Medicine (St Vincent's) - Research Publications

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    Assessment of the cobas® HBV RNA investigational assay in the setting of nucleoside analog therapy cessation
    Jackson, K ; Bonanzinga, S ; Edwards, R ; Visvanathan, K ; Li, X ; Hall, S ; Kuchta, A ; Canchola, JA ; Thompson, AJ (WILEY, 2022-12)
    HBV RNA is used as a marker of cccDNA transcription and is applicable in the setting of nucleos(t)ide analog (NA) treatment, which suppresses HBV DNA. Traditional assays for quantification of HBV RNA rely on labor-intensive 3'RACE assays targeting the polyA tail. In this study, the high-throughput Roche cobas®HBV RNA investigational assay was assessed on the Roche cobas® 6800 automated platform. Of 969 samples collected for a NA treatment cessation trial, and tested on the cobas assay, 249 were analyzed for sensitivity, reproducibility, sample type applicability, and results were compared to a RACE-based assay. Results of 97 paired serum and plasma samples demonstrated an excellent correlation of 0.98. However, 14.5% of plasma samples yielded detectable (below the limit of quantification) results, when the paired serum was undetectable, and plasma was shown to yield a statistically significant (p < 0.001) greater mean 0.119 log10 copies/ml. Quantification of 152 samples showed good correlation (0.91) between the cobas and RACE assays. The cobas assay demonstrated superior lower limit of quantification, 10 copies/ml, which resulted in detection of 13.2% more samples than the RACE assay. Reproducibility and linear range of the automated assay were also confirmed. The Roche cobas assay for HBV RNA is sensitive and highly recommended.
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    The impact of point-of-care hepatitis C testing in needle and syringe exchange programs on linkage to care and treatment uptake among people who inject drugs: An Australian pilot study
    Howell, J ; Traeger, MW ; Williams, B ; Layton, C ; Doyle, JS ; Latham, N ; Draper, B ; Bramwell, F ; Membrey, D ; McPherson, M ; Roney, J ; Stoove, M ; Thompson, AJ ; Hellard, ME ; Pedrana, A (WILEY, 2022-05)
    Point-of-care (POC) diagnostics overcome barriers to conventional hepatitis C (HCV) testing in people who inject drugs. This study assessed impact on hepatitis C treatment uptake of POC HCV testing in needle and syringe exchange programs (NSPs). Rapid EC was a single-arm interventional pilot study of HCV POC testing conducted in three inner-city community clinics with NSPs. Twelve months after the POC testing, a retrospective medical record and Pharmaceutical Benefits Scheme audit was performed to determine the number of HCV RNA-positive participants who were prescribed HCV treatment. 70 HCV RNA-positive Rapid EC study participants were included. 44 (63%) were prescribed DAAs; 26 (59%) completed treatment and 15 (34%) had SVR testing, all of whom were cured. Age ≥ 40 years (aOR 3.45, 95% CI 1.10-11.05, p = .03) and secondary school education (aOR 5.8, 95% CI 1.54-21.80, p = .009) had higher likelihood of being prescribed DAAs, whereas homelessness was inversely associated with prescription of DAAs (aOR 0.30, 95% CI 0.09-1.04, p = .057). Median time to receive a DAA script from date of diagnosis was seven days (IQR 0 to 14 days), and time to filling the DAA prescription was 2 days (IQR 0-12 days). In conclusion, provision of POC testing through NSPs was effective for linking new clients to HCV treatment and reduced the time to treatment. Further studies are needed to define the most cost-effective use of POC testing in models of care for people who inject drugs to increase HCV treatment uptake.
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    Monitoring quality of care in hepatocellular carcinoma: A modified Delphi consensus
    Maharaj, AD ; Lubel, J ; Lam, E ; Clark, PJ ; Duncan, O ; George, J ; Jeffrey, GP ; Lipton, L ; Liu, H ; McCaughan, G ; Neo, E-L ; Philip, J ; Strasser, S ; Stuart, K ; Thompson, A ; Tibballs, J ; Tu, T ; Wallace, MC ; Wigg, A ; Wood, M ; Zekry, A ; Greenhill, E ; Ioannou, LJ ; Ahlenstiel, G ; Bowers, K ; Clarke, SJ ; Dev, A ; Fink, M ; Goodwin, M ; Karapetis, CS ; Levy, MT ; Muller, K ; O'Beirne, J ; Pryor, D ; Seow, J ; Shackel, N ; Tallis, C ; Butler, N ; Olynyk, JK ; Reed-Cox, K ; Zalcberg, JR ; Roberts, SK (LIPPINCOTT WILLIAMS & WILKINS, 2022-11)
    Although there are several established international guidelines on the management of hepatocellular carcinoma (HCC), there is limited information detailing specific indicators of good quality care. The aim of this study was to develop a core set of quality indicators (QIs) to underpin the management of HCC. We undertook a modified, two-round, Delphi consensus study comprising a working group and experts involved in the management of HCC as well as consumer representatives. QIs were derived from an extensive review of the literature. The role of the participants was to identify the most important and measurable QIs for inclusion in an HCC clinical quality registry. From an initial 94 QIs, 40 were proposed to the participants. Of these, 23 QIs ultimately met the inclusion criteria and were included in the final set. This included (a) nine related to the initial diagnosis and staging, including timing to diagnosis, required baseline clinical and laboratory assessments, prior surveillance for HCC, diagnostic imaging and pathology, tumor staging, and multidisciplinary care; (b) thirteen related to treatment and management, including role of antiviral therapy, timing to treatment, localized ablation and locoregional therapy, surgery, transplantation, systemic therapy, method of response assessment, and supportive care; and (c) one outcome assessment related to surgical mortality. Conclusion: We identified a core set of nationally agreed measurable QIs for the diagnosis, staging, and management of HCC. The adherence to these best practice QIs may lead to system-level improvement in quality of care and, ultimately, improvement in patient outcomes, including survival.
