Hepatotoxicity during TB treatment in people with HIV/AIDS related to NAT2 polymorphisms in Pernambuco, Northeast Brazil.

INTRODUCTION AND OBJECTIVE: Hepatotoxicity during tuberculosis (TB) treatment is frequent and may be related to the Arylamine N-Acetyltransferase (NAT2) acetylator profile, in which allele frequencies differ according to the population. The aim of this study was to investigate functional polymorphisms in NAT2 associated with the development of hepatotoxicity after initiating treatment for TB in people living with HIV/AIDS (PLWHA) in Pernambuco, Northeast Brazil. MATERIAL AND METHODS: This was a prospective cohort study that investigated seven single nucleotide polymorphisms located in the NAT2 coding region in 173 PLWHA undergoing TB treatment. Hepatotoxicity was defined as elevated aminotransferase levels and identified as being three times higher than it was before initiating TB treatment, with associated symptoms of hepatitis. A further 80 healthy subjects, without HIV infection or TB were used as a control group. All individuals were genotyped by direct sequencing. RESULTS: The NAT2*13A and NAT2*6B variant alleles were significantly associated with the development of hepatotoxicity during TB treatment in PLWHA (p<0.05). Individual comparisons between the wild type and each variant genotype revealed that PLWHA with signatures NAT2*13A/NAT2*13A (OR 4.4; CI95% 1.1-18.8; p 0.037) and NAT2*13A/NAT2*6B (OR 4.4; CI95% 1.5-12.7; p 0.005) significantly increased the risk of hepatotoxicity. CONCLUSION: This study suggests that NAT2*13A and NAT2*6B variant alleles are risk factors for developing hepatotoxicity, and PLWHA with genotypes NAT2*13A/NAT2*13A and NAT2*13A/NAT2*6B should be targeted for specific care to reduce the risk of hepatotoxicity during treatment for tuberculosis.

Knowledge, attitudes and practices on tuberculosis transmission and prevention among auxiliary healthcare professionals in three Brazilian high-burden cities: a cross-sectional survey.

BACKGROUND: Tuberculosis elimination requires treatment of latently infected high-risk persons, such as contacts of index cases. Identification and referral of tuberculosis contacts for investigation are major barriers in the contact cascade-of-care. These tasks rely heavily on auxiliary primary healthcare workers in many low- and middle-income countries. We aimed to understand their knowledge, attitudes and practices (KAP) regarding contact investigation in Brazil. METHODS: We conducted a cross-sectional KAP survey on tuberculosis transmission and prevention among 135 auxiliary healthcare workers in three tuberculosis high-burden Brazilian cities. Trained interviewers applied a translated version of a previously applied questionnaire. Open answers were classified in pre-defined objective categories and analysed quantitatively. Answers were further classified as satisfactory or not according to criteria set by a panel of three specialists. RESULTS: Although 66% had received tuberculosis training in the past 10 years, only 19% were trained for tuberculosis prevention. 64% could not clearly distinguish latent tuberculosis infection (LTBI) from active tuberculosis; 63% did not know how to diagnose LTBI and 52% did not know how to prevent progression to active tuberculosis. Most believed that it is important to investigate adult (99%) and child (96%) contacts for LTBI. However, not all invite contacts - children (81%) or adults (71%) - to the clinic, despite only 24% perceiving difficulties for investigation. CONCLUSIONS: Gaps in KAP among auxiliary health workers have been reported in other areas, such as obstetrics and other infectious diseases. To the best of our knowledge, this is the first KAP survey on tuberculosis transmission and prevention among auxiliary health care workers, and relevant gaps were also found. Knowledge gaps were notably related to LTBI management, including how to recognize it and prevent progression to active tuberculosis through treatment, despite most recognizing the importance of investigating contacts. Auxiliary healthcare workers in three Brazilian high-burden cities have important knowledge gaps despite their perception of the importance of tuberculosis prevention among contacts. They need to incorporate contact referral as one of their tasks to enable progress toward the target of tuberculosis elimination.

Economic burden of HIV and TB/HIV coinfection in a middle-income country: a costing analysis alongside a pragmatic clinical trial in Brazil.

