Publications by authors named "Kumar Visvanathan"

73 Publications

Safety, pharmacokinetics, and pharmacodynamics of the oral TLR8 agonist selgantolimod in chronic hepatitis B.

Hepatology 2021 Mar 11. Epub 2021 Mar 11.

Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.

Background & Aims: In patients with chronic hepatitis B (CHB) infection, activation of toll-like receptor 8 (TLR8) may induce antiviral immunity and drive functional cure. Selgantolimod, a novel TLR8 agonist, was evaluated in CHB patients who were virally suppressed on oral antiviral treatment (OAV) or viremic not on OAV.

Approach & Results: In this Phase 1b study, patients were randomized 4:1 to receive either selgantolimod or placebo once-weekly. Virally suppressed patients received either 1.5 mg (for two weeks) or 3 mg (for two weeks or four weeks). Viremic patients received 3 mg for two weeks. The primary endpoint was safety as assessed by adverse events (AEs), laboratory abnormalities, and vital sign examination. Pharmacokinetic and pharmacodynamic parameters were assessed by plasma analysis. A total of 38 patients (28 virally suppressed, 10 viremic) were enrolled from 6 sites in Australia, New Zealand, and South Korea. Twenty patients (53%) experienced an AE and 32 (84%) had laboratory abnormalities, all of which were mild or moderate in severity. The most common AEs were headache (32%), nausea (24%) and dizziness (13%). With a half-life of 5 hours, no accumulation of selgantolimod was observed with multiple-dosing. Selgantolimod induced transient dose-dependent increases in serum cytokines, including IL-12p40 and IL-1RA, that are important for the expansion and activity of multiple T- cell subsets and innate immunity.

Conclusion: Selgantolimod was safe and well-tolerated in virally suppressed and viremic CHB patients and elicited cytokine responses consistent with target engagement. Further studies with longer durations of selgantolimod treatment are required to evaluate efficacy.
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http://dx.doi.org/10.1002/hep.31795DOI Listing
March 2021

A qualitative exploration of enablers for hepatitis B clinical management among ethnic Chinese in Australia.

J Viral Hepat 2021 Jun 18;28(6):925-933. Epub 2021 Mar 18.

Burnet Institute, Melbourne, VIC, Australia.

An estimated 18% of people living with chronic hepatitis B (CHB) in Australia were born in China. While guideline-based care, including regular clinical monitoring and timely treatment, prevent CHB-related cirrhosis, cancer and deaths, over three-quarters of people with CHB do not receive guideline-based care in Australia. This qualitative study aimed to identify enablers to engagement in CHB clinical management among ethnic Chinese people attending specialist care. Participants self-identified as of Chinese ethnicity and who attended specialist care for CHB clinical management were interviewed in Melbourne in 2019 (n = 30). Semi-structured interviews covered experiences of diagnosis and engagement in clinical management services, and advice for people living with CHB. Interviews were recorded with consent; data were transcribed verbatim and thematically analysed. Receiving clear information about the availability of treatment and/or the necessity of long-term clinical management were the main enablers for participants to engage in CHB clinical management. Additional enablers identified to maintain regular clinical monitoring included understanding CHB increases risks of cirrhosis and liver cancer, using viral load indicators to visualize disease status in patient-doctor communication; expectations from family, peer group and medical professionals; use of a patient recall system; availability of interpreters or multilingual doctors; and largely subsidized healthcare services. In conclusion, to support people attending clinical management for CHB, a holistic response from community, healthcare providers and the public health sector is required. There are needs for public health programmes directed to communicate (i) CHB-related complications; (ii) availability of effective and cheap treatment; and that (iii) long-term engagement with clinical management and its benefits.
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http://dx.doi.org/10.1111/jvh.13495DOI Listing
June 2021

CD8 tumor-infiltrating lymphocytes within the primary tumor of patients with synchronous metastatic colorectal carcinoma do not track with survival.

Clin Transl Immunology 2020 17;9(7):e1155. Epub 2020 Jul 17.

Peter MacCallum Cancer Centre Melbourne VIC Australia.

Objectives: Tumor-infiltrating lymphocytes (TIL), particularly CD8 TILs in patients with colorectal cancer (CRC), are highly prognostic in the early-disease stages (I-II). In metastatic disease (stage IV; mCRC), their influence is less well defined. It has presumably failed to contain tumor cells to the primary site; however, is this evident? We explored the prognostic impact of TILs at the primary site in patients who presented with mCRC.

Methods: Treatment-naïve patients (109) with mCRC were assessed for CD8 TILs and PD-L1 expression. Microsatellite instability (MSI) was evaluated by IHC for PMS2 and MSH6 proteins and/or by PCR using the Bethesda panel.

Results: Microsatellite instability-high tumors had significantly more CD8 TILs, with no significant survival advantage observed between MSI-H and microsatellite stable (MSS) tumors (12 vs 19 months,  = 0.304). TIL density for all cases had no impact on OS (low: 20 vs high: 13 months,  = 0.426), while PD-L1 of 1% or higher was associated with reduced mean survival (9.6 vs 18.9 months;  = 0.038). MSI-H tumors and associated immune cells had higher PD-L1 expression than in MSS cases. A positive correlation between PD-L1 on immune cells and CD8+ve TILs was found. A subset of MSS tumors had relatively high TILs approximating that of MSI-H tumors.

Conclusion: In contrast to early-stage CRC, the immune response in primary tumors of patients with mCRC does not appear to influence survival. A subgroup of MSS tumors was identified with increased TILs/PD-L1 comparable to MSI-H tumors, traditionally not be considered for immune checkpoint blockade and perhaps should be.
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http://dx.doi.org/10.1002/cti2.1155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484874PMC
July 2020

Validation of the TREAT-B score for hepatitis B treatment eligibility in a large Asian cohort: TREAT-B improves with age.

