Introduction

Hepatocellular carcinoma (HCC) is the most frequent primary liver tumor, emerging on the background of cirrhosis in the vast majority of cases. It is characterized by high vascularization and recent evidence showed a derangement in the metabolism of nitrogen substrates in HCC. Antiangiogenic therapy is the standard of care for patients with advanced HCC or intermediate HCC ineligible to locoregional treatments (1). However, these therapies are burdened by significant toxicity and high costs. Hence, it is important to early identify responders who can benefit from these agents and non-responders who can be candidate to alternative treatments (2). 13N-ammonia is a PET perfusion tracer that is mainly metabolized in the liver (3).

Aims & Methods

The aim of the present study was to assess the potential role of PET-CT with 13N-ammonia to evaluate early response to antiangiogenic agents in advanced HCC patients, correlating 13N-ammonia PET-CT response with CT mRECIST response. Secondary aims of the study were to evaluate 13N-ammonia PET-CT perfusion parameters (K1 and k2) in HCC lesions, non-neoplastic liver and the liver of patients without liver diseases undergoing PET-CT for cardiologic indications and to correlate HCC perfusion parameters with outcomes of response to treatment.
Eighteen consecutive patients (mean age: 67.3 ± 9.0 years) with advanced HCC underwent contrast-enhanced CT and dynamic PET-CT with 13N-ammonia (acquisition time 20 minutes; 370 mBq) before (baseline) and 8-10 weeks after (post-therapy) the start of antiangiogenic treatment. For each patient, quantitative analysis was performed: volumes of interest (VOIs) were drawn on the descending aorta, on up to five HCC lesions and on two non-neoplastic liver areas using baseline and follow-up contrast-enhanced CT, and transferred on baseline and follow-up PET-CT, respectively. K1 (ml/cm3/min), k2 (min-1) and K1/k2 parameters were estimated using one-tissue compartment model. For each patient, percentage changes in K1 and k2 parameters in HCC lesions (∆K1, ∆k2, ∆K1/k2) between baseline and follow-up PET-CT were correlated to mRECIST response criteria, used as standard reference.

Results

The comparison between CT mRECIST and PET-CT response demonstrated significant concordance (p=0.044).
At baseline, HCC lesions showed higher median K1 values than non-neoplastic liver (0.94 (IQR 0.67) vs. 0.42 (IQR 0.34), p=0.0003) and liver of patients without liver diseases (0.94 (IQR 0.67) vs. 0.44 (IQR 0.13), p=0.001). Median k2 values were also higher in HCC lesions compared with non-neoplastic liver (0.17 (IQR 0.14) vs. 0.07 (IQR 0.06), p=0.0006) and liver of patients without liver diseases (0.17 (IQR 0.14) vs. 0.04 (IQR 0.07), p<0.0001) at baseline.
The comparison of perfusion parameters between responders and non-responders according to mRECIST criteria showed no significant difference at both baseline and follow-up PET-CT.
Early progressors after treatment had higher baseline K1 values compared with early non-progressors (median 1.45 (IQR 0.78) vs. 0.68 (IQR 0.46), p=0.03). Similarly, median k2 values were inversely associated with early progression (early progressors 0.22 (IQR 0.13) vs. early non-progressors 0.14 (IQR 0.11)) with a trend towards statistical significance (p=0.07).

Conclusion

Dynamic 13N-ammonia PET-CT may be a promising metabolic tool to predict response to antiangiogenic therapy in patients with advanced HCC. Particularly, values of PET perfusion parameters may help to evaluate the response of antiangiogenic therapy and predict liver decompensation and death in patients with advanced HCC.

References

1) European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma. J Hepatol. 2018;69(1):182-236.
2) Faivre S, Rimassa L, Finn RS. Molecular therapies for HCC: Looking outside the box. J Hepatol. 2020;72(2):342-52.
3) Cheng KT. [13N]-ammonia. In: Molecular Imaging and Contrast Agent Database (MICAD). 2004.

Introduction

Treatment strategy of hepatocellular carcinoma (HCC) is a complex decision-making process that considers several variables in clinical practice. A “multiparametric therapeutic approach” has been proposed (Lancet Oncol 2023): the feasibility of all treatments is evaluated systematically in a hierarchical order, to match each patient with the optimal therapy.

