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1.
J Infect Dis ; 215(7): 1085-1093, 2017 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-28329061

RESUMO

Background: We studied whether 48 weeks of pegylated interferon alfa-2b (peginterferon) add-on therapy increases serological response in hepatitis B virus (HBV) envelope antigen (HBeAg)-positive patients receiving nucleos(t)ide analogue (NA) therapy, compared with continued NA monotherapy. Methods: This randomized trial included HBeAg-positive patients with compensated liver disease who were treated with entecavir/tenofovir for >12 months and had an HBV DNA load of <2000 IU/mL. Patients were randomly assigned in a 1:1 ratio to 48 weeks of peginterferon add-on therapy (n = 39) or continued NA monotherapy (n = 38). Response (defined as HBeAg seroconversion with an HBV DNA load of <200 IU/mL) was assessed at week 48, with responders discontinuing NA therapy at week 72. Results: The primary end point (response at week 96) was achieved in 18% of patients who were assigned peginterferon add-on therapy versus 8% of patients assigned NA monotherapy (P = .31). Among 58 interferon-naive patients, add-on therapy led to a greater frequency of HBeAg seroconversion (30% vs 7%; P = .034) and response (26% vs 7%; P = .068) at week 96, compared with monotherapy. Among 8 responders at week 48 who discontinued NA therapy at week 72, 6 patients (75%) maintained a response until week 96 (4 of 6 [67%] in the add-on therapy group vs 2 of 2 [100%] in the monotherapy group; P = 1.00). Adverse events were mainly related to peginterferon. Conclusion: The primary end point was negative, but peginterferon add-on therapy appeared to result in a greater frequency of HBeAg seroconversion, compared with NA monotherapy, in interferon-naive patients receiving NA therapy. Clinical Trials Registration: NCT01532843.


Assuntos
Antivirais/administração & dosagem , Guanina/análogos & derivados , Hepatite B Crônica/tratamento farmacológico , Interferon-alfa/administração & dosagem , Polietilenoglicóis/administração & dosagem , Tenofovir/uso terapêutico , Adulto , China , DNA Viral/sangue , Quimioterapia Combinada , Feminino , Guanina/uso terapêutico , Antígenos E da Hepatite B/sangue , Vírus da Hepatite B , Humanos , Interferon alfa-2 , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Países Baixos , Proteínas Recombinantes/administração & dosagem , Resultado do Tratamento
2.
J Gastroenterol Hepatol ; 31(11): 1882-1887, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27008918

RESUMO

BACKGROUND AND AIM: The incidence and consequences of flares during first-line nucleos(t)ide analogue therapy are largely unknown. We aimed to investigate the incidence and outcome of alanine aminotransferase (ALT) flares during long-term entecavir (ETV) in chronic hepatitis B (CHB). METHODS: CHB patients treated with ETV monotherapy from 11 European centers were studied. Flare was defined as > 3× increase in ALT compared with baseline or lowest on-treatment level and an absolute ALT > 3× ULN. Flares were designated as host-induced (preceded by hepatitis B virus (HBV)-DNA decline), virus-induced (HBV-DNA increase), or indeterminate (stable HBV-DNA). RESULTS: Seven hundred and twenty-nine patients were treated with ETV for median of 3.5 years. Thirty patients developed a flare with cumulative incidence of 6.3% at year 5. Baseline hepatitis B e antigen (HBeAg)-positivity (HR 2.84; P = 0.005) and high HBV-DNA (Hazard ratio (HR) 1.30; P = 0.003) predicted flares. There were 12 (40%) host-induced, 7 (23%) virus-induced, and 11 (37%) indeterminate flares. Host-induced flares occurred earlier than virus-induced (median: 15 vs 83 weeks; P = 0.027) or indeterminate flares (15 vs 109 weeks; P = 0.011). Host-induced flares were associated with biochemical remission, and HBeAg (n = 3) and hepatitis B surface antigen (n = 2) seroconversions were exclusively observed among patients with these flares. Virus-induced flares were associated with ETV resistance (n = 2) and non-compliance (n = 1). CONCLUSION: The incidence of ALT flares during ETV was low in this real-life cohort. ETV can be safely continued in patients with host-induced flares. Treatment adherence and drug resistance must be assessed in patients with virus-induced flares.


