days (range: 6-497). Sixteen (76%) case-patients died.

Multi-locus sequence typing (MLST) is the 'gold standard' genotyping technique for many microorganisms. This classification approach satisfies the requirements for a high-resolution, standardized, and archivable taxonomic system. Here, we describe the development of a novel MLST system to assist with the investigation of an unusual cluster of surgical site infections caused by Bipolaris spp. in post-operative cardiothoracic surgery (POCS) patients during January, 2008-December, 2013 in the southeastern US. We also used the same MLST system to perform retrospective analysis on isolates from a 2012 Bipolaris endophthalmitis outbreak caused by a contaminated product. This MLST system showed high intraspecies discriminatory power for B. spicifera, B. hawaiiensis, and B. australiensis. Based on relatedness of the isolates, the MLST data supported the hypothesis that infections in the POCS cluster were from different environmental sources while confirming the endophthalmitis outbreak resulted from a point-source, which was a contaminated medication.

On December 28, 2012, the New York State Department of Health (NYSDOH) and the Mycotic Diseases Branch, Centers for Disease Control and Prevention (CDC) were notified of Coccidioides spp. contamination in commercially-distributed tubes of Rhesus monkey kidney (RhMK) cells from Company A; Coccidioides posadasii was later identified through gene-specific PCR in two lots (A491216-B and A491206-T) (2)....

BACKGROUND: Fungal infections are rare complications of injections for treatment of chronic pain. In September 2012, we initiated an investigation into fungal infections associated with injections of preservative-free methylprednisolone acetate that was purchased from a single compounding pharmacy. METHODS: Three lots of methylprednisolone acetate were recalled by the pharmacy; examination of unopened vials later revealed fungus. Notification of all persons potentially exposed to implicated methylprednisolone acetate was conducted by federal, state, and local public health officials and by staff at clinical facilities that administered the drug. We collected clinical data on standardized case-report forms, and we tested for the presence of fungi in isolates and specimens by examining cultures and performing polymerase-chain-reaction assays and histopathological and immunohistochemical testing. RESULTS: As of October 19, 2012, more than 99% of 13,534 potentially exposed persons had been contacted. As of December 10, there were 590 reported cases of infection in 19 states, with 37 deaths (6%). As of November 26, laboratory evidence of Exserohilum rostratum was present in specimens from 100 case patients (17%). Additional data were available for 386 case patients (65%); 300 of these patients (78%) had meningitis. Case patients had received a median of 1 injection (range, 1 to 6) of implicated methylprednisolone acetate. The median age of the patients was 64 years (range, 16 to 92), and the median incubation period was 20 days (range, 0 to 120); 33 patients (9%) had a stroke. CONCLUSIONS: Analysis of preliminary data from a large multistate outbreak of fungal infections showed substantial morbidity and mortality. The infections were associated with injection of a contaminated glucocorticoid medication from a single compounding pharmacy. Rapid public health actions included prompt recall of the implicated product, notification of exposed persons, and early outreach to clinicians.