Aims & Methods

The aim of the study is to validate the reliability of the new multiparametric decisional framework (MPDF) and the impact of the different variables included in the framework on the final treatment decision in clinical practice. This is a prospective ongoing study with a first monocentric phase (A) and a second multicentric validation phase. Primary endpoints are: 1) adherence to MPDF for treatment allocation, 2) identification of the relative weight of variables involved in this MPDF for treatment decision, while secondary endpoints are overall survival and radiological response after treatment. The study includes all consecutive patients with HCC managed in each center from September 1^st, 2023. The disease is staged according to Barcelona Clinic Liver Cancer (BCLC) classification, while patient’s characterization is conducted by Charlson Comorbidity Index (CCI), Liver Frailty Index (LFI), Child-Pugh (CPT) and ALBI, MELD and skeletal muscle mass index by CT. Each patient is allocated to treatment according to MPDF, BCLC 2022 was the benchmark.

Results

As of November 1st, 2023, 48 patients were recruited into phase A of the study [median age 70 (52-87) years, 81% male, 37% HCV, 27% first treatment for HCC]. Thirteen (27%) patients were classified BCLC 0, 17 (35%) A, 6 (12.5%) B, 6 (12.5%) C and 6 (12.5%) D. The median CCI was 8 (4-13), the median LFI was 4.15 (2.99-4.81). Thirty-nine (81%) patients were in CPT class A, 7 (15%) in B and 2 (4%) in C, while 32 (67%) were classified ALBI grade 1 and 16 (33%) ALBI grade 2, and the median MELD score was 8.5 (6-22). Forty-four (92%) patients received treatment through a multidisciplinary team (MDT). According to the MPDF, 9 (19%) patients were allocated to liver transplant, 5 (10%) to laparoscopic surgical resection, 10 (21%) to microwave thermal ablation (MWTA), 7 (15%) to transarterial treatments (4 TACE and 3 TARE), 3 (6%) to other locoregional therapies (2 MWTA+TACE and 1 electrochemotherapy), 6 (13%) to systemic treatment and 5 (10%) to palliative care only. In 4 cases, the MDT decided for reassessment at 3 months. The treatment allocation was coherent to the BCLC 2022 in 69% BCLC 0, 82% BCLC A, 83% BCLC B, 67% BCLC C and 100% BCLC D.

Conclusion

Preliminary data of our ongoing prospective study suggest that personalized approach for HCC treatment by MPDF is feasible in clinical practice and might help ensuring a customized approach in a standardized framework. Updated data will be presented at the meeting.

Introduction

Alcohol use disorder (AUD) remains a significant global health concern. Despite the availability of various pharmacological and behavioural interventions, alcohol-related mortality is rising.

Aims & Methods

This systematic review aimed to critically evaluate the existing literature on the role of glucagon-like peptide receptor 1 analogues (GLP-1 RAs) in people with AUD.
Electronic search was conducted on Ovid Medline, EMBASE, Cochrane Central and PsycINFO from inception to March 2024. Grey literature was searched. The primary outcome of the review was to explore the impact of GLP-1 RAs on self-reported alcohol intake in people with AUD. The extracted data were organized and synthesized to identify key findings and trends evaluating the potential impact of GLP-1 RAs on alcohol consumption in AUD. Narrative synthesis was done to provide a coherent and detailed narrative of the evidence, highlighting significant findings, relationships, and implications. PROSPERO (CRD42024531982).

