Bedaquiline-pretomanid-moxifloxacin-pyrazinamide for drug-sensitive and drug-resistant pulmonary tuberculosis treatment: a phase 2c, open-label, multicentre, partially randomised controlled trial.

BACKGROUND: The current tuberculosis (TB) drug development pipeline is being re-populated with candidates, including nitroimidazoles such as pretomanid, that exhibit a potential to shorten TB therapy by exerting a bactericidal effect on non-replicating bacilli. Based on results from preclinical and early clinical studies, a four-drug combination of bedaquiline, pretomanid, moxifloxacin, and pyrazinamide (BPaMZ) regimen was identified with treatment-shortening potential for both drug-susceptible (DS) and drug-resistant (DR) TB. This trial aimed to determine the safety and efficacy of BPaMZ. We compared 4 months of BPaMZ to the standard 6 months of isoniazid, rifampicin, pyrazinamide, and ethambutol (HRZE) in DS-TB. 6 months of BPaMZ was assessed in DR-TB. METHODS: SimpliciTB was a partially randomised, phase 2c, open-label, clinical trial, recruiting participants at 26 sites in eight countries. Participants aged 18 years or older with pulmonary TB who were sputum smear positive for acid-fast bacilli were eligible for enrolment. Participants with DS-TB had Mycobacterium tuberculosis with sensitivity to rifampicin and isoniazid. Participants with DR-TB had M tuberculosis with resistance to rifampicin, isoniazid, or both. Participants with DS-TB were randomly allocated in a 1:1 ratio, stratified by HIV status and cavitation on chest radiograph, using balanced block randomisation with a fixed block size of four. The primary efficacy endpoint was time to sputum culture-negative status by 8 weeks; the key secondary endpoint was unfavourable outcome at week 52. A non-inferiority margin of 12% was chosen for the key secondary outcome. Safety and tolerability outcomes are presented as descriptive analyses. The efficacy analysis population contained patients who received at least one dose of medication and who had efficacy data available and had no major protocol violations. The safety population contained patients who received at least one dose of medication. This study is registered with ClinicalTrials.gov (NCT03338621) and is completed. FINDINGS: Between July 30, 2018, and March 2, 2020, 455 participants were enrolled and received at least one dose of study treatment. 324 (71%) participants were male and 131 (29%) participants were female. 303 participants with DS-TB were randomly assigned to 4 months of BPaMZ (n=150) or HRZE (n=153). In a modified intention-to-treat (mITT) analysis, by week 8, 122 (84%) of 145 and 70 (47%) of 148 participants were culture-negative on 4 months of BPaMZ and HRZE, respectively, with a hazard ratio for earlier negative status of 2·93 (95% CI 2·17-3·96; p<0·0001). Median time to negative culture (TTN) was 6 weeks (IQR 4-8) on 4 months of BPaMZ and 11 weeks (6-12) on HRZE. 86% of participants with DR-TB receiving 6 months of BPaMZ (n=152) reached culture-negative status by week 8, with a median TTN of 5 weeks (IQR 3-7). At week 52, 120 (83%) of 144, 134 (93%) of 144, and 111 (83%) of 133 on 4 months of BPaMZ, HRZE, and 6 months of BPaMZ had favourable outcomes, respectively. Despite bacteriological efficacy, 4 months of BPaMZ did not meet the non-inferiority margin for the key secondary endpoint in the pre-defined mITT population due to higher withdrawal rates for adverse hepatic events. Non-inferiority was demonstrated in the per-protocol population confirming the effect of withdrawals with 4 months of BPaMZ. At least one liver-related treatment-emergent adverse effect (TEAE) occurred among 45 (30%) participants on 4 months of BPaMZ, 38 (25%) on HRZE, and 33 (22%) on 6 months of BPaMZ. Serious liver-related TEAEs were reported by 20 participants overall; 11 (7%) among those on 4 months of BPaMZ, one (1%) on HRZE, and eight (5%) on 6 months of BPaMZ. The most common reasons for discontinuation of trial treatment were hepatotoxicity (ten participants [2%]), increased hepatic enzymes (nine participants [2%]), QTcF prolongation (three participants [1%]), and hypersensitivity (two participants [<1%]). INTERPRETATION: For DS-TB, BPaMZ successfully met the primary efficacy endpoint of sputum culture conversion. The regimen did not meet the key secondary efficacy endpoint due to adverse events resulting in treatment withdrawal. Our study demonstrated the potential for treatment-shortening efficacy of the BPaMZ regimen for DS-TB and DR-TB, providing clinical validation of a murine model widely used to identify such regimens. It also highlights that novel, treatment-shortening TB treatment regimens require an acceptable toxicity and tolerability profile with minimal monitoring in low-resource and high-burden settings. The increased risk of unpredictable severe hepatic adverse events with 4 months of BPaMZ would be a considerable obstacle to implementation of this regimen in settings with high burdens of TB with limited infrastructure for close surveillance of liver biochemistry. Future research should focus on improving the preclinical and early clinical detection and mitigation of safety issues together and further efforts to optimise shorter treatments. FUNDING: TB Alliance.

