ABSTRACT
BACKGROUND AND AIMS: Decompensated-cirrhosis encompasses several stages with different prognosis, such as bleeding, ascites and bleeding-plus-ascites. Development of further-decompensation worsens survival, while non-selective ß-blockers (NSBBs) can modify the risk. However, how this applies to each stage is uncertain. We aimed to investigate, in each stage of decompensated-cirrhosis, the influence of further-decompensation on mortality and whether changes in portal-pressure (HVPG) under NSBBs influence these outcomes. METHODS: Patients with variceal bleeding were consecutively included differentiating those with bleeding-alone from those who also had ascites. Patients with ascites and high-risk varices referred for primary-prophylaxis were also investigated. A baseline haemodynamic study was performed and was repeated after 1-3-months under NSBBs. Outcomes were investigated by competing-risk. RESULTS: Totally 103 patients had bleeding-alone, 186 bleeding-plus-ascites and 187 ascites-alone. Mean follow-up was 32-months (IQR, 12-60). Patients with bleeding-plus-ascites had higher HVPG and were more hyperdynamic than patients with ascites-alone and these than those with bleeding-alone. At each stage, the mortality risk was more than twice in patients developing further-decompensation vs. those without (p < .001). In each stage, HVPG-decrease under NSBBs showed better discrimination to predict further-decompensation than the baseline MELD, Child-Pugh or HVPG, by time-dependent ROC-curves (c-statistic >70%). At each stage, patients without HVPG-decreases, either ≥10% or ≥20% from the baseline, had higher risk of further-decompensation (sHR from 2.43 to 6.73, p < .01) and worse survival. CONCLUSIONS: In each stage of decompensated cirrhosis, mortality risk significantly and very markedly increase with further-decompensation. HVPG-non-response to NSBBs may adequately stratify the risk of further decompensation and death, in each stage. This suggests potential benefit with pre-emptive therapies in HVPG-non-responders at each-stage.
Subject(s)
Ascites , Esophageal and Gastric Varices , Gastrointestinal Hemorrhage , Hypertension, Portal , Liver Cirrhosis , Portal Pressure , Humans , Hypertension, Portal/physiopathology , Hypertension, Portal/mortality , Hypertension, Portal/etiology , Liver Cirrhosis/complications , Liver Cirrhosis/mortality , Liver Cirrhosis/physiopathology , Female , Male , Ascites/physiopathology , Ascites/mortality , Ascites/etiology , Middle Aged , Gastrointestinal Hemorrhage/mortality , Gastrointestinal Hemorrhage/etiology , Gastrointestinal Hemorrhage/physiopathology , Esophageal and Gastric Varices/mortality , Esophageal and Gastric Varices/physiopathology , Esophageal and Gastric Varices/etiology , Aged , Prognosis , Adrenergic beta-Antagonists/therapeutic use , ROC CurveABSTRACT
In Mediterranean rocky shores, the black sea urchin Arbacia lixula is often associated with communities dominated by encrusting corallines, devoid of fleshy algae. While it is commonly known as a diurnal herbivore, this species also migrates at night from hidden to more exposed habitats. Here, we provide the first experimental evidence of an adjustment to a predominant nocturnal behaviour in a population of A. lixula. Sea urchin densities changed from nearly zero during daytime to more than 16 urchins m-2 at night in treatment plots where the sea urchins were removed. We suggest that the observed behaviour was triggered by our experimental manipulations and was a response to the presence of dead conspecifics and small predatory fishes attracted by the urchin culling. Further research is needed to assess whether our findings can be generalised to the behaviour of A. lixula in areas where sea urchins are under strong pressure from diurnal predators. In these cases, it is important to perform sea urchin density counts at night to avoid misleading assessments about the herbivore pressure in a littoral area.
ABSTRACT
Objectives: Limited screening and delays in diagnosis and linkage-to-care are barriers for hepatitis C virus (HCV) elimination. The LiverTAI study focused on patients tested for HCV using AI technologies to describe their demographic and clinical characteristics and pre-testing patient journeys, reflecting clinical practice in hospitals. Patients and methods: LiverTAI is a retrospective, secondary analysis of electronic health records (EHRs) from 6 tertiary Spanish hospitals, extracting unstructured clinical data using natural language processing (NLP) EHRead® technology. Adult subjects with an HCV testing procedure from January 2014 to December 2018 were grouped according to HCV seropositivity and viremia. Results: From 2,440,358 patients, 16,261 patients were tested for HCV (13,602 [83.6%] HCV seronegative; 2659 [16.4%] seropositive). Active HCV viremia appeared in 37.7% (n=1003) of patients, 18.6% (n=494) had negative viremia, and 43.7% (n=1162) unknown viremia. Patient journeys showed core departments (Gastroenterology, Internal Medicine, and Infectious Disease) and others including Emergency perform ample HCV testing in Spanish hospitals, whereas Medical Oncology lags. Patients were PCR-tested and genotyped significantly faster in core departments (p<.001). Conclusions: Our results highlight hospital departments responsible for HCV testing. However, further testing was sub-optimal during the study period. Therefore, we underscore the need for HCV screening and reflex testing to accelerate diagnosis and linkage-to-care.(AU)
