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BACKGROUND: We evaluated patient safety within a randomized crossover trial comparing electronic directly observed therapy (eDOT) to in-person DOT (ipDOT) in persons undergoing TB treatment in New York City, NY, USA. METHODS: Participant symptoms, symptom severity, and clinical management were documented. We assessed adverse event reports (AERs) by DOT method during the two-period crossover. Using Cox proportional-hazards mixed-effects models, we estimated the adjusted hazard ratio (aHR) of participants reporting an adverse event (AE) vs. not reporting an AE. RESULTS: Of 211 participants, 57 (27.0%) reported AEs during the two-period crossover; of these, 54.4% (31/57) were reported while using eDOT vs. 45.6% (26/57) while using ipDOT. Controlling for study group and period, the aHR for eDOT vs. ipDOT was 0.98 (95% CI 0.49-1.93). Although statistically not significant, the wide confidence intervals suggest that a significant association cannot be entirely ruled out. Gastrointestinal symptoms were most frequently reported (42.1%, 24/57). AER types and severity did not differ significantly by DOT method. Days from symptom onset to medical attention was similar across DOT methods (median: 1.0 day, IQR 0.0-2.0). No participants switched DOT methods due to AERs or monitoring concerns. CONCLUSION: Further evaluation to ascertain whether AERs differ when patients use eDOT vs. ipDOT is warranted.

A recent landmark trial showed a 4-month regimen of rifapentine, pyrazinamide, moxifloxacin, and isoniazid (PZMH) to be noninferior to the 6-month standard of care. Here, two murine models of tuberculosis were used to test whether novel regimens replacing rifapentine and isoniazid with bedaquiline and another drug would maintain or increase the sterilizing activity of the regimen. In BALB/c mice, replacing rifapentine in the PZM backbone with bedaquiline (i.e., BZM) significantly reduced both lung CFU counts after 1 month and the proportion of mice relapsing within 3 months after completing 1.5 months of treatment. The addition of rifabutin to BZM (BZMRb) further increased the sterilizing activity. In the C3HeB/FeJ mouse model characterized by caseating lung lesions, treatment with BZMRb resulted in significantly fewer relapses than PZMH after 2 months of treatment. A regimen combining the new DprE1 inhibitor OPC-167832 and delamanid (BZOD) also had superior bactericidal and sterilizing activity compared to PZM in BALB/c mice and was similar in efficacy to PZMH in C3HeB/FeJ mice. Thus, BZM represents a promising backbone for treatment-shortening regimens. Given the prohibitive drug-drug interactions between bedaquiline and rifampin or rifapentine, the BZMRb regimen represents the best opportunity to combine, in one regimen, the treatment-shortening potential of the rifamycin class with that of BZM and deserves high priority for evaluation in clinical trials. Other 4-drug BZM-based regimens and BZOD represent promising opportunities for extending the spectrum of treatment-shortening regimens to rifamycin- and fluoroquinolone-resistant tuberculosis.

Christian Lienhardt and co-authors discuss the conclusions of the PLOS Medicine Collection on advances in clinical trial design for development of new tuberculosis treatments., Competing Interests: The authors have declared that no competing interests exist.

Christian Lienhardt and colleagues discuss the importance of communication and coordination between regulators, researchers, and policy makers to ensure tuberculosis trials provide high-quality evidence for policy decisions., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: At the CDC, AAV serves as part of a research group doing clinical trials in tuberculosis. His group (TBTC) works often in collaboration with pharmaceutical companies, who may provide modest support, such as drug supplies or funding for PK sub-studies. One company, Sanofi, has provided 6 unrestricted grants to the CDC Foundation over the years 2007–2015 totaling ~$2.8 million to facilitate or support TBTC work related to rifapentine. These funds have supported several PK sub-studies, supported 3 contract research staff, have funded travel to TBTC scientific meetings for invited speakers (all in coach class), and have supported expenses related to fulfillment of company requests for data and data formats as part of their efforts to use TBTC data to support regulatory filings. None of these funds have otherwise benefited members of his research group.

