RESUMO
BACKGROUND & AIMS: The interaction between HBV replication and immune modulatory effects mediated by IFNα therapy is not well understood. We characterized the impact of HBV DNA replication on the early IFNα-induced immunomodulatory mechanisms. METHODS: We interrogated the transcriptional, serum cytokine/chemokine and cellular immune profiles of 28 patients with HBeAg+ chronic HBV infection (CHB) randomly assigned to one of 4 treatment cohorts (untreated n=5, weekly dosing of 360 µg Pegasys [PegIFNα] n=11, daily dose of 300 mg Viread [tenofovir disoproxil fumarate, TDF] n=6, or a combination of both n=6). Samples were characterized at multiple early time points through day 14 of therapy, after which all patients were given standard of care (180 µg Pegasys injected subcutaneously, weekly). RESULTS: PegIFNα induced a distinct and rapid up-regulation of IFN signaling pathway that coincided with increase detection of distinct serum cytokines/chemokines (IL-15, IL-6, and CXCL-10) and the up-regulation of the frequency of proliferating NK and activated total CD8+ T cells. IFNα treatment alone did not result in rapid decay of HBV replication and was not able to restore the defective HBV-specific T cell response present in CHB patients. In addition, the IFNα immune-stimulatory effects diminished after the first dose, but this refractory effect was reduced in patients where HBV replication was simultaneously inhibited with TDF. CONCLUSIONS: We present here the first comprehensive description of the early effects of IFNα treatment on immune and viral biomarkers in HBeAg+ CHB patients. Our results show that PegIFNα-induced innate immune activation directly benefits from the suppression of HBV replication.
Assuntos
Antivirais/uso terapêutico , Vírus da Hepatite B/fisiologia , Hepatite B Crônica/tratamento farmacológico , Interferon-alfa/uso terapêutico , Polietilenoglicóis/uso terapêutico , Replicação Viral/efeitos dos fármacos , Adolescente , Adulto , Estudos de Coortes , Hepatite B Crônica/imunologia , Hepatite B Crônica/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Proteínas Recombinantes/uso terapêutico , Linfócitos T/imunologiaRESUMO
UNLABELLED: The aims of this study were to evaluate the usefulness of quantitative hepatitis B e antigen (HBeAg) values for predicting HBeAg seroconversion in patients treated with peginterferon alfa-2a and to assess the dynamic changes in quantitative HBeAg during therapy, compared with conventional measures of serum hepatitis B virus DNA. Data were analyzed from a large, randomized, multinational phase III registration trial involving 271 HBV-infected HBeAg-positive patients who received peginterferon alfa-2a plus oral placebo for 48 weeks. HBeAg levels were measured serially during therapy using a microparticle enzyme immunoassay validated with in-house reference standards obtained from the Paul Ehrlich Institute (PEIU/mL). In patients who achieved HBeAg seroconversion, levels of HBeAg consistently decreased during treatment and remained at their lowest level during the 24 weeks of posttreatment follow-up. After 24 weeks of treatment, 4% of patients with the highest levels of HBeAg (>or=100 PEIU/mL) achieved HBeAg seroconversion, yielding a negative predictive value of 96%, which was greater than that obtained for levels of HBV DNA (86%). Late responders to peginterferon alfa-2a could also be differentiated from nonresponders by continued decrease in HBeAg values, which were not evident by changes in HBV DNA. CONCLUSION: These analyses suggest quantitative HBeAg is a useful adjunctive measurement for predicting HBeAg seroconversion in patients treated with peginterferon when considering both sensitivity and specificity compared with serum HBV DNA.
Assuntos
Antivirais/uso terapêutico , DNA Viral/sangue , Antígenos E da Hepatite B/sangue , Vírus da Hepatite B/genética , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/virologia , Interferon-alfa/uso terapêutico , Polietilenoglicóis/uso terapêutico , Biomarcadores/sangue , Monitoramento de Medicamentos/métodos , Hepatite B Crônica/sangue , Humanos , Interferon alfa-2 , Lamivudina/uso terapêutico , Valor Preditivo dos Testes , Proteínas Recombinantes , Resultado do TratamentoRESUMO
BACKGROUND: Current treatments for chronic hepatitis B are suboptimal. In the search for improved therapies, we compared the efficacy and safety of pegylated interferon alfa plus lamivudine, pegylated interferon alfa without lamivudine, and lamivudine alone for the treatment of hepatitis B e antigen (HBeAg)-positive chronic hepatitis B. METHODS: A total of 814 patients with HBeAg-positive chronic hepatitis B received either peginterferon alfa-2a (180 microg once weekly) plus oral placebo, peginterferon alfa-2a plus lamivudine (100 mg daily), or lamivudine alone. The majority of patients in the study were Asian (87 percent). Most patients were infected with hepatitis B virus (HBV) genotype B or C. Patients were treated for 48 weeks and followed for an additional 24 weeks. RESULTS: After 24 weeks of follow-up, significantly more patients who received peginterferon alfa-2a monotherapy or peginterferon alfa-2a plus lamivudine than those who received lamivudine monotherapy had HBeAg seroconversion (32 percent vs. 19 percent [P<0.001] and 27 percent vs. 19 percent [P=0.02], respectively) or HBV DNA levels below 100,000 copies per milliliter (32 percent vs. 22 percent [P=0.01] and 34 percent vs. 22 percent [P=0.003], respectively). Sixteen patients receiving peginterferon alfa-2a (alone or in combination) had hepatitis B surface antigen (HBsAg) seroconversion, as compared with 0 in the group receiving lamivudine alone (P=0.001). The most common adverse events were those known to occur with therapies based on interferon alfa. Serious adverse events occurred in 4 percent, 6 percent, and 2 percent of patients receiving peginterferon alfa-2a monotherapy, combination therapy, and lamivudine monotherapy, respectively. Two patients receiving lamivudine monotherapy had irreversible liver failure after the cessation of treatment--one underwent liver transplantation, and the other died. CONCLUSIONS: In patients with HBeAg-positive chronic hepatitis B, peginterferon alfa-2a offers superior efficacy over lamivudine, on the basis of HBeAg seroconversion, HBV DNA suppression, and HBsAg seroconversion.
