Is the presence of an intrathecal synthesis of immunoglobulins associated with neurocognitive impairment in HIV-infected patients?

Worldwide, the incidence of HIV-associated dementia has decreased However, the prevalence of HIV-associated neurocognitive disorders (HAND), mostly the milder forms, i.e. mild neurocognitve disorders (MND) and asymptomatic neurocognitive impairments (ANI) has increased in the combined antiretroviral therapy (cART) era. Indeed, 20% to 60% of well- treated HIV-infected patients, i.e. with undetectable HIV viremia, still present HAND in the cART era. HAND are characterized by psychomotor slowing, memory loss, and attention deficit. Possible explanations for this paradoxical phenomenon encompass: increased survival of HIV- infected patients thank to cART, low grade inflammation of the brain insufficient penetrance of antiretroviral drugs through the blood brain barrier (BBB), or on the contrary, toxic effect of some antiretroviral drugs. These somewhat contradictory hypotheses underline our poor understanding of HAND physiopathology. Here, we aim at determining whether the intrathecal synthesis of immunoglobulins G (IgG), hereafter referred as cerebrospinal fluid oligoclonal band (CSF OB), may help us in better understanding the immunopathogenesis of cognitive disorders. By analogy with other infection, such as syphilis or neuroborreliosis (9, 10), one can assume that, in the case of HIV-infected patients, the CSF OB are directed against HIV proteins (11). Nevertheless, in the case of HIV, the meaning of such CSF OB is unclear. Indeed, it is unknown whether this intrathecal inflammatory reaction is beneficial (viral control) or harmful (brain parenchyma destruction by the different inflammatory factors). Here, we looked at the association between CSF OB and cognitive disorders in HIV-infected patients, hypothesizing that if these CSF OB are protective, one should see an inverse correlation with the presence of cognitive disorders.

HIV - recentes avanços na pesquisa de fármacos

The development of new antiretroviral drugs is a dynamic process that is continuously fueled by identification of new molecular targets and new compounds for know targets. The current available drugs can be classified into five categories: nucleoside analogues reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors and entry inhibitors (fusion inhibitors and CCR5 antagonist). In addition, the maturation inhibitors may be considered as potential target for chemotherapeutic intervention. This review presents some anti-HIV agents that have already gone through the advance development process for final approval for the treatment of AIDS.

Incidence et facteurs de risque d’hémorragie intracrânienne et d’infarctus aigu du myocarde chez les personnes vivant avec le virus d’immunodéficience humaine

Objectif : Étudier le risque d’hémorragies intracrâniennes et d’infarctus du myocarde chez les patients vivant avec le VIH. Méthode : J’ai réalisé deux études de cohorte au sein de la banque de données de la Régie de l’assurance maladie du Québec. J’ai défini la cohorte des patients VIH-positifs, y ai étudié l’incidence d’hémorragies intracrâniennes et d’infarctus du myocarde, et l’ai comparée à une cohorte VIH-négative de même âge et de même sexe. J’ai étudié l’association entre ces évènements et l’exposition aux antirétroviraux au moyen d’études cas-témoin nichées dans la cohorte des patients VIH-positifs. Résultats : Le VIH est associé à un risque plus élevé d’hémorragies intracrâniennes, particulièrement au stade SIDA. Les patients VIH-positif sont également plus à risque de subir un infarctus du myocarde, et certains antirétroviraux sont associés à un risque plus grand. Conclusion : Les banques de données médico-administratives représentent un moyen valable d’étudier les comorbidités non-infectieuses chez les patients atteints du VIH.

Melanoníquia em pacientes HIV positivos utilizando zidovudina

Um dos eventos adversos da zidovudina, um fármaco anti-retroviral, é o desenvolvimento de melanoníquia. Foram avaliados 19 pacientes adultos tratados com zidovudina evidenciando linhas ungueais, um efeito colateral incomum por vezes relatado. As funções hepática, renal, pancreática, bem como a função metabólica destes doentes também foram avaliados. Foram também obtidos marcadores imunológicos e a taxa de adesão ao tratamento.Os nossos resultados sugerem que a melanoníquia, como a macrocitose, podem estar associadas à utilização de terapia anti-retroviral.