Inflammasome genetic variants are associated with tuberculosis, HIV-1 infection, and TB/HIV-immune reconstitution inflammatory syndrome outcomes.

Background: Tuberculosis (TB) and AIDS are the leading causes of infectious diseases death worldwide. Here, we investigated the relationship between from single nucleotide polymorphisms (SNPs) of the NLRP3, CARD8, AIM2, CASP-1, IFI16, and IL-1ß inflammasome genes, as well as the profiles of secreted proinflammatory cytokines (e.g., IL-1ß, IL-18, IL-33, and IL-6) with the TB clinical profiles, TB-HIV coinfection, and IRIS onset. Methods: The individuals were divided into four groups: TB-HIV group (n=88; 11 of them with IRIS), HIV-1 group (n=20), TB group (n=24) and healthy volunteers (HC) group (n=10), and were followed up at INI/FIOCRUZ and HGNI (Rio de Janeiro/Brazil) from 2006 to 2016. Real-time PCR was used to determine the genotypes of the Single Nucleotide Polymorphism (SNPs), and ELISA was used to measure the plasma cytokine levels. Unconditional logistic regression models were used to perform risk estimations. Results: A higher risk for extrapulmonary TB was associated with the TT genotype (aOR=6.76; P=0.026) in the NLRP3 rs4612666 Single Nucleotide Polymorphism (SNP) and the C-C-T-G-C haplotype (aOR=4.99; P= 0.017) in the NLRP3 variants. This same Single Nucleotide Polymorphism (SNP) was associated with lower risk against extrapulmonary TB when the carrier allele C (aOR=0.15; P=0.021) was present. Among those with HIV-1 infections, a higher risk for TB onset was associated with the GA genotype (aOR=5.5; P=0.044) in the IL1-ß rs1143634 Single Nucleotide Polymorphism (SNP). In contrast, lower risk against TB onset was associated with the A-G haplotype (aOR=0.17; P= 0.026) in the CARD8 variants. Higher IL-6 and IL-33 levels were observed in individuals with TB. A higher risk for IRIS onset was associated with CD8 counts ≤ 500 cells/mm3 (aOR=12.32; P=0.010), the presence of extrapulmonary TB (aOR=6.6; P=0.038), and the CT genotype (aOR=61.06; P=0.026) or carrier allele T (aOR=61.06; P=0.026) in the AIM2 rs2276405 Single Nucleotide Polymorphism (SNP), whereas lower risk against IRIS onset was associated with the AT genotype (aOR=0.02; P=0.033) or carrier allele T (aOR=0.02; P=0.029) in the CARD8 rs2043211 Single Nucleotide Polymorphism (SNP) and the T-G haplotype (aOR=0.07; P= 0.033) in the CARD8 variants. No other significant associations were observed. Conclusions: Our results depict the involvement of genetic polymorphisms of crucial innate immunity genes and proinflammatory cytokines in the clinical outcomes related to TB-HIV coinfection.

Homozygotes NAT2*5B slow acetylators are highly associated with hepatotoxicity induced by anti-tuberculosis drugs.

BACKGROUND: Distinct N-acetyltransferase 2 (NAT2) slow acetylators genotypes have been associated with a higher risk to develop anti-tuberculosis drug-induced hepatotoxicity (DIH). However, studies have not pointed the relevance of different acetylation phenotypes presented by homozygotes and compound heterozygotes slow acetylators on a clinical basis. OBJECTIVES: This study aimed to investigate the association between NAT2 genotypes and the risk of developing DIH in Brazilian patients undergoing tuberculosis treatment, focusing on the discrimination of homozygotes and compound heterozygotes slow acetylators. METHODS/FINDINGS: The frequency of NAT2 genotypes was analysed by DNA sequencing in 162 patients undergoing tuberculosis therapy. The mutation analyses revealed 15 variants, plus two new NAT2 mutations, that computational simulations predicted to cause structural perturbations in the protein. The multivariate statistical analysis revealed that carriers of NAT2*5/*5 slow acetylator genotype presented a higher risk of developing anti-tuberculosis DIH, on a clinical basis, when compared to the compound heterozygotes presenting NAT2*5 and any other slow acetylator haplotype [aOR 4.97, 95% confidence interval (CI) 1.47-16.82, p = 0.01]. CONCLUSION: These findings suggest that patients with TB diagnosis who present the NAT2*5B/*5B genotype should be properly identified and more carefully monitored until treatment outcome in order to prevent the occurrence of anti-tuberculosis DIH.

