Metabolic-associated fatty liver disease and hepatocellular carcinoma: a prospective study of characteristics and response to therapy.

BACKGROUND AND AIM: The rising incidence of hepatocellular carcinoma (HCC) in Australia is related to increasing rates of metabolic-associated fatty liver disease (MAFLD). This study aimed to prospectively characterize the metabolic profile, lifestyle, biometric features, and response to treatment of HCC patients in an Australian population. METHOD: Multicenter prospective cohort analysis of newly diagnosed HCC patients at six multidisciplinary team meetings over a 2-year period. RESULTS: Three hundred and thirteen (313) newly diagnosed HCC patients with MAFLD (n = 77), MAFLD plus other liver disease (n = 57) (the "mixed" group), and non-MAFLD (n = 179) were included in the study. Alcohol-associated liver disease (ALD) (43%) and MAFLD (43%) were the most common underlying liver diseases. MAFLD-HCC patients were older (73 years vs 67 years vs 63 years), more likely to be female (40% vs 14% vs 20%), less likely to have cirrhosis (69% vs 88% vs 85%), showed higher ECOG, and were less likely to be identified by screening (29% vs 53% vs 45%). Metabolic syndrome was more prevalent in the MAFLD and mixed groups. The severity of underlying liver disease and HCC characteristics were the same across groups. While the MAFLD population self-reported more sedentary lifestyles, reported dietary patterns were no different across the groups. Dyslipidemia was associated with tumor size, and those taking statins had a lower recurrence rate. CONCLUSION: Equal to ALD, MAFLD is now the most common underlying liver disease seen in HCC patients in Australia. Future HCC prevention screening and treatment strategies need to take this important group of patients into consideration.

Early viral-specific T-cell testing predicts late cytomegalovirus reactivation following liver transplantation.

INTRODUCTION: Although antiviral prophylaxis is effective in preventing early cytomegalovirus (CMV) reactivation following liver transplantation (OLT), it predisposes patients to late CMV after prophylaxis has ceased. QuantiFERON-CMV (QFN-CMV, Qiagen, The Netherlands) measures an individual's viral-specific immune response. METHODS: Fifty-nine OLT recipients were prospectively monitored post-OLT in an observational cohort study. QFN-CMV was performed at regular time-points. An absolute QFN-CMV <0.1 IU/mL was considered non-reactive. RESULTS: 50/59 (84.7%) had a reactive QFN-CMV by M6. 38/59 (64.4%) had antiviral prophylaxis or treatment before M6, with 31/38 (81.6%) developing a reactive QFN-CMV by 6 months. Over 90% already had a reactive result as early as 3 months post transplant, 3 patients (5.08%) developed late CMV between 6-12 months (median 251 days)-all had a non-reactive M6 QFN-CMV. And 2/3 experienced CMV disease. Non-reactive M6 QFN-CMV was significantly associated with late CMV (OR = 54.4, PPV = 0.33, NPV = 1.00, P = .003). CONCLUSION: Although only 5% of recipients developed late CMV, 2/3 suffered CMV disease. M6 QFN-CMV has an excellent NPV for late CMV, suggesting patients who exhibit a robust ex vivo immune response at M6 can safely cease CMV monitoring. Furthermore, >90% already express viral-specific immunity as early as 3 months. Conceivably, antiviral prophylaxis could be discontinued early in these patients.

Impact of viral hepatitis aetiology on survival outcomes in hepatocellular carcinoma: A large multicentre cohort study.

While HBV and HCV are risk factors for HCC, uncertainty exists as to whether these viral infections have prognostic significance in HCC. Thus, we compared the overall survival of patients with HBV, HCV and nonviral HCC, and evaluated whether the presence of HBV and HCV predicts patient outcomes. We conducted a multicentre study of HCC cases diagnosed at six Melbourne tertiary hospitals between Jan 2000-Dec 2014. Patient demographics, liver disease and tumour characteristics and patient outcomes were obtained from hospital databases, computer records and the Victorian Death Registry. Survival outcomes were compared between HBV, HCV and nonviral hepatitis cases and predictors of survival determined using Cox proportional hazards regression. There were 1436 new HCC cases identified including 776 due to viral hepatitis (HBV 235, HCV 511, HBV-HCV 30) and 660 from nonviral causes. The median survival of HBV, HCV and nonviral HCC patients was 59.1, 28.4 and 20.9 months, respectively (P<.0001). On multivariate analysis, independent risk factors for survival included HCC aetiology, gender, BCLC stage, serum AFP, total number and size of lesions, and serum creatinine and albumin. After adjusting for these and method of detection, HBV remained an independent predictor of improved overall survival when compared to both nonviral (HR 0.60%, 95% CI 0.35-0.98; P=.03) and HCV-related HCC (HR 0.51%, 95% CI 0.30-0.85; P=.01). In this large multicentre study, HBV is independently associated with improved overall survival compared with HCV and nonviral-related HCC. Further studies are needed to determine the underlying factor(s) responsible.

