Faculty Bibliography

BACKGROUND & AIMS/OBJECTIVE:To evaluate the safety and tolerability of the fixed-dose, single-tablet regimen sofosbuvir/velpatasvir (SOF/VEL) for the treatment of hepatitis C virus (HCV) infection in three Phase 3 studies in patients with and without compensated cirrhosis. METHODS:Data from three registrational trials (ASTRAL-1, NCT02201940; ASTRAL-2, NCT02220998; ASTRAL-3, NCT02201953) were pooled by treatment regimen. Researchers assessed treatment-emergent adverse events (TEAEs) and laboratory abnormalities in patients randomized to SOF/VEL or placebo for 12 weeks in ASTRAL-1 and SOF/VEL for 12 weeks in ASTRAL-2 and ASTRAL-3. RESULTS:Overall, 1035 patients were treated with SOF/VEL, and 116 patients received placebo. Rates of any TEAE were generally similar between patients receiving SOF/VEL (79.4%) and those receiving placebo (76.7%). The majority of TEAEs were mild to moderate, with 23 (2.2%) treatment-emergent serious AEs in patients treated with SOF/VEL. Of these treatment-emergent serious AEs, none led to premature study discontinuation, nor were they considered related to treatment. Presence of compensated cirrhosis, greater age, and mild renal impairment did not impact incidence or severity of TEAEs with SOF/VEL treatment. The most common TEAEs (incidence ≥10%) were headache, fatigue, nausea, and nasopharyngitis in patients receiving SOF/VEL; similar rates were observed in placebo-treated patients. Three deaths (<1%) were reported in patients treated with SOF/VEL, all posttreatment and none assessed as related to study treatment. CONCLUSION/CONCLUSIONS:Similar to that of placebo, SOF/VEL treatment of HCV infection had a safety/tolerability profile that was not affected by baseline factors, such as the presence of compensated cirrhosis, mild renal impairment, or advanced age.

Background: Hepatitis delta virus (HDV) requires hepatitis B virus (HBV) for its replication. HDV infection leads to the most severe form of viral hepatitis, which is associated with an increased risk of liver-related morbidity and mortality. HDV prevalence and characteristics of patients with HDV infection are not well described. We aim to evaluate the epidemiology and characteristics of patients with HDV in a comprehensive claims dataset of commercially insured adults in the US.
Method(s): Commercially insured adults (>= 18 years of age) with HBV or HDV infection were identified with >= 1 inpatient claim or >= 2 outpatient claims (according to International Classification of Diseases, Ninth and Tenth Revisions, Clinical Modification diagnosis codes) >= 30 days apart for HBV monoinfection or HDV infection using the All-Payer Claims Database from 1/1/2014 to 12/31/2020 (study period). HDV prevalence was calculated as the proportion of patients with HDV among those with HBV over the study period; a subcohort was identified with the earliest HDV diagnosis defined as the index date from 1/1/2015 to 12/31/2019 and with >= 12 months continuous enrollment before and after the index date. Age, sex, race, income, education, and geographic region at the index date were collected. Comorbidities were assessed during the 12-month pre-index period. Continuous variables were summarized by mean 7plusmn; standard deviation, and categorical variables by frequencies and proportions.
Result(s): Among 105,509 adults with HBV, 4,694 (4.4%) had HDV infection. Among 2,871 adults with HDV identified in the subcohort, mean age was 47.5 (7plusmn; 12.1) years, and 53.0% were male. Among adults with HDV with available data on race and socioeconomic status, 47.1% were White, 33.6% were Black, and 18.0% were Asian; 65.5% reported high school as their highest education; mean annual household income was $44,756 (7plusmn; $47,829); and 35.9% and 33.3% lived in the northeast and north-central US regions, respectively. At baseline, 16.9% of patients had compensated cirrhosis, 10.1% had decompensated cirrhosis, 2.8% had liver cancer, and 1.9% had received a liver transplant. Mean Charlson Comorbidity Index score was 1.6 (7plusmn; 2.2). Hypertension (41.9%), diabetes (39.6%), history of smoking (25.9%), substance use disorder (25.9%), and HIV infection (24.9%) were the top five comorbidities.
Conclusion(s): HDV infection prevalence was 4.4% among commercially insured adults with HBV in the US. Patients with HDV infection have a high comorbidity burden. These findings underscore a need for earlier identification, diagnosis, and treatment of HDV infection among patients with HBV, which may mitigate future disease progression

GOALS AND BACKGROUND/OBJECTIVE:A panel of 9 experts in nonalcoholic steatohepatitis gathered to assess multiple components of the diagnostic process. MATERIALS AND METHODS/METHODS:The Clinical Assertion Statements covered screening of patients with type 2 diabetes for high-risk nonalcoholic fatty liver disease, which-if any-noninvasive tests could determine whether to delay or defer biopsy, whether primary care providers and endocrinologists should routinely calculate Fibrosis-4 Fibrosis-4 so should read Fibrosis 4 (FIB-4) scores in patients with nonalcoholic fatty liver disease or those at risk for it, optimal noninvasive tests to stage fibrosis, the need to consider fibrosis in patients with normal transaminase levels, periodic monitoring for progressive fibrosis, whether patients should undergo biopsy before pharmacotherapy, and the clinical utility of genetic testing. RESULTS AND CONCLUSIONS/CONCLUSIONS:Evidence was presented to support or refute each Clinical Assertion Statement; the panel voted on the nature of the evidence, level of support, and level of agreement with each Statement. Panel level of agreement and rationale of each Clinical Assertion Statement are reported here.

