Publications by authors named "Faouzi Saliba"

129 Publications

Intensive care management of acute-on-chronic liver failure.

J Hepatol 2021 Jul;75 Suppl 1:S163-S177

Medical Intensive Care Unit, Department of General Internal Medicine, University Hospitals Leuven, Herestraat 49, B-3000, Leuven, Belgium.

The syndrome of acute-on-chronic liver failure combines deterioration of liver function in a patient with chronic liver disease, with the development of extrahepatic organ failure and high short-term mortality. Its successful management demands a rapid and coherent response to the development of dysfunction and failure of multiple organ systems in an intensive care unit setting. This response recognises the features that distinguish it from other critical illness and addresses the complex interplay between the precipitating insult, the many organ systems involved and the disordered physiology of underlying chronic liver disease. An evidence base is building to support the approaches currently adopted and outcomes for patients with this condition are improving, but mortality remains unacceptably high. Herein, we review practical considerations in critical care management, as well as discussing key knowledge gaps and areas of controversy that require further focussed research.
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http://dx.doi.org/10.1016/j.jhep.2020.10.024DOI Listing
July 2021

Intra-abdominal hypertension and abdominal compartment syndrome in the critically ill liver cirrhotic patient-prevalence and clinical outcomes. A multicentric retrospective cohort study in intensive care.

PLoS One 2021 13;16(5):e0251498. Epub 2021 May 13.

University of Tartu, Tartu University Hospital, Tartu, Estonia.

Background: Liver cirrhosis and ascites are risk factors for intra-abdominal hypertension (IAH) and abdominal compartment syndrome (ACS); however, data is scarce. We aimed to determine the prevalence of IAH/ACS in a population of critically ill cirrhotic patients with acute medical illness in intensive care and to assess for risk factors and clinical outcomes.

Methods: This was a multicentric retrospective cohort study including two general ICUs and pooled data from a multicentric study between January 2009 and October 2019.

Results: A total of 9,345 patients were screened, and 95 were included in the analysis. Mean age was 56.7±1.3 years, and 79% were male. Liver cirrhosis etiology included alcohol in 45.3% and alcohol plus hepatitis C virus in 9.5%. Precipitating events included infection in 26% and bleeding in 21% of cases. Mean severity score MELD and SAPS II were 26.2±9.9 and 48.5±15.3, respectively, at ICU admission. The prevalence of IAH and ACS was respectively 82.1% and 23.2% with a mean value of maximum IAP of 16.0±5.7 mmHg and IAH grades: absent 17.9%, I 26.3%, II 33.7%, III 17.9%, and IV 4.2%. Independent risk factors for IAH were alcoholic cirrhosis (p = 0.01), West-Haven score (p = 0.01), and PaO2/FiO2 ratio (p = 0.02); as well as infection (p = 0.048) for ACS. Overall, 28-day mortality was 52.6% associated with higher IAP and ACS, and independent risk factors were MELD (p = 0.001), white blood cell count (p = 0.03), PaO2/FiO2 ratio (p = 0.03), and lactate concentration (p = 0.04) at ICU admission.

Conclusions: This study demonstrates a very high prevalence of IAH/ACS in the critically ill cirrhotic patient in intensive care. Increased IAP and ACS were associated with severity of disease and adverse outcomes and independent risk factors for IAH were alcoholic cirrhosis, hepatic encephalopathy and PO2/FiO2 ratio, as well as infection for ACS. Early diagnosis, prevention, and treatment of IAH/ACS might improve outcome in critically ill cirrhotic patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0251498PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8118291PMC
May 2021

Liver transplantation for patients with acute-on-chronic liver failure (ACLF) in Europe: results of the ELITA/EF-CLIF collaborative study (ECLIS).

J Hepatol 2021 Apr 24. Epub 2021 Apr 24.

Department of hepatogastroenterology, Hepatology and Liver Transplantation Unit, HCL Hopital de la Croix-Rousse, Lyon, France.

Background And Aims: Liver transplantation (LT) has been proposed to be an effective salvage therapy even for the sickest patients with acute-on-chronic liver failure (ACLF). This large collaborative study was designed to address the current clinical practice and outcomes of ACLF patients wait listed (WL) for LT in Europe.

Methods: Retrospective study including 308 consecutive ACLF patients, listed in 20 centres across 8 European countries, from January 2018 to June 2019.

Results: 2677 patients received a LT, 1216 (45.4%) for decompensated cirrhosis (DC). Of these, 234 (19.2%) had ACLF at LT: ACLF-1, 58 (4.8%); ACLF-2, 78 (6.4%); and ACLF-3, 98 (8.1%). Wide variations were observed amongst countries: France and Germany had high rates of ACLF-2/3 (27-41%); Italy, Switzerland, Poland and Netherlands had medium rates (9-15%); and United Kingdom and Spain had low rates (3-5%) (p <.0001). One-year probability of survival after LT for patients with ACLF was 81% (95% CI 74-87). Pre-LT arterial lactate levels >4 mmol/L (HR 3.14, 95% CI 1.37-7.19), recent infection from multi-drug resistant organisms (HR 3.67, 95% CI 1.63-8.28), and renal replacement therapy (HR 2.74, 95% CI 1.37-5.51) were independent predictors of post-LT mortality. During the same period, 74 patients with ACLF died on the WL. In an intention-to-treat analysis, one-year survival of ACLF patients on the LT WL was 73% for ACLF-1 or -2 and 50% for ACLF-3.

Conclusion: The results reveal wide variations in listing patients with ACLF in Europe despite favorable post-LT survival. Risk factors for mortality were identified, allowing a more precise prognostic assessment of ACLF patients for potential LT.

Lay Summary: Acute on chronic liver failure (ACLF) is a severe clinical condition for which liver transplantation is an effective therapeutic option. This study has demonstrated that in Europe, referral and access to liver transplantation (LT) for patients with ACLF needs to be harmonized to avoid inequities. Post-LT survival for patients with ACLF was >80% after 1 year and some factors have been identified for selecting patients with favorable outcomes.
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http://dx.doi.org/10.1016/j.jhep.2021.03.030DOI Listing
April 2021

High trough levels of everolimus combined to sorafenib improve patients survival after hepatocellular carcinoma recurrence in liver transplant recipients.

Transpl Int 2021 May 1. Epub 2021 May 1.

AP-HP Hôpital Paul Brousse, Centre Hépato-Biliaire, Inserm UMR-S 1193, Université Paris- Saclay, Villejuif, France.

Recurrence of hepatocellular carcinoma (HCC) following liver transplantation (LT) occurs in 10%-20% of patients transplanted for HCC. The treatment of HCC recurrence after LT remains a challenge. Consecutive patients who underwent LT for HCC between 2005 and 2015 at our center were recruited. Characteristics of patients with recurrence, modalities of treatment and outcome were collected retrospectively. Patient survival was analyzed according to HCC recurrence therapeutic strategy. Among 306 transplanted patients, 43 patients (14.1%) developed recurrence with a median survival time after recurrence of 10.9 months (95%CI: 6.6-18.6). Survival of patients treated with Sorafenib (SOR) and everolimus (EVL) (n = 19) was significantly better than that of the group treated with other strategies (n = 24) (P = 0.001). Multivariable analysis demonstrated that SOR plus EVL therapy and absence of dissemination at diagnosis of recurrence were independent predictive factors of prolonged survival after recurrence. Among the patients who treated with EVL, survival of patients with controlled EVL blood trough levels ≥5 ng/ml was significantly better compared to those with EVL trough levels <5 ng/ml (P = 0.021). Combination therapy of sorafenib and everolimus was an independent predictor for better survival after HCC recurrence. Patients with controlled everolimus trough level ≥5 ng/ml might get the best survival benefit.
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http://dx.doi.org/10.1111/tri.13897DOI Listing
May 2021

Efficacy and Safety of Everolimus With Reduced Tacrolimus in Liver Transplant Recipients: 24-month Results From the Pooled Analysis of Two Randomized Controlled Trials.

