Análise do perfil de resposta inflamatória em pacientes com hepatite C crônica em tratamento com Antivirais de Ação Direta
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2021-03-01
Autores
Winckler, Fernanda Cristina
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Universidade Estadual Paulista (Unesp)
Resumo
O objetivo do estudo foi avaliar o perfil da resposta inflamatória de pacientes com hepatite C crônica cirróticos (F4) e não cirróticos (Fγ e ≤Fβ) durante o tratamento com Antivirais de Ação Direta (AADs). Os pacientes foram recrutados no Ambulatório de hepatites virais da disciplina de Gastroenterologia da UNESP-Botucatu. As amostras foram coletadas e analisadas em dois ou três períodos (Basal (TW0) e doze semanas após o término do tratamento (POS12) ou TW0, Fim de Tratamento (FT) e POS12). As análises das amostras foram realizadas por citometria de fluxo, por imunofenotipagem para contagem celular de Linfócitos T (LT), Natural killer (NK) e monócitos, método CBA (Cytometric Bead Array®) e Imunoensaio LEGENDplex™ para análise de quimiocinas e citocinas. As análises estatísticas foram realizadas usando os seguintes testes: análise de células por Mann-Whitney e Friedman seguida do teste de Dunn, citocinas e quimiocinas pelo teste não paramétrico de Wilcoxon, Mann-Whitney e Kruskal-Wallis. A população total recrutada foi de 189 pacientes, desses, 189 tiveram análise de quimiocinas e 188 análise de citocinas nos períodos TW0 e POS12, 102 análise de LT em TW0 e 36 pacientes cirróticos tiveram análise de células em TW0, FT e POS12. Quando comparamos os níveis de LT de TW0 entre os subgrupos ≤Fγ x F4 mostramos que há diferença significativa entre eles (CD4 p=0,01; CD8 p=0,02). Nossa análise comparando Linfócitos T (CD4 p=< 0.001; CD8 p=< 0.001) e NK totais (p=0,01) em pacientes cirróticos com Resposta Virológica Sustentada (RVS) entre períodos mostrou melhora nos níveis dessas células em POS12. A análise de quimiocinas mostrou que os níveis da maioria delas mudam significativamente em POS12 (IP10 p=0,000; MCP-1 p=0,001; RANTES p=0,000; IL8 p=0,000). Independente da resposta ao tratamento mostramos que o tratamento com AADs altera significativamente o perfil inflamatório dos pacientes, apesar de um número pequeno de não RVS (n=9 (4,9%)). No POS12 observamos que os níveis das citocinas eram mais elevados no grupo F4, ou seja, o tratamento propicia aumento nos níveis de algumas citocinas independentemente da fibrose, todavia, pacientes F4 tem uma resposta mais exacerbada nesse período. Quando comparamos os períodos TW0xPOS12 nos subgrupos ≤Fγ e F4, observamos que as citocinas IL10, ILβ, IL17 e TGF-����� não apresentaram mudanças significantes em F4 e apenas IP10 (p=0,000), MCP-1 (p=0,000), MIG (p=0,053), IL8 (p=0,000), TNF-α (p=0,056) e TGF-����� (p=0,049) mudaram significativamente em ≤Fγ. Todas as quimiocinas diminuíram os níveis em pacientes com RVS. Podemos concluir que o tratamento com AADs levaram a uma exacerbação na produção de linfócitos T e citocinas pró-inflamatórias em pacientes cirróticos com RVS podendo propiciar benefícios clínicos à essa população, no entanto, estudos complementares são recomendados para afirmar estes achados e identificar os benefícios a longo prazo.