Assuntos
Antivirais/uso terapêutico , Hepatite B Crônica/tratamento farmacológico , Interferon-alfa/uso terapêutico , Lamivudina/uso terapêutico , Polietilenoglicóis/uso terapêutico , Adolescente , Adulto , Idoso , Alanina Transaminase/sangue , Antivirais/administração & dosagem , Antivirais/efeitos adversos , DNA Viral/sangue , Método Duplo-Cego , Farmacorresistência Viral , Quimioterapia Combinada , Feminino , Antígenos de Superfície da Hepatite B/sangue , Antígenos E da Hepatite B/sangue , Vírus da Hepatite B/genética , Vírus da Hepatite B/isolamento & purificação , Humanos , Interferon alfa-2 , Interferon-alfa/efeitos adversos , Lamivudina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis/efeitos adversos , Proteínas RecombinantesRESUMO
BACKGROUND/AIMS: Hepatitis B and C viruses (HBV and HCV) are two clinically distinct but related diseases. Pooled data from five studies of peginterferon alpha-2a in patients with chronic HCV infection (CHC) were compared with two studies of the drug in patients with chronic HBV infection (CHB). METHOD: The HBV studies included both hepatitis B e antigen (HBeAg)-positive (n=271) and HBeAg-negative (n=177) patients; 791 patients took part in the HCV trials. In all studies, patients were treated with 180 microg peginterferon alpha-2a monotherapy once weekly for 48 weeks. The number of adverse events (AEs), discontinuations and dose modifications were documented. Health-related quality of life (HRQL) was assessed using the Short-Form 36 questionnaire. Safety was assessed throughout the treatment period. A 24-week treatment-free follow-up period was also included. RESULTS: Differences (HBV vs HCV) were observed in the incidence of AEs (88-89 vs 96-100%), serious AEs (4-5 vs 7-16%) and treatment withdrawals (6-8 vs 17-33%). The frequency of depression-related events was lower in CHB patients (4 vs 22%, P<0.001), as was the impact of treatment on HRQL. CONCLUSIONS: The safety and tolerability of peginterferon alpha-2a in patients with CHB compares favourably with that observed in CHC patients, with a lower incidence of common interferon-related AEs and a significantly lower incidence of depression.
Assuntos
Hepatite B Crônica/tratamento farmacológico , Hepatite C Crônica/tratamento farmacológico , Interferon-alfa/administração & dosagem , Polietilenoglicóis/administração & dosagem , Qualidade de Vida , Adulto , Relação Dose-Resposta a Droga , Esquema de Medicação , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Hepatite B Crônica/diagnóstico , Hepatite B Crônica/mortalidade , Hepatite C Crônica/diagnóstico , Hepatite C Crônica/mortalidade , Humanos , Interferon alfa-2 , Interferon-alfa/efeitos adversos , Testes de Função Hepática , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Polietilenoglicóis/efeitos adversos , Probabilidade , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Proteínas Recombinantes , Valores de Referência , Medição de Risco , Índice de Gravidade de Doença , Taxa de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND & AIMS: It has yet to be firmly established whether host IFNL3 (IL28B) genotype influences interferon responsiveness in patients with chronic hepatitis B. We investigated associations between single-nucleotide polymorphisms (SNPs) in the IFNL3 region and response to peginterferon alfa-2a in 701 patients enrolled in three large, randomized, international studies. METHODS: Responses were defined as hepatitis B surface antigen (HBsAg) loss and/or hepatitis B e antigen (HBeAg) seroconversion plus hepatitis B virus (HBV) DNA <2000 IU/ml in HBeAg-positive patients, and HBsAg loss and/or HBV DNA <2000 IU/ml in HBeAg-negative patients (24 weeks after end of treatment). Associations between treatment response and the number of copies of the poor-response allele at three SNPs (rs8099917, rs12980275, rs12979860) were explored with logistic regression models in Asian and white patients. RESULTS: The HBeAg-positive and -negative populations comprised 465 (92% Asian, 50% HBV genotype C) and 236 (79% Asian, 41% HBV genotype C) patients, respectively, and had respective response rates of 26% and 47%. The IFNL3 genotype was strongly associated with ethnicity. There was no association between IFNL3 genotype and treatment response in HBeAg-positive or -negative patients. Independent predictors of treatment response were: sex, HBV DNA level and alanine aminotransferase level in HBeAg-positive Asian patients; age in HBeAg-negative Asian patients; and HBV DNA in HBeAg-negative white patients. CONCLUSIONS: This is the largest analysis to date of associations between IFNL3 genotype and peginterferon response in patients with chronic hepatitis B. The data suggest that IFNL3 polymorphism is not a major determinant of the response to peginterferon alfa-2a in either HBeAg-positive or HBeAg-negative patients.