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    The Hidden Epidemic: The Prevalence and Impact of Concurrent Liver Diseases in Patients Undergoing Liver Transplantation in Australia and New Zealand
    Howell, J ; Majumdar, A ; Fink, M ; Byrne, M ; McCaughan, G ; Strasser, SI ; Crawford, M ; Hodgkinson, P ; Stuart, KA ; Tallis, C ; Chen, J ; Wigg, A ; Jones, R ; Jaques, B ; Jeffrey, G ; Adams, L ; Wallace, MC ; Gane, E ; Thompson, A ; Gow, P (LIPPINCOTT WILLIAMS & WILKINS, 2022-08)
    UNLABELLED: Prevalence of concurrent liver diseases among liver transplant recipients and impact on posttransplant outcomes are unknown. METHODS: This retrospective study included adult liver transplants between January 1' 1985' and December 31' 2019' from the Australian and New Zealand Liver and Intestinal Transplant Registry. Up to 4 liver disease causes were recorded for each transplant; concurrent liver diseases were defined as >1 liver disease indication for transplantation, excluding hepatocellular carcinoma. Impact on posttransplant survival was determined using Cox regression. RESULTS: A total of 840 (15%) of 5101 adult liver transplant recipients had concurrent liver diseases. Recipients with concurrent liver diseases were more likely male (78% versus 64%) and older (mean age 52 versus 50 y). A higher proportion of liver transplants for hepatitis B (12% versus 6%), hepatitis C (33% versus 20%), alcohol liver disease (23% versus 13%), and metabolic-associated fatty liver disease (11% versus 8%, all P < 0.001) were identified when all indications were included than with primary diagnosis only. The number and proportion of liver transplants performed for concurrent liver diseases have increased from 8 (6%) during Era 1 (1985-1989) to 302 (20%) during Era 7 (2015-2019; P < 0.001). Concurrent liver diseases were not associated with increased posttransplant mortality (adjusted hazard ratio, 0.98, 95% confidence interval, 0.84-1.14). CONCLUSIONS: Concurrent liver diseases are increasing among adult liver transplant recipients in Australia and New Zealand; however, they do not appear to impact posttransplant survival. Reporting all liver disease causes in the transplant registry reports provides more accurate estimates of liver disease burden.
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    Real-world monitoring progress towards the elimination of hepatitis C virus in Australia using sentinel surveillance of primary care clinics; an ecological study of hepatitis C virus antibody tests from 2009 to 2019 (vol 150, E7, 2022)
    Lee Wilkinson, A ; Pedrana, A ; Traeger, MW ; Asselin, J ; El-Hayek, C ; Nguyen, L ; Polkinghorne, V ; Doyle, JS ; Thompson, AJ ; Howell, J ; Scott, N ; Dimech, W ; Guy, R ; Hellard, M ; Stoove, M (CAMBRIDGE UNIV PRESS, 2022-03-04)
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    Discontinuation of nucleot(s)ide analogue therapy in HBeAg-negative chronic hepatitis B: a meta-analysis
    Hall, SAL ; Vogrin, S ; Wawryk, O ; Burns, GS ; Visvanathan, K ; Sundararajan, V ; Thompson, A (BMJ PUBLISHING GROUP, 2022-08)
    BACKGROUND AND AIMS: Sustained virological suppression and hepatitis B surface antigen (HBsAg) loss have been described after nucleot(s)ide analogue (NA) discontinuation for patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB). We performed a meta-analysis of the clinical outcomes after NA discontinuation for HBeAg-negative CHB. METHODS: Studies involving NA cessation in HBeAg-negative CHB individuals with a median follow-up of ≥12 months were included. Participants were HBeAg-negative at the time of NA initiation. Random effects meta-analyses were performed for the following clinical outcomes: (1) virological relapse (VR) at 6 and 12 months; (2) clinical relapse (CR) at 6 and 12 months and (3) HBsAg loss. Effect of other variables was estimated using subgroup analysis and meta-regression. Studies including patients stopping entecavir (ETV) and/or tenofovir disoproxil fumarate (TDF) were considered separately to studies including patients stopping older generation NA. RESULTS: N=37 studies met inclusion criteria. Cumulative incidence of VR and CR after stopping ETV/TDF was 44% and 17% at 6 months and 63% and 35% at 12 months. Similar relapse rates were observed after stopping older NAs. Among patients stopping ETV/TDF, TDF cessation was associated with increased CR rates at 6 months versus ETV. There was an association between follow-up ≥4 years and HBsAg loss rates when stopping older NAs. Hepatic decompensation and hepatocellular carcinoma were rare but occurred more frequently in studies including cirrhotic individuals. CONCLUSION: VR is common after NA discontinuation, however, CR was only seen in one-third of patients at 12 months. Stopping NA therapy can be followed by HBsAg clearance, and rates are higher with longer follow-up.
