Aplastic anemia and severe pancytopenia during treatment with peg-interferon, ribavirin and telaprevir for chronic hepatitis C

Telaprevir and Boceprevir are the first direct acting antivirals approved for chronic hepatitis C in combination with peg-interferon alfa and ribavirin. Pancytopenia due to myelotoxicity caused by these drugs may occur, but severe hematological abnormalities or aplastic anemia (AA) have not been described. We collected all cases of severe pancytopenia observed during triple therapy with telaprevir in four Spanish centers since approval of the drug in 2011. Among 142 cirrhotic patients receiving treatment, 7 cases of severe pancytopenia (5%) were identified and three were consistent with the diagnosis of AA. Mean age was 59 years, five patients had compensated cirrhosis and two patients had severe hepatitis C recurrence after liver transplantation. Severe pancytopenia was diagnosed a median of 10 wk after the initiation of therapy. Three patients had pre-treatment hematological abnormalities related to splenomegaly. In six patients, antiviral treatment was interrupted at the onset of hematological abnormalities. Two patients died due to septic complications and one patient due to acute alveolar hemorrhage. The remaining patients recovered. Severe pancytopenia and especially AA, are not rare during triple therapy with telaprevir in patients with advanced liver disease. Close monitoring is imperative in this setting to promptly detect serious hematological disorders and to prevent further complications

High frequency of acute decompensation and cancer in patients with compensated cirrhosis due to nonalcoholic fatty liver disease : A retrospective cohort study

The natural history of compensated cirrhosis due to nonalcoholic fatty liver disease (NAFLD) has not been completely characterized. The aim of the present study was to assess the incidence and risk factors of acute decompensation of cirrhosis, hepatocellular carcinoma, and extrahepatic cancers. This was a multicenter, retrospective, cohort study including 449 patients with compensated cirrhosis due to NAFLD. We calculated cumulative incidences and used competitive risk analysis to determine the risk factors associated with decompensation and cancer development. Over a median of 39 months of follow-up, 124 patients (28%) presented acute decompensation. The most frequent decompensation was ascites (21%) followed by hepatic encephalopathy (15%), variceal bleeding (9%), and spontaneous bacterial peritonitis (3%). Acute-on-chronic liver failure was diagnosed in 6% of patients during follow-up. Liver function parameters and specifically an albumin level below 40 g/L were independently associated with an increased risk of decompensation. The presence of ischemic heart disease was independently associated with acute decompensation. Seventy-eight patients (18%) developed hepatocellular carcinoma or extrahepatic cancers during follow-up (51 and 27, respectively). Conclusion : Patients with compensated cirrhosis due to NAFLD are at high risk of severe liver complications, such as the development of acute decompensation, in a relative short follow-up time. This population is at high risk of hepatic and extrahepatic cancers. The analysis of a large contemporary cohort of 449 patients with compensated cirrhosis due to non-alcoholic fatty liver disease shows a high frequency of acute decompensations (AD) and development of cancer during 39 months of follow-up. Almost 28% of the cohort developed acute decompensation and 18% developed hepatocellular carcinoma (HCC) or extrahepatic cancer. Predictors of decompensation are mainly related to liver function and portal hypertension

High prevalence of non-alcoholic fatty liver disease in patients with a first episode of acute ischemic stroke. Impact on disability and death

IntroductionNon-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, and it is associated with an increased risk of overall mortality being cardiovascular disease the most common cause of mortality. Strategies are needed to identify high risk groups for NAFLD to improve screening approaches. Moreover, there is a lack of information about the prevalence of NAFLD on patients with acute ischemic stroke (AIS) and the influence of NAFLD on the prognosis of the stroke. The aim of the study was to define the prevalence of NAFLD in patients with a first episode of AIS and the secondary aims were to evaluate the prevalence of NAFLD at different ages and its impact on the severity and prognosis of the AIS.Materials and methodsObservational study including consecutive patients admitted for the first AIS from January 2005 to May 2018. Patients with harmful alcohol intake, other liver diseases and malignancies were excluded. Sociodemographic data, cardiovascular risk factors, comorbidities, and blood test at admission were reviewed. NAFLD and liver fibrosis were assessed with the serological scores Fatty Liver Index (FLI) and Fibrosis-4 respectively. NAFLD was defined by a FLI>60. Stroke severity and prognosis were evaluated with the National Institute of Health Stroke Scale and modified Rankin Scale respectively in patients aged from 40 to 79 years old.ResultsWe included 1601 patients, 52.4% were female and median (IQR) age of 77 (66 – 83) years. The 41% of the total cohort had a FLI>60 with different prevalence according to age in decades: in 30-39 years: 35.7%; in 40-49: 47.5%; in 50-59: 51.1%, in 60-69: 56%, in 70-79: 41.4%; in 80-89: 34.9% (p<0.001). The presence of NAFLD did not impact on the severity or the prognosis of stroke. However, patients with NAFLD were younger than those without NAFLD (74 vs. 78; p<0.001).ConclusionPresence of NAFLD did not impact on disability and death after the stroke. However, patients with a first episode of stroke showed a high prevalence of NAFLD, especially at intermediate ages, and therefore, screening for NAFLD should be advisable

