Incidence, predictive factors and clinical significance of development of portal vein thrombosis in cirrhosis: A prospective study.

BACKGROUND AND AIMS: The role of portal vein thrombosis (PVT) in the natural history of cirrhosis is controversial. There are few prospective studies validating risk factors for development of PVT. We analysed the incidence, factors associated with PVT development and its influence on cirrhosis decompensations and orthotopic liver transplant (OLT)-free survival. METHODS: In this prospective observational study between January 2014 and March 2019, 445 consecutive patients with chronic liver disease were screened and finally 241 with cirrhosis included. Factors associated with PVT development and its influence on cirrhosis decompensations and OLT-free survival by time dependent covariate coding were analysed. RESULTS: Majority of patients belonged to Child-Pugh class A 184 (76.3%) and the average MELD score was 10 ± 5. Previous cirrhosis decompensations occurred in 125 (52.1%), 63 (26.1%) were on NSBB and 59 (27.2%) had undergone banding for bleeding prophylaxis. Median follow-up was 29 (1-58) months. Cumulative incidence of PVT was 3.7% and 7.6% at 1 and 3 years. Previous decompensation of cirrhosis and low platelet counts but not NSBB independently predicted the development of PVT. During follow-up, 82/236 (34.7%) patients developed cirrhosis decompensations. OLT-free survival was 100% and 82.8% at 3 years, with and without PVT respectively. MELD score, but not PVT, independently predicted cirrhosis decompensations (HR 1.14; 95%CI:1.09-1.19) and OLT-free survival (HR 1.16;95%CI:1.11-1.21). CONCLUSION: Previous decompensations of cirrhosis and thrombocytopenia predict PVT development in cirrhosis suggesting a pathophysiologic role for severity of portal hypertension. PVT development did not independently predict cirrhosis decompensations or lower OLT-free survival.

Mortality Associated with Hepatobiliary Disease in Portugal between 2006 and 2012.

INTRODUCTION: Hepatobiliary disease is becoming a major public health problem, and recent data suggest that the burden of liver disease is higher than previously thought. Our aim was to quantify the mortality from hepatobiliary disease in Portugal and to compare this with the mortality related o other causes over a 7-year period (2006-2012). MATERIALS AND METHODS: A statistical analysis of mortality data according to cause, sex, age, and region from the National Statistics Institute in Portugal was carried out. The data related to 14 causes of death, the most frequent of which were alcoholic liver disease (ALD) (International Classification of Diseases code K70), unspecified cirrhosis of liver (UCL) (K74.6), hepatocellular carcinoma (HCC) (C22.0), unspecified malignant neoplasm of liver (C22.9), and cholangiocarcinoma (C22.1). RESULTS: Between 2006 and 2012, 18,279 deaths (24.5/100,000) from hepatobiliary disease were registered in Portugal, constituting the 8th leading cause of death. The main causes of death from hepatobiliary disease were ALD (7.1/100,000), UCL (5.5/100,000), and HCC (4.3/100,000), with a male predominance (72%). ALD was the main aetiology in younger age groups (40-65 years), while primary neoplasms of the liver and the intrahepatic bile ducts were predominant in the elderly (>80 years). The mortality related to HCC increased by 66% between 2006 and 2012. CONCLUSION: These data outline the burden of hepatobiliary disease in Portugal (8th cause of death) and highlight a potential impact on economic productivity.