J Hepatol 2020 11 1;73(5):1282-1284. Epub 2020 Sep 1.

Department of Gastroenterology, St Vincent's Hospital Melbourne, 41 Victoria Pde, Fitzroy 3068, Victoria, Australia; Department of Medicine, University of Melbourne, 41 Victoria Pde, Fitzroy 3068, Victoria, Australia.

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http://dx.doi.org/10.1016/j.jhep.2020.06.031DOI Listing
November 2020

The Yin and the Yang of Treatment for Chronic Hepatitis B-When to Start, When to Stop Nucleos(t)ide Analogue Therapy.

Viruses 2020 08 25;12(9). Epub 2020 Aug 25.

Gastroenterology Department, St Vincent's Hospital Melbourne, 41 Victoria Pde, Fitzroy, VIC 3065, Australia.

Over 257 million individuals worldwide are chronically infected with the Hepatitis B Virus (HBV). Nucleos(t)ide analogues (NAs) are the first-line treatment option for most patients. Entecavir (ETV) and tenofovir disoproxil fumarate (TDF) are both potent, safe antiviral agents, have a high barrier to resistance, and are now off patent. They effectively suppress HBV replication to reduce the risk of cirrhosis, liver failure, and hepatocellular carcinoma (HCC). Treatment is continued long-term in most patients, as NA therapy rarely induces HBsAg loss or functional cure. Two diverging paradigms in the treatment of chronic hepatitis B have recently emerged. First, the public health focussed "treat-all" strategy, advocating for early and lifelong antiviral therapy to minimise the risk of HCC as well as the risk of HBV transmission. In LMICs, this strategy may be cost saving compared to monitoring off treatment. Second, the concept of "stopping" NA therapy in patients with HBeAg-negative disease after long-term viral suppression, a personalised treatment strategy aiming for long-term immune control and even HBsAg loss off treatment. In this manuscript, we will briefly review the current standard of care approach to the management of hepatitis B, before discussing emerging evidence to support both the "treat-all" strategy, as well as the "stop" strategy, and how they may both have a role in the management of patients with chronic hepatitis B.
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http://dx.doi.org/10.3390/v12090934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7552074PMC
August 2020

Serum alanine aminotransferase flares in chronic hepatitis B infection: the good and the bad.

Lancet Gastroenterol Hepatol 2020 04 10;5(4):406-417. Epub 2020 Feb 10.

Toronto Centre for Liver Disease, Toronto General Hospital, University of Toronto, Toronto, ON, Canada. Electronic address:

Chronic hepatitis B virus (HBV) infection follows a dynamic and variable course. At different stages in the disease, hepatitis flares might occur, which can be challenging to predict and manage. Flares are believed to be primarily immune-mediated and might mark transitions to inactive disease or clearance of infection, but in certain scenarios they might also lead to hepatic decompensation or death. As such, understanding of the clinical significance of flares in different patient populations and different scenarios is important for optimal management. In this Review, we summarise what is known about flares in different stages of chronic HBV infection; describe flares in the context of the natural history of chronic infection; summarise the immunological mechanisms underlying flares, and describe flares in different clinical scenarios. Each section reviews existing knowledge and highlights key unanswered questions that need to be addressed to improve the understanding of flares, hopefully providing insights into their pathogenesis that can be used to improve current clinical management and ideally to further develop new curative therapeutic approaches for HBV infection. We also propose a working definition of an ALT flare to facilitate future research.
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http://dx.doi.org/10.1016/S2468-1253(19)30344-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7158588PMC
April 2020

The QuantiFERON Monitor assay is predictive of infection post allogeneic hematopoietic cell transplantation.

Transpl Infect Dis 2020 Jun 29;22(3):e13260. Epub 2020 Feb 29.

University of Melbourne, Melbourne, Vic., Australia.

Introduction: Following allogeneic hematopoietic stem cell transplantation (alloHCT), excessive immunosuppression can be complicated by infection, while inadequate immunosuppression can result in graft-vs-host disease (GVHD). An accurate method to assess overall immune status post HCT is lacking. The QuantiFERON Monitor (QFM) assay measures interferon gamma (IFN-γ) release from whole blood following incubation with both innate (Toll-like receptor 7, TLR7) and adaptive (CD3 antibody) stimulants and may result in a more complete assessment of the immune system.

Methods: Whole blood samples were prospectively collected from alloHCT recipients at conditioning followed by days 10, 30, 60, 90, 120, and 180 post-transplant and assayed by the QFM test. IFN-γ levels were correlated to time post HCT and episodes of infection and GVHD.

Results: Forty patients were enrolled in the study (68% male; median age 47 years; 58% matched related donors, 42% unrelated; 33% myeloablative). Post-stimulation IFN-γ levels rose steadily over the first 180 days post transplantation. IFN-γ levels were significantly lower in those with active infection compared to those without during the neutropenic period (P < .001). The assay was predictive of CMV reactivation (VL > 1000 copies/mL) post alloHCT (P = .001).

Conclusion: This is a promising assay to demonstrate immune recovery and predict risk of infection after alloHCT and may allow tailoring of immunosuppression, antimicrobial treatment, and prophylaxis.
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http://dx.doi.org/10.1111/tid.13260DOI Listing
June 2020

Safety, pharmacokinetics, and antiviral effects of ABI-H0731, a hepatitis B virus core inhibitor: a randomised, placebo-controlled phase 1 trial.

Lancet Gastroenterol Hepatol 2020 02 9;5(2):152-166. Epub 2019 Nov 9.

Assembly Biosciences, San Francisco, CA, USA.

Background: Therapies with novel mechanisms of action against hepatitis B virus (HBV) infection are being explored with the goal of achieving a functional cure (sustained off-treatment response) without requiring lifelong therapy. We aimed to evaluate the pharmacokinetics, safety, and antiviral activity of ABI-H0731, an investigational inhibitor of the HBV core protein.