Fluence and polarisation dependence of GaAs based Lateral Photo-Dember terahertz emitters.

We characterise THz output of lateral photo-Dember (LPD) emitters based on semi-insulating (SI), unannealed and annealed low temperature grown (LTG) GaAs. Saturation of THz pulse power with optical fluence is observed, with unannealed LTG GaAs showing highest saturation fluence at 1.1 ± 0.1 mJ cm(-2). SI-GaAs LPD emitters show a flip in signal polarity with optical fluence that is attributed to THz emission from the metal-semiconductor contact. Variation in optical polarisation affects THz pulse power that is attributed to a local optical excitation near the metal contact.

Hepatitis C recurrence: the Achilles heel of liver transplantation.

Hepatitis C virus (HCV) infection is the most common indication for liver transplantation worldwide; however, recurrence post transplant is almost universal and follows an accelerated course. Around 30% of patients develop aggressive HCV recurrence, leading to rapid fibrosis progression (RFP) and culminating in liver failure and either death or retransplantation. Despite many advances in our knowledge of clinical risks for HCV RFP, we are still unable to accurately predict those most at risk of adverse outcomes, and no clear consensus exists on the best approach to management. This review presents a critical overview of clinical factors shown to influence the course of HCV recurrence post transplant, with particular focus on recent data identifying the important role of metabolic factors, such as insulin resistance, in HCV recurrence. Emerging data for genetic markers of HCV recurrence and their usefulness for predicting adverse outcomes will also be explored.

Liver transplantation for the treatment of homozygous familial hypercholesterolaemia in an era of emerging lipid-lowering therapies.

Homozygous familial hypercholesterolaemia (FH) causes severe premature coronary artery disease because of very high levels of low density lipoprotein (LDL)-cholesterol. Standard lipid-lowering drugs and LDL-apheresis may not be sufficiently effective. Liver transplantation replaces defective LDL receptors and vastly improves the lipid profile, and we present the first report of an Australian adult to receive this treatment. Emerging drug treatments for FH may be alternatives to LDL-apheresis and transplantation, but long-term safety and efficacy data are lacking for all of these options.

Toll-like receptor 3 and 7/8 function is impaired in hepatitis C rapid fibrosis progression post-liver transplantation.

Recurrence of hepatitis C (HCV) postliver transplant is universal, with a subgroup developing rapid hepatic fibrosis. Toll-like receptors (TLRs) are critical to innate antiviral responses and HCV alters TLR function to evade immune clearance. Whether TLRs play a role in rapid HCV recurrence posttransplant is unknown. We stimulated peripheral blood mononuclear cells (PBMCs) from 70 patients with HCV postliver transplant with TLR subclass-specific ligands and measured cytokine production, TLR expression and NK cell function. Rate of fibrosis progression was calculated using posttransplant liver biopsies graded by Metavir scoring (F0-4; R=fibrosis stage/year posttransplant; rapid fibrosis defined as >0.4 units/year). Thirty of 70 (43%) patients had rapid fibrosis progression. PBMCs from HCV rapid-fibrosers produced less IFNα with TLR7/8 stimulation (p=0.039), less IL-6 at baseline (p=0.027) and with TLR3 stimulation (p=0.008) and had lower TLR3-mediated monocyte IL-6 production (p=0.028) compared with HCV slow fibrosers. TLR7/8-mediated NKCD56 dim cell secretion of IFNγ was impaired in HCV rapid fibrosis (p=0.006) independently of IFNα secretion and TLR7/8 expression, while cytotoxicity remained preserved. Impaired TLR3 and TLR7/8-mediated cytokine responses may contribute to aggressive HCV recurrence postliver transplantation through impaired immune control of HCV and subsequent activation of fibrogenesis.

Investigation of the role of the lateral photo-Dember effect in the generation of terahertz radiation using a metallic mask on a semiconductor.