INTRODUÇÃO: A doença hepatobiliar representa um importante problema para a saúde pública e dados recentes sugerem que o seu impacto é superior ao que se pensava. O nosso objetivo foi quantificar a mortalidade por doença hepatobiliar em Portugal e compará-la com a mortalidade por outras causas, durante um período de sete anos (2006­2012). MATERIAIS E MÉTODOS: Foi feita uma análise estatística da mortalidade por doença hepatobiliar em Portugal, de acordo com a causa de morte, sexo, idade e região geográfica, com dados fornecidos pelo Instituto Nacional de Estatística. Foram estudadas 14 causas de morte, sendo as principais a doença hepatica alcoólica (código da Classificação Internacional de Doenças, 10a versão: K70), cirrose hepatica não especificada (K74.6), carcinoma hepatocelular (C22.0), neoplasia maligna do fígado não especificada (C22.9) e colangiocarcinoma (C22.1). RESULTADOS: Entre 2006 e 2012 foram registadas 18,279 mortes (24.5/100,000) por doença hepatobiliar em Portugal, sendo a 8a causa de morte no país. As principais causas de morte por doença hepatobiliar foram a doença hepatica alcoólica (7.1/100,000), cirrose hepática não especificada (5.5/100,000) e carcinoma hepatocelular (4.3/ 100,000), com predominância no sexo masculino (72%). A doença hepática alcoólica foi a principal causa de morte nos grupos etários mais jovens (40­65 anos), enquanto que a neoplasia do fígado e vias biliares intra-hepáticas foi a principal causa nos idosos (>80 anos). A mortalidade por carcinoma hepatocelular aumentou 66% de 2006 a 2012. CONCLUSÕES: Este estudo salienta o impacto que a doença hepatobiliar tem em Portugal (8a causa de morte), o que representa um potencial impacto para a produtividade do país.

The burden of alcoholism in fifteen years of cirrhosis hospital admissions in Portugal.

BACKGROUND & AIMS: Deploying a longitudinal perspective, we observe how cirrhosis caused mortality rates in Portugal are converging with the levels reported in the European Union (15 countries). However, we still lack analysis of the burden of alcoholic cirrhosis in terms of hospital admissions and associated mortality. As Portugal may be considered a paradigmatic case in Europe, our aim was to characterize the evolution of hospital admissions for alcoholic cirrhosis between 1993 and 2008 and draw conclusions for other countries. METHODS: Retrospective analysis of the hepatic cirrhosis admissions in 97 Portuguese state hospitals was carried out based on the National Registry. RESULTS: We report a convergence in terms of mortality rates resulting from cirrhosis between Portugal and European Union (a differential of 6.7 deaths per 100 000 habitants in 1994 to 0.4 in 2008). We accounted for 81 543 hospital admissions for cirrhosis: 84% for alcoholic cirrhosis and 16% for non-alcoholic cirrhosis. Hospital admissions have increased 29% in men and with no increase in women. In the male, alcoholic cirrhosis patient group aged between 40 and 54, the rise in hospital admissions was more pronounced with an increase of around 45%. These patients underwent longer lengths of stay and reported higher mortality rates and passing away 20 years earlier than the average national expectancy of life. CONCLUSIONS: These data draw attention to the burden of alcohol consumption not only in Portugal but also in other countries and its impacts on hospital systems and on policy making.

ABT-450/r-ombitasvir and dasabuvir with or without ribavirin for HCV.

BACKGROUND: The interferon-free regimen of ABT-450 with ritonavir (ABT-450/r), ombitasvir, and dasabuvir with or without ribavirin has shown efficacy in inducing a sustained virologic response in a phase 2 study involving patients with hepatitis C virus (HCV) genotype 1 infection. We conducted two phase 3 trials to examine the efficacy and safety of this regimen in previously untreated patients with HCV genotype 1 infection and no cirrhosis. METHODS: We randomly assigned 419 patients with HCV genotype 1b infection (PEARL-III study) and 305 patients with genotype 1a infection (PEARL-IV study) to 12 weeks of ABT-450/r-ombitasvir (at a once-daily dose of 150 mg of ABT-450, 100 mg of ritonavir, and 25 mg of ombitasvir), dasabuvir (250 mg twice daily), and ribavirin administered according to body weight or to matching placebo for ribavirin. The primary efficacy end point was a sustained virologic response (an HCV RNA level of <25 IU per milliliter) 12 weeks after the end of treatment. RESULTS: The study regimen resulted in high rates of sustained virologic response among patients with HCV genotype 1b infection (99.5% with ribavirin and 99.0% without ribavirin) and among those with genotype 1a infection (97.0% and 90.2%, respectively). Of patients with genotype 1b infection, 1 had virologic failure, and 2 did not have data available at post-treatment week 12. Among patients with genotype 1a infection, the rate of virologic failure was higher in the ribavirin-free group than in the ribavirin group (7.8% vs. 2.0%). In both studies, decreases in the hemoglobin level were significantly more common in patients receiving ribavirin. Two patients (0.3%) discontinued the study drugs owing to adverse events. The most common adverse events were fatigue, headache, and nausea. CONCLUSIONS: Twelve weeks of treatment with ABT-450/r-ombitasvir and dasabuvir without ribavirin was associated with high rates of sustained virologic response among previously untreated patients with HCV genotype 1 infection. Rates of virologic failure were higher without ribavirin than with ribavirin among patients with genotype 1a infection but not among those with genotype 1b infection. (Funded by AbbVie; PEARL-III and PEARL-IV ClinicalTrials.gov numbers, NCT01767116 and NCT01833533.).