OBJECTIVE: The objective of this study was to measure the costs of people living with HIV (PLHIV) as well as active tuberculosis (TB/HIV), latent tuberculosis infection (LTBI/HIV) or without TB (HIV/AIDS). METHODS: We analysed the costs through the entire pathway of care during the prediagnosis and treatment periods from the Brazilian public health system perspective. We applied a combination of bottom-up and top-down approaches to capture and estimate direct medical and non-medical costs. We measured the mean cost per patient per type of care (inpatient, outpatient and emergency care) and disease category (HIV/AIDS, HIV/AIDS death, TB/HIV, TB/HIV death and LTBI/HIV). RESULTS: Between March 2014 and March 2016 we recruited 239 PLHIV. During the follow-up 26 patients were diagnosed and treated for TB and 5 received chemoprophylaxis for LTBI. During the prediagnosis and treatment period, the mean total costs for HIV or AIDS and AIDS death categories were US$1558 and US$2828, respectively. The mean total costs for TB/HIV and TB/HIV death categories were US$5289.0 and US$8281, respectively. The mean total cost for the LTBI/HIV category was US$882. CONCLUSIONS: Patients with TB/HIV impose a higher economic burden on the health system than HIV/AIDS and LTBI/HIV. Patients with LTBI/HIV were the lowest cost group among all disease categories, indicating that preventive TB treatment can avoid the further costs treating active TB. TRIAL REGISTRATION NUMBER: RBR-22t943, Results.

Guillain-Barré syndrome during the Zika virus outbreak in Northeast Brazil: An observational cohort study.

OBJECTIVE: To determine the clinical phenotype of Guillain-Barré syndrome (GBS) after Zika virus (ZIKV) infection, the anti-glycolipid antibody signature, and the role of other circulating arthropod-borne viruses, we describe a cohort of GBS patients identified during ZIKV and chikungunya virus (CHIKV) outbreaks in Northeast Brazil. METHODS: We prospectively recruited GBS patients from a regional neurology center in Northeast Brazil between December 2014 and February 2017. Serum and CSF were tested for ZIKV, CHIKV, and dengue virus (DENV), by RT-PCR and antibodies, and serum was tested for GBS-associated antibodies to glycolipids. RESULTS: Seventy-one patients were identified. Forty-eight (68%) had laboratory evidence of a recent arbovirus infection; 25 (52%) ZIKV, 8 (17%) CHIKV, 1 (2%) DENV, and 14 (29%) ZIKV and CHIKV. Most patients with a recent arbovirus infection had motor and sensory symptoms (72%), a demyelinating electrophysiological subtype (67%) and a facial palsy (58%). Patients with a recent infection with ZIKV and CHIKV had a longer hospital admission and more frequent mechanical ventilation compared to the other patients. No specific anti-glycolipid antibody signature was identified in association with arbovirus infection, although significant antibody titres to GM1, GalC, LM1, and GalNAc-GD1a were found infrequently. CONCLUSION: A large proportion of cases had laboratory evidence of a recent infection with ZIKV or CHIKV, and recent infection with both viruses was found in almost one third of patients. Most patients with a recent arbovirus infection had a sensorimotor, demyelinating GBS. We did not find a specific anti-glycolipid antibody signature in association with arbovirus-related GBS.

Guillain-Barré syndrome related to Zika virus infection: A systematic review and meta-analysis of the clinical and electrophysiological phenotype.

BACKGROUND: The Zika virus (ZIKV) has been associated with Guillain-Barré syndrome (GBS) in epidemiological studies. Whether ZIKV-associated GBS is related to a specific clinical or electrophysiological phenotype has not been established. To this end, we performed a systematic review and meta-analysis of all published studies on ZIKV-related GBS. METHODS: We searched Pubmed, EMBASE and LILACS, and included all papers, reports or bulletins with full text in English, Spanish or Portuguese, reporting original data of patients with GBS and a suspected, probable or confirmed recent ZIKV infection. Data were extracted according to a predefined protocol, and pooled proportions were calculated. RESULTS: Thirty-five studies were included (13 single case reports and 22 case series, case-control or cohort studies), reporting on a total of 601 GBS patients with a suspected, probable or confirmed ZIKV infection. Data from 21 studies and 587 cases were available to be summarized. ZIKV infection was confirmed in 21%, probable in 22% and suspected in 57% of cases. ZIKV PCR was positive in 30% (95%CI 15-47) of tested patients. The most common clinical features were: limb weakness 97% (95%CI 93-99), diminished/absent reflexes 96% (95%CI 88-100), sensory symptoms 82% (95%CI 76-88), and facial palsy 51% (95%CI 44-58). Median time between infectious and neurological symptoms was 5-12 days. Most cases had a demyelinating electrophysiological subtype and half of cases were admitted to the Intensive Care Unit (ICU). Heterogeneity between studies was moderate to substantial for most variables. CONCLUSIONS: The clinical phenotype of GBS associated with ZIKV infection reported in literature is generally a sensorimotor demyelinating GBS with frequent facial palsy and a severe disease course often necessitating ICU admittance. Time between infectious and neurological symptoms and negative PCR in most cases suggests a post-infectious disease mechanism. Heterogeneity between studies was considerable and results may be subject to reporting bias. This study was registered on the international Prospective Register of Systematic Reviews (CRD42018081959).