Results

Seven studies comprising 88,163 participants were included; of these, 38,746 (43.9%) were treated with GLP-1 RAs. Pooled mean age was 49.6 years (SD=10.5), 56.9% (n=50,151/88157) were male, and if the study provided ethnicity 87.5 % (n=426/487) were white. An RCT comparing exenatide with placebo found no significant difference in self-reported alcohol measures at 26 weeks (percentage point reduction: heavy drink days: 6.0, 95% CI -7.4 to 19.4, p=0.37; total alcohol consumption: -42.0 g/30 days, 95% CI -507.7 to 423.7, p=0.86; days without alcohol use: -10.5, 95% CI -2.6 to 23.4, p=0.11). But in participants (n=30) with BMI > 30 kg/m², exenatide compared with placebo was associated with a significant reduction in heavy drinking days (percentage point reduction 23.6, 95% CI, –44.4 to –2.7, P=0.034) and in total alcohol consumed (-1,205 g, 95% CI, –2,206 to –204, P= 0.026). Another RCT showed dulaglutide users compared to placebo were 29% more likely to reduce weekly alcohol consumption (relative effect size: 0.71, p=0.04). In an observational study, authors reported with liraglutide (n=42) 21.4% stopped and 78.6% reduced drinking (p<0.05). A prospective cohort control study showed people on semaglutide or tirzepatide (n=153) compared to no medication significantly reduced number of alcoholic drinks consumed and binge drinking (p<0.05). In a case series (n=6) semaglutide use was associated with a 9.5-point reduction in alcohol use disorder identification test score. A population-based study from Denmark (n=87,676) reported that at 90 days people on GLP-1 RAs compared to one on dipeptidyl peptidase-4 inhibitors (DPP-4) were less likely to experience alcohol-related events ( HR 0. 46, 95% CI 0.24 to 0.86) and effect remained positive long term (356-4619 days: HR 0.72, 95% CI 0.60–0.86). Two qualitative studies examining Reddit social media posts from people on GLP-1 RAs noted over two-thirds addressed a reduction in alcohol consumption. Functional brain imaging suggested significant reductions in cue reactivity were observed in the ventral striatum [F(1,31) = 4.744, P = 0.037, partial η2 = 0.133], dorsal striatum [F(1,31) = 6.124, P = 0.019, partial η2 = 0.165], and putamen [F(1,31) = 4.730, P = 0.037, partial η2 = 0.132] after 26 weeks of exenatide treatment compared with placebo (Table 1). Two studies were of high quality, two medium, and three low.

Conclusion

GLP-1 RAs show promise in reducing alcohol consumption and improving outcomes in individuals with AUD, although heterogeneous study findings warrant further research to establish true effectiveness and safety of GLP-1 RAs in AUD.

References

1. Alcohol use and burden for 195 countries and territories, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet (London, England). 2018;392(10152):1015-35.
2. Klausen MK, et al. The role of glucagon-like peptide 1 (GLP-1) in addictive disorders. British Journal of Pharmacology. 2022;179(4):625-41.
3. Klausen MK, et al. Exenatide once weekly for alcohol use disorder investigated in a randomized, placebo-controlled clinical trial. JCI Insight. 2022;7(19).
4. Probst L, et al. Effects of dulaglutide on alcohol consumption during smoking cessation. JCI Insight. 2023;8(22).
5. SANJAY KALRA BK, AMIT SHARMA. Change in Alcohol Consumption Following Liraglutide Initiation: A Real Life Experience. Clinical Diabetes2024.
6. Quddos F, et al. Semaglutide and Tirzepatide reduce alcohol consumption in individuals with obesity. Scientific Reports. 2023;13(1):20998.
7. Bremmer MP, Hendershot CS. Social Media as Pharmacovigilance: The Potential for Patient Reports to Inform Clinical Research on Glucagon-Like Peptide 1 (GLP-1) Receptor Agonists for Substance Use Disorders. Journal of Studies on Alcohol and Drugs. 2023;85(1):5-10.
8. Wium-Andersen IK, et al Osler M. Use of GLP-1 receptor agonists and subsequent risk of alcohol-related events. A nationwide register-based cohort and self-controlled case series study. Basic & Clinical Pharmacology & Toxicology. 2022;131(5):372-9.

Introduction

Tulisokibart is a monoclonal antibody that targets tumor necrosis factor-like cytokine 1A (TL1A), a regulator of inflammation and fibrosis in inflammatory bowel disorders. In the Phase 2 ARTEMIS-UC study, a significantly higher proportion of participants on tulisokibart compared to placebo achieved clinical remission after 12 weeks of induction treatment in patients with moderate to severe active ulcerative colitis (UC) and conventional or advanced treatment failure.¹ In a post hoc analysis from ARTEMIS-UC, re-induction and delayed induction treatment with tulisokibart were effective in participants who did not respond during the initial induction period.² We explored the efficacy and safety of tulisokibart maintenance therapy up to 1 year during the open-label extension of ARTEMIS-UC among patients who responded to induction, re-induction, and delayed induction.

