Background: Pyrimethamine and sulfadiazine (P-S) combination is effective and considered the mainstay therapy for cerebral toxoplasmosis (CT). Alternative treatment regimens are available, but their relative efficacy and tolerability are not well known. Particularly, trimephoprim-sulfamethaxozole (TMP-SMX) shows potential advantages (i.e., tolerability, posology, parenteral formulation, cost, and accessibility) but its use is infrequent when P-S is available. Methods: We searched PubMed and 4 other databases to identify randomized controlled trials (RCTs) and cohort studies comparing different regimens for the treatment of HIV-associated CT. Two independent reviewers searched and identified studies and extracted data. Risk ratios (RRs) were pooled across studies using random-effects models. Results: Nine studies were included (5 RCTs, 3 retrospective cohorts, 1 prospective cohort). Treatment with P-S has the same or better clinical efficacy than P-C or TMP-SMX in terms of partial or complete response clinical response (P-C vs P-S: RR 0.87, 95%CI 0.70-1.08; TMP-SMX vs P-S: RR 0.97, 95%CI 0.78-1.21) and radiological response (P-C vs P-S: RR 0.92, 95%CI 0.82-1.03). Safety profile in terms of skin rash (P-C vs P-S: RR 0.81, 95%CI 0.56-1.17; TMP-SMX vs P-S: RR 0.17, 95%CI 0.02-1.29), liver impairment (P-C vs P-S: RR 0.48, 95%CI 0.24-0.97) and drug discontinuation due to adverse events (P-C vs P-S: RR 0.32, 95%CI 0.07-1.47) were worse with P-S regimen. Conclusion: The available evidence fails to identify any one superior regimen for the treatment of CT. However, P-S regimen has worse safety profile than P-C or TMP-SMX. Although current evidence does not allow a definitive recommendation, use of TMP-SMX for treatment of HIV-associated CT is consistent with the available data. More large studies comparing alternative therapies are needed. / IDWeek, Evento que se llevó a cabo del 7 -11 de Octubre de 2015, en la ciudad de San Diego, CA, EE.UU. Evento Sesión HIV: Other Opportunistic Infections in HIV. Saturday, October 10, 2015. Room: Poster Hall

El texto completo de este trabajo no está disponible en el Repositorio Académico UPC por restricciones de la casa editorial donde ha sido publicado. / OBJECTIVES: The objective of this study was to perform a systematic review and meta-analysis of the literature to evaluate the efficacy and safety of therapies for cerebral toxoplasmosis in HIV-infected adults. The pyrimethamine plus sulfadiazine (P-S) combination is considered the mainstay therapy for cerebral toxoplasmosis and pyrimethamine plus clindamycin (P-C) is the most common alternative treatment. Although trimethoprim-sulfamethoxazole (TMP-SMX) has potential advantages, its use is infrequent. METHODS: We searched PubMed and four other databases to identify randomized controlled trials (RCTs) and cohort studies. Two independent reviewers searched the databases, identified studies and extracted data. Risk ratios (RRs) were pooled across studies using random-effects models. RESULTS: Nine studies were included (five RCTs, three retrospective cohort studies and one prospective cohort study). In comparison to P-S, treatment with P-C or TMP-SMX was associated with similar rates of partial or complete clinical response [P-C: RR 0.87; 95% confidence interval (CI) 0.70-1.08; TMP-SMX: RR 0.97; 95% CI 0.78-1.21], radiological response (P-C: RR 0.92; 95% CI 0.82-1.03), skin rash (P-C: RR 0.81; 95% CI 0.56-1.17; TMP-SMX: RR 0.17; 95% CI 0.02-1.29), gastrointestinal impairment (P-C: RR 5.16; 95% CI 0.66-40.11), and drug discontinuation because of adverse events (P-C: RR 0.32; 95% CI 0.07-1.47). Liver impairment was more frequent with P-S than P-C (P-C vs. P-S: RR 0.48; 95% CI 0.24-0.97). CONCLUSIONS: The current evidence fails to identify a superior regimen in terms of relative efficacy or safety for the treatment of HIV-associated cerebral toxoplasmosis. Use of TMP-SMX as preferred treatment may be consistent with the available evidence and other real-world considerations. Larger comparative studies are needed. / Revisión por pares

