Diagnostic and prognostic significance of cell death markers in patients with cirrhosis and acute decompensation.

BACKGROUND: The transition from compensated to decompensated liver cirrhosis is a hallmark of disease progression, however, reliable predictors to assess the risk of decompensation in individual patients from routine diagnostics are lacking. Here, we characterize serum levels of cell death-associated markers and routine biochemistry from patients with chronic liver disease with and without decompensation. METHODS: A post-hoc analysis was based on prospectively collected clinical data from 160 patients with chronic liver disease, stably compensated or decompensated at baseline or during follow-up, over a median period of 721 days. Serum levels of damage-associated molecular patterns (DAMPs) and routine biochemistry are quantified at baseline (for all patients) and during follow-up (for patients with acute decompensation). The panel of DAMPs assessed in this study comprises high-mobility group-box protein 1 (HMGB1), cytochrome C (cyt C), soluble Fas-ligand (sFasL), interleukin 6 (IL-6), soluble cytokeratin-18 (CK18-M65) and its caspase-cleaved fragment CK18-M30. RESULTS: In this cohort study, 80 patients (50%) were diagnosed with alcoholic liver cirrhosis, 60 patients (37.5%) with hepatitis C virus- and 20 patients (13.5%) with hepatitis B virus-related liver cirrhosis. At baseline, 17 patients (10.6%) showed decompensated liver disease and another 28 patients (17.5%) developed acute decompensation during follow-up (within 24 months). One hundred fifteen patients showed stable liver disease (71.9%). We found DAMPs significantly elevated in patients with decompensated liver disease versus compensated liver disease. Patients with acute decompensation during follow-up showed higher baseline levels of IL-6, sFasL, CK18-M65 and-M30 (P<0.01) compared to patients with stably compensated liver disease. In multivariate analyses, we found an independent association of baseline serum levels of sFasL (P = 0.02; OR = 2.67) and gamma-glutamyl transferase (GGT) (P<0.001; OR = 2.1) with acute decompensation. Accuracy of the marker combination for predicting acute decompensation was high (AUC = 0.79). Elevated aminotransferase levels did not correlate with decompensated liver disease and acute decompensation. CONCLUSIONS: DAMPs are elevated in patients with decompensated liver disease and patients developing acute decompensation. The prognostic value of a marker combination with soluble Fas-ligand and GGT in patients with liver cirrhosis should be further evaluated.

Molecular Surveillance of Carbapenem-Resistant Gram-Negative Bacteria in Liver Transplant Candidates.

Background: Carbapenem-resistant Gram-negative bacteria (CRGN) cause life-threatening infections due to limited antimicrobial treatment options. The occurrence of CRGN is often linked to hospitalization and antimicrobial treatment but remains incompletely understood. CRGN are common in patients with severe illness (e.g., liver transplantation patients). Using whole-genome sequencing (WGS), we aimed to elucidate the evolution of CRGN in this vulnerable cohort and to reconstruct potential transmission routes. Methods: From 351 patients evaluated for liver transplantation, 18 CRGN isolates (from 17 patients) were analyzed. Using WGS and bioinformatic analysis, genotypes and phylogenetic relationships were explored. Potential epidemiological links were assessed by analysis of patient charts. Results: Carbapenem-resistant (CR) Klebsiella pneumoniae (n=9) and CR Pseudomonas aeruginosa (n=7) were the predominating pathogens. In silico analysis revealed that 14/18 CRGN did not harbor carbapenemase-coding genes, whereas in 4/18 CRGN, carbapenemases (VIM-1, VIM-2, OXA-232, and OXA-72) were detected. Among all isolates, there was no evidence of plasmid transfer-mediated carbapenem resistance. A close phylogenetic relatedness was found for three K. pneumoniae isolates. Although no epidemiological context was comprehensible for the CRGN isolates, evidence was found that the isolates resulted of a transmission of a carbapenem-susceptible ancestor before individual radiation into CRGN. Conclusion: The integrative epidemiological study reveals a high diversity of CRGN in liver cirrhosis patients. Mutation of carbapenem-susceptible ancestors appears to be the dominant way of CR acquisition rather than in-hospital transmission of CRGN or carbapenemase-encoding genetic elements. This study underlines the need to avoid transmission of carbapenem-susceptible ancestors in vulnerable patient cohorts.