Aims & Methods

Participants (≥18 years) were randomized to intravenous (IV) tulisokibart 1000 mg on day 1 and 500 mg at weeks 2, 6, and 10 or placebo. The study population consisted of 2 cohorts based on a genetic diagnostic test (Dx) assessing likelihood for responding to anti-TL1A treatment. Cohort 1 included participants stratified by Dx results while Cohort 2 included only Dx positive participants. Cohort 1 is the population used in this analysis. Participants were classified as induction responders (defined as reduction of ≥2 points and ≥30% in modified Mayo score from baseline, accompanied by a reduction ≥1 in rectal bleeding subscore or absolute rectal bleeding subscore ≤1 at week 12) or induction nonresponders. Induction non-responders in the tulisokibart and placebo groups were assigned to an open label 12-week re-induction with the aforementioned tulikosibart induction dosing regimen. Cohort 1 induction, re-induction, and delayed induction responders were randomized (stratified by Dx status) to open-label IV tulisokibart 100 mg or 250 mg every 4 weeks.

Results

In Cohort 1, 47 tulisokibart induction responders, 13 re-induction responders, and 29 delayed induction responders were randomized to open-label maintenance treatment with tulisokibart 100 mg or 250 mg every 4 weeks. Maintenance of treatment effect was generally similar with a trend for higher efficacy with tulisokibart 250 mg vs 100 mg maintenance treatment observed across the 3 groups. The safety profile of tulisokibart maintenance treatment was similar across the 3 groups, with no new safety signals being observed.

Conclusion

Tulisokibart was effective as a maintenance treatment in patients with moderate to severe UC. The effect was generally similar across Cohort 1 tulisokibart induction responders, re-induction responders, and delayed induction responders. Tulisokibart maintenance treatment was well tolerated across the 3 groups, with no identified safety signals. Altogether, this suggests that a second induction regimen in tulisokibart non-responders may result in a long-term efficacy benefit without increased safety risk. Larger trials are needed to confirm these findings.

Table: Efficacy and fecal calprotectin

References

1. Sands et al. N Engl J Med 2024; 26;391:1119-1129
2. Hoque et al. J Crohns Colitis 2025; 19(suppl 1):i1158-i1159

Disclosure

Sami Hoque: ​Received Lecture fees and research grants from Tillotts, Ferring and Eli Lilly.
Bruce E. Sands: Travel fees from Eli Lilly and Company, Janssen Research & Development, LLC, Takeda Development Center Americas, Inc.; Received food & beverage from AnX Robotica Corp.; Grant from Janssen Research & Development, LLC; Owns stock options in Ventyx Biosciences; Consulting fees from AbbVie, Abivax, Aclaris Therapeutics, Adiso Therapeutics, Agomab Therapeutics, Alimentiv, Amgen, AnaptysBio, Arena Pharmaceuticals, Artizan Biosciences, Artugen Therapeutics, AstraZeneca, Biora Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb Company, Celltrion Healthcare, Celltrion Healthcare, Connect Biopharm, Cytoki Pharma, Eli Lilly and Company, Entera, Enveda Biosciences, Equilium, Evommune, F. Homann-La Roche AG, Ferring, Fresenius Kabi USA, LLC, Galapagos, Genentech USA, Inc., Gilead Sciences , GlaxoSmithKline, GossamerBio, HMP Acquisition, Imhotex, Immunic, Immunyx Pharma Ltd., Index Pharmaceuticals, Innovation Pharmaceuticals, Janssen Biotech, Inc., Janssen Scientific Affairs, LLC, Johnson & Johnson Health Care Systems Inc., Kaleido, Kallyope, Kyowa Kirin Co., Ltd, Merck & Co., Inc., Microba, Microbiotica Limited, MiroBio, Mobius Care, Morphic Therapeutic, MRM Health, Nexus Therapeutics, Nimbus Therapeutics, Odyssey Therapeutics, Pfizer, Progenity Inc., Prometheus Biosciences, Protagonist Therapeutics, Q32 Bio, Rasayana Therapeutics, Recludix Pharma, Recludix Pharma, SANOFI US SERVICES INC., Spyre Therapeutics, Surrozen, Synlogic Operating Company, Takeda Pharmaceuticals International, Inc., Target RWE, Teva Branded Pharmaceutical Products R&D, Theravance Biopharma Inc., TLL Pharmaceutical, VectivBio AG, Ventyx Biosciences
Brian G. Feagan: Consulting fees from Abbvie, Adiso Therapeutics, Agomab, Alimentiv Inc, Allianthera, Amgen Canada, AnaptysBio, Applied Molecular Transport, Arena Pharma, Biora Therapeutics, Blackbird Laboratories, Boehringer Ingelheim AB, Bristol-Myers Squibb, Celgene, Celsius Therapeutics, Connect BioPharma, Duality, Eli Lilly and Company, Galapagos, Genentech, Gilead Sciences, GlaxoSmithKline, Janssen Global Services, LLC, JapanTobacco, Klick Health, Mage Biologics, Mestag Therapeutics, Mobius Therapeutics, LLC, Monte Rosa Therapeutics, Nexys Therapeutics, Nimbus Discovery Inc, Orphagen Inc., PFIZER CANADA INC, Prometheus, SANOFI US SERVICES INC., Seres Therapeutics, Sobi, Inc, Spyre Therapeutics, Surrozen, Synedgen, Takeda Canada, Takeda Development Center Americas, Inc., Televant, Tillotts, Triastek Inc.
Mark Yen: Employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.
Bin Dong: Employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.
Wen Zhou: Employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.
Silvio Danese: Consulting fees from AbbVie, Allergan, Amgen, AstraZeneca, Biogen, Boehringer Ingelheim, Celgene, Celltrion Healthcare, Ferring, Gilead Sciences, Hospira, Inc., Janssen Biotech, Johnson & Johnson Health Care Systems Inc., Pfizer, Sandoz, UCB Inc., Vifor (International) Ltd.