Context: Latent tuberculosis infection diagnosis and treatment is a strategic priority for eliminating tuberculosis in the U.S. The Centers for Disease Control and Prevention has recommended the short-course regimen of 3-month isoniazid-rifapentine administered by directly observed therapy. However, longer-duration regimens remain the most widely prescribed latent tuberculosis infection treatments. Limitation on adoption of 3-month isoniazid-rifapentine in the U.S. might be because of patients' preference for self-administered therapy, providers' lack of familiarity with 3-month isoniazid-rifapentine, or lack of resources to support directly observed therapy. This review examines the most recent evidence regarding 3-month isoniazid-rifapentine's effectiveness, safety, and treatment completion when directly compared with other latent tuberculosis infection regimens primarily comprising 9-month isoniazid treatment., Evidence Acquisition: Using Community Guide methodology, reviewers identified, evaluated, and summarized available evidence published during January 2006-June 2017. Analysis of the data was completed in 2017., Evidence Synthesis: The analysis included 15 unique studies. Three-month isoniazid-rifapentine was determined to be equal to other latent tuberculosis infection regimens in effectiveness (OR=0.89, 95% CI=0.46, 1.70), and has higher treatment completion (87.5%, 95% CI=83.2%, 91.3%) compared with other latent tuberculosis infection regimens (65.9%, 95% CI=53.5%, 77.3%). Three-month isoniazid-rifapentine was associated with similar risk to other latent tuberculosis infection regimens for adverse events (relative risk=0.59, 95% CI=0.23, 1.52); discontinuing treatment because of adverse events (relative risk=0.48, 95% CI=0.17, 1.34); and death (relative risk=0.79, 95% CI=0.56, 1.11)., Conclusions: The 3-month isoniazid-rifapentine regimen is as safe and effective as other recommended latent tuberculosis infection regimens and achieves significantly higher treatment completion rates., (Published by Elsevier Inc.)

Background: Availability of an ultra-short-course drug regimen capable of curing patients with tuberculosis in 2 to 3 mo would significantly improve global control efforts. Because immediate prospects for novel treatment-shortening drugs remain uncertain, we examined whether better use of existing drugs could shorten the duration of treatment. Rifapentine is a long-lived rifamycin derivative currently recommended only in once-weekly continuation-phase regimens. Moxifloxacin is an 8-methoxyfluoroquinolone currently used in second-line regimens., Methods and Findings: Using a well-established mouse model with a high bacterial burden and human-equivalent drug dosing, we compared the efficacy of rifapentine- and moxifloxacin-containing regimens with that of the standard daily short-course regimen based on rifampin, isoniazid, and pyrazinamide. Bactericidal activity was assessed by lung colony-forming unit counts, and sterilizing activity was assessed by the proportion of mice with culture-positive relapse after 2, 3, 4, and 6 mo of treatment. Here, we demonstrate that replacing rifampin with rifapentine and isoniazid with moxifloxacin dramatically increased the activity of the standard daily regimen. After just 2 mo of treatment, mice receiving rifapentine- and moxifloxacin-containing regimens were found to have negative lung cultures, while those given the standard regimen still harbored 3.17 log10 colony-forming units in the lungs (p < 0.01). No relapse was observed after just 3 mo of treatment with daily and thrice-weekly administered rifapentine- and moxifloxacin-containing regimens, whereas the standard daily regimen required 6 mo to prevent relapse in all mice., Conclusions: Rifapentine should no longer be viewed solely as a rifamycin for once-weekly administration. Our results suggest that treatment regimens based on daily and thrice-weekly administration of rifapentine and moxifloxacin may permit shortening the current 6 mo duration of treatment to 3 mo or less. Such regimens warrant urgent clinical investigation.

