RESUMEN
BACKGROUND & AIMS: Perinatal transmission of hepatitis B virus still occurs despite immunoprophylaxis in approximately 9% of children from highly viraemic mothers. Antiviral therapy in this setting has been suggested, however with limited evidence to direct agent choice. METHODS: We conducted a multi-centre, prospective, opt-in observational study of antiviral safety and efficacy in pregnant women with high viral load (>7 log IU/ml); lamivudine was used from 2007 to 2010 and tenofovir disoproxil fumarate (TDF) from late 2010. Outcomes of treated and untreated cohorts were compared. RESULTS: 120 women with 130 pregnancies used TDF (58), lamivudine (52 including four who switched due to TDF intolerance) and no therapy (20). 96% were HBeAg positive, with baseline viral load mean 7.8 log IU/ml (±0.72) and ALT median 25 U/L (18.75-33). Duration of antiviral theraphy before birth was mean 58 days (±19) TDF and 53 (±14) lamivudine. Viral load declined by 3.64 log IU/ml (±0.9) TDF and 2.81 log IU/ml (±1.33) lamivudine. Virologic failure (birth viral load >7 IU/ml) occurred in 3% and 18% respectively. Congenital abnormality rate and neonatal growth centiles were similar across cohorts. Perinatal transmission reduced significantly to 2% and 0% in TDF and lamivudine cohorts, compared with 20% in untreated. CONCLUSIONS: TDF in this setting is safe, effective and more potent than lamivudine. Antiviral therapy did not adversely impact obstetric or infant parameters. More TDF intolerance occurred than expected. Perinatal transmission was significantly reduced in antiviral therapy cohorts.
Asunto(s)
Adenina/análogos & derivados , Antivirales/efectos adversos , Antivirales/uso terapéutico , Hepatitis B/prevención & control , Hepatitis B/transmisión , Organofosfonatos/efectos adversos , Organofosfonatos/uso terapéutico , Complicaciones Infecciosas del Embarazo/prevención & control , Adenina/efectos adversos , Adenina/uso terapéutico , Adulto , Estudios de Cohortes , Femenino , Enfermedades Gastrointestinales/inducido químicamente , Enfermedades Gastrointestinales/epidemiología , Hepatitis B/tratamiento farmacológico , Virus de la Hepatitis B/fisiología , Humanos , Incidencia , Lamivudine/efectos adversos , Lamivudine/uso terapéutico , Embarazo , Complicaciones Infecciosas del Embarazo/tratamiento farmacológico , Resultado del Embarazo , Estudios Prospectivos , Tenofovir , Factores de Tiempo , Resultado del Tratamiento , Carga ViralRESUMEN
We sought to develop a clinically useful index comprising standard and physiologically relevant variables to predict the probability of significant hepatic fibrosis in subjects with chronic hepatitis C virus (HCV) infection. Fibrosis was graded as mild (stages F0 or F1) or significant (stages F2-F4). Thirty-five clinical and laboratory parameters were analyzed initially in 176 patients with detectable HCV RNA to derive a fibrosis probability index (FPI) to predict significant fibrosis. This index then was validated in a second group of 126 subjects. Among 18 variables associated with severe fibrosis on univariate analysis, multiple logistic regression analysis identified age, aspartate aminotransferase (AST), total cholesterol level, insulin resistance (by homeostasis model), and past alcohol intake as independent predictors of significant fibrosis. The area under the receiver operating characteristic (ROC) curves was 0.84 for the initial cohort and 0.77 for the validation cohort. In the initial cohort, the sensitivity of the FPI based on these five predictors was 96%, and the negative predictive value was 93% at a score of >/=0.2. At scores >/=0.8, the FPI was 94% specific and had a positive predictive value of 87%. In conclusion, an FPI using routinely assessed markers and incorporating a measure of insulin resistance can reliably predict the probability of significant hepatic fibrosis in most patients with chronic HCV infection. Such an index should prove useful to guide decision making regarding the need for liver biopsy, and potentially for avoiding or deferring biopsy in a large proportion of patients with mild liver disease.
