Faculty Bibliography

OBJECTIVE:Surveillance tools for early cancer detection are suboptimal, including hepatocellular carcinoma (HCC), and biomarkers are urgently needed. Extracellular vesicles (EVs) have gained increasing scientific interest due to their involvement in tumour initiation and metastasis; however, most extracellular RNA (exRNA) blood-based biomarker studies are limited to annotated genomic regions. DESIGN/METHODS:EVs were isolated with differential ultracentrifugation and integrated nanoscale deterministic lateral displacement arrays (nanoDLD) and quality assessed by electron microscopy, immunoblotting, nanoparticle tracking and deconvolution analysis. Genome-wide sequencing of the largely unexplored small exRNA landscape, including unannotated transcripts, identified and reproducibly quantified small RNA clusters (smRCs). Their key genomic features were delineated across biospecimens and EV isolation techniques in prostate cancer and HCC. Three independent exRNA cancer datasets with a total of 479 samples from 375 patients, including longitudinal samples, were used for this study. RESULTS:ExRNA smRCs were dominated by uncharacterised, unannotated small RNA with a consensus sequence of 20 nt. An unannotated 3-smRC signature was significantly overexpressed in plasma exRNA of patients with HCC (p<0.01, n=157). An independent validation in a phase 2 biomarker case-control study revealed 86% sensitivity and 91% specificity for the detection of early HCC from controls at risk (n=209) (area under the receiver operating curve (AUC): 0.87). The 3-smRC signature was independent of alpha-fetoprotein (p<0.0001) and a composite model yielded an increased AUC of 0.93. CONCLUSION/CONCLUSIONS:These findings directly lead to the prospect of a minimally invasive, blood-only, operator-independent clinical tool for HCC surveillance, thus highlighting the potential of unannotated smRCs for biomarker research in cancer.

BACKGROUND AND AIMS/OBJECTIVE:Although chronic HCV infection increases mortality, thousands of patients remain diagnosed-but-untreated (DBU). We aimed to (1) develop a DBU phenotyping algorithm, (2) use it to facilitate case finding and linkage to care, and (3) identify barriers to successful treatment. APPROACH AND RESULTS/UNASSIGNED:We developed a phenotyping algorithm using Java and SQL and applied it to ~2.5 million EPIC electronic medical records (EMRs; data entered January 2003 to December 2017). Approximately 72,000 EMRs contained an HCV International Classification of Diseases code and/or diagnostic test. The algorithm classified 10,614 cases as DBU (HCV-RNA positive and alive). Its positive and negative predictive values were 88% and 97%, respectively, as determined by manual review of 500 EMRs randomly selected from the ~72,000. Navigators reviewed the charts of 6,187 algorithm-defined DBUs and they attempted to contact potential treatment candidates by phone. By June 2020, 30% (n = 1,862) had completed an HCV-related appointment. Outcomes analysis revealed that DBU patients enrolled in our care coordination program were more likely to complete treatment (72% [n = 219] vs. 54% [n = 256]; P < 0.001) and to have a verified sustained virological response (67% vs. 46%; P < 0.001) than other patients. Forty-eight percent (n = 2,992) of DBU patients could not be reached by phone, which was a major barrier to engagement. Nearly half of these patients had Fibrosis-4 scores ≥ 2.67, indicating significant fibrosis. Multivariable logistic regression showed that DBUs who could not be contacted were less likely to have private insurance than those who could (18% vs. 50%; P < 0.001). CONCLUSIONS:The digital DBU case-finding algorithm efficiently identified potential HCV treatment candidates, freeing resources for navigation and coordination. The algorithm is portable and accelerated HCV elimination when incorporated in our comprehensive program.

The availability of pangenotypic direct-acting antivirals for treatment of hepatitis C (HCV) has provided an opportunity to simplify patient pathways. Recent clinical practice guidelines have recognised the need for simplification to ensure that elimination of HCV as a public health concern remains a priority. Despite the move towards simplified treatment algorithms, there remains some complexity in the recommendations for the management of genotype 3 patients with compensated cirrhosis. In an era where additional clinical trial data are not anticipated, clinical guidance should consider experience gained in real-world settings. Although more experience is required for some pangenotypic therapeutic options, on the basis of published real-world data, there is already sufficient evidence to consider a simplified approach for genotype 3 patients with compensated cirrhosis. The coronavirus disease 2019 (COVID-19) pandemic has highlighted the need to minimise the need for complex patient pathways and clinical practice guidelines need to continue to evolve in order to ensure that patient outcomes remain optimised.