Non-invasive assessment of fibrosis regression and portal hypertension in patients with advanced chronic hepatitis C virus (HCV)-associated liver disease and sustained virologic response (SVR): 3 years follow-up of a prospective longitudinal study.

Long-term effects on cirrhosis and portal hypertension of direct antiviral agent (DAA)-based eradication of hepatitis C virus (HCV) are still under debate. We analysed dynamics of liver and spleen elastography to assess potential regression of cirrhosis and portal hypertension 3 years post-treatment. Fifty-four patients with HCV-associated cirrhosis and DAA-induced SVR were included. Liver and spleen stiffness were measured at baseline (BL), end of treatment (EOT), 24 weeks after EOT (FU24) and 1, 2 and 3 (FU144) years post-treatment by transient liver elastography (L-TE) and point shear wave elastography (pSWE) using acoustic radiation force impulse (ARFI) of the liver (L-ARFI) and spleen (S-ARFI). Biochemical, virological and clinical data were also obtained. Liver stiffness assessed by L-TE decreased between BL [median (range), 32.5(9.1-75) kPa] and EOT [21.3(6.7-73.5) kPa; p < .0001] and EOT and FU144 [16(4.1-75) kPa; p = .006]. L-ARFI values improved between EOT [2.5(1.2-4.1) m/s] and FU144 [1.7(0.9-4.1) m/s; p = .001], while spleen stiffness remained unchanged. Overall, L-TE improved in 38 of 54 (70.4%) patients at EOT and 29 of 38 (76.3%) declined further until FU144, whereas L-ARFI values decreased in 30/54 (55.6%) patients at EOT and continued to decrease in 28/30 (93.3%) patients at FU144. Low bilirubin and high albumin levels at BL were associated with improved L-ARFI values (p = .048) at EOT or regression of cirrhosis (<12.5 kPa) by L-TE at FU144 (p = .005), respectively. Liver stiffness, but not spleen stiffness, continued to decline in a considerable proportion of patients with advanced liver disease after HCV eradication.

Colonization with multidrug-resistant organisms is associated with in increased mortality in liver transplant candidates.

OBJECTIVES: Rising prevalence of multidrug-resistant organisms (MDRO) is a major health problem in patients with liver cirrhosis. The impact of MDRO colonization in liver transplantation (LT) candidates and recipients on mortality has not been determined in detail. METHODS: Patients consecutively evaluated and listed for LT in a tertiary German liver transplant center from 2008 to 2018 underwent screening for MDRO colonization including methicillin-resistant Staphylococcus aureus (MRSA), multidrug-resistant gram-negative bacteria (MDRGN), and vancomycin-resistant enterococci (VRE). MDRO colonization and infection status were obtained at LT evaluation, planned and unplanned hospitalization, three months upon graft allocation, or at last follow-up on the waiting list. RESULTS: In total, 351 patients were listed for LT, of whom 164 (47%) underwent LT after a median of 249 (range 0-1662) days. Incidence of MDRO colonization increased during waiting time for LT, and MRDO colonization was associated with increased mortality on the waiting list (HR = 2.57, p<0.0001. One patients was colonized with a carbapenem-resistant strain at listing, 9 patients acquired carbapenem-resistant gram-negative bacteria (CRGN) on the waiting list, and 4 more after LT. In total, 10 of these 14 patients died. CONCLUSIONS: Colonization with MDRO is associated with increased mortality on the waiting list, but not in short-term follow-up after LT. Moreover, colonization with CRGN seems associated with high mortality in liver transplant candidates and recipients.

Current Challenges in the Post-Transplant Care of Liver Transplant Recipients in Germany.