Study Objective: To characterize the bidirectional interaction between twice-daily nelfinavir and twice-weekly rifabutin and isoniazid in patients with tuberculosis and human immunodeficiency virus (HIV) infection., Design: Prospective cohort study., Setting: Three clinical research centers., Patients: Seven patients with HIV-related tuberculosis., Intervention: Rifabutin 300 mg and isoniazid 15 mg/kg (maximum dose 900 mg) twice/week were administered for at least 2 weeks during the continuation phase of tuberculosis treatment. Antiretroviral therapy with nelfinavir 1250 mg twice/day and two nucleoside reverse transcriptase inhibitors was then added., Measurements and Main Results: Patients underwent blood sampling for pharmacokinetic analysis during the continuation phase of tuberculosis therapy and after a median of 21 days after the addition of antiretroviral treatment. When rifabutin was coadministered with nelfinavir, its area under the concentration-time curve from 0-21 hours (AUC(0-21)) increased 22% (geometric mean 5.01 microg.hr/ml [90% confidence interval (CI) 3.25-7.71] with nelfinavir vs 4.10 microg.hr/ml [90% CI 3.18-5.27] without nelfinavir; geometric mean ratio 1.22 [90% CI 0.78-1.92]). Also, the AUC(0-21) for the active metabolite, desacetylrifabutin, increased significantly (geometric mean ratio 3.46, 90% CI 1.84-6.47, p=0.009). In the presence of rifabutin, the pharmacokinetic parameters of nelfinavir and its principal metabolite M8 were similar to those of patients not taking rifabutin. No drug interaction between nelfinavir and isoniazid was detected., Conclusions: Coadministration of rifabutin and isoniazid without dosage adjustment during twice-weekly tuberculosis therapy with nelfinavir-based antiretroviral therapy resulted in rifabutin exposures within the acceptable ranges for safety and efficacy. Therefore, this combination is an appropriate option for the simultaneous treatment of tuberculosis and HIV infection when tuberculosis therapy is given twice weekly.

Rationale: Recent studies have demonstrated that intermittent administration of rifamycin-based regimens results in higher rates of tuberculosis relapse and treatment failure compared with daily therapy. Twice-weekly treatment with rifampin, isoniazid, and pyrazinamide may be improved by increasing Mycobacterium tuberculosis exposure to rifamycin by substituting rifapentine for rifampin., Methods: To test this hypothesis, we compared the activities of standard daily and twice-weekly rifampin plus isoniazid-based regimens to those of twice-weekly rifapentine plus isoniazid- or moxifloxacin-containing regimens in the murine model of tuberculosis. Relapse rates were assessed after 4, 5, and 6 mo of treatment to assess stable cure. Single- and multiple-dose pharmacokinetics of rifampin and rifapentine were also determined., Results: After 2 mo of treatment, twice-weekly therapy with rifapentine (15 or 20 mg/kg), moxifloxacin, and pyrazinamide was significantly more active than standard daily or twice-weekly therapy with rifampin, isoniazid, and pyrazinamide. Stable cure was achieved after 4 mo of twice-weekly rifapentine plus isoniazid- or moxifloxacin-containing therapy, but only after 6 mo of standard daily therapy. Twice-weekly rifapentine (15 mg/kg) displayed more favorable pharmacodynamics than did daily rifampin (10 mg/kg)., Conclusions: By virtue of the enhanced rifamycin exposure, twice-weekly regimens containing rifapentine (15 or 20 mg/kg) may permit shortening the current treatment duration by 2 mo. Such regimens warrant clinical investigation.

Rationale: Treatment of tuberculosis with an efficacious once-weekly regimen would be a significant achievement in improving patient adherence. Currently, the only recommended once-weekly continuation phase regimen of isoniazid plus rifapentine (10 mg/kg) is inferior to standard twice-weekly therapy with isoniazid plus rifampin and is, therefore, restricted to non-high-risk patients. The substitution of moxifloxacin, a new 8-methoxyfluoroquinolone, for isoniazid and an increase in the dose of rifapentine could augment the activity of once-weekly regimens., Methods: To test this hypothesis we evaluated the sterilizing activity of improved once-weekly rifapentine-based continuation phase regimens in a murine model that mimics the treatment of high-risk patients with tuberculosis. The bactericidal activity of standard daily therapy and standard intermittent therapy ("Denver" regimen) was also assessed to evaluate the effect of intermittent drug administration during the initial phase of therapy., Results: After 2 mo of treatment, lung colony-forming unit counts were 1 log(10) lower in mice treated with standard daily therapy than with the Denver regimen. During the continuation phase, the sterilizing activity of once-weekly moxifloxacin plus rifapentine (15 mg/kg) was significantly greater than that of the predominantly twice-weekly Denver regimen of isoniazid plus rifampin. No significant difference in sterilizing activity was detected between once-weekly isoniazid plus rifapentine (15 mg/kg) and the Denver regimen., Conclusions: These results suggest that the efficacy of the once-weekly isoniazid plus rifapentine continuation phase regimen can be increased by substituting moxifloxacin for isoniazid and by increasing the dose of rifapentine to a clinically acceptable level of 15 mg/kg.

