Longitudinal outcomes of obeticholic acid therapy in ursodiol-nonresponsive primary biliary cholangitis: Stratifying the impact of add-on fibrates in real-world practice.

BACKGROUND: Suboptimal response to ursodeoxycholic acid occurs in 40% of primary biliary cholangitis (PBC) patients, affecting survival. Achieving a deep response (normalisation of alkaline phosphatase [ALP] and bilirubin ≤0.6 upper limit of normal) improves survival. Yet, the long-term effectiveness of second-line treatments remains uncertain. AIMS: To evaluate the long-term effectiveness of obeticholic acid (OCA) ± fibrates. Focusing on biochemical response (ALP ≤1.67 times the upper limit of normal, with a decrease of at least 15% from baseline and normal bilirubin levels), normalisation of ALP, deep response and biochemical remission (deep response plus aminotransferase normalisation). METHODS: We conducted a longitudinal, observational, multicentre study involving ursodeoxyccholic acid non-responsive PBC patients (Paris-II criteria) from Spain and Portugal who received OCA ± fibrates. RESULTS: Of 255 patients, median follow-up was 35.1 months (IQR: 20.2-53). The biochemical response in the whole cohort was 47.2%, 61.4% and 68.6% at 12, 24 and 36 months. GLOBE-PBC and 5-year UK-PBC scores improved (p < 0.001). Triple therapy (ursodeoxycholic acid plus OCA plus fibrates) had significantly higher response rates than dual therapy (p = 0.001), including ALP normalisation, deep response and biochemical remission (p < 0.001). In multivariate analysis, triple therapy remained independently associated with biochemical response (p = 0.024), alkaline phosphatase normalisation, deep response and biochemical remission (p < 0.001). Adverse effects occurred in 41.2% of cases, leading to 18.8% discontinuing OCA. Out of 55 patients with cirrhosis, 12 developed decompensation. All with baseline portal hypertension. CONCLUSION: Triple therapy was superior in achieving therapeutic goals in UDCA-nonresponsive PBC. Decompensation was linked to pre-existing portal hypertension.

Effectiveness and safety of ombitasvir, paritaprevir, ritonavir ± dasabuvir ± ribavirin: An early access programme for Spanish patients with genotype 1/4 chronic hepatitis C virus infection.

Over the last 5 years, therapies for hepatitis C virus (HCV) infection have improved significantly, achieving sustained virologic response (SVR) rates of up to 100% in clinical trials in patients with HCV genotype 1. We investigated the effectiveness and safety of ombitasvir/paritaprevir/ritonavir±dasabuvir in an early access programme. This was a retrospective, multicentre, national study that included 291 treatment-naïve and treatment-experienced patients with genotype 1 or 4 HCV infection. Most patients (65.3%) were male, and the mean age was 57.5 years. The mean baseline viral load was 6.1 log, 69.8% had HCV 1b genotype, 72.9% had cirrhosis and 34.7% were treatment-naïve. SVR at 12 weeks posttreatment was 96.2%. Four patients had virological failure (1.4%), one leading to discontinuation. There were no statistical differences in virological response according to genotype or liver fibrosis. Thirty patients experienced serious adverse events (SAEs) (10.3%), leading to discontinuation in six cases. Hepatic decompensation was observed in five patients. Four patients died during treatment or follow-up, three of them directly related to liver failure. Multivariate analyses showed a decreased probability of achieving SVR associated with baseline albumin, bilirubin and Child-Pugh score B, and a greater probability of developing SAEs related to age and albumin. This combined therapy was highly effective in clinical practice with an acceptable safety profile and low rates of treatment discontinuation.

A prospective study of T- and B-lymphocyte subpopulations, CD81 expression levels on B cells and regulatory CD4(+) CD25(+) CD127(low/-) FoxP3(+) T cells in patients with chronic HCV infection during pegylated interferon-alpha2a plus ribavirin treatment.