The study objective was evaluate the inflammatory response profile of chronic hepatitis C patients cirrhotic (F4) and non-cirrhotic (≤Fγ) during treatment with Direct Action Antivirals (DAAs). Subjects were recruited at the Outpatient Clinic for Viral Hepatitis in the Gastroenterology discipline at UNESP-Botucatu. The samples were collected and analyzed in two or three moments (Baseline (TW0) and Follow-up at 12 weeks after end of treatment (FU12) or TW0, End of treatment (EOT) and FU12). Samples analysis were performed by flow cytometry, immunophenotyping for cells count of T lymphocytes (TL), natural killer (NK) and monocytes, Cytometric Bead Array® (CBA) and LEGENDplex ™ immunoassay methods for chemokine and cytokine analysis. Statistical analysis were performed by follow tests: Mann-Whitney and Friedman followed by Dunn test to cells analysis, Wilcoxon, Mann- Whitney and Kruskal-Wallis non-parametric test to chemokine and cytokine analysis. The total population included were 189 subjects , of these, 189 had analysis of chemokines and 188 analysis of cytokines in periods TW0 and POS12, 102 analysis of TL in TW0 and 36 cirrhotic patients had analysis of cells in TW0, FT and POS12. When we compare the levels of T lymphocytes of TW0 between the subgroups ≤Fγ x F4, we show that there is a significant difference between them (CD4 p = 0.01; CD8 p = 0.02). Our analysis comparing T lymphocytes (CD4 p = <0.001; CD8 p = <0.001) and total NK (p = 0.01) in cirrhotic patients with Sustained Virological Response (SVR) between periods showed improvement in the levels of these cells at POS12. Chemokine analysis showed that the levels of most of them change significantly at POS12 (IP10 p = 0.000; MCP-1 p = 0.001; RANTES p = 0.000; IL8 p = 0.000). Regardless of the response to treatment, we show that treatment with AADs significantly alters the inflammatory profile of patients, despite a small number of non-SVRs (n = 9 (4.9%)). At POS12, we observed that cytokine levels were higher in the F4 group, that is, the treatment provides an increase in the levels of some cytokines regardless of fibrosis, however, F4 patients have a more exacerbated response in this period. When comparing the TW0xPOS12 periods in the subgroups ≤Fγ and F4, we observed that the cytokines IL10, ILβ, IL17 and TGF-����� did not show significant changes in F4 and only IP10 (p = 0.000), MCP-1 (p = 0.000), MIG (p = 0.053), IL8 (p = 0.000), TNF-α (p = 0.056) and TGF-����� (p = 0.049) changed significantly by ≤Fγ. All chemokines decreased levels in subjects with SVR . We can conclude that treatment with AADs led to an exacerbation in the production of T-lymphocytes and pro-inflammatory cytokines in cirrhotic patients with SVR, which may provide clinical benefits to this population, however, we recommended complementary studiesto affirm these findings and identify the benefits long term.
The study objective was evaluate the inflammatory response profile of chronic hepatitis C patients cirrhotic (F4) and non-cirrhotic (≤Fγ) during treatment with Direct Action Antivirals (DAAs). Subjects were recruited at the Outpatient Clinic for Viral Hepatitis in the Gastroenterology discipline at UNESP-Botucatu. The samples were collected and analyzed in two or three moments (Baseline (TW0) and Follow-up at 12 weeks after end of treatment (FU12) or TW0, End of treatment (EOT) and FU12). Samples analysis were performed by flow cytometry, immunophenotyping for cells count of T lymphocytes (TL), natural killer (NK) and monocytes, Cytometric Bead Array® (CBA) and LEGENDplex ™ immunoassay methods for chemokine and cytokine analysis. Statistical analysis were performed by follow tests: Mann-Whitney and Friedman followed by Dunn test to cells analysis, Wilcoxon, Mann- Whitney and Kruskal-Wallis non-parametric test to chemokine and cytokine analysis. The total population included were 189 subjects , of these, 189 had analysis of chemokines and 188 analysis of cytokines in periods TW0 and POS12, 102 analysis of TL in TW0 and 36 cirrhotic patients had analysis of cells in TW0, FT and POS12. When we compare the levels of T lymphocytes of TW0 between the subgroups ≤Fγ x F4, we show that there is a significant difference between them (CD4 p = 0.01; CD8 p = 0.02). Our analysis comparing T lymphocytes (CD4 p = <0.001; CD8 p = <0.001) and total NK (p = 0.01) in cirrhotic patients with Sustained Virological Response (SVR) between periods showed improvement in the levels of these cells at POS12. Chemokine analysis showed that the levels of most of them change significantly at POS12 (IP10 p = 0.000; MCP-1 p = 0.001; RANTES p = 0.000; IL8 p = 0.000). Regardless of the response to treatment, we show that treatment with AADs significantly alters the inflammatory profile of patients, despite a small number of non-SVRs (n = 9 (4.9%)). At POS12, we observed that cytokine levels were higher in the F4 group, that is, the treatment provides an increase in the levels of some cytokines regardless of fibrosis, however, F4 patients have a more exacerbated response in this period. When comparing the TW0xPOS12 periods in the subgroups ≤Fγ and F4, we observed that the cytokines IL10, ILβ, IL17 and TGF-����� did not show significant changes in F4 and only IP10 (p = 0.000), MCP-1 (p = 0.000), MIG (p = 0.053), IL8 (p = 0.000), TNF-α (p = 0.056) and TGF-����� (p = 0.049) changed significantly by ≤Fγ. All chemokines decreased levels in subjects with SVR . We can conclude that treatment with AADs led to an exacerbation in the production of T-lymphocytes and pro-inflammatory cytokines in cirrhotic patients with SVR, which may provide clinical benefits to this population, however, we recommended complementary studiesto affirm these findings and identify the benefits long term.
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Palavras-chave
Antivirais de ação direta, Hepatite C, Resposta inflamatória, Resposta virológica sustentada, Tratamento, Direct Action Antivirals, Hepatitis C, Inflammatory response, Sustained virological response, Treatment