Background: Exposure to first-line anti-tuberculosis (TB) drugs varies significantly between individuals and populations. We developed population pharmacokinetic (PopPK) models using observational data from persons receiving fixed-dose combination (FDC) to evaluate the association of HIV, DM, and toxicity with drug exposure. Methods: RePORT-Brazil participants with drug-susceptible, culture-confirmed pulmonary TB treated with rifampin, isoniazid, pyrazinamide, and ethambutol (FDC) were included. Samples were obtained at month 1 of TB treatment. Age, sex, weight, DM- (according to glycated hemoglobin, non-DM ≤5·7%, pre-DM 5·8–6·4%, and DM ≥6·5%), HIV-status, and NAT2 profiles were examined. Adverse drug reactions (ADRs) were graded for severity. Liquid chromatography/Mass Spectrometry quantified drug concentration. Time since last dose was self-reported; samples >8h post-dose and with undetectable levels were excluded. Monolix® was used for model building and individual parameter estimation. AUC0-8 exposures were compared by DM-, HIV-status, and ADRs. Findings​: Of 388 unique samples (one per participant), 49 (13%) were excluded. Rifampin had the highest rate of undetectable levels (n=45, 13%), which was associated with shorter self-reported time between dose intake and sample collection (median 1·8 vs 3·0 hours, p<0·001) but not with other baseline characteristics. One-compartment PopPK models adequately described all drugs. AUC0-8 was lower among people with HIV (PWH) for rifampin (p=0·008) and ethambutol (p=0·022). Pre-DM and DM were associated with lower rifampin exposure (p=0·026 and p=0·004, respectively), and pre-DM with lower pyrazinamide exposure (p=0·027). PWH were more likely to experience grade ≥2 ADRs compared to HIV-negative individuals (30% vs 15%, p=0·003). Isoniazid exposure was higher among participants with grade ≥2 ADRs compared to those without (79·7 vs 73·5 mg·h/L, p=0·02). Interpretation: In people receiving TB treatment, four PopPK models demonstrated lower rifampin and ethambutol exposure among PWH, lower rifampin exposure with pre-DM and DM, lower pyrazinamide exposure with pre-DM, and higher isoniazid exposure among those with grade ≥2 ADRs. Funding: National Institutes of Health

Tuberculosis (TB) treatment is highly effective, but response to therapy varies by geography and population subgroups. We assessed differences in TB treatment response in a representative and heterogeneous Brazilian population. We estimated genetic ancestry according to major genetic ancestry groups (African, European, and Amerindian) in the Regional Prospective Observational Research in Tuberculosis (RePORT)-Brazil cohort using ADMIXTURE software. RePORT-Brazil is an observational prospective cohort study of individuals with newly-diagnosed, culture-confirmed, pulmonary TB. Outcomes attributed to TB treatment included Grade 2 or higher adverse drug reaction (ADR), Grade 3 or higher ADR, hepatic ADR, and failure/recurrence. Genetic ancestry proportions were evaluated as predictors in univariate and multivariable logistic regression models for each outcome, and in stratified models for each genetic ancestry group. There were 930 pulmonary TB patients included in this study. In multivariable models we observed a decreased risk of Grade 2 + ADR when African ancestry proportion increased by 10