Orientador: Lenice do Rosário de Souza / Resumo: Introdução: A aids caracteriza-se por comprometimento do sistema nervoso central, cujas células são importantes alvos para o vírus da imunodeficiência humana (HIV). Alterações neurológicas acometem cerca de 40% a 70% das pessoas que vivem com HIV/aids, chegando a 90% ou mais em estudos de necropsia. A toxoplasmose cerebral é a infecção mais comum, acomete cerca de 3% a 40% dos pacientes com aids e é a causa mais comum de lesão expansiva focal. Alguns critérios clínicos e radiológicos são utilizados para definição de seu diagnóstico. Objetivo: avaliar os dados epidemiológicos, clínicos, terapêuticos e as alterações cerebrais tomográficas no diagnóstico presuntivo de toxoplasmose cerebral em indivíduos com aids. Casuística e métodos: foram estudados, retrospectivamente, 28 pacientes com diagnóstico presuntivo de toxoplasmose cerebral, que realizaram exames de imagem a partir da suspeita clínica, atendidos no período de junho de 2012 a dezembro de 2018 e que realizaram tratamento específico para a infecção oportunista. A coleta de dados foi realizada por meio de consulta aos prontuários médicos dos pacientes que apresentaram critérios de inclusão para o estudo. Os exames de imagem foram avaliados com auxílio de médico radiologista do Serviço. As análises foram descritivas com cálculo de médias e desvios padrão para variáveis quantitativas e frequências e percentuais para variáveis categorizadas. Os sintomas pré e pós-tratamento foram comparados pelo teste qui-quadrado. Resultado... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Introduction: AIDS is characterized by impairment of the central nervous system, whose cells are important targets for the human immunodeficiency virus (HIV). Neurological changes affect about 40% to 70% of people living with HIV / AIDS, reaching 90% or more in necropsy studies. Cerebral toxoplasmosis is the most common infection, affecting about 3% to 40% of AIDS patients and is the most common cause of focal expansive lesion. Some clinical and radiological criteria are used to define its diagnosis. Objective: to evaluate epidemiological, clinical, therapeutic and tomographic brain changes in the presumptive diagnosis of cerebral toxoplasmosis in individuals with AIDS. Patients and Methods: 28 patients with a presumptive diagnosis of cerebral toxoplasmosis, who underwent imaging from the clinical suspicion, were studied retrospectively from June 2012 to December 2018 and who underwent specific treatment for the opportunistic infection. The data collection was done by consulting the medical records of the patients who presented inclusion criteria for the study. The imaging exams were evaluated with the assistance of the radiologist of the Service. The analyzes were descriptive with calculation of means and standard deviations for quantitative variables and frequencies and percentages for categorized variables. Pre and post-treatment symptoms were compared by the chi-square test. Results: the majority of the patients were men (53.6%), with a mean age of 39.8 years. Headache wa... (Complete abstract click electronic access below) / Mestre

A recent systematic literature and meta-analysis reported relative efficacy of trimethoprim-sulfamethoxazole (TMP-SMX) for the treatment of toxoplasmic encephalitis (TE) in HIV-infected adults. Here, we estimated relapse rates during secondary prophylaxis with TMP-SMX, and further explored differences in relapse rates prior to introduction of highly active antiretroviral therapy (HAART) and the widespread adoption of HAART. A systematic search of PubMed, Embase, and Cochrane Central Register of Controlled Trials yielded 707 studies whereby 663 were excluded after abstract screening, and 38 were excluded after full review leaving 6 studies for extraction. We performed double data extraction with a third-party adjudicator. Study designs varied with only one randomized study, four prospective cohorts and one retrospective cohort. Relapse rates were transformed using the Freeman-Tukey method and pooled using both fixed-effect and random-effects meta-analysis models. The TMP-SMX relapse rate was 16.4% (95% CI = 6.2% to 30.3%) based on random-effects models. When the disaggregated pre-HAART studies (n = 4) were included, the relapse rate was 14.9% (random effects; 95% CI = 3.7% to 31.9%). Analysis of two post-HAART studies indicated a relapse rate of 19.2% (random effects; 95% CI = 2.8% to 45.6%). Comparing the relapse rates between pre- and post-HAART studies were contrary to what might be expected based on known benefits of HAART therapy in this population. Nevertheless, cautious interpretation is necessary considering the heterogeneity of the included studies and a limited number of subjects receiving TMP-SMX reported in the post-HAART era.