Asunto(s)
Hepatitis C Crónica/diagnóstico , Resistencia a la Insulina , Cirrosis Hepática/diagnóstico , Índice de Severidad de la Enfermedad , Adulto , Biomarcadores , Estudios de Cohortes , Femenino , Hepatitis C Crónica/epidemiología , Humanos , Cirrosis Hepática/epidemiología , Cirrosis Hepática/virología , Modelos Logísticos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Prevalencia , Probabilidad , Reproducibilidad de los Resultados , Factores de Riesgo , Sensibilidad y EspecificidadRESUMEN
OBJECTIVES: Fibrotic severity, biochemical indices of poor liver function, and sporadic transmission are independent predictors of liver complications among people with chronic hepatitis C. After accounting for these factors, we tested whether interferon treatment or the treatment response reduces the rate of liver cancer, liver-related death or transplantation, and other liver complications during extended follow-up. METHODS: Liver clinic cohort of 455 patients with histologically proven chronic hepatitis C was followed prospectively for median 9 yr (IQ 6, 11 yr); 384 received interferon, 343 completed a treatment course. Liver complications were assessed in relation to treatment and treatment response in univariate and multivariate models, and survival to onset of liver-related complications was determined. RESULTS: The annual incidence of total liver complications was 1.5% in treated and 2.9% in untreated patients and appeared quasilinear throughout 9-yr follow-up. Interferon treatment did not influence the rate of liver complications. However, the rate of complications increased exponentially with transition of the treatment response from sustained viral response (SVR), through response-relapse to nonresponse (or no treatment). By univariate analysis, response to interferon treatment was a significant predictor of complications. After adjustment for fibrosis score, serum albumin concentration and mode of transmission in a multivariate model, treatment response just failed to reach significance (p= 0.058) as a predictor of outcome. CONCLUSIONS: Response to antiviral therapy, and particularly SVR, appears to reduce liver complications in chronic hepatitis C. However, in the absence of an antiviral treatment response, a course of interferon does not reduce risks of liver cancer or liver failure.
Asunto(s)
Antivirales/uso terapéutico , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/tratamiento farmacológico , Interferón-alfa/uso terapéutico , Adulto , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Humanos , Hepatopatías/tratamiento farmacológico , Hepatopatías/etiología , Hepatopatías/mortalidad , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Tasa de Supervivencia , Factores de TiempoRESUMEN
OBJECTIVE: We tested whether fibrotic progression in chronic hepatitis C could be predicted by liver tests, antipyrine clearance, or platelet count. METHODS: In 58 patients (6 untreated, 52 interferon-treated), a second liver biopsy was taken median 4.5 yr after first histologic diagnosis. We used receiver operating characteristic curves to determine whether changes in conventional liver tests, antipyrine clearance, or platelet count were predictive of altered hepatic fibrosis score. RESULTS: Apart from a weak association with change in ALT, conventional liver tests (albumin, bilirubin, prothrombin time) failed to correlate with changes (Delta) in hepatic fibrosis, but there were significant correlations between deltaantipyrine clearance or deltaplatelet count and deltafibrosis score (p < 0.01). As indicated by areas under the receiver operating characteristic curves, the diagnostic accuracy of deltaantipyrine clearance for fibrotic progression was 68%; for Deltaplatelet count it was 80%. With defined cut-off values (-0.05 ml/min/kg for deltaantipyrine clearance; -41 x 10(9)/L for deltaplatelet count), the negative predictive values for fibrotic progression were 85% with antipyrine clearance and 89% with platelet count. Corresponding positive predictive values were 48% and 91%, respectively. CONCLUSIONS: Changes in antipyrine clearance and platelet count are more sensitive than conventional tests for indicating fibrotic change in chronic hepatitis C. Both could be used to reliably identify those who do not have fibrotic progression, and platelet count also has a high positive predictive value for disease progression.
