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Safety and efficacy of vebicorvir administered with entecavir in treatment-naïve patients with chronic hepatitis B virus infection

Sulkowski, Mark S; Agarwal, Kosh; Ma, Xiaoli; Nguyen, Tuan T; Schiff, Eugene R; Hann, Hie-Won L; Dieterich, Douglas T; Nahass, Ronald G; Park, James S; Chan, Sing; Han, Steven-Huy B; Gane, Edward J; Bennett, Michael; Alves, Katia; Evanchik, Marc; Yan, Ran; Huang, Qi; Lopatin, Uri; Colonno, Richard; Ma, Julie; Knox, Steven J; Stamm, Luisa M; Bonacini, Maurizio; Jacobson, Ira M; Ayoub, Walid S; Weilert, Frank; Ravendhran, Natarajan; Ramji, Alnoor; Kwo, Paul Yien; Elkhashab, Magdy; Hassanein, Tarek; Bae, Ho S; Lalezari, Jacob P; Fung, Scott K; Yuen, Man-Fung
BACKGROUND AND AIMS/OBJECTIVE:Nucleos(t)ide reverse transcriptase inhibitors do not completely suppress hepatitis B virus (HBV) DNA in chronic HBV infection (cHBV). Vebicorvir (VBR) is an investigational core inhibitor which interferes with multiple aspects of HBV replication. This phase 2 trial (NCT03577171) evaluated the efficacy and safety of VBR in combination with entecavir (ETV) in treatment-naïve patients with cHBV. METHODS:HBV DNA from Baseline to W12 and W24. RESULTS:IU/mL HBV DNA (-5.33 [1.59]) vs PBO+ETV (-4.20 [0.98]; p=0.0084). Greater mean reductions in pregenomic RNA were observed at W12 and W24 in patients receiving VBR+ETV vs PBO+ETV (p<0.0001 and p<0.0001). Changes in viral antigens were similar in both groups. No drug interaction between VBR and ETV was observed. Two patients experienced HBV DNA rebound during treatment, with no resistance breakthrough detected. Safety of VBR+ETV was similar to PBO+ETV. All treatment-emergent adverse events and laboratory abnormalities were Grade 1/2. There were no deaths, serious AEs, or evidence of drug-induced liver injury. CONCLUSIONS:In this 24-week study, VBR+ETV provided additive antiviral activity over PBO+ETV in treatment-naïve patients with cHBV with a favourable safety and tolerability profile. LAY SUMMARY/BACKGROUND:Hepatitis B is a long-lasting viral infection of the liver. This study demonstrates that vebicorvir (a core inhibitor) with entecavir is generally safe, well tolerated, and demonstrates greater antiviral activity compared with entecavir alone in treatment-naïve patients chronically infected with hepatitis B virus. This study supports continued evaluation of vebicorvir in the treatment of chronic hepatitis B. CLINICAL TRIAL NUMBER/BACKGROUND:NCT03577171.
PMID: 35697332
ISSN: 1600-0641
CID: 5282552

Efficacy and safety of vebicorvir administered in virologically-suppressed patients with chronic hepatitis B virus infection