Pulses of coherent terahertz radiation can be efficiently generated by a lateral diffusion current after ultrafast generation of photo-carriers near a metal interface on the surface of a semiconductor, this is known as the lateral photo-Dember effect. We investigate how the emission depends on the pump spot position, size, power and how it is affected by the application of an applied external bias. We study the role of the metallic mask and how it suppresses emission from the carriers diffusing under it due to a reduction of available radiation states both theoretically and experimentally.

Identifying the superior measure of rapid fibrosis for predicting premature cirrhosis after liver transplantation for hepatitis C.

BACKGROUND: Hepatitis C virus (HCV) recurrence post liver transplant is universal, with a subgroup of patients developing rapid hepatic fibrosis. Various clinical definitions of rapid fibrosis (RF) have been used to identify risks for rapid progression, but their comparability and efficacy at predicting adverse outcomes has not been determined. METHODS: Retrospective data analysis was conducted on 100 adult patients with HCV who underwent liver transplantation at a single center. We measured year 1 fibrosis progression (RF defined as METAVIR F score ≥ 1 at 1-year liver biopsy), time to METAVIR F2-stage fibrosis, and fibrosis rate (calculated using liver biopsies graded by METAVIR scoring F0-4; fibrosis rate = fibrosis stage/year post transplant). RF was defined as ≥ 0.5 units/year. RESULTS: Multivariate analysis revealed that donor age and peak HCV viral load were significant risks for RF, when fibrosis rate was used to define RF. Advanced donor age was a risk for rapid progression to F2-stage fibrosis, whereas genotype 2 or 3 HCV infection was protective. Fibrosis rate had the strongest correlation with time to cirrhosis development (P < 0.0001, r = -0.76) and was the most accurate predictor of rapid graft cirrhosis (P < 0.0001, area under the curve 0.979, sensitivity 100%, specificity 94%). CONCLUSION: Different measures of RF progression identify different risks for RF and are not directly comparable. Fibrosis rate was the most accurate predictor of rapid graft cirrhosis.

Epidemiology of hepatitis B-associated hepatocellular carcinoma in Victoria.

BACKGROUND: Chronic hepatitis B (HBV) and cirrhosis are major risk factors for hepatocellular carcinoma (HCC). The proportion and characteristics of cases with cirrhosis are not well documented. AIM: Our aim was to compare demographic, viral and tumour characteristics of HBV-associated HCC in an Australian cohort, in patients with and without cirrhosis. METHODS: Existing HCC databases at six Melbourne teaching hospitals were reviewed for cases associated with HBV. Patient demographics, HBV viral characteristics, presence of cirrhosis, serum alpha-fetoprotein and tumour size were assessed. Mode of diagnosis was recorded through surveillance or symptoms, and treatment was either palliative, percutaneous or surgical. RESULTS: We identified 197 cases of HBV-related HCC. The mean age was 57.9 ± 12.9 years; 83% were male, and 55.3% and 35.3% were of Asian and European descent respectively. Of 168 patient with available data, 146 (87%) had cirrhosis versus 22 (13%) without. Patients with cirrhosis tended to be older (median 60 vs 52 years, P = 0.078). Asian patients were more likely to have HCC without cirrhosis than Europeans (17% vs 6%, P = 0.04). There were no other differences identified between cirrhotic and non-cirrhotic patients. Thirty-four per cent of patients had tumours greater than 5 cm at diagnosis, and 47% were diagnosed after presenting with symptoms. Twelve patients with HBV-HCC were outside current screening guidelines. CONCLUSION: Most patients in Melbourne with HBV-associated HCC have cirrhosis. HCC characteristics in non-cirrhotic and cirrhotic patients were similar. The large number of patients detected through symptoms and with large tumours reinforces the need for vigilance in screening.

Epidemiology and outcomes of primary sclerosing cholangitis: an Australian multicentre retrospective cohort study.

