Avaliação das características virais do HIV-1 e imunopatológicas em pacientes coinfectados HCV/HIV-1

Orientadora: Profa Dra. Sonia Mara RaboniTese (doutorado) - Universidade Federal do Paraná, Setor de Ciências da Saúde, Programa de Pós-Graduação em Medicina Interna e Ciências da Saúde. Defesa : Curitiba, 11/02/2019Inclui referênciasResumo: As infecções pelo HIV-1 e hepatites virais são as principais causas de doenças crônicas no mundo e apresentam algumas semelhanças em relação às vias de transmissão. Além disso, a resposta ao tratamento é influenciada por múltiplos fatores virais e do hospedeiro. O desenvolvimento de doença hepática é variável entre indivíduos com fatores de risco semelhantes, sugerindo que a intensidade do processo inflamatório é um importante contribuinte. Sendo assim, o objetivo deste trabalho foi de compreender as características virais do HIV-1 e da imunopatogênese da coinfecção HCV/HIV-1. Para isto, foram avaliadas características epidemiológicas, clínicas, genéticas e virológicas em pacientes coinfectados com HCV/HIV-1 dos Ambulatórios de Infectologia e de Coinfecção e Hepatites Virais do Hospital de Clínicas da Universidade Federal do Paraná (HC-UFPR). Este trabalho foi dividido em três estudos, sendo que, no primeiro, avaliou-se 30 indivíduos coinfectados com HCV/HIV- 1, onde realizou-se a subtipagem dos genes pol e/ou env do HIV-1, 47,4% (n = 18) dos pacientes foram identificados como C; 31,6% (n = 12) subtipo B e 21% (n = 8) como formas recombinantes (CRFs); 61,1% (n=20) dos pacientes HCV/HIV-1 realizaram tratamento para o HCV com interferon-? peguilado em combinação com ribavirina. A avaliação do polimorfismo do gene da IL28B rs12979860, mostrou a presença do genótipo favorável C/C para o desenvolvimento da resposta virológica sustentada (RVS) em 50% (n=20) dos pacientes tratados para o HCV. No segundo estudo, avaliou-se um total de 37 pacientes monoinfectados com HCV e 41 coinfectados com HCV/HIV-1, destes, 3 (7%) coinfectados foram a óbito, dois devido a complicações hepáticas; 23 (56,1%) realizaram tratamento interferon-? peguilado em combinação com ribavirina e 12 (52,1%) tratados apresentaram RVS. Em relação à anemia induzida pela ribavirina, todos os pacientes tratados (n = 23) apresentaram o SNP do gene da ITPA favorável para esse evento, e anemia esteve presente em 38,5% dos monoinfectados e em 65,2% dos coinfectados. No terceiro trabalho, foram avaliados um total de 30 indivíduos com monoinfecção por HCV, 37 coinfectados com HCV/HIV-1, 38 infectados pelo HIV-1 e 11 controles saudáveis. Comparando-se os grupos, os pacientes infectados pelo HCV (mono e coinfectados pelo HIV-1) apresentaram índices mais elevados de IL-8 no plasma em comparação aos infectados pelo HIV-1 (p= 0,0075 e p= 0,0004, respectivamente). Índices maiores de IP-10 foram encontrados em pacientes mono infectados pelo HCV (940,8 pg/mL; IQR 703,5 - 1508,0 pg/mL) em comparação com pacientes infectados pelo HIV-1 (p = 0,0011) e, podem sugerir, como já identificado em outros estudos, que os pacientes com HCV apresentam maior predisposição a ativar o sistema imune. Com a disponibilidade de antivirais de ação direta (DAAs) para o tratamento da infecção crônica pelo vírus da hepatite C, regimes livres de interferon têm sido implementados em todo o mundo. No entanto, no cenário da coinfecção HCV/HIV-1, a ribavirina continuará a compor alguns esquemas terapêuticos, portanto avaliar o risco de toxicidade poderá auxiliar no monitoramento dos pacientes. Compreender os mecanismos fisiopatológicos de ambas as infecções possibilitará sua comparação com outras infecções virais que atingem o fígado, para os quais ainda não são disponibilizadas terapias eficazes. Palavras-chave: Coinfecção. IL28B. ITPA. Marcadores Inflamatórios.Abstract: HIV-1 infections and viral hepatitis are the main causes of chronic diseases in the world and have some similarities with regard to the transmission routes. In addition, the response to treatment is influenced by multiple viral and host factors. The development of liver disease is variable among individuals with similar risk factors, suggesting that the intensity of the inflammatory process is an important contributor. Thus, the objective of this work was to understand the viral characteristics of HIV-1 and the immunopathogenesis of HCV / HIV-1 coinfection. For this, epidemiological, clinical, genetic and virological characteristics were evaluated in patients coinfected with HCV / HIV-1 of the Infectology and Coinfection and Viral Hepatitis of Clinics Hospital of the Federal University of Paraná (HC-UFPR). This study was divided into three studies. In the first one, 30 HCV / HIV-1 coinfected individuals were evaluated, where the pol and / or env subtyping was performed, 47.4% (n = 18) of the patients were identified as C; 31.6% (n = 12) subtype B and 21% (n = 8) as recombinant forms (CRFs); 61.1% (n = 20) of HCV / HIV-1 patients were treated for HCV with pegylated interferon-? in combination with ribavirin. The evaluation of the IL28B gene polymorphism rs12979860, showed the presence of the favorable C / C genotype for the development of sustained virological response (SVR) in 50% (n = 20) of patients treated for HCV. In the second study, a total of 37 monoinfected patients with HCV and 41 coinfected with HCV / HIV-1 were evaluated. Of these, 3 (7%) coinfected died, two due to hepatic complications; 23 (56.1%) underwent pegylated interferon-? therapy in combination with ribavirin and 12 (52.1%) treated presented SVR. Regarding ribavirin-induced anemia, all patients had ITP gene SNP favorable for this event, and anemia was present in 38.5% of monoinfected and 65.2% of coinfected patients. In the third study, a total of 30 individuals with HCV monoinfection, 37 HCV / HIV- 1 coinfected, 38 HIV-1 infected and 11 healthy controls were evaluated. Comparing the groups, patients infected with HCV (mono and HIV-1 coinfected) had higher rates of plasma IL-8 compared to those infected with HIV-1 (p = 0.0075 and p = 0.0004, respectively). The highest IP-10 levels were found in HCV-infected mono patients (940.8 pg / mL; IQR 703.5 - 1508.0 pg / mL) compared to HIV-1-infected patients (p = 0.0011) may suggest, as already identified in other studies, that HCV patients are more likely to activate the immune system. With the availability of direct-acting antivirals (DAAs) for the treatment of chronic hepatitis C virus infection, interferon-free regimens have been implemented worldwide. However, in the scenario of HIV-1 / HCV coinfection, ribavirin will continue to compose some therapeutic regimens, so evaluating the risk of toxicity may help in the monitoring of patients. Understanding the pathophysiological mechanisms of both infections will make it possible to compare them with other viral infections that reach the liver, for which effective therapies are not yet available. Key words: Coinfection. IL28B. ITPA. Inflammatory Markers

