Elevated Plasma Matrix Metalloproteinase 8 Associates With Sputum Culture Positivity in Pulmonary Tuberculosis.

Current methods for tuberculosis treatment monitoring are suboptimal. We evaluated plasma matrix metalloproteinase (MMP) and procollagen III N-terminal propeptide concentrations before and during tuberculosis treatment as biomarkers. Plasma MMP-1, MMP-8, and MMP-10 concentrations significantly decreased during treatment. Plasma MMP-8 was increased in sputum Mycobacterium tuberculosis culture-positive relative to culture-negative participants, before (median, 4993 pg/mL [interquartile range, 2542-9188] vs 698 [218-4060] pg/mL, respectively; P = .004) and after (3650 [1214-3888] vs 720 [551-1321] pg/mL; P = .008) 6 months of tuberculosis treatment. Consequently, plasma MMP-8 is a potential biomarker to enhance tuberculosis treatment monitoring and screen for possible culture positivity.

Tuberculosis and risk of acute myocardial infarction: a propensity score-matched analysis.

Several pathogens have been associated with increased cardiovascular disease (CVD) risk. Whether this occurs with Mycobacterium tuberculosis infection is unclear. We assessed if tuberculosis disease increased the risk of acute myocardial infarction (AMI). We identified patients with tuberculosis index claims from a large de-identified database of ~15 million adults enrolled in a U.S. commercial insurance policy between 2008 and 2010. Tuberculosis patients were 1:1 matched to patients without tuberculosis claims using propensity scores. We compared the occurrence of index AMI claims between the tuberculosis and non-tuberculosis cohorts using Kaplan-Meier curves and Cox Proportional Hazard models. Data on 2026 patients with tuberculosis and 2026 propensity-matched patients without tuberculosis were included. AMI was more frequent in the tuberculosis cohort compared with the non-tuberculosis cohort, 67 (3·3%) vs. 32 (1·6%) AMI cases, respectively, P < 0·01. Tuberculosis was associated with an increased risk of AMI (adjusted hazard ratio (HR) 1·98, 95% confidence intervals (CI) 1·3-3·0). The results were similar when the analysis was restricted to pulmonary tuberculosis (adjusted HR 2·43, 95% CI 1·5-4·1). Tuberculosis was associated with an increased risk of AMI. CVD risk assessment should be considered in tuberculosis patients. Mechanistic studies of tuberculosis and CVD are warranted.

Body mass index and the risk of incident noncommunicable diseases after starting antiretroviral therapy.

OBJECTIVES: Obesity and HIV infection are associated with an increased incidence of noninfectious comorbid medical conditions, but the relationship between body mass index (BMI) and the development of noncommunicable diseases (NCDs) among individuals on antiretroviral therapy (ART) has not been well characterized. METHODS: A cohort study of adults initiating ART between 1998 and 2010 at an academic centre with systematic laboratory and clinical data collection, including AIDS and NCD diagnoses, was carried out. The relationship between BMI at ART initiation and the risk of incident cardiovascular, hepatic, renal or oncological NCDs was assessed using Cox proportional hazard models. BMI was fitted using restricted cubic splines and models adjusted for age, sex, race, CD4 count, protease inhibitor use, year of initiation, and prior AIDS-defining illness. RESULTS: Among 1089 patients in the analysis cohort, 54% had normal BMI, 28% were overweight, and 18% were obese. Baseline BMI was associated with developing an incident NCD (P<0.01), but the relationship was nonlinear. Compared with a BMI of 25 kg/m(2) , a BMI of 30 kg/m(2) conferred a lower risk of an incident NCD diagnosis [adjusted hazard ratio (AHR) 0.59; 95% confidence interval (CI) 0.40, 0.87]. This protective effect was attenuated at a BMI of 35 kg/m(2) (AHR 0.78; 95% CI 0.49, 1.23). Results were similar in sensitivity analyses incorporating tobacco, alcohol and illicit drug use, statin and antihypertensive exposure, and virological suppression. CONCLUSIONS: Overweight individuals starting ART have a lower risk of developing NCDs compared with normal BMI individuals, which may reflect a biological effect of adipose tissue or differences in patient or provider behaviours.