BACKGROUND Tuberculosis/human immunodeficiency virus (TB/HIV) coinfection is associated with advanced HIV disease and variable responses to antiretroviral therapy (ART). OBJECTIVES We examined whether baseline HIV severity markers, ART regimes, or human genetic variants influenced HIV-1 virologic suppression in HIV-associated TB. METHODS We included TB/HIV participants from Regional Prospective Observational Research in Tuberculosis (RePORT)-Brazil study, who received standard TB therapy and antiretroviral treatment. The primary endpoint was HIV-1 virologic suppression (≤ 1,000 copies/mL); Baseline characteristics, viral load (VL), CD4 cell count, timing of ART initiation, and ART regimens were included. We genotyped UGT1A1 (rs887829; integrase strand transfer inhibitor-related) and CYP2B6 [rs3745274, rs28399499, rs4803419; efavirenz (EFZ)-related]; all have defined normal, intermediate, and slow genotypes. Genotyping was performed by MassARRAY iPLEX Gold; Kaplan-Meier curves compared time-to-suppression with log-rank tests; Cox proportional hazards models estimated hazard ratios. FINDINGS Among 194 participants, 68% (n = 132) achieved virologic suppression (≤ 1,000 copies/mL). Median time-to-suppression: 84 days [95% confidence interval (CI): 42-125]. Participants with higher baseline viral load (BVL) (≥ 5 log10 copies/mL) had delayed suppression compared with those with lower VL (< 5 log10; log-rank χ² = 75.9; p < 0.001). Individuals with CD4 ≤ 200 cells/µL suppressed more slowly than those with CD4 > 200 cells/µL (log-rank χ² = 29.6; p < 0.001). Participants starting ART before TB treatment achieved suppression faster than ART-naïve individuals (32 vs. 147 days; log-rank χ² = 48.5; p < 0.001). Higher BVL was associated with reduced hazard of suppression [adjusted hazard ratio (aHR) = 0.67; 95% CI: 0.61-0.75], while higher baseline CD4 count increased the hazard of suppression (per 100 cells/µL: aHR = 1.11; 95% CI: 1.01-1.21). ART-naïve status was associated with lower hazard of suppression in univariate analysis (Hazard Ratio = 0.51; 95% CI: 0.36-0.72) but not after adjustment. ART regimen class and pharmacogenetic metabolizer profiles were not significantly associated with virologic suppression. MAIN CONCLUSIONS BVL and CD4 count were the strongest determinants of virologic suppression in TB/HIV patients. Suppression rates were low, and neither ART regimen nor pharmacogenetic profiles significantly influenced the likelihood of suppression.

Background Tuberculosis (TB) treatment-related adverse drug reactions (TB-ADR) can negatively affect adherence and treatment success rates. Methods We developed two prediction models for TB-ADR. We included drug-susceptible pulmonary TB participants who initiated standard TB therapy. TB-ADR were determined by physician-assigned attributions of causality, and described according to affected organ system, timing, and grade. Potential predictors of TB-ADR included concomitant medication (CM) use, HIV-status, glycated hemoglobin (HbA1c), age, body mass index (BMI), sex, substance use, and TB drug metabolism variables (e.g., NAT2 acetylator profile). Bootstrapped backwards selection was used to develop the models. Cox proportional hazards regression was used to evaluate TB-ADR risk. Results There were 156 TB-ADR among 102 (11%) of the 945 participants included. Most TB-ADR were hepatic (n=82;53%), grade 2 (n=121;78%), and occurred in NAT2 slow acetylators (n=62;61%). The main prediction model included CM use, HbA1c, alcohol-use, HIV-infection, BMI, and age. The alternative model included the same variables, except replaced BMI with NAT2 . Both models had good performance and fit. CM use and HIV-infection increased TB-ADR risk. Conclusions The model with only clinical variables and that with NAT2 were highly predictive of TB-ADR. The NAT2 model provides rationale to evaluate isoniazid dose adjustment and ADR risk.

