Faculty Bibliography

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.

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: 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 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: 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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Objectives: Here, we describe changes in HBV treatment in the 24 months after TAF approval as observed in a US network of 10 HBV-care centers.
Method(s): Data were retrospectively obtained from patient records through an electronic registry at enrollment (Nov 2016) with further collection at each patient visit. Of 1037 enrolled patients, 725 patients with 24-month follow up were included in this study.
Result(s): 7% (50/725) patients were untreated at enrollment and throughout the observation period (Nov 2016 to Dec 2018). Reasons for non-treatment: 82% (41/50) low HBV DNA, 54% (27/50) normal liver function, 8% (4/50) patient decision, 6% (3/50) HBeAg negative, 2% (1/50) does not meet guidelines, and 2% (1/50) unspecified. In Jan 2017 (end of enrollment), 58% (418/725) patients received tenofovir disoproxil fumarate (TDF), 23% (168/725) entecavir (ETV), and 2% (14/725) TAF. In Dec 2018 (end of the observation period), 30% (218/725) received TDF, 21% (152/725) ETV, and 35% (254/725) TAF. 37% (271/725) patients switched therapies for reasons of safety/side effects (58%, 156/271), physician preference (25%, 69/271), efficacy (8%, 23/271), or insurance/cost (6%, 17/271). Most switches were to TAF (91%, 246/271) from TDF (88%, 217/246). Rate of switching differed by site of care; compared to community practices, academic sites had a lower switch rate (26% [114/441] vs 55% [157/284]). Treatment switches in both academic (81%, 92/114) and community (98%, 154/157) sites were mainly to TAF, but the therapies prior to TAF were more varied in the academic sites.
Conclusion(s): In this study, 7% of patients were untreated while 37% received >1 regimen during the observation window. Reasons for non-treatment were mainly low HBV DNA and normal liver function. For the population receiving treatment, initial regimens were mostly TDF and ETV. Switches away from initial therapy was mainly due to safety/side effects concerns and were predominately to TAF.
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BACKGROUND:Despite significant morbidity and mortality among patients with decompensated cirrhosis, reported rates of advance directive (AD) completion and goals of care discussions (GCDs) between patients and providers are very low. We aimed to improve these rates by implementing a hepatologist-led advance care planning (ACP) intervention. MEASURES/METHODS:Rates of AD and GCD completion, as well as self-reported barriers to ACP. INTERVENTION/METHODS:Provider-led ACP in patients with decompensated cirrhosis without a prior documented AD. OUTCOMES/RESULTS:Sixty-two patients were seen over 115 clinic visits. After the intervention, AD completion rates increased from 8% to 31% and GCD completion rates rose from 0% to 51%. Women (P = 0.048) and nonmarried adults (P = 0.01) had greater changes in AD completion compared to men and married adults, respectively. Needing more time during visits was seen as the major barrier to ACP among providers. CONCLUSIONS/LESSONS LEARNED/UNASSIGNED:Addressing provider and system-specific barriers dramatically improved documentation rates of ACP.

Background: Standard of care nucleos(t)ide analogs (Nrtl) are effective in chronic HBV (CHB) infection, but achieve low rates of sustained responses off therapy. The combination of the HBV Core Inhibitor ABI-H0731 (731) with a Nrtl has demonstrated potent antiviral activity in prior clinical studies and is being evaluated in a long-term treatment study.
Method(s): Studies ABI-H0731-201 and ABI-H0731-202 were 24-wk double-blind, placebo (Pbo)-controlled studies in CHB patients (pts). After 24 wks of treatment, pts could enter the open-label extension study ABI-H0731-211 and receive 731+Nrtl for up to an additional 52 wks. The study diagram summarizes study design, patient flow and monitored parameters. This interim report summarizes data for HBeAg+ pts only.
Result(s): Final Wk 24 results confirmed greater mean Iog10 declines in HBV DNA (5.27 vs 3.99; p=0.017) and RNA (2.34 vs 0.61; p<0.001) are achieved with 731+ETV vs ETV in Study 202. By Wk 24 in Study 201, the proportion of pts on 731+Nrtl vs Nrtl achieving DNA "TND" was 69% vs 0% (p<0.001), and the proportion of pts achieving RNA <35 U/mL whose baseline RNA > 35 U/mL was 52% vs 0% (p=0.0013) respectively. There are 64 HBeAg+ pts currently on treatment in Study 211, having received an overall treatment duration of >32 wks. Among the 27 HBeAg+ pts receiving 731+Nrtl in Study 201, 41% (11/27) have now achieved DNA TND along with RNA <35 U/mL and HBeAg <1 lU/mL At their last timepoint, Study 202 (Rx naive) pts now in Study 211 (n=22) have demonstrated mean DNA and RNA declines of 6.1 and 3.0 logs, respectively, with observed mean log changes of >0.6 for HBeAg (11 pts >0.5, 4 pts >1.0), >0.8 log for HBcrAg (7 pts >1.0, 3 pts >2.0) and >0.4 log for HBsAg (7 pts >0.5, 3 pts >1.0). When, administered in combination with Nrtl for up to 1 year, 731 has been well-tolerated, with only mild/moderate adverse events and lab abnormalities, and only a single discontinuation due to a Grade 1 rash.
Conclusion(s): ABI-H0731 continues to exhibit a favorable safety and tolerability profile in pts treated for up to 1 yr. The combination of 731+Nrtl results in faster, deeper declines in HBV DNA and RNA than Nrtl alone, as well as subsequent declines in the surrogate markers of cccDNA (pgRNA, HBeAg and HBcrAg) predictive of cccDNA pool depletion, and HBsAg. The emergent data supports the continued development of ABI-H0731. Updated safety and efficacy data will be presented