Background and aims: ABI-H0731 (731) is a first-generation HBV core inhibitor in development for the treatment of chronic hepatitis B infection (CHB). In the Phase 2a studies 202 and 201, treatment naive (TN) and virally suppressed (VS) HBeAg-positive patients (pts) with CHB were randomized 1:1 to 731 or placebo (Pbo) with NrtI in a blinded manner for 24 weeks. The combination of 731+NrtI was well tolerated and demonstrated faster and greater reductions in HBV DNA and pgRNA than NrtI alone. Following study completion, eligible pts entering an open-label extension study 211 received 731+NrtI for up to an additional 76 weeks. Here we report the updated data from study 211 through the current last reported observation.
Method(s): For TN pts, HBV DNA was measured by COBAS TaqMan 2.0 (LLOQ = 20 IU/mL) and pgRNA by an in-house quantitative PCR assay (LLOQ = 135 U/mL). For VS pts, HBV DNA was measured by an in-house semi-quantitative PCR assay (LLOD = 5 IU/mL) and pgRNA by an in-house semi-quantitative RT-PCR assay (LLOD = 5 IU/mL). For all pts, quantitative HBeAg and HBsAg were measured by Abbott Architect (LLOQ = 0.11 IU/mL and 0.05 IU/mL, respectively) and HBcrAg by Lumipulse G (LLOD = 1 kU/mL). Safety was assessed by adverse events (AEs) and laboratory parameters.
Result(s): Of the 23 TN pts from study 202, median (range) treatment duration 57 (36-83) weeks, 21 pts have DNA declines to <100 IU/mL and 6 pts have pgRNA declines to <500 U/mL. Declines of >=1 log or at 5% was upper respiratory tract infection (4 pts, 6%). Most laboratory abnormalities were Grade 1 or 2. Transient or intermittent Grade 3 elevations in ALT were observed in 2 pts (3%), both of whom continue on study drug.
Conclusion(s): Results from the ongoing Phase 2a extension study demonstrate continued declines in HBV DNA, pgRNA and viral antigens in pts treated with 731+NrtI. 731 continues to exhibit a favorable safety and tolerability profile in pts treated for over 1 year. The data support the continued development of 731.
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Background and aims: Globally, the prevalence of non-alcoholic fatty liver disease (NAFLD) is rising. It is imperative to identify high-risk patients whose disease may progress to significant liver fibrosis (>=F2). The American Association for the Study of Liver Diseases (AASLD) has no firm guidelines for non-alcoholic steatohepatitis (NASH) screening in high risk individuals due to inadequate data cost effective and treatment options.
Method(s): This cost-effectiveness analysis was developed to compare the value of screening in type 2 diabetes (T2D) patients for NASH against not screening. A Markov model was used to conduct a costutility analysis of 3 NAFLD screening methods consisting of combinations of ultrasound (US), alanine aminotransferase (ALT) determination followed by (1) liver biopsy alone, or (2) transient elastography for detection of patients more likely to have significant fibrosis (>=F2) followed by liver biopsy or (3) transient elastography alone. Post-detection, patients were hypothetically treated with weight reduction induced by intensive lifestyle intervention (ILI). Data provided by Vilar-Gomez et al. showed that 10% of patients who received the ILI were expected to lose over 10% of their bodyweight in 12 months. Costs (USD) and quality-adjusted life years (QALYs) were discounted at 3%; the time horizon is lifetime. The threshold incremental cost-effectiveness ratio (<=$100,000 as well as <=$50,000 per QALY) used is based on that favored by the Institute for Clinical and Economic Review.
Result(s): Screening >=55-year-old patients with T2D/NAFLD using US and ALT, followed by transient elastography, to detect significant fibrosis (>=F2) is a cost-effective strategy versus no screening, when detected patients were immediately treated with a 1-year duration with ILI. Screening with liver biopsy was not cost-effective, because of disutility associated with biopsy. [Table presented]
Conclusion(s): Non-invasive screening patients with T2D/NAFLD in the U.S. is cost effective and can be considered to decrease the burden of the disease.