Assuntos
Antivirais/efeitos adversos , Guanina/análogos & derivados , Hepatite B Crônica/tratamento farmacológico , Adulto , Alanina Transaminase/sangue , Antivirais/uso terapêutico , Biomarcadores/sangue , DNA Viral/sangue , Feminino , Seguimentos , Guanina/efeitos adversos , Guanina/uso terapêutico , Antígenos de Superfície da Hepatite B/sangue , Antígenos E da Hepatite B/sangue , Vírus da Hepatite B/genética , Vírus da Hepatite B/isolamento & purificação , Hepatite B Crônica/enzimologia , Hepatite B Crônica/virologia , Humanos , Masculino , Pessoa de Meia-Idade
3.
Clin Gastroenterol Hepatol ; 14(10): 1481-1489.e5, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-26872398

RESUMO

BACKGROUND & AIMS: Measurements of hepatitis B surface antigen (HBsAg) and hepatitis B virus (HBV) DNA might help to identify carriers of inactive HBV. We assessed the performance of repeated measurements of HBsAg over a median time period of 8 years. METHODS: We performed a retrospective study of 292 HBe antigen-negative patients with chronic HBV infection, normal levels of alanine aminotransferase (ALT), levels of HBV DNA <20,000 IU/mL, and no cirrhosis who visited the outpatient clinics at 8 tertiary care centers in Europe, Asia, and Australia from 1990 through 2011. Patients were determined to be carriers of inactive HBV (level of HBV DNA <2000 IU/mL and serum levels of ALT that remained normal) or to have HBV activity (level of HBV DNA fluctuating >2000 IU/mL and/or abnormal levels of ALT) after each year of follow-up. Patients were followed for a median time of 8 years (range, 4-9 years). Dynamic regression analysis was used to study changes in level of HBsAg and HBV phase and to update the risk of HBV activity. RESULTS: One year after study enrollment, 189 patients (65%) had inactive HBV and 103 patients (35%) had HBV activity. Based on dynamic analysis, the probability that a patient would have HBV at any following year differed according to level of HBsAg; odds were 97% for patients with initial level of HBsAg <100 IU/mL, 85% for patients with initial levels 100-1000 IU/mL, and 76% for patients with initial levels >1000 IU/mL (P < .001). Having inactive virus for any 2 consecutive years predicted having inactive virus in any third year. However, 15% of patients with level of HBsAg >100 IU/mL had HBV activity in the third year. The combination of HBsAg level <100 IU/mL and HBV DNA level <2000 IU/mL identified patients whose virus remained inactive for the entire follow-up period, with 98% specificity and a positive predictive value of 97%, for all HBV genotypes. Patients with HBV activity who had levels of HBV DNA <5000 IU/mL and decreases in HBsAg of 0.5 log IU/mL or more for 1 year had a high probability of becoming carriers of inactive HBV in the next year. CONCLUSIONS: In a retrospective, dynamic analysis of almost 300 patients with chronic HBV infection, we found that levels of HBsAg <100 IU/mL identify patients with inactive virus with a high level of specificity. HBsAg levels should therefore be used to define phases of HBV infection in HBe antigen-negative patients.


Assuntos
Portador Sadio/diagnóstico , Testes Diagnósticos de Rotina/métodos , Antígenos de Superfície da Hepatite B/sangue , Hepatite B Crônica/diagnóstico , Adulto , Idoso , Alanina Transaminase/sangue , Ásia , Austrália , DNA Viral/sangue , Europa (Continente) , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Pacientes Ambulatoriais , Estudos Retrospectivos , Sensibilidade e Especificidade , Centros de Atenção Terciária
4.
Dig Liver Dis ; 47(7): 577-83, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25936691