Improving long-term patient and graft survival after liver transplantation (LT) remains a major challenge. Compared to the early phase after LT, long-term morbidity and mortality of the recipients not only depends on complications immediately related to the graft function, infections, or rejection, but also on medical factors such as de novo malignancies, metabolic disorders (e.g., new-onset diabetes, osteoporosis), psychiatric conditions (e.g., anxiety, depression), renal failure, and cardiovascular diseases. While a comprehensive post-transplant care at the LT center and the connected regional networks may improve outcome, there is currently no generally accepted standard to the post-transplant management of LT recipients in Germany. We therefore described the structure and standards of post-LT care by conducting a survey at 12 German LT centers including transplant hepatologists and surgeons. Aftercare structures and form of cost reimbursement considerably varied between LT centers across Germany. Further discussions and studies are required to define optimal structure and content of post-LT care systems, aiming at improving the long-term outcomes of LT recipients.

Prevention and Management of CMV Infections after Liver Transplantation: Current Practice in German Transplant Centers.

Human cytomegalovirus (CMV) remains a major cause of mortality and morbidity in human liver transplant recipients. Anti-CMV therapeutics can be used to prevent or treat CMV in liver transplant recipients, but their toxicity needs to be balanced against the benefits. The choice of prevention strategy (prophylaxis or preemptive treatment) depends on the donor/recipient sero-status but may vary between institutions. We conducted a series of consultations and roundtable discussions with German liver transplant center representatives. Based on 20 out of 22 centers, we herein summarize the current approaches to CMV prevention and treatment in the context of liver transplantation in Germany. In 90% of centers, transient prophylaxis with ganciclovir or valganciclovir was standard of care in high-risk (donor CMV positive, recipient CMV naive) settings, while preemptive therapy (based on CMV viremia detected during (bi) weekly PCR testing for circulating CMV-DNA) was preferred in moderate- and low-risk settings. Duration of prophylaxis or intense surveillance was 3-6 months. In the case of CMV infection, immunosuppression was adapted. In most centers, antiviral treatment was initiated based on PCR results (median threshold value of 1000 copies/mL) with or without symptoms. Therefore, German transplant centers report similar approaches to the prevention and management of CMV infection in liver transplantation.

AFP ratio predicts HCC recurrence after liver transplantation.

BACKGROUND/AIMS: Hepatocellular carcinoma (HCC) is a leading indication for liver transplantation (LT) worldwide. Early identification of patients at risk for HCC recurrence is of paramount importance since early treatment of recurrent HCC after LT may be associated with increased survival. We evaluated incidence of and predictors for HCC recurrence, with a focus on the course of AFP levels. METHODS: We performed a retrospective, single-center study of 99 HCC patients who underwent LT between January 28th, 1997 and May 11th, 2016. A multi-stage proportional hazards model with three stages was used to evaluate potential predictive markers, both by univariate and multivariable analysis, for influences on 1) recurrence after transplantation, 2) mortality without HCC recurrence, and 3) mortality after recurrence. RESULTS: 19/99 HCC patients showed recurrence after LT. Waiting time was not associated with overall HCC recurrence (HR = 1, p = 0.979). Similarly, waiting time did not affect mortality in LT recipients both with (HR = 0.97, p = 0.282) or without (HR = 0.99, p = 0.685) HCC recurrence. Log10-transformed AFP values at the time of LT (HR 1.75, p = 0.023) as well as after LT (HR 2.07, p = 0.037) were significantly associated with recurrence. Median survival in patients with a ratio (AFP at recurrence divided by AFP 3 months before recurrence) of 0.5 was greater than 70 months, as compared to a median of only 8 months in patients with a ratio of 5. CONCLUSION: A rise in AFP levels rather than an absolute threshold could help to identify patients at short-term risk for HCC recurrence post LT, which may allow intensification of the surveillance strategy on an individualized basis.

The Epidemiology of Acute Liver Failure.