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    Stopping nucleot(s)ide analogues in non-cirrhotic HBeAg-negative chronic hepatitis B patients: HBsAg loss at 96 weeks is associated with low baseline HBsAg levels
    Hall, SAL ; Burns, GS ; Anagnostou, D ; Vogrin, S ; Sundararajan, V ; Ratnam, D ; Levy, MT ; Lubel, JS ; Nicoll, AJ ; Strasser, S ; Sievert, W ; Desmond, P ; Ngu, MC ; Angus, P ; Sinclair, M ; Meredith, C ; Matthews, G ; Revill, PA ; Jackson, K ; Littlejohn, M ; Bowden, DS ; Locarnini, SA ; Visvanathan, K ; Thompson, AJ (WILEY, 2022-07)
    BACKGROUND AND AIMS: Current guidelines recommend long-term nucleot(s)ide analogue (NA) therapy for patients with HBeAg-negative chronic hepatitis B (CHB). However, disease remission has been described after stopping NA therapy, as well as HBsAg loss. METHODS: We performed a prospective multi-centre cohort study of stopping NA therapy. Inclusion criteria were HBeAg-negative CHB, the absence of cirrhosis and HBVDNA5× ULN occurred in 35 (32%); ALT flares were not associated with HBsAg loss. There were no unexpected safety issues. CONCLUSION: Virological reactivation was very common after stopping NA therapy and occurred earlier after stopping TDF versus ETV. The majority of patients had ALT <2× ULN at week 96, but only one-third achieved disease remission and HBsAg loss was rare. Very low HBsAg levels at baseline were uncommon but predicted for HBsAg loss and disease remission.
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    Hepatitis B Virus Flares After Nucleot(s)ide Analogue Cessation Are Associated With Activation of Toll-Like Receptor Signaling Pathways
    Al Hall, S ; Burns, GS ; Mooney, BJ ; Millen, R ; Morris, R ; Vogrin, S ; Sundararajan, V ; Ratnam, D ; Levy, MT ; Lubel, JS ; Nicoll, AJ ; Strasser, S ; Sievert, W ; Desmond, P ; Ngu, MC ; Angus, P ; Sinclair, M ; Meredith, C ; Matthews, G ; Revill, PA ; Jackson, K ; Littlejohn, M ; Bowden, S ; Locarnini, SA ; Thompson, AJ ; Visvanathan, K (OXFORD UNIV PRESS INC, 2022-12-28)
    BACKGROUND: We evaluated the patterns of peripheral Toll-like receptor (TLR) signaling activity and the expression of TLRs and natural killer (NK) cell activation in a cohort of patients experiencing severe hepatitis flares after stopping nucleot(s)ide analogues (NAs) therapy. METHODS: Samples were collected longitudinally from patients with chronic hepatitis B who were enrolled in a prospective study of NA discontinuation. Patients experiencing hepatitis flares were compared with patients with normal alanine aminotransferase. Peripheral blood mononuclear cells (PBMCs) were stimulated with TLR ligands and cytokine secretion in the cell culture supernatant measured. Expression of TLR2/4, NKG2D, NKp46, and triggering receptor expressed on myeloid cells 1 (TREM-1) on monocytes, NK, and NK-T cells was measured. RESULTS: Seventeen patients with severe reactivation hepatitis flares were compared to 12 nonflare patients. Hepatitis flares were associated with increased activity of TLR2-8 and TLR9 signaling in PBMCs at the time of peak flare compared to baseline. Hepatitis flares were also associated with (1) upregulation of TLR2 and (2) TREM-1 receptor expression on NK. There were no differences at baseline between flare patients and nonflare patients. CONCLUSIONS: Hepatitis flares off NA therapy have a significant innate inflammatory response with upregulation of TLR signaling on peripheral monocytes and TLR2 and TREM-1 expression on NK cells. This implicates the innate immune system in the immunopathogenesis of hepatitis B flares.