Body mass index and early CD4 T-cell recovery among adults initiating antiretroviral therapy in North America, 1998-2010.

OBJECTIVES: Adipose tissue affects several aspects of the cellular immune system, but prior epidemiological studies have differed on whether a higher body mass index (BMI) promotes CD4 T-cell recovery on antiretroviral therapy (ART). The objective of this analysis was to assess the relationship between BMI at ART initiation and early changes in CD4 T-cell count. METHODS: We used the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) data set to analyse the relationship between pre-treatment BMI and 12-month CD4 T-cell recovery among adults who started ART between 1998 and 2010 and maintained HIV-1 RNA levels < 400 copies/mL for at least 6 months. Multivariable regression models were adjusted for age, race, sex, baseline CD4 count and HIV RNA level, year of ART initiation, ART regimen and clinical site. RESULTS: A total of 8381 participants from 13 cohorts contributed data; 85% were male, 52% were nonwhite, 32% were overweight (BMI 25-29.9 kg/m(2) ) and 15% were obese (BMI > 30 kg/m(2) ). Pretreatment BMI was associated with 12-month CD4 T-cell change (P < 0.001), but the relationship was nonlinear (P < 0.001). Compared with a reference of 22 kg/m(2) , a BMI of 30 kg/m(2) was associated with a 36 cells/µL [95% confidence interval (CI) 14, 59 cells/µL] greater CD4 T-cell count recovery among women and a 19 cells/µL (95% CI 9, 30 cells/µL) greater recovery among men at 12 months. At a BMI > 30 kg/m(2) , the observed benefit was attenuated among men to a greater degree than among women, although this difference was not statistically significant. CONCLUSIONS: A BMI of approximately 30 kg/m(2) at ART initiation was associated with greater CD4 T-cell recovery at 12 months compared with higher or lower BMI values, suggesting that body composition may affect peripheral CD4 T-cell recovery.

A comparison of interview methods to ascertain fluoroquinolone exposure before tuberculosis diagnosis.

SUMMARY Fluoroquinolone use before tuberculosis (TB) diagnosis delays the time to diagnosis and treatment, and increases the risk of fluoroquinolone-resistant TB and death. Ascertainment of fluoroquinolone exposure could identify such high-risk patients. We compared four methods of ascertaining fluoroquinolone exposure in the 6 months prior to TB diagnosis in culture-confirmed TB patients in Tennessee from January 2007 to December 2009. The four methods included a simple questionnaire administered to all TB suspects by health department personnel (FQ-Form), an in-home interview conducted by research staff, outpatient and inpatient medical record review, and TennCare pharmacy database review. Of 177 TB patients included, 72 (41%) received fluoroquinolones during the 6 months before TB diagnosis. Fluoroquinolone exposure determined by review of inpatient and outpatient medical records was considered the gold standard for comparison. The FQ-Form had 61% [95% confidence interval (CI) 48-73] sensitivity and 93% (95% CI 85-98) specificity (agreement 79%, kappa = 0.56) while the in-home interview had 28% (95% CI 18-40) sensitivity and 99% (94-100%) specificity (agreement 68%, kappa = 0.29). A simple questionnaire administered by health department personnel identified fluoroquinolone exposure before TB diagnosis with moderate reliability.

Tuberculosis and the risk of infection with other intracellular bacteria: a population-based study.

SUMMARY Persons who develop tuberculosis (TB) may have subtle immune defects that could predispose to other intracellular bacterial infections (ICBIs). We obtained data on TB and five ICBIs (Chlamydia trachomatis, Salmonella spp., Shigella spp., Yersinia spp., Listeria monocytogenes) reported to the Tennessee Department of Health, USA, 2000-2011. Incidence rate ratios (IRRs) comparing ICBIs in persons who developed TB and ICBIs in the Tennessee population, adjusted for age, sex, race and ethnicity were estimated. IRRs were not significantly elevated for all ICBIs combined [IRR 0.87, 95% confidence interval (CI) 0.71-1.06]. C. trachomatis rate was lowest in the year post-TB diagnosis (IRR 0.17, 95% CI 0.04-0.70). More Salmonella infections occurred in extrapulmonary TB compared to pulmonary TB patients (IRR 14.3, 95% CI 1.67-122); however, this appeared to be related to HIV co-infection. TB was not associated with an increased risk of other ICBIs. In fact, fewer C. trachomatis infections occurred after recent TB diagnosis. Reasons for this association, including reduced exposure, protection conferred by anti-TB drugs or macrophage activation by Mycobacterium tuberculosis infection warrant further investigation.

