Publications by authors named "Craig Haifer"

15 Publications

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Editorial: outcomes following a second switch-evaluating clinical outcomes and patient perspectives in IBD.

Aliment Pharmacol Ther 2021 05;53(9):1038-1039

Department of Gastroenterology, Fiona Stanley Hospital, Perth, WA, Australia.

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http://dx.doi.org/10.1111/apt.16325DOI Listing
May 2021

Catastrophe prevention: Acute severe ulcerative colitis.

Authors:
Craig Haifer

J Gastroenterol Hepatol 2021 Apr;36 Suppl 1:34

Department of Gastroenterology, Concord Repatriation General Hospital, Sydney, New South Wales, Australia.

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http://dx.doi.org/10.1111/jgh.15459DOI Listing
April 2021

Long-Term Bacterial and Fungal Dynamics following Oral Lyophilized Fecal Microbiota Transplantation in Clostridioides difficile Infection.

mSystems 2021 Feb 2;6(1). Epub 2021 Feb 2.

School of Medical Sciences, University of New South Wales, Sydney, Australia

Oral lyophilized fecal microbiota transplantation (FMT) is effective in recurrent infection (CDI); however, limited data exist on its efficacy in primary CDI and long-term microbial engraftment. Patients with primary or recurrent CDI were prospectively enrolled to receive oral FMT. Changes in the bacterial and fungal communities were characterized prior to and up to 6 months following treatment. A total of 37 patients with CDI (15 primary, 22 recurrent) were treated with 6 capsules each containing 0.35-g lyophilized stool extract. A total of 33 patients (89%) had sustained CDI cure, of whom 3 required a second course. There were no safety signals identified. FMT significantly increased bacterial diversity and shifted composition toward donor profiles in responders but not in nonresponders, with robust donor contribution observed to 6 months following FMT ( < 0.001). Responders showed consistent decreases in and increases in sp. to levels seen in donors. Mycobiome profiling revealed an association with FMT failure and increases in one taxon, as well as coexclusion relationships between sp. and bacterial taxa enriched in both donors and responders. Primary CDI was associated with more robust changes in the bacterial community than those with recurrent disease. Oral FMT leads to durable microbial engraftment in patients with primary and recurrent CDI, with several microbial taxa being associated with therapy outcome. Novel coexclusion relationships between bacterial and fungal species support the clinical relevance of transkingdom dynamics. infection (CDI) is a substantial health concern worldwide, complicated by patterns of increasing antibiotic resistance that may impact primary treatment. Orally administered fecal microbiota transplantation (FMT) is efficacious in the management of recurrent CDI, with specific bacterial species known to influence clinical outcomes. To date, little is known about the efficacy of FMT in primary CDI and the impact of the mycobiome on therapeutic outcomes. We performed matched bacterial and fungal sequencing on longitudinal samples from a cohort of patients treated with oral FMT for primary and recurrent CDI. We validated many bacterial signatures following oral therapy, confirmed engraftment of donor microbiome out to 6 months following therapy, and demonstrated coexclusion relationships between and two bacterial species in the gut microbiota, which has potential significance beyond CDI, including in the control of gut colonization by this fungal species.
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http://dx.doi.org/10.1128/mSystems.00905-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857531PMC
February 2021

Switching Australian patients with moderate to severe inflammatory bowel disease from originator to biosimilar infliximab: a multicentre, parallel cohort study.

Med J Aust 2021 02 17;214(3):128-133. Epub 2020 Oct 17.

Fiona Stanley Hospital, Perth, WA.

Objective: To examine whether non-medical switching of patients with inflammatory bowel disease (IBD) from originator infliximab to a biosimilar (CT-P13, Inflectra) is safe and clinically non-inferior to continued treatment with originator infliximab.

Design: Prospective, open label, multicentre, parallel cohort, non-inferiority study in seven Australian hospitals over 48 weeks, May 2017 - October 2019.

Participants: Adults (18 years or older) with IBD receiving maintenance originator infliximab (Remicade) who had been in steroid-free clinical remission for at least 12 weeks.

Intervention: Managed program for switching patients in four hospitals from originator to biosimilar infliximab (CT-P13); patients in three other hospitals continued to receive originator infliximab (control).

Main Outcome Measures: Clinical disease worsening requiring infliximab dose escalation or change in therapy.

Results: The switch group included 204 patients, the control group 141 patients with IBD. Ten patients in the control group (7%) and 16 patients switched to CT-P13 (8%) experienced clinical deterioration; the adjusted risk difference (control v switch group) was -1.1 percentage points (95% CI, -6.1 to 8.2 percentage points), within our pre-specified non-inferiority margin of 15 percentage points. Serious adverse events leading to infliximab discontinuation were infrequent in both the switch (six, 3%) and control (six, 4%) groups.