BACKGROUND AND AIMS: Little is known regarding the epidemiology and outcomes of patients with primary sclerosing cholangitis (PSC) in Australia. We, therefore, evaluated the epidemiology and clinical outcomes of PSC in a large cohort of Australian patients and compared these to the general population. METHODS: We conducted a multicentre, retrospective cohort study of PSC patients at nine tertiary liver centers across three Australian states, including two liver transplant centers. RESULTS: A total of 413 PSC patients with 3,285 person-years of follow-up were included. Three hundred and seventy-one (90%) patients had large duct PSC and 294 (71%) had associated inflammatory bowel disease. A total of 168 (41%) patients developed cirrhosis (including 34 at the time of PSC diagnosis) after a median of 15.8 (95% CI 12.4, NA) years. The composite endpoint of death or liver transplantation occurred in 49 (12%) and 78 (19%) patients, respectively, with a median transplant-free survival of 13.4 (95% CI 12.2-15) years. Compared to the general population, PSC accounted for a 240-fold increased risk of development of cholangiocarcinoma (CCA) and CCA-related death. CCA risk was increased with older age of PSC diagnosis, presence of dominant stricture and colectomy. Compared to same-aged counterparts in the general population, PSC patients who were diagnosed at an older age or with longer disease duration had reduced relative survival. CONCLUSION: In this large retrospective cohort study of PSC patients in Australia, increased age and time from diagnosis was associated with increased mortality and morbidity particularly from CCA and development of cirrhosis, necessitating need for liver transplant.

What is associated with being active in arthritis? Analysis from the Obstacles to Action study.

BACKGROUND: Many adults with arthritis do not achieve physical activity levels recommended for good health. This study aimed to identify factors associated with physical activity participation in people with arthritis. METHODS: 1106 out of 8163 adults with self-reported arthritis were identified from the 2003 Obstacles to Action study. Participants were classified as active if they reported 30 min of moderate activity > or = 5 days a week or 20 min of vigorous activity > or = 3 days a week (n = 613), or insufficiently active if they did not (n = 438). Sociodemographic factors, attitudes, self-efficacy, motivators and barriers to being active were analysed. RESULTS: Active people with arthritis had a lower burden of chronic disease than insufficiently active people (18% with three or more chronic medical conditions vs 33%, P < 0.0001). Active participants believed more strongly in the benefits of physical activity, reported higher levels of encouragement from others and had greater overall levels of self-efficacy when compared with the less active participants (P for all <0.0001). Arthritis, fatigue and discomfort were ranked by both groups as the top three barriers. However, the active participants reported lower impact scores for these barriers than the inactive group (P for all <0.0001). These findings persisted after adjusting for occupational status, body mass index and comorbidities. CONCLUSION: Active adults with arthritis have lower levels of chronic disease, greater self-efficacy and fewer psychosocial barriers. Recognition of such barriers and motivators may be useful when designing intervention programmes to help people with arthritis initiate or intensify physical activity participation.

Evidence for association of an interleukin 23 receptor variant independent of the R381Q variant with rheumatoid arthritis.

OBJECTIVE: The rare allele of a non-synonymous interleukin 23 receptor (IL23R) single nucleotide polymorphism (SNP) rs11209026 (p.Arg381Gln) confers strong protection against Crohn disease (CD) and psoriasis. Other IL23R variants also exhibit association with CD, genetically independent of rs11209026. In rheumatoid arthritis (RA), IL23 is an important determinant of the production of IL17A, a cytokine of consequence in inflammation and bone destruction. While there is no previous support for strong association of IL23R with RA, the possibility of a weaker role for IL23R variants in the aetiology of RA cannot be eliminated. METHODS: A New Zealand RA cohort was tested for association with six IL23R SNPs and the resulting data combined with a reanalysis of the Wellcome Trust Case Control Consortium data and a previously published Spanish data set. The combined data set totals over 3000 Caucasian cases and 3800 controls, which has sufficient power to detect a risk of as low as odds ratio (OR) = 1.2. RESULTS: Our data emphasise the lack of association of rs11209026 with RA (OR 1.01, 95% confidence interval (CI) 0.88 to 1.16, p = 0.86). However there was some evidence for association of rs1343151 with RA (OR 1.14, 95% CI 1.06 to 1.22, p = <0.001). CONCLUSIONS: While requiring further replication, these data further support a role for the IL17A/IL23 pathway in RA. Understanding how different variants of IL23R associate, at varying levels of strength, with contrasting groups of immune-mediated diseases (CD, psoriasis, ankylosing spondylitis, RA) will enhance knowledge on the aetiology of these diseases.

Evidence for an influence of chemokine ligand 3-like 1 (CCL3L1) gene copy number on susceptibility to rheumatoid arthritis.