Isoniazid preventive therapy completion in children under 5 years old who are contacts of tuberculosis cases in Lima, Peru: study protocol for an open-label, cluster-randomized superiority trial.

BACKGROUND: Children < 5 years old in contact with TB cases are at high risk for developing severe and fatal forms of TB. Contact investigation, BCG vaccination, and isoniazid preventive therapy (IPT) are the most effective strategies to prevent TB among children. However, the implementation of IPT faces challenges at several stages of the cascade of care of TB infection among children, particularly those less than 5 years old. In Peru, a large proportion of children do not complete IPT, which highlights the need to design effective interventions that enhance preventive therapy adherence and completion. Although the body of evidence for such interventions has grown, interventions in medium TB incidence settings are lacking. This study aims to test the effectiveness, acceptability, and feasibility of an intervention package to increase information and motivation to complete IPT among children < 5 who have been prescribed IPT. METHODS: An open-label, cluster-randomized superiority trial will be conducted in two districts in South Lima, Peru. Thirty health facilities will be randomized as clusters, 10 to the intervention and 20 to control (standard of care). We aim to recruit 10 children from different households in each cluster. Participants will be caretakers of children aged < 5 years old who initiated IPT. The intervention consists of educational material, and short message services (SMS) reminders and motivators. The primary outcomes will be the proportion of children who picked up > 90% of the 24 weeks of IPT (22 pick-ups) and the proportion of children who picked up the 24 weeks of IPT. The standard of care is a weekly pick-up with monthly check-ups in a health facility. Feasibility and acceptability of the intervention will be assessed through an interview with the caretaker. DISCUSSION: Unfavorable outcomes of TB in young children, high effectiveness of IPT, and low rates of IPT completion highlight the need to enhance adherence and completion of IPT among children < 5 years old. Testing of a context-adapted intervention is needed to improve IPT completion rates and therefore TB prevention in young children. TRIAL REGISTRATION: ClinicalTrials.gov NCT03881228. Registered on March 19, 2019.

Microcolonies in fluoroquinolone agar proportion susceptibility testing of Mycobacterium tuberculosis: an indicator of drug resistance.

Microcolony growth of Mycobacterium tuberculosis on agar proportion susceptibility testing is neither well-defined nor previously reported with fluoroquinolone susceptibility testing. We describe here M. tuberculosis microcolony growth with fluoroquinolones, and assess its clinical significance. We screened 797 M. tuberculosis isolates for ofloxacin resistance (2.0 µg/mL) by agar proportion; 19 ofloxacin-resistant and 38 ofloxacin-susceptible isolates were selected for more detailed susceptibility testing with ofloxacin, ciprofloxacin, levofloxacin (all at 2.0 µg/mL) and moxifloxacin (0.5 µg/mL). The 57 isolates were also tested at two concentrations both above and below the critical concentrations. Microcolonies were defined as colonies 0.2-0.4 mm in diameter; confirmed microcolonies were present on repeat testing. Of the 57 isolates tested in detail, 7 grew microcolonies, of which 2 (0.3% of all isolates tested) had confirmed microcolonies on repeat testing (6 tests performed, and microcolonies were present on at least 4). Both M. tuberculosis isolates were ofloxacin-resistant on screening, and had ofloxacin minimum inhibitory concentration (MIC) >8 µg/mL. The five other isolates were ofloxacin-susceptible on screening, but had regular colony growth (i.e., resistance) at the drug concentration that initially resulted in microcolonies (ofloxacin 0.5 or 1.0 µg/mL). Microcolonies were observed infrequently with fluoroquinolone susceptibility testing, but when confirmed, they were associated with drug resistance.

Factors associated with screening failure and study withdrawal in multidrug-resistant TB.