Transplantation 2020 Jul 22. Epub 2020 Jul 22.

Asan Medical Center, Ulsan University College of Medicine, Seoul, Republic of Korea China Medical University Hospital, Taichung, Taiwan AP-HP Hôpital Paul Brousse, Villejuif; Université Paris-Saclay, INSERM Unit 935, and 1193, France Medanta, Medicity Hospital, Gurgaon, India Chang Gung Memorial Hospital, Tao-Yuan, Lin-Ko, Taiwan Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy University Hospital Gasthuisberg, KU Leuven, Leuven, Belgium Seoul National University College of Medicine, Seoul, Republic of Korea University Medical Center Eppendorf, Hamburg, Germany Yonsei University College of Medicine, Seoul, Republic of Korea Cleveland Clinic Foundation, Cleveland, OH, United States Samsung Medical Center, Seoul, Republic of Korea Kyoto University Hospital, Kyoto, Japan Toronto General Hospital, Toronto, Canada Novartis Pharma AG, Basel, Switzerland Novartis Pharma KK, Tokyo, Japan University of Toronto, Toronto, Canada.

Background Methods: Data from two randomized liver transplant trials (N=772; H2304 [deceased donor, n=488], H2307 [living donor, n=284]) were pooled to further evaluate the efficacy and safety of everolimus with reduced tacrolimus (EVR+rTAC) versus standard TAC (sTAC) regimen at Month 24.

Results: EVR+rTAC was comparable to sTAC for composite efficacy failure of treated biopsy-proven acute rejection (tBPAR), graft loss, or death (9.8% vs 10.8%, difference -1.0%, 95% confidence interval -5.4 to 3.4; P=0.641) at Month 24. EVR+rTAC was superior to sTAC for the mean change in estimated glomerular filtration rate (eGFR) from randomization to Month 24 (-8.37 vs -13.40 mL/min/1.73 m2; P=0.001). A sub-analysis of renal function by chronic kidney disease (CKD) stage at randomization showed significantly lower decline in eGFR from randomization to Month 24 for patients with CKD stage 1/2 (eGFR ≥60 mL/min/1.73 m2) in EVR+rTAC group versus sTAC (-12.82 vs -17.67 mL/min/1.73 m2, P=0.009). In patients transplanted for hepatocellular carcinoma (HCC) beyond Milan criteria, HCC recurrence was numerically lower although not statistically significant with EVR+rTAC versus sTAC group (5.9% [1/17] vs 23.1% [6/26], P=0.215), while comparable in patients within Milan criteria (2.9% [3/102] vs 2.1% [2/96], P=1.000), irrespective of pretransplant alpha-fetoprotein levels.

Discussions: EVR+rTAC versus sTAC showed comparable efficacy and safety with significantly better renal function, particularly in patients with normal/mildly decreased renal function (CKD stage 1/2) at randomization, and a trend towards lower HCC recurrence in patients transplanted with HCC beyond Milan at Month 24. Further long-term data would be required to confirm these results.
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http://dx.doi.org/10.1097/TP.0000000000003394DOI Listing
July 2020

Risk factors of de novo malignancies after liver transplantation: a French national study on 11004 adult patients.

Clin Res Hepatol Gastroenterol 2021 Mar 11;45(4):101514. Epub 2021 Mar 11.

Hôpital Jean Minjoz, Service d'Hépatologie et Soins Intensifs Digestifs, Besançon, France.

Background: After liver transplantation (LT),de novo malignancies are one of the leading causes of late mortality. The aim of the present retrospective study was to identify the risk factors of de novo malignancies in a large cohort of LT recipients in France, using Fine and Gray competing risks regression analysis.

Methods: The study population consisted in 11004 adults transplanted between 2000 and 2013, who had no history of pre-transplant malignancy, except primary liver tumor. A Cox model adapted to the identification of prognostic factors (competitive risks) was used.

Results: From the entire cohort, one (or more)de novo malignancy was reported in 1480 L T recipients (13.45%). The probability to develop a de novo malignancy after LT was 2.07% at 1 year, 13.30% at 5 years, and 28.01% at 10 years. Of the known reported malignancies, the most common malignancies were hematological malignancy (22.36%), non-melanoma skin cancer (19.53%) and lung cancer (12.36%). According to Fine and Gray competing risks regression multivariate analysis, were significant risk factors for post-LT de novo malignancy: recipient age (Subdistribution Hazard Ratio (SHR) = 1.03 95%CI 1.03-1.04), male gender (SHR = 1.45 95%CI 1.27-1.67), non-living donor (SHR = 1.67 95%CI 1.14-2.38), a first LT (SHR = 1.35 95%CI 1.09-1.69) and the type of initial liver disease (alcohol-related liver disease (SHR = 1.63 95%CI 1.22-2.17), primary sclerosing cholangitis (SHR = 1.98 95%CI 1.34-2.91), and primary liver tumor (SHR = 1.88 95%CI 1.41-2.54)). Initial immunosuppressive regimen had no significant impact.

Conclusion: The present study confirms that LT recipient characteristics are associated with the risk ofde novo malignancy and this underlines the need for personalized screening in order to improve survival.
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http://dx.doi.org/10.1016/j.clinre.2020.07.019DOI Listing
March 2021

Covid-19 in liver transplant recipients: the French SOT COVID registry.

Clin Res Hepatol Gastroenterol 2021 Jan 28;45(4):101639. Epub 2021 Jan 28.

AP-HP, Hôpital Paul Brousse, Centre Hépato-Biliaire, INSERM, Unité 1193, Villejuif, France.

Background: Notwithstanding the ongoing coronavirus disease-2019 (Covid-19) pandemic, information on its clinical presentation and prognosis in organ transplant recipients remains limited. The aim of this registry-based observational study was to report the characteristics and clinical outcomes of liver transplant (LT) recipients included in the French nationwide Registry of Solid Organ Transplant Recipients with Covid-19.

Methods: COVID-19 was diagnosed in patients who had a positive PCR assay for SARS-CoV-2 or in presence of typical lung lesions on imaging or specific SARS-CoV-2 antibodies. Clinical and laboratory characteristics, management of immunosuppression, treatment for Covid-19, and clinical outcomes (hospitalization, admission to intensive care unit, mechanical ventilation, or death) were recorded.

Results: Of the 104 patients, 67 were admitted to hospital and 37 were managed at home (including all 13 children). Hospitalized patients had a median age of 65.2 years (IQR: 58.1 - 73.2 years) and two thirds were men. Most common comorbidities included overweight (67.3%), hypertension (61.2%), diabetes (50.7%), cardiovascular disease (20.9%) and respiratory disease (16.4%). SARS-CoV-2 infection was identified after a median of 92.8 months (IQR: 40.1 - 194.7 months) from LT. During hospitalization, antimetabolites, mTOR inhibitor, and CNIs were withdrawn in 41.9%, 30.0% and 12.5% of patients, respectively. The composite endpoint of severe Covid-19 within 30 days after diagnosis was reached by 33.0% of the adult patients. The 30-day mortality rate was 20.0%, and 28.1% for hospitalized patients. Multivariate analysis identified that age was independently associated with mortality.