BACKGROUND: Acute liver failure (ALF) is a life-threatening event associated with high mortality. Currently, only estimates are available for its incidence. The aim of the study was to assess the incidence of ALF in Germany, using the accounting data of the largest statutory health insurance company, which represents 26.5 million people. METHODS: The analysis included patients insured from 1 January 2014 to 31 December 2018. Coding with the International Statistical Classification of Diseases and Related Health Problems and the German operation and procedure codes were used to identify the patients, whose age, sex, liver transplantations (LT), and fatal outcomes were then recorded and extrapolated to the total population. As a validity check, the extrapolated LT results were compared with the LT that were actually performed. RESULTS: The calculated incidence of ALF was 1.13/100 000 person-years, representing 4652 cases. Women were more often affected (52% versus 48%, p < 0.001). The overall rate of mortality within 3 months was 47%. A total of 203 LT were recorded in 176 patients. Men received 41% of the LT, women 59% (p < 0.137). The 1-year overall mortality rate after LT was 20%. The 203 calculated transplantations corresponded to 228 actually performed transplantations. CONCLUSION: The incidence of ALF was higher than previously estimated for Germany, with only a very low rate of LT despite high mortality. When extrapolating ny, it must be borne in mind that those insured by the company concerned do not represent a valid sample.

Quinolone and Multidrug Resistance Predicts Failure of Antibiotic Prophylaxis of Spontaneous Bacterial Peritonitis.

BACKGROUND: The efficacy of antibiotic prophylaxis to prevent spontaneous bacterial peritonitis (SBP) in patients colonized with multidrug-resistant organisms (MDROs) is unknown. We evaluated the effectiveness of fluoroquinolone-based SBP prophylaxis in an era and area of frequent antibiotic resistance. METHODS: This is a prospective observational study in patients with liver cirrhosis and an indication for fluoroquinolone-based prophylaxis of SBP. Patients were recruited and followed in a large German tertiary reference center with comprehensive microbiological and clinical monitoring performed at baseline and after 30, 60, 90, and 180 days of prophylaxis. RESULTS: Overall, 77 patients received antibiotic prophylaxis for an average of 93 days. Baseline prevalence of colonization with MDROs was high (N = 39, 50.6%). At least one de novo MDRO was detected in 27 patients (35.1%) during antibiotic prophylaxis; 33 patients (42.9%) developed secondary infections, including 14 cases (17.9%) of infections with MDROs, and 13 cases (16.9%) of de novo/recurrent SBP. Thirty patients (39.0%) died during follow-up. Significantly higher risks of SBP development during antibiotic prophylaxis were observed for patients with versus without any apparent MDROs (P = .009), vancomycin-resistant enterococci (P = .008), multidrug-resistant gram-negative bacteria (P = .016), or quinolone-resistant gram-negative bacteria (QR-GNB) (P = .015). In competing risk analysis, QR-GNB were independently associated with prophylaxis failure (hazard ratio, 3.39; P = .045) and infections with QR-GNB were independently associated with death before SBP (subdistribution hazard risk, 6.47; P = .034). CONCLUSIONS: Antibiotic prophylaxis of SBP appears to be less efficient in patients with known MDROs. Regular MDRO screening seems to be useful to tailor treatment of secondary infections and re-evaluate antibiotic prophylaxis in case of selection of quinolone resistance.

Key role of renal biopsy in management of progressive chronic kidney disease in liver graft recipients.