SETTING: Multidrug-resistant TB (MDR-TB) clinical trial in Lima, Peru and Cape Town, South Africa.OBJECTIVE: To identify baseline factors associated with screening failure and study withdrawal in an MDR-TB clinical trial.DESIGN: We screened patients for a randomized, blinded, Phase II trial which assessed culture conversion over the first 6 months of treatment with varying doses of levofloxacin plus an optimized background regimen (ClinicalTrials.gov: NCT01918397). We identified factors for screening failure and study withdrawal using Poisson regression to calculate prevalence ratios and Cox proportional hazard regression to calculate hazard ratios. We adjusted for factors with P < 0.2.RESULTS: Of the 255 patients screened, 144 (56.5%) failed screening. The most common reason for screening failure was an unsuitable resistance profile on sputum-based molecular susceptibility testing (n = 105, 72.9%). No significant baseline predictors of screening failure were identified in the multivariable model. Of the 111 who were enrolled, 33 (30%) failed to complete treatment, mostly for non-adherence and consent withdrawal. No baseline factors predicted study withdrawal in the multivariable model.CONCLUSION: No baseline factors were independently associated with either screening failure or study withdrawal in this secondary analysis of a MDR-TB clinical trial.

Prevalence and clinical characteristics of pulmonary TB among pregnant and post-partum women.

SETTING: Antenatal care (ANC) and postpartum care (PPC) clinic in Manhiça District, Mozambique.OBJECTIVE: To estimate the prevalence of TB among pregnant and post-partum women and describe the clinical characteristics of the disease in a rural area of Southern Mozambique.METHODS: We conducted a cross-sectional TB prevalence study among pregnant and post-partum women recruited from September 2016 to March 2018 at the Manhiça Health Care Center (MHC). We recruited two independent cohorts of women consecutively presenting for routine pregnancy or post-partum follow-up visits.RESULTS: A total of 1,980 women from the ANC clinic and 1,010 from the PPC clinic were enrolled. We found a TB prevalence of 505/100,000 (95% CI: 242-926) among pregnant women and 297/100,000 (95% CI: 61-865) among post-partum women. Among HIV-positive pregnant women, TB prevalence was 1,626/100,000 (95% CI: 782-2,970) and among postpartum HIV-positive women, TB prevalence was 984/100,000 (95% CI: 203-2,848).CONCLUSIONS: The burden of TB was not higher in postpartum women than in pregnant women. Most TB cases were detected in HIV-positive women. TB screening and diagnostic testing among pregnant and postpartum women attending ANC and PPC clinics in Manhiça District is acceptable and feasible.

Potentially preventable tuberculosis among HIV-infected persons in the era of highly active antiretroviral treatment.

OBJECTIVE: To characterize the proportion of tuberculosis (TB) cases that could have been prevented among human immunodeficiency virus (HIV) infected persons receiving care in the era of highly active antiretroviral treatment (HAART). DESIGN: We conducted an observational cohort study among HIV-infected patients with >or=2 out-patient visits at the Comprehensive Care Center, Nashville, Tennessee, USA, between 1 January 1998 and 31 December 2005. METHODS: A potentially preventable TB case was defined as a case in which the patient received no screening tuberculin skin test (TST) prior to TB diagnosis or a case in which a patient with a positive screening TST did not complete treatment for latent infection. RESULTS: Of 3601 HIV-infected persons in care (13 905 person-years [p-y] of follow-up), 29 developed TB (230/100,000 p-y). Of the 29, 20 (69%) had not had TST performed as part of routine screening. Of the nine patients screened, four had a positive test, three of whom completed treatment for latent TB infection. Of 29 TB cases, 21 (72%) were therefore potentially preventable. CONCLUSIONS: Most TB cases in this cohort were potentially preventable had the patients undergone a screening TST followed by treatment of latent infection if they had a positive TST.

HIV-related tuberculosis: mortality risk in persons without vs. with culture-confirmed disease.