In a recent experimental study using the mouse model of tuberculosis, treatment with a combination of rifampin, moxifloxacin, and pyrazinamide was able to shorten the time to negative lung cultures by up to 2 months compared with the standard regimen of rifampin, isoniazid, and pyrazinamide. To confirm that this substitution of moxifloxacin for isoniazid permits a shorter duration of treatment, a second study was performed in which mice were assessed for relapse after treatment with combination therapy for 3, 4, 5, or 6 months. Although no relapse was observed among mice treated for at least 4 months with rifampin, moxifloxacin, and pyrazinamide, mice treated with rifampin, isoniazid, and pyrazinamide required 6 months of treatment before no relapse could be detected. For mice treated with rifampin, moxifloxacin, and pyrazinamide, similar efficacy was noted whether pyrazinamide was administered for 1 month, 2 months, or the entire duration of therapy. These results suggest that the use of rifampin, moxifloxacin, and pyrazinamide may substantially shorten the duration of therapy needed to cure human tuberculosis and that the full benefit of pyrazinamide in this regimen may be realized after just 1 month of treatment.

After a 20% increase in tuberculosis (TB) cases between 1986 and 1992, TB cases in the United States have declined from 1993 through 1997, an average of 5 to 7 per cent per year. In this paper, we review trends and the current epidemiology of TB in the US, present a brief history of TB control efforts in the country, and present the key strategies for TB control in the US. We describe the current organizational structure of TB services in the US, the role of the private sector in TB control, and how TB control is funded. Finally we discuss the mechanisms by which TB policy is developed. The US model represents a categorical disease program that combines a centralized role of the national government in development of policy, funding, and in the maintenance of national surveillance, and a decentralized role of state and local jurisdictions, which adapt and implement national guidelines and which are responsible for day-to-day program activities. Given the relative success of this combined approach, other countries facing the challenge of maintaining an effective TB control program in the face of increased decentralization of health services may find this description useful.

Background: To improve measles control in Kinshasa, Zaire, a project to increase vaccine coverage was begun in 1988, and in 1989, the city vaccination programme changed measles vaccination policy from Schwartz vaccine at age 9 months to medium titre Edmonston Zagreb (EZ) vaccine at age 6 months. We report the impact of the programme on measles incidence and mortality., Methods: Data on vaccine coverage were obtained from cluster sample surveys conducted every 1-2 years and from routine reports of vaccine doses administered. Data on measles incidence and mortality were obtained from sentinel surveillance sites. The serological response to EZ measles vaccine was evaluated at a health centre in 1989 and in a community survey in 1990., Results: Measles vaccine coverage estimated in cluster surveys increased from 50% of the 1984 birth cohort to 89% of the 1989 birth cohort, accepting either a home-based record or a verbal history of vaccination. Reported measles incidence per 10,000 [corrected] population decreased by over 90%, from 37.5 in 1980 (early vaccination years) to 1.6 in 1991. There was a relative decrease in the proportion of cases aged < 9 months (32% of cases in 1986-1987 and 23% of cases in 1990-1991) and an increase in the proportion aged > 23 months (29% of cases in 1986-1987 and 43% in 1990-1991). According to ELISA assays, 74-76% of children seroresponded to EZ vaccine administered at age 6-7 months under routine programme conditions., Conclusions: Measles can be controlled in urban areas, although it is difficult to determine how great a contribution vaccination at age 6 months makes over and above the achievement of high coverage.

As part of the Combatting Childhood Communicable Diseases (CCCD) project funded by the US Agency for International Development (USAID), the Zairian CCCD programme conducted surveys in the rural health zones of Kingandu and Pai-Kongila, Zaire, in 1984-1985 and 1988-1989 to determine whether a strategy of selective primary health care would affect childhood mortality. This paper describes the changes in the medical care infrastructure and the increasing coverage of selected services. The strategies evaluated were vaccination, oral rehydration therapy, and treatment of febrile episodes with antimalarial drugs for children; and tetanus vaccination and malaria prophylaxis for pregnant women. The health infrastructure in the Kingandu and Pai-Kongila Health Zones expanded considerably from 1984 to 1989, with health centres increasing from 7 to 18. During this period, economic conditions deteriorated moderately, with the nation experiencing nearly 700% inflation. Medical care costs remained stable because of external subsidies. Use of health services was assessed in 1984, 1988, and 1989. Between 1984 and 1989, the proportion of children aged 12-23 months vaccinated against measles increased from 22% to 71%. Coverage with other vaccine antigens increased similarly. Women's knowledge of the correct recipe for the preparation of sugar-salt solution increased from 0% to 61%. Reported treatment at home with sugar-salt or oral rehydration solution increased from 6% to 53%. The proportion of children with febrile episodes who were treated presumptively for malaria with chloroquine remained unchanged (47% in 1984; 44% in 1988). We conclude that, despite a moderate deterioration in economic conditions, Kingandu and Pai-Kongila Health Zones achieved remarkable increases in use of selected health services between 1984 and 1989, especially in vaccination coverage.