Chronic hepatitis C virus (HCV) infection has the greatest health impact in patients with advanced liver disease. The direct-acting antiviral (DAA) regimen glecaprevir/pibrentasvir (G/P) is approved for treatment of HCV-infected patients without cirrhosis and with compensated cirrhosis. However, events of liver decompensation/failure have been reported in patients treated with protease-inhibitor-containing DAA regimens, often in patients with advanced liver disease. This study examines the safety of on-label G/P treatment in patients with compensated cirrhosis (F4 at baseline) with markers of advanced liver disease. Patients with cirrhosis were categorized into 4 subgroups, based on different noninvasive markers of advanced liver disease identified using laboratory measures: platelet count < or ≥100 x 10⁹ /L, and Child-Pugh score 5 or 6. Separate analyses were performed using pooled data from clinical trials and from real-world post-marketing observational studies. G/P was well tolerated in patients with platelet count ≥100 x 10⁹ /L (n=800), platelet count <100 x 10⁹ /L (n=215), a Child-Pugh score of 5 (n=915), and a Child-Pugh score of 6 (n=95). In the clinical trial and real-world cohorts two patients and no patients experienced a serious adverse event (AE) possibly related to study drug, respectively; three patients and no patients experienced an AE of special interest for hepatic decompensation and hepatic failure. This analysis reaffirms G/P's safety profile in indicated patients with compensated cirrhosis, including those with markers of more advanced liver disease. Increasing the number of patients treated with short-duration G/P therapy may contribute to meeting HCV elimination targets.

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.

Background: JNJ-3989 is composed of 2 siRNA trigger molecules targeting the HBsAg and HBx protein open reading frame. Treatment of CHB patients with Q4W s.c. injections of JNJ-3989 (40-200mg) +/- once-daily oral 250mg JNJ-6379 (CAM-N) in combination with nucleos( t)ide analogues for 48 weeks in the REEF-1 study (NCT03982186) led to dose-dependent reductions in hepatitis B virus (HBV) markers. Here, viral sequence variability in the siRNA S-/ X-trigger target regions and their impact on JNJ-3989- induced viral antigen decline was evaluated.
Method(s): HBV DNA was extracted from baseline (BL) plasma samples and HBV genome was sequenced using next generation sequencing (NGS) in NCT patients. BL nucleotide (nt) polymorphisms were defined as changes versus the universal HBV reference sequence (sequence read frequency >15%).
Result(s): Overall, S-and X-gene BL sequence data was available for 162 (94.2%) and 161 (93.6%) of NCT patients. 18 (11.1%) and 23 (14.2%) patients had 1 or more nt polymorphisms in the S-/ X-trigger target regions; 17 and 21 patients had single nt polymorphism in S-and X-trigger target region (S-position 273 [N=15] or 261 [N=2] and X-position 1799 [N=19] or 1794 [N=2]). Three patients had 2 nt polymorphisms in S-trigger (273+276 [N=1]) and X-trigger (1795+1799 [N=2]) target regions. Four patients overall had combination of single nt polymorphisms 273 and 1799 in S-/ X-target region. Among JNJ-3989 treated patients with Week 48 HBsAg and baseline S-/ X-gene sequence data available (N=116), there was no apparent impact of nt polymorphisms on JNJ-3989 induced HBsAg decline across the 3 JNJ-3989 dose groups. Compared to 40 of 88 (45%) without any nt polymorphisms in S-and X-trigger target region, 5 of 10 (50%) and 7 of 11 (64%) patients with single nt polymorphism at positions 273 (S) or 1799 (X), respectively, achieved >=2.0 log10 IU/mL HBsAg decline at Week 48. All 3 JNJ-3989 treated patients with less prevalent single nt polymorphisms in S-( 261 [N=2]) or X-gene (1794 [N=1]) achieved >=2.0 log10 IU/mL decline in HBsAg at Week 48. 3 of 4 JNJ-3989 treated patients with >=1 nt polymorphisms also achieved >=2.0 log10 IU/ mL HBsAg decline at Week 48. There was also no apparent impact of BL nt polymorphism in S-/ X-trigger target region on HBeAg decline.
Conclusion(s): Baseline nt polymorphisms in the JNJ-3989 S-and X-trigger target region were present in~10% of NCT patients and had no apparent impact on JNJ-3989 induced viral antigen declines

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.

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.

The hepatitis B virus (HBV) is highly infectious, with over 292 million chronically infected people worldwide and up to 2.4 million in the United States. Following infection, clinically silent liver damage can ensue, but symptoms or signs of advanced disease, including cirrhosis and hepatocellular carcinoma, can take decades to emerge. HBV has the heaviest public health burden of all hepatitis viruses and has now surpassed other major communicable diseases (eg, HIV, diarrheal disease, malaria, tuberculosis) as a leading cause of death globally. Preventing transmission is essential, and efforts are in place to reinforce screening, vaccination, and routine follow-up. Three safe and effective vaccines are available in the United States and other countries for HBV prevention, and the benefits of vaccination in preventing infection and its sequelae have been substantiated. For the first time in over 25 years, a new Food and Drug Administration-approved vaccine is available that offers a high degree of immunogenicity after 2, rather than 3, injections. Persistent challenges include the underutilization of vaccination, choice of vaccine, incomplete vaccinations, varying needs in different populations, management of nonresponders or those with undocumented or incompletely documented vaccination courses, and questions about whether and when booster injections may be needed. A panel of US academic hepatologists with expertise and experience in preventing and managing HBV infection have collaborated to write this practical clinical paper intended to guide clinicians in vaccinating for HBV and address questions that regularly arise in the clinic.