BACKGROUND: Tuberculosis (TB) diagnosis in human immunodeficiency virus (HIV) positive persons is difficult, particularly in resource-limited settings. The relationship between TB culture status and mortality in HIV-positive persons treated for TB is unclear. METHODS: We evaluated HIV-positive adults treated for TB at or after their first HIV clinic visit in Argentina, Brazil, Chile, Honduras, Mexico or Peru from 2000 to 2015. Anti-tuberculosis treatment included 2 months of isoniazid, rifampicin (RMP)/rifabutin (RBT), pyrazinamide ± ethambutol, followed by continuation phase treatment with isoniazid + RMP/RBT. RESULTS: Of 759 TB-HIV patients, 238 (31%) were culture-negative, 228 (30%) had unknown culture status or did not undergo culture and 293 (39%) were culture-positive. The median CD4 at TB diagnosis was 96 (interquartile range 40-228); 636 (84%) received concurrent antiretroviral therapy (ART) and anti-tuberculosis treatment. There were 123 (16%) deaths: 90/466 (19%) with TB culture-negative, unknown or not performed vs. 33/293 (11%) who were TB culture-positive (P = 0.005). In Kaplan-Meier analysis, mortality in TB patients without culture-confirmed disease was higher (P = 0.002). In a Cox model adjusted for age, sex, CD4, ART timing, disease site and stratified by study site, mortality in persons without culture-confirmed TB was not significantly increased compared to those with culture-positive TB (hazard ratio 1.39, 95%CI 0.89-2.16, P = 0.15). CONCLUSION: Most HIV-positive patients treated for TB did not have culture-confirmed TB, and mortality tended to be higher in patients without culture-confirmed disease, although the association was not statistically different after adjusting for other variables. Accurate TB diagnosis in HIV-positive persons is crucial.

Normal chest radiography in pulmonary tuberculosis: implications for obtaining respiratory specimen cultures.

SETTING: Urban tuberculosis (TB) clinic, Nashville, Tennessee, USA. OBJECTIVE: Chest radiographs (CXRs) help in the diagnosis of pulmonary TB, but may be normal. Mycobacterium tuberculosis in culture is diagnostic of TB, but cultures are not routinely obtained in resource-poor settings. We examined rates and risk factors for pulmonary TB associated with normal CXR. DESIGN: An observational cohort study was performed among all respiratory culture-positive TB cases referred to the Nashville Health Department from October 1992 to July 2003. Clinical factors, demographics and underlying medical conditions were assessed. RESULTS: Of 601 study patients, 53 (9%) had normal CXRs: 31/138 (22%) were human immunodeficiency virus (HIV) infected and 22/463 (5%) were non-HIV-infected/unknown (P<0.001). Among HIV-infected patients, normal CXR was more likely in persons with renal failure (13% vs. 3%, P=0.048). Among non-HIV-infected/unknown patients, normal CXR was more likely in those who were asymptomatic at presentation (32% vs. 13%, P=0.022). In multivariable logistic regression analysis, HIV infection was associated with an increased risk of normal CXR (odds ratio [OR] 6.61, P<0.0001); factors associated with reduced risk were dyspnea (OR 0.24, P=0.026), positive sputum smear (OR 0.45, P=0.028) and cough (OR 0.48, P=0.038). CONCLUSIONS: The rate of normal CXR among persons with culture-confirmed pulmonary TB was high. Respiratory specimen cultures should be obtained in TB suspects with a normal CXR, particularly HIV-infected persons.

Older age at first tuberculosis diagnosis is associated with tuberculosis recurrence in HIV-negative persons.

SETTING: Tuberculosis (TB) clinic in Durban, South Africa. OBJECTIVE: To assess the factors associated with TB recurrence among human immunodeficiency virus (HIV) negative adults and children. DESIGN: We conducted a retrospective longitudinal study from January 2000 to December 2012. We defined recurrence as a TB episode occurring within the study period after treatment completion or cure of a previous episode. We used a multivariable Poisson regression model to assess the factors associated with the number of recurrences among HIV-negative patients. RESULTS: Among 17 941 patients with known HIV status, 3653 (20%) were HIV-negative; of these, 235 (6%) had one recurrence, 21 (1%) had two recurrences and 4 (0.1%) had three recurrences. The median follow-up time from the end of treatment for the first episode was 3.0 years (interquartile range 1.9-4.2). Age at the first TB episode was significantly associated with the number of TB recurrences: younger patients had the lowest rate of recurrence, with a steady increase in rates until age 40 years, after which rates stabilized. CONCLUSIONS: TB recurrence rates among HIV-negative patients were higher at increased age at the first TB episode. Further translational studies are needed to clarify the factors that drive multiple TB recurrences in older age, including impaired immunity, the results of which have implications for TB vaccine development.