Homozygotes NAT2*5B slow acetylators are highly associated with hepatotoxicity induced by anti-tuberculosis drugs

BACKGROUND Distinct N-acetyltransferase 2 (NAT2) slow acetylators genotypes have been associated with a higher risk to develop anti-tuberculosis drug-induced hepatotoxicity (DIH). However, studies have not pointed the relevance of different acetylation phenotypes presented by homozygotes and compound heterozygotes slow acetylators on a clinical basis. OBJECTIVES This study aimed to investigate the association between NAT2 genotypes and the risk of developing DIH in Brazilian patients undergoing tuberculosis treatment, focusing on the discrimination of homozygotes and compound heterozygotes slow acetylators. METHODS/FINDINGS The frequency of NAT2 genotypes was analysed by DNA sequencing in 162 patients undergoing tuberculosis therapy. The mutation analyses revealed 15 variants, plus two new NAT2 mutations, that computational simulations predicted to cause structural perturbations in the protein. The multivariate statistical analysis revealed that carriers of NAT2*5/*5 slow acetylator genotype presented a higher risk of developing anti-tuberculosis DIH, on a clinical basis, when compared to the compound heterozygotes presenting NAT2*5 and any other slow acetylator haplotype [aOR 4.97, 95% confidence interval (CI) 1.47-16.82, p = 0.01]. CONCLUSION These findings suggest that patients with TB diagnosis who present the NAT2*5B/*5B genotype should be properly identified and more carefully monitored until treatment outcome in order to prevent the occurrence of anti-tuberculosis DIH.

Correction: Anemia in tuberculosis cases: A biomarker of severity?

[This corrects the article DOI: 10.1371/journal.pone.0245458.].

Anemia in tuberculosis cases: A biomarker of severity?

INTRODUCTION: Anemia is a common condition at tuberculosis diagnosis, and there is evidence that its prevalence is higher in patients with tuberculosis than in those infected with Mycobacterium tuberculosis and healthy controls. Information about anemia during tuberculosis diagnosis is still scarce in the Brazilian population. The aim of this study was to describe the prevalence of anemia in patients with tuberculosis cared for at a referral center and its association with clinical forms of tuberculosis and other characteristics of these patients. MATERIALS AND METHODS: This was a retrospective cross-sectional study of tuberculosis patients diagnosed from January 2015 to December 2018 at the Clinical Research Laboratory on Mycobacteria (LAPCLIN-TB) of Evandro Chagas National Institute of Infectious Diseases (INI)/Oswaldo Cruz Foundation (Fiocruz). A database of an ongoing cohort study underway at this service since 2000 provided the baseline information on tuberculosis cases extracted from a visit template. Exploratory and logistic regression analyses were performed to verify associations between anemia and demographic characteristics, socioeconomic status, clinical conditions, and laboratory results. RESULTS: Of the 328 cases reviewed, 70 were excluded, with258 retained. The prevalence of anemia was 61.2% (27.5% mild, 27.5% moderate and 6.2% severe). Among patients with anemia, 60.8% had normochromic normocytic anemia, and 27.8% showed hypochromic microcytic anemia. In logistic regression analysis, anemia was associated with a history of weight loss >10%, hospitalizations, coinfection with HIV, increased platelet count and microcytosis. Anemia was more frequent in the most severe clinical forms, such as meningeal and disseminated tuberculosis. CONCLUSIONS: Anemia was highly prevalent in tuberculosis patients at diagnosis, predominantly as normochromic normocytic anemia and in mild and moderate forms. It was associated with baseline characteristics and conditions indicative of severe disease, suggesting that anemia could be a biomarker of tuberculosis severity.