Risk areas for hepatitis A, B and C in the municipality of Maringá, Paraná State, Brazil 2007-2010

Viral hepatitis is a major public health problem in Brazil and worldwide. We retrospectively analyzed 338 cases of hepatitis A, B and C in Maringá, Paraná State from 2007 through 2010. The hepatitis A virus was present in 5.6% of the cases, hepatitis B in 44.7% and hepatitis C in 49.7%. Most of the patients affected were male (55.3%), white (79.6%) and had some primary education (42.9%). Of the 338 cases analyzed, 13.0% had comorbidities. The cases were concentrated in large-population census zones, but it was concluded that the spatial distribution of viral hepatitis in Maringá occurred randomly rather than show any regular pattern

Profile of HIV subtypes in HIV/HBV- and HIV/HCV-coinfected patients in Southern Brazil

Abstract INTRODUCTION: HIV and viral hepatitis infections are major causes of chronic disease worldwide and have some similarities with regard to routes of transmission, epidemiology, front barriers faced during access of treatment, and strategies for a global public health response. The objective was to describe the HIV-1 subtypes, viral tropism and single-nucleotide polymorphisms (SNPs) of interleukin 28B (IL28B) from a case series of HIV/viral hepatitis coinfected patients from southern Brazil. METHODS: Clinical and epidemiological data were evaluated by a review of medical records. Periodic blood draws were taken to determine the viral and host characteristics. RESULTS: This study included 38 patients with HIV/HBV or HIV/HCV coinfection; the median age was 49 years. Thirty-seven (97.4%) were on antiretroviral therapy, 32 (84.2%) had an undetectable viral load, a median CD4+ T-cell count of 452 cells/mm3. HIV-1 subtyping showed 47.4 and 31.6% of patients with subtypes C and B, respectively. Analysis of viral co-receptor usage showed a predominance of the R5 variant (64.7%), with no significant difference between the subtypes. Twenty patients with HIV/HCV coinfection were eligible to receive HCV therapy with pegylated-interferon-alpha plus ribavirin, and 10/20 (50%) of them achieved sustained virological response. SNPs of IL28B were evaluated in 93.3% of patients with HIV/HCV coinfection, and 17 (60.7%) presented the CC genotype. CONCLUSIONS: In the present case series, a higher frequency of HIV subtype C was found in coinfected patients. However such findings need to be prospectively evaluated with the inclusion of data from regional multicenter analyses