Aim: Valoctocogene roxaparvovec (AAV5-hFVIII-SQ) is a gene therapy evaluated in the phase 3 GENEr8-1 trial that provides endogenous factor VIII (FVIII) production to prevent bleeding in people with severe hemophilia A and represents an alternative to emicizumab, a recombinant antibody mimicking the function of FVIII. Individuals receiving emicizumab were excluded from GENEr8-1 enrollment since emicizumab was then an investigational therapy. This study aimed to utilize pharmacokinetic simulations to provide guidance on maintaining hemostatic control while transitioning patients from emicizumab to valoctocogene roxaparvovec gene therapy. Methods: A published emicizumab pharmacokinetic model, based on data from the HAVEN clinical trials, was used to simulate in vivo emicizumab concentrations and merged with FVIII activity time-course data for 134 GENEr8-1 participants to estimate bleeding risk at weekly intervals post-infusion with valoctocogene roxaparvovec. The analysis examined 3 approved emicizumab dosing regimens for 2 transition scenarios; first, the last emicizumab dose given the same day as infusion, and second, given 4 weeks after valoctocogene roxaparvovec. Results: Discontinuation of emicizumab the day of valoctocogene roxaparvovec infusion compared with continued dosing for 4 weeks offered similar levels of hemostatic control. The time course for bleeding risk was comparable across the emicizumab dosing regimens for both scenarios. An algorithm to provide guidance for discontinuing emicizumab was developed based on these results. To guide how treatment decisions for emicizumab discontinuation may vary among individuals, theoretical case examples were developed based on participants of GENEr8-1. Conclusions: Regardless of the emicizumab dose or dosing regimen, pharmacokinetic simulations showed no meaningful difference in the risk of bleeding related to FVIII and FVIII equivalent activity determined by the dynamic balance of decaying emicizumab levels and increasing gene therapy–derived endogenous FVIII. These original data suggest individuals on emicizumab prophylaxis can safely transition to valoctocogene roxaparvovec. COIs for presenting author. Suresh Agarwal is an employee and stockholder of BioMarin Pharmaceutical Inc.

The household and non-household contacts of patients with tuberculosis (TB) face varying degrees of risk of infection by Mycobacterium tuberculosis. To quantify new infection and to determine the risk factors associated with new infection among named contacts in San Francisco, CA, USA. We performed a cohort study in patients with culture-positive pulmonary TB. We analyzed patient, contact, environmental and bacterial characteristics. Of the 2422 contacts named by 256 patients, 149 (6.2%) had new infection due to recent transmission from 79 (30.9%) patients. Of the 149 new infections, 87 (58.4%) occurred among household contacts and 62 (41.6%) among non-household contacts. Numerous acid-fast bacilli in sputum (odds ratio [OR] 2.64, 95%CI 1.32-5.25) and contacts being named by more than one patient (OR 2.90, 95%CI 1.23-6.85) were associated with new infection among household contacts. Being older than 50 years (OR 1.93, 95%CI 1.09-3.41) and an Asian/Pacific Islander (OR 3.09, 95%CI 1.50-6.37) were associated with new infection among non-household contacts. Fewer than one third of patients caused new infection to his/her contacts. A substantial proportion of transmission resulting in new infection occurred outside of the household. The risk factors for infection among household and non-household contacts are different and should be considered when prioritizing control interventions. .