Objetivos: El cribado limitado, los retrasos diagnósticos y la vinculación a la atención sanitaria son obstáculos para la eliminación del virus de la hepatitis C (VHC). El estudio LiverTAI se centró en analizar pacientes testeados para VHC mediante tecnologías de IA para describir sus características demográficas, clínicas y los recorridos de los pacientes antes del test, reflejando la práctica clínica en los hospitales. Pacientes y métodos: LiverTAI es un análisis retrospectivo y secundario de las historias clínicas electrónicas (HCE) de 6 hospitales españoles de tercer nivel, en el que se extraen datos clínicos no estructurados mediante la tecnología EHRead® de procesamiento del lenguaje natural (PLN). Los sujetos adultos con un test de VHC desde enero de 2014 hasta diciembre de 2018 se agruparon según la seropositividad y la viremia del VHC. Resultados: De 2.440.358 pacientes, 16.261 fueron testeados para VHC (13.602 [83,6%] seronegativos al VHC; 2.659 [16,4%] seropositivos). La viremia activa del VHC apareció en el 37,7% (n=1.003) de los pacientes, el 18,6% (n=494) mostró viremia negativa y el 43,7% (n=1.162), viremia desconocida. Los recorridos de los pacientes mostraron que los departamentos core (gastroenterología, medicina interna y enfermedades infecciosas) y otros, incluyendo urgencias, realizan numerosos test de VHC en los hospitales españoles, mientras que oncología médica se queda atrás. Los pacientes fueron sometidos a la prueba de la PCR y el genotipo significativamente más rápido en los departamentos core (p<0,001). Conclusiones: Nuestros resultados destacan los departamentos hospitalarios responsables de realizar test de VHC mediante pruebas serológicas. Sin embargo, las pruebas posteriores (PCR, genotipado) experimentaban retrasos durante el periodo de estudio. Por lo tanto, subrayamos la necesidad de realizar el cribado del VHC y de diagnóstico en un solo paso para acelerar el diagnóstico y la vinculación a la atención sanitaria.(AU)
Subject(s)
Humans , Hepacivirus , Natural Language Processing , Artificial Intelligence , Electronic Health Records , Biomedical Technology , Gastroenterology , Gastrointestinal Diseases , Retrospective Studies , SpainABSTRACT
OBJECTIVES: Limited screening and delays in diagnosis and linkage-to-care are barriers for hepatitis C virus (HCV) elimination. The LiverTAI study focused on patients tested for HCV using AI technologies to describe their demographic and clinical characteristics and pre-testing patient journeys, reflecting clinical practice in hospitals. PATIENTS AND METHODS: LiverTAI is a retrospective, secondary analysis of electronic health records (EHRs) from 6 tertiary Spanish hospitals, extracting unstructured clinical data using natural language processing (NLP) EHRead® technology. Adult subjects with an HCV testing procedure from January 2014 to December 2018 were grouped according to HCV seropositivity and viremia. RESULTS: From 2,440,358 patients, 16,261 patients were tested for HCV (13,602 [83.6%] HCV seronegative; 2659 [16.4%] seropositive). Active HCV viremia appeared in 37.7% (n=1003) of patients, 18.6% (n=494) had negative viremia, and 43.7% (n=1162) unknown viremia. Patient journeys showed core departments (Gastroenterology, Internal Medicine, and Infectious Disease) and others including Emergency perform ample HCV testing in Spanish hospitals, whereas Medical Oncology lags. Patients were PCR-tested and genotyped significantly faster in core departments (p<.001). CONCLUSIONS: Our results highlight hospital departments responsible for HCV testing. However, further testing was sub-optimal during the study period. Therefore, we underscore the need for HCV screening and reflex testing to accelerate diagnosis and linkage-to-care.
Subject(s)
Hepacivirus , Hepatitis C , Adult , Humans , Hepacivirus/genetics , Retrospective Studies , Viremia , Electronic Health Records , Natural Language Processing , Spain/epidemiology , Hepatitis C/diagnosis , Hepatitis C/epidemiologyABSTRACT
The cartography of shallow water macroalgal assemblages allows the assessment of water quality in coastal water bodies through the application of CARLIT. In this study, we have applied CARLIT to assess the ecological status of Algerian coastal water bodies for the first time. The surveyed zone is still in a good ecological status since 52% have a good to a high ecological Status. CARLIT index is well correlated with anthropogenic pressures and has proved suitable for the evaluation of the ecological status of coastal waters. Comparison between EQR values and EEI-c shows a similar pattern of change. CARLIT method allowed the collection of accurate information on the distribution and abundance of shallow-water communities. We also provide a cartographic baseline of the coastal assemblages useful for further evaluations on their geographic extension and for the implementation of a monitoring project on water quality in Algerian coast.
Subject(s)
Ecosystem , Environmental Monitoring , Algeria , Mediterranean Sea , Water QualityABSTRACT
BACKGROUND/AIMS: Despite secondary-prophylaxis with ß-blockers and endoscopic-variceal-ligation rebleeding is frequent, particularly within the first-6-weeks. Early-rebleeding may have greater impact on death-risk than late rebleeding, which may affect therapy. We assessed whether the influence of rebleeding on long-term survival of patients on secondary-prophylaxis is greater in patients with early-rebleeding. METHODS: 369 patients with cirrhosis were consecutively included once recovered from first variceal-bleeding. The impact of rebleeding on survival was investigated according to whether it occurred within 6-weeks (early-rebleeding) or later (late-rebleeding). RESULTS: During 46-months of follow-up (IQR: 14-61), 45 patients (12%) had early-rebleeding, 74(20%) had late-rebleeding and 250(68%) had not rebleeding. Mortality risk was higher in early-rebleeding group vs. late-rebleeding (HRâ¯=â¯0.476, 95%CIâ¯=â¯0.318-0.712, p < 0.001) and was similar in late-rebleeding group vs. no-rebleeding (HRâ¯=â¯0.902, 95%CIâ¯=â¯0.749-1.086, pâ¯=â¯0.271). Adjusting for baseline risk-factors, early-rebleeding was independently associated with mortality-risk (HRâ¯=â¯1.58, 95%CIâ¯=â¯1.02-2.45; pâ¯=â¯0.04). Child-Pugh&MELD scores improved at 3rd-4th-week only in patients without early-rebleeding (p < 0.05). Presence of ascites or encephalopathy, MELD-score>12 and HVPG>20â¯mmHg identified patients at risk of early-rebleeding. CONCLUSIONS: Patients with early-rebleeding have higher risk of death than patients without rebleeding and even than those rebleeding later. Our results suggest that patients at risk of early rebleeding might benefit from preemptive therapies such as early-TIPS.
