RESUMO
Pegylated IFNα (PEG-IFN) is one of the treatment options for chronic HBV (CHB) patients. However, the high patient treatment burden and limited response rate together clearly ask for biomarkers to predict PEG-IFN response. Soluble CD14 (sCD14) is considered a marker for immune activation and has been shown to predict clinical outcome of HIV infection. However, studies on sCD14 in CHB infection are inconclusive, and its relationship with clinical outcome is largely unknown. Here, we measured sCD14 levels in CHB patients and investigated whether changes in sCD14 level related to PEG-IFN response. Serum sCD14 levels were determined in 15 healthy controls, 15 acute self-limited HBV, 60 CHB patients in different disease phases and 94 HBeAg+ CHB patients at week 0 and week 12 of a 52-week PEG-IFN treatment. Response to PEG-IFN treatment was defined as HBeAg seroconversion or HBeAg loss at 26 weeks post-treatment. The mean sCD14 level in acute HBV patients (3.0 µg/mL) was significantly higher than in CHB patients (2.4 µg/mL) and healthy controls (2.4 µg/mL). In CHB patients receiving PEG-IFN, a significant increase in sCD14 was found after 12-week treatment (median week 0:2.1 µg/mL; week 12:3.7 µg/mL). After 12-week treatment, the fold change (FC = w12/w0) in sCD14 was significantly higher in responders compared to nonresponders (HBeAg seroconversion: median FCresponder = 2.1 vs FCnonresponder = 1.6; HBeAg loss: median FCresponder = 2.2 vs FCnonresponder = 1.5). Receiver operating characteristic curves demonstrated that FC-sCD14wk12/wk0 levels can be of significant value as a stopping rule to select patients at week 12 who are not likely to benefit from further PEG-IFN treatment.
Assuntos
Antivirais/uso terapêutico , Antígenos E da Hepatite B/sangue , Hepatite B Crônica/tratamento farmacológico , Interferon-alfa/uso terapêutico , Receptores de Lipopolissacarídeos/sangue , Polietilenoglicóis/uso terapêutico , Adulto , Feminino , Genótipo , Vírus da Hepatite B , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Curva ROC , Ensaios Clínicos Controlados Aleatórios como Assunto , Proteínas Recombinantes/uso terapêutico , Resultado do Tratamento , Carga Viral , Adulto JovemRESUMO
BACKGROUND & AIMS: A limited number of patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B respond to treatment with peginterferon alfa (PEG-IFN). We investigated whether IL28B genotypes are associated with response. METHODS: We studied 205 HBeAg-positive patients who were treated with PEG-IFN (some were also treated with lamivudine) at 11 European and Asian hospitals; genotype analysis was performed for IL28B rs12980275 and rs12979860. Response was defined as HBeAg loss with the appearance of antibodies to hepatitis B e antigen (anti-HBe) at the end of PEG-IFN therapy (HBeAg seroconversion), along with HBeAg seroconversion and hepatitis B surface antigen clearance during long-term follow-up. RESULTS: The patients were infected with hepatitis B virus (HBV) genotypes A (13%), B (20%), C (47%), and D (13%). The proportions of IL28B genotypes were 77%, 19%, and 5% for AA/AG/GG at rs12980275 and also for CC/CT/TT at rs12979860, respectively. IL28B genotype was significantly associated with HBeAg seroconversion at the end of treatment (P < .001); the adjusted odds ratio for seroconversion was 3.16 (95% confidence interval [CI], 1.26-8.52; P = .013) for AA versus AG/GG at rs12980275 after adjustment for HBV genotype, age, levels of HBV DNA and alanine aminotransferase, and combination therapy. IL28B genotype was independently associated with an increased probability of HBeAg seroconversion during long-term follow-up (adjusted hazard ratio [HR], 2.14; 95% CI, 1.14-4.31; P = .018 for AA vs AG/GG by Cox regression analysis). Similar results were obtained for rs12979860. IL28B genotype was also associated with hepatitis B surface antigen clearance (HR, 3.47 for AA vs AG/GG; 95% CI, 1.04-13.48; P = .042). CONCLUSIONS: Polymorphisms near IL28B are independently associated with serologic response to PEG-IFN in patients with HBeAg-positive chronic hepatitis B.
Assuntos
Antivirais/uso terapêutico , Antígenos E da Hepatite B/sangue , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B Crônica/tratamento farmacológico , Interferon-alfa/uso terapêutico , Interleucinas/genética , Polietilenoglicóis/uso terapêutico , Polimorfismo Genético , Adulto , Ásia , Biomarcadores/sangue , Distribuição de Qui-Quadrado , DNA Viral/sangue , Quimioterapia Combinada , Europa (Continente) , Feminino , Genótipo , Antígenos de Superfície da Hepatite B/sangue , Vírus da Hepatite B/genética , Vírus da Hepatite B/imunologia , Hepatite B Crônica/diagnóstico , Hepatite B Crônica/genética , Hepatite B Crônica/imunologia , Humanos , Interferon alfa-2 , Interferons , Estimativa de Kaplan-Meier , Lamivudina/uso terapêutico , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fenótipo , Modelos de Riscos Proporcionais , Proteínas Recombinantes/uso terapêutico , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Carga Viral , Adulto JovemRESUMO
The combination of ribavirin and peginterferon is the current standard of anti-viral treatment for chronic HCV patients. However, little is known on the mode of action of ribavirin in the anti-viral treatment of HCV patients. To investigate the immunomodulatory mechanism of ribavirin, we studied peginterferon alone versus peginterferon and ribavirin in chronic HBV patients. The addition of ribavirin did not affect the number of myeloid dendritic cells (mDC) or plasmacytoid dendritic cells (pDC), nor did it enhance T-helper-1 cell activity or T-cell proliferation. In contrast, it increased upregulation of activation markers on mDC and pDC, which was sustained throughout treatment. However, the addition of ribavirin had no effect on IFNα production by pDC. Our findings demonstrate that, although ribavirin does not lead to a viral load decline, in vivo treatment with ribavirin affects the activation of pDC and mDC in chronic HBV patients.