Turning the Tide on Hepatitis C Virus-Related Liver Transplantation: The Return on Investment in Hepatitis C Virus Treatment in Australia and New Zealand.

Introduction of universal access to direct-acting antiviral (DAA) therapy for hepatitis C virus (HCV) in Australia and New Zealand on March 1st , 2016, has had a major impact on the number of people with chronic HCV infection, but the impact on liver transplantation rates is unknown. We conducted a retrospective registry study including all adult liver transplantations from the Australia and New Zealand Liver and Intestinal Liver Transplant Registry (ANZLITR) data set. Interrupted time series analysis determined the impact of DAAs in 2016 on the number of HCV liver transplantations per year. Cox regression analysis was used to determine the impact of DAAs on post-liver transplantation survival. Between January 1, 1990, and December 31, 2019 5318 adult liver transplantations were performed, and 29% (1531) were for HCV infection. Prior to the introduction of DAAs, there was a mean increase of 3.5 adult liver transplantations performed for HCV per annum, but between 2016 and 2019 there was a mean decrease of 7.9 adult liver transplantations per annum (P < 0.001). Similarly, the proportion of liver transplantations performed for HCV increased from 9% (1990) to 33% in 2016 and then fell to 23% in 2019 (P < 0.001). The number and proportion of patients with HCV added to the liver transplantation waiting list also fell in 2016 (P < 0.001) when compared with other indications. The introduction of DAAs was associated with a 31% reduction in death after liver transplantation, adjusted for age at transplant and hepatocellular carcinoma (HCC; hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.48-0.99; P = 0.047). The number of adult liver transplantations performed for HCV-related liver cirrhosis and HCC has reduced since the introduction of universal access to DAAs in 2016 in Australia and New Zealand.

Increasing Incidence of Nonalcoholic Steatohepatitis as an Indication for Liver Transplantation in Australia and New Zealand.

The worldwide increase in obesity and diabetes has led to predictions that nonalcoholic steatohepatitis (NASH) will become the leading indication for orthotopic liver transplantation (OLT). Data supporting this prediction from outside the United States are limited. Thus, we aimed to determine trends in the frequency of NASH among adults listed and undergoing OLT in Australia and New Zealand (ANZ) from 1994 to 2017. Data from the ANZ Liver Transplant Registry were analyzed with patients listed for fulminant liver failure, retransplantation, or multivisceral transplants excluded. Nonparametric trend, Spearman rank correlation, and regression analysis were used to assess trends in etiologies of liver disease over time. Of 5016 patient wait-list registrants, a total of 3470 received an OLT. The percentage of patients with NASH activated for OLT increased significantly from 2.0% in 2003 to 10.9% in 2017 (trend analyses; P < 0.001). In 2017, NASH was the third leading cause of chronic liver disease (CLD) among wait-list registrants behind chronic hepatitis C virus (HCV; 29.5%) and alcohol (16.1%). Similarly, significant increases over time in the percentage of patients undergoing OLT were observed for HCV and NASH (all trend analyses; P < 0.001) but with significant reductions in primary sclerosing cholangitis and cryptogenic cirrhosis (both P < 0.05). By 2017, NASH was the third leading cause of liver disease among patients undergoing OLT (12.4%) and behind chronic HCV (30.2%) and alcohol (18.2%). NASH also became the third most frequent etiology of CLD in patients transplanted (13.8%) with concomitant hepatocellular carcinoma by 2017. In conclusion, NASH is increasing as a primary etiology of liver disease requiring listing and liver transplantation in ANZ.

Intention-to-treat analysis of liver transplantation, resection and thermal ablation for hepatocellular carcinoma in a single centre.

BACKGROUND: potentially curative treatment options for hepatocellular carcinoma (HCC) include liver transplantation (LT), liver resection (LR) and thermal ablation (TA). Long term intent-to-treat (ITT) analysis from a single-centre using all three modalities contemporaneously has not been published. METHODS: An ITT analysis was undertaken of all patients with HCC listed for LT, or have undergone LR or TA. RESULTS: 444 patients were identified; 145 were listed for LT (121 underwent LT), 190 underwent LR and 109 underwent TA. One and 3-year overall survival (OS) was similar among LT, LR and TA (88/77%, 88/64% and 95/72%) whereas 5-year OS was higher following LT than LR or TA (73% vs. 54% vs. 49%). Disease-free survival at 1- and 5-years was higher for LT (97% and 84%) than LR (66% and 35%) or TA (73%, and 19%). CONCLUSION: LT offered the lowest rate of cancer recurrence and highest chance of long-term survival. Differences in outcome likely reflect a combination of cancer-related factors (AFP, micro- and macrovascular invasion), patient-related factors (performance status, co-morbidities and psychosocial issues) and treatment type. Two thirds of patients treated by LR and three quarters treated by TA had HCC recurrence by 5 years, reinforcing the need for close long-term surveillance.