Licença compulsória para medicamentos como política pública: o caso do anti-retroviral efavirenz

O objetivo deste estudo é avaliar o processo de implementação da Licença Compulsória no caso do anti-retroviral efavirenz. Esta pesquisa é de caráter descritivo, o meio de investigação foi o estudo de caso e foi conduzido com entrevistas semi-estruturadas contendo questões abertas para um conjunto de atores representativos da área da Saúde Pública que participaram do processo da licença compulsória residentes nos estados do Rio de Janeiro e São Paulo e no Distrito Federal durante os meses de outubro a dezembro de 2009. Permitiu-se que esses indivíduos se expressassem mais ou menos livremente de forma que eles produzissem discursos. Para a análise dos discursos, utilizou-se a técnica do Discurso do Sujeito Coletivo (DSC). Os resultados demonstraram que o Brasil possui capacitação tecnológica para desenvolver e produzir anti-retrovirais em um prazo relativamente curto. Os resultados mostram ainda que a Licença Compulsória ajudou a refrear os gastos com anti-retrovirais e que o instrumento pode ser utilizado para garantir o acesso da população a medicamentos anti-retrovirais de alto custo e estratégicos para o Sistema Único de Saúde em um ambiente de recursos limitados sempre que se chegar a um impasse na negociação para redução de preços com os laboratórios farmacêuticos transnacionais.

Atenção ao usuário em um centro de referência HIV/Aids: perspectiva de profissionais e usuários

We study the health care focused on care in an intercessor and dialogical relationship with the User, which involves the construction of therapeutic projects essential to the quality of the treatment of the user in health services, and it is necessary individual and collective actions. It is intended to acknowledge and analyze the perception of social subjects, users and professionals on the treatment given to a user of a Specialized Outpatient Service (Serviço Ambulatorial Especializado SAE) in STD/HIV/AIDS state reference in Natal, RN. The study is structured in a transdisciplinary vision of science and knowledge, theoretical and methodological principles that give meaning to the expression of the institutional features of care and health care reconnecting them to the social context. As a research strategy we seek the expressions of 56 subjects of social research, which agreed to participate in the sample, from a symbolic map of the attention, coupled with the techniques of observation and semi-structured interview. For the analysis of the results, five categories of analysis were established: the meaning of the service, care perception, process of communication and interaction, treatment perception and organization and evaluation of the service. It is argued that the attention and care are developed in a technical health care assistance to the disease, focusing on attention based on treatment, on diagnostic and drug therapy of antiretroviral drugs, reflecting the traditional biomedical paradigm of attention to the disease. This is also the mode of organization of practical actions in daily SAE: the therapy proves to be fragmented in several specialties, vertical and feeds the same model, generating tension and overload for professionals; showing impersonal care focused on structured and informative technology, unrelated to an interactive dialogic. From the speech of the subjects, the SAE is understood as the place of confrontation with the disease, but also enables greater elaboration of the illness by meeting their peers. Living with HIV and AIDS is living with concern, apprehension and fear, but mainly with the stigma, prejudice and exclusion, which require that the disease is kept in secret. There is a movement of forces and power, expressed in the knowledge-power of those who dominate the technical and administrative capabilities, devices that concentrate the maintenance of the medicalization of care, rapid consultations and with little attention, making it difficult to interact with and listen to, combined with structural failures, organizational and inadequate management of the service. We conclude that there are dimensions that are not considered in the internal dynamics of the care service multiple forms, characterized by care conflicting models, marked by individual interventions related to the disease. The subject is not considered together with his speech as technical discourse is imposed and care production based on material technology is observed

Changes of metabolic and inflammatory markers in HIV infection: glucose, lipids, serum Hs-CRP and myeloperoxidase

Objective: HIV infection is exacerbated through additional pro-atherogenic mechanisms related to the processes of immune activation, inflammation, coagulation, and the modification of lipoproteins (e.g., particles of high density lipoprotein), contributing to increased cardiovascular risk. The aim of this study was to analyze the serum concentrations of myeloperoxidase (MPO) and other laboratory parameters in HIV-infected patients treated or not with antiretroviral drugs compared to non-infected individuals.Materials/Methods: The study included 154 volunteers: 47 non-infected individuals (control group - CON), 27 infected and untreated individuals (NTARv group) and 80 treated individuals (TARV group). We analyzed the counts of CD4+ lymphocytes and the viral load of the infected patients, along with the blood count, fasting glucose, total serum cholesterol (CHOL), HDL cholesterol, LDL cholesterol, triglycerides, MPO and high-sensitivity C-reactive protein (CRP) of all study participants.Results: There were significant increases in glucose, CHOL, LDL cholesterol, and triglycerides in the TARV group and significant reductions in the levels of HDL cholesterol for the TARV and NTARV groups. Significantly elevated levels of Hs-CRP were observed only in the TARV group, while levels of MPO were significantly higher in the TARV and NTARV groups compared to the control group. A correlation of MPO with Hs-CRP (r = 0.21, p = 0.032) was observed for HIV-infected patients, but MPO did not correlate significantly with the other analyzed parameters.Conclusions: The investigation of early biomarkers for cardiovascular risk evaluation, such as MPO, contributes to the clinical monitoring of HIV-infected individuals. The serum levels of MPO correlated with Hs-CRP and were high in HIV-infected individuals, indicating a possible predictor of cardiovascular events in these patients. (c) 2012 Elsevier B.V. All rights reserved.