Conclusion: Switching patients with IBD from originator to biosimilar infliximab is safe and non-inferior to continuing treatment with originator infliximab. Moreover, the introduction of biosimilar infliximab, by increasing market competition, has resulted in substantial cost savings for the Pharmaceutical Benefits Scheme.
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http://dx.doi.org/10.5694/mja2.50824DOI Listing
February 2021

The role of faecal microbiota transplantation in the treatment of inflammatory bowel disease.

Curr Opin Pharmacol 2020 12 7;55:8-16. Epub 2020 Oct 7.

Concord Clinical School, The University of Sydney, New South Wales, Australia; Department of Gastroenterology, Concord Repatriation General Hospital, New South Wales, Australia; Department of Gastroenterology, Macquarie University & Macquarie University Hospital, New South Wales, Australia. Electronic address:

Purpose Of The Review: Faecal microbiota transplantation (FMT) has emerged as a potent form of therapeutic microbial manipulation. There is much interest in exploring its potential in conditions such as inflammatory bowel disease (IBD) where disturbances in the gastrointestinal microbiota play a crucial role in disease pathogenesis.

Recent Findings: There are 4 randomized controlled trials of FMT as induction therapy in ulcerative colitis, with meta-analyses suggesting significant benefit over placebo. Allied microbial studies have identified potential microbial and metabolic predictors of therapeutic efficacy and highlighted the importance of optimizing future donor and patient selection. Recent literature has evaluated the use of complementary microbial manipulation through pre-antibiotics to improve treatment efficacy. Studies have also assessed the durability of FMT response and its use in maintenance therapy of UC. While data on FMT are more limited in Crohn's disease and pouchitis, cohort and pilot randomized controlled data a now also emerging in these areas.
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http://dx.doi.org/10.1016/j.coph.2020.08.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7538387PMC
December 2020

Faecal microbiota transplantation as an elixir of youth.

Hepatobiliary Surg Nutr 2020 Aug;9(4):488-489

Concord Clinical School, The University of Sydney, Sydney, Australia.

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http://dx.doi.org/10.21037/hbsn.2019.11.17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7423562PMC
August 2020

Australian consensus statements for the regulation, production and use of faecal microbiota transplantation in clinical practice.

Gut 2020 05 11;69(5):801-810. Epub 2020 Feb 11.

The University of Sydney, Sydney, New South Wales, Australia

Objective: Faecal microbiota transplantation (FMT) has proved to be an extremely effective treatment for recurrent infection, and there is interest in its potential application in other gastrointestinal and systemic diseases. However, the recent death and episode of septicaemia following FMT highlights the need for further appraisal and guidelines on donor evaluation, production standards, treatment facilities and acceptable clinical indications.

Design: For these consensus statements, a 24-member multidisciplinary working group voted online and then convened in-person, using a modified Delphi approach to formulate and refine a series of recommendations based on best evidence and expert opinion. Invitations to participate were directed to Australian experts, with an international delegate assisting the development. The following issues regarding the use of FMT in clinical practice were addressed: donor selection and screening, clinical indications, requirements of FMT centres and future directions. Evidence was rated using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system.

Results: Consensus was reached on 27 statements to provide guidance on best practice in FMT. These include: (1) minimum standards for donor screening with recommended clinical selection criteria, blood and stool testing; (2) accepted routes of administration; (3) clinical indications; (4) minimum standards for FMT production and requirements for treatment facilities acknowledging distinction between single-site centres (eg, hospital-based) and stool banks; and (5) recommendations on future research and product development.

Conclusions: These FMT consensus statements provide comprehensive recommendations around the production and use of FMT in clinical practice with relevance to clinicians, researchers and policy makers.
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http://dx.doi.org/10.1136/gutjnl-2019-320260DOI Listing
May 2020

Vitamin D metabolites are lower with active Crohn's disease and spontaneously recover with development of remission.

Therap Adv Gastroenterol 2019 26;12:1756284819865144. Epub 2019 Jul 26.

St Vincent's Hospital, Department of Gastroenterology, Sydney, Australia.

Background: Vitamin D deficiency is associated with active Crohn's disease (CD). However, it remains unclear if lower 25-hydroxyvitamin D [25(OH)D] concentration is the cause, or consequence, of intestinal inflammation. Existing literature has focused on circulating 25(OH)D rather than the active metabolite 1,25(OH)D, or its breakdown product, 24,25(OH)D. We aimed to characterise vitamin D metabolism in a cohort of patients with active and inactive CD.