Liver transplantation in Australia and New Zealand.

Liver transplantation (LT) in Australia and New Zealand began in 1985. Over this time until December 2014, LT took place in 3700 adults and 800 children. LT is regulated with 1 unit, supported by the government, per state or region. Currently approximately 270 transplants take place per year. Organ donation rates are moderate in Australia (17 per 1 million of population) but very low in New Zealand (11 per 1 million of population). All the units share organ donors for fulminant hepatic failure cases (status 1). Recipient listing criteria and organ allocation criteria are commonly agreed to via National and Trans-Tasman agreements, which are published online. Current survival rates indicate approximately 94% 1-year survival with median survival in adults of approximately 20 years, whereas 75% of children are alive at 20 years. All units collaborate in research projects via the Australia and New Zealand Liver Transplant Registry and have published highly cited articles particularly on the prevention of hepatitis B virus recurrence. Outcomes for indigenous populations have also been analyzed. In conclusion, LT in Australia and New Zealand is well developed with transparent processes related to criteria for listing and organ allocation together with publication of outcomes. Liver Transplantation 22 830-838 2016 AASLD.

Nature and outcomes of the increased incidence of colorectal malignancy after liver transplantation in Australasia.

OBJECTIVES: To examine whether incidence of colorectal malignancy is increased in Australasian liver transplant recipients compared with the general population of Australia, and to assess the characteristics and outcomes of colorectal malignancy in this patient group. DESIGN, SETTING AND PATIENTS: Data on patients who underwent orthotopic liver transplantation (OLTx) and had a diagnosis of de-novo colorectal malignancy after transplantation during the period 1985-2011 were obtained from the Australia and New Zealand Liver Transplant Registry, and these data were compared with colorectal malignancy data from the Australian Institute of Health and Welfare. MAIN OUTCOME MEASURES: Time from OLTx to diagnosis of colorectal malignancy, stage of colorectal malignancy at diagnosis, patient survival, and standardised incidence ratio (SIR) for colorectal malignancy. RESULTS: Forty-eight of 3735 recipients (1.3%) were diagnosed with colorectal malignancy at a median of 7.3 years after OLTx. More advanced colorectal malignancy (regional or metastatic disease) was evident at diagnosis in 20 of the 48 patients; these patients tended to be younger than patients with less advanced malignancy (P = 0.01) and diagnosed sooner after OLTx (P = 0.005). Despite treatment predominantly with surgery, 19 of the 48 patients died from the malignancy. The overall SIR for colorectal malignancy liver transplant recipients compared with the general population of Australia was 2.80 (95% CI, 2.06-3.71). CONCLUSIONS: The incidence of colorectal malignancy is increased in liver transplant recipients in comparison with the general population. Of concern is the tendency for advanced malignancy to be diagnosed in younger patients. These data highlight the importance of considering whether specific guidelines for colorectal malignancy screening in the Australasian adult liver transplant population are needed.

Incentives for organ donation: proposed standards for an internationally acceptable system.

Incentives for organ donation, currently prohibited in most countries, may increase donation and save lives. Discussion of incentives has focused on two areas: (1) whether or not there are ethical principles that justify the current prohibition and (2) whether incentives would do more good than harm. We herein address the second concern and propose for discussion standards and guidelines for an acceptable system of incentives for donation. We believe that if systems based on these guidelines were developed, harms would be no greater than those to today's conventional donors. Ultimately, until there are trials of incentives, the question of benefits and harms cannot be satisfactorily answered.

Expansion of Liver Transplantation Criteria for Hepatocellular Carcinoma from Milan to UCSF in Australia and New Zealand and Justification for Metroticket 2.0.