Background The roles of host and pathogen factors in determining innate immune responses to M. tuberculosis are not fully understood. In this study, we examined host macrophage immune responses of 3 race/ethnic groups to 3 genetically and geographically diverse M. tuberculosis lineages. Methods Monocyte-derived macrophages from healthy Filipinos, Chinese and non-Hispanic White study participants (approximately 45 individuals/group) were challenged with M. tuberculosis whole cell lysates of clinical strains Beijing HN878 (lineage 2), Manila T31 (lineage 1), CDC1551 (lineage 4), the reference strain H37Rv (lineage 4), as well as with Toll-like receptor 2 agonist lipoteichoic acid (TLR2/LTA) and TLR4 agonist lipopolysaccharide (TLR4/LPS). Following overnight incubation, multiplex assays for nine cytokines: IL-1β, IL-2, IL-6, IL-8, IL-10, IL-12p70, IFNγ, TNFα, and GM-CSF, were batch applied to supernatants. Results Filipino macrophages produced less IL-1, IL-6, and more IL-8, compared to macrophages from Chinese and Whites. Race/ethnicity had only subtle effects or no impact on the levels of IL-10, IL-12p70, TNFα and GM-CSF. In response to the Toll-like receptor 2 agonist lipoteichoic acid (TLR2/LTA), Filipino macrophages again had lower IL-1 and IL-6 responses and a higher IL-8 response, compared to Chinese and Whites. The TLR2/LTA-stimulated Filipino macrophages also produced lower amounts of IL-10, TNFα and GM-CSF. Race/ethnicity had no impact on IL-12p70 levels released in response to TLR2/LTA. The responses to TLR4 agonist lipopolysaccharide (TLR4/LPS) were similar to the TLR2/LTA responses, for IL-1, IL-6, IL-8, and IL-10. However, TLR4/LPS triggered the release of less IL-12p70 from Filipino macrophages, and less TNFα from White macrophages. Conclusions Both host race/ethnicity and pathogen strain influence the innate immune response. Such variation may have implications for the development of new tools across TB therapeutics, immunodiagnostics and vaccines.

BACKGROUND The impact of demographic, clinical, and bacterial factors on new infection by Euro-American lineage Mycobacterium tuberculosis among contacts of patients with tuberculosis (TB) has not been evaluated. OBJECTIVE To describe the risk factors for new infection by Euro-American M. tuberculosis sublineages in San Francisco, California. DESIGN We included contacts of patients with TB due to Euro-American M. tuberculosis. Sublineages were determined by large-sequence polymorphisms. We used tuberculin skin testing or QuantiFERON®-TB Gold In-Tube to identify contacts with new infection. Regression models with generalized estimating equations were used to determine the risk factors for new infection. RESULTS We included 1488 contacts from 134 patients with TB. There were 79 (5.3%) contacts with new infection. In adjusted analyses, contacts of patients with TB due to region of difference 219 M. tuberculosis sublineage were less likely to have new infection (OR 0.23, 95%CI 0.06-0.84) than those with other sublineages. Other risk factors for new infection were contacts exposed to more than one patient with TB, contacts exposed for 30 days, or contacts with a history of smoking or excessive alcohol consumption. CONCLUSIONS In addition to well-known exposure and clinical characteristics, bacterial characteristics independently contribute to the transmissibility of TB in San Francisco.

SETTING The impact of the genetic characteristics of Mycobacterium tuberculosis on the clustering of multidrug-resistant tuberculosis (MDR-TB) has not been analyzed together with clinical and demographic characteristics. OBJECTIVE To determine factors associated with genotypic clustering of MDR-TB in a community-based study. DESIGN We measured the proportion of clustered cases among MDR-TB patients and determined the impact of clinical and demographic characteristics and that of three M. tuberculosis genetic characteristics: lineage, drug resistance-associated mutations, and rpoA and rpoC compensatory mutations. RESULTS Of 174 patients from California and Texas included in the study, the number infected by East-Asian, Euro-American, Indo-Oceanic and East-African-Indian M. tuberculosis lineages were respectively 70 (40.2%), 69 (39.7%), 33 (19.0%) and 2 (1.1%). The most common mutations associated with isoniazid and rifampin resistance were respectively katG S315T and rpoB S531L. Potential compensatory mutations in rpoA and rpoC were found in 35 isolates (20.1%). Hispanic ethnicity (OR 26.50, 95%CI 3.73-386.80), infection with an East-Asian M. tuberculosis lineage (OR 30.00, 95%CI 4.20-462.40) and rpoB mutation S531L (OR 4.03, 95%CI 1.05-23.10) were independent factors associated with genotypic clustering. CONCLUSION Among the bacterial factors studied, East-Asian lineage and rpoB S531L mutation were independently associated with genotypic clustering, suggesting that bacterial factors have an impact on the ability of M. tuberculosis to cause secondary cases.

(41%) or not changing (44%) the overall quality of care and perceived their practice style differences as neutral or beneficial. Twenty-eight percent of primary care physicians believed that the quality of the physician-patient relationship decreased; 69% reported that hospitalists did not affect their income; 53% believed that hospitalists decreased their workload; and 50% believed that hospitalists increased practice satisfaction. In a multivariate model predicting physician perceptions, internists, physicians who attributed loss of income to hospitalists, and physicians in mandatory hospitalist systems viewed hospitalists less favorably. Conclusions: Practicing primary care physicians have generally favorable perceptions of hospitalists’ effect on patients and on their own practice satisfaction, especially in voluntary hospitalist systems that decrease the workload of primary care physicians and do not threaten their income. Primary care physicians, particularly internists, are less accepting of mandatory hospitalist systems.