Methods: Fifty-four patients with CD and not on corticosteroids or vitamin D supplements, were enrolled in a 6-month prospective cohort study. Sera were collected on enrolment and at 6 months and tested for 25(OH)D, 1,25(OH)D, 24,25(OH)D using liquid chromatography tandem mass spectroscopy as well as vitamin-D-binding protein.

Results: There were no differences in 25(OH)D or 1,25(OH)D levels between participants with active inactive disease. Levels of 24,25(OH)D were significantly lower in those with active compared with inactive disease (mean 3.9 6.0 µmol/l;  = 0.007) and therefore the ratio of 25(OH)D:24,25(OH)D was higher (mean 17.3 11.1;  = 0.001). In those patients with active disease who achieved remission, there was a mean increase in 25(OH)D of 32.3 nmol/l (i.e. to a level in the sufficient range) and 24,25(OH)D of 2.1 µmol/l. These increases were not seen in patients with persistently active or inactive disease.

Conclusion: Levels of 24,25(OH)D, but not 25(OH)D, were lower in patients with active CD, and spontaneously increased with resolution of underlying inflammation. The utility of 24,25(OH)D as a biomarker of disease activity and vitamin D status in CD warrants further exploration.
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http://dx.doi.org/10.1177/1756284819865144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6661794PMC
July 2019

Safety of drugs used for the treatment of Crohn's disease.

Expert Opin Drug Saf 2019 05 6;18(5):357-367. Epub 2019 May 6.

a Department of Gastroenterology and Liver Services , Concord Hospital , Sydney , Australia.

Introduction: Medications in treating Crohn's disease (CD) have evolved over the last two decades, particularly with the use of biologic agents. There are, however, concerns about the safety and adverse events associated with these medications. The authors review the safety profile of immunosuppressive medications used in Crohn's disease in adult patients.

Areas Covered: The authors performed a literature search until October 2018 to examine safety data on thiopurines, methotrexate, anti-TNFα agents, vedolizumab and ustekinumab. The authors focused on 'trial' and 'real-world' data for the biologic agents. Safety in pregnancy and the elderly are also presented.

Expert Opinion: Available data in CD suggest that immunosuppressive medications are relatively safe, although there are concerns about an elevated risk of serious infections, skin cancer and lymphoma particularly with thiopurines and anti-TNFα agents. Data on vedolizumab and ustekinumab suggest these newer biologic agents are well tolerated; however, longer term data in CD are required to identify risks with extended use. Apart from methotrexate, there appear to be no adverse congenital outcomes with exposure of drugs during pregnancy.
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http://dx.doi.org/10.1080/14740338.2019.1612874DOI Listing
May 2019

A Global Survey of Gastroenterologists' Travel Advice to Patients with Inflammatory Bowel Disease on Immunosuppressive Agents and Management of Those Visiting Tuberculosis-Endemic Areas.

J Crohns Colitis 2018 Nov;12(11):1261-1269

Gastroenterology and Liver Services, Sydney Local Health District, Concord Hospital, Sydney, Australia.

Background: With increasing use of biological therapies and immunosuppressive agents, patients with inflammatory bowel disease[IBD] have improved clinical outcome and international travel in this group is becoming common. Adequate pre-travel advice is important. We aim to determine the proportion of gastroenterologists who provided pre-travel advice, and to assess their management strategies for patients on biological therapies visiting tuberculosis[TB]-endemic areas.

Methods: A 57-question survey was distributed to IBD physicians in 23 countries. We collected physicians' demographics, and using a standardized Likert scale, assessed physicians' agreement with stated treatment choices.

Results: A total of 305 gastroenterologists met inclusion criteria. Overall, 52% would discuss travel-related issues: travellers' diarrhoea [TD], travel-specific vaccines, medical care and health insurance abroad, and TB. They were more likely to advise patients not to travel to TB-endemic area if on both anti-tumour necrosis factor [TNF] and azathioprine, than if on vedolizumab and azathioprine [47% vs 17.6%, p < 0.01]. More IBD physicians agreed with vedolizumab monotherapy vs anti-TNF monotherapy [29.9% vs 23%, p < 0.01]. Two-thirds would continue all IBD treatments and not cease any medications. Chest X-ray and interferon-gamma-release assay were the preferred methods to assess for active and latent TB infection. Knowledge on vaccines among IBD physicians was inadequate (survey mean [SD] scores 10.76 [±6.8]). However, they were more familiar with the societal guidelines on management of venous thromboembolism and TD (mean scores 14.9 [±5.3] and 11.9 [±3.9] respectively).