Methods: This phase 1, randomised, placebo-controlled study was done in two parts. In part 1, healthy adults without hepatitis B aged 18-65 years at one clinical research centre in New Zealand (eight participants per dose cohort) were randomly assigned (3:1) to receive single oral doses of ABI-H0731 (100, 300, 600, or 1000 mg) or matching placebo, or once-daily or twice-daily doses of ABI-H0731 800 mg or matching placebo for 7 days. In part 2, adults aged 18-65 years at clinical research centres in New Zealand, Australia, the UK, Hong Kong, Taiwan, and South Korea with chronic HBV (12 participants per dose cohort) were randomly assigned (5:1) to receive ABI-H0731 (100, 200, 300, or 400 mg) or matching placebo once daily for 28 days. In part 2, participants were required to have HBeAg-positive or HBeAg-negative chronic HBV infection, with serum HBV DNA concentrations of at least 2 × 10 IU/mL (HBeAg-positive) or 2 × 10 IU/mL (HBeAg-negative) and serum alanine aminotransferase concentrations less than seven times the upper limit of normal. Both parts used simple randomisation, with study participants, site personnel, and study monitors masked to treatment assignments. The primary study objective was dose-related safety and tolerability of ABI-H0731 in healthy volunteers and in participants with chronic HBV infection, assessed in all treated participants. Key secondary assessments included pharmacokinetic analyses and virological responses. This study is registered with ClinicalTrials.gov, identifier NCT02908191 and is completed.

Findings: 48 [61%] of 79 healthy volunteers were enrolled in the single-ascending or multiple-ascending dose phase of part 1 between Nov 16, 2016, and Jan, 27, 2017. 38 [55%] of 69 HBV-infected participants were enrolled in part 2 between June 15, 2017, and March 15, 2018. All adverse events were non-specific and of mild or moderate intensity apart from a single HBV-infected participant given the 400 mg dose who developed a severe (grade 3) maculopapular rash and terminated treatment. Overall, the most frequent adverse events of any grade among the 74 participants who received ABI-H0731 were headache (11 [15%]), influenza-like illness (seven [9%]), and dizziness (six [8%]); the most frequent adverse events considered treatment-related were rash (four [5%]) and dizziness (three [4%]). In part 1, ABI-H0731 reached maximum plasma concentrations (T) in 2·50-4·17 h; the mean plasma half-life (t) was 23·5-28·4 h. In part 2, mean maximum HBV DNA declines from baseline were 1·7 log IU/mL in the 100 mg dose cohort, 2·1 log IU/mL in the 200 mg dose cohort, and 2·8 log IU/mL in the 300 mg dose cohort. Across dose cohorts, serum HBV RNA declines correlated with HBV DNA declines.

Interpretation: No pattern of treatment-emergent adverse events was observed at ABI-H0731 doses up to 300 mg in individuals with chronic hepatitis B. ABI-H0731 was rapidly absorbed and exhibited a plasma half-life supportive of once-daily dosing. Dose-dependent decreases in serum HBV DNA and RNA concentrations are consistent with the proposed mechanism of action.

Funding: Assembly Biosciences.
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http://dx.doi.org/10.1016/S2468-1253(19)30346-2DOI Listing
February 2020

Screening and Prophylaxis to Prevent Hepatitis B Reactivation: Other Populations and Newer Agents.

Clin Liver Dis 2019 08 5;23(3):521-534. Epub 2019 Jun 5.

University of Melbourne, Grattan Street, Parkville, Victoria 3010, Australia; St Vincent's Hospital, 41 Victoria Street, Fitzroy, Victoria 3065, Australia.

Because of the relatively high prevalence of both hepatitis B infection and various forms of autoimmune inflammatory diseases treated with aggressive immunotherapy, reactivation of hepatitis B occurs in a substantial number of patients. The risk of reactivation depends on the degree and duration of immunosuppression. A large number of drug treatments have resulted in reactivation of hepatitis B virus infection and, based on the mechanisms and extent of immunosuppression, recommendations for some of the newer classes of immunosuppressive drugs are provided.
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http://dx.doi.org/10.1016/j.cld.2019.04.012DOI Listing
August 2019

Screening and Prophylaxis to Prevent Hepatitis B Reactivation: Patients with Hematological and Solid Tumor Malignancies.

Clin Liver Dis 2019 08 6;23(3):511-519. Epub 2019 Jun 6.

University of Melbourne, Grattan Street, Parkville, Victoria 3010, Australia; St Vincent's Hospital, 41 Victoria Street, Fitzroy, Victoria 3065, Australia.

Patients with malignancies require chemotherapy and other immunosuppressive therapies for treatment. Because of this immunosuppression, in patients who have ever been exposed to hepatitis B it is possible for reactivation to occur. This reactivation can be fatal. Reactivation is particularly likely in patients who receive B cell-active agents such as rituximab. The occurrence of reactivation flares may also delay further chemotherapy, which can negatively affect the outcome of the underlying malignancy. Accordingly, it is important to screen patients for markers of hepatitis B and institute antiviral prophylaxis to prevent reactivation.
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http://dx.doi.org/10.1016/j.cld.2019.04.011DOI Listing
August 2019

Screening and Prophylaxis to Prevent Hepatitis B Reactivation: Transplant Recipients.

Clin Liver Dis 2019 08 6;23(3):493-509. Epub 2019 Jun 6.

University of Melbourne, Grattan Street, Parkville, Victoria 3010, Australia; St Vincent's Hospital, 41 Victoria Street, Fitzroy, Victoria 3065, Australia.