Asunto(s)
Antipirina/farmacocinética , Hepatitis C Crónica/patología , Hepatitis C Crónica/fisiopatología , Cirrosis Hepática/fisiopatología , Adulto , Anciano , Antiinflamatorios no Esteroideos/sangre , Antiinflamatorios no Esteroideos/farmacocinética , Antipirina/sangre , Antivirales/uso terapéutico , Biopsia , Progresión de la Enfermedad , Femenino , Hepatitis C Crónica/sangre , Hepatitis C Crónica/tratamiento farmacológico , Humanos , Interferones/uso terapéutico , Cirrosis Hepática/sangre , Cirrosis Hepática/patología , Pruebas de Función Hepática , Masculino , Persona de Mediana Edad , Recuento de Plaquetas , Valor Predictivo de las Pruebas , Curva ROCRESUMEN
AIM: To determine effectiveness of treatment for hepatitis C outside clinical trials, by testing the hypothesis that apparent effectiveness and tolerability of interferon alfa-2b/ribavirin combination therapy would be less in a hospital liver clinic setting. DESIGN: Retrospective analysis of all patients in one centre commencing interferon alfa-2b/ribavirin therapy, but not in clinical trials, between 1998 and 2000. MAIN OUTCOME MEASURES: Effectiveness as sustained virological response (SVR); tolerability as premature discontinuation of treatment. RESULTS: The 121 patients had similar demographic and viral characteristics as those in Australian trials (age, 44 +/- 10 years; males, 66%; genotype 1, 44%; genotype 3, 36%), but 38% had advanced fibrosis, including 17% with cirrhosis. Sixty (50%) were previously untreated, 38 (31%) had relapsed after initial response (response relapse) and 23 (19%) were non-responders to interferon monotherapy. Sustained viral response (SVR) was achieved in 53% of patients overall: 47% of patients with genotype 1 HCV, 71% of patients with genotype 3. For patients with genotype 1 HCV, SVR was 43% in those previously untreated, 63% in response relapsers, and 38% in non-responders. Corresponding SVRs for genotype 3 were 65%, 87% and 33%. These results are similar to those obtained in published trials. Only 7% of our patients discontinued treatment because of adverse effects, fewer than reported in most clinical trials. Dose reduction was required in 18% of patients. CONCLUSIONS: In a hospital clinic setting the effectiveness of interferon alfa-2b/ribavirin combination therapy appears equivalent to published results from clinical trials.
Asunto(s)
Antivirales/administración & dosificación , Hepatitis C Crónica/tratamiento farmacológico , Interferón-alfa/administración & dosificación , Ribavirina/administración & dosificación , Adulto , Antivirales/efectos adversos , Quimioterapia Combinada , Femenino , Genotipo , Hepacivirus/genética , Hepatitis C Crónica/virología , Humanos , Interferón alfa-2 , Interferón-alfa/efectos adversos , Masculino , Proteínas Recombinantes , Recurrencia , Estudios Retrospectivos , Ribavirina/efectos adversos , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: Hepatic steatosis is common in hepatitis C, but the relative importance of host and viral factors is controversial. In the present prospective study, we examined metabolic factors associated with non-alcoholic fatty liver and viral genotype as predictors of steatosis and fibrosis in chronic hepatitis C infection. METHODS: In 124 chronic hepatitis C patients, the association between liver histology and the following was investigated: demographic and anthropometric data, alcohol intake, alanine aminotransferase (ALT), total cholesterol, low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol, triglyceride, transferrin saturation, ferritin, insulin, c-peptide, glucose and insulin resistance (homeostasis model). RESULTS: By multivariate analysis, genotype 3 was associated with increased steatosis grade (P = 0.02). There were significant pairwise interactions between genotype 3 status and total cholesterol (P = 0.01), current alcohol intake (P = 0.04) and serum ALT (P = 0.01). This showed that the etiology of steatosis was different in patients with genotype 3 and those with non-genotype 3 chronic hepatitis C infection. In genotype 3 patients, the degree of steatosis was inversely associated with serum cholesterol (P = 0.005) and positively associated with serum triglyceride (P = 0.02). There was no association between body mass index (BMI) and the extent of steatosis. Among patients with other genotypes, the steatosis grade was strongly influenced by BMI (P < 0.0001) and serum ALT (P < 0.01). Independent predictors of fibrosis were age (P = 0.001), past alcohol intake (P = 0.04), ALT (P = 0.002), serum insulin (P = 0.001) and portal inflammation (P < 0.001). CONCLUSIONS: Hepatitis C genotype 3 may interfere with pathways of hepatic lipid metabolism, whereas increased BMI appears to be a more important pathogenic factor in other genotypes. Although steatosis and BMI were not associated with hepatic fibrosis, their relationship with serum insulin suggests that metabolic factors related to insulin action could influence fibrogenesis in hepatitis C.