Subject(s)
Adrenergic beta-Antagonists/therapeutic use , Esophageal and Gastric Varices/therapy , Gastrointestinal Hemorrhage/mortality , Gastrointestinal Hemorrhage/prevention & control , Liver Cirrhosis/complications , Adult , Aged , Combined Modality Therapy , Esophageal and Gastric Varices/etiology , Esophageal and Gastric Varices/mortality , Esophageal and Gastric Varices/physiopathology , Female , Gastrointestinal Hemorrhage/etiology , Gastrointestinal Hemorrhage/physiopathology , Hepatic Encephalopathy/etiology , Humans , Ligation/methods , Liver Cirrhosis/mortality , Male , Middle Aged , Portasystemic Shunt, Transjugular Intrahepatic/adverse effects , Portasystemic Shunt, Transjugular Intrahepatic/mortality , Prospective Studies , Recurrence , Secondary Prevention , Severity of Illness Index , Spain/epidemiology , Survival Analysis , Time Factors , Treatment OutcomeABSTRACT
BACKGROUND & AIMS: Clinically significant portal hypertension (CSPH), defined as a hepatic venous pressure gradient (HVPG) ≥10 mmHg, persists 24 weeks after sustained virological response (SVR) in up to 78% of patients with HCV-related cirrhosis treated with direct-acting antivirals. These patients remain at risk of decompensation. However, long-term paired clinical and hemodynamic data are not available for this population. METHODS: We conducted a prospective multicenter study in 226 patients with HCV-related cirrhosis and CSPH who achieved SVR after antiviral therapy. Patients with CSPH 24 weeks after end of treatment (SVR24) were offered another hemodynamic assessment 96 weeks after end of treatment (SVR96). RESULTS: All patients were clinically evaluated. Out of 176 patients with CSPH at SVR24, 117 (66%) underwent an HVPG measurement at SVR96. At SVR96, 55/117 (47%) patients had HVPG <10 mmHg and 53% had CSPH (65% if we assume persistence of CSPH in all 59 non-evaluated patients). The proportion of high-risk patients (HVPG ≥16 mmHg) diminished from 41% to 15%. Liver stiffness decreased markedly after SVR (median decrease 10.5 ± 13 kPa) but did not correlate with HVPG changes (30% of patients with liver stiffness measurement <13.6 kPa still had CSPH). Seventeen (7%) patients presented with de novo/additional clinical decompensation, which was independently associated with baseline HVPG ≥16 mmHg and history of ascites. CONCLUSIONS: Patients achieving SVR experienced a progressive reduction in portal pressure during follow-up. However, CSPH may persist in up to 53-65% of patients at SVR96, indicating persistent risk of decompensation. History of ascites and high-risk HVPG values identified patients at higher risk of de novo or further clinical decompensation. LAY SUMMARY: As a major complication of cirrhosis, clinically significant portal hypertension (CSPH) is associated with adverse clinical outcomes. Herein, we show that CSPH persists at 96 weeks in just over half of patients with HCV-related cirrhosis, despite HCV elimination by direct-acting antivirals. Despite viral cure, patients with CSPH at the start of antiviral treatment remain at long-term risk of hepatic complications and should be managed accordingly.
Subject(s)
Antiviral Agents/therapeutic use , Hepatitis C, Chronic , Hypertension, Portal , Liver Cirrhosis , Liver , Disease Progression , Elasticity Imaging Techniques/methods , Female , Follow-Up Studies , Hemodynamics , Hepacivirus/isolation & purification , Hepatitis C, Chronic/complications , Hepatitis C, Chronic/drug therapy , Hepatitis C, Chronic/epidemiology , Humans , Hypertension, Portal/diagnosis , Hypertension, Portal/etiology , Hypertension, Portal/physiopathology , Liver/diagnostic imaging , Liver/pathology , Liver Cirrhosis/complications , Liver Cirrhosis/physiopathology , Liver Cirrhosis/virology , Male , Middle Aged , Risk Assessment/methods , Risk Assessment/statistics & numerical data , Spain/epidemiology , Sustained Virologic Response , TimeABSTRACT
BACKGROUND & AIMS: Whether the effect of ß-blockers on arterial pressure and/or cardiac function may offset the benefit of reducing portal pressure in advanced cirrhosis is controversial. Herein, we aimed to evaluate the systemic and splanchnic hemodynamic effects of ß-blockers in decompensated vs. compensated cirrhosis and to investigate the influence of systemic hemodynamic changes on survival times in decompensated cirrhosis. METHODS: Patients with cirrhosis and high-risk esophageal varices, without previous bleeding, were consecutively included and grouped according to the presence or absence of decompensation (ascites with or without overt encephalopathy). Systemic and hepatic hemodynamic measurements were performed before starting ß-blockers and again after 1 to 3 months of treatment (short-term). RESULTS: Four hundred and three patients were included (190 decompensated and 213 compensated). At baseline, decompensated patients had higher portal pressure than compensated patients and were more hyperdynamic, with higher cardiac output (CO) and lower arterial pressure. Under ß-blockers, decompensated patients had lower portal pressure decrease (10 ± 18% vs. 15 ± 12%; p <0.05) and had greater reductions in heart rate (p <0.001) and CO (17 ± 15% vs. 10 ± 21%; p <0.01). Among patients with decompensated cirrhosis, those who died had a greater decrease in CO with ß-blockers than survivors (21 ± 14% vs. 15 ± 16%; p <0.05) and CO under ß-blockers independently predicted death by competing-risk regression analysis, with good diagnostic accuracy (C-index 0.74; 95% CI 0.66-0.83). Death risk was higher in decompensated patients with CO <5 L/min vs. CO ≥5 L/min (subdistribution hazard ratio 0.44; 95% CI 0.25-0.77; p = 0.004). CONCLUSIONS: In patients with high-risk varices treated to prevent first bleeding, the systemic hemodynamic response to ß-blockers is greater and the portal pressure decrease is smaller in those with decompensated cirrhosis. The short-term effect of ß-blockers on CO might adversely influence survival in decompensated cirrhosis. LAY SUMMARY: ß-blockers are often used to reduce the risk of variceal bleeding in patients with cirrhosis. However, it is not known whether the effect of ß-blockers on arterial pressure and/or cardiac function may offset the benefit of reducing portal pressure. Herein, we show that in patients with decompensated cirrhosis the potentially detrimental systemic effects of ß-blockers are greater than in compensated patients, while the beneficial pressure lowering effects are reduced. The short-term effect of ß-blockers on cardiac output may adversely influence survival in patients with decompensated cirrhosis.