OBJECTIVE: There is increasing evidence that gene copy-number variation influences phenotypic variation. Chemokine ligand 3-like 1 (CCL3L1) is encoded by a variable copy-number gene, and binds to several pro-inflammatory cytokine receptors, including chemokine receptor 5 (CCR5). Considering lymphocyte recruitment by beta-chemokines is a feature of autoimmunity, and that the CCR5Delta32 variant is associated with protection to rheumatoid arthritis (RA), we hypothesised that CCL3L1 copy-number influences susceptibility to RA and type 1 diabetes (T1D). METHODS: We measured CCL3L1 copy-number in 1136 RA cases from New Zealand (NZ) and the UK, 252 NZ T1D cases and a total of 1470 controls. All subjects were ancestrally Caucasian. RESULTS: A copy-number higher than 2 (the most common copy number) was a risk factor for RA in the NZ cohort (odds ratio (OR) 1.34, 95% CI 1.08-1.66, p = 0.009) but not the smaller UK RA cohort (OR 1.09, 95% CI 0.75-1.60, p = 0.643). There was evidence for association in the T1D cohort (OR 1.46, 95% CI 0.98-2.20, p = 0.064) and in the combined RA/T1D cohort (OR 1.30, 95% CI 1.00-1.54, p = 0.003). Genetic interaction between CCL3L1 dosage and CCR5 genotype was found; the increased genetic risk conferred by higher CCL3L1 copy-number was ablated by a dysfunctional CCR5 (CCR5Delta32). CONCLUSIONS: These data suggest that increased CCL3L1 expression may enhance inflammatory responses and increase the chance of autoimmune disease. Genetic interaction data were consistent with a biologically plausible model; CCR5Delta32 protects against RA and T1D by blocking signalling through the CCR5 pathway, mitigating the pro-inflammatory effects of excess CCL3L1.

A modified Delphi exercise to determine the extent of consensus with OMERACT outcome domains for studies of acute and chronic gout.

OBJECTIVES: To reach consensus with recommendations made by an OMERACT Special Interest Group (SIG). METHODS: Rheumatologists and industry representatives interested in gout rated and clarified, in three iterations, the importance of domains proposed by the OMERACT SIG for use in acute and chronic gout intervention studies. Consensus was defined as a value of less than 1 of the UCLA/RAND disagreement index. RESULTS: There were 33 respondents (61% response rate); all agreed the initial items were necessary, except "total body urate pool". Additional domains were suggested and clarification sought for defining "joint inflammation" and "musculoskeletal function". Items that demonstrated no clear decision were re-rated in the final iteration. There were six highly rated items (rating 1-2) with four slightly lower rating items (rating 3) for acute gout; and 11 highly rated items with eight slightly lower ratings for chronic gout. CONCLUSIONS: Consensus is that the following domains be considered mandatory for acute gout studies: pain, joint swelling, joint tenderness, patient global, physician global, functional disability; and for chronic gout studies: serum urate, gout flares, tophus regression, health-related quality of life, functional disability, pain, patient global, physician global, work disability and joint inflammation. Several additional domains were considered discretionary.

Acid-base balance in combined severe hepatic and renal failure: a quantitative analysis.

BACKGROUND: Severe hepatic failure (SHF) commonly leads to major changes in acidbase balance status. However, the direct effects of liver failure per se on acid base balance are poorly understood because this condition is usually associated with acute renal failure (ARF). AIM: To assess the effect of SHF on acid-base balance. DESIGN: Retrospective laboratory investigation. SUBJECTS: Thirty-seven critically ill patients with SHF complicated by ARF, and 42 patients with severe ARF without liver failure prior to renal replacement therapy. INTERVENTION: Retrieval of clinical and laboratory data from prospective unit and laboratory databases. METHODS: Quantitative acid-base assessment using Stewart-Figge methodology. Comparison of findings between the two groups. Comparison of demographic and clinical features. RESULTS: Patients with combined SHF and ARF were younger and had significantly higher mean bilirubin, ALT and INR levels (p<0.0001). Their mean lactate concentration was higher (6.4 vs. 2.1 mmol/L; p<0.0001) leading to a greater anion gap (25.8 vs. 16.1 mmol/L; p<0.0001). The ionized calcium concentration (1.00 vs. 1.15 mmol/L; p<0.0001) was lower but the strong ion difference apparent (SIDa) was greater (42.0 vs. 38.0 mEq/L; p<0.005) due to hypochloremia. The albumin concentration was low but higher than in control patients (28 vs. 24 g/L; p<0.01) and the calculated strong ion gap (SIG) was greater (12.6 vs. 9.3 mEq/L; p<0.01). The base excess was similar to controls and the pH was preserved in the near normal range by marked hypocapnea. CONCLUSIONS: Combined SHF and ARF is a syndrome with unique acid-base changes due mostly to lactic metabolic acidosis and, in smaller part, to the accumulation of unmeasured anions. This acidosis, like that of ARF, is attenuated by hypoalbuminemia, by a unique preservation of the SIDa due to hypochloremia, and by marked hypocapnea.