Isoniazid-monoresistant tuberculosis is associated with poor treatment outcomes in Durban, South Africa.

SETTING: A large tuberculosis (TB) clinic in Durban, South Africa. OBJECTIVE: To determine the association between isoniazid (INH) monoresistant TB and treatment outcomes. DESIGN: We performed a retrospective longitudinal study of patients seen from 2000 to 2012 to compare episodes of INH-monoresistant TB with those of drug-susceptible TB using logistic regression with robust standard errors. INH-monoresistant TB was treated with modified regimens. RESULTS: Among 18 058 TB patients, there were 19 979 TB episodes for which drug susceptibility testing was performed. Of these, 557 were INH-monoresistant and 16 311 were drug-susceptible. Loss to follow-up, transfer, and human immunodeficiency virus (HIV) co-infection (41% had known HIV status) were similar between groups. INH-monoresistant episodes were more likely to result in treatment failure (4.1% vs. 0.6%, P < 0.001) and death (3.2% vs. 1.8%, P = 0.01) than drug-susceptible episodes. After adjustment for age, sex, race, retreatment status, and disease site, INH-monoresistant episodes were more likely to have resulted in treatment failure (OR 6.84, 95%CI 4.29-10.89, P < 0.001) and death (OR 1.81, 95%CI 1.11-2.95, P = 0.02). CONCLUSION: INH monoresistance was associated with worse clinical outcomes than drug-susceptible TB. Our findings support the need for rapid diagnostic tests for INH resistance and improved treatment regimens for INH-monoresistant TB.

Factors associated with non-completion of follow-up: 33-month latent tuberculous infection treatment trial.

SETTING: A post-hoc exploratory analysis of a randomized, open-label clinical trial that enrolled 8053 participants from the United States, Canada, Brazil, and Spain. OBJECTIVE: To assess factors associated with non-completion of study follow-up (NCF) in a 33-month latent tuberculous infection treatment trial, PREVENT TB. DESIGN: Participants were randomized to receive 3 months of weekly directly observed therapy vs. 9 months of daily self-administered therapy. NCF was defined as failing to be followed for at least 993 days (33 months) from enrollment. Possible factors associated with NCF were analyzed using univariate and multivariate regression via Cox proportional hazard model. RESULTS: Of 7061 adults selected for analysis, 841 (11.9%) did not complete study follow-up. Homelessness, young age, low education, history of incarceration, smoking, missing an early clinic visit, receiving isoniazid only, and male sex were significantly associated with NCF. Similar results were found in the North American region (United States and Canada) only. In Brazil and Spain, the only significant factor was missing an early clinic visit. CONCLUSIONS: Study subjects at higher risk for NCF were identified by characteristics known at enrollment or in early follow-up. Evaluation of follow-up in other trials might help determine whether the identified factors consistently correlate with retention.

Pediatric multidrug-resistant tuberculosis clinical trials: challenges and opportunities.

On June 17, 2016, RESIST-TB, IMPAACT, Vital Strategies, and New Ventures jointly hosted the Pediatric Multidrug Resistant Tuberculosis Clinical Trials Landscape Meeting in Arlington, Virginia, USA. The meeting provided updates on current multidrug-resistant tuberculosis (MDR-TB) trials targeting pediatric populations and adult trials that have included pediatric patients. A series of presentations were given that discussed site capacity needs, community engagement, and additional interventions necessary for clinical trials to improve the treatment of pediatric MDR-TB. This article presents a summary of topics discussed, including the following: current trials ongoing and planned; the global burden of MDR-TB in children; current regimens for MDR-TB treatment in children; pharmacokinetics of second-line anti-tuberculosis medications in children; design, sample size, and statistical considerations for MDR-TB trials in children; selection of study population, design, and treatment arms for a trial of novel pediatric MDR-TB regimens; practical aspects of pediatric MDR-TB treatment trials; and strategies for integrating children into adult tuberculosis trials. These discussions elucidated barriers to pediatric MDR-TB clinical trials and provided insight into necessary next steps for progress in this field. Investigators and funding agencies need to respond to these recommendations so that important studies can be implemented, leading to improved treatment for children with MDR-TB.