Subject(s)
Adrenergic beta-Antagonists/pharmacology , Esophageal and Gastric Varices/etiology , Hemodynamics/drug effects , Hypertension, Portal/drug therapy , Liver Cirrhosis/complications , Liver/physiopathology , Disease Progression , Esophageal and Gastric Varices/physiopathology , Female , Follow-Up Studies , Humans , Hypertension, Portal/etiology , Hypertension, Portal/physiopathology , Liver Cirrhosis/mortality , Liver Cirrhosis/physiopathology , Male , Middle Aged , Retrospective Studies , Survival Rate/trends , Time FactorsABSTRACT
BACKGROUND AND AIM: Accurate information on the epidemiology of hepatitis C and B infection is mandatory to establish a national/regional plan. We aim to update the prevalence of hepatitis C and B infection in Catalonia using point-of-care tests to analyze the risk factors related and to implement a linkage-to-care circuit. METHODS: This is a community-based study. A random list of adult individuals was retrieved from censuses of primary care centers. Point-of-care tests for anti-hepatitis C virus (HCV) and HBV surface antigen (HBsAg) and a questionnaire for risk factor assessment were performed. Positive results were validated and a circuit for linkage-to-care was established. RESULTS: A total of 3328 individuals were included. The anti-HCV and HBsAg overall prevalence were lower than expected [1.02%, 95% confidence interval (CI) 0.65-1.39; and 0.52%, 95% CI 0.26-0.77, respectively]. Anti-HCV positive subjects were mostly (88%) autochthonous. The prevalence increased with age; only 12% were under age 40. The associated risk factors were drug use, blood transfusion, relative with HCV, and diabetes. Notably, the prevalence of active infection was only 0.49% (95% CI 0.23-0.74), 40% less than previously reported, reflecting the impact of direct acting antiviral therapy. Differently, HBsAg positive subjects were mostly foreign migrants (53%) with no other risk factors. Despite the implementation of a linkage-to-care circuit, one third of HBsAg positive subjects were lost. CONCLUSIONS: The prevalence of HCV infection was lower than previously reported, showing a strong impact of direct acting antiviral therapy in the last years. Because of hepatitis B universal vaccination, HBV infection in Catalonia is mainly associated with migrant population. Linkage-to-care in patients with hepatitis B was challenging and warrants additional efforts.
Subject(s)
Antiviral Agents/administration & dosage , Hepatitis B/diagnosis , Hepatitis C/diagnosis , Hepatitis C/epidemiology , Administration, Oral , Adult , Age Factors , Aged , Aged, 80 and over , Biomarkers/blood , Female , Hepatitis B/drug therapy , Hepatitis B/epidemiology , Hepatitis B Surface Antigens/blood , Hepatitis C/drug therapy , Hepatitis C Antibodies/blood , Humans , Male , Middle Aged , Point-of-Care Testing , Prevalence , Risk Factors , Spain/epidemiology , Surveys and QuestionnairesABSTRACT
A percentage of hepatitis C virus (HCV)-infected patients fail direct acting antiviral (DAA)-based treatment regimens, often because of drug resistance-associated substitutions (RAS). The aim of this study was to characterize the resistance profile of a large cohort of patients failing DAA-based treatments, and investigate the relationship between HCV subtype and failure, as an aid to optimizing management of these patients. A new, standardized HCV-RAS testing protocol based on deep sequencing was designed and applied to 220 previously subtyped samples from patients failing DAA treatment, collected in 39 Spanish hospitals. The majority had received DAA-based interferon (IFN) α-free regimens; 79% had failed sofosbuvir-containing therapy. Genomic regions encoding the nonstructural protein (NS) 3, NS5A, and NS5B (DAA target regions) were analyzed using subtype-specific primers. Viral subtype distribution was as follows: genotype (G) 1, 62.7%; G3a, 21.4%; G4d, 12.3%; G2, 1.8%; and mixed infections 1.8%. Overall, 88.6% of patients carried at least 1 RAS, and 19% carried RAS at frequencies below 20% in the mutant spectrum. There were no differences in RAS selection between treatments with and without ribavirin. Regardless of the treatment received, each HCV subtype showed specific types of RAS. Of note, no RAS were detected in the target proteins of 18.6% of patients failing treatment, and 30.4% of patients had RAS in proteins that were not targets of the inhibitors they received. HCV patients failing DAA therapy showed a high diversity of RAS. Ribavirin use did not influence the type or number of RAS at failure. The subtype-specific pattern of RAS emergence underscores the importance of accurate HCV subtyping. The frequency of "extra-target" RAS suggests the need for RAS screening in all three DAA target regions.