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    Epigenetic Silencing of RIPK3 in Hepatocytes Prevents MLKL -mediated Necroptosis From Contributing to Liver Pathologies
    Preston, SP ; Stutz, MD ; Allison, CC ; Nachbur, U ; Gouil, Q ; Bang, MT ; Duvivier, V ; Arandjelovic, P ; Cooney, JP ; Mackiewicz, L ; Meng, Y ; Schaefer, J ; Bader, SM ; Peng, H ; Valaydon, Z ; Rajasekaran, P ; Jennison, C ; Lopaticki, S ; Farrell, A ; Ryan, M ; Howell, J ; Croagh, C ; Karunakaran, D ; Schuster-Klein, C ; Murphy, JM ; Fifis, T ; Christophi, C ; Vincan, E ; Blewitt, ME ; Thompson, A ; Boddey, JA ; Doerflinger, M ; Pellegrini, M (W B SAUNDERS CO-ELSEVIER INC, 2022-12)
    BACKGROUND & AIMS: Necroptosis is a highly inflammatory mode of cell death that has been implicated in causing hepatic injury including steatohepatitis/ nonalcoholic steatohepatitis (NASH); however, the evidence supporting these claims has been controversial. A comprehensive, fundamental understanding of cell death pathways involved in liver disease critically underpins rational strategies for therapeutic intervention. We sought to define the role and relevance of necroptosis in liver pathology. METHODS: Several animal models of human liver pathology, including diet-induced steatohepatitis in male mice and diverse infections in both male and female mice, were used to dissect the relevance of necroptosis in liver pathobiology. We applied necroptotic stimuli to primary mouse and human hepatocytes to measure their susceptibility to necroptosis. Paired liver biospecimens from patients with NASH, before and after intervention, were analyzed. DNA methylation sequencing was also performed to investigate the epigenetic regulation of RIPK3 expression in primary human and mouse hepatocytes. RESULTS: Identical infection kinetics and pathologic outcomes were observed in mice deficient in an essential necroptotic effector protein, MLKL, compared with control animals. Mice lacking MLKL were indistinguishable from wild-type mice when fed a high-fat diet to induce NASH. Under all conditions tested, we were unable to induce necroptosis in hepatocytes. We confirmed that a critical activator of necroptosis, RIPK3, was epigenetically silenced in mouse and human primary hepatocytes and rendered them unable to undergo necroptosis. CONCLUSIONS: We have provided compelling evidence that necroptosis is disabled in hepatocytes during homeostasis and in the pathologic conditions tested in this study.
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    Quality of upper GI endoscopy: a prospective cohort study on impact of endoscopist education
    Yang, LS ; Thompson, AJ ; Taylor, ACF ; Desmond, P ; Holt, BA (MOSBY-ELSEVIER, 2022-03)
    BACKGROUND AND AIMS: Guidelines on quality of upper GI (UGI) endoscopy have been proposed by the British Society of Gastroenterology (BSG) and European Society of Gastrointestinal Endoscopy (ESGE). However, these guidelines have not been evaluated in clinical practice. We aimed to measure the impact of endoscopist education on the quality of gastroscopy based on these guidelines and the association between compliance with guidelines and the detection of clinically significant premalignant pathology such as Barrett's esophagus (BE), esophageal squamous dysplasia, gastric intestinal metaplasia (GIM), and Helicobacter pylori. METHODS: Endoscopists participated in a 1-hour education session on recommended performance measures and endoscopic detection of premalignant pathologies. A controlled before and after study was performed, measuring compliance with guidelines and rates of detection of pathology in control and intervention groups. RESULTS: Over 2 years, 2719 procedures were performed: 1412 in the control group and 1307 in the intervention group. The proportion of procedures complying with guidelines was higher in the intervention group. The use of biopsy sampling protocols (eg, management of precancerous conditions of the stomach, 52% vs 91%; P = .007) and standardized terminology (eg, Forrest classification, 24% vs 68%; P < .001) was significantly higher. Detection of H pylori was higher in the intervention group (5.5% vs 9.8%, P = .003). Minimum inspection time of 7 minutes was associated with detection of BE (7.4% vs 2.0%, P < .001). CONCLUSIONS: A simple endoscopist education session enhanced the quality of UGI endoscopy by improving compliance with BSG and ESGE recommendations and increasing the detection of clinically significant pathology. A minimum inspection time of 7 minutes was associated with increased diagnostic yield and may be a feasible quality indicator for clinical practice.