Background: Human genetic variants can affect TB and HIV drug metabolism, which may lead to toxicity or treatment failure. We evaluated associations between genetic variants of antiretroviral therapy (ART) and HIV-1 outcomes among TB/HIV patients. Methods: We included RePORT-Brazil participants with TB/HIV who initiated standard TB treatment [2 months of isoniazid/rifampicin (or rifabutin)/pyrazinamide/ethambutol, then 4 months or more of isoniazid/rifampicin (or rifabutin)], and ART. The endpoint was HIV-1 virologic suppression (defined as <1,000 HIV-1 RNA copies/mL, for primary analysis, and <50 HIV-1 RNA copies/mL, for secondary analysis) after at least 2 weeks of ART. We compared non-nucleoside reverse transcriptase inhibitor (NNRTI)-based and integrase strand transfer inhibitor (INSTI)-based ART regimens. We genotyped CYP2B6 (rs3745274, rs28399499, rs4803419; affects efavirenz metabolism) and UGT1A1 (rs887829; affects dolutegravir and raltegravir metabolism); all have defined normal, intermediate, and slow genotypes. Genotyping was performed by MassARRAY iPLEX Gold. We compared outcome proportions (Fisher’s test) and time-to- virologic suppression (survival analysis, Wilcoxon-Gehan test). Results: Among 194 TB/HIV participants included, efavirenz was the most frequent NNRTI ([n=76], one participant received etravirine), and raltegravir was the most frequent INSTI (n=88). The overall virologic suppression was suboptimal, with 32% (n=62) of participants not achieving HIV-1 virologic suppression. Among them, 36% (n=28) used efavirenz-based ART and were more likely to be CYP2B6 normal metabolizers (n=8, 44%); and 30% (n=30) used INSTI-based ART and the UGT1A1 normal genotype was also the most common (n=13, 50%). The median time to virologic suppression for efavirenz-based ART was 184 days (95% Confidence Interval (CI)160-207), and for INSTI-based ART, 188 days (95% CI 144-231) (p=0.84). No significant associations were found comparing the proportions and time to virologic suppression among CYP2B6 and UGT1A1genotypes. Conclusions: In this observational cohort of patients treated for TB/HIV, the proportion of participants achieving virologic suppression was low, and genetic variants affecting ART metabolism were not significantly associated with the likelihood of virologic suppression.

BackgroundThe impact of previous SARS-CoV-2 infection on the systemic immune response during tuberculosis (TB) disease has not been explored.MethodsAn observational, cross-sectional cohort was established to evaluate the systemic immune response in persons with pulmonary tuberculosis with or without previous SARS-CoV-2 infection. Those participants were recruited in an outpatient referral clinic in Rio de Janeiro, Brazil. TB was defined as a positive Xpert-MTB/RIF Ultra and/or a positive culture of Mycobacterium tuberculosis from sputum. Stored plasma was used to perform specific serology to identify previous SARS-CoV-2 infection (TB/Prex-SCoV-2 group) and confirm the non- infection of the tuberculosis group (TB group). Plasmatic cytokine/chemokine/growth factor profiling was performed using Luminex technology. Tuberculosis severity was assessed by clinical and laboratory parameters. Participants from TB group (4.55%) and TB/Prex-SCoV-2 (0.00%) received the complete COVID-19 vaccination.ResultsAmong 35 participants with pulmonary TB, 22 were classified as TB/Prex-SCoV-2. The parameters associated with TB severity, together with hematologic and biochemical data were similar between the TB and TB/Prex-SCoV-2 groups. Among the signs and symptoms, fever and dyspnea were significantly more frequent in the TB group than the TB/Prex-SCoV-2 group (p < 0,05). A signature based on lower amount of plasma EGF, G-CSF, GM-CSF, IFN-α2, IL-12(p70), IL-13, IL-15, IL-17, IL-1β, IL-5, IL-7, and TNF-β was observed in the TB/Prex-SCoV-2 group. In contrast, MIP-1β was significantly higher in the TB/Prex-SCoV-2 group than the TB group.ConclusionTB patients previously infected with SARS-CoV-2 had an immunomodulation that was associated with lower plasma concentrations of soluble factors associated with systemic inflammation. This signature was associated with a lower frequency of symptoms such as fever and dyspnea but did not reflect significant differences in TB severity parameters observed at baseline.