Darunavir: A Critical Review of Its Properties, Use and Drug Interactions

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Avaliação de serviços de assistência ambulatorial em aids, Brasil: estudo comparativo 2001/2007

OBJETIVO: Avaliar os serviços do Sistema Único de Saúde brasileiro de assistência ambulatorial a adultos vivendo com aids em 2007 e comparar com a avaliação de 2001. MÉTODOS: Os 636 serviços cadastrados no Ministério da Saúde em 2007 foram convidados a responder a um questionário previamente validado (Questionário Qualiaids) com 107 questões de múltipla escolha sobre a organização da assistência prestada. Analisaram-se as frequências das respostas de 2007 comparando-as com as obtidas em 2001 na forma de variação percentual (VP). RESULTADOS: Responderam o questionário 504 (79,2%) serviços. Cerca de 100,0% dos respondentes relataram ter pelo menos um médico, suprimento sem falhas de antirretrovirais e de exames CD4 e carga viral. Vários aspectos mostraram melhor desempenho em 2007 comparados a 2001: registro de número de faltas à consulta médica (de 18,3 para 27,0%, VP: 47,5%), agendamento de consulta em menos de 15 dias no início da terapia antirretroviral (de 55,3 para 66,2%, VP: 19,7%) e participação organizada do usuário (de 5,9 para 16,7%, VP: 183,1%). Houve manutenção de dificuldades: pequena variação na disponibilidade de exames especializados em até 15 dias, como endoscopia (31,9 para 34,5%, VP: 8,1%), e a piora de indicadores como tempo ideal de acesso a consultas especializadas (55,9 para 34,5% em cardiologia, VP negativa de 38,3%). O tempo médio despendido nas consultas médicas de seguimento manteve-se baixo: 15 minutos ou menos (52,5 para 49,5%, VP negativa de 5,8%). CONCLUSÕES: A avaliação de 2007 mostrou que os serviços contam com os recursos essenciais para a assistência ambulatorial. Houve melhoras em muitos aspectos em relação a 2001, mas persistem desafios. Pouco tempo dedicado à consulta médica pode estar vinculado ao número insuficiente de médicos e/ou à baixa capacidade de escuta e diálogo. A acessibilidade prejudicada a consultas especializadas mostra a dificuldade das infraestruturas locais do Sistema Único de Saúde.

In Vitro and In Vivo Activities of Ruthenium(II) Phosphine/Diimine/Picolinate Complexes (SCAR) against Mycobacterium tuberculosis

Rifampicin, discovered more than 50 years ago, represents the last novel class of antibiotics introduced for the first-line treatment of tuberculosis. Drugs in this class form part of a 6-month regimen that is ineffective against MDR and XDR TB, and incompatible with many antiretroviral drugs. Investments in R&D strategies have increased substantially in the last decades. However, the number of new drugs approved by drug regulatory agencies worldwide does not increase correspondingly. Ruthenium complexes (SCAR) have been tested in our laboratory and showed promising activity against Mycobacterium tuberculosis. These complexes showed up to 150 times higher activity against MTB than its organic molecule without the metal (free ligand), with low cytotoxicity and high selectivity. In this study, promising results inspired us to seek a better understanding of the biological activity of these complexes. The in vitro biological results obtained with the SCAR compounds were extremely promising, comparable to or better than those for first-line drugs and drugs in development. Moreover, SCAR 1 and 4, which presented low acute toxicity, were assessed by Ames test, and results demonstrated absence of mutagenicity. © 2013 Pavan et al.