Outcomes of HIV-positive patients with cryptococcal meningitis in the Americas.

BACKGROUND: Cryptococcal meningitis (CM) is associated with substantial mortality in HIV-infected patients. Optimal timing of antiretroviral therapy (ART) in persons with CM represents a clinical challenge, and the burden of CM in Latin America has not been well described. Studies suggest that early ART initiation is associated with higher mortality, but data from the Americas are scarce. METHODS: HIV-infected adults in care between 1985-2014 at participating sites in the Latin America (the Caribbean, Central and South America network (CCASAnet)) and the Vanderbilt Comprehensive Care Clinic (VCCC) and who had CM were included. Survival probabilities were estimated. Risk of death when initiating ART within the first 2 weeks after CM diagnosis versus initiating between 2-8 weeks was assessed using dynamic marginal structural models adjusting for site, age, sex, year of CM, CD4 count, and route of HIV transmission. FINDINGS: 340 patients were included (Argentina 58, Brazil 138, Chile 28, Honduras 27, Mexico 34, VCCC 55) and 142 (42%) died during the observation period. Among 151 patients with CM prior to ART 56 (37%) patients died compared to 86 (45%) of 189 with CM after ART initiation (p=0.14). Patients diagnosed with CM after ART had a higher risk of death (p=0.03, log-rank test). The probability of survival was not statistically different between patients who started ART within 2 weeks of CM (7/24, 29%) vs. those initiating between 2-8 weeks (14/53, 26%) (p=0.96), potentially due to lack of power. INTERPRETATION: In this large Latin-American cohort, patients with CM had very high mortality rates, especially those diagnosed after ART initiation. This study reflects the overwhelming burden of CM in HIV-infected patients in Latin America.

Mortality in a large tuberculosis treatment trial: modifiable and non-modifiable risk factors.

SETTING: North America. OBJECTIVES: Tuberculosis (TB) patients in North America often have characteristics that may increase overall mortality. Identifying modifiable risk factors would allow for improvements in outcome. DESIGN: We evaluated mortality in a large TB treatment trial conducted in the United States and Canada. Persons with culture-positive pulmonary TB were enrolled after 2 months of treatment, treated for 4 more months under direct observation, and followed for 2 years (total observation: 28 months). Cause of death was determined by death certificate, autopsy, and/or clinical observation. RESULTS: Of 1075 participants, 71 (6.6%) died: 15/71 (21.1%) HIV-infected persons, and 56/1004 (5.6%) non-HIV-infected persons (P < 0.001). Only one death was attributed to TB. Cox multivariate regression analysis identified four independent risk factors for death after controlling for age: malignancy (hazard ratio [HR] 5.28, P < 0.0001), HIV (HR 3.89, P < 0.0001), daily alcohol (HR 2.94, P < 0.0001), and being unemployed (HR 1.99, P = 0.01). The risk of death increased with the number of independent risk factors present (P < 0.0001). Extent of disease and treatment failure/relapse were not associated with an increased risk of death. CONCLUSIONS: Death due to TB was rare. Interventions to treat malignancy, HIV, and alcohol use in TB patients are needed to reduce mortality in this patient population.

Fluoroquinolones for the treatment and prevention of multidrug-resistant tuberculosis.

Although fluoroquinolones (FQs) play an important role in the treatment of multidrug-resistant tuberculosis (MDR-TB), there are several issues that need to be addressed to optimize their effectiveness and minimize toxicity. This includes identification of the optimal dose of FQs such as levofloxacin (LVX) and moxifloxacin, and the optimal role of FQs in combination with other anti-tuberculosis drugs, particularly those with overlapping toxicity, such as QT prolongation. While the ability of FQs to penetrate into cavities and granulomas is likely beneficial, suboptimal sensitivity of genotypic tests to detect FQ resistance could negatively affect treatment outcomes of FQ-containing regimens. Several trials are underway to evaluate the safety and effectiveness of FQs as part of combination MDR-TB therapy; there are also two planned studies of LVX to prevent tuberculosis among close contacts of MDR-TB.