SETTING:Immunosuppressive conditions have been associated with low sensitivity of interferon-gamma release assays (IGRAs) and the tuberculin skin test (TST) for the diagnosis of tuberculosis (TB). However, no systematic analysis of patient and bacterial characteristics has been performed before.OBJECTIVE:To determine the sensitivity and the risk factors for false-negative QuantiFERON(®)-TB (QFT) assay and TST in TB patients.DESIGN:We performed a retrospective analysis of data collected in a community-based study of TB in San Francisco, CA, USA. We included 300 TB patients who underwent QFT and TST.RESULTS:The risk factors for false-negative QFT were human immunodeficiency virus infection and the use of QuantiFERON(®)-TB Gold. In patients with sputum smear-negative TB, diabetes mellitus (DM) was associated with false-negative QFT (OR 2.85, 95%CI 1.02-7.97, P = 0.045). TST sensitivity was higher than QFT sensitivity in DM patients (OR 9.46, 95%CI 2.53-35.3).CONCLUSIONS:In San Francisco, QFT sensitivity was lower than that of TST, especially in patients with DM. Stratified analysis by sputum smear results showed that this association was specific to smear-negative TB. In contrast, TST was not affected by the presence of DM.

Setting The impact of diabetes on tuberculosis in United States and foreign-born populations in San Francisco has not been studied. Objective To determine the characteristics, prevalence and temporal trends of diabetes in US and foreign-born persons attending the San Francisco Tuberculosis Clinic. Design We analyzed data from individuals seeking medical attention at the San Francisco Tuberculosis Clinic. We included patients with diagnosis of tuberculosis, latent infection, or not infected with Mycobacterium tuberculosis. We assessed the temporal trend and the characteristics of individuals with and without diabetes. Result Between 2005 and 2012, there were 4371 (19.0%) individuals without evidence of tuberculosis infection, 17,856 (77.6%) with latent tuberculosis, and 791 (3.4%) with tuberculosis. 66% were born in the United States, China, Mexico, and the Philippines. The prevalence of diabetes was the highest among individuals with tuberculosis and increased during the study period. Patients with tuberculosis and diabetes were more likely to be male, older than 45 years and born in the Philippines. There was a disproportionate association of TB and DM relative to LTBI and DM among Filipinos in individuals older than 45 years old. Conclusions Our data suggest that Filipinos older than 45 years old are more likely to have tuberculosis probably due to a higher prevalence of diabetes. In San Francisco, tuberculosis-screening programs in individuals with diabetes and latent tuberculosis may be beneficial in patients older than 45 years old especially from the Philippines.

RATIONALEIn San Francisco, 70% of the tuberculosis cases occur among foreign-born persons, mainly from China, the Philippines, and Mexico. We postulate that there are differences in the characteristics and risk factors for tuberculosis among these populations.OBJECTIVESTo determine the clinical, epidemiological and microbiological characteristics of tuberculosis caused by recent infection and rapid evolution in the major groups of foreign-born and the U.S.-born populations.METHODSWe analyzed data from a 20-year prospective community-based study of the molecular epidemiology of tuberculosis in San Francisco. We included all culture-positive tuberculosis cases in the City during the study period.MEASUREMENTS AND MAIN RESULTSWe calculated and compared incidence rates, clinical and microbiological characteristics, and risk factors for being a secondary case between the various foreign-born and U.S.-born tuberculosis populations. Between 1991 and 2010, there were 4,058 new cases of tuberculosis, of which 1,226 (30%) were U.S.-born and 2,832 (70%) were foreign-born. A total of 3,278 (81%) were culture positive, of which 2,419 (74%) had complete data for analysis. The incidence rate, including the incidence rate of tuberculosis due to recent infection and rapid evolution, decreased significantly in the U.S.-born and the major foreign-born populations. The clinical and microbiological characteristics and the risk factors for tuberculosis due to recent infection differed among the groups.CONCLUSIONSThere are differences in the characteristics and the risk factors for tuberculosis due to recent transmission among the major foreign-born and U.S.-born populations in San Francisco. These differences should be considered for the design of targeted tuberculosis control interventions.