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Background and Aims: Nucleos(t)ide reverse transcriptase inhibitors (NrtI) are the standard of care for the treatment of chronic HBV (CHB) infection. While these agents achieve viral suppression in most patients (pts), sustained response is rarely achieved following cessation of treatment. The HBV core inhibitor ABI-H0731 (731) in combination with a NrtI is currently being evaluated in Phase 2 clinical studies.
Method(s): ABI-H0731-201 is a double-blind, placebo (Pbo)-controlled study in NrtI-suppressed pts with CHB. Patients were randomized 3:2 to receive 731 (300 mg QD) +NrtI or Pbo+NrtI for 24 wks. Eligible pts had HBV DNA <=LLOQ for >= 6 mos, HBsAg >1000 IU/mL, ALT <=5x ULN and Metavir F0-F2. HBV DNA was measured by COBAS TaqMan 2.0 (LLOQ = 20 IU/mL) and an in-house (ASMB) semi-quantitative PCR assay (LLOQ = 5 IU/mL). HBV pgRNA was measured by an ASMB RT-qPCR assay (LLOQ = 35 IU/mL). Safety was assessed through reporting of adverse events (AE) and laboratory abnormalities. This report summarizes the antiviral activity and safety for the HBeAg-negative pts only.
Result(s): Of the 26 HBeAg-negative pts enrolled in the study, 16 received 731+NrtI and 10 received Pbo+NrtI. Overall, the mean (range) age was 48 (34-64) years, 16 (62%) were male, 21 (81%) were Asian. Results are shown in the table. Treatment with 731+NrtI resulted in a higher proportion of pts achieving TND by the ASMB HBV DNA assay compared with Pbo+NrtI. At baseline and throughout the study, the pgRNA and HBcrAg levels were low and the HBsAg levels did not change. The safety profile of 731+NrtI was similar to Pbo +NrtI. Both treatments were well-tolerated, with no serious adverse events or discontinuations due to AEs. All AEs and lab abnormalities were mild or moderate in severity. Only one pt receiving 731+NrtI reported a Grade 1 rash that resolved on study without treatment interruption. No Grade 3 ALT elevations were observed. [Table presented]
Conclusion(s): In 24weeks of treatment, a higher proportion of HBeAg-negative pts receiving 731+NrtI achieved HBV DNA TND by highly sensitive PCR methodology compared to Pbo+NrtI. 731 has a favorable safety and tolerability profile. These data suggest the contribution of 731 to the standard of care in achieving deeper viral suppression and support continued treatment with 731+NrtI in the open-label Phase 2 study ABI-H0731-211.
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Background and Aims: Previously we reported increased HBV suppression, ALT normalization, and improved renal function with TAF treatment. However, certain patients that would potentially benefit from switching to TAF, e.g. with impaired renal function, remained on non-TAF therapies. Here we further examined variables associated with TAF adoption from approval (Nov 2016) to Dec 2018.
Method(s): Patients enrolled in the TRIO HBV registry from 6 academic and 4 community centers in the US were included in this study. TAF initiation was assessed using Kaplan-Meier methods with subsequent log-rank tests. Overall TAF initiation rates were compared using z-tests.
Result(s): Study population (n = 1037): predominantly male (599, 58%), Asian (887, 86%), <60 years old (700, 68%), from academic centers (611, 59%), with HBV DNA suppression (951/1035, 92%), and receiving tenofovir disoproxil fumarate (TDF [640, 62%]) at enrollment. A history of HCC (inactive) was present for 2% (25) patients, 4% (44) fatty liver, 10% (103) diabetes, 13% (131) hyperlipidemia, 23% (237) hypertension, and 8% (78) osteopenia/osteoporosis. At enrollment, 5% (48/965) had FIB4 >3.25, 6% (65/1030) had eGFR <60 ml/min, and 29% (304/1035) had elevated ALT (>25 U/L in females or >35 U/L in males). In the study window, 396 (38%) patients initiated TAF. Adoption was significantly higher in patients receiving TDF at enrollment (52% v. 12% non-TDF, p < 0.001), at community practices (56% v. 25% academic, p < 0.001), and without HCC history (39% v. 8%, p = 0.005), fatty liver (39% v. 8%, p < 0.001), or hyperlipidemia (39% v. 28%, p = 0.005). Adoption was not significantly different by age, insurance type, osteopenia/osteoporosis, eGFR, FIB4, or ALT. [Figure] Reasons for initiating TAF were provided for 365/396 patients: 66% (241/365) indicated safety/side effects, 27% (99/365) physician preference, and 6% (21/365) efficacy.