Cinètica de l'antigen de superfície del virus de l'hepatitis B durant i després del tractament antiviral en pacients amb hepatitis crònica B antigen e negatiu

Aquesta tesi es composa de 2 estudis realitzats en pacients amb hepatitis crònica B, HBeAg negatiu que és la forma més freqüent en el nostre medi, per tal d'avaluar la cinètica de l'antigen de superfície (HBsAg) durant i després del tractament antiviral. El primer estudi és un estudi retrospectiu en que es va analitzar la cinètica de l'HBsAg durant el tractament antiviral amb anàlegs de nucleos(t)ids (AN). Vam demostrar que el descens és molt lent, però que una petita proporció de pacients (14%) pot presentar una cinètica de descens accelerat i que la reducció de l'HBsAg > 0,3 log UI/ml als 3 anys, identificava els pacients amb probabilitat de perdre l'HBsAg en els següents anys. El segon estudi va avaluar la cinètica de l'HBsAg abans i després de la retirada de tractament amb AN. La cinètica de l'HBsAg durant el tractament pot predir la pèrdua de l'HBsAg després de la retirada de tractament. En el nostre estudi, l'11,5% del pacients van perdre l'HBsAg durant el primer any després de parar el tractament. La meitat dels pacients amb una disminució >1 log UI/ml durant el tractament poden eliminar l'HBsAg durant el primer any després de la retirada de l'AN. D'altra banda, la parada de l'AN en pacients que havien rebut tractament durant més de 6 anys va provocar un descens accelerat de l'HBsAg (3 vegades superior) respecte a l'any previ a la parada.Esta tesis se compone de 2 estudios realizados en pacientes con hepatitis crónica B, HBeAg negativo que es la forma más frecuente en nuestro medio, a fin de evaluar la cinética del antígeno de superficie (HBsAg) durante y después del tratamiento antiviral. El primer estudio es un estudio retrospectivo en el que se analizó la cinética del HBsAg durante el tratamiento antiviral con análogos de nucleós(t)idos (AN). En este estudio demostramos que el descenso es muy lento, pero que una pequeña proporción de pacientes (14%) puede presentar una cinética de descenso acelerado y que la reducción del HBsAg > 0,3 log UI/ml a los 3 años, identificaba a los pacientes con probabilidad de perder el HBsAg en los siguientes años. El segundo estudio evaluó la cinética del HBsAg antes y después de la retirada de tratamiento con AN. La cinética del HBsAg durante el tratamiento puede predecir la pérdida de HBsAg después de la retirada de tratamiento. En nuestro estudio, el 11,5% de los pacientes perdieron el HBsAg durante el primer año después de parar el tratamiento. La mitad de los pacientes con una disminución >1 log UI/ml durante el tratamiento pueden eliminar el HBsAg durante el primer año después de la retirada del AN. Por otra parte, la parada de la AN en pacientes que habían recibido tratamiento durante más de 6 años provocó un descenso acelerado del HBsAg (3 veces superior) respecto al año previo a la parada.This thesis consists of 2 studies, performed in HBeAg negative chronic hepatitis B patients, which is the most common form in our setting, evaluating the kinetics of HBsAg during and after antiviral treatment. The first study is a retrospective study evaluating the kinetics of HBsAg before and during antiviral treatment with nucleos(t)ides analogues (NA). We showed that HBsAg decline is very slow during treatment, but a small proportion of patients (14%) may have an accelerated decline. The reduction at 3 years of HBsAg> 0,3 log IU/mL, identified patients with probability of losing HBsAg in the following years. The second study evaluated the kinetics of HBsAg before and after treatment withdrawal. The kinetics of HBsAg during treatment may predict the loss of HBsAg after treatment withdrawal. In our study, 11,5% of patients lost HBsAg in the first year after stopping treatment. Half of the patients with a decrease> 1 log IU/ml during treatment eliminated HBsAg during the first year after withdrawal of NA. On the other hand, stopping the NA in patients who had been treated for more than 6 years resulted in an accelerated decrease in HBsAg (3 times higher) compared to the year before treatment cessation