Benefits of curing hepatitis C infection.

The hepatitis C virus (HCV) infection is one of the most important chronic viral infections worldwide and affects 3% of the world population, approximately 170-200 million people. The consequences of chronic infection are liver cirrhosis and hepatocellular carcinoma, which develop in 20-30% of the patients, leading to hepatic failure, need for liver transplantation and death. The hepatitis C virus is a RNA virus that is prevalent worldwide and is classified by the World Health Organization (International Agency for Research on Cancer) as one of the six oncogenic viruses. Hepatocellular carcinoma is one of the most important cancers and is fifth worldwide, but third in men in terms of mortality. Hepatitis C kills approximately 350,000 people every year, surpassing HIV infection in many countries as a cause of death. Hepatitis C virus can kill in different ways: it can cause cirrhosis, cancer or severe liver disease in people co-infected with HIV. Hepatitis C treatment started in the mid 1980s with a 6% efficacy rate among patients taking thrice-weekly injections of human interferon. This therapy had numerous side effects. The efficacy of hepatitis C treatment has increased, and currently, the efficacy of the so-called direct antiviral agents (DAAs) is 80-90%. The benefits of a cure are enormous and include a lifetime negative serum HCV RNA, disappearance of HCV in the liver, regression of cirrhosis, decreased risk of developing hepatocellular carcinoma, disappearance of oesophageal varices, no more risk of HCV transmission to sexual partners or children, and increased survival. At present, hepatitis C can be considered a curable disease.

Retreatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin.

BACKGROUND: In this phase 3 trial we evaluated the efficacy and safety of the interferon-free combination of ABT-450 with ritonavir (ABT-450/r), ombitasvir (also known as ABT-267), dasabuvir (also known as ABT-333), and ribavirin for the retreatment of HCV in patients who were previously treated with peginterferon-ribavirin. METHODS: We enrolled patients with HCV genotype 1 infection and no cirrhosis who had previously been treated with peginterferon-ribavirin and had a relapse, a partial response, or a null response. Patients were randomly assigned in a 3:1 ratio to receive coformulated ABT-450/r-ombitasvir (at a once-daily dose of 150 mg of ABT-450, 100 mg of ritonavir, and 25 mg of ombitasvir) and dasabuvir (250 mg twice daily) with ribavirin (1000 or 1200 mg daily) or matching placebos during the 12-week double-blind period. The primary end point was the rate of sustained virologic response 12 weeks after the end of study treatment. The primary efficacy analysis compared this rate among patients assigned to the active regimen with a historical response rate (65%) among previously treated patients with HCV genotype 1 infection and no cirrhosis who had received retreatment with telaprevir and peginterferon-ribavirin. RESULTS: A total of 394 patients received at least one study-drug dose. In the active-regimen group, 286 of 297 patients had a sustained virologic response at post-treatment week 12, for an overall rate of 96.3% (95% confidence interval, 94.2 to 98.4). This rate was noninferior and superior to the historical control rate. Rates were 95.3% among patients with a prior relapse (82 of 86 patients), 100% among patients with a prior partial response (65 of 65 patients), and 95.2% among patients with a prior null response (139 of 146 patients). Pruritus occurred more frequently with the active regimen (in 13.8% of patients) than with placebo (5.2%, P=0.03). Three patients in the active-regimen group (1.0%) discontinued the study drugs owing to adverse events. Hemoglobin values of grade 2 (8.0 to <10.0 g per deciliter) and grade 3 (6.5 to <8.0 g per deciliter) occurred in 4.7% and 0.3% of patients in the active-regimen group, respectively. CONCLUSIONS: Rates of response to a 12-week interferon-free combination regimen were more than 95% among previously treated patients with HCV genotype 1 infection, including patients with a prior null response. (Funded by AbbVie; SAPPHIRE-II ClinicalTrials.gov number, NCT01715415.).