Background Successful tuberculosis (TB) treatment is necessary for disease control. The World Health Organization (WHO) has a target TB treatment success rate of >= 90%. We assessed whether the different types of unfavorable TB treatment outcome had different predictors. Methods Using data from Regional Prospective Observational Research for Tuberculosis-Brazil, we evaluated biological and behavioral factors associated with each component of unsuccessful TB outcomes, recently updated by WHO (death, loss to follow-up [LTFU], and treatment failure). We included culture-confirmed, drug-susceptible, pulmonary TB participants receiving standard treatment in 2015-2019. Multinomial logistic regression models with inverse probability weighting were used to evaluate the distinct determinants of each unsuccessful outcome. Results Of 915 participants included, 727 (79%) were successfully treated, 118 (13%) were LTFU, 44 (5%) had treatment failure, and 26 (3%) died. LTFU was associated with current drug-use (adjusted odds ratio [aOR] = 5.3; 95% confidence interval [CI], 3.0-9.4), current tobacco use (aOR = 2.9; 95% CI, 1.7-4.9), and being a person living with HIV (PLWH) (aOR = 2.0; 95% CI, 1.1-3.5). Treatment failure was associated with PLWH (aOR = 2.7; 95% CI, 1.2-6.2) and having diabetes (aOR = 2.2; 95% CI, 1.1-4.4). Death was associated with anemia (aOR = 5.3; 95% CI, 1.4-19.7), diabetes (aOR = 3.1; 95% CI, 1.4-6.7), and PLWH (aOR = 3.9; 95% CI, 1.3-11.4). Direct observed therapy was protective for treatment failure (aOR = 0.5; 95% CI, .3-.9) and death (aOR = 0.5; 95% CI, .2-1.0). Conclusions The treatment success rate was below the WHO target. Behavioral factors were most associated with LTFU, whereas clinical comorbidities were correlated with treatment failure and death. Because determinants of unsuccessful outcomes are distinct, different intervention strategies may be needed to improve TB outcomes. High rates of unsuccessful treatment outcomes in a cohort of patients with tuberculosis in Brazil. Behavioral factors (drug and alcohol use) influenced losses to follow-up and clinical comorbidities (human immunodeficiency virus, diabetes, and anemia) affected treatment failure and death.

Background Despite widespread availability of curative therapy, tuberculosis (TB) treatment outcomes remain suboptimal. Clinical prediction models can inform treatment strategies to improve outcomes. Using baseline clinical data, we developed a prediction model for unsuccessful TB treatment outcome and evaluated the incremental value of human immunodeficiency virus (HIV)-related severity and isoniazid acetylator status. Methods Data originated from the Regional Prospective Observational Research for Tuberculosis Brazil cohort, which enrolled newly diagnosed TB patients in Brazil from 2015 through 2019. This analysis included participants with culture-confirmed, drug-susceptible pulmonary TB who started first-line anti-TB therapy and had >= 12 months of follow-up. The end point was unsuccessful TB treatment: composite of death, treatment failure, regimen switch, incomplete treatment, or not evaluated. Missing predictors were imputed. Predictors were chosen via bootstrapped backward selection. Discrimination and calibration were evaluated with c-statistics and calibration plots, respectively. Bootstrap internal validation estimated overfitting, and a shrinkage factor was applied to improve out-of-sample prediction. Incremental value was evaluated with likelihood ratio-based measures. Results Of 944 participants, 191 (20%) had unsuccessful treatment outcomes. The final model included 7 baseline predictors: hemoglobin, HIV infection, drug use, diabetes, age, education, and tobacco use. The model demonstrated good discrimination (c-statistic = 0.77; 95% confidence interval, .73-.80) and was well calibrated (optimism-corrected intercept and slope, -0.12 and 0.89, respectively). HIV-related factors and isoniazid acetylation status did not improve prediction of the final model. Conclusions Using information readily available at treatment initiation, the prediction model performed well in this population. The findings may guide future work to allocate resources or inform targeted interventions for high-risk patients. We detail the development and internal validation of a prognostic model, including 7 easily collected variables that accurately predict unsuccessful pulmonary tuberculosis treatment outcome. The model can be applied at the point of care with a nomogram or web application.

Drug-induced uveitis is a rare condition and usually based on a temporal relationship between drug use and the occurrence of uveitis. Some drugs, such as rifabutin, are well-known causative agents of uveitis. The pathogenesis is unclear, but the disease seems to be associated with direct toxicity. A non-granulomatous anterior uveitis is the most common presentation. Although the prognosis is good, atypically severe cases can occur.