Current perspectives on nucleos(t)ide analogue therapy for the long-term treatment of hepatitis B virus

The hepatitis B virus (HBV) infection remains a global public health problem. This review presents updated recommendations for the optimal current treatment of choice with nucleos(t)ide analogues (NA). Current clinical practice guidelines on the management of chronic hepatitis B (CHB) by the Asian Pacific Association for the Study of the Liver, the European Association for the Study of the Liver and the American Association for the Study of Liver Diseases have been considered. Patients with chronic HBV infection are at increased risk of liver disease progression to cirrhosis and hepatocellular carcinoma (HCC) development. The main goal of therapy is to improve survival preventing disease progression and HCC. The induction of long-term suppression of HBV replication represents the main endpoint of current treatment strategies, while hepatitis B surface antigen (HBsAg) loss is the optimal endpoint. The typical indication for treatment requires elevated HBV desoxyribonucleic acid (DNA), elevated alanine aminotransferase and/or at least moderate histological lesions, while all cirrhotic patients with detectable HBV DNA should be treated. The long-term administration of a potent NA with high barrier to resistance, ie, entecavir, tenofovir disoproxil fumarate or tenofovir alafenamide, represents the treatment of choice. However, HBsAg seroclearance is anecdotal with NA. Treated patients should be monitored for therapy response, adherence, risk of disease progression, and risk of HCC development. This review aims to assess the evolving trends on the potent NA and the new perspectives on finite therapy

Elastography is unable to exclude cirrhosis after sustained virological response in HCV-infected patients with advanced chronic liver disease

Acord transformatiu CRUE-CSICBackground: Liver fibrosis and transient elastography (TE) correlation in hepatitis C virus (HCV)-infected patients with compensated advanced chronic liver disease (cACLD) after the sustained virological response (SVR) is unknown. Aims: To evaluate TE accuracy at identifying cirrhosis 3 years after HCV-eradication. Methods: Prospective, multi-centric study including HCV-cACLD patients before direct-acting antivirals (DAA). Diagnostic accuracy of TE (area under ROC, AUROC) to identify cirrhosis 3 years after SVR was evaluated. Results: Among 746 HCV-infected patients (95.4% with TE ≥10 kPa), 76 (10.2%) underwent a liver biopsy 3 years after SVR. Before treatment, 46 (63%) showed a TE>15 kPa. The TE before DAA was the best variable for predicting cirrhosis (METAVIR, F4) after SVR (AUROC = 0.79). Liver function parameters, serological non-invasive tests (APRI and FIB-4), and TE values improved after SVR. However, liver biopsy 3 years after HCV elimination (median time = 38.4 months) showed cirrhosis in 41 (53.9%). Multivariate analysis (OR (95% CI), P) showed that HCV-genotype 3 (20.81 (2.12-201.47),.009), and TE before treatment (1.21 (1.09-1.34), <.001) were the only variables associated with cirrhosis after SVR. However, the accuracy of TE after SVR was poor (AUROC = 0.75) and 6 (27.3%) out of 22 patients with a TE <8 kPa had cirrhosis. Similar results were found with APRI and FIB-4 scores. Conclusions: Cirrhosis is present, 3 years after SVR, in more than half of HCV-cACLD patients even with the normalisation of liver function parameters, serological non-invasive tests and TE values. The low diagnostic accuracy of non-invasive methods after SVR reinforces the need for long-term surveillance

Aplastic Anemia and Severe Myelosuppression with Boceprevir or Simeprevir-Containing Hepatitis C Virus Treatment