Tuberculosis incidence in patients with human immunodeficiency virus, treated with isoniazid for latent tuberculosis infection

Tuberculosis is the leading cause of death amongst adults with human immunodeficiency virus (HIV) infection. The lifetime risk of tuberculosis disease for a person with latent infection is estimated at 5-10% with most cases occurring within five years of initial infection. The World Health Organization recommends isoniazid preventive therapy (IPT) for latent tuberculosis treatment, amongst other strategies. The aim was to assess tuberculosis incidence, survival (free of tuberculosis) and associated factors in HIV-positive patients. IPT was offered to participants with a positive (≥5mm) tuberculin skin test. Participants were followed from February 2003-December 2016. Kaplan-Meier was used for survival analysis. Variables with p-value ≤ 0.2 in the univariate analysis entered into the multivariate Cox-Model, keeping those with p-value ≤ 0.05. The 95% confidence interval of incidence of tuberculosis was estimated using Poisson distribution. One hundred nineteen patients completed the IPT and were followed for a median duration of 110.7 months (IQR 93.1-121.0). The probability of developing tuberculosis (10 years post-IPT) was 5.4%. Tuberculosis incidence was 0.58/100 patient/years (CI 95% 0.213-1.264). IPT over 6 months provided long-term protection against tuberculosis. AIDS-defining illness was the only statistically significant variable (HR=5.67) in the multivariate model.

Primary Prophylaxis to Prevent Tuberculosis Infection in Prison Inmates: A Randomized, Double-Blind, Placebo-Controlled Trial.

In many low- and middle-income countries, tuberculosis (TB) incidence in prisons is high, exposing incarcerated populations to an elevated risk of TB infection. We conducted a randomized, double-blind, placebo-controlled trial among HIV-negative male inmates of a high TB burden prison to determine whether isoniazid given twice weekly (900 mg) for 12 months prevents TB infection. The primary outcome was QuantiFERON-TB Gold in Plus (QFT) conversion to ≥ 0.35 international units per milliliter (IU/mL) at 6 months; secondary outcomes included alternative QFT thresholds (≥ 0.7, ≥ 2.0, and ≥ 4.0 IU/mL). In total, 467 participants were randomly assigned to intervention (N = 258) or control (N = 209). In an interim analysis of participants who had completed 6 months of follow-up (N = 170), QFT conversion occurred in 20.8% (19/91) and 21.5% (17/79) of participants in intervention and control arms (efficacy: 2.9%, P = 0.91), respectively. The trial was then stopped according to the trial protocol, and the remaining participants prematurely discontinued. In an analysis of secondary outcomes, the intervention arm had significantly lower rates of conversion at a cutoff of ≥ 2.0 IU/mL (efficacy: 82.6%, P < 0.01). In conclusion, 900 mg of isoniazid, administered twice a week, did not effectively prevent QFT conversion at a cutoff point ≥ 0.35 IU/mL in a trial of QFT-negative inmates. Higher QFT cutoffs are associated with sustained conversion and greater protection. Future clinical trials that evaluate protection for latent infection should use the highest cutoff than that recommended by the manufacturer.

Clinical and genetic markers associated with tuberculosis, HIV-1 infection, and TB/HIV-immune reconstitution inflammatory syndrome outcomes.

BACKGROUND: Tuberculosis (TB) and AIDS are the leading causes of infectious disease death worldwide. In some TB-HIV co-infected individuals treated for both diseases simultaneously, a pathological inflammatory reaction termed immune reconstitution inflammatory syndrome (IRIS) may occur. The risk factors for IRIS are not fully defined. We investigated the association of HLA-B, HLA-C, and KIR genotypes with TB, HIV-1 infection, and IRIS onset. METHODS: Patients were divided into four groups: Group 1- TB+/HIV+ (n = 88; 11 of them with IRIS), Group 2- HIV+ (n = 24), Group 3- TB+ (n = 24) and Group 4- healthy volunteers (n = 26). Patients were followed up at INI/FIOCRUZ and HGNI (Rio de Janeiro/Brazil) from 2006 to 2016. The HLA-B and HLA-C loci were typed using SBT, NGS, and KIR genes by PCR-SSP. Unconditional logistic regression models were performed for Protection/risk estimation. RESULTS: Among the individuals with TB as the outcome, KIR2DS2 was associated with increased risk for TB onset (aOR = 2.39, P = 0.04), whereas HLA-B*08 and female gender were associated with protection against TB onset (aOR = 0.23, P = 0.03, and aOR = 0.33, P = 0.01, respectively). Not carrying KIR2DL3 (aOR = 0.18, P = 0.03) and carrying HLA-C*07 (aOR = 0.32, P = 0.04) were associated with protection against TB onset among HIV-infected patients. An increased risk for IRIS onset was associated with having a CD8 count ≤500 cells/mm3 (aOR = 18.23, P = 0.016); carrying the KIR2DS2 gene (aOR = 27.22, P = 0.032), the HLA-B*41 allele (aOR = 68.84, P = 0.033), the KIR2DS1 + HLA-C2 pair (aOR = 28.58, P = 0.024); and not carrying the KIR2DL3 + HLA-C1/C2 pair (aOR = 43.04, P = 0.034), and the KIR2DL1 + HLA-C1/C2 pair (aOR = 43.04, P = 0.034), CONCLUSIONS: These results suggest the participation of these genes in the immunopathogenic mechanisms related to the conditions studied. This is the first study demonstrating an association of HLA-B*41, KIR2DS2, and KIR + HLA-C pairs with IRIS onset among TB-HIV co-infected individuals.