Orientador: Cláudio Lúcio Rossi / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-19T13:51:41Z (GMT). No. of bitstreams: 1 Nascimento_FernandaSantos_D.pdf: 5313856 bytes, checksum: fd526ebe03ae5465c13afe95ffe8df9a (MD5) Previous issue date: 2012 / Resumo: A neurotoxoplasmose é considerada uma grave complicação em pacientes com comprometimento do sistema imune e em crianças congenitamente infectadas pelo Toxoplasma gondii. O presente estudo abordou três aspectos da neurotoxoplasmose, o diagnóstico molecular, a resposta imune e a relação desta infecção com transtornos mentais. Com relação ao diagnóstico molecular, a eficiência das técnicas de nested-PCR (nPCR) e PCR convencional (PCRc) em detectar DNA do T. gondii foi avaliada em nove amostras de líquido cefalorraquidiano (LCR) de pacientes com neurotoxoplasmose, cinco amostras de LCR de pacientes com outras desordens neurológicas (dois com neurocriptococose, dois com neurosífilis e um com neurocisticercose) e amostras artificiais contendo diferentes concentrações do parasito. A nPCR foi positiva em todos os nove pacientes com neurotoxoplasmose, enquanto a PCRc foi positiva em somente cinco casos. As duas técnicas de PCR foram negativas em LCR de pacientes com outras desordens neurológicas. Nas amostras artificiais, a concentração de taquizoítos detectada por nPCR foi dez vezes menor do que aquela detectada por PCRc. Para avaliar a resposta imune, anticorpos das subclasses da IgG anti-T. gondii foram pesquisados em 19 amostras de LCR de pacientes com neurotoxoplasmose, utilizando ELISA padronizada com uma preparação antigênica de cistos do parasito. Os anticorpos IgG1, IgG2, IgG3 e IgG4 foram detectados em 84,2%, 73,7%, 36,8% e 36,8% dos pacientes, respectivamente. Não foram encontradas diferenças significativas entre as sensibilidades e as médias das absorbâncias das reações ELISA para IgG1 e IgG2, porém, as sensibilidades e as médias das absorbâncias das reações para essas duas subclasses foram significativamente maiores do que as encontradas nas reações ELISA para IgG3 e IgG4. A associação entre toxoplasmose e transtornos mentais foi investigada comparando as prevalências e/ou as concentrações dos anticorpos IgG, IgM e IgA anti-T. gondii, detectados por reações imunoenzimáticas, em amostras de soro de 41 pacientes com esquizofrenia, 38 pacientes com transtornos do humor e 95 voluntários sadios. Os anticorpos IgG foram detectados em 43,9% dos pacientes com esquizofrenia, 52,6% dos pacientes com transtornos do humor e 28,4% dos voluntários sadios. A prevalência da IgG e as concentrações desse anticorpo nos pacientes com transtornos do humor foram significativamente maiores do que as encontradas em voluntários sadios (p=0,0204 e p=0,0059, respectivamente). Por outro lado, não foram encontradas diferenças significativas nesses dois parâmetros entre pacientes com esquizofrenia e voluntários sadios ou entre os pacientes com esquizofrenia e transtornos do humor. Os anticorpos IgA foram detectados em um paciente (2,6%) com transtorno do humor e em um (1,1%) voluntário sadio, enquanto os anticorpos IgM foram detectados em dois pacientes (5,2%) com transtornos do humor. O presente estudo indica que a nPCR pode ser uma ferramenta potencialmente útil para a confirmação diagnóstica da infecção do sistema nervoso central pelo T. gondii e sugere que esse parasito poderia ser um dos possíveis fatores causais dos transtornos do humor. Estudos adicionais são necessários para compreender melhor a fisiopatologia da neurotoxoplasmose e sua associação com outras doenças / Abstract: Neurotoxoplasmosis is considered a serious complication in patients with an impaired immune system and in children congenitally infected by Toxoplasma gondii. The present study addressed three aspects of neurotoxoplasmosis, namely, the molecular diagnosis, the immune response and the relationship of this infection to mental disorders. With regard to molecular diagnosis, the ability of nested-PCR (nPCR) and conventional PCR (cPCR) to detect T. gondii DNA was assessed in nine cerebrospinal fluid (CSF) samples from patients with neurotoxoplasmosis, five CSF samples from patients with other neurological disorders (two with neurocryptococcosis, two with neurosyphilis and one with neurocysticercosis) and artificial samples containing different concentrations of the parasite. The nPCR was positive in all nine patients with neurotoxoplasmosis whereas the cPCR was positive in only five cases. Both PCR procedures were negative in CSF from patients with other neurologic disorders. In the artificial samples, the tachyzoite concentrations detected by nPCR were ten times lower than those detected by cPCR. To assess the immune response, 19 CSF samples from patients with neurotoxoplasmosis were screened for IgG subclass antibodies to T. gondii using an ELISA standardized with an antigenic preparation from parasite cysts. IgG1, IgG2, IgG3 and IgG4 antibody subclasses were detected in 84.2%, 73.7%, 36.8% and 36.8% of the patients, respectively. There were no significant differences in the ELISA sensitivities and mean absorbances for IgG1 and IgG2, whereas the sensitivities and mean absorbances for these two IgG subclasses were significantly higher than for IgG3 and IgG4. The association between toxoplasmosis and mental disorders was investigated by comparing the prevalences and/or the concentrations of anti-T. gondii IgG, IgM and IgA antibodies screened by immunoenzymatic reactions in serum samples from 41 patients with schizophrenia, 38 patients with mood disorders and 95 healthy volunteers. IgG antibodies were detected in 43.9% of patients with schizophrenia, 52.6% of patients with mood disorders and 28.4% of healthy individuals. The prevalence of IgG and the concentration of this antibody in patients with mood disorders were significantly greater than in healthy volunteers (p=0.0204 and p=0.0059, respectively). In contrast, there were no significant differences in these two parameters between patients with schizophrenia and healthy volunteers, or between patients with schizophrenia and patients with mood disorders. IgA antibodies were detected in one patient (2.6%) with mood disorders and in one (1.1%) healthy volunteer, whereas IgM antibodies were detected in two patients (5.2%) with mood disorders. The present study indicates that nPCR may be a potentially useful tool for the diagnosis of T. gondii infection of the central nervous system and suggests that this parasite could be a possible cause of mood disorders. Further studies are necessary to improve our understanding of the physiopathology of neurotoxoplasmosis and its association with other diseases / Doutorado / Ciencias Biomedicas / Doutor em Ciências Médicas