Neurological disease in adults with Zika and chikungunya virus infection in Northeast Brazil: a prospective observational study.

BACKGROUND: Since 2015, the arthropod-borne viruses (arboviruses) Zika and chikungunya have spread across the Americas causing outbreaks, accompanied by increases in immune-mediated and infectious neurological disease. The spectrum of neurological manifestations linked to these viruses, and the importance of dual infection, are not known fully. We aimed to investigate whether neurological presentations differed according to the infecting arbovirus, and whether patients with dual infection had a different disease spectrum or severity. METHODS: We report a prospective observational study done during epidemics of Zika and chikungunya viruses in Recife, Pernambuco, a dengue-endemic area of Brazil. We recruited adults aged 18 years or older referred to Hospital da Restauração, a secondary-level and tertiary-level hospital, with suspected acute neurological disease and a history of suspected arboviral infection. We looked for evidence of Zika, chikungunya, or dengue infection by viral RNA or specific IgM antibodies in serum or CSF. We grouped patients according to their arbovirus laboratory diagnosis and then compared demographic and clinical characteristics. FINDINGS: Between Dec 4, 2014, and Dec 4, 2016, 1410 patients were admitted to the hospital neurology service; 201 (14%) had symptoms consistent with arbovirus infection and sufficient samples for diagnostic testing and were included in the study. The median age was 48 years (IQR 34-60), and 106 (53%) were women. 148 (74%) of 201 patients had laboratory evidence of arboviral infection. 98 (49%) of them had a single viral infection (41 [20%] had Zika, 55 [27%] had chikungunya, and two [1%] had dengue infection), whereas 50 (25%) had evidence of dual infection, mostly with Zika and chikungunya viruses (46 [23%] patients). Patients positive for arbovirus infection presented with a broad range of CNS and peripheral nervous system (PNS) disease. Chikungunya infection was more often associated with CNS disease (26 [47%] of 55 patients with chikungunya infection vs six [15%] of 41 with Zika infection; p=0·0008), especially myelitis (12 [22%] patients). Zika infection was more often associated with PNS disease (26 [63%] of 41 patients with Zika infection vs nine [16%] of 55 with chikungunya infection; p≤0·0001), particularly Guillain-Barré syndrome (25 [61%] patients). Patients with Guillain-Barré syndrome who had Zika and chikungunya dual infection had more aggressive disease, requiring intensive care support and longer hospital stays, than those with mono-infection (median 24 days [IQR 20-30] vs 17 days [10-20]; p=0·0028). Eight (17%) of 46 patients with Zika and chikungunya dual infection had a stroke or transient ischaemic attack, compared with five (6%) of 96 patients with Zika or chikungunya mono-infection (p=0·047). INTERPRETATION: There is a wide and overlapping spectrum of neurological manifestations caused by Zika or chikungunya mono-infection and by dual infections. The possible increased risk of acute cerebrovascular disease in patients with dual infection merits further investigation. FUNDING: Fundação do Amparo a Ciência e Tecnologia de Pernambuco (FACEPE), EU's Horizon 2020 research and innovation programme, National Institute for Health Research. TRANSLATIONS: For the Portuguese and Spanish translations of the abstract see Supplementary Materials section.

Prevalence and socioeconomic factors associated with smoking in people living with HIV by sex, in Recife, Brazil.