RESUMO

BACKGROUND: Real-life prospective data on adherence to nucleos(t)ide analogues in chronic hepatitis B patients are scarce. AIMS: We investigated adherence to entecavir in relation to virological response. METHODS: In this prospective study, we provided 100 consecutive chronic hepatitis B patients with a medication dispenser that monitored entecavir intake during 16 weeks therapy. Hepatitis B virus (HBV) DNA was measured at baseline and after 16 weeks. Beliefs about medicines were evaluated using a questionnaire. RESULTS: Adherence over 16 weeks averaged 85 ± 17%, with 70% of patients exhibiting good (i.e. ≥ 80%) adherence. Patients with poor (i.e. <80%) adherence were significantly younger (p=0.01), with more often indifferent attitudes towards entecavir (p=0.03) Viral breakthrough did not occur during the study. Adherence in patients with HBV DNA after 16 weeks > 20 IU/mL (n=18) and ≤ 20 IU/mL (n=81) averaged 83% and 91% respectively (p=0.19). In multivariate analysis, adherence was not a significant predictor of HBV DNA negativity (adjusted OR 1.02; p=0.34), after adjustment for duration of entecavir treatment (p<0.001) and HBe-status (p=0.001). CONCLUSIONS: 70% of chronic hepatitis B patients exhibited good adherence to entecavir, with younger age and an indifferent attitude being risk factors for poor adherence. Poor adherence was not an independent predictor of virological response.


Assuntos
Antivirais/uso terapêutico , Guanina/análogos & derivados , Hepatite B Crônica/tratamento farmacológico , Adesão à Medicação/estatística & dados numéricos , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Esquema de Medicação , Feminino , Guanina/uso terapêutico , Conhecimentos, Atitudes e Prática em Saúde , Hepatite B Crônica/psicologia , Humanos , Masculino , Adesão à Medicação/psicologia , Pessoa de Meia-Idade , Estudos Prospectivos , Inquéritos e Questionários , Resultado do Tratamento , Adulto Jovem
5.
J Hepatol ; 62(2): 363-70, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25195548

RESUMO

BACKGROUND & AIMS: The risk of hepatocellular carcinoma (HCC) in Caucasian patients with chronic hepatitis B (CHB), treated with entecavir (ETV) or tenofovir (TDF), is unclear. We evaluated the incidence and predictors of HCC and the accuracy of existing HCC risk scores in Caucasian CHB patients receiving ETV/TDF. METHODS: This large, multicentre, retrospective cohort study included 1666 adult Caucasian CHB patients under ETV/TDF for 39 months. CHB without cirrhosis, compensated and decompensated cirrhosis were present in 67%, 39%, and 3% of patients, respectively. The predictability of baseline parameters and three risk scores (GAG-HCC, CU-HCC, and REACH-B), developed in Asian patients, was assessed. RESULTS: The cumulative probability of HCC was 1.3%, 3.4%, and 8.7% at year-1, year-3, and year-5 after ETV/TDF onset. Older age and lower platelets were strong independent HCC predictors in the total population and in the subgroups of cirrhotic and non-cirrhotic patients, while liver disease severity was an independent HCC predictor in the total population and in the cirrhotics. GAG-HCC, CU-HCC, and REACH-B risk scores were associated with HCC development only in the univariable but not in the multivariable analyses and offered poor to modest predictability. CONCLUSIONS: HCC can still develop in Caucasian CHB patients treated with ETV/TDF. Besides the well-known predictors of HCC, such as older age, male gender and more advanced liver disease, lower platelets represent an independent factor of higher HCC risk. The applicability and predictability of HCC risk scores developed in Asian patients are poor or modest in Caucasian CHB patients, for whom different risk scores are required.


Assuntos
Adenina/análogos & derivados , Carcinoma Hepatocelular/etnologia , Guanina/análogos & derivados , Neoplasias Hepáticas/etnologia , Organofosfonatos/uso terapêutico , População Branca , Adenina/uso terapêutico , Adulto , Antivirais/uso terapêutico , Carcinoma Hepatocelular/etiologia , Feminino , Seguimentos , Grécia/epidemiologia , Guanina/uso terapêutico , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/etnologia , Humanos , Incidência , Neoplasias Hepáticas/etiologia , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Estudos Retrospectivos , Inibidores da Transcriptase Reversa/uso terapêutico , Fatores de Risco , Espanha/epidemiologia , Tenofovir , Fatores de Tempo , Turquia/epidemiologia
6.
Gut ; 64(8): 1289-95, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25011935