Organ transplantation is a lifesaving procedure for many patients. To prevent rejection or graft-versus-host disease, recipients require long-term immunosuppression. In patients who have ever been exposed to hepatitis B, it is possible for reactivation to occur; this includes patients who are anti-hepatitis B core antibody-positive only or both anti-hepatitis B core antibody-positive and hepatitis B surface antibody-positive. The susceptibility to this varies with the nature of the transplant. Hepatitis B can be transmitted from donor to recipient. It is important to assess the hepatitis B status and formulate a strategy to prevent transmission and prevent reactivation.
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http://dx.doi.org/10.1016/j.cld.2019.04.010DOI Listing
August 2019

Screening and Prophylaxis to Prevent Hepatitis B Reactivation: Introduction and Immunology.

Clin Liver Dis 2019 08 6;23(3):487-492. Epub 2019 Jun 6.

University of Melbourne, Grattan Street, Parkville, Victoria 3010, Australia; St Vincent's Hospital, 41 Victoria Street, Fitzroy, Victoria 3065, Australia.

Current recommendations concerning hepatitis C virus (HBV) reactivation are limited, with nearly all guidelines focused on its occurrence in patients with hematological malignancies or some solid tumors, who are treated with immunosuppressive therapies. Few of the guidelines address reactivation in patients receiving immunosuppression with organ transplants or treatment with any of the many immunosuppressive agents in use today for the treatment of multiple different diseases, or in patients receiving the direct-acting antivirals used in the treatment of hepatitis C virus (HCV). This article covers the immunology of HBV reactivation, mechanisms of viral clearance, and recommendations for screening and prophylaxis.
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http://dx.doi.org/10.1016/j.cld.2019.04.009DOI Listing
August 2019

Secreted and intracellular cytokines are complementary measures for human monocytes treated with Toll-like receptor agonists.

J Immunol Methods 2019 01 3;464:131-137. Epub 2018 Nov 3.

Department of Medicine, University of Melbourne, Melbourne, Australia; Immunology Research Centre, St. Vincent's Hospital, Melbourne, VIC, Australia. Electronic address:

Cytokine production by human peripheral blood mononuclear cells including monocytes, is frequently assessed by measuring secreted cytokines using enzyme linked immunosorbent assay (ELISA), whereby the total concentration of one cytokine of interest is obtained without information regarding the cell type responsible for making the cytokine. Cytokines can be retained inside the cell using protein transport inhibitors. Subsequent analysis by flow cytometry not only identifies the cell type producing the cytokine but can semi-quantitate the amount of cytokine produced by measuring the geometric mean fluorescence intensity (gMFI) and is amenable to analyzing more than one protein associated with the same cell (multiplexing). We hypothesized that a more comprehensive and biologically meaningful cytokine profile could be acquired by measuring both secreted and the retained intracellular cytokines in parallel cultures of magnetic-sorted CD14+ monocytes. Peripheral monocytes were isolated from 18 healthy donors and treated with standardized molecules that stimulate cytokine production; Toll-like receptor (TLR)4 agonist (lipopolysaccharide, LPS) or TLR7/8 agonist (R848). Pro-inflammatory cytokines (interleukin (IL)-6, IL-8 and tumour necrosis factor (TNF)) secreted into the culture medium were measured by ELISA. Parallel cultures were treated with LPS and R848 in the presence of brefeldin A (protein transport inhibitor) and the accumulated intracellular cytokines measured by flow cytometry. Each cytokine (IL-6/IL-8/TNF) gave a unique general pattern when secreted versus intracellular cytokine measurements (frequency and gMFI) were plotted to determine correlation. For monocytes treated with the TLR4 agonist, secreted IL-8 correlated with the frequency of IL-8 positive cells (R = 0.559, p = .016) and not with the amount (gMFI) of IL-8 per cell. In contrast, monocytes treated with the TLR7/8 agonist showed no correlation of secreted IL-8 with the frequency of IL-8 positive cells, but with this treatment secreted IL-6 was correlated with an increase in the frequency of IL-6 positive cells (R = 0.501, p = .034). TNF secretion from monocytes treated with either the TLR4 or TLR7/8 agonist did not correlate with the frequency or gMFI of TNF positive cells. However, there were significant correlations between the TLR4 and TLR7/8 induced TNF response (secreted and gMFI). We conclude that there are fundamental differences in secreted and intracellular IL-6/IL-8/TNF production after monocytes are treated with TLR agonists. Furthermore, secreted and intracellular cytokine analyses are complementary measures that should be used in parallel to explore inflammatory response and cytokine biology.
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http://dx.doi.org/10.1016/j.jim.2018.11.003DOI Listing
January 2019

Levels of regulatory B cells do not predict serological responses to hepatitis B vaccine.

Hum Vaccin Immunother 2018 06 11;14(6):1483-1488. Epub 2018 Apr 11.

a Department of Infectious diseases , Aarhus University Hospital , Aarhus N , Midtjylland , Denmark.

This study investigated the immunomodulatory influence of IL10 producing B regulatory cells, Bregs (CD19+CD24hiCD38hi) to standard Twinrix® vaccination. We also investigated HBsAg specific T-cell mediated IFN-γ responses to Twinrix® which in theory could provide effective immunity despite low anti-HBs titer. A total of 309 hepatitis B negative health care students and workers completed a standard Twinrix® vaccination schedule (0, 1 and 6 months). Depending on the vaccination response the participants were divided in to non-, low- and high responders according to anti-HBs titer (<10, <100 and >1000 mIU/mL respectively) two months after completed vaccination schedule. Blood samples from baseline and after vaccination from all non- and low-responders (23 participants) and the same number of high-responders were used for flow cytometric analyses of IL10 producing Bregs and T-cell mediated IFN-γ responses. A decrease in levels of IL10 producing Bregs was observed after vaccination in high responders compared to non- and low-responders. Compiling non-and low-responders against high-responders showed a lower T-cell mediated IFN-γ response at baseline in non-and low-responders when stimulated with Engerix® vaccine. In contrary no positive correlation between IL10 producing Bregs or IFN-γ positive T-cells and anti-HBs titer was observed. Hence this study cannot prove that levels of IL10 producing Bregs or IFN-γ positive T cell affect HBV vaccine response.
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http://dx.doi.org/10.1080/21645515.2018.1441653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6037437PMC
June 2018

Clinical variation in the use of echocardiography in Staphylococcus aureus bacteraemia: a multi-centre cohort study.