AIMS: Chronic kidney disease (CKD) is a common complication after liver transplantation (LT). The etiology of CKD is broad and may only be assessed accurately by renal histology. The current study aimed to analyze the safety of renal biopsy in daily clinical practice as well as its usefulness regarding management of CKD after LT. METHODS: We performed a retrospective analysis of clinical data and renal biopsies obtained from patients with severe renal impairment (overt proteinuria, progressive deterioration of renal function) after LT with respect to safety, etiology of renal disease, and therapeutic consequences. RESULTS: Renal biopsies were obtained from 14 patients at median (minimum-maximum) 3 (0.2-12) years after LT. No major complications associated with renal biopsy were observed. Histomorphological alterations were varied (nephrosclerosis, n = 5; IgA-glomerulonephritis, n = 4; tenofovir-associated nephropathy, membranoproliferative glomerulonephritis type 1, membranous glomerulonephritis, amyloid A amyloidosis, and calcineurin inhibitor nephropathy, n = 1, respectively). The diagnosis of specific renal diseases other than calcineurin-inhibitor nephrotoxicity facilitated specific treaments and avoided unnecessary modification of immunosuppression in the majority of patients. CONCLUSIONS: Renal biopsy in patients with CKD after LT seems safe and may offer specific therapeutic options. Furthermore, unnecessary changes of immunosuppression can be avoided in a considerable number of patients.

Liver Transplantation in Acute-on-Chronic Liver Failure: Considerations for a Systematic Approach to Decision Making.

BACKGROUND: Acute-on-chronic liver failure (ACLF) is a complex disease with deteriorating liver and kidney function and associated organ failure in patients with chronic liver disease. METHODS: This is a concise overview for bedside and algorithmic decision making in patients with ACLF based on the most recent literature. RESULTS: Diagnosis and dynamics of ACLF can be easily monitored with the CLIF-C-ACLF calculator, which delivers grading for ACLF and estimates the risk of mortality, as the natural transplant-free course of ACLF is often fatal. Transplantation offers the best results in patients with ACLF that do not recover spontaneously. However, marginal donor organs should be avoided. CONCLUSION: ACLF is an increasingly relevant indication with good outcome after liver transplantation. Adequate donor rates may reduce the incidence by means of timely transplantation of acute decompensated patients in lower stages of urgency. Future challenges comprise specific allocation of donor organs to this group of patients that are at a similar risk of mortality when compared to acute liver failure.

Successful direct acting antiviral (DAA) treatment of HCV/HIV-coinfected patients before and after liver transplantation.

OBJECTIVES: The aim of this multicenter retrospective study was to investigate safety and efficacy of direct acting antiviral (DAA) treatment in the rare subgroup of patients with HCV/HIV-coinfection and advanced liver cirrhosis on the liver transplant waiting list or after liver transplantation, respectively. METHODS: When contacting 54 German liver centers (including all 23 German liver transplant centers), 12 HCV/HIV-coinfected patients on antiretroviral combination therapy were reported having received additional DAA therapy while being on the waiting list for liver transplantation (patient characteristics: Child-Pugh A (n = 6), B (n = 5), C (n = 1); MELD range 7-21; HCC (n = 2); HCV genotype 1a (n = 8), 1b (n = 2), 4 (n = 2)). Furthermore, 2 HCV/HIV-coinfected patients were denoted having received DAA therapy after liver transplantation (characteristics: HCV genotype 1a (n = 1), 4 (n = 1)). RESULTS: Applied DAA regimens were SOF/DAC (n = 7), SOF/LDV/RBV (n = 3), SOF/RBV (n = 3), PTV/r/OBV/DSV (n = 1), or PTV/r/OBV/DSV/RBV (n = 1), respectively. All patients achieved SVR 12, in the end. In one patient, HCV relapse occurred after 24 weeks of SOF/DAC therapy; subsequent treatment with 12 weeks PTV/r/OBV/DSV achieved SVR 12. One patient underwent liver transplantation while on DAA treatment. Analysis of liver function revealed either stable parameters or even significant improvement during DAA therapy and in follow-up. MELD scores were found to improve in 9/13 therapies in patients on the waiting list for liver transplantation; in only 2 patients a moderate increase of MELD scores persisted at the end of follow-up. CONCLUSION: DAA treatment was safe and highly effective in this nation-wide cohort of patients with HCV/HIV-coinfection awaiting liver transplantation or being transplanted.

Low Serum Levels of (Dihydro-)Ceramides Reflect Liver Graft Dysfunction in a Real-World Cohort of Patients Post Liver Transplantation.