Subject(s)
Antiviral Agents/therapeutic use , Drug Resistance, Multiple, Viral/genetics , Hepacivirus/drug effects , Hepacivirus/genetics , Mutation , Antiviral Agents/pharmacology , Cohort Studies , Drug Therapy, Combination , Genotype , Hepatitis C/drug therapy , High-Throughput Nucleotide Sequencing , Humans , Spain , Treatment FailureABSTRACT
BACKGROUND: Direct-acting antivirals (DAAs) show high efficacy and safety in HCV-cirrhotic patients, but most maintain clinically significant portal hypertension after sustained virological response (SVR). Non-invasive Baveno and expanded-Baveno criteria can identify patients without high-risk gastroesophageal varices (GEV) who have no need for endoscopic surveillance. However, data after SVR are scarce. We performed a multicenter study to evaluate SVR effects over GEV and diagnostic accuracy of non-invasive criteria after SVR. METHODS: HCV-cirrhotic patients receiving DAAs and baseline endoscopic evaluation were included (November 2014-October 2015). GEV were classified as low risk (LR-GEV) (< 5 mm) or high risk (HR-GEV) (≥ 5 mm or with risk signs). Transient elastography (TE) and endoscopy were performed during follow-up. RESULTS: SVR was achieved in 230 (93.1%) of 247 included patients, 151 (65.7%) with endoscopic follow-up. Among 64/151 (42.4%) patients without baseline GEV, 8 (12.5%) developed GEV after SVR. Among 50/151 (33.1%) with baseline LR-GEV, 12 (24%) developed HR-GEV. Patients with GEV progression showed TE ≥ 25 kPa before treatment (64.7%) or ≥ 20 kPa after SVR (66.7%). Only 6% of patients without GEV and LSM < 25 kPa before treatment, and 10% of those with baseline LSM < 25 kPa and LSM < 20 kPa after SVR showed GEV progression after 36 months. The negative predictive value of Baveno and expanded-Baveno criteria to exclude HR-GEV was maintained after SVR (100% and 90.7%, respectively). CONCLUSIONS: HCV-cirrhotic patients can develop HR-GEV after SVR. Surveillance is especially recommended in those with GEV before antiviral treatment. Baveno and expanded-Baveno criteria can be safely applied after SVR. https://clinicaltrials.gov: NCT02758509.
Subject(s)
Antiviral Agents/therapeutic use , Esophageal and Gastric Varices/etiology , Hepatitis C, Chronic/complications , Hepatitis C, Chronic/drug therapy , Liver Cirrhosis/complications , Sustained Virologic Response , Adult , Aged , Aged, 80 and over , Disease Progression , Elasticity Imaging Techniques , Endoscopy, Gastrointestinal , Esophageal and Gastric Varices/diagnostic imaging , Female , Hepatitis C, Chronic/physiopathology , Humans , Liver Cirrhosis/diagnostic imaging , Liver Cirrhosis/virology , Male , Middle Aged , Predictive Value of Tests , Prospective Studies , Risk Factors , Young AdultABSTRACT
BACKGROUND & AIMS: Around 5% of patients with chronic hepatitis C virus (HCV) infection treated with direct-acting antiviral (DAA) agents do not achieve sustained virological response (SVR). The currently approved retreatment regimen for prior DAA failure is a combination of sofosbuvir, velpatasvir, and voxilaprevir (SOF/VEL/VOX), although there is little data on its use in clinical practice. The aim of this study was to analyse the effectiveness and safety of SOF/VEL/VOX in the real-world setting. METHODS: This was a prospective multicentre study assessing the efficacy of retreatment with SOF/VEL/VOX in patients who had experienced a prior DAA treatment failure. The primary endpoint was SVR 12â¯weeks after the completion of treatment (SVR12). Data on safety and tolerability were also recorded. RESULTS: A total of 137 patients were included: 75% men, 35% with liver cirrhosis. Most were infected with HCV genotype (GT) 1 or 3. The most common prior DAA combinations were sofosbuvir plus an NS5A inhibitor or ombitasvir/paritaprevir/r+dasabuvir. A total of 136 (99%) patients achieved undetectable HCV RNA at the end of treatment. Overall SVR12 was 95% in the 135 patients reaching this point. SVR12 was lower in patients with cirrhosis (89%, pâ¯=â¯0.05) and those with GT3 infection (80%, pâ¯<0.001). Patients with GT3 infection and cirrhosis had the lowest SVR12 rate (69%). Of the patients who did not achieve SVR12, 1 was reinfected and 7 experienced treatment failure (6 GT3, 1 GT1a). The presence of resistance-associated substitutions did not impact SVR12. Adverse effects were mild and non-specific. CONCLUSION: Real-world data show that SOF/VEL/VOX is an effective, safe rescue therapy for patients with prior DAA treatment failure despite the presence of resistance-associated substitutions. However, patients with liver cirrhosis infected by GT3 remain the most-difficult-to-treat group. LAY SUMMARY: Treatment with sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) for 12â¯weeks is the current recommendation for the 5% of patients infected with HCV who do not achieve eradication of the virus under treatment with direct-acting antivirals. In a Spanish cohort of 137 patients who failed a previous combination of direct-acting antivirals, a cure rate of 95% was achieved with SOF/VEL/VOX. Genotypic characteristics of the virus (genotype 3) and the presence of cirrhosis were factors that decreased the rate of cure. Treatment with SOF/VEL/VOX is an effective and safe rescue therapy due to its high efficacy and very good safety profile.