Eur J Clin Microbiol Infect Dis 2018 Mar 22;37(3):469-474. Epub 2018 Jan 22.

School of Public Health and Preventative Medicine, Monash University, Melbourne, Australia.

The objective of this investigation was to assess whether between-hospital variation in echocardiography usage for patients with Staphylococcus aureus bacteraemia (SAB) is explained by differences in patients' pre-test probability of endocarditis. This was a retrospective cohort study at three neighbouring hospitals in Australia. Consecutive episodes of SAB were reviewed for the presence of three endocarditis risk factors (community onset, prolonged bacteraemia and the presence of an intracardiac prosthetic device) and the performance and results of all echocardiography studies within 30 days. Multivariate logistic regression was used to examine the effect of hospital site on the performance of (i) transoesophageal and (ii) transthoracic echocardiography controlling for major endocarditis risk factors. Significant variation in echocardiography usage was demonstrated between sites in a total cohort of 1167 episodes of SAB. None of the three sites were found to exhibit echocardiography usage that could be considered consistent with current guidelines, and each differed from the guidelines in different ways. Hospital site, rather than endocarditis risk factors, was the strongest predictor of transthoracic echocardiography use; however, the use of transoesophageal echocardiography was strongly predicted by endocarditis risk factors. Variation in echocardiography use between these hospitals is not adequately explained by differences in the risk factor profile of their SAB cohorts.
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http://dx.doi.org/10.1007/s10096-018-3192-zDOI Listing
March 2018

A novel immune function biomarker identifies patients at risk of clinical events early following liver transplantation.

Liver Transpl 2017 04;23(4):487-497

Liver Transplant Unit.

Balancing immunosuppression after liver transplant is difficult, with clinical events common. We investigate whether a novel immune biomarker based on a laboratory platform with widespread availability that measures interferon γ (IFNγ) after stimulation with a lyophilized ball containing an adaptive and innate immune stimulant can predict events following transplantation. A total of 75 adult transplant recipients were prospectively monitored in a blinded, observational study; 55/75 (73.3%) patients experienced a total of 89 clinical events. Most events occurred within the first month. Low week 1 results were significantly associated with risk of early infection (area under the receiver operating characteristic curve [AUROC], 0.74; P = 0.008). IFNγ ≤ 1.30 IU/mL (likelihood ratio positive, 1.93; sensitivity, 71.4%; specificity, 63.0%) was associated with the highest risk for infection with minimal rejection risk. Nearly half the cohort (27/60, 45.0%) expressed IFNγ ≤ 1.30 IU/mL. Moreover, an elevated week 1 result was significantly associated with the risk of rejection within the first month after transplant (AUROC, 0.77; P = 0.002), but no episodes of infection. On multivariate logistic regression, IFNγ ≥ 4.49 IU/mL (odds ratio, 4.75) may be an independent predictor of rejection (P = 0.05). In conclusion, low IFNγ suggesting oversuppression is associated with infections, whereas high IFNγ indicating undersuppression is associated with rejection. This assay offers the potential to allow individualization and optimization of immunosuppression that could fundamentally alter the way patients are managed following transplantation. Liver Transplantation 23 487-497 2017 AASLD.
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http://dx.doi.org/10.1002/lt.24730DOI Listing
April 2017

Immune function biomarker QuantiFERON-monitor is associated with infection risk in cirrhotic patients.

World J Hepatol 2016 Dec;8(35):1569-1575

Siddharth Sood, Department of Gastroenterology and Hepatology, University of Melbourne, Royal Melbourne Hospital, Parkville, VIC 3050, Australia.

Aim: To investigate whether a novel immune function biomarker QuantiFERON-Monitor (QFM) can identify cirrhotic patients at greatest risk of infection.

Methods: Adult cirrhotic patients on the liver transplant waiting list were recruited for this observational cohort study from a tertiary liver transplant referral unit. The immune function biomarker, QFM was performed using the same method as the widely available Quantiferon-gold assay, and measures output in interferon gamma in IU/mL after dual stimulation of the innate and adaptive immune systems. Ninety-one cirrhotic patients were recruited, with 47 (52%) transplanted on the day of their QFM. The remaining 44 (48%) were monitored for infections until transplant, death, or census date of 1 February 2014.

Results: Cirrhotic patients express a median QFM significantly lower than healthy controls (94.5 IU/mL 423 IU/mL), demonstrating that they are severely immunosuppressed. Several factors including model for end stage liver disease, presence of hepatocellular carcinoma, bilirubin, international normalized ratio and haemoglobin were associated with QFM on univariate analysis. Disease aetiology did not appear to impact QFM. On multivariate analysis, only Child-Pugh score and urea were significantly associated with a patient's immune function as objectively measured by QFM. In the 44 patients who were not transplanted immediately after their blood test and could be monitored for subsequent infection risk, 13 (29.5%) experienced a pre-transplant infection a median 20 d (range 2-182) post-test. QFM < 214 IU/mL was associated with HR = 4.1 ( = 0.01) for infection. A very low QFM < 30 IU/mL was significantly associated ( = 0.003) with death in three patients who died while awaiting transplantation (HR = 56.6).

Conclusion: QFM is lower in cirrhotics, allowing objective determinations of an individual's unique level of immune dysfunction. Low QFM was associated with increased susceptibility to infection.
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http://dx.doi.org/10.4254/wjh.v8.i35.1569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5165271PMC
December 2016

High cut-off hemofiltration versus standard hemofiltration: effect on plasma cytokines.

Int J Artif Organs 2016 Nov 10;39(9):479-486. Epub 2016 Nov 10.