Introduction

We evaluated celiac disease (CeD)-related symptoms and comorbidities in two US healthcare databases after CeD diagnosis according to the presence/absence of CeD-related symptoms or comorbidities before diagnosis.

Aims & Methods

This matched case–control study used data from two US healthcare databases: 1) MarketScan^® Commercial and Medicare Supplemental database (collection period: 2002−2023); 2) Optum Clinformatics^® Data Mart (Optum CDM; collection period: 2007−2023). Patients with CeD had ≥ 1 inpatient or ≥ 2 outpatient International Classification of Diseases (ICD)-9 or -10 codes (579.0 and K90.0, respectively) at any time during the collection period. Patients were matched in a 1:5 ratio with controls without CeD (no CeD ICD-9/-10 codes at any time during data collection) for age at diagnosis, sex, region, and diagnosis year. All individuals had continuous medical and pharmacy enrollment for 2 years pre/post CeD diagnosis. Odds ratios (ORs) and 95% confidence intervals (CIs) for symptoms/comorbidities after CeD diagnosis were estimated by generalized multivariate logistic regression comparing cases vs matched controls stratified by those with (persistent) or without (new-onset) the relevant symptom/comorbidity pre-diagnosis. Symptoms assessed included abdominal pain, bloating, diarrhea, headache, nausea/vomiting, and tiredness. Comorbidities assessed included depression/anxiety, irritable bowel syndrome (IBS), and iron deficiency anemia (IDA).

Results

The numbers of CeD cases and controls were 39,814 and 198,961 in MarketScan, and 18,357 and 91,754 in Optum CDM, respectively. In both databases, CeD diagnosis was significantly positively associated with having CeD-related symptoms/comorbidities 2 years after CeD diagnosis regardless of pre-diagnosis status; and the strengths of associations were greater among patients with new-onset than with persistent symptoms/comorbidities after CeD diagnosis.
In MarketScan, the ORs (95% CI) in patients with new-onset symptoms were highest for bloating (7.98 [7.32–8.71]), diarrhea (6.83 [6.48–7.19]), and nausea/vomiting (3.75 [3.49–4.04]), and in those with new-onset comorbidities for IBS (8.30 [7.65–9.00]), IDA (6.35 [5.94–6.79]), and depression/anxiety (2.12 [2.04–2.20]). The ORs (95% CI) in patients with persistent symptoms were 2.47 (1.86–3.27) for bloating, 2.47 (2.21–2.76) for diarrhea, and 2.46 (2.05–2.96) for nausea/vomiting, and in those with persistent comorbidities were 1.38 (1.16–1.64) for IBS, 1.93 (1.70–2.18) for IDA, and 1.42 (1.34–1.51) for depression/anxiety.
In Optum CDM, the ORs (95% CI) in patients with new-onset symptoms were highest for bloating (6.15 [5.56–6.80]), diarrhea (5.85 [5.48–6.24]), and nausea/vomiting (3.38 [3.08–3.70]), and in those with new-onset comorbidities for IBS (6.17 [5.56–6.85]), IDA (5.31 [4.89–5.77]), and depression/anxiety (2.10 [1.99–2.21]). The ORs (95% CI) in patients with persistent symptoms were 2.25 (1.70–2.97) for bloating, 2.51 (2.22–2.84) for diarrhea, and 2.77 (2.23–3.43) for nausea/vomiting, and in those with persistent comorbidities were 1.40 (1.15–1.71) for IBS, 2.54 (2.17–2.97) for IDA, and 1.50 (1.38–1.62) for depression/anxiety.