Conclusion: In our large nationwide study, Covid-19 in LT recipients was associated with a high mortality rate.
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http://dx.doi.org/10.1016/j.clinre.2021.101639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843027PMC
January 2021

Hyperkalemia influences the outcome of patients with cirrhosis with acute decompensation (AD) and acute-on-chronic liver failure (ACLF).

Dig Liver Dis 2021 Jun 11;53(6):738-745. Epub 2021 Jan 11.

Liver Unit, Hospital Clinic, Spain; Institut d'Investigacions Biomediques August Pi I Sunyer (IDIBAPS), y Centro de Investigaciones en Red Hepaticas y Digestivas (CIBERehd), Barcelona, Catalonia, Spain; Faculty of Medicine and health sciences, University of Barcelona. Electronic address:

Introduction: The presence of hyperkalemia in different clinical scenarios has been described as a risk factor for mortality. Information about this electrolyte disorder in patients with cirrhosis is limited and there are no data in patients with acute-on-chronic liver failure (ACLF).

Aim: The aim of this study was to investigate whether hyperkalemia is a risk factor for mortality in patients with cirrhosis and acute decompensation (AD) with and without ACLF.

Methods: We performed an analysis of the Chronic Liver Failure Consortium CANONIC database in 1,314 consecutive patients admitted to 29 European centers with AD both with and without associated ACLF (294 and 1020 respectively). Hyperkalemia was defined as serum potassium ≥ 5.0 mEq/L. All patients had at least one valid measure of serum potassium from admission and/or through the whole hospitalization.

Results: 1314 patients were admitted with AD and 294 of them had ACLF at admission. Prevalence of hyperkalemia was significantly higher in ACLF versus AD (22.4% and 8.6% respectively, p<0.001). Hyperkalemia was associated with an increased 90, 180 and 360-day mortality risk in ACLF compared to AD (HR 10 vs 2.3 at 90-day p<0.001, 8.9 vs 3.1 at 180-day, p<0.001 and 5.8 vs 3.8 at 360-day, p<0.001). In a multivariate analysis, the presence of hyperkalemia during admission was independently associated with 90-day mortality [HR 2.4 (1.7 - 3.4)]. Variability of potassium between two valid measures ≥ 0.9 mg/dl was always also associated with a higher mortality rate. Addition of hyperkalemia to MELD score (MELD-K model) improved the accuracy to predict 90-day mortality risk.

Conclusions: Hyperkalemia is an independent risk factor of mortality in patients with AD and ACLF. Addition of hyperkalemia to the MELD score improves diagnostic accuracy to predict 90-day mortality in patients with AD and ACLF.
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http://dx.doi.org/10.1016/j.dld.2020.12.009DOI Listing
June 2021

De novo hepatocellular carcinoma in a non-cirrhotic allograft 27 years after liver transplantation: A case report.

Am J Transplant 2021 05 23;21(5):1953-1958. Epub 2021 Jan 23.

Centre Hépato-Biliaire, AP-HP Hôpital Paul Brousse, Inserm UMR-S 1193, Université Paris-Saclay, Villejuif, France.

Hepatocellular carcinoma recurrence after liver transplantation is a well-known complication but the development of de novo hepatocellular carcinoma in non-cirrhotic allograft with no previous history of hepatic malignancy either in the donor or the recipient is extremely rare. A 33-year-old man underwent deceased donor liver transplantation due to HBV-HDV cirrhosis in 1991. The donor was healthy, with negative viral serology. Pretransplant assessment and explant liver pathology revealed no tumor. He developed an 8 cm mediastinal thymus cancer in 2014, a chronic myeloid leukemia in 2015 and a 16 mm renal cell carcinoma in 2017. After 27 years, in 2018, his routine follow-up sonography showed incidentally a 37 mm hepatic nodule in segment VII which revealed after percutaneous liver guided biopsy a hepatocellular carcinoma. As no extra hepatic metastasis was noted, segmentectomy was done. The pathological report confirmed a moderately differentiated hepatocellular carcinoma nodule of 50 mm diameter with absence of microvascular invasion and the non-tumoral liver showed histological features of NASH (SAF score: S1A2F3, NAS score: A3F3 and LAFSc:5) with absence of HBsAg and HBcAg. This case emphasizes the importance of long-term close surveillance by imaging of the graft even in the absence of viral recurrence and graft cirrhosis.
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http://dx.doi.org/10.1111/ajt.16476DOI Listing
May 2021

Validation of a Capillary Dry Blood Sample MITRA-Based Assay for the Quantitative Determination of Systemic Tacrolimus Concentrations in Transplant Recipients.

Ther Drug Monit 2021 06;43(3):358-363

Astellas Pharma Europe, Ltd, Addlestone.

Background: Tacrolimus is a narrow therapeutic index medication, which requires therapeutic drug monitoring to optimize dosing based on systemic exposure. MITRA microsampling offers a convenient, minimally invasive approach for the collection of capillary blood samples from a finger prick versus conventional venous blood sampling for quantitation of tacrolimus blood concentrations. However, the suitability of MITRA microsampling for the determination of tacrolimus concentrations requires assessment in clinical settings.

Methods: Paired venous (2 mL) and capillary (10 μL) blood samples were collected pre-tacrolimus dose and 1 and 3 hours postdose during routine outpatient visits from stable adult liver or kidney transplant patients receiving prolonged-release tacrolimus. Tacrolimus concentrations were determined by liquid chromatography-tandem mass spectrometry, and the concentrations obtained by the 2 sampling methods were compared by linear regression and Bland-Altman agreement analyses.

Results: Samples were available for 82 transplant recipients (kidney, n = 41; liver, n = 41). A high correlation was observed between tacrolimus concentrations in capillary and venous blood samples (Pearson correlation coefficient, 0.97; Lin concordance coefficient, 0.87; slope of the fitted line, >1.0). Tacrolimus concentrations in capillary samples were 22.5% higher on average than in the corresponding venous blood samples (95% limits of agreement, 0.5%-44.6%). Similar results were observed in both transplant subgroups.

Conclusions: MITRA finger prick sampling provides a convenient alternative to venipuncture for therapeutic drug monitoring in transplant recipients maintained on prolonged-release tacrolimus. When using the finger prick MITRA method, the positive bias in tacrolimus concentrations observed with this technique, when compared with venipuncture, needs to be taken into consideration.
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http://dx.doi.org/10.1097/FTD.0000000000000847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8115740PMC
June 2021

PREDICT identifies precipitating events associated with the clinical course of acutely decompensated cirrhosis.

J Hepatol 2021 May 20;74(5):1097-1108. Epub 2020 Nov 20.

Medical University of Innsbruck, Innsbruck, Austria.

Background & Aims: Acute decompensation (AD) of cirrhosis may present without acute-on-chronic liver failure (ACLF) (AD-No ACLF), or with ACLF (AD-ACLF), defined by organ failure(s). Herein, we aimed to analyze and characterize the precipitants leading to both of these AD phenotypes.