Changes in the NK Cell Repertoire Related to Initiation of TB Treatment and Onset of Immune Reconstitution Inflammatory Syndrome in TB/HIV Co-infected Patients in Rio de Janeiro, Brazil-ANRS 12274.

Tuberculosis (TB) is the most common comorbidity and the leading cause of death among HIV-infected individuals. Although the combined antiretroviral therapy (cART) during TB treatment improves the survival of TB/HIV patients, the occurrence of immune reconstitution inflammatory syndrome (IRIS) in some patients poses clinical and scientific challenges. This work aimed to evaluate blood innate lymphocytes during therapeutic intervention for both diseases and their implications for the onset of IRIS. Natural killer (NK) cells, invariant NKT cells (iNKT), γδ T cell subsets, and in vitro NK functional activity were characterized by multiparametric flow cytometry in the following groups: 33 TB/HIV patients (four with paradoxical IRIS), 27 TB and 25 HIV mono-infected subjects (prior to initiation of TB treatment and/or cART and during clinical follow-up to 24 weeks), and 25 healthy controls (HC). Concerning the NK cell repertoire, several activation and inhibitory receptors were skewed in the TB/HIV patients compared to those in the other groups, especially the HCs. Significantly higher expression of CD158a (p = 0.025), NKp80 (p = 0.033), and NKG2C (p = 0.0076) receptors was detected in the TB/HIV IRIS patients than in the non-IRIS patients. Although more NK degranulation was observed in the TB/HIV patients than in the other groups, the therapeutic intervention did not alter the frequency during follow-up (weeks 2-24). A higher frequency of the γδ T cell population was observed in the TB/HIV patients with inversion of the Vδ2+/Vδ2- ratio, especially for those presenting pulmonary TB, suggesting an expansion of particular γδ T subsets during TB/HIV co-infection. In conclusion, HIV infection impacts the frequency of circulating NK cells and γδ T cell subsets in TB/HIV patients. Important modifications of the NK cell repertoire were observed after anti-TB treatment (week 2) but not during the cART/TB follow-up (weeks 6-24). An increase of CD161+ NK cells was related to an unfavorable outcome. Despite the low number of cases, a more preserved NK cell profile was detected in IRIS patients previous to treatment, suggesting a role for these cells in IRIS onset. Longitudinal evaluation of the NK repertoire showed the impact of TB treatment and implicated these cells in TB pathogenesis in TB/HIV co-infected patients.

Tuberculosis-HIV treatment with rifampicin or rifabutin: are the outcomes different?

BACKGROUND: Rifamycins are a group of antibiotics mainly used in the treatment of tuberculosis (TB), however they interact with antiretroviral therapy (ART). Rifabutin allows more regimens options for concomitant imunodeficiency virus (HIV) treatment compared to rifampicin. OBJECTIVE: Compare the outcomes of TB-HIV co-infected patients who used rifampicin or rifabutin. METHODS: We analysed data from a prospective cohort study at National Institute of Infectious Diseases Evandro Chagas, Rio de Janeiro (RJ), Brazil. Patients who were treated for TB and HIV with rifampicin or rifabutin, from February 2011 to September 2016 were included. FINDINGS: There were 130 TB-HIV patients, of whom 102 were treated with rifampicin and 28 with rifabutin. All patients in the rifabutin-treated group and 55% of the rifampicin-treated group patients were ART-experienced. Patients treated with rifampicin had similar abandon and cure rates, interruptions in treatment due to adverse reactions, immune reconstitution inflammatory syndrome and a similar mortality rate as those treated with rifabutin. However, rifampicin-treated patients had higher CD4 counts and more frequently undetectable HIV viral load by the end of treatment (67% versus 18%, p < 0.001) compared to rifabutin-treated patients, even when only ART-experienced patients were evaluated (66,6% versus 36,3%, p = 0.039). CONCLUSIONS: Patients who used rifabutin had worst immune and virological control. This group had more ART-experienced patients. New and simpler regimens are needed for patients who do not respond to previous antiretroviral therapies.

Tuberculosis-HIV treatment with rifampicin or rifabutin: are the outcomes different?