SETTING:Mycobacterium tuberculosis is classified into six phylogenetic lineages, each of which can be divided into sublineages. Sublineages of the same lineage have phenotypic differences, including their capacity to cause disease (pathogenicity).OBJECTIVE:1) To test the hypothesis that different sublineages of lineage 4, which causes most of the tuberculosis (TB) in the United States, have varying ability to cause secondary cases as determined by genotypic clustering, a proxy for pathogenicity; and 2) to determine if spoligotype and mycobacterial interspersed repetitive units (MIRU) typing could infer sublineage.DESIGN:We included TB cases caused by lineage 4 strains from our community-based study in San Francisco. Sublineage was determined by regions of difference. Genotypic clustering was determined by insertion sequence 6110 and polymorphic guanine-cytosine-rich sequence. Associations between sublineages and patient characteristics were evaluated with adjusted and unadjusted analyses.RESULTS:The most frequent sublineage was H37Rv-like. In the adjusted analysis, sublineage 183 was associated with clustering and homelessness. We found that strains from different sublineages had convergent spoligotype and MIRU types.CONCLUSIONS:Sublineage 183 is associated with genotypic clustering, evidence of its being more able to cause secondary cases than the other lineage 4 sublineages. This finding suggests that bacterial factors contribute to the pathogenesis of TB. Spoligotype and MIRU type cannot be used to infer sublineage.

This article evaluates the accuracy of reporting do not resuscitate (DNR) orders in administrative data for use in risk-adjusted hospital assessments. We compared DNR reporting by 48 California hospitals in 2005 patient discharge data (PDD) with gold-standard assessments made by registered nurses (RNs) who reabstracted 1,673 records of patients with myocardial infarction, pneumonia, or heart failure. The PDD agreed with the RN reabstraction in 1,411 (84.3%) cases. The administrative data did not reflect a DNR order in 71 of 512 records where the RN indicated there was (14% false negative rates), and reflected a DNR order in 191 of 1,161 records where the RN indicated there was not (16% false positive rate). The accuracy of DNR was more problematic for patients who died, suggesting that hospital-reported DNR is problematic for capturing patient preferences for resuscitation that can be used for risk-adjusted outcomes assessments.

Previously reported associations between race/ethnicity and tuberculosis infection have lacked sufficient adjustment for socioeconomic factors. We analyzed race/ethnicity and self-reported tuberculosis infection data from the Coronary Artery Risk Development in Young Adults (CARDIA) study, a well-characterized cohort of 5115 black and white participants, and found that after adjusting for sociodemographic and clinical factors, black participants were more likely to report tuberculosis infection and/or disease (odds ratio, 2.0; 95% confidence interval, 1.5-2.9).

OBJECTIVE: To estimate agreement and correlation between the tuberculin skin test and an interferon gamma release assay for detecting latent tuberculosis (TB) infection in pregnant women. METHODS: We conducted a cross-sectional study of pregnant women initiating prenatal care at a university-affiliated public hospital between January 5, 2009, and March 15, 2010. Eligible women received a questionnaire about TB history and risk factors as well as the tuberculin skin test and phlebotomy for the interferon gamma release assay. Agreement and correlation between tests were estimated, and different cutoffs for interferon gamma release assay positivity were used to assess effect on agreement. Furthermore, predictors of test positivity and test discordance were evaluated using multivariable analysis. RESULTS: Of the 220 enrolled women, 199 (90.5%) returned for tuberculin skin test evaluation. Over 70% were Hispanic and 65% were born in a country with high TB prevalence. Agreement between the tuberculin skin test and interferon gamma release assay was 77.39 (&kgr;=0.26). This agreement was not significantly changed using different cutoffs for the assay. Birth bacille Calmette-Guérin vaccination was associated with tuberculin skin test positivity (odds ratio [OR] 4.33, 95% confidence interval [CI] 1.4–13.48, P=.01), but not interferon gamma release assay positivity. There were no statistically significant predictors of the tuberculin skin test and interferon gamma release assay result discordance; however, birth in a high-prevalence country was marginally associated with tuberculin skin test-positive and interferon gamma release assay-negative results (OR 2.94, 95% CI 0.86–9.97 P=.08). CONCLUSION: Comparing the tuberculin skin test and interferon gamma release assay results in pregnancy, concordance and agreement were poor. Given that much is still unknown about the performance of interferon gamma release assays in pregnancy, further research is necessary before the tuberculin skin test is abandoned for screening of latent TB infection in pregnancy. LEVEL OF EVIDENCE: III