Patients after orthopic liver transplantation (OLT) are at risk of developing graft dysfunction. Sphingolipids (SL's) have been identified to play a pivotal role in the regulation of hepatocellular apoptosis, inflammation and immunity. We aimed to investigate the serum SL profile in a prospective real-world cohort of post-OLT patients. From October 2015 until July 2016, 149 well-characterized post-OLT patients were analyzed. SL's were assessed in serum probes via Liquid Chromatography/Tandem Mass Spectrometry. Twenty-nine (20%) patients had a biopsy proven graft rejection with decreased C20-ceramide (Cer) (p = 0.042), C18-dihydroceramide (DHC) (p = 0.022) and C24DHC (p = 0.060) levels. Furthermore, C18DHC (p = 0.044) and C24DHC (p = 0.011) were significantly down-regulated in patients with ischemic type biliary lesions (ITBL; n = 15; 10%). One-hundred and thirty-three patients (89%) have so far received tacrolimus as the main immunosuppressive agent with observed elevations of C14Cer (p = 0.052), C18Cer (p = 0.049) and C18:1Cer (p = 0.024). Hepatocellular carcinoma (HCC) pre-OLT was associated with increases in C24:1Cer (p = 0.024) and C24:1DHC (p = 0.024). In this large prospective cross-sectional study of patients, post-OLT serum levels of (very-)long chain (dihydro-)ceramides associate with graft rejection, ITBL, tacrolimus intake and HCC pre-OLT. Hence, serum SL's may be indicative of graft complications. Further research is necessary to identify their diverse mechanistic role in regulating immunity and inflammation in patients post-OLT.

Liver transplantation for chronic hepatitis C virus infection in the United States 2002-2014: An analysis of the UNOS/OPTN registry.

Chronic hepatitis C virus (HCV) infection is a leading cause for orthotopic liver transplantation (OLT) in the U.S. We investigated characteristics of HCV-infected patients registered for OLT, and explored factors associated with mortality. Data were obtained from the United Network for Organ Sharing and Organ Procurement and Transplantation network (UNOS/OPTN) registry. Analyses included 41,157 HCV-mono-infected patients ≥18 years of age listed for cadaveric OLT between February 2002 and June 2014. Characteristics associated with pre- and post-transplant survival and time trends over the study period were determined by logistic and Cox proportional hazard regression analyses and Poisson regressions. Most patients were white (69.1%) and male (70.8%). At waitlist registration, mean age was 54.6 years and mean MELD was 16. HCC was recorded in 26.9% of the records. A total of 51.2% of the patients received an OLT, 21.0% died or were too sick; 15.6% were delisted and 10.4% were still waiting. Factors associated with increased waitlist mortality were older age, female gender, blood type 0, diabetes, no HCC and transplant region (p<0.001). OLT recipient characteristics associated with increased risk for post OLT mortality were female gender, age, diabetes, race (p<0,0001), and allocation MELD (p = 0.005). Donor characteristics associated with waitlist mortality included age, ethnicity (p<0.0001) and diabetes (p<0.03). Waitlist registrations and OLTs for HCC significantly increased from 14.4% to 37.3% and 27.8% to 38.5%, respectively (p<0.0001). Pre- and post-transplant survival depended on a variety of patient-, donor-, and allocation- characteristics of which most remain relevant in the DAA-era. Still, intensified HCV screening strategies and timely and effective treatment of HCV are highly relevant to reduce the burden of HCV-related OLTs in the U.S.

Conversion From Sirolimus to Everolimus in Long-Term Liver Graft Recipients.