BACKGROUND Rifamycins are a group of antibiotics mainly used in the treatment of tuberculosis (TB), however they interact with antiretroviral therapy (ART). Rifabutin allows more regimens options for concomitant imunodeficiency virus (HIV) treatment compared to rifampicin. OBJECTIVE Compare the outcomes of TB-HIV co-infected patients who used rifampicin or rifabutin. METHODS We analysed data from a prospective cohort study at National Institute of Infectious Diseases Evandro Chagas, Rio de Janeiro (RJ), Brazil. Patients who were treated for TB and HIV with rifampicin or rifabutin, from February 2011 to September 2016 were included. FINDINGS There were 130 TB-HIV patients, of whom 102 were treated with rifampicin and 28 with rifabutin. All patients in the rifabutin-treated group and 55% of the rifampicin-treated group patients were ART-experienced. Patients treated with rifampicin had similar abandon and cure rates, interruptions in treatment due to adverse reactions, immune reconstitution inflammatory syndrome and a similar mortality rate as those treated with rifabutin. However, rifampicin-treated patients had higher CD4 counts and more frequently undetectable HIV viral load by the end of treatment (67% versus 18%, p < 0.001) compared to rifabutin-treated patients, even when only ART-experienced patients were evaluated (66,6% versus 36,3%, p = 0.039). CONCLUSIONS Patients who used rifabutin had worst immune and virological control. This group had more ART-experienced patients. New and simpler regimens are needed for patients who do not respond to previous antiretroviral therapies.

Cutaneous tuberculosis and HIV infection at a referral centre in Rio de Janeiro, Brazil.

BACKGROUND: Cutaneous tuberculosis (CTB) is a rare extrapulmonary form of tuberculosis (TB). Despite the increase in the number of cases of TB and HIV, few cases of CTB have been reported. OBJECTIVE: To describe CTB cases among patients with HIV infection from a cohort with tuberculosis. METHODS: We describe a series of 15 CTB and HIV cases, based on secondary data from 2000 to 2016. Diagnosis was based on isolation of Mycobacterium tuberculosis in culture or clinical response to anti-tuberculous treatment associated with positive smear or histopathologic findings from affected skin or an adjacent lymph node. FINDINGS: Scrofuloderma was present in 12 (80%) patients and solitary gumma in three (20%) patients. One case of scrofuloderma was associated with papulonecrotic tuberculid. Seven (46.6%) patients had pulmonary TB. Diagnosis was based on culture in nine patients (60%). The median CD4 cell count was 262 cells/µL. All patients were cured at the end of treatment (median time 6 months). Three patients presented with immune reconstitution inflammatory syndrome. CONCLUSIONS: In this study, CTB associated with HIV infection presented as localised forms or in association with pulmonary TB. In patients with HIV who have subacute and chronic skin lesions, CTB should be considered in differential diagnosis, which may represent a good opportunity for early diagnosis of active TB.

Uso da Análise dos Modos de Falha e seus Efeitos (FMEA) como ferramenta para mapear os riscos em um estudo clínico / Use of Mode and Effects Analysis (FMEA) as a tool to map the risks involved in a clinical study

Introdução: O presente estudo descreve a aplicação da ferramenta de gerenciamento de riscos Análise de Modo e Efeito de Falha (Failure Mode Effects Analysis ­ FMEA) a uma pesquisa clínica que estabelecerá um tratamento de indivíduos simultaneamente infectados por HIV e tuberculose. Objetivo: Demonstrar a importância da análise de riscos associada aos protocolos de estudos clínicos na salvaguarda do participante e dos dados do estudo, e como padrão de qualidade do estudo. Método: Os procedimentos demandados na execução do protocolo clínico e os potenciais modos de falha a eles associados foram estipulados com base na programação de visitas do participante ao centro do estudo. Os modos de falha foram valorados entre 1 e 10 de acordo com: Gravidade, Ocorrência e Detectabilidade, calculando-se o Número de Prioridade de Risco (NPR) pela multiplicação dos três valores. Resultados: Num painel de 25 procedimentos e 60 modos de falha, 50% resultaram em NPR > 120; seis deles contendo mais de cinco modos de falha. Os maiores riscos foram associados à estratégia DOT (NPR 294), à coleta de sangue (NPR 288), ao Termo de Consentimento Livre e Esclarecido (NPR 270) e a coletas de dados do participante (NPR 240). Conclusões: Os resultados demonstraram a importância da FMEA como instrumento de avaliação de riscos em estudos clínicos, alinhando-se com recomendações de órgãos normalizadores internacionais.