Gambro Dialysatoren GmbH, Research & Development, Hechingen - Germany.

Purpose: To study the effects of continuous veno-venous hemofiltration (CVVH) with high cut-off filters (CVVH-HCO) on plasma cytokine levels, sieving coefficient and clearance compared to CVVH using standard filters (CVVH-Std) in a nested cohort within a double-blind randomized controlled trial in severe acute kidney injury (AKI) patients.

Methods: We measured plasma and post-filter levels of IL-6, TNF-alpha, IL-8, IL-1 beta, RANTES, IL-10, IFN-gamma and IFN-alpha in both study groups. We also measured cytokine levels in the ultrafiltrate and calculated sieving coefficients and clearances.

Results: By 72 hours of treatment, IL-6 had decreased during both treatments (p = 0.009 and 0.005 respectively). In contrast, IL-10 had decreased with CVVH-Std (p = 0.03) but not CVVH-HCO (p = 0.135). None of the other cytokines showed changes over time. There were also no significant between group differences in plasma levels for each cytokine over the 72-hour treatment period. For all cytokines combined, however, the median sieving coefficient was higher for CVVH-HCO (0.31 vs. 0.16; p = 0.042) as was the mass removal rate by ultrafiltration (p = 0.027). While overall combined cytokine levels had fallen to 62.2% of baseline at 72 hours for CVVH-HCO (p<0.0001) and to 75.9% of baseline with CVVH-Std (p = 0.008) there were no between group differences.

Conclusions: CVVH-HCO achieved greater combined sieving coefficient and mass removal rate by ultrafiltration for a group of key cytokines than CVVH-Std. However, this effect did not differentially lower their plasma level over the first 72 hours. Our study does not support the use of CVVH-HCO to lower cytokines in critically ill patients with AKI.
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http://dx.doi.org/10.5301/ijao.5000527DOI Listing
November 2016

An Overview of the Innate and Adaptive Immune System in Inflammatory Bowel Disease.

Inflamm Bowel Dis 2017 01;23(1):2-13

*Department of Gastroenterology, The Austin Hospital, Melbourne, Australia; †Department of Gastroenterology, St Vincent's Hospital, Melbourne, Australia; ‡Department of Medicine, Austin Academic Centre, University of Melbourne, Melbourne, Australia; and §Department of Medicine, Eastern Hill Academic Centre, University of Melbourne, Melbourne, Australia.

Inflammatory bowel diseases (IBDs) are thought to develop as a result of complex interactions between host genetics, the immune system and the environment including the gut microbiome. Although an improved knowledge of the immunopathogenesis of IBDs has led to great advances in therapy such as the highly effective anti-tumor necrosis factor class of medications, a significant proportion of patients with Crohn's disease and ulcerative colitis do not respond to anti-tumor necrosis factor antibodies. Further understanding of the different immune pathways involved in the genesis of chronic intestinal inflammation is required to help find effective treatments for IBDs. In this review, the role of the mucosal innate and adaptive immune system in IBD is summarized, highlighting new areas of discovery which may hold the key to identifying novel predictive or prognostic biomarkers and new avenues of therapeutic discovery.
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http://dx.doi.org/10.1097/MIB.0000000000000955DOI Listing
January 2017

Toll-like Receptor Expression and Signaling in Peripheral Blood Mononuclear Cells Correlate With Clinical Outcomes in Acute Hepatitis C Virus Infection.

J Infect Dis 2016 09 9;214(5):739-47. Epub 2016 Jun 9.

Department of Infectious Diseases, Royal Melbourne Hospital.

Background: Mechanisms by which spontaneous clearance of acute hepatitis C occurs are unclear. A critical role for the innate immune system and IFNL4 polymorphisms has been proposed. This study investigates whether Toll-like receptor (TLR) expression and signaling during acute hepatitis C correlates with clinical outcomes.

Methods: Participants identified from the Australian Trial in Acute Hepatitis C and the Networks study were followed longitudinally from the time of diagnosis of acute hepatitis C. Peripheral blood mononuclear cells (PBMCs) and plasma were collected at and 2 time points after diagnosis. At each time point, TLR2, TLR4, and CD86 expression on peripheral blood monocytes, natural killer (NK) cells, and NK T cells was measured, as well as the response of PBMCs to stimulation with TLR ligands. Cytokine and chemokine levels were measured in stimulated PBMCs and plasma.

Results: We identified 20 participants with acute hepatitis C (10 with hepatitis C virus [HCV] monoinfection and 10 with HCV and human immunodeficiency virus coinfection). Eleven participants (55%) spontaneously cleared HCV. Acute hepatitis C and spontaneous clearance was associated with lower TLR4 expression on monocytes (P = .009) and NK cells (P = .029). Acute hepatitis C and spontaneous clearance was also associated with a reduced interferon γ response to TLR4 (P = .038) and TLR7/8 stimulation (P = .035), a reduced interleukin 6 response to TLR7/8 stimulation (P = .037), and reduced IFN-γ-inducible protein 10 (IP-10) response to TLR2 stimulation (P = .042). Lower plasma IP-10 levels were associated with spontaneous clearance (P = .001).

Conclusions: These findings implicate TLR4 signaling as playing a critical role in the outcome of acute hepatitis C.
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http://dx.doi.org/10.1093/infdis/jiw235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4978374PMC
September 2016

Nucleosome levels and toll-like receptor expression during high cut-off haemofiltration: a pilot assessment.

Crit Care Resusc 2015 Dec;17(4):239-43

Gambro Dialysatoren GmbH, Research and Development, Hechingen, Germany.

Objectives: To measure plasma nucleosome levels and expression of toll-like receptors (TLRs) in a pilot cohort of patients with severe acute kidney injury (AKI) within a randomised controlled trial of continuous venovenous haemofiltration with high cut-off filters (CVVH-HCO) v standard filters (CVVH-std).