Immunosuppression by inhibition of the mechanistic target of rapamycin (mTOR) is a promising approach after liver transplantation. The mTOR inhibitor sirolimus was used in selected liver graft recipients despite safety concerns and lack of approval. Everolimus is another mTOR inhibitor approved after liver transplantation. It is currently unknown, whether conversion of sirolimus to everolimus is safe in long-term liver graft recipients. Long-term liver graft recipients treated with sirolimus were converted to everolimus. A systematical analysis of biochemical and clinical data before and after conversion was performed. Sixteen patients were included (female/male, 8/8). Median (range) age at conversion was 66 years (49-78 years), and patients were converted at a median (range) of 10.1 years (4.0-22.3 years) after liver transplantation. In the majority of patients, no dose adjustment was needed after conversion. No rejection and no cytomegalovirus replication episodes were observed. Furthermore, no differences were found with respect to kidney function, diabetes mellitus, or blood pressure before and after conversion. Bilirubin serum concentration was lower, whereas aspartate aminotransaminase, alanine aminotransferase, and triglycerides serum concentrations were higher after conversion to everolimus. Neither clinical- nor graft-associated significant complications were observed after conversion from sirolimus to everolimus in long-term liver graft recipients. Everolimus-based immunosuppression may be offered to patients after liver transplantation formerly treated with sirolimus.

Concise review: Interferon-free treatment of hepatitis C virus-associated cirrhosis and liver graft infection.

Chronic hepatitis C is a major reason for development of cirrhosis and hepatocellular carcinoma and a leading cause for liver transplantation. The development of direct-acting antiviral agents lead to (pegylated) interferon-alfa free antiviral therapy regimens with a remarkable increase in sustained virologic response (SVR) rates and opened therapeutic options for patients with advanced cirrhosis and liver graft recipients. This concise review gives an overview about most current prospective trials and cohort analyses for treatment of patients with liver cirrhosis and liver graft recipients. In patients with compensated cirrhosis Child-Pugh-Turcotte (CTP) class A, all approved agents are safe and SVR rates do not significantly differ from patients without cirrhosis in general. In patients with decompensated cirrhosis CTP class B or C, daclastasvir, ledipasvir, velpatasvir, and sofosbuvir are approved, and SVR rates higher than 90% can be achieved. Especially for patients with a model of end stage liver disease score higher than 15 and therefore eligible for liver transplantation, data is scarce. Reported SVR rates in patients with cirrhosis CTP class C are lower compared to patients with a less severe liver disease. In liver transplant recipients with a maximum of CTP class A, SVR rates are comparable to patients without LT. Patients with decompensated graft cirrhosis should be treated on an individual basis.

Pre- and Post-Transplant Antiviral Therapy (HBV, HCV).

BACKGROUND: Hepatitis B virus (HBV)- and hepatitis C virus (HCV)-associated liver cirrhosis is a major indication for liver transplantation. This concise review gives an overview about current interferon (IFN)-free treatment options before and after liver transplantation in HBV- or HCV-associated liver disease. METHODS: A PubMed database search using the terms hepatitis B, hepatitis C, cirrhosis, and liver transplantation was performed to identify significant clinical studies as well as national and international guidelines. RESULTS: Studies investigating IFN-free treatment in patients with decompensated HBV as well as in HCV-associated cirrhosis are scarce. Hepatic recompensation during antiviral therapy seems more frequent in patients with HBV than in those with HCV-associated cirrhosis. Graft hepatitis B or C is characterized by an accelerated and unfavorable course. Graft infection prophylaxis is safe and efficacious in HBV-related liver transplantation. Eradication of HCV prior to liver transplantation prevents HCV graft infection, and IFN-free treatment of established HCV graft infection is safe and associated with high sustained virologic response rates. CONCLUSION: Patients with HBV-associated cirrhosis should be treated prior to liver transplantation, and receive a continuing graft infection prophylaxis thereafter. Patients with HCV-associated decompensated cirrhosis may be considered as candidates for antiviral therapy prior to liver transplantation or may be treated subsequently.

Clinical value of on-treatment HCV RNA levels during different sofosbuvir-based antiviral regimens.