Background: Expansion in liver transplantation (LT) criteria for HCC from Milan to UCSF has not adversely impacted overall survival, prompting further expansion towards Metroticket 2.0 (MT2). In this study, we compared patient survival post-transplant before and after 2007 and long-term outcomes for LT within Milan versus UCSF criteria (to determine the true benefit of the expansion of criteria) and retrospectively validated the MT2 criteria. Methods: Retrospective analysis of ANZLITR (including all patients transplanted for HCC since July 1997). The entire cohort was divided based on criteria used at the time of listing, namely, Milan era (1997−2006) and the UCSF era (2007−July 2015). Results: The overall 5- and 10-year cumulative survival rates for the entire cohort of 691 patients were 78% and 69%, respectively. Patients transplanted in UCSF era had significantly higher 5- and 10-year survival rates than in the Milan era (80% vs. 73% and 72% vs. 65%, respectively; p = 0.016). In the UCSF era, the 5-year survival rate for patients transplanted within Milan criteria was significantly better than those transplanted outside Milan but within UCSF criteria (83% vs. 73%; p < 0.024). Patients transplanted within the MT2 criteria had a significantly better 5- and 10-year survival rate as compared to those outside the criteria (81% vs. 64% and 73% vs. 50%, respectively; p = 0.001). Conclusion: Overall survival following LT for HCC has significantly improved over time despite expanding criteria from Milan to UCSF. Patients fulfilling the MT2 criteria have a survival comparable to the UCSF cohort. Thus, expansion of criteria to MT2 is justifiable.

Evidence for reduced selection pressure on the hepatitis B virus core gene in hepatitis B e antigen-negative chronic hepatitis B.

The mechanisms underlying the high levels of hepatitis B virus (HBV) replication that cause hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (e-CHB) are unknown. Impaired anti-HBV immunity, which may be measurable as a relaxation of selection pressure on the virus, is possible. A group of Tongans (n = 345) with a chronic HBV infection, including seven with e-CHB, were genotyped at HLA class I. The repertoire of HBV core-gene codons under positive selection pressure was defined by phylogenetic analysis (by using the paml program) of 708 cloned sequences extracted from the 67 of these 345 subjects with the same repertoire of HLA class I alleles as the seven e-CHB individuals and matched controls (see below). The frequency of non-synonymous mutations at these codons was measured in longitudinal data from 15 subjects. Finally, the number of non-synonymous mutations at these codons was compared in seven groups comprised of one subject with e-CHB and 1-3 HLA class I-matched controls with an inactive, HBeAg-negative chronic HBV infection (e-InD). Nineteen codons in the core gene were under positive selection pressure. There was a high frequency of new non-synonymous mutations at these codons (P<0.0001) in longitudinal data. The mean number of these 19 codons with non-synonymous mutations was lower (P = 0.02) in HBV from subjects with e-CHB (4.4±0.5 codons per subject) versus those with e-InD (6.4±0.4 codons per subject). There is a subtle relaxation in selection pressure on the HBV core gene in e-CHB. This may be due to impaired antiviral immunity, and could contribute to the high levels of viral replication that cause liver inflammation in this disease.

Associations between HLA class I alleles and escape mutations in the hepatitis B virus core gene in New Zealand-resident Tongans.

The full repertoire of hepatitis B virus (HBV) peptides that bind to the common HLA class I molecules found in areas with a high prevalence of chronic HBV infection has not been determined. This information may be useful for designing immunotherapies for chronic hepatitis B. We identified amino acid residues under positive selection pressure in the HBV core gene by phylogenetic analysis of cloned DNA sequences obtained from HBV DNA extracted from the sera of Tongan subjects with inactive, HBeAg-negative chronic HBV infections. The repertoires of positively selected sites in groups of subjects who were homozygous for either HLA-B*4001 (n = 10) or HLA-B*5602 (n = 7) were compared. We identified 13 amino acid sites under positive selection pressure. A significant association between an HLA class I allele and the presence of nonsynonymous mutations was found at five of these sites. HLA-B*4001 was associated with mutations at E77 (P = 0.05) and E113 (P = 0.002), and HLA-B*5602 was associated with mutations at S21 (P = 0.02). In addition, amino acid mutations at V13 (P = 0.03) and E14 (P = 0.01) were more common in the seven subjects with an HLA-A*02 allele. In summary, we have developed an assay that can identify associations between HLA class I alleles and HBV core gene amino acids that mutate in response to selection pressure. This is consistent with published evidence that CD8(+) T cells have a role in suppressing viral replication in inactive, HBeAg-negative chronic HBV infection. This assay may be useful for identifying the clinically significant HBV peptides that bind to common HLA class I molecules.

Biliary complications following orthotopic liver transplantation: a 10-year audit.