Safety and effectiveness of umbilical hernia repair in patients with cirrhosis.

PURPOSE: Umbilical hernia is a common complication in patients with cirrhosis. Early studies have reported a high morbidity and mortality associated with hernia repair. The traditional approach has been to non-operatively manage umbilical hernias in patients with cirrhosis. There are emerging data suggesting that an elective repair is a preferable approach. This study examined the outcomes of umbilical hernia repair in patients with advanced liver disease and compared this with a control group of non-cirrhotic patients. METHODS: Prospective data were collected regarding the outcome of umbilical hernia repairs performed between 2004 and 2013 at the Austin Hospital, Melbourne, Australia. Outcomes at 90 days were compared between patients with and without cirrhosis. RESULTS: 79 patients with cirrhosis and 249 controls were analysed. Of the patients with cirrhosis, 9% were classified as Child-Pugh A, 61% were Child-Pugh B and 30% were Child-Pugh C. Emergency repairs for complicated hernias was undertaken in 18% of the cirrhosis population and 10% in controls (P = 0.10). Post-operative complications occurred more commonly in patients with cirrhosis (26%) compared with controls (11%) (P < 0.01). Emergency hernia repairs were associated with a higher complication rate in both patients with cirrhosis (62%) and controls (20%) (P = 0.01). There was no significant difference in the rate of hernia recurrence as assessed by clinical examination between patients with cirrhosis (2.7%) and controls (6.8%) (P = 0.17) nor in 90-day mortality between patients with cirrhosis (n = 1, 1.3%) and the controls (n = 0) (P = 0.43). CONCLUSIONS: Within the limitations of a small study cohort and therefore an underpowered study, elective surgical repair of umbilical hernias in patients with cirrhosis, including decompensated cirrhosis, may not be associated with a significant increase in mortality when compared to a control cohort. Whilst complications are higher in cirrhotic patients, there is no difference in the rate of hernia recurrence. Emergency repairs of umbilical hernias are associated with a high complication rate in cirrhotic patients.

Sofosbuvir and daclatasvir therapy in patients with hepatitis C-related advanced decompensated liver disease (MELD ≥ 15).

BACKGROUND: Antiviral therapy for hepatitis C has the potential to improve liver function in patients with decompensated cirrhosis. AIMS: To examine the virological response and effect of viral clearance in patients with decompensated hepatitis C cirrhosis all with MELD scores ≥15 following sofosbuvir/daclatasvir ± ribavirin. METHODS: We prospectively collected data on patients who commenced sofosbuvir/daclatasvir for 24-weeks under the Australian patient supply program (TOSCAR) and analysed outcomes including sustained viral response at 12 weeks (SVR12), death and transplant. RESULTS: 108 patients (M/F, 79/29; median age 56years; Child-Pugh 10; MELD 16; genotype 1/3, 55/47) received sofosbuvir/daclatasvir and two also received ribavirin. On intention-to-treat, the SVR12 rate was 70% (76/108). Seventy-eight patients completed 24-weeks therapy. SVR12 was achieved in 56 of these patients on per-protocol-analysis (76%). SVR12 was 80% in genotype 1 compared to 69% in genotype 3. Thirty patients failed to complete therapy. In patients achieving SVR12, median MELD and Child-Pugh fell from 16(IQR15-17) to 14(12-17) and 10(9-11) to 8(7-9), respectively (P<.001). In those who died, MELD increased from 16 to 23 at death (P=.036). Patients who required transplantation had a significantly higher baseline MELD (20) compared to those patients completing treatment (16) (P=.0010). The odds ratio for transplant in patients with baseline MELD ≥20 was 13.8(95%CI 2.78-69.04). CONCLUSIONS: SVR12 rates with sofosbuvir/daclatasvir in advanced liver disease are lower than in compensated disease. Although treatment improves MELD and Child-Pugh in most patients, a significant proportion will die or require transplantation. In those with MELD ≥20, it may be better to delay treatment until post-transplant.