Subject(s)
Carbamates , Hepatitis C, Chronic , Heterocyclic Compounds, 4 or More Rings , Liver Cirrhosis/diagnosis , Macrocyclic Compounds , Sofosbuvir , Sulfonamides , Adult , Aminoisobutyric Acids , Antiviral Agents/administration & dosage , Antiviral Agents/adverse effects , Carbamates/administration & dosage , Carbamates/adverse effects , Cyclopropanes , Drug Combinations , Drug Monitoring/methods , Drug Resistance, Viral , Female , Hepacivirus/genetics , Hepatitis C, Chronic/drug therapy , Hepatitis C, Chronic/epidemiology , Hepatitis C, Chronic/virology , Heterocyclic Compounds, 4 or More Rings/administration & dosage , Heterocyclic Compounds, 4 or More Rings/adverse effects , Humans , Lactams, Macrocyclic , Leucine/analogs & derivatives , Macrocyclic Compounds/administration & dosage , Macrocyclic Compounds/adverse effects , Male , Middle Aged , Proline/analogs & derivatives , Quinoxalines , Sofosbuvir/administration & dosage , Sofosbuvir/adverse effects , Spain/epidemiology , Sulfonamides/administration & dosage , Sulfonamides/adverse effects , Sustained Virologic Response , Treatment OutcomeABSTRACT
BACKGROUND & AIMS: Despite direct-acting antivirals being highly effective at eradicating hepatitis C virus infection, their impact on the development of hepatocellular carcinoma (HCC) remains controversial. We analyzed the clinical and radiological outcome of cirrhotic patients treated with interferon-free regimens to estimate the risk of developing HCC. METHODS: This was a retrospective multicenter study focusing on cirrhotic patients treated with direct-acting antivirals until December 2016. Clinical and radiologic characteristics were collected before the start of antiviral therapy, at follow-up and at HCC development. Diagnosis of HCC was centrally validated and its incidence was expressed as HCC/100 person-years. RESULTS: A total of 1,123 patients were included (60.6% males, 83.8% Child-Pugh A) and 95.2% achieved a sustained virologic response. Median time of follow-up was 19.6â¯months. Seventy-two patients developed HCC within a median of 10.3â¯months after starting antiviral treatment. HCC incidence was 3.73 HCC/100 person-years (95% CI 2.96-4.70). Baseline liver function, alcohol intake and hepatic decompensation were associated with a higher risk of HCC. The relative risk was significantly increased in patients with non-characterized nodules at baseline 2.83 (95% CI 1.55-5.16) vs. absence of non-characterized nodules. When excluding these patients, the risk remained increased. CONCLUSION: These data expose a clear-cut time association between interferon-free treatment and HCC. The mechanisms involved in the increased risk of HCC emergence in the short term require further investigation. LAY SUMMARY: In this cohort of cirrhotic patients, interferon-free therapies achieved a high rate of sustained virologic response (>95%); however, we reported a risk of de novo hepatocellular carcinoma of 3.73 per 100 person-years and a clear-cut time association with antiviral therapy. The time association between starting direct-acting antivirals and developing hepatocellular carcinoma, together with the association with the presence of non-characterized nodules at baseline ultrasound, suggests that antiviral therapy elicits a mechanism (probably immune-related) that primes the growth and clinical recognition of hepatocellular carcinoma early during follow-up. As a result, short-term liver cancer risk is significantly increased.
Subject(s)
Antiviral Agents/therapeutic use , Carcinoma, Hepatocellular/etiology , Hepatitis C/drug therapy , Liver Cirrhosis/complications , Liver Neoplasms/etiology , Aged , Carcinoma, Hepatocellular/epidemiology , Carcinoma, Hepatocellular/mortality , Carcinoma, Hepatocellular/pathology , Female , Hepatitis C/complications , Humans , Incidence , Liver Neoplasms/epidemiology , Liver Neoplasms/mortality , Liver Neoplasms/pathology , Male , Middle Aged , Retrospective Studies , Sustained Virologic Response , Time FactorsABSTRACT
BACKGROUND & AIMS: The interferon-free regimen paritaprevir/ritonavir, ombitasvir + dasabuvir (PTV/r/OBV/DSV) has shown high efficacy in patients with hepatitis C virus (HCV) genotype 1b infection when administered for 8 or 12 weeks, but data regarding the 8-week treatment are scarce. The aim of our study was to assess the efficacy and safety of the 8-week administration of PTV/r/OBV/DSV in a real-world cohort. METHODS: We performed a multicentre observational study from Spanish Hepa-C database including patients receiving 8 weeks of PTV/r/OBV/DSV (October 2016-November 2017). Those with advanced fibrosis, with non-genotype 1b or who were treatment-experienced were excluded. RESULTS: A total of 211 patients were registered from 23 Spanish centres; eleven were excluded. At baseline, 42.5% (n = 85) were male, median (range) age was 57 (23-86), ALT was 45 (11-494) IU/mL, viral load was 6.1 (3.3-8.2) log10 IU/mL, and 74.5% had mild liver fibrosis (F0-F1) and 25.5% moderate fibrosis (F2). At the end of treatment (EOT), HCV viral load was undetectable in 100% (200/200). Seven patients relapsed after treatment discontinuation. Sustained virological response (SVR12) rates by intention-to-treat analysis were 96% (192/200). Regarding treatment safety, 2 patients developed ALT elevation >5x ULN, but there were no treatment discontinuations. One patient died 7 weeks after EOT. CONCLUSION: Treatment with PTV/r/OBV/DSV in genotype 1b-infected treatment-naive patients with mild-moderate fibrosis shows excellent efficacy and safety in real life, similarly to clinical trials. Clinicaltrials.gov, number: NCT03122132.