BACKGROUND:Tuberculosis is a leading cause of death worldwide, yet the determinants of death are not well understood. We sought to determine risk factors for mortality during treatment of drug-susceptible pulmonary tuberculosis under program settings.METHODS:Retrospective chart review of patients with drug-susceptible tuberculosis reported to the San Francisco Tuberculosis Control Program from 1990-2001.RESULTS:Of 565 patients meeting eligibility criteria, 37 (6.6%) died during the study period. Of 37 deaths, 12 (32.4%) had tuberculosis listed as a contributing factor. In multivariate analysis controlling for follow-up time, four characteristics were independently associated with mortality: HIV co-infection (HR = 2.57, p = 0.02), older age at tuberculosis diagnosis (HR = 1.52 per 10 years, p = 0.001); initial sputum smear positive for acid fast bacilli (HR = 3.07, p = 0.004); and experiencing an interruption in tuberculosis therapy (HR = 3.15, p = 0.002). The association between treatment interruption and risk of death was due to non-adherence during the intensive phase of treatment (HR = 3.20, p = 0.001). The median duration of treatment interruption did not differ significantly in either intensive or continuation phases between those who died and survived (23 versus 18 days, and 37 versus 29 days, respectively). No deaths were directly attributed to adverse drug reactions.CONCLUSIONS:In addition to advanced age, HIV and characteristics of advanced tuberculosis, experiencing an interruption in anti-tuberculosis therapy, primarily due to non-adherence, was also independently associated with increased risk of death. Improving adherence early during treatment for tuberculosis may both improve tuberculosis outcomes as well as decrease mortality.

OBJECTIVE:To test the accuracy of reporting present-on-admission (POA) and to assess whether POA reporting accuracy differs by hospital characteristics.DATA SOURCES:We performed an audit of POA reporting of secondary diagnoses in 1,059 medical records from 48 California hospitals.STUDY DESIGN:We used patient discharge data (PDD) to select records with secondary diagnoses that are powerful predictors of mortality and could potentially represent comorbidities or complications among patients who either had a primary procedure of a percutaneous transluminal coronary angioplasty or a primary diagnosis of acute myocardial infarction, community-acquired pneumonia, or congestive heart failure. We modeled the relationship between secondary diagnoses POA reporting accuracy (over-reporting and under-reporting) and hospital characteristics.DATA COLLECTION:We created a gold standard from blind reabstraction of the medical records and compared the accuracy of the PDD against the gold standard.PRINCIPAL FINDINGS:The PDD and gold standard agreed on POA reporting in 74.3 percent of records, with 13.7 percent over-reporting and 11.9 percent under-reporting. For-profit hospitals tended to overcode secondary diagnoses as present on admission (odds ratios [OR] 1.96; 95 percent confidence interval [CI] 1.11, 3.44), whereas teaching hospitals tended to undercode secondary diagnoses as present on admission (OR 2.61; 95 percent CI 1.36, 5.03).CONCLUSIONS:POA reporting of secondary diagnoses is moderately accurate but varies by hospitals. Steps should be taken to improve POA reporting accuracy before using POA in hospital assessments tied to payments.

Monitoring the incidence of human immunodeficiency virus (HIV) infection among men who have sex with men (MSM) is imperative for developing targeted prevention programs and evaluating their effectiveness. The authors used California counseling and testing data to estimate the temporal trend in HIV incidence among MSM in California. HIV incidence rates were retrospectively calculated among MSM who had received at least 1 HIV test at a public California counseling and testing site between 1997 and 2007 and had a prior HIV-negative test from any HIV testing source. All study subjects were weighted on the basis of the interval between the last HIV-negative test and the current HIV test to account for the right-truncation bias introduced by more frequent testers. The authors observed that the HIV incidence rate among MSM in California increased from 2.0/100 person-years (95% confidence interval (CI): 1.8, 2.2) in 1997 to 2.4/100 person-years (95% CI: 2.2, 2.6) in 2003 and then decreased to 1.9/100 person-years (95% CI: 1.7, 2.0) in 2006. Trend analyses showed that both the increase (P < 0.001) and the decrease (P < 0.01) were statistically significant. The study showed that HIV incidence among MSM in California had decreased since 2003.