BACKGROUND & AIMS: The European Association for the Study of the Liver (EASL) guidelines recommend HCV RNA measurements at specific time points during sofosbuvir(SOF)-therapy. However, it remains unclear, how these results should be interpreted. We aimed to analyze whether on-treatment HCV RNA levels predict relapse comparing the CobasAmpliPrep/CobasTaqMan v2.0 (CAP/CTM) and Abbott RealTime HCV (ART) assays. METHODS: Samples were collected from 298 patients (HCV genotypes; GT1-5) at weeks (w) 0, 1, 2, 4, 8, 12, 16, 20 and 24 during SOF-based therapy at two university clinics and tested for HCV RNA level by CAP/CTM and ART. Patients were treated with SOF/ribavirin (RBV) 12/24 w (n=99), pegylated-interferon-alfa (PegIFN)/SOF/RBV 12 w (n=51), SOF/simeprevir (SMV)±RBV 12 w (n=69) or SOF/daclatasvir±RBV 12/24 w (n=79). RESULTS: HCV RNA levels during the first 4weeks of SOF/RBV therapy were significantly lower in GT3 patients who achieved SVR compared with those who relapsed. All GT3 patients with a week 2 result <45IU/ml by CAP/CTM achieved SVR but only 33% of those with ⩾45IU/ml (p=0.0003). Similar results were documented with ART and 60IU/ml as cut-off (SVR: 100% vs. 29%; p=0.0002). In contrast, HCV RNA levels during early treatment phases were not significantly related to relapse in patients treated with other SOF-based regimens. Residual HCV RNA was frequently detected by ART at later stages of therapy. However, SVR rates remained high in these patients. At the end of SOF/SMV±RBV therapy HCV RNA was detectable with ART in 20% of patients, of whom 92% achieved SVR. CONCLUSIONS: HCV RNA levels assessed at week 2 of SOF/RBV therapy can predict relapse in GT3-patients. Detectable HCV RNA results at later stages during SOF-based therapy may occur frequently with the more sensitive ART. However, this should not lead to treatment extension. LAY SUMMARY: We analyzed the predictive value of hepatitis C virus (HCV) RNA levels measured at different time points for treatment efficacy. We found that the level of HCV RNA measured at week 2 of antiviral therapy can be used to predict treatment success in patients with HCV genotype 3 infection treated with sofosbuvir and ribavirin but not in patients treated with other sofosbuvir-based regimens. Low level HCV RNA is frequently detected by the RealTime HCV assay during later stages of antiviral therapy. However, this is not associated with reoccurrence of HCV RNA after the end of treatment.

Lactic acidosis in patients with hepatitis C virus cirrhosis and combined ribavirin/sofosbuvir treatment.

BACKGROUND & AIMS: Sofosbuvir (SOF) based interferon-alfa free antiviral therapy has become the treatment of choice for patients with chronic hepatitis C virus (HCV) infection. Little is known about safety of drug combinations using two nucleos(t)ide polymerase inhibitors in patients with HCV associated advanced cirrhosis. Here, we report frequent occurrence of lactic acidosis associated with acute-on-chronic hepatic decompensation during ribavirin (RBV) plus SOF based antiviral therapy. METHODS: Thirty-five patients with chronic hepatitis C and advanced fibrosis, compensated cirrhosis, and decompensated cirrhosis without and after liver transplantation were treated with SOF based antiviral therapy with and without RBV. Adverse events including lactic acidosis (pH <7.35, lactate >20 mg/dl) were recorded 24 weeks before and during (mean ±SD, 18±11 weeks) antiviral therapy. Efficacy was determined by assessment of serum HCV RNA. RESULTS: We observed severe adverse events in 15/35 (43%) patients before (24 weeks) and in 12/35 (34%) patients during antiviral therapy, the majority in association with acute-on-chronic hepatic decompensation. Lactic acidosis occurred in 5/35 (14%) patients during therapy, while no event of lactic acidosis was observed prior to therapy. Lactic acidosis was associated with hepatic decompensation including renal failure and infection, and was severe (pH <7.3) in two patients. CONCLUSIONS: RBV in combination with SOF based antiviral therapy in patients with HCV associated advanced cirrhosis may be associated with the development of lactic acidosis. Impaired renal function, and higher MELD/Child-Pugh scores were identified as potential risk factors.