Subject(s)
Anilides/therapeutic use , Antiviral Agents/therapeutic use , Carbamates/therapeutic use , Hepatitis C, Chronic/drug therapy , Liver Cirrhosis/virology , Macrocyclic Compounds/therapeutic use , Sulfonamides/therapeutic use , Uracil/analogs & derivatives , 2-Naphthylamine , Adult , Aged , Aged, 80 and over , Cyclopropanes , Drug Therapy, Combination , Female , Genotype , Hepacivirus/genetics , Hepatitis C, Chronic/pathology , Humans , Lactams, Macrocyclic , Male , Middle Aged , Proline/analogs & derivatives , Prospective Studies , Spain , Sustained Virologic Response , Uracil/therapeutic use , Valine , Viral Load , Young AdultABSTRACT
BACKGROUND & AIMS: Drug-drug interactions (DDIs) with ombitasvir/paritaprevir/ritonavir with or without dasabuvir and with or without ribavirin (OBV/PTV/r ± DSV ± RBV) are common in clinical trials. Our aim was to analyze the prevalence and management of potential DDIs and adverse events (AEs) related to DDIs in patients with chronic hepatitis C (CHC) receiving OBV/PTV/r ± DSV ± RBV in clinical practice. METHODS: 177 CHC patients started OBV/PTV/r ± DSV ± RBV in 4 Spanish hospitals and were screened for potential DDIs using the University of Liverpool database. Patients were classified according to the most serious potential DDIs at baseline and AEs during therapy. RESULTS: At least one potential DDI was found in 110 (62.1%) patients: 100 (56.5%) had at least one manageable potential DDI and 10 (5.6%) at least one contraindicated. Patients with potential DDIs were receiving a higher number of concomitant drugs (4 vs. 2, P < 0.001). Routine medication was modified at baseline due to potential DDIs in 49 (27.7%) patients. During antiviral treatment, 67 (37.9%) patients presented at least one AE. In 9 (4.5%) patients, a DDI was suspected between OBV/PTV/r ± DSV ± RBV and the concomitant drug, requiring antiviral discontinuation in 4 patients. CONCLUSIONS: Potential DDIs are frequent with OBV/PTV/r ± DSV ± RBV, although a change in baseline medication is made in only one-quarter of patients. More than half of potential DDIs were only followed, and only 5% of patients developed AEs in which the implication of DDIs could not be excluded.
Subject(s)
Anilides/adverse effects , Carbamates/adverse effects , Drug-Related Side Effects and Adverse Reactions/epidemiology , Hepatitis C, Chronic/drug therapy , Macrocyclic Compounds/adverse effects , Ribavirin/adverse effects , Ritonavir/adverse effects , Sulfonamides/adverse effects , Uracil/analogs & derivatives , 2-Naphthylamine , Adult , Aged , Aged, 80 and over , Anilides/administration & dosage , Carbamates/administration & dosage , Cyclopropanes , Drug Interactions , Drug Therapy, Combination , Female , Humans , Lactams, Macrocyclic , Macrocyclic Compounds/administration & dosage , Male , Middle Aged , Proline/analogs & derivatives , Ribavirin/administration & dosage , Ritonavir/administration & dosage , Sulfonamides/administration & dosage , Uracil/administration & dosage , Uracil/adverse effects , ValineABSTRACT
The aims of this study were to describe the evolution of acute hepatitis C virus (HCV) infections since 2004 and to determine its associated factors. Acute HCV infections diagnosed in Barcelona from 2004 to 2015 were included. Incidence ratios (IR) were then estimated for sex and age groups. Cases were grouped between 2004-2005, 2006-2011 and 2012-2015, and their incidence rate ratios (IRR) were calculated. In addition, risk factors for acute HCV infection were identified using multinomial logistic regression for complete, available and multiple imputed data. 204 new HCV cases were identified. Two peaks of higher IR of acute HCV infection in 2005 and 2013 were observed. Men and those aged 35-54 had higher IR. IRR for men was 2.9 times greater than in women (95% confidence intervals (CI): 1.8 â 4.7). Factors related to the period 2012-2015 (versus 2006-2011) were: a) sexual risk factor for transmission versus nosocomial (relative-risk ratio (RRR): 13.0; 95% CI: 2.3 â 72.1), b) higher educated versus lower (RRR: 5.4; 95% CI: 1.6 â 18.7), and c) HIV co-infected versus not HIV-infected (RRR: 53.1; 95% CI: 5.7 â 492.6). This is one of the few studies showing IR and RRRs of acute HCV infections and the first focused on a large city in Spain. Sexual risk for transmission between men, higher educational level and HIV co-infection are important factors for understanding current HCV epidemic. There has been a partial shift in the pattern of the risk factor for transmission from nosocomial to sexual.
Subject(s)
Hepatitis C/epidemiology , Adult , Europe/epidemiology , Female , Humans , Male , Middle Aged , Risk Factors , Spain/epidemiologyABSTRACT
BACKGROUND & AIMS: Patients with hepatitis C virus-associated cirrhosis and clinical significant portal hypertension (CSPH, hepatic venous pressure gradient [HVPG] 10 mmHg or greater), despite achieving sustained virological response (SVR) to therapy, remain at risk of liver decompensation. We investigated hemodynamic changes following SVR in patients with CSPH and whether liver stiffness measurements (LSMs) can rule out the presence of CSPH. METHODS: We performed a multicenter prospective study of 226 patients with hepatitis C virus-associated cirrhosis and CSPH who had SVR to interferon-free therapy at 6 Liver Units in Spain. The portal pressure gradient was determined based on HVPG at baseline and 24 weeks after therapy; patients also underwent right-heart catheterization and LSM at these time points. Primary outcomes were effects of SVR on the hepatic, pulmonary, and systemic hemodynamics; factors related to HVPG ≥10% reduction and to CSPH persistence; and whether LSMs can rule out the presence of CSPH after SVR. RESULTS: Most patients (75%) had esophageal varices, 21% were Child-B, and 29% had at least 1 previous episode of liver decompensation. Overall, HVPG decreased from 15 (IQR: 12-18) before treatment to 13 (10-16) mmHg after SVR (reduction of 2.1 ± 3.2 mmHg; P < .01). However, CSPH persisted in 78% of patients. HVPG decreased by 10% or more from baseline in 140 patients (62%). Baseline level of albumin below 3.5 g/dL was the only negative factor associated with an HVPG reduction of 10% or more. LSM decreased from 27 (20-37) kPa before treatment to 18 (14-28) kPa after SVR (P < .05). One third of patients with a reduction in LSM to below 13.6 kPa after SVR still had CSPH. A higher baseline HVPG and a lower decrease in LSM after treatment were associated with persistence of CSPH after SVR. Systemic hemodynamics improved after SVR. Interestingly, pulmonary hypertension was present in 13 patients at baseline and 25 after SVR, although only 3 patients had increased pulmonary resistance. CONCLUSIONS: In a multicenter prospective study of patients with hepatitis C virus-associated cirrhosis, an SVR to all-oral therapy significantly reduced HVPG, compared with before treatment. Nevertheless, CSPH persists in most patients despite SVR, indicating persistent risk of decompensation. In this population, changes in LSM do not correlate with HVPG and cut-off values are not reliable in ruling out CSPH after SVR.