RESUMO

BACKGROUND: Hepatocellular carcinoma (HCC) risk-scores may predict HCC in Asian entecavir (ETV)-treated patients. We aimed to study risk factors and performance of risk scores during ETV treatment in an ethnically diverse Western population. METHODS: We studied all HBV monoinfected patients treated with ETV from 11 European referral centres within the VIRGIL Network. RESULTS: A total of 744 patients were included; 42% Caucasian, 29% Asian, 19% other, 10% unknown. At baseline, 164 patients (22%) had cirrhosis. During a median follow-up of 167 (IQR 82-212) weeks, 14 patients developed HCC of whom nine (64%) had cirrhosis at baseline. The 5-year cumulative incidence rate of HCC was 2.1% for non-cirrhotic and 10.9% for cirrhotic patients (p<0.001). HCC incidence was higher in older patients (p<0.001) and patients with lower baseline platelet counts (p=0.02). Twelve patients who developed HCC achieved virologic response (HBV DNA <80 IU/mL) before HCC. At baseline, higher CU-HCC and GAG-HCC, but not REACH-B scores were associated with development of HCC. Discriminatory performance of HCC risk scores was low, with sensitivity ranging from 18% to 73%, and c-statistics from 0.71 to 0.85. Performance was further reduced in Caucasians with c-statistics from 0.54 to 0.74. Predicted risk of HCC based on risk-scores declined during ETV therapy (all p<0.001), but predictive performances after 1 year were comparable to those at baseline. CONCLUSIONS: Cumulative incidence of HCC is low in patients treated with ETV, but ETV does not eliminate the risk of HCC. Discriminatory performance of HCC risk scores was limited, particularly in Caucasians, at baseline and during therapy.


Assuntos
Carcinoma Hepatocelular/etnologia , Guanina/análogos & derivados , Hepatite B Crônica/tratamento farmacológico , Neoplasias Hepáticas/etnologia , Medição de Risco , População Branca , Adulto , Antivirais , Carcinoma Hepatocelular/etiologia , DNA Viral/análise , Feminino , Seguimentos , Guanina/uso terapêutico , Vírus da Hepatite B/genética , Hepatite B Crônica/complicações , Hepatite B Crônica/etnologia , Humanos , Incidência , Neoplasias Hepáticas/etiologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Reino Unido/epidemiologia
7.
Antivir Ther ; 19(4): 423-7, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24296674

RESUMO

BACKGROUND: Several factors have been related to response to pegylated interferon (PEG-IFN) in chronic hepatitis B (CHB). The occurrence of anti-IFN antibodies is associated with non-response to PEG-IFN in chronic hepatitis C. This study investigated the association between anti-IFN antibodies and response to PEG-IFN in CHB. METHODS: Presence of anti-IFN antibodies was assessed at baseline and at 3 and 6 months post-treatment in 323 CHB patients treated with PEG-IFN for 1 year. RESULTS: At baseline, anti-IFN antibodies were detected in 112 (35%) patients. Prevalence was higher in HBeAg-negative compared to HBeAg-positive CHB (43% versus 31%, respectively; P=0.03). Detection of anti-IFN antibodies was not associated with age, sex or HBV genotype. Presence of anti-IFN antibodies at baseline was associated with previous IFN therapy failure (P=0.04), which remained after adjustment for HBeAg status (OR 2.0, 95% CI 1.1, 3.7; P=0.03). Presence of anti-IFN antibodies at baseline was not associated with response, nor with HBV DNA or HBsAg decline (all P-values>0.3). Overall, 56 of 211 (27%) patients without anti-IFN at baseline developed anti-IFN antibodies after PEG-IFN treatment. Response rates did not differ between patients who developed anti-IFN antibodies and patients who did not develop anti-IFN antibodies during treatment (P=0.1). CONCLUSIONS: Anti-IFN antibodies may frequently be detected in CHB patients, and presence is associated with previous IFN therapy. However, presence or development of anti-IFN antibodies after PEG-IFN therapy is not associated with non-response to PEG-IFN treatment in CHB. There appears to be no future role for anti-IFN antibodies in predicting response to PEG-IFN in CHB.