BACKGROUND: Biliary complications following liver transplantation result in major morbidity. We undertook a 10-year audit of the incidence, management and outcomes of post-transplant biliary complications at the New Zealand Liver Transplant Unit. METHODS: Prospectively collected data on 348 consecutive liver transplants performed between February 1998 and October 2008 were reviewed. The minimum follow-up was 6 months. RESULTS: A total of 309 adult and 39 paediatric transplants were performed over the study period. Of these, 296 (85%) were whole liver grafts and 52 (15%) were partial liver grafts (24 split-liver, eight reduced-size and 20 live-donor grafts). There were 80 biliary complications, which included 63 (18%) strictures and 17 (5%) bile leaks. Partial graft, a paediatric recipient and a Roux-en-Y biliary anastomosis were independent predictors of biliary strictures. Twenty-five (40%) strictures were successfully managed non-operatively and 38 (60%) required surgery (31 biliary reconstructions, three segmental resections and four retransplants). Seven (41%) bile leaks required surgical revision and 10 (59%) were managed non-operatively. There was no mortality related directly to biliary complications. CONCLUSIONS: Biliary complications affected one in five transplant recipients. Paediatric status, partial graft and Roux-en-Y anastomosis were independently associated with the occurrence of biliary strictures. Over half of the affected patients required surgical revision, but no mortality resulted from biliary complications.

Cardiovascular mortality following liver transplantation: predictors and temporal trends over 30 years.

AIMS: There has been significant evolution in operative and post-transplant therapies following liver transplantation (LT). We sought to study their impact on cardiovascular (CV) mortality, particularly in the longer term. METHODS AND RESULTS: A retrospective cohort study was conducted of all adult LTs in Australia and New Zealand across three 11-year eras from 1985 to assess prevalence, modes, and predictors of early (≤30 days) and late (>30 days) CV mortality. A total of 4265 patients were followed-up for 37 409 person-years. Overall, 1328 patients died, and CV mortality accounted for 228 (17.2%) deaths. Both early and late CV mortality fell significantly across the eras (P < 0.001). However, CV aetiologies were consistently the leading cause of early mortality and accounted for ∼40% of early deaths in the contemporary era. Cardiovascular deaths occurred significantly later than non-cardiac aetiologies (8.8 vs. 5.2 years, P < 0.001). On multivariable Cox regression, coronary artery disease [hazard ratio (HR) 4.6, 95% confidence interval (CI) 1.2-21.6; P = 0.04] and era of transplantation (HR 0.44; 95% CI 0.28-0.70; P = 0.01) were predictors of early CV mortality, while advancing age (HR 1.05, 95% CI 1.02-1.10; P = 0.005) was an independent predictors of late CV mortality. Most common modes of CV death were cardiac arrest, cerebrovascular events, and myocardial infarction. CONCLUSION: Despite reductions in CV mortality post-LT over 30 years, they still account for a substantial proportion of early and late deaths. The late occurrence of CV deaths highlights the importance of longitudinal follow-up to study the efficacy of targeted risk-reduction strategies in this unique patient population.

Excellent Contemporary Graft Survival for Adult Liver Retransplantation: An Australian and New Zealand Registry Analysis From 1986 to 2017.

BACKGROUND: Liver retransplantation is technically challenging, and historical outcomes are significantly worse than for first transplantations. This study aimed to assess graft and patient survival in all Australian and New Zealand liver transplantation units. METHODS: A retrospective cohort analysis was performed using data from the Australia and New Zealand Liver Transplant Registry. Graft and patient survival were analyzed according to era. Cox regression was used to determine recipient, donor, or intraoperative variables associated with outcomes. RESULTS: Between 1986 and 2017, Australia and New Zealand performed 4514 adult liver transplants, 302 (6.7%) of which were retransplantations (278 with 2, 22 with 3, 2 with 4). The main causes of graft failure were hepatic artery or portal vein thrombosis (29%), disease recurrence (21%), and graft nonfunction (15%). Patients retransplanted after 2000 had a graft survival of 85% at 1 year, 75% at 5 years, and 64% at 10 years. Patient survival was 89%, 81%, and 74%, respectively. This was higher than retransplantations before 2000 (P < 0.001). Univariate analysis found that increased recipient age (P = 0.001), recipient weight (P = 0.019), and donor age (P = 0.011) were associated with decreased graft survival prior to 2000; however, only increased patient weight was significant after 2000 (P = 0.041). Multivariate analysis found only increased recipient weight (P = 0.042) and donor age (P = 0.025) was significant prior to 2000. There was no difference in survival for second and third retransplants or comparing time to retransplant. CONCLUSIONS: Australia and New Zealand have excellent survival following liver retransplantation. These contemporary results should be utilized for transplant waitlist methods.

Hepatic venous outflow obstruction in piggyback liver transplantation: single centre experience.