The addition of the new protease inhibitors (PIs) to peg-interferon (IFN) and ribavirin (RBV), approved for chronic hepatitis C, has clearly improved sustained virological response (SVR) rates although several adverse events have been reported with this regimens, including mild hematological toxicity. Moreover, severe pancytopenia and aplastic anemia during triple therapy with telaprevir has recently been described in seven patients. We report here two cases of severe agranulocytosis/aplastic anemia using boceprevir or simeprevir in interferon-based combination and 2 additional cases of severe myelosupression in IFN-free therapy with sofosbuvir and simeprevir plus RBV. Our observations suggest that PIs could have a sort of class-effect in developing severe hematologic toxicity or, at least, an additive interaction with other potentially myelotoxic agents such as IFN or RBV that are used in the classical regimens against HCV. Unfortunately, the mechanisms behind this phenomenon are currently unknown. In conclusion, given the lifethreatening character of these complications, close monitoring is mandatory in patients under PIs based therapy to promptly detect serious hematological toxicities and to carefully evaluate treatment discontinuation. Prospective studies assessing the usefulness of RBV in the era of new IFN-free combinations are needed

Hepatitis B surface antigen and hepatitis B core-related antigen kinetics after adding pegylated-interferon to nucleos(t)ids analogues in hepatitis B e antigen-negative patients

Background: Hepatitis B e antigen-negative chronic hepatitis B patients under nucleos(t)ids analogues (NAs) rarely achieve hepatitis B surface antigen (HBsAg) loss. Aim: To evaluate if the addition of pegylated interferon (Peg-IFN) could decrease HBsAg and hepatitis B core-related antigen (HBcrAg) levels and increase HBsAg loss rate in patients under NAs therapy. Methods: Prospective, non-randomized, open-label trial evaluating the combination of Peg-IFN 180 µg/week plus NAs during forty-eight weeks vs NAs in monotherapy. Hepatitis B e antigen-negative non-cirrhotic chronic hepatitis B patients of a tertiary hospital, under NAs therapy for at least 2 years and with undetectable viral load, were eligible. Patients with hepatitis C virus, hepatitis D virus or human immunodeficiency virus co-infection and liver transplanted patients were excluded. HBsAg and HBcrAg levels (log10 U/mL) were measured at baseline and during ninety-six weeks. HBsAg loss rate was evaluated in both groups. Adverse events were recorded in both groups. The kinetic of HBsAg for each treatment group was evaluated from baseline to weeks 24 and 48 by the slope of the HBsAg decline (log10 IU/mL/week) using a linear regression model. Results: Sixty-five patients were enrolled, 61% receiving tenofovir and 33% entecavir. Thirty-six (55%) were included in Peg-IFN-NA group and 29 (44%) in NA group. After matching by age and treatment duration, baseline HBsAg levels were comparable between groups (3.1 vs 3.2) (P = 0.25). HBsAg levels at weeks 24, 48 and 96 declined in Peg-IFN-NA group (-0.26, -0.40 and -0.44) and remained stable in NA group (-0.10, -0.10 and -0.10) (P < 0.05). The slope of HBsAg decline in Peg-IFN-NA group (-0.02) was higher than in NA group (-0.00) (P = 0.015). HBcrAg levels did not change. Eight (22%) patients discontinued Peg-IFN due to adverse events. The HBsAg loss was achieved in 3 (8.3%) patients of the Peg-IFN-NA group and 0 (0%) of the NA group. Conclusion: The addition of Peg-IFN to NAs caused a greater and faster decrease of HBsAg levels compared to NA therapy. Side effects of Peg-IFN can limit its use in clinical practice

On-therapy HBsAg kinetics can predict HBsAg loss after nucleos(t)ide analogues interruption in HBeAg-negative patients. The cup is half full and half empty