Yuen, Man-Fung; Agarwal, Kosh; Ma, Xiaoli; Nguyen, Tuan T; Schiff, Eugene R; Hann, Hie-Won L; Dieterich, Douglas T; Nahass, Ronald G; Park, James S; Chan, Sing; Han, Steven-Huy B; Gane, Edward J; Bennett, Michael; Alves, Katia; Evanchik, Marc; Yan, Ran; Huang, Qi; Lopatin, Uri; Colonno, Richard; Ma, Julie; Knox, Steven J; Stamm, Luisa M; Bonacini, Maurizio; Jacobson, Ira M; Ayoub, Walid S; Weilert, Frank; Ravendhran, Natarajan; Ramji, Alnoor; Kwo, Paul Yien; Elkhashab, Magdy; Hassanein, Tarek; Bae, Ho S; Lalezari, Jacob P; Fung, Scott K; Sulkowski, Mark S
BACKGROUND AND AIMS/OBJECTIVE:Hepatitis B virus (HBV) nucleos(t)ide reverse transcriptase inhibitors (NrtI) do not completely suppress HBV replication. Previous reports indicate persistent viremia during NrtI treatment despite HBV DNA being undetectable. HBV core inhibitors may enhance viral suppression when combined with NrtIs. This phase 2 trial (NCT03576066) evaluated the efficacy and safety of the investigational core inhibitor, vebicorvir (VBR), in virologically-suppressed patients on NrtI. METHODS:Noncirrhotic, NrtI-suppressed patients with chronic HBV were randomised to VBR 300 mg once daily or matching placebo (PBO) for 24 weeks. Treatment was stratified by hepatitis B "e" antigen (HBeAg) status. The primary endpoint was change from Baseline in serum HBeAg or hepatitis B surface antigen (HBsAg) after 24 weeks. RESULTS:Of 73 patients enrolled, 47 and 26 were HBeAg positive and negative. In HBeAg positive and negative patients, there were no differences in the change from Baseline at Week 24 for HBsAg or HBeAg. Using a novel, high-sensitivity assay to detect HBV DNA, a greater proportion of patients with detectable HBV DNA at Baseline receiving VBR+NrtI achieved DNA target not detected at Week 24 compared to PBO+NrtI. In HBeAg positive patients, a greater change from Baseline in HBV pregenomic (pg)RNA was observed at Week 24 with VBR+NrtI vs PBO+NrtI. Treatment-emergent adverse events (TEAEs) in VBR+NrtI patients included upper respiratory tract infection, nausea, and pruritus. No serious adverse events, Grade 4 TEAEs, or deaths were reported. CONCLUSIONS:In this 24-week study, VBR+NrtI demonstrated a favourable safety and tolerability profile. While there were no significant changes in viral antigen levels, enhanced viral suppression was evident by greater changes in DNA and pgRNA with the addition of VBR compared to NrtI alone. LAY SUMMARY/BACKGROUND:Core inhibitors represent a novel approach to treating chronic HBV infection, with mechanisms of action distinct from existing treatments. In this study, vebicorvir added to existing therapy reduced HBV replication to a greater extent than existing treatment and was generally safe and well tolerated. CLINICAL TRIALS NUMBER/BACKGROUND:NCT03576066.
PMID: 35460726
ISSN: 1600-0641
CID: 5205352

First-line therapies for hepatitis B in the United States: A 3-year prospective and multicenter real-world study after approval of tenofovir alefenamide

Pan, Calvin Q; Afdhal, Nezam H; Ankoma-Sey, Victor; Bae, Ho; Curry, Michael P; Dieterich, Douglas; Frazier, Lynn; Frick, Andrew; Hann, Hie-Won; Kim, W Ray; Kwo, Paul; Milligan, Scott; Tong, Myron J; Reddy, K Rajender
Real-world data are limited on tenofovir alafenamide (TAF). We aimed to study TAF real-world outcomes with other first-line regimens for chronic hepatitis B (CHB). We enrolled patients with CHB from 10 centers retrospectively and followed them for 36 months prospectively. We analyzed switching patterns of antiviral therapy and treatment outcomes of TAF, tenofovir disoproxil fumarate (TDF), and entecavir therapy. For efficacy and safety, we analyzed a subset of patients with complete data at 24 months after switching to TAF or remaining on TDF or entecavir. Among 1037 enrollees, 889 patients were analyzed. The mean age was 52%, and 72% were hepatitis B e antigen-negative. After enrollment, shifts in therapies were mostly in reduced use of TDF from 63% to 30% due to switching to TAF. Clinical parameters were compared at enrollment or initiation to measures at 24 months for patients remaining on TAF (187), TDF (229), or entecavir (181). At 24 months, a significantly higher portion of patients on TAF achieved hepatitis B virus (HBV) DNA ≤ 20 IU/ml (93% vs. 86%; p = 0.012) and normalized alanine aminotransferase (ALT) (66% vs. 56%; p = 0.031) with stable estimated glomerular filtration rates (eGFRs). However, a higher percentage of the patient with eGFR < 60 ml/mi/1.7 m2 was observed in the TDF-treated group (9% vs. 4%; p = 0.010). In patients who remained on entecavir or TDF for 24 months, ALT and HBV-DNA results did not differ significantly from baseline. Treatment of CHB in the United States has significantly shifted from TDF to TAF. Our data suggest that switching from TDF or entecavir to TAF may result in increased frequency of ALT normalization and potential clearance of viremia at the 24-month time point.
PMID: 35445803
ISSN: 2471-254x
CID: 5218442

Treatment Algorithm for Managing Chronic Hepatitis B Virus Infection in the United States: 2021 Update