Methods: The multicenter, prospective, observational PREDICT study (NCT03056612) included 1,273 non-electively hospitalized patients with AD (No ACLF = 1,071; ACLF = 202). Medical history, clinical data and laboratory data were collected at enrolment and during 90-day follow-up, with particular attention given to the following characteristics of precipitants: induction of organ dysfunction or failure, systemic inflammation, chronology, intensity, and relationship to outcome.

Results: Among various clinical events, 4 distinct events were precipitants consistently related to AD: proven bacterial infections, severe alcoholic hepatitis, gastrointestinal bleeding with shock and toxic encephalopathy. Among patients with precipitants in the AD-No ACLF cohort and the AD-ACLF cohort (38% and 71%, respectively), almost all (96% and 97%, respectively) showed proven bacterial infection and severe alcoholic hepatitis, either alone or in combination with other events. Survival was similar in patients with proven bacterial infections or severe alcoholic hepatitis in both AD phenotypes. The number of precipitants was associated with significantly increased 90-day mortality and was paralleled by increasing levels of surrogates for systemic inflammation. Importantly, adequate first-line antibiotic treatment of proven bacterial infections was associated with a lower ACLF development rate and lower 90-day mortality.

Conclusions: This study identified precipitants that are significantly associated with a distinct clinical course and prognosis in patients with AD. Specific preventive and therapeutic strategies targeting these events may improve outcomes in patients with decompensated cirrhosis.

Lay Summary: Acute decompensation (AD) of cirrhosis is characterized by a rapid deterioration in patient health. Herein, we aimed to analyze the precipitating events that cause AD in patients with cirrhosis. Proven bacterial infections and severe alcoholic hepatitis, either alone or in combination, accounted for almost all (96-97%) cases of AD and acute-on-chronic liver failure. Whilst the type of precipitant was not associated with mortality, the number of precipitant(s) was. This study identified precipitants that are significantly associated with a distinct clinical course and prognosis of patients with AD. Specific preventive and therapeutic strategies targeting these events may improve patient outcomes.
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http://dx.doi.org/10.1016/j.jhep.2020.11.019DOI Listing
May 2021

Influence of everolimus-based treatment on circulating regulatory T cells after liver transplantation: Comparative study with tacrolimus-based therapy.

Clin Res Hepatol Gastroenterol 2020 Nov 13:101559. Epub 2020 Nov 13.

UMR_S 938, CDR Saint-Antoine, F-75012 Paris, France; Liver Transplantation Unit, AP-HP, Hôpital de la Pitié-Salpêtrière, 75012 Paris, France.

Liver transplantation remains the only treatment for terminal liver diseases. However, immunosuppressive drugs required for allograft acceptance are toxic and may be responsible for severe side effects. Modulating the immune system to induce tolerance is a promising approach to reduce immunosuppressive regimen. More particularly, promoting natural CD4 CD25 FoxP3 Tregs could be crucial in achieving tolerance. Contrary to calcineurin inhibitors, reports indicate that mTOR inhibitors may have a positive impact on Tregs. Here we present the first randomized prospective clinical study where Tregs levels from liver transplanted patients receiving either tacrolimus or everolimus were monitored for 6 months, starting from the day of transplantation. A total of 30 patients from four centers were monitored. Blood samples were obtained at day 0, day 14, one month, three months and six months post-transplantation. Flow-cytometry immunophenotyping of Tregs (CD4 CD25 CD127 FoxP3) and functional assays with Tregs were performed to assess their immunosuppressive capacity. Levels of Tregs were significantly reduced after one month of standard tacrolimus-based immunosuppressive regimen (p<0.05). Four months after conversion, levels of Tregs from patients treated with everolimus was significantly higher than patients under tacrolimus (p<0.02). Functional assays demonstrated that Tregs conserved their capacity to suppress the proliferation of activated PBMC.
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http://dx.doi.org/10.1016/j.clinre.2020.10.004DOI Listing
November 2020

Undetectable -Mutant Clones in Plasma: Possible Implication for Anti-EGFR Therapy and Prognosis in Patients With -Mutant Metastatic Colorectal Cancer.

JCO Precis Oncol 2020 16;4. Epub 2020 Sep 16.

Oncogenetics Department, Assistance Publique-Hôpitaux de Paris, Paul Brousse Hospital, Université Paris-Saclay, Villejuif, France.

Purpose: Combining cetuximab with chemotherapy provides clinical benefit to 60% of the patients with wild-type (-wt) metastatic colorectal cancer (mCRC). This pilot study investigated the efficacy of cetuximab-based chemotherapy in a sample of patients (40%) with mutation (-mt) in their primary tumor whose circulating tumor DNA (ctDNA) was -wt.

Materials And Methods: The occurrence of Kirsten rat sarcoma viral oncogene homolog (), neuroblastoma rat sarcoma viral oncogene homolog (NRAS), V-raf murine sarcoma viral oncogene homolog B1 (), and mutations was determined in ctDNA by using a new ultrasensitive analysis based on mass spectrometry detection. All consenting patients with confirmed -mt mCRC had disease progression on previous chemotherapy that contained no anti-epidermal growth factor receptor (EGFR). The patients with -wt ctDNA received cetuximab + fluorouracil, leucovorin, and irinotecan (FOLFIRI), whereas those with -mt ctDNA were treated with the oncologist's choice of therapy.

Results: Of 16 registered patients, 11 were male and five female. They were age 48 to 81 years, and they had unresectable metastatic adenocarcinoma from the colon (n = 11) or rectum (n = 5), with a median of two metastatic sites. They had received a median number of three previous chemotherapy protocols. Plasma genotyping identified -mt in seven patients (44%) and -wt in nine patients (56%). In the patients with wt ctDNA, objective tumor response rate was 50.0%, including one complete response and four partial responses after a median number of 6 courses of cetuximab + FOLFIRI (range, 1 to 16 courses). Two of the nine patients had stable disease, and two had progressive disease. No grade 3 to 4 toxicities were encountered. One-year survival rates were 60.0% for the patients with -wt ctDNA and 17.9% for those with -mt ctDNA. Median overall survival times were not reached and 4.7 months, respectively.

Conclusion: Patients with -mt mCRC whose plasma biopsies contained -wt could benefit from cetuximab-based therapy, a hypothesis to be tested in a prospective randomized trial.
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http://dx.doi.org/10.1200/PO.19.00400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529530PMC
September 2020

Early versus Late Hepatocellular Carcinoma Recurrence after Transplantation: Predictive Factors, Patterns and Long-term Outcome.

Transplantation 2020 Sep 1. Epub 2020 Sep 1.

Background: Hepatocellular carcinoma (HCC) is currently the first indication of liver transplantation (LT) in Europe and Asia-Pacific region and the third in USA. HCC recurrence is the main complication affecting short- and medium-term outcome after LT.

Methods: A total of 433 consecutive adult recipients transplanted for HCC between 2000 and 2017 (mean age: 57.8 ± 8.5 years; 83.8% were males) with a mean follow-up of 74.6 ± 58.6 months were included. Patients had to meet Milan criteria and since 2014, AFP score to be listed. Patients with HCC recurrence were classified into early (≤ 2years) and late recurrence (> 2years) and were retrospectively reviewed.