Conclusion(s): Safety/side effects was stated as a primary reason for initiating TAF, yet osteopenia/osteoporosis, suboptimal eGFR, ALT, or FIB4 were not associated with significantly higher TAF adoption. These data suggest that prevention, rather than observation of detrimental clinical measures, accounted for most TAF adoption. Most patients with renal or bone disease were not switched to TAF which may be due to access, an issue which will be further explored.
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Background and Aims: TAF provides similar efficacy to tenofovir disoproxil fumarate (TDF) but with an improved safety profile particularly for bone loss and renal injury. However, continued benefit with longer-term TAF has not been sufficiently studied. Here we evaluate virologic suppression rates, eGFR, fibrosis, and ALT at 48+ weeks of TAF therapy in US clinical practice.
Method(s): TRIO has developed a national HBV network consisting of 6 academic and 4 community-based centers serving 17 US States to understand real-world HBV treatment. Of the 1037 patients enrolled from Jan 2017,270 patients initiated TAF and remained on therapy for 48+ weeks as of Jan 2019. Lab measurement data at baseline and at or after (but nearest) 48 weeks of TAF therapy were collected. Elevated ALT was defined as >35 U/L for males and?>25 U/L for females, HBV suppression was assigned for HBV DNA measures <=2000 IU/ml. Comparisons between baseline and 48-week measures were made using McNemar's test (for dichotomous variables), Bowker's test (for multi-level variables) or t-test (for continuous variables). To identify variables associated with elevated ALT, eGFR >0 ml/min, or FIB4 >1.45 at 48 weeks, logistic regressions were conducted with adjustments for multicollinearity of variables.
Result(s): The study population (n = 270) was mostly male (59%), Asian (89%), and under or normal weight (60%) with a mean age of 53 years. Prior to initiating TAF, 81% of the patients received TDF, 8% entecavir, 6% were treatment naive, 2% TDF/emtricitabine, 1% lamivudine, and 1% adefovir dipivoxil. As of Jan 2019, mean (median) TAF duration was 508 (512) days and ranged from 338 to 803 days. In paired analyses (Table), statistically significant changes were reduced mean ALT and increased DNA suppression; changes in FIB4 and eGFR were not significantly different between baseline and 48 weeks. Variables associated with elevated ALT and eGFR >0 ml/min at 48 weeks were baseline elevated ALT (p < 0.001) and baseline eGFR >0 ml/min (p < 0.001), respectively. For FIB4?>1.45 at 48 weeks, significantly associated variables were baseline FIB4 >1.45 (p < 0.001) and Medicare as primary coverage (p = 0.010, collinear with Age >=50).
Conclusion(s): This study of HBV-infected individuals receiving TAF for 48+ weeks found that statistically significant improvements occurred in ALTand HBV DNA suppression. Continued monitoring is ongoing to understand changes in these and other measures with longer term TAF.
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BACKGROUND:/L) can complicate the management of patients with chronic liver disease by significantly increasing the potential risk of bleeding during or after invasive procedures. The current standard-of-care treatment for severe thrombocytopenia is platelet transfusion. Novel agents that target the thrombopoietin pathway, including receptor agonists avatrombopag and lusutrombopag, have recently shown promise in clinical trials as alternatives to platelet transfusion. AIM/OBJECTIVE:To review treatment options for severe thrombocytopenia, including platelet transfusion and thrombopoietin-receptor agonists, with the aim of producing a simplified treatment algorithm. METHODS:A panel of five liver disease specialists were assigned sections of the manuscript to research and present at a consensus meeting in April 2019, with the goal of creating an easy-to-use, effective treatment plan for severe thrombocytopenia in patients with chronic liver disease. RESULTS:Through discussion and collaborative decision making, a simplified algorithm was developed to provide guidance to healthcare professionals on treating severe thrombocytopenia in patients with chronic liver disease undergoing elective medical procedures in the United States. As part of these guidelines, we outline the use of the US Food and Drug Administration-approved thrombopoietin-receptor agonists avatrombopag and lusutrombopag as well tolerated and effective alternatives to platelet transfusion. CONCLUSIONS:This algorithm provides guidance for the management of severe thrombocytopenia to reduce bleeding risks in patients with chronic liver disease undergoing elective procedures, while reducing requirement for platelet transfusion.