Introduction: This study describes the application of the Failure Mode and Effects Analysis (FMEA) as a tool for risk management during clinical research to establish the treatment of patients simultaneously infected with HIV and tuberculosis. Objective: To demonstrate the importance of risk analysis associated with clinical trial protocols in safeguarding the participant and study data, and as a study's quality standard. Method: Procedures demanded by the clinical protocol were detailed and then associated with failure modes based on the programmed visits of the participant to the study center. The failure modes were rated between 1 and 10 according to: Severity, Occurrence and Detectability, and the Risk Priority Number (RPN) was calculated by multiplying the three values. Results: In a panel of 25 procedures and 60 failure modes, 50% resulted in RPN > 120; six of which contained more than five failure modes. The highest risks were associated with the DOT strategy (RPN 294), blood collection (RPN 288), the Informed Consent Term (RPN 270) and participant data collection (RPN 240). Conclusions: The results demonstrate the importance of FMEA as a tool to assess risks in clinical studies, in line with the recommendations of international standardization organizations.

Cutaneous tuberculosis and HIV infection at a referral centre in Rio de Janeiro, Brazil

BACKGROUND Cutaneous tuberculosis (CTB) is a rare extrapulmonary form of tuberculosis (TB). Despite the increase in the number of cases of TB and HIV, few cases of CTB have been reported. OBJECTIVE To describe CTB cases among patients with HIV infection from a cohort with tuberculosis. METHODS We describe a series of 15 CTB and HIV cases, based on secondary data from 2000 to 2016. Diagnosis was based on isolation of Mycobacterium tuberculosis in culture or clinical response to anti-tuberculous treatment associated with positive smear or histopathologic findings from affected skin or an adjacent lymph node. FINDINGS Scrofuloderma was present in 12 (80%) patients and solitary gumma in three (20%) patients. One case of scrofuloderma was associated with papulonecrotic tuberculid. Seven (46.6%) patients had pulmonary TB. Diagnosis was based on culture in nine patients (60%). The median CD4 cell count was 262 cells/µL. All patients were cured at the end of treatment (median time 6 months). Three patients presented with immune reconstitution inflammatory syndrome. CONCLUSIONS In this study, CTB associated with HIV infection presented as localised forms or in association with pulmonary TB. In patients with HIV who have subacute and chronic skin lesions, CTB should be considered in differential diagnosis, which may represent a good opportunity for early diagnosis of active TB.

Risk factors for increased immune reconstitution in response to Mycobacterium tuberculosis antigens in tuberculosis HIV-infected, antiretroviral-naïve patients.

BACKGROUND: Little is known regarding the restoration of the specific immune response after combined antiretroviral therapy (cART) and anti-tuberculosis (TB) therapy introduction among TB-HIV patients. In this study, we examined the immune response of TB-HIV patients to Mycobacterium tuberculosis (Mtb) antigens to evaluate the response dynamics to different antigens over time. Moreover, we also evaluated the influence of two different doses of efavirenz and the factors associated with immune reconstitution. METHODS: This is a longitudinal study nested in a clinical trial, where cART was initiated during the baseline visit (D0), which occurred 30 ± 10 days after the introduction of anti-TB therapy. Follow-up visits were performed at 30, 60, 90 and 180 days after cART initiation. The production of IFN-γ upon in vitro stimulation with Mtb antigens purified protein derivative (PPD), ESAT-6 and 38 kDa/CFP-10 using ELISpot was examined at baseline and follow-up visits. RESULTS: Sixty-one patients, all ART-naïve, were selected and included in the immune reconstitution analysis; seven (11.5%) developed Immune Reconstitution Inflammatory Syndrome (IRIS). The Mtb specific immune response was higher for the PPD antigen followed by 38 kDa/CFP-10 and increased in the first 60 days after cART initiation. In multivariate analysis, the variables independently associated with increased IFN-γ production in response to PPD antigen were CD4+ T cell counts <200 cells/mm3 at baseline, age, site of tuberculosis, 800 mg efavirenz dose and follow-up CD4+ T cell counts. Moreover, the factors associated with the production of IFN-γ in response to 38 kDa/CFP-10 were detectable HIV viral load (VL) and CD4+ T cell counts at follow-up visits of ≥200 cells/mm3. CONCLUSIONS: These findings highlight the differences in immune response according to the specificity of the Mtb antigen, which contributes to a better understanding of TB-HIV immunopathogenesis. IFN-γ production elicited by PPD and 38 kDa/CFP-10 antigens have a greater magnitude compared to ESAT-6 and are associated with different factors. The low response to ESAT-6, even during immune restoration, suggests that this antigen is not adequate to assess the immune response of immunosuppressed TB-HIV patients.

Dietary counseling adherence during tuberculosis treatment: A longitudinal study.