Results: Patients who developed recurrence (75 patients, 17%) had more tumors outside Milan and UCSF criteria, high AFP score and microvascular invasion at pathology. Early recurrence developed in 46 patients (61.3%); the overall 5 and 10-year survival rates of these patients from time of LT were 6.7% and 0%, which were significantly lower than those with late recurrence respectively 64.0% and 27.1% (p<0.001). The median survival times from the diagnosis of HCC recurrence were 15 and 17 months respectively in the two groups (p<0.001). Multivariable cox regression analysis identified alcoholic cirrhosis as etiology of the underlying liver disease (HR=3.074; p=0.007), bi-lobar tumor at time of LT (HR=2.001; p=0.037), and a tumor size (>50mm) in the explant (HR=1.277; p=0.045) as independent predictors of early recurrence.

Conclusion: Improving the prediction of early HCC recurrence could optimize patient selection for LT, potential adjuvant therapy with new targeted drugs and hence improve long-term survival.
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http://dx.doi.org/10.1097/TP.0000000000003434DOI Listing
September 2020

Time to Conversion to an Everolimus-Based Regimen: Renal Outcomes in Liver Transplant Recipients From the EVEROLIVER Registry.

Liver Transpl 2020 11 12;26(11):1465-1476. Epub 2020 Oct 12.

Unité de Transplantation Hépatique, Hôpital Edouard Herriot, Lyon, France.

Longterm use of a calcineurin inhibitor (CNI)-based regimen is one of the major reasons for chronic renal failure in liver transplantation recipients (LTRs). The Everolimus Liver registry (EVEROLIVER) evaluated renal function in LTRs who were converted to everolimus (EVR). This observational registry included all LTRs receiving EVR across 9 centers from France. Data are being collected in an electronic database over 10 years (12 visits/patient) to evaluate efficacy, renal function (estimated glomerular filtration rate [eGFR]), and safety of EVR use in clinical practice, and the current analysis is reporting up to 60 months of findings. Until September 2017, 1045 patients received EVR after a mean time of 3.6 ± 5.1 years. CNI withdrawal was feasible in 57.7% of patients as of month 60. Mean eGFR improved in patients with baseline eGFR <60 mL/minute/1.73 m and was maintained in those with baseline eGFR ≥60 mL/minute/1.73 m . Among patients with chronic kidney disease (CKD; baseline eGFR <60 mL/minute/1.73 m ), 55% converted to EVR within 3 months (early conversion) and 39.4% converted between 4 and 12 months after transplantation (mid-conversion) experienced improvement in eGFR (≥60 mL/minute/1.73 m ) at month 36. Only 20.9% and 17.4% among those converted beyond 12 months (late conversion) experienced improvement respectively at month 36 and 60. A logistic regression analysis in patients with CKD stage ≥3 demonstrated that late conversion, age, and female sex were associated with nonimprovement of eGFR (≥60 mL/minute/1.73 m ). Data from this real-life use of EVR indicate that renal function was maintained from the preconversion period until month 36 even in patients with advanced CKD. However, early rather than late conversion appears to be a safe approach to preserve longterm renal function in LTRs.
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http://dx.doi.org/10.1002/lt.25879DOI Listing
November 2020

Impact of negative air pressure in ICU rooms on the risk of pulmonary aspergillosis in COVID-19 patients.

Crit Care 2020 09 1;24(1):538. Epub 2020 Sep 1.

Liver Intensive Care Unit, Centre Hépato-Biliaire, AP-HP, Hôpital Paul-Brousse, Université Paris-Saclay, Inserm U1193, 12 Avenue Paul Vaillant Couturier, F-94804, Villejuif, France.

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http://dx.doi.org/10.1186/s13054-020-03221-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7458783PMC
September 2020

Outcome of patients treated with molecular adsorbent recirculating system albumin dialysis: A national multicenter study.

JGH Open 2020 Aug 17;4(4):757-763. Epub 2020 May 17.

Service d'Anesthesie reanimation, Hôpital Saint-Eloi Montpellier France.

Background And Aim: The molecular adsorbent recirculating system (MARS) is the most widely used device to treat liver failure. Nevertheless, data from widespread real-life use are lacking.

Methods: This was a retrospective multicenter study conducted in all French adult care centers that used MARS between 2004 and 2009. The primary objective was to evaluate patient survival according to the liver disease and listing status. Factors associated with mortality were the secondary objectives.

Results: A total of 383 patients underwent 393 MARS treatments. The main indications were acute liver failure (ALF, 32.6%), and severe cholestasis (total bilirubin >340 μmol/L) (37.2%), hepatic encephalopathy (23.7%), and/or acute kidney injury-hepatorenal syndrome (22.9%) most often among patients with chronic liver disease. At the time of treatment, 34.4% of the patients were listed. Overall, the hospital survival rate was 49% (95% CI: 44-54%) and ranged from 25% to 81% depending on the diagnosis of the liver disease. In listed patients those not listed, the 1-year survival rate was markedly better in the setting of nonbiliary cirrhosis (59% 15%), early graft nonfunction (80% 0%), and late graft dysfunction (72% 0%) (all  < 0.001). Among nonbiliary cirrhotic patients, hospital mortality was associated with the severity of liver disease (HE and severe cholestasis) and not being listed for transplant. In ALF, paracetamol etiology and ≥3 MARS sessions were associated with better transplant-free survival.

Conclusion: Our study suggests that MARS should be mainly used as a bridge to liver transplantation. Survival was correlated with being listed for most etiologies and with the intensity of treatment in ALF.
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http://dx.doi.org/10.1002/jgh3.12359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7411551PMC
August 2020

The PREDICT study uncovers three clinical courses of acutely decompensated cirrhosis that have distinct pathophysiology.

J Hepatol 2020 10 13;73(4):842-854. Epub 2020 Jul 13.

CHTMAD Vila Real, Vila Real, Portugal.

Background & Aims: Acute decompensation (AD) of cirrhosis is defined as the acute development of ascites, gastrointestinal hemorrhage, hepatic encephalopathy, infection or any combination thereof, requiring hospitalization. The presence of organ failure(s) in patients with AD defines acute-on-chronic liver failure (ACLF). The PREDICT study is a European, prospective, observational study, designed to characterize the clinical course of AD and to identify predictors of ACLF.

Methods: A total of 1,071 patients with AD were enrolled. We collected detailed pre-specified information on the 3-month period prior to enrollment, and clinical and laboratory data at enrollment. Patients were then closely followed up for 3 months. Outcomes (liver transplantation and death) at 1 year were also recorded.

Results: Three groups of patients were identified. Pre-ACLF patients (n = 218) developed ACLF and had 3-month and 1-year mortality rates of 53.7% and 67.4%, respectively. Unstable decompensated cirrhosis (UDC) patients (n = 233) required ≥1 readmission but did not develop ACLF and had mortality rates of 21.0% and 35.6%, respectively. Stable decompensated cirrhosis (SDC) patients (n = 620) were not readmitted, did not develop ACLF and had a 1-year mortality rate of only 9.5%. The 3 groups differed significantly regarding the grade and course of systemic inflammation (high-grade at enrollment with aggravation during follow-up in pre-ACLF; low-grade at enrollment with subsequent steady-course in UDC; and low-grade at enrollment with subsequent improvement in SDC) and the prevalence of surrogates of severe portal hypertension throughout the study (high in UDC vs. low in pre-ACLF and SDC).

Conclusions: Acute decompensation without ACLF is a heterogeneous condition with 3 different clinical courses and 2 major pathophysiological mechanisms: systemic inflammation and portal hypertension. Predicting the development of ACLF remains a major future challenge. CLINICALTRIALS.