OBJECTIVES/GOALS: Many clinical prediction models have been developed to guide tuberculosis (TB) treatment, but their results and methods have not been formally evaluated. We aimed to identify and synthesize existing models for predicting TB treatment outcomes, including bias and applicability assessment. METHODS/STUDY POPULATION: Our review will adhere to methods that developed specifically for systematic reviews of prediction model studies. We will search PubMed, Embase, Web of Science, and Google Scholar (first 200 citations) to identify studies that internally and/or externally validate a model for TB treatment outcomes (defined as one or multiple of cure, treatment completion, death, treatment failure, relapse, default, and lost to follow-up). Study screening, data extraction, and bias assessment will be conducted independently by two reviewers with a third party to resolve discrepancies. Study quality will be assessed using the Prediction model Risk Of Bias Assessment Tool (PROBAST). RESULTS/ANTICIPATED RESULTS: Our search strategy yielded 6,242 articles in PubMed, 10,585 in Embase, 10,511 in Web of Science, and 200 from Google Scholar, totaling 27,538 articles. After de-duplication, 14,029 articles remain. After screening titles, abstracts, and full-text, we will extract data from relevant studies, including publication details, study characteristics, methods, and results. Data will be summarized with narrative review and in detailed tables with descriptive statistics. We anticipate finding disparate outcome definitions, contrasting predictors across models, and high risk of bias in methods. Meta-analysis of performance measures for model validation studies will be performed if possible. DISCUSSION/SIGNIFICANCE OF IMPACT: TB outcome prediction models are important but existing ones have not been rigorously evaluated. This systematic review will synthesize TB outcome prediction models and serve as guidance to future studies that aim to use or develop TB outcome prediction models.

Background: Tuberculosis (TB) outcome prediction models are important for informing clinical practice and TB management policies, but existing models have not been systematically reviewed.Design/Methods: PubMed, Embase, Web of Science, and Google Scholar were searched for studies published January 1, 1995 - January 9, 2020. Studies that developed a model to predict pulmonary TB treatment outcomes were included. Study screening, data extraction, and quality assessment were conducted independently by two reviewers. Study quality was evaluated using the Prediction model Risk Of Bias Assessment Tool (PROBAST). The study was pre-registered on OSF (https://osf.io/rz3wp).Findings: 14,739 articles were identified, 536 underwent full-text review, and 33 studies presenting 37 prediction models were included. Model outcomes included death (n=16, 43%), treatment failure (n=6, 16%), default (n=6, 16%) or a composite outcome (n=9, 25%). Most models (n=29, 78%) measured discrimination (median c-statistic=0.75; IQR: 0.68-0.84), and 17 (46%) reported calibration, often the Hosmer-Lemeshow test (n=13). Nineteen (51%) models were internally validated, and six (16%) were externally validated. Eighteen studies (54%) mentioned missing data, and of those half (n=9) used complete case analysis. The most common predictors included age, sex, extrapulmonary TB, body mass index (BMI), chest x-ray results, previous TB, and HIV. Risk of bias varied across studies, but all studies had high risk of bias in their analysis.Interpretation: TB outcome prediction models are heterogeneous with disparate outcome definitions, predictors, and methodology. We do not recommend applying any in clinical settings without external validation, and encourage future researchers adhere to guidelines for developing and reporting of prediction models.Funding Statement: This work was supported by the National Center for Advancing Translational Sciences [CTSA Award No. TL1TR000447 to L.S.P.].Declaration of Interests: None declared.

Angionvasive mucormycosis is an emerging fungal disease known to affect mainly diabetics or subjects with profound neutropenia. Infection usually occurs through the inhalation route, but cutaneous inoculation may occur after trauma or burns. However, mucormycosis remains unusual in HIV infection. We report a fatal case of cutaneous mucormycosis due to Rhizopus arrhizus involving the scalp following herpes zoster infection. The patient was a 42-year-old man with advanced AIDS failing on salvage antiretroviral therapy. The fungus was diagnosed on the basis of histopathology and culture. Our case emphasizes the need to consider mucormycosis in the differential diagnosis of necrotic cutaneous lesions in patients with late-stage HIV disease.