Asunto(s)
Hígado Graso/genética , Hígado Graso/metabolismo , Genotipo , Hepatitis C Crónica/genética , Hepatitis C Crónica/metabolismo , Cirrosis Hepática/genética , Cirrosis Hepática/metabolismo , Adulto , Anciano , Estudios de Cohortes , Hígado Graso/etiología , Femenino , Hepatitis C Crónica/complicaciones , Humanos , Cirrosis Hepática/etiología , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Estudios Prospectivos , Factores de Riesgo , Índice de Severidad de la EnfermedadRESUMEN
Nonalcoholic steatohepatitis (NASH) is a disorder characterized by hepatic steatosis, inflammation, and fibrosis. Leptin is an adipocyte-derived antiobesity hormone that in rodents prevents "lipotoxicity" by limiting triglyceride accumulation and also regulates matrix deposition (fibrosis) during wound healing. We therefore determined serum leptin levels in patients with NASH to determine whether relationships existed between leptin levels and severity of hepatic steatosis or fibrosis. We used a radioimmunoassay to determine serum [total] leptin concentrations in 27 men and 20 women with NASH and 47 controls matched for gender and body mass index (BMI; and partly for age). Serum leptin values were correlated with hepatic steatosis, fibrosis, and inflammation (each categorized semiquantitatively on liver histology), and with anthropometric indices, serum lipids, glucose, insulin, c-peptide, and alanine aminotransferase (ALT) levels. Compared with the controls, mean serum leptin levels were raised in both men and women with NASH (men 14 +/- 11 ng/mL vs. 7.2 +/- 4.1 ng/mL, P =.003; women 35 +/- 16 ng/mL vs. 15 +/- 8.2 ng/mL, P <.001). Leptin values correlated with serum c-peptide levels but not with BMI. In a multivariate analysis, serum leptin (P =.027), serum c-peptide (P =.001), and age (P =.027) were selected as independent predictors of the severity of hepatic steatosis. However, serum leptin was not an independent predictor of hepatic inflammation or fibrotic severity. In conclusion, hyperleptinemia occurs in NASH and is not explained simply by gender, obesity, or the presence of type 2 diabetes. Furthermore, leptin levels correlate directly with the severity of hepatic steatosis but not with inflammation or fibrosis. We propose that the relationship between leptin and steatosis reflects a pathogenic role of leptin in hepatic insulin resistance and/or a failure of the antisteatotic actions of leptin ("peripheral leptin resistance").
Asunto(s)
Hígado Graso/sangre , Leptina/sangre , Cirrosis Hepática/sangre , Triglicéridos/metabolismo , Adulto , Anciano , Péptido C/sangre , Femenino , Hepatitis/sangre , Humanos , Insulina/sangre , Resistencia a la Insulina/fisiología , Masculino , Persona de Mediana Edad , Análisis Multivariante , Índice de Severidad de la Enfermedad , Factores SexualesRESUMEN
There is conflicting evidence regarding inheritance of hemochromatosis gene (HFE) mutations and influence of hepatic iron deposition as cofactors for development of fibrosis in patients with nonalcoholic steatohepatitis (NASH). We studied hepatic iron content (Perls' stain grade), frequency of HFE mutations, and serum iron indices in 93 patients with NASH from a multiethnic background; 59 (63%) were of Anglo-Celtic origin. Data on C282Y mutations were available for all 93 patients and on H63D for 69 patients. Respective controls were 206 (for C282Y, 141 [69%] of whom were Anglo-Celtic) and 180 (for H63D) blood donors. Hyperferritinemia was present in 38 patients (40%) with NASH, but transferrin saturation was increased (>55%) in only 5 (5%). Liver biopsy specimens showed advanced fibrosis in 31 (33%) (cirrhosis in 20%). Altogether, 9 biopsy specimens (10%) showed increased iron: 7 (8%) with grade 2 and 2 (2%) with grade 3 iron staining. Only 1 biopsy specimen with increased iron showed advanced fibrosis. The frequency of C282Y heterozygosity was increased in Anglo-Celtic patients with NASH compared with ethnic blood donor controls (22% vs. 9.2%; P =.035); there were no C282Y homozygotes in the NASH cohort. Although there was a trend toward higher serum ferritin levels among C282Y heterozygotes with NASH, there were no differences in histologic grades of steatosis, inflammation, or fibrosis between individuals with and without C282Y. The frequencies of compound C282Y/H63D heterozygotes (n = 1) or H63D heterozygotes (n = 10) were not increased in NASH. Multivariate analysis identified female sex, diabetes mellitus, and more severe liver inflammation but not HFE mutations, serum ferritin, iron saturation, or hepatic iron staining as independent predictors of hepatic fibrosis. In conclusion, hepatic iron is not a factor linked to hepatic fibrogenesis in patients with NASH. HFE mutations do not confer an additional risk of hepatic fibrosis in this disorder.