Gov Number: NCT03056612.

Lay Summary: Herein, we describe, for the first time, 3 different clinical courses of acute decompensation (AD) of cirrhosis after hospital admission. The first clinical course includes patients who develop acute-on-chronic liver failure (ACLF) and have a high short-term risk of death - termed pre-ACLF. The second clinical course (unstable decompensated cirrhosis) includes patients requiring frequent hospitalizations unrelated to ACLF and is associated with a lower mortality risk than pre-ACLF. Finally, the third clinical course (stable decompensated cirrhosis), includes two-thirds of all patients admitted to hospital with AD - patients in this group rarely require hospital admission and have a much lower 1-year mortality risk.
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http://dx.doi.org/10.1016/j.jhep.2020.06.013DOI Listing
October 2020

When Is a Critically Ill Cirrhotic Patient Too Sick to Transplant? Development of Consensus Criteria by a Multidisciplinary Panel of 35 International Experts.

Transplantation 2021 Mar;105(3):561-568

Department of Hepatobiliopancreatic Surgery and Liver Transplantation, Beaujon hospital, AP-HP.Nord, Inserm UMR_S1149, Inserm et Université de Paris, Paris, France.

Background: Critically ill cirrhotic patients are increasingly transplanted, but there is no consensus about futile liver transplantation (LT). Therefore, the decision to delay or deny LT is often extensively debated. These debates arise from different opinions of futility among transplant team members. This study aims to achieve a multinational and multidisciplinary consensus on the definition of futility in LT and to develop well-articulated criteria for not proceeding with LT due to futility.

Methods: Thirty-five international experts from anesthesiology/intensive care, hepatology, and transplant surgery were surveyed using the Delphi method. More than 70% of similar answers to a question were necessary to define agreement.

Results: The panel recommended patient and graft survival at 1 year after LT to define futility. Severe frailty and persistent fever or <72 hours of appropriate antimicrobial therapy in case of ongoing sepsis were considered reasons to delay LT. A simple assessment of the number of organs failing was considered the most appropriate way to decide whether LT should be delayed or denied, with respiratory, circulatory and metabolic failures having the most influence in this decision. The thresholds of severity of organ failures contraindicating LT for which a consensus was achieved were a Pao2/FiO2 ratio<150 mm Hg, a norepinephrine dose >1 μg/kg per minute and a serum lactate level >9 mmol/L.

Conclusions: Our expert panel provides a consensus on the definition of futile LT and on specific criteria for postponing or denying LT. A framework that may facilitate the decision if a patient is too sick for transplant is presented.
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http://dx.doi.org/10.1097/TP.0000000000003364DOI Listing
March 2021

Improved prediction of mortality by combinations of inflammatory markers and standard clinical scores in patients with acute-on-chronic liver failure and acute decompensation.

J Gastroenterol Hepatol 2021 Jan 9;36(1):240-248. Epub 2020 Jul 9.

European Foundation for the Study of Chronic Liver Failure (EF-CLIF), Barcelona, Spain.

Background And Aim: Acute-on-chronic liver failure (ACLF) is a sinister prognosis, and there is a need for accurate biomarkers and scoring systems to better characterize ACLF patients and predict prognosis. Systemic inflammation and renal failure are hallmarks in ACLF disease development and progression. We hypothesized that the combination of specific inflammatory markers in combination with clinical scores are better predictors of survival than the originally developed CLIF-C acute decompensation (AD) and CLIF-C ACLF scores.

Methods: We reevaluated all previously measured inflammatory markers in 522 patients from the CANONIC study, 342 without and 180 with ACLF. We used the Harrell's C-index to determine the best marker alone or in combination with the original scores and calculated new scores for prediction of mortality in the original CANONIC cohort.

Results: The best markers to predict 90-day mortality in patients without ACLF were the plasma macrophage activation markers soluble (s)CD163 and mannose receptor (sMR). Urinary neutrophil gelatinase associated lipocalin (UNGAL) and sCD163 were predictors for 28-day mortality in patients with ACLF. The newly developed CLIF-C AD + sMR score in patients without ACLF improved 90-day mortality prediction compared with the original CLIF-C AD score (C-index 0.82 [0.78-0.86] vs 0.74 [0.70-0.78, P = 0.004]). Further, the new CLIF-C ACLF + sCD163 + UNGAL improved the original CLIF-C ACLF score for 28-day mortality (0.85 [0.79-0.91] vs 0.75 [0.70-0.80], P = 0.039).

Conclusions: The capability of these inflammatory markers to improve the original prognostic scores in cirrhosis patients without and with ACLF points to a key role of macrophage activation and inflammation in the development and progression of AD and ACLF.
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http://dx.doi.org/10.1111/jgh.15125DOI Listing
January 2021

An Accurate Data Preparation Approach for the Prediction of Mortality in ACLF Patients using the CANONIC Dataset.

Annu Int Conf IEEE Eng Med Biol Soc 2019 Jul;2019:1371-1377

The incidence of chronic liver disease has increased in Europe and can lead to Acute on Chronic Liver Failure (ACLF) which is associated with high levels of mortality due to multisystem organ failure. The characteristics of the ACLF patients can change very rapidly within a short period of time. Continuous assessment of their recovery status is critical for clinicians to adjust and deliver effective treatment. The aim of this paper is to validate the usefulness of a data preparation approach by combining different criteria to replace missing values, balance target-class variables, select useful patient characteristics and optimise hyperparameters of machine learning models for the prediction of ACLF associated mortality rates. A key step in the data preparation is a feature selection Mutual Information (MI) based multivariate approach to build smaller, and yet equally and in some cases more informative, subsets of patient characteristics than those frequently proposed for the prediction of mortality, from patients with ACLF in the CANONIC dataset. The usefulness of the data preparation approach proposed to predict mortality was evaluated by training the XGBoost and Logistic Regression models with the prepared data. Evaluations of the models trained using a test set provided evidence of an overall high accuracy in the prediction of the mortality rates of patients for days after their diagnosis, and in some cases even higher when reduced and more informative subsets of patient characteristics were found.
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http://dx.doi.org/10.1109/EMBC.2019.8857239DOI Listing
July 2019

Chronic alcohol consumption, a novel risk factor of liver transplantation or death in patients with acute liver failure.

Liver Int 2020 01;40(1):45-46

Centre Hépato-Biliaire, AP-HP, Hôpital Paul Brousse, Villejuif, France.

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http://dx.doi.org/10.1111/liv.14169DOI Listing
January 2020

Blood metabolomics uncovers inflammation-associated mitochondrial dysfunction as a potential mechanism underlying ACLF.

J Hepatol 2020 04 25;72(4):688-701. Epub 2019 Nov 25.

Service de Pharmacologie et Immuno-Analyse (SPI), Laboratoire d'Etude du Métabolisme des Médicaments, CEA, INRA, Université Paris Saclay, MetaboHUB, F-91191 Gif-sur-Yvette, France.

Background & Aims: Acute-on-chronic liver failure (ACLF), which develops in patients with cirrhosis, is characterized by intense systemic inflammation and organ failure(s). Because systemic inflammation is energetically expensive, its metabolic costs may result in organ dysfunction/failure. Therefore, we aimed to analyze the blood metabolome in patients with cirrhosis, with and without ACLF.