Conclusion: Half of IBD specialists would provide pre-travel advice to IBD patients and two-thirds would advise continuing all IBD medications even when travelling to TB-endemic areas. More education on vaccinations would be particularly helpful for IBD physicians.
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http://dx.doi.org/10.1093/ecco-jcc/jjy110DOI Listing
November 2018

Entyvio lengthen dose-interval study: lengthening vedolizumab dose interval and the risk of clinical relapse in inflammatory bowel disease.

Eur J Gastroenterol Hepatol 2018 07;30(7):735-740

Gastroenterology and Liver Services, Concord Repatriation General Hospital.

Background: Vedolizumab (VDZ), an α4β7 anti-integrin antibody, is efficacious in the induction and maintenance of remission in ulcerative colitis (UC) and Crohn's disease (CD). In the GEMINI long-term safety study, enrolled patients received 4-weekly VDZ. Upon completion, patients were switched to 8-weekly VDZ in Australia. The clinical success rate of treatment de-escalation for patients in remission on VDZ has not been described previously.

Aim: To determine the proportion of patients who relapsed after switching from 4 to 8-weekly VDZ, the mean time to relapse, and the recapture rate when switching back to 8-weekly dosing.

Materials And Methods: This was a retrospective, observational, multicenter study of patients previously recruited into GEMINI long-term safety in Australia. Data on the demographics and biochemical findings were collected.

Results: There were 34 patients [23 men, mean age 49.1 (±13.1) years] and their mean disease duration was 17.6 (±8.5) years. The mean 4-weekly VDZ infusion duration was 286.5 (±48.8) weeks. A total of five (15%) patients relapsed on dose-interval increase (4/17 UC, 1/17 CD) at a median duration from dose interval lengthening to flare of 14 weeks (interquartile range=6-25). Eighty percent (4/5) of patients re-entered remission following dose-interval decrease back to 4-weekly. No clinical predictors of relapse could be determined because of the small cohort size.

Conclusion: The risk of patients relapsing when switching from 4 to 8-weekly VDZ ∼15% and is similar between CD and UC. Dose-interval decrease recaptures 80% of patients who relapsed. Therapeutic drug monitoring of VDZ may be of clinical relevance.
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http://dx.doi.org/10.1097/MEG.0000000000001150DOI Listing
July 2018

Expert-led didactic versus self-directed audiovisual training of confocal laser endomicroscopy in evaluation of mucosal barrier defects.

Endosc Int Open 2018 Jan 16;6(1):E115-E122. Epub 2018 Jan 16.

Faculty of Medicine, UNSW Australia, Sydney, Australia.

Background And Study Aims:  Confocal laser endomicroscopy (CLE) allows mucosal barrier defects along the intestinal epithelium to be visualized during endoscopy. Training in CLE interpretation can be achieved didactically or through self-directed learning. This study aimed to compare the effectiveness of expert-led didactic with self-directed audiovisual teaching for training inexperienced analysts on how to recognize mucosal barrier defects on endoscope-based CLE (eCLE).

Materials And Methods:  This randomized controlled study involved trainee analysts who were taught how to recognize mucosal barrier defects on eCLE either didactically or through an audiovisual clip. After being trained, they evaluated 6 sets of 30 images. Image evaluation required the trainees to determine whether specific features of barrier dysfunction were present or not. Trainees in the didactic group engaged in peer discussion and received feedback after each set while this did not happen in the self-directed group. Accuracy, sensitivity, and specificity of both groups were compared.

Results : Trainees in the didactic group achieved a higher overall accuracy (87.5 % vs 85.0 %,  = 0.002) and sensitivity (84.5 % vs 80.4 %,  = 0.002) compared to trainees in the self-directed group. Interobserver agreement was higher in the didactic group (k = 0.686, 95 % CI 0.680 - 0.691,  < 0.001) than in the self-directed group (k = 0.566, 95 % CI 0.559 - 0.573,  < 0.001). Confidence (OR 6.48, 95 % CI 5.35 - 7.84,  < 0.001) and good image quality (OR 2.58, 95 % CI 2.17 - 2.82,  < 0.001) were positive predictors of accuracy.

Conclusion:  Expert-led didactic training is more effective than self-directed audiovisual training for teaching inexperienced analysts how to recognize mucosal barrier defects on eCLE.
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http://dx.doi.org/10.1055/s-0043-114664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5770263PMC
January 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

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
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