OBJECTIVES:To report that dengue fever (DF) could have triggered Plasmodium ovale wallikeri malaria.METHODS:A retrospective case report of P. ovale malaria and DF in a single patient in Rio de Janeiro, Brazil, who had lived in Angola, is presented.RESULTS:On the second week of illness, the patient was referred to our research service. As symptoms had persisted up to day 14, malaria was also considered, based on the patient's long-standing epidemiological history. On day 16 of illness, a thick blood smear was positive for P. ovale (3480 parasites/mm(3)), PCR for malaria was positive for P. ovale wallikeri, and the kinetics of dengue virus (DENV) antibodies suggested a recent primary dengue infection.CONCLUSIONS:Concurrent infections of DENV and malaria have rarely been reported; the actual impact of these sequential or simultaneous infections remains unknown. Therefore, DF must be considered as a potential co-morbidity for malaria, because of its influence on fluid electrolyte management. The case presented showed consistent temporal, clinical, and laboratory evidence that the relapse or the long incubation period of P. ovale malaria may have been triggered by a recent DF episode. To the authors' knowledge, this is the first report of DENV and P. ovale co-infection.

INTRODUCAO: Os esforcos de deteccao precoce do câncer de prostata, identificados em fases clinicas e patologicas iniciais, levou ao aumento no numero de biopsias e, por vezes, indefinicao do diagnostico histologico de adenocarcinoma devido a presenca de carcinomas minimos ou alteracoes pseudoneoplasicas, como proliferacao atipica de pequenos acinos (PAPA). Nesses casos, o uso da imuno-histoquimica (IMH) para evidenciar a presenca de celulas basais tornou-se uma pratica comum em laboratorios de patologia. OBJETIVOS: O presente estudo visa a avaliar a incidencia de PAPA e de adenocarcinoma minimo em dois laboratorios de patologia do interior, bem como avaliar a contribuicao da IMH e da rebiopsia no diagnostico do câncer de prostata. METODOS: Foram revistas 641 biopsias de prostata por agulha realizadas entre janeiro de 2005 e dezembro de 2010. Dos 73 casos diagnosticados como PAPA (11,38%), 35 foram submetidos ao exame imuno-histoquimico, usando anticorpos anti-34sE12 e p63, assim como sete casos diagnosticados como adenocarcinoma minimo (1,1%). Resultados: Os resultados mostraram que a tecnica foi conclusiva em 31 casos (88,57%), com diagnostico final de adenocarcinoma em 19 pacientes (54,28%); 12 (34,28%) com lesoes benignas; e apenas quatro (11,42%) inconclusivos (PAPA). CONCLUSAO: Os resultados sugerem que IMH deve ser rotineiramente usada em biopsias limitrofes e casos de PAPA, pois contribui significativamente para o diagnostico de câncer de prostata.

Introduction: Efforts for the identification of prostate cancer in the initial clinical and pathological stages led to an increase in the number of biopsies, sometimes making the histological diagnosis of adenocarcinoma difficult. This is due to the presence of minimal carcinoma or atypical glands suspicious for carcinoma, also known as atypical small acinar proliferation (ASAP). In these cases, the use of immunohistochemistry (IHC) has become a common practice in laboratories of pathology. Objectives: The aims of this study were to assess the incidence of diagnoses of ASAP and minimal adenocarcinoma in two laboratories of pathology and to evaluate the contribution of IHC and repeat biopsy to the diagnosis of prostate cancer. Methods: We reviewed 641 sets of modified sextant needle biopsies of the prostate performed in two laboratories of pathology between January 2005 and December 2010. IHC using 34βE12 and p63 antibodies was performed on 35 of 73 (11.38%) cases diagnosed as ASAP and on 7 (1.1%) cases diagnosed as minimal adenocarcinoma. Results: The incidence of ASAP diagnosis was 11.38% (n = 73). IHC was performed in 35 of the 73 ASAP cases and provided conclusive results in 31 cases (88.57%), resulting in a final diagnosis of adenocarcinoma in 19 patients (54.28%), benign lesions in 12 patients (34 28%); only 4 (11.42%) were inconclusive. Conclusion: The results suggest that IHC should be routinely used in evaluation of borderline biopsies and in ASAP cases. IHC strongly contributes to the diagnosis of prostate cancer. abstract key words Prostate