BACKGROUND: The World Health Organization (WHO) recommends the use of dietary counseling to overcome malnutrition for patients with tuberculosis, with or without HIV, however the response to nutritional treatment depends on patient's adherence to nutritional counseling. OBJECTIVE: Identify the degree of adherence to dietary counseling and predictors of adherence among patients undergoing tuberculosis treatment. DESIGN: Observational prospective follow-up study conducted in adults treating for tuberculosis with or without HIV. Self-reported adherence and 24-h diet recall were checked. Diet counseling according to WHO strategy was offered at each visit for all patients. The endpoint was the adherence to the recommended dietary allowance (RDA) and total calories consumed during tuberculosis treatment. Data were mainly analyzed with marginal models to estimate adjusted trajectories. RESULTS: Sixty-eight patients were included in the study. The maximum probability of total calories consumption of at least one RDA was 80%. The adherence to dietary counseling was low regardless of HIV infection. The negative determinants of adherence were the presence of loss of appetite and nausea/vomiting. For patients with loss of appetite and nausea/vomiting, the probability of total calories consumption of at least one RDA is less than 20% at any time. CONCLUSION: The loss of appetite and nausea/vomiting are highly prevalents and were the main causes of non-adherence to dietary counseling.

Factors Associated with Clinical and Topographical Features of Laryngeal Tuberculosis.

INTRODUCTION: Laryngeal tuberculosis (LTB) is the most frequent granulomatous disease of the larynx and represents less than 2% of extrapulmonary TB cases. There are no pathognomonic clinical and endoscopic features of this disease and studies on LTB that can assist in its diagnostic characterization are lacking. OBJECTIVE: To identify factors associated with clinical and topographical features of LTB. METHOD: a retrospective cross-sectional study was conducted from the medical records of 36 patients with confirmed LTB diagnosis. RESULTS: Dysphonia and cough were the main symptoms presented by patients and the true vocal folds the most frequently affected site. The average of the duration of the disease evolution was significantly higher in patients with dysphonia than in patients without this symptom. We observed association between dysphonia and true vocal fold lesions and between odynophagia and lesions in the epiglottis, arytenoids and aryepiglottic folds. Odynophagia was more frequent in individuals with lesions in four or more laryngeal sites. Weight loss equal or above 10% of the body weight was more frequent in patients with odynophagia as first symptom and in patients with ulcerated lesion. Dyspnea on exertion was more frequent in individuals with more extensive laryngeal lesions. The percentage of smokers with lesions in four or more laryngeal sites was greater than that found in non-smokers. Laryngeal tissue fragment bacilloscopy and culture examinations were less positive than sputum ones. CONCLUSIONS: Smoking appears to be associated with the development of more extensive LTB lesions, and LTB with dyspnea on exertion and odynophagia with consequent impairment of nutritional status. We emphasize the need for histopathologic confirmation, once positive sputum bacteriological examinations seem not to necessarily reflect laryngeal involvement.

Perspectives of Patients, Doctors and Medical Students at a Public University Hospital in Rio de Janeiro Regarding Tuberculosis and Therapeutic Adherence.

INTRODUCTION: The World Health Organization (WHO) identifies 8.7 million new cases of tuberculosis (TB) annually around the world. The unfavorable outcomes of TB treatment prevent the achievement of the WHO's cure target. GOAL: To evaluate existing intersections in the conceptions relative to the knowledge of TB, the experience of the illness and the treatment. METHODS: Doctors, medical students and patients were selected from a public university in Rio de Janeiro, Brazil, from 2011 to 2013. The data were obtained by semi-structured individual and focus group interviews, participant observation and a field journal. The inclusion of patients was interrupted due to saturation, and the inclusion of doctors and medical students stopped due to exhaustion. The theoretical background included symbolic Interactionism, and the analysis used rounded Theory. The analysis prioritized the actions/interactions axis. RESULTS: Twenty-three patients with pulmonary TB, seven doctors and 15 medical students were included. In the interviews, themes such as stigma, self-segregation, and difficulties in assistance emerged, in addition to defense mechanisms such as denial, rationalization, isolation and other mental mechanisms, including guilt, accountability and concealment of the disease. Aspects related to the assistance strategy, the social support network, bonding with the healthcare staff and the doctor-patient relationship were highlighted as adherence enablers. Doctors and students recommended an expansion of the theoretical and practical instruction on TB during medical students' education. The existence of health programs and policies was mentioned as a potential enabler of adherence. CONCLUSION: The main concepts identified were the stigma, self-segregation, guilt, responsibility, concealment and emotional repercussions. In relation to the facilitation of therapeutic adherence, the concepts identified were the bonds with healthcare staff, the doctor-patient relationship, assistance and educational health strategies.