Altres ajuts: Acord transformatiu CRUE-CSICBackground. Nucleos(t)ide analogues withdrawal may improve HBsAg loss rates. However, conditions to select patients are not well established.Aims to evaluate the impact of HBsAg kinetics before treatment interruption on post-treatment response. Methods. Longitudinal, ambispective study in non-cirrhotic chronic hepatitis B HBeAg-negative patients, analysing on-treatment and post-treatment HBsAg kinetics. On-treatment HBsAg kinetics diagnostic accuracy (AUROC) to identify HBsAg loss was evaluated. Results. 52 HBeAg-negative patients stopped treatment after 8.2 years, and 6 (11.5%) achieved HBsAg loss one year after withdrawal. Multivariate analysis showed that on-treatment HBsAg kinetics was related to HBsAg loss (OR=0.10; 95%CI=0.016-0.632; p = 0.014) with a high diagnostic accuracy (AUROC=0.935). A significant HBsAg decline ≥1 log10 IU/mL showed a positive and negative predictive value of 50% and of 97.6%, respectively. After treatment interruption, HBsAg decline speed (log10 IU/mL/year) accelerated in patients treated >6 years (from -0.06 to -0.20, p<0.05) and remained stable in treated <6 years (from -0.12 to -0.12 p=ns). Conclusions. On-treatment HBsAg kinetics can predict post-treatment HBsAg loss rate. Half of patients with a significant HBsAg decline can eliminate HBsAg the first year after withdrawal. Post-treatment HBsAg decline is faster not only in patients who lost the HBsAg but also in those who remain HBsAg-positive. HBsAghepatitis B surface antigenHBeAghepatitis B e antigenNAnucleos(t)ides analoguesHBVhepatitis B virusORodds ratioCIconfidence intervalCHBchronic hepatitis BETVentecavirTDFtenofovir disoproxil fumarateEoTend of treatmentTEtransient elastographyVRvirological relapseCRclinical relapseALTalanine aminotransferaseULNupper limit of normalityILinterleukinIQRinterquartile rangePeg-IFNpegylated interferonAUROCarea under receiver operating characteristicSsensitivitySpspecificityPPVpositive predictive valueNPVnegative predictive value+LRpositive likelihood ratio-LRnegative likelihood ratio

Impact of the COVID-19 pandemic on the care and outcomes of people with NAFLD-related cirrhosis

Background & aims: The COVID-19 pandemic has had a major negative impact on health systems and many chronic diseases globally. We aimed to evaluate the impact of the first year of the pandemic on the outcomes of people with NAFLD cirrhosis. Methods: We conducted a before-after study in four University hospitals in Catalonia, Spain. Study subperiods were divided into Pre-pandemic (March/2019-February/2020) vs. Pandemic (March/2020-February/2021). The primary outcome was the rate of first liver-related event (LRE). Overall clinical outcomes (LREs plus cardiovascular plus all-cause mortality) were also assessed. Results: A total of 354 patients were included, all of whom were compensated at the beginning of the study period; 83 individuals (23.5%) had a history of prior hepatic decompensation. Mean age was 67.3 years and 48.3% were female. Median BMI was 31.2 kg/m2 and type 2 diabetes was present in 72.8% of patients. The rates of first LRE in the Pre-pandemic and Pandemic periods were 7.4% and 11.3% (p = 0.12), respectively. Whilst the rate of overall events was significantly higher in the Pandemic period (9.9% vs. 17.8%; p = 0.009), this was strongly associated with COVID-19-related deaths. The rate of worsened metabolic status was significantly higher in the Pandemic period (38.4% vs. 46.1%; p = 0.041), yet this was not associated with the risk of first LRE during the Pandemic period, whereas type 2 diabetes (odds ratio [OR] 3.77; 95% CI 1.15-12.32; p = 0.028), albumin 2.67 (OR 15.74; 95% CI 2.01-123.22; p = 0.009) were identified as risk factors in the multivariable analysis. Conclusion: Overall, people with NAFLD cirrhosis did not present poorer liver-related outcomes during the first year of the pandemic. Health system preparedness seems key to ensure that people with NAFLD cirrhosis receive appropriate care during health crises.Lay summary: Mobility restrictions and social stress induced by the COVID-19 pandemic have led to increased alcohol drinking and worsened metabolic control (e.g., weight gain, poor control of diabetes) in a large proportion of the population in many countries. We aimed to analyze whether people with cirrhosis due to non-alcoholic fatty liver disease, who are particularly vulnerable to such lifestyle modifications, were significantly impacted during the first year of the pandemic. We compared the clinical situation of 354 patients one year before the pandemic and one year after. We found that although metabolic control was indeed worse after the first year of the pandemic and patients presented worse clinical outcomes, the latter was mostly due to non-liver causes, namely COVID-19 itself. Moreover, the care provided to these patients did not worsen during the first year of the pandemic.TB has received educational and research support from Gilead and Abbvie. JMP reports having received consulting fees from Boehringer Ingelheim and Novo Nordisk. He has received speaking fees from Gilead, and travel expenses from Gilead, Rubió, Pfizer, Astellas, MSD, CUBICIN, and Novo Nordisk. He has received educational and research support from Gilead, Pfizer, Astellas, Accelerate, Novartis, Abbvie, ViiV, and MSD, and funds from European Commission/EFPIA IMI2 853966-2, IMI2 777377, H2020 847989, and ISCIII PI19/01898. Other authors: nothing to disclose. None of the authors have any personal conflict with regards to the present manuscript