Methods: We performed untargeted metabolomics using liquid chromatography coupled to high-resolution mass spectrometry in serum from 650 patients with AD (acute decompensation of cirrhosis, without ACLF), 181 with ACLF, 43 with compensated cirrhosis, and 29 healthy individuals.

Results: Of the 137 annotated metabolites identified, 100 were increased in patients with ACLF of any grade, relative to those with AD, and 38 comprised a distinctive blood metabolite fingerprint for ACLF. Among patients with ACLF, the intensity of the fingerprint increased across ACLF grades, and was similar in patients with kidney failure and in those without, indicating that the fingerprint reflected not only decreased kidney excretion but also altered cell metabolism. The higher the ACLF-associated fingerprint intensity, the higher the plasma levels of inflammatory markers, tumor necrosis factor α, soluble CD206, and soluble CD163. ACLF was characterized by intense proteolysis and lipolysis; amino acid catabolism; extra-mitochondrial glucose metabolism through glycolysis, pentose phosphate, and D-glucuronate pathways; depressed mitochondrial ATP-producing fatty acid β-oxidation; and extra-mitochondrial amino acid metabolism giving rise to metabotoxins.

Conclusions: In ACLF, intense systemic inflammation is associated with blood metabolite accumulation and profound alterations in major metabolic pathways, in particular inhibition of mitochondrial energy production, which may contribute to the development of organ failures.

Lay Summary: Acute-on-chronic liver failure (ACLF), which develops in patients with cirrhosis, is characterized by intense systemic inflammation and organ failure(s). Because systemic inflammation is energetically expensive, its metabolic costs may result in organ dysfunction/failure. We identified a 38-metabolite blood fingerprint specific for ACLF that revealed mitochondrial dysfunction in peripheral organs. This may contribute to organ failures.
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http://dx.doi.org/10.1016/j.jhep.2019.11.009DOI Listing
April 2020

Early Switch From Tacrolimus to Everolimus After Liver Transplantation: Outcomes at 2 Years.

Liver Transpl 2019 12;25(12):1822-1832

Hôpital Pitié Salpêtrière, AP-HP, Paris, France.

The observational CERTITUDE study follows liver transplant patients who completed the SIMCER trial. SIMCER randomized patients at month 1 after transplant to everolimus (EVR) with stepwise tacrolimus (TAC) withdrawal or to standard TAC, both with basiliximab induction and mycophenolic acid ± steroids. After completing SIMCER at 6 months after transplant, 65 EVR-treated patients and 78 TAC-treated patients entered CERTITUDE. At month 24 after transplant, 34/65 (52.3%) EVR-treated patients remained calcineurin inhibitor (CNI) free. Mean estimated glomerular filtration rate (eGFR) was significantly higher with EVR versus TAC during months 3-12. At month 24, eGFR values were 83.6 versus 75.3 mL/minute/1.73 m , respectively (P = 0.90) and adjusted mean change in eGFR from randomization was -8.0 versus -13.5 mL/minute/1.73 m (P = 0.15). At month 24, 45.9%, 31.1%, and 23.0% of EVR-treated patients had chronic kidney disease stages 1, 2, and 3, respectively, versus 25.7%, 45.7%, and 28.6% of TAC-treated patients (P = 0.05). Treated biopsy-proven acute rejection affected 4 EVR-treated patients and 2 TAC patients during months 6-24. Adverse events led to study discontinuation in 15.4% and 7.7% of EVR-treated and TAC-treated patients, respectively. Grade 3 or 4 hematological events were rare in both groups. A CNI-free EVR-based maintenance regimen appears feasible in approximately half of liver transplant patients. It preserves renal function effectively with good efficacy without compromising safety or hematological tolerance.
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http://dx.doi.org/10.1002/lt.25664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7383505PMC
December 2019

Maribavir for Preemptive Treatment of Cytomegalovirus Reactivation.

N Engl J Med 2019 09;381(12):1136-1147

From the Hematology Department, University Hospitals Leuven, KU Leuven, Leuven (J.M.), and the Section of Hematology, Cliniques Universitaires Saint-Luc, Brussels (X.P.) - both in Belgium; the Hematology Department, Henri Mondor Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP) and University Paris-Est-Créteil, Créteil (C.C.), and AP-HP Hôpital Paul Brousse, Villejuif (F.S.) - all in France; the Medical University of Vienna, General Hospital, Vienna (P.J.); Shire, Wayne, PA (M.U., S.V.); Shire, Lexington, MA (J.W., A.W.); and the Department of Infectious Diseases, University Hospital Essen, University Duisburg-Essen, Essen, Germany (O.W.).

Background: Maribavir is a benzimidazole riboside with activity against cytomegalovirus (CMV). The safety and efficacy of maribavir for preemptive treatment of CMV infection in transplant recipients is not known.

Methods: In a phase 2, open-label, maribavir dose-blinded trial, recipients of hematopoietic-cell or solid-organ transplants (≥18 years of age, with CMV reactivation [1000 to 100,000 DNA copies per milliliter]) were randomly assigned to receive maribavir at a dose of 400, 800, or 1200 mg twice daily or the standard dose of valganciclovir for no more than 12 weeks. The primary efficacy end point was the percentage of patients with a response to treatment, defined as confirmed undetectable CMV DNA in plasma, within 3 weeks and 6 weeks after the start of treatment. The primary safety end point was the incidence of adverse events that occurred or worsened during treatment.

Results: Of the 161 patients who underwent randomization, 159 received treatment, and 156 had postbaseline data available - 117 in the maribavir group and 39 in the valganciclovir group. The percentage of patients with postbaseline data available who had a response to treatment within 3 weeks was 62% among those who received maribavir and 56% among those who received valganciclovir. Within 6 weeks, 79% and 67% of patients, respectively, had a response (risk ratio, 1.20; 95% confidence interval, 0.95 to 1.51). The percentages of patients with a response to treatment were similar among the maribavir dose groups. Two patients who had a response to treatment had a recurrence of CMV infection within 6 weeks after starting maribavir at a dose of 800 mg twice daily; T409M resistance mutations in CMV UL97 protein kinase developed in both patients. The incidence of serious adverse events that occurred or worsened during treatment was higher in the maribavir group than in the valganciclovir group (52 of 119 patients [44%] vs. 13 of 40 [32%]). A greater percentage of patients in the maribavir group discontinued the trial medication because of an adverse event (27 of 119 [23%] vs. 5 of 40 [12%]). A higher incidence of gastrointestinal adverse events was reported with maribavir, and a higher incidence of neutropenia was reported with valganciclovir.

Conclusions: Maribavir at a dose of at least 400 mg twice daily had efficacy similar to that of valganciclovir for clearing CMV viremia among recipients of hematopoietic-cell or solid-organ transplants. A higher incidence of gastrointestinal adverse events - notably dysgeusia - and a lower incidence of neutropenia were found in the maribavir group. (Funded by ViroPharma/Shire Development; EudraCT number, 2010-024247-32.).
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http://dx.doi.org/10.1056/NEJMoa1714656DOI Listing
September 2019

Sepsis Management with a Blood Purification Membrane: European Experience.

Blood Purif 2019 12;47 Suppl 3:1-9. Epub 2019 Apr 12.

Baxter, Baxter Deutschland GmbH, Unterschleissheim, Germany.