Assuntos
Anticorpos/imunologia , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/imunologia , Interferons/imunologia , Interferons/uso terapêutico , Adulto , Feminino , Genótipo , Antígenos E da Hepatite B/imunologia , Vírus da Hepatite B/genética , Vírus da Hepatite B/imunologia , Hepatite B Crônica/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Falha de Tratamento , Resultado do Tratamento , Carga Viral , Adulto Jovem
8.
J Hepatol ; 58(5): 898-903, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23376362

RESUMO

BACKGROUND & AIMS: Serum levels of interferon-gamma inducible protein 10 (IP-10) are a marker for immune activity, and may predict response to peginterferon (PegIFN) therapy in chronic hepatitis B. METHODS: IP-10 was measured at baseline and on-treatment week 12 in 210 HBeAg-positive patients treated with PegIFN for 52 weeks. Response to treatment was assessed at 6 months post-treatment and defined as HBeAg loss, combined response (HBeAg loss with HBV DNA <10,000 c/ml) or HBsAg loss. RESULTS: Median baseline IP-10 levels were 158 pg/ml. Higher baseline IP-10 was associated with more HBV DNA, HBeAg and HBsAg decline from week 4 onwards, and IP-10 was higher in patients who achieved HBeAg loss (p=0.001) and combined response (p=0.052). A combination of high IP-10 (>150 pg/ml) with absence of precore (PC) and core promoter (BCP) mutants strongly predicted combined response and HBsAg loss: 48% of patients with high IP-10 and no detectable mutants achieved a combined response (p<0.001). A minimal non-significant decline from baseline was observed to week 12 (0.015 log pg/ml, p=0.52 compared to baseline), but decline was somewhat more pronounced in patients who achieved HBeAg loss (0.05 logpg/ml, versus an increase of 0.05 in patients without HBeAg loss, p=0.04). CONCLUSIONS: Higher pre-treatment IP-10 levels are associated with an increased probability of HBeAg loss after PegIFN therapy. A combination of high baseline IP-10 and absence of PC and BCP mutants identified patients with the highest probability of combined response and HBsAg loss. There appears little use for on-treatment quantification of IP-10 for prediction of response to PegIFN.


Assuntos
Antivirais/uso terapêutico , Quimiocina CXCL10/sangue , Antígenos E da Hepatite B/sangue , Hepatite B Crônica/sangue , Hepatite B Crônica/tratamento farmacológico , Interferon-alfa/uso terapêutico , Polietilenoglicóis/uso terapêutico , Adulto , Biomarcadores/sangue , DNA Viral/sangue , Feminino , Antígenos de Superfície da Hepatite B/sangue , Vírus da Hepatite B/genética , Hepatite B Crônica/imunologia , Humanos , Interferon alfa-2 , Masculino , Pessoa de Meia-Idade , Mutação/genética , Valor Preditivo dos Testes , Proteínas Recombinantes/uso terapêutico , Resultado do Tratamento , Proteínas do Core Viral/genética
10.
World J Surg ; 34(1): 20-7, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19898894

RESUMO

BACKGROUND: Several studies have been performed to identify risk factors for abdominal wound dehiscence. No risk model had yet been developed for the general surgical population. The objective of the present study was to identify independent risk factors for abdominal wound dehiscence and to develop a risk model to recognize high-risk patients. Identification of high-risk patients offers opportunities for intervention strategies. METHODS: Medical registers from January 1985 to December 2005 were searched. Patients who had primarily undergone appendectomies or nonsurgical (e.g., urological) operations were excluded. Each patient with abdominal wound dehiscence was matched with three controls by systematic random sampling. Putative relevant patient-related, operation-related, and postoperative variables were evaluated in univariate analysis and subsequently entered in multivariate stepwise logistic regression models to delineate major independent predictors of abdominal wound dehiscence. A risk model was developed, which was validated in a population of patients who had undergone operation between January and December 2006. RESULTS: A total of 363 cases and 1,089 controls were analyzed. Major independent risk factors were age, gender, chronic pulmonary disease, ascites, jaundice, anemia, emergency surgery, type of surgery, postoperative coughing, and wound infection. In the validation population, risk scores were significantly higher (P < 0.001) for patients with abdominal wound dehiscence (n = 19) compared to those without (n = 677). Resulting scores ranged from 0 to 8.5, and the risk for abdominal wound dehiscence over this range increased exponentially from 0.02% to 70.1%. CONCLUSIONS: The validated risk model shows high predictive value for abdominal wound dehiscence and may help to identify patients at increased risk.


Assuntos
Abdome/cirurgia , Medição de Risco/métodos , Deiscência da Ferida Operatória/etiologia , Adulto , Fatores Etários , Idoso , Estudos de Casos e Controles , Comorbidade , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Probabilidade , Curva ROC , Sistema de Registros , Fatores de Risco , Fatores Sexuais
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