ß-2 microglobulina e citocinas séricas como indicadores de falha terapêutica aos anti-retrovirais

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Caracterização molecular da resistência genotípica secundária aos antirretrovirais em pacientes com Aids e prevalência de subtipos do HIV-1 nos Estados do Pará e Amazonas, Brasil: 2002 a 2006

A resistência às drogas antirretrovirais é o inevitável resultado da incompleta supressão da replicação do HIV-1. No presente estudo foi caracterizado o perfil de resistência genética aos antirretrovirais em amostras sorológicas provenientes dos estados do Amazonas e Pará, Região Norte do Brasil, no período de 2002 a 2006. Um total de 127 amostras de plasmas obtidas de pacientes HIV positivos e/ou Aids foram submetidas ao teste de resistência pelo ViroSeq^TM Genotyping System (Celera Diagnostic-Abbott, USA). Considerando a informação genética derivada das regiões da protease e/ou transcriptase reversa do HIV-1, o subtipo B foi observado em 85% dos casos; seguido por ambos subtipo F1 e forma recombinante BF1 (4,6%) e CF1 (0,8%). A mutação M184V (81,1%) foi a mais comumente observada associada aos NRTI, em indivíduos positivos com TARV no estado do Pará, e a mutação T215F/Y (56,3%) em indivíduos do estado do Amazonas. A mutação K103N foi a mais prevalente (em torno de 33,5%) para os NNRTI em ambos os estados. O perfil de mutação de resistência associado ao gene da protease mostrou a mutação minor L63P como a mais frequente em ambos os estados. O estudo revelou a importância da identificação de mutações associadas com resistência às drogas antirretrovirais para o uso em futuros esquemas terapêuticos. Os resultados deste estudo foram similares aos outros realizados em várias regiões do Brasil.

Coexistencia de variantes HIV-1 com insercao dipeptidica no gene da transcriptase reversa

O objetivo desta comunicação foi descrever a detecção de coexistência de variantes HIV-1 com inserções de dois aminoácidos entre os códons 69 e 70 da transcriptase reversa. Tais variantes foram isoladas de paciente do sexo masculino, 16 anos de idade, em tratamento no interior do estado de São Paulo. Após confirmação de falha terapêutica, foi realizado teste de resistência a antirretrovirais, a partir do qual foram detectadas duas variantes contendo inserções dos aminoácidos Ser-Gly/Ser-Ala no códon 69 da transcriptase reversa, além da mutação T69S. Tais inserções possuem baixa prevalência, não foram relatadas em caráter de coexistência no Brasil e estão relacionadas com a resistência a múltiplas drogas, tornando o achado relevante do ponto de vista epidemiológico.

Alterações mamográficas em mulheres que vivem com HIV-aids

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Replicative phenotyping adds value to genotypic resistance testing in heavily pre-treated HIV-infected individuals--the Swiss HIV Cohort Study

Background Replicative phenotypic HIV resistance testing (rPRT) uses recombinant infectious virus to measure viral replication in the presence of antiretroviral drugs. Due to its high sensitivity of detection of viral minorities and its dissecting power for complex viral resistance patterns and mixed virus populations rPRT might help to improve HIV resistance diagnostics, particularly for patients with multiple drug failures. The aim was to investigate whether the addition of rPRT to genotypic resistance testing (GRT) compared to GRT alone is beneficial for obtaining a virological response in heavily pre-treated HIV-infected patients. Methods Patients with resistance tests between 2002 and 2006 were followed within the Swiss HIV Cohort Study (SHCS). We assessed patients' virological success after their antiretroviral therapy was switched following resistance testing. Multilevel logistic regression models with SHCS centre as a random effect were used to investigate the association between the type of resistance test and virological response (HIV-1 RNA <50 copies/mL or ≥1.5log reduction). Results Of 1158 individuals with resistance tests 221 with GRT+rPRT and 937 with GRT were eligible for analysis. Overall virological response rates were 85.1% for GRT+rPRT and 81.4% for GRT. In the subgroup of patients with >2 previous failures, the odds ratio (OR) for virological response of GRT+rPRT compared to GRT was 1.45 (95% CI 1.00-2.09). Multivariate analyses indicate a significant improvement with GRT+rPRT compared to GRT alone (OR 1.68, 95% CI 1.31-2.15). Conclusions In heavily pre-treated patients rPRT-based resistance information adds benefit, contributing to a higher rate of treatment success.