Methods: We measured plasma nucleosome levels using the Cell Death Detection ELISA PLUS (10X) assay kit. We analysed plasma levels for correlation with disease severity and compared the effects of CVVH-HCO and CVVH-std on plasma nucleosome levels over the first 72 hours. We studied cell surface TLR expression on CD14-positive monocytes in a subcohort of CVVH-HCO patients.

Results: We did not detect nucleosomes in normal human plasma, but found elevated nucleosome levels in patients with severe AKI. Nucleosome levels at randomisation correlated weakly with Acute Physiology and Chronic Health Evaluation III scores (Pearson ρ=0.475, P=0.016). Treatment with CVVH-HCO or CVVH-std had no effect on nucleosome levels over 72 hours. The mean fluorescence intensity (MFI) ratios of TLR2 and TLR4 expression were elevated throughout the 72-hour period (range for TLR2, 0.97-3.98; range for TLR4, 0.91-10.18) and did not appear to decrease as a result of treatment with CVVH-HCO.

Conclusions: Nucleosome concentration was elevated in the plasma of patients with severe AKI and mildly correlated with disease severity, but was not affected by treatment with CVVH-HCO or CVVH-std. Similarly, levels of TLR2 and TLR4 expression did not decrease over time during CVVHCrit HCO treatment.
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December 2015

Managing HBV in pregnancy. Prevention, prophylaxis, treatment and follow-up: position paper produced by Australian, UK and New Zealand key opinion leaders.

Gut 2016 Feb 15;65(2):340-50. Epub 2015 Oct 15.

Department of Infectious Diseases, Royal Melbourne Hospital, Melbourne, Victoria, Australia.

Hepatitis B during pregnancy presents unique management issues for both the mother and fetus. These include the lack of a current cohesive strategy for treatment and follow-up of mothers and their babies; the uncertain risk of postpartum HBV flares; the lack of randomised trial data on the safety and efficacy of antiviral treatment in pregnancy; the lack of head-to-head studies comparing different antivirals in pregnancy; and the lack of epidemiologic information regarding infection across different populations globally. This position paper provides a comprehensive review of the management of women with HBV infection prior to conception, throughout each stage of pregnancy and postpartum, as well as recommendations and clinical approaches for the follow-up of children born to infected mothers, based on available evidence in the literature and recommendations from international experts. Prevention of perinatal transmission is an important component of global efforts to reduce the burden of chronic HBV since vertical transmission is responsible for most of the chronic infection worldwide.
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http://dx.doi.org/10.1136/gutjnl-2015-310317DOI Listing
February 2016

Targeted individual prophylaxis offers superior risk stratification for cytomegalovirus reactivation after liver transplantation.

Liver Transpl 2015 Dec 5;21(12):1478-85. Epub 2015 Nov 5.

Liver Transplant Unit Victoria, Austin Health, Melbourne, Australia.

Cytomegalovirus (CMV) can reactivate following liver transplantation. Management of patients currently considered low risk based on pretransplant serology remains contentious, with universal prophylaxis and preemptive strategies suffering from significant deficiencies. We hypothesized that a CMV-specific T cell assay performed early after transplant as part of a preemptive strategy could better stratify "low-risk" (recipient seropositive) patients. We conducted a prospective, blinded, observational study in 75 adult recipients. QuantiFERON-cytomegalovirus was performed both before and at multiple times after transplant. Low-risk patients (n = 58) were monitored as per unit protocol and treatment was commenced if CMV > 1000 copies/mL (DNAemia). Twenty patients needed antiviral treatment for other reasons and were censored (mainly for rejection or herpes simplex virus infection); 19/38 (50%) of the remaining low-risk patients developed DNAemia at mean 34.6 days after transplant. A week 2 result of <0.1 IU/mL was significantly associated with risk of subsequent DNAemia (hazard ratio [HR], 6.9; P = 0.002). The positive predictive value of 80% suggests these patients are inappropriately labeled low risk and are actually at high likelihood of CMV reactivation. A secondary cutoff of <0.2 IU/mL was associated with moderate risk (HR, 2.8; P = 0.01). In conclusion, a protocol based on a single early CMV-specific T cell based assay would offer improved risk stratification and individualization of patient management after transplant. This could offer improved drug and service utilization and potentially result in significant improvements over both currently used protocols to manage supposedly low-risk patients.
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http://dx.doi.org/10.1002/lt.24216DOI Listing
December 2015

The oral toll-like receptor-7 agonist GS-9620 in patients with chronic hepatitis B virus infection.

J Hepatol 2015 Aug 27;63(2):320-8. Epub 2015 Feb 27.

Seoul National University College of Medicine, Seoul, Republic of Korea.

Background & Aims: GS-9620 is an oral agonist of toll-like receptor 7, a pattern-recognition receptor whose activation results in innate and adaptive immune stimulation. We evaluated the safety, pharmacokinetics, and pharmacodynamics of GS-9620 in patients with chronic hepatitis B.

Methods: In two double-blind, phase 1b trials of identical design, 49 treatment-naïve and 51 virologically suppressed patients were randomized 5:1 to receive GS-9620 (at doses of 0.3mg, 1mg, 2mg, 4mg) or placebo as a single dose or as two doses seven days apart. Pharmacodynamic assessment included evaluation of peripheral mRNA expression of interferon-stimulated gene 15 (ISG15), serum interferon gamma-induced protein 10 and serum interferon (IFN)-alpha.

Results: Overall, 74% of patients were male and 75% were HBeAg negative at baseline. No subject discontinued treatment due to adverse events. Fifty-eight percent experienced ⩾1 adverse event, all of which were mild to moderate in severity. The most common adverse event was headache. No clinically significant changes in HBsAg or HBV DNA levels were observed. Overall, a transient dose-dependent induction of peripheral ISG15 gene expression was observed peaking within 48 hours of dosing followed by return to baseline levels within seven days. Higher GS-9620 dose, HBeAg positive status, and low HBsAg level at baseline were independently associated with greater probability of ISG15 response. Most patients (88%) did not show detectable levels of serum IFN-alpha at any time point.