Conclusion

CeD diagnosis was significantly associated with having CeD-related symptoms/comorbidities 2 years after CeD diagnosis, with greater associations among patients with new-onset symptoms/comorbidities than those with persistent symptoms/comorbidities. These results emphasize the clinical burden of CeD and the need for improved treatment options.

Disclosure

FZ has served as a speaker for Werfen and a consultant for Takeda. MA, SM, VG, SG, IP, NC, and DAL are employees and shareholders of Takeda Development Center Americas, Inc. and receive stock or stock options. BL has nothing to disclose.

Clinical Case Summary

A 51-year-old woman living with HIV was admitted due to abdominal pain, dry cough, and elevated inflammation parameters. Upon admission, she had been under integrase-inhibitor based antiretroviral therapy for 4 months and showed a suppressed HIV viral load and a CD4+ cell count of 680/µL.
Empiric antibiosis with ceftriaxone was established. Contrast-enhanced computed tomography revealed extensive (14x11x9cm), lobulated, cystic structures in liver segment VIII, perforating the diaphragm and extending to the right lower pulmonary lobe. Gas inclusions were suggestive of bronchial communication. Similar mediastinal alterations were detected between vena cava and thoracic spine (4.7cm), leading to vascular compression. Pericardial involvement could be ruled out according to echocardiography.
The imaging results corresponded well with the patient's history of cystic echinococcosis, for which she reported to have undergone surgery with partial liver resection in an emergency setting ten years prior in Bulgaria, her country of origin. While no surgical documentation could be retrieved from the intervention, a history of cyst rupture and/or intraoperative spreading of echinococcosis may be assumed.
Due to the patient's dry cough, microbial sputum analysis was not possible. However, serum ELISA and Westernblot showed positive results for Echinococcus granulosus. The patient was consecutively started on anthelminthic therapy with albendazole 400mg b.i.d.. Due to stagnation of laboratory alterations and persisting abdominal tenderness, antibiosis was switched to piperacillin/tazobactam and ultimately escalated to meropenem.
The treatment of choice in this complex setting of multiorgan involvement of cystic echinococcosis would be surgical resection in a two-cavity approach (thorax and abdomen) under continuation of anthelminthic therapy/secondary prophylaxis with albendazole. However, the patient eventually refused further medical treatment against medical advice.

References

Figure 1: Computed tomography-based transverse (soft-tissue-window settings) (a) and coronal sections (lung-window settings) (b) of the thorax are demonstrated. The hydatid cyst of the right hemithorax is well-appreciated using soft-tissue windowing (a). Both window settings (a and b) clearly depict the approaching bronchi that communicate with the hydatid lesion.

Disclosure

Caroline Schwarz received travel support from Gilead, Abbvie, and Gebro; speaking honoraria from Abbvie and Gilead; and payments for consulting from Gilead.
Michael Gschwantler received grant support from Abbvie, Gilead and Merck Sharp & Dohme; speaking honoraria from Abbvie, Gilead, Janssen, Roche, Intercept, and Merck Sharp & Dohme; consulting/advisory board fees from Abbvie, Gilead, Janssen, Roche, Intercept, Norgine, AstraZeneca, Falk, Shionogi, and Merck Sharp & Dohme; and travel support from Abbvie and Gilead.
All other authors declare no conflicts of interest.