Martin, Paul; Nguyen, Mindie H; Dieterich, Douglas T; Lau, Daryl T-Y; Janssen, Harry L A; Peters, Marion G; Jacobson, Ira M
BACKGROUND & AIMS/OBJECTIVE:Chronic hepatitis B (CHB) infection remains the most frequent etiology of hepatocellular carcinoma globally as well as a major cause of cirrhosis. Despite vaccination, substantial numbers of persons have already been infected with hepatitis B virus and remain at risk of progressive liver disease. METHODS:In 2004, a CHB management algorithm was developed by a panel of North American hepatologists, which was subsequently updated in 2006, 2008, and 2015. Since the most recent version, several developments have altered the management of CHB. Tenofovir alafenamide, with a more favorable safety profile than tenofovir disoproxil fumarate, has been introduced as an initial antiviral choice as well as an alternative for long-term therapy. Quantitation of hepatitis B surface antigen is becoming more widely available in clinical practice, with implications for monitoring response to treatment. Additionally, there has been a shift in how the natural history of CHB is perceived, as newer evidence has challenged the concept that during the immunotolerant phase of infection disease progression is not a concern. Finally, recent analyses indicate that in the United States, the average age of patients with CHB has increased, implying that the presence of comorbidities, including metabolic liver disease, increasing use of biologics associated with aging will increasingly affect disease management. RESULTS:This updated algorithm is intended to serve as a guide to manage CHB while new antiviral strategies are developed. CONCLUSIONS:Recommendations have been based on evidence from the scientific literature, when possible, as well as clinical experience and consensus expert opinion. Points of continued debate and areas of research need are also described.
PMID: 34329775
ISSN: 1542-7714
CID: 5275842

A Digital Case-Finding Algorithm for Diagnosed but Untreated Hepatitis C: A Tool for Increasing Linkage to Treatment and Cure

Wyatt, Brooke; Perumalswami, Ponni V; Mageras, Anna; Miller, Mark; Harty, Alyson; Ma, Ning; Bowman, Chip A; Collado, Francina; Jeon, Jihae; Paulino, Lismeiry; Dinani, Amreen; Dieterich, Douglas; Li, Li; Vandromme, Maxence; Branch, Andrea D
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.
PMID: 34333777
ISSN: 1527-3350
CID: 5077042

Guidelines Have a Key Role in Driving HCV Elimination by Advocating for Simple HCV Care Pathways

Mangia, Alessandra; Albanese, Anthony P; Bourliére, Marc; Craxi, Antonio; Dieterich, Douglas; Solomon, Sunil; Vanstraelen, Kim; Hernandez, Candido; Turnes, Juan
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.
PMID: 33590446
ISSN: 1865-8652
CID: 4882212

Review article: a treatment algorithm for patients with chronic liver disease and severe thrombocytopenia undergoing elective medical procedures in the United States

Dieterich, Douglas T; Bernstein, David; Flamm, Steven; Pockros, Paul J; Reau, Nancy
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.
PMID: 32813292
ISSN: 1365-2036
CID: 4583762

Antiviral activity and safety of the hepatitis B core inhibitor ABI-H0731 administered with a nucleos(t)ide reverse transcriptase inhibitor in patients with HBeAg-negative chronic hepatitis B infection [Meeting Abstract]

Fung, S; Sulkowski, M; Lalezari, J; Schiff, E R; Dieterich, D; Hassanein, T; Kwo, P; Elkhashab, M; Nahass, R; Ayoub, W; Han, S -H; Bonacini, M; Alves, K; Zayed, H; Huang, Q; Colonno, R; Knox, S; Ramji, A; Bennett, M; Gane, E; Ravendhran, N; Park, J; Jacobson, I; Bae, H; Chan, S; Hann, H -W; Ma, X; Nguyen, T; Yuen, M -F
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.
ISSN: 1600-0641
CID: 4781832

Longer-term experience with tenofovir alafenamide (TAF) in HBV-infected patients; changes in EGFR, FIB4, ALT, and DNA suppression [Meeting Abstract]

Reddy, R; Curry, M; Bae, H; Dieterich, D; Ankoma-Sey, V; Pan, C; Hann, H -W; Tong, M; Kim, W R; Kwo, P; Frazier, L; Cox, K; Milligan, S; Afdhal, N
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.
ISSN: 1600-0641
CID: 4781792

Screening for non-alcoholic fatty liver disease in persons with type 2 diabetes in the U.S. is cost effective: A comprehensive economical analysis [Meeting Abstract]

Noureddin, M; Jones, C; Gomez, E V; Alkhouri, N; Therapondos, G; Mantry, P; Girgrah, N; Mitchell, E; Shea, K; Sussman, N L; Fuchs, M; Diaz, D V F; Dinani, A; Dieterich, D; Rinella, M
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.
ISSN: 1600-0641
CID: 4781802