Subject(s)
Antiviral Agents/administration & dosage , Hepatitis C/drug therapy , Hypertension, Portal/physiopathology , Liver Cirrhosis/physiopathology , Portal Pressure , Pulmonary Circulation , Administration, Oral , Aged , Cardiac Catheterization , Drug Therapy, Combination , Female , Hepatitis C/diagnosis , Humans , Hypertension, Portal/diagnosis , Hypertension, Portal/virology , Liver/pathology , Liver Cirrhosis/pathology , Liver Cirrhosis/virology , Male , Middle Aged , Prospective Studies , Spain , Sustained Virologic Response , Time Factors , Treatment OutcomeABSTRACT
OBJECTIVES: Interferon-free therapies have an improved safety and efficacy profile. However, data in elderly patients, who have frequently advanced liver disease, associated comorbidities, and use concomitant medications are scarce. The im of this study was to assess the effectiveness and tolerability of all-oral regimens in elderly patients in real-life clinical practice. METHODS: Retrospective analysis of hepatitis C virus (HCV) patients aged ≥65 years receiving interferon-free regimens within the Spanish National Registry (Hepa-C). RESULTS: Data of 1,252 patients were recorded. Of these, 955 (76%) were aged 65-74 years, 211 (17%) were aged 75-79 years, and 86 (7%) were aged ≥80 years at the start of antiviral therapy. HCV genotype-1b was predominant (88%) and 48% were previous non-responders. A significant proportion of patients had cirrhosis (922; 74%), of whom 11% presented decompensated liver disease. The most used regimens were SOF/LDV (33%), 3D (28%), and SOF/SMV (26%). Ribavirin was added in 49% of patients. Overall, the sustained virological response (SVR12) rate was 94% without differences among the three age categories. Albumin ≤3.5 g/dl was the only independent negative predictor of response (0.25 (0.15-0.41); P<0.01). Regarding tolerability, the rate of severe adverse events increased with age category (8.8, 13, and 14%; P=0.04). In addition, the main predictors of mortality (2.3%) were age ≥75 years (2.59 (1.16-5.83); P =0.02) and albumin ≤3.5 (17 (6.3-47); P <0.01). CONCLUSIONS: SVR rates with interferon-free regimens in elderly patients are high and comparable to the general population. Baseline low albumin levels (≤3.5 g/dl) was the only predictor of treatment failure. Importantly, the rate of severe adverse events and death increased with age. Elderly patients (≥75 years) or those with advanced liver disease (albumin ≤3.5) presented higher mortality. Thus a careful selection of patients for antiviral treatment is recommended.
Subject(s)
Antiviral Agents/therapeutic use , Hepatitis C, Chronic/drug therapy , Interferons/therapeutic use , Aged , Aged, 80 and over , Antiviral Agents/administration & dosage , Antiviral Agents/adverse effects , Female , Health Services for the Aged , Hepacivirus/genetics , Hepatitis C, Chronic/blood , Hepatitis C, Chronic/mortality , Hepatitis C, Chronic/virology , Humans , Interferons/administration & dosage , Interferons/adverse effects , Male , Retrospective Studies , Severity of Illness Index , Spain , Surveys and Questionnaires , Viral LoadABSTRACT
BACKGROUND AND AIMS: Hepatitis C (HCV) therapy with Sofosbuvir (SOF)/Simeprevir (SMV) in clinical trials and real-world clinical practice, showed high rates of sustained virological response (SVR) in non-cirrhotic genotype (GT)-1 and GT-4 patients. These results were slightly lower in cirrhotic patients. We investigated real-life effectiveness and safety of SOF/SMV with or without ribavirin (RBV) in a large cohort of cirrhotic patients. METHODS: This collaborative multicentre study included data from 968 patients with cirrhosis infected with HCV-GT1 or 4, treated with SOF/SMV±RBV in 30 centres across Spain between January-2014 and December-2015. Demographic, clinical, virological and safety data were analysed. RESULTS: Overall SVR was 92.3%; the majority of patients were treated with RBV (62%) for 12 weeks (92.4%). No significant differences in SVR were observed between genotypes (GT1a:94.3%; GT1b:91.7%; GT4:91.1%). Those patients with more advanced liver disease (Child B/C, MELD≥10) or portal hypertension (platelet count≤100×109 /L, transient elastography≥21 Kpa) showed significantly lower SVR rates (84.4%-91.9%) than patients with less advanced liver disease (93.8%-95.9%, P<.01 in all cases). In the multivariate analysis, the use of RBV, female gender, baseline albumin≥35 g/L, MELD<10 and lack of exposure to a triple therapy regimen were independent predictors of SVR (P<.05). Serious adverse events (SAEs) and SAE-associated discontinuation events occurred in 5.9% and 2.6%. CONCLUSIONS: In this large cohort of cirrhotic patients managed in the real-world setting in Spain, SOF/SMV±RBV yielded to excellent SVR rates, especially in patients with compensated liver cirrhosis. In addition, this combination showed to be safe, with low rates of SAEs and early discontinuations.