Conclusions: Oral GS-9620 was safe, well tolerated, and associated with induction of peripheral ISG15 production in the absence of significant systemic IFN-alpha levels or related symptoms.
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http://dx.doi.org/10.1016/j.jhep.2015.02.037DOI Listing
August 2015

Clinical and virological predictors of hepatic flares in pregnant women with chronic hepatitis B.

Gut 2015 Nov 27;64(11):1810-5. Epub 2014 Nov 27.

Department of Infectious Diseases, Alfred Hospital and Monash University, Melbourne, Victoria, Australia Victorian Infectious Diseases Service, Royal Melbourne Hospital at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.

Background: Unique immunological changes occur during pregnancy; the impact of which, on virological and biochemical markers of hepatitis B infection is not well established. Rapid changes in the immunological profile post partum and consequent rebound of the inflammatory response may result in hepatic flares.

Methods: Women with chronic hepatitis B were recruited during pregnancy into this observational study. Demographic and clinical data were collected together with virological and biochemical parameters at two time points during pregnancy (early and late) and two time points post partum (between 6 weeks and 12 weeks and at 12 months). Outcomes analysed included changes in HBV DNA, hepatitis B e antigen (HBeAg) status and flares of hepatitis.

Results: One hundred and twenty-six women were recruited. Twenty-seven women out of 108 with postpartum bloods (25%) met our definition of a postpartum flare (ALT range 38-1654). Using univariate analysis HBeAg status, younger age, gravida and parity were associated with a flare. On multivariate analysis HBeAg positivity at baseline fell just outside of statistical significance in predicting a postpartum flare (p=0.051).

Conclusions: 25% of women with chronic hepatitis B will demonstrate increased liver inflammation in the postpartum period. This is usually asymptomatic and resolves spontaneously. This is more likely if the woman is HBeAg-positive at baseline (2.56 times the risk), although flares also commonly occur in HBeAg-negative women.
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http://dx.doi.org/10.1136/gutjnl-2014-308211DOI Listing
November 2015

Age: HIV knows no boundary.

Med J Aust 2014 Oct;201(8):481-2

St Vincent's Hospital, Melbourne, VIC, Australia.

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http://dx.doi.org/10.5694/mja14.00737DOI Listing
October 2014

Macrophage migration inhibitory factor: a potential biomarker for cardiovascular disease in persons with HIV?

AIDS 2014 Jul;28(11):1693-4

aDepartment of Medicine, Monash University bDepartment of Infectious Diseases, Alfred Hospital cDepartment of Infectious Diseases, Monash Medical Centre dBurnet Institute, Melbourne, Victoria, Australia.

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http://dx.doi.org/10.1097/QAD.0000000000000276DOI Listing
July 2014

A novel biomarker of immune function and initial experience in a transplant population.

Transplantation 2014 Apr;97(8):e50-1

1Liver Transplant Unit Victoria Austin Health, University of Melbourne Melbourne, Australia 2Cellestis Ltd, Melbourne Australia 3Innate Immunity Laboratory St. Vincent's Hospital, University of Melbourne Melbourne, Australia.

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http://dx.doi.org/10.1097/TP.0000000000000078DOI Listing
April 2014

ITPA genotype protects against anemia during peginterferon and ribavirin therapy but does not influence virological response.

Hepatology 2014 Jun 25;59(6):2152-60. Epub 2014 Apr 25.

St Vincent's Hospital, University of Melbourne, Melbourne, VIC, Australia; Department of Medicine, University of Melbourne, Melbourne, VIC, Australia.

Unlabelled: On-treatment anemia is associated with higher sustained virological response (SVR) rates during peginterferon plus ribavirin (RBV) therapy. Inosine triphosphatase (ITPA) variants causing ITPase deficiency have been shown to protect against RBV-induced anemia. However, ITPase activity has not been associated with SVR. To study this discrepancy, we examined the relationships between ITPase activity, on-treatment anemia, SVR, and RBV levels in hepatitis C virus genotype 1 (HCV-1) patients from the CHARIOT study. ITPA genotype (rs7270101, rs1127354) was used to define ITPase activity in 546 patients. Plasma RBV levels were measured using high-performance liquid chromatography (HPLC). Relationships between ITPase activity, on-treatment hemoglobin (Hb) levels, RBV levels, and SVR were tested using regression modeling, survival analysis, and locally weighted scatterplot smoothing (LOWESS) plot analysis. Hb decline was independently associated with SVR (P<0.0001). ITPase deficiency was present in 35%. ITPase deficiency strongly protected against Hb decline (P<0.0001), but was not associated with SVR (P=0.28). The probability of SVR increased with lower nadir Hb for both wild-type and deficient ITPase activity, but the association curve shifted to describe a parallel relationship at higher Hb levels in patients with ITPase deficiency. In a subset (n=203), we tested the hypothesis that the association between Hb decline and SVR reflected RBV levels rather than actual Hb level. RBV levels were associated with on-treatment Hb decline and SVR, but not ITPase activity. In regression models, adjustment for RBV levels attenuated the association between Hb decline and SVR.

Conclusion: ITPase deficiency protects against RBV-induced anemia, but is not associated with SVR. Our data suggest that the relationship between Hb decline and SVR is not mechanistic, but is linked to RBV levels.
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http://dx.doi.org/10.1002/hep.27022DOI Listing
June 2014

TLR2 and TLR4 in healthy children: age and gender differences.

J Paediatr Child Health 2013 Dec;49(12):1082-3

Department of Gastroenterology and Clinical Nutrition, Royal Children's Hospital, Melbourne, Victoria, Australia.

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http://dx.doi.org/10.1111/jpc.12437DOI Listing
December 2013