A systematic review of hepatitis C virus epidemiology in Europe, Canada and Israel.

BACKGROUND AND AIM: Decisions on public health issues are dependent on reliable epidemiological data. A comprehensive review of the literature was used to gather country-specific data on risk factors, prevalence, number of diagnosed individuals and genotype distribution of the hepatitis C virus (HCV) infection in selected European countries, Canada and Israel. METHODOLOGY: Data references were identified through indexed journals and non-indexed sources. In this work, 13,000 articles were reviewed and 860 were selected based on their relevance. RESULTS: Differences in prevalence were explained by local and regional variances in transmission routes or different public health measures. The lowest HCV prevalence (≤ 0.5%) estimates were from northern European countries and the highest (≥ 3%) were from Romania and rural areas in Greece, Italy and Russia. The main risk for HCV transmission in countries with well-established HCV screening programmes and lower HCV prevalence was injection drug use, which was associated with younger age at the time of infection and a higher infection rate among males. In other regions, contaminated glass syringes and nosocomial infections continue to play an important role in new infections. Immigration from endemic countries was another factor impacting the total number of infections and the genotype distribution. Approximately 70% of cases in Israel, 37% in Germany and 33% in Switzerland were not born in the country. In summary, HCV epidemiology shows a high variability across Europe, Canada and Israel. CONCLUSION: Despite the eradication of transmission by blood products, HCV infection continues to be one of the leading blood-borne infections in the region.

Lymphocyte T helper-specific reactivity in sustained responders to interferon and ribavirin with negativation (seroreversion) of anti-hepatitis C virus.

BACKGROUND: Seroreversion, negativation of anti-hepatitis C virus previously positive, is sometimes found in some chronic hepatitis C-sustained responders (SRs) to antiviral therapy. AIMS: To determine the probability of seroreversion in SR treatment with Interferon and Ribavirin, and lymphocyte T helper (CD4+) reactivity to HCV antigens. METHODS: Thirty SR were followed on average for 54.8 months. Anti-HCV was tested by third generation test. Peripheral blood mononuclear cells (PBMCs) were isolated from venous blood and cultured to evaluate CD4+ proliferation in response to 2 microg/ml of eight HCV recombinant antigens from core, NS3, NS4, NS5 regions. RESULTS: Seroreversion was verified in 23% of patients (7/30), appearing at 47.5+/-24.0 months. The probability of anti-HCV loss in this group was 25% at 56 months after ending therapy. In 57% (4/7), anti-HCV returned to positive. These 7 SR patients with seroreversion also showed weaker CD4+ reactivity in 5% of tests (3/56) than the remaining 23 anti-HCV-positive SRs who showed stronger reactivity in 18% of tests (33/184), P=0.036. CONCLUSIONS: One-quarter of the SR showed seroreversion of anti-HCV and weaker CD4+ specific HCV proliferation than those who remained anti-HCV positive. The data suggest that complete viral eradication is a possible and achievable clinical objective.