In early summer, 1979, a large outbreak of hepatitis A occurred in an Oklahoma day-care center. A total of 41 cases were confirmed, all in adults. Of the 115 non-employee households represented by children in the center, 19 households (16.5%) had one or more cases of hepatitis. Hepatitis occurred in 29% of the households with at least one non-toilet-trained child, compared to 2% of the households without such a child (p = 0.00004). At least four (15%) of 27 center employees had hepatitis. Of 26 cases tested serologically, all were positive for hepatitis A antibody (anti-HAV), and 24 of these 26 were also positive for anti-HAV of immunoglobulin class M (anti-HAV IgM), at an average time after onset of illness of 80 days (range, 38-142 days). Three of ten persons remained anti-HAV IgM-positive 164 days after onset.

In a controlled experiment 15 (79%) of 19 severely alcoholic men but only 1 of 22 controls had a serum concentration of greater than or equal to 5 mumol/l 2,3-butanediol after ingestion of distilled spirits. Another diol, 1,2-propanediol, was found in a concentration of greater than or equal to 5 mumol/l in all patients' specimens after drinking; but it was also present in lower concentrations in the reference specimens of most of the patients. These data are consistent with the experimental evidence that ethanol can be metabolised in rats to produce 2,3-butanediol and with the epidemiological hypothesis that severely alcoholic men metabolise ethanol by a different pathway than do control subjects.

The number of persons in the United States potentially in contact with rabid humans has increased in recent years because of labor-intensive medical care, longer survival times, and care in two or more hospitals. Many of these persons request rabies prophylaxis, and their physicians prescribe it because of their insecurity, a situation that is expensive and often unnecessary. Records of the Centers for Disease Control and the literature were reviewed to examine the current practice of prophylaxis of contacts and the actual need for it. Rabies virus is present in a variety of human fluids and tissues during the first five weeks of illness, but there are only four well-documented reports of human-to-human transmission--all in corneal transplant recipients. Prophylaxis of contacts of 14 rabid patients was predominantly for saliva exposure to open wounds or mucous membranes and was given most often to medical personnel having the greatest contact with the patient. Although it has never been documented, human-to-human transmission of rabies following saliva exposure remains a theoretical possibility. Virus shedding by rabid patients should be studied thoroughly in the future. Recommendations for managing contacts of rabid patients are presented.

In the period July 15, 1977, through March 30, 1982, there were at least 51 sudden, unexplained deaths in the United States among refugees from Southeast Asia. These deaths involved relatively young (median age, 33 years), previously healthy persons. All except one were male, and all died at night. Available data from studies among young adults in this country suggest that this specific phenomenon has an unusually high incidence among Laotian and Kampuchean refugees and, furthermore, has not previously been observed in the United States. Interviews with families of the decedents and a case-control study have failed to establish causal factors, but emotional stress cannot be ruled out as a contributing element. While reviews of the forensic investigations have confirmed the absence of important common pathological or toxicological findings, preliminary findings of special postmortem cardiac studies, now in progress, suggest that at least some of these deaths may be associated with developmentally abnormal conduction system pathways. Further studies are required to confirm this association, to define the apparently sleep-induced mechanism that triggers these deaths, and to explain the male preponderance in this disorder.

Important biochemical clues from animal and human studies as well as epidemiologic studies of twins and adoptees suggest that genetic factors may predispose to alcohol addiction. This paper critically examines the epidemiology and biochemistry literature to assess the strength of the evidence supporting a genetic element in alcohol addiction. Then, a biochemical hypothesis is presented that involves the identification of specific metabolic pathways, pathway controls, and metabolites that may be unique to alcoholics, and which has been tested by experiment.