Background: Septic shock is a leading cause of acute kidney injury (AKI). Endotoxins and cytokine levels are associated with the occurrence and severity of AKI, and different blood purification devices are available to remove them from circulation. One such device, oXiris, is a hollow-fibre purification filter that clears both endotoxins and cytokines. Due to limited evidence, clinical use of this device is not currently advocated in guidelines. However, clinics do regularly use this device, and there is a critical need for guidance on the application of it in sepsis with and without AKI.

Method: A modified Delphi-based method was used to collate -European experts' views on the indication(s), initiation and discontinuation criteria and success measures for oXiris.

Results: A panel of 14 participants was selected based on known clinical expertise in the areas of critical care and sepsis management, as well as their experience of using the oXiris blood purification device. The participants used different criteria to initiate treatment with oXiris in sepsis patients with and without AKI. Septic shock with AKI was the priority patient population, with oXiris used to rapidly improve haemodynamic parameters. Achieving haemodynamic stability within 72 h was a key factor for determining treatment success.

Conclusion: In the absence of established guidelines, users of hollow-fibre purification devices such as oXiris may benefit from standardised approaches to selecting patients and initiating and terminating treatment, as well as measuring success. Further evidence in the form of randomised clinical trials is urgently required.
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http://dx.doi.org/10.1159/000499355DOI Listing
May 2019

Addressing Profiles of Systemic Inflammation Across the Different Clinical Phenotypes of Acutely Decompensated Cirrhosis.

Front Immunol 2019 19;10:476. Epub 2019 Mar 19.

Department of Hepatology and Gastroenterology, University Clinic Innsbruck, Innsbruck, Austria.

Patients with acutely decompensated cirrhosis (AD) may or may not develop acute-on-chronic liver failure (ACLF). ACLF is characterized by high-grade systemic inflammation, organ failures (OF) and high short-term mortality. Although patients with AD cirrhosis exhibit distinct clinical phenotypes at baseline, they have low short-term mortality, unless ACLF develops during follow-up. Because little is known about the association of profile of systemic inflammation with clinical phenotypes of patients with AD cirrhosis, we aimed to investigate a battery of markers of systemic inflammation in these patients. Upon hospital admission baseline plasma levels of 15 markers (cytokines, chemokines, and oxidized albumin) were measured in 40 healthy controls, 39 compensated cirrhosis, 342 AD cirrhosis, and 161 ACLF. According to EASL-CLIF criteria, AD cirrhosis was divided into three distinct clinical phenotypes (AD-1: Creatinine<1.5, no HE, no OF; AD-2: creatinine 1.5-2, and or HE grade I/II, no OF; AD-3: Creatinine<1.5, no HE, non-renal OF). Most markers were slightly abnormal in compensated cirrhosis, but markedly increased in AD. Patients with ACLF exhibited the largest number of abnormal markers, indicating "full-blown" systemic inflammation (all markers). AD-patients exhibited distinct systemic inflammation profiles across three different clinical phenotypes. In each phenotype, activation of systemic inflammation was only partial (30% of the markers). Mortality related to each clinical AD-phenotype was significantly lower than mortality associated with ACLF ( < 0.0001 by gray test). Among AD-patients baseline systemic inflammation (especially IL-8, IL-6, IL-1ra, HNA2 independently associated) was more intense in those who had poor 28-day outcomes (ACLF, death) than those who did not experience these outcomes. Although AD-patients exhibit distinct profiles of systemic inflammation depending on their clinical phenotypes, all these patients have only partial activation of systemic inflammation. However, those with the most extended baseline systemic inflammation had the highest the risk of ACLF development and death.
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http://dx.doi.org/10.3389/fimmu.2019.00476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6434999PMC
September 2020

Re: Association Between Renal Dysfunction and Major Adverse Cardiac Events After Liver Transplantation: Evidence From an International Randomized Trial of Everolimus-Based Immunosuppression.

Ann Transplant 2019 03 29;24:174. Epub 2019 Mar 29.

Transplantation Center, Cleveland Clinic, Cleveland, OH, USA.

Ann Transplant. 2018 Oct 26;23:751-757. doi: 10.12659/AOT.911030. PMID: 30361470, PMCID: PMC6248043 In the paper, the sentence on page 754, first column, lines 4, 5, and 6 has been incorrectly written:  At the month 24 study visit, mean (SD) eGFR was 74.7 (26.1), 67.8 (21.0), and 77.5 (26.2) mL/min/1.73 m2 in the EVR/rTAC, TAC Elimination, and TAC Control groups, respectively (p=0.007). The corrected sentence should read:  At the 24-month study visit, mean (SD) eGFR was 74.7 (26.1), 67.8 (21.0), and 77.5 (26.2) mL/min/1.73 m2 in the EVR/rTAC, TAC Control, and TAC Elimination groups, respectively (p=0.007).
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http://dx.doi.org/10.12659/AOT.916307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6453550PMC
March 2019

Liver transplantation in patients with liver failure related to exertional heatstroke.

J Hepatol 2019 03 4;70(3):431-439. Epub 2018 Dec 4.

AP-HP Hôpital Paul-Brousse, Centre Hépato-Biliaire, Liver Intensive Care Unit, Villejuif F-94800, France; INSERM, Unité 1193, Université Paris-Saclay, Villejuif F-94800, France; DHU Hepatinov, Villejuif F-94800, France.

Background & Aims: Severe acute liver injury is a grave complication of exertional heatstroke. Liver transplantation (LT) may be a therapeutic option, but the criteria for LT and the optimal timing of LT have not been clearly established. The aim of this study was to define the profile of patients who require transplantation in this context.

Methods: This was a multicentre, retrospective study of patients admitted with a diagnosis of exertional heatstroke-related severe acute liver injury with a prothrombin time (PT) of less than 50%. A total of 24 male patients were studied.

Results: Fifteen of the 24 patients (median nadir PT: 35% [29.5-40.5]) improved under medical therapy alone and survived. Nine of the 24 were listed for emergency LT. At the time of registration, the median PT was 10% (5-12) and all had numerous dysfunctional organs. Five patients (nadir PT: 12% [9-12]) were withdrawn from the list because of an elevation of PT values that mainly occurred between day 2 and day 3. Ultimately, 4 patients underwent transplantation as their PT persisted at <10%, 3 days (2.75-3.25) after the onset of exertional heatstroke, and they had more than 3 organ dysfunctions. Of these 4 patients, 3 were still alive 1 year later. Histological analysis of the 4 explanted livers demonstrated massive or sub-massive necrosis, and little potential for effective mitoses, characterised by a "mitonecrotic" appearance.

Conclusion: The first-line treatment for exertional heatstroke-related severe acute liver injury is medical therapy. LT is only a rare alternative and such a decision should not be taken too hastily. A persistence of PT <10%, without any signs of elevation after a median period of 3  days following the onset of heatstroke, was the trigger that prompted LT, was the trigger adopted in order to decide upon LT.

Lay Summary: Acute liver injury due to heatstroke can progress to acute liver failure with organ dysfunction despite medical treatment; in such situations, liver transplantation (LT) may offer a therapeutic option. The classic criteria for LT appear to be poorly adapted to heatstroke-related acute liver failure. We confirmed thatmedication is the first-line therapy acute liver injury caused by heatstroke, with LT only rarely necessary. A decision to perform LT should not be made hastily. Fluctuations in prothrombin time and the patient's clinical status should be considered even in the event of severe liver failure.
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http://dx.doi.org/10.1016/j.jhep.2018.11.024DOI Listing
March 2019