Resolution of hepatitis C virus (HCV) infection requires a complex interplay between innate and adaptative immune responses. The role of lymphocyte subpopulations during combined antiviral treatment remains to be defined. This study was conducted to assess the effect of pegylated interferon-alpha2a (pegIFN-α2a) and ribavirin treatment on peripheral blood lymphocytes, mainly on CD81 expression on B cells and CD4(+) CD25(+) CD127(low/-) FoxP3(+) regulatory T cells (Tregs) in patients with chronic HCV infection. Thirty-five patients with chronic HCV infection who started pegIFN-α2a and ribavirin treatment were enrolled. Peripheral blood mononuclear cells (PBMC) were obtained at baseline before treatment (BT), mid-treatment (MT), the end of treatment (ET) and 24weeks post-treatment (PT). During combined antiviral treatment, a significant decrease in the percentage of CD3(+) , CD8(+) , CD3(+) gamma/delta (γδ)(+) , CD19(+) lymphocyte subpopulations and Tregs was observed. There was also a significant increase in the percentage of the CD4(+) lymphocyte subpopulation and in CD81 expression levels on CD19(+) B cells when BT was compared with ET (all P<0.05). Seventeen patients were nonresponders (NR) and 18 had a sustained virological response (SVR). At baseline, NR patients had higher CD81 expression levels on CD19(+) B cells (P=0.017) and a higher Tregs percentage (P=0.025) than SVR patients. Our results suggest that immunomodulation fluctuates during antiviral treatment and that percentage CD81 expression levels on B cells and Tregs might be useful as an immunological prognostic factor for pegIFN-α2a and ribavirin treatment response in chronic HCV infection.

Monitorización y biopsia / Monitoring and biopsy

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Clinical usefulness of total hepatitis C virus core antigen quantification to monitor the response to treatment with peginterferon alpha-2a plus ribavirin*.

SUMMARY: Early virological response may predict outcome following treatment with peginterferon alpha-2a and ribavirin in patients chronically infected with hepatitis C virus (HCV). As total HCV core antigen may constitute an alternative direct marker to HCV RNA for assessing the levels of viraemia in such patients, we evaluated the correlation between HCV core antigen and HCV RNA, and whether HCV core antigen at baseline, 4 and 12 weeks after treatment could predict sustained virological response (SVR) to combined therapy, in comparison with HCV RNA. A total of 290 serum samples from 58 previously treatment naïve chronic HCV patients were examined for HCV core antigen and HCV-RNA by means of quantitative HCV RNA when receiving combination therapy for the first time. SVR was significantly associated with basal HCV core antigen but not with HCV RNA. There was a good correlation between HCV core antigen and HCV RNA (r(2) = 0.781). The negative predictive value of HCV core antigen testing in predicting nonresponse at weeks 4 and 12 were 75 and 100%, and for undetectable or a 2-log drop in HCV RNA were 69.6 and 75% respectively. HCV core antigen detection is quick, and easy to perform alternative to HCV RNA, and could be used as a marker of HCV viraemia for monitoring the progress of therapy.

[Presinusoidal portal hypertension due to portal thrombosis in a patient with Alagille's syndrome]. / Hipertensión portal presinusoidal por trombosis portal en una paciente con síndrome de Alagille.

We present the case of a 16-year old woman with Alagille's syndrome, who had upper gastrointestinal bleeding due to rupture of esophageal varices secondary to presinusoidal portal hypertension without liver fibrosis. Portal thrombosis is a manifestation previously unreported in association to this syndrome.

Propranolol plus isosorbide-5-mononitrate for portal hypertension in cirrhosis: long-term hemodynamic and renal effects.

The effect on kidney function, vasoactive systems and ascites outcome of long-term treatment with propranolol plus isosorbide-5-mononitrate, a combined therapy proven more effective than propranolol alone in decreasing portal pressure in the cirrhotic patient, is unknown. Thirty cirrhotic patients who survived acute variceal bleeding and were treated with propranolol plus isosorbide-5-mononitrate were studied. Portal and systemic hemodynamics (n = 15), inulin clearance, free water clearance, plasma renin activity, aldosterone concentration and prostaglandin E2 excretion (n = 20) were measured before and after 3 mo of treatment. In addition, data on ascites outcome in the entire series after a mean follow-up of 9.6 mo were compared with those of 30 patients undergoing elective sclerotherapy and with those of 30 patients treated with propranolol alone matched for age, sex, presence of ascites, Child-Pugh class and mean follow-up length included in other randomized controlled trials. Combined therapy significantly decreased the hepatic venous pressure gradient and azygos blood flow. In addition, no changes in inulin clearance, free water clearance, plasma renin activity, aldosterone concentration and prostaglandin E2 excretion occurred, despite a mild decrease in mean arterial pressure. Moreover, no differences among the three groups of patients studied in ascites outcome were found. These results suggest that long-term treatment with propranolol plus isosorbide-5-mononitrate does not impair kidney function, vasoactive systems or ascites outcome in cirrhotic patients.