INTRODUCTION: Smoking is the leading cause of preventable death in the world. The prevalence of smoking is higher in people infected with HIV than in the general population. Although it is biologically plausible that smoking increases the morbidity and mortality of people living with HIV/AIDS, few studies in developing countries have analyzed the determinants and consequences of smoking in HIV infected people. OBJECTIVE: To estimate the prevalence of smoking and identify the socioeconomic factors associated with smoking and smoking cessation in patients with HIV by sex. METHODS: A cross-sectional study was conducted with baseline data, obtained from an ongoing prospective cohort study of patients with HIV attending two referral centers in Recife, Northeast Region of Brazil, between July 2007 and October 2009. RESULTS: The prevalence of current smoking was 28.9%. For both sexes, smoking was independently associated with heavy alcohol drinking and marijuana use. Among women, smoking was associated with living alone, not being married and illiteracy; and among men, being 40 years or older, low income and using crack. Compared with ex-smokers, current smokers were younger and more likely to be unmarried, heavy drinkers and marijuana users. CONCLUSIONS: It is important to incorporate smoking cessation interventions for the treatment of heavy alcohol drinkers and marijuana users with HIV/AIDS, which may increase life expectancy and quality of life, as smoking is related to risk of death, relapse of tuberculosis, and non communicable diseases.

Neonatal BCG vaccine and response to the tuberculin test in BCG vaccinated children in contact with tuberculosis patients in Recife, Brazil.

This case-control study analyses the association between the tuberculin response and the neonatal BCG vaccine in 330 children under 15 who are home contacts of tuberculosis patients, taking into account risk factors for the transmission of infection. Interviews were conducted with 330 children, their parents or legal guardians. Chest X-rays were taken and the tuberculin test (TT) applied using 0.1 ml of PPD RT23, taking an induration reading of > or = 10 mm as the cut-off point for a positive test result. Prior BCG vaccination was ascertained by observing the presence of a scar on the deltoid region of the right arm. Six children were excluded because they had signs/symptoms of pulmonary tuberculosis, thereby reducing the final sample to 324 children. The multivariate analysis showed that being exposed to a patient with pulmonary lesions with cavities (OR = 3.14; CI: 1.59-6.20; p = 0.000), a positive sputum smear (OR = 3.65; CI: 1.52-8.78; p = 0.002) or a positive culture (OR = 4.42; CI: 1.39-14.1; p = 0.005), being under five (OR = 0.47; CI: 0.22-0.99; p = 0.045) are independently associated with a positive TT. The fact that a prior BCG scar is not associated with a positive response to the TT indicates the need to re-open discussion of the guidelines which exist in many poor countries where tuberculosis is still a serious public health problem. Such guidelines include those issued by the Brazilian Ministry of Health, which considers the child under 15 in contact with a tuberculosis case to be infected only if there is a TT of 10 mm or more and the child received no prior BCG vaccination.

Evaluation of PCR for diagnosis of American cutaneous leishmaniasis in an area of endemicity in northeastern Brazil.

PCR-based approaches targeting kinetoplast DNA were evaluated for the diagnosis of American cutaneous leishmaniasis (ACL) in regions of endemicity in northeastern Brazil. A total of 119 cutaneous biopsy specimens from patients with ACL and nonleishmaniasis cutaneous lesions were studied. Two PCR-based systems were used; one was specific for the subgenus Viannia, and the other was specific for the genus Leishmania. The PCR specific for the subgenus Viannia had a sensitivity of 95.4%, whereas the genus-specific PCR detected the target DNA in 88.2% of the samples tested. The specificities of the assays, determined with samples from a group with nonleishmaniasis cutaneous lesions, was 100%. The results of the conventional tests indicate that the sensitivities of the PCR-based methods were significantly higher than those of smear examination, histological staining, and isolation by culture (P < 0.05). Antibodies specific for Leishmania braziliensis were detected by indirect immunofluorescence in 82.9% of the patients tested. Parasites were isolated from 40 of 86 patients (46.5%). Sixty-seven percent of dermal scrapings and 66.2% of stained tissue sections were positive by microscopy. Amplified products from the subgenus-specific PCR hybridized with the Leishmania panamensis minicircle, confirming infection consistent with L. braziliensis. The evidence available at present incriminates L. braziliensis as the only causative agent of ACL in the state of Pernambuco in Brazil.