Asunto(s)
Hígado Graso/etnología , Hígado Graso/genética , Antígenos HLA/genética , Antígenos de Histocompatibilidad Clase I/genética , Hierro/metabolismo , Cirrosis Hepática/genética , Hígado/metabolismo , Proteínas de la Membrana , Adulto , Anciano , Australia , Biopsia , Estudios de Cohortes , Etnicidad , Hígado Graso/complicaciones , Femenino , Ferritinas/sangre , Proteína de la Hemocromatosis , Heterocigoto , Homocigoto , Humanos , Hígado/patología , Cirrosis Hepática/etiología , Cirrosis Hepática/patología , Masculino , Persona de Mediana Edad , Mutación , Estudios Prospectivos , Transferrina/metabolismoRESUMEN
OBJECTIVES: In chronic hepatitis B patients treated with lamivudine, the incidence of drug resistance increases with the duration of therapy. The effect of drug resistance on hepatic synthetic function is not well defined. The aim of the present study was to assess the effect of lamivudine therapy on hepatic synthetic function in patients with moderately severe chronic hepatitis B and, particularly, to determine the effect of drug resistance. METHODS: Hepatic synthetic function was assessed using serial measurements of serum albumin in 38 patients (26 with cirrhosis) in an open-label treatment program. RESULTS: An initial antiviral response (hepatitis B virus [HBV] DNA undetectable by hybridization assay) occurred in all patients, and nine of 22 (41%) hepatitis B e antigen-positive cases underwent hepatitis B e antigen seroconversion. Among 29 patients with undetectable serum HBV DNA at the end of observation, the mean serum albumin concentration rose from 39.9 +/- 0.7 to 43.2 +/- 0.6 g/L, corresponding to a yearly increase of 1.85 g/L (p < 0.001). This was largely attributable to an increase among cirrhotic patients. Nine patients (24%) developed resistance to lamivudine, all after 12 months of treatment. Among them, the mean serum albumin concentration had increased from 39.6 +/- 1.2 to 42.9 +/- 0.8 g/L before resistance emerged, but then decreased to 39.3 +/- 1.7 g/L (p = 0.01) at the time of reappearance of HBV DNA. CONCLUSION: Suppression of viral replication by lamivudine improves hepatic synthetic function in chronic hepatitis B patients, but emergence of drug resistance is associated with a rapid decline in serum albumin, at least to pretreatment levels.
Asunto(s)
Antivirales/farmacología , Farmacorresistencia Viral/fisiología , Hepatitis B Crónica/sangre , Hepatitis B Crónica/tratamiento farmacológico , Lamivudine/farmacología , Hígado/efectos de los fármacos , Hígado/fisiopatología , Albúmina Sérica/análisis , Albúmina Sérica/efectos de los fármacos , Adulto , Antivirales/uso terapéutico , Femenino , Hepatitis B Crónica/fisiopatología , Humanos , Lamivudine/uso terapéutico , Masculino , Persona de Mediana Edad , Factores de Tiempo , Resultado del TratamientoRESUMEN
Nonalcoholic steatohepatitis (NASH) is often linked with disorders that are clearly associated with insulin resistance (IR): obesity, type 2 diabetes mellitus, and hypertriglyceridemia. We tested the hypotheses that (1) IR is an essential requirement for the development of NASH and (2) a high association between IR and liver disease is relatively specific for NASH. We measured body mass index (BMI), waist/hip ratio, and fasting serum lipid, insulin, C-peptide, and glucose levels in 66 patients with NASH (21 with advanced fibrosis and 45 with mild fibrosis). IR was determined by the homeostasis model assessment (HOMA). We also determined the strength of the association of NASH with insulin resistance syndrome (IRS) as defined by World Health Organization criteria. To assess whether the finding of IR was relatively specific to NASH rather than simply to obesity or liver disease, we compared the results of a subset of 36 patients with less-severe NASH with 36 age- and sex-matched patients with chronic hepatitis C virus (HCV) of comparable fibrotic severity. IR was confirmed in 65 patients (98%) with NASH, and 55 (87%) fulfilled minimum criteria for IRS. IR was found in lean as well as in overweight and obese patients. The IR values and the prevalence of IRS (75% vs. 8.3%) were significantly higher in those with NASH than in comparable cases of HCV. Hyperinsulinemia was attributable to increased insulin secretion rather than decreased hepatic extraction. In conclusion, most patients with NASH have IRS, and there is a near-universal association between NASH and IR irrespective of obesity. IR is present in mild as well as advanced cases of NASH but is unusual in chronic HCV of similar fibrotic severity.