BACKGROUND: Hepatic venous outflow obstruction (HVOO) is a rare but serious complication in liver transplantation (LT). METHODS: We conducted a retrospective analysis of HVOO with venography and gradient measurement in consecutive LT from a single centre. RESULTS: Five hundred and six LTs were performed in 486 patients with a median age of 49 years (range 3 months to 71 years). Nineteen (3.8%) cases of HVOO were identified. Diagnosis was confirmed at a median of 26 days post-LT (1-2312). The incidence fell from 5.5% in the first 253 LT, to 2.0% in the second 253 (P = 0.03). Seventeen were due to narrowing at the anastomosis and two cases were due to thrombosis. In adult patients, reconstruction of the supra-hepatic donor inferior vena cava (IVC) onto two veins versus modified 2-3 hepatic veins did not alter the likelihood of HVOO. 17/19 cases were managed successfully by stenting or venoplasty. Two paediatric patients with early onset HVOO had attempted surgical thrombectomy, one was successful and the other required retransplantation. CONCLUSION: The incidence of HVOO appears to fall with increasing experience and does not appear to be related to the number of veins the donor IVC is anastomosed to in adult recipients.

Pre- and postoperative immunonutrition in patients undergoing liver transplantation: a pilot study of safety and efficacy.

BACKGROUND & AIMS: Malnutrition is common in patients with end-stage liver disease and is a risk factor for post-transplant morbidity. The goal of this study was to assess the safety of an immune-enhancing diet in patients undergoing liver transplantation and to investigate its effects on nutritional status. METHODS: Fifteen consecutive patients received oral Impact (0.6l/d) for a median 54 (range 10-168)d pre-transplant and enteral Impact was started early after transplant. Total body protein was measured prior to commencing supplemental Impact, immediately prior to transplant and 10, 15, 30, 90, and 180 days post-transplant. The results were compared with those from 17 patients who received standard nutritional intervention. RESULTS: All study patients tolerated Impact pre- and postoperatively and there were no safety concerns. Over the preoperative period total body protein increased significantly (P = 0.017). In 7 patients followed for 6 months post-transplant, a significant (P = 0.026) loss of body protein occurred over the first 15 postoperative days which was regained by 6 months. In the patients who did not receive Impact, body protein did not change preoperatively and the loss after surgery was not regained. Infectious complications occurred in 5/15 (33%) Impact patients and 12/17 (71%) non-Impact patients (P = 0.074). CONCLUSIONS: In patients with end-stage liver disease, our results suggest the possibility that Impact may have a role in improving preoperative nutritional status, hastening recovery after transplant, and reducing postoperative infectious complications. These potential benefits need to be confirmed in a randomised controlled trial.

The New Zealand Liver Transplant Unit: Auckland District Health Board.

New Zealand is a geographically isolated country with 4.55 million inhabitants. It has endemic hepatitis B (HBV) infection that is especially evident in Maori and Pacific Island communities and impacts indications for liver transplantation. The country has a socialised medical system that allows for full coverage of the assessment for, and completion of liver transplants in suitable recipients. Between February 1998 and December 2014, the New Zealand Liver Transplant Unit (NZLTU) had performed 595 liver transplants in 568 patients, indicating a crude re-transplant rate of 4.8%. Overall 1, 5, and 10 year patient survival rates for all adult (96%, 89%, and 81%, respectively) and pediatric (93%, 92%, and 92%, respectively) recipients compare very favourably with international outcomes from Europe and the United States. Eligibility criteria could be modestly expanded if deceased donor rates improved from the current level of around 10 per million of population per year. This somewhat meagre supply of deceased donor organs, along with significant waiting list attrition, has necessitated the use of living donors, which have been used in more than 50 recipients to date. Despite these limitations, the NZLTU has contributed to improvements in the outcome of transplantation for HBV and hepatitis C through the development of effective antiviral prophylaxis regimes. Furthermore, innovative changes have been made to the manner in which pediatric patients are transitioned to the adult service.

Health economics and health technology assessment: perspectives from Australia and New Zealand.

Formal health economics and health technology assessment (HTA)processes, including cost-effectiveness and cost-utility analysis, are variably used to inform decisions about public and private health service funding and service provision. In general, pharmaceuticals have been subject to more sophisticated health economic analyses and HTAs and for a longer time than either devices or procedures. HTA has been performed by a number of different entities. While HTA shares many common features across the world, its uses, approaches, applications,and impact differ throughout the world. This article will discuss some of the general attributes of HTA and will focus on its specific applications in Australia and New Zealand.