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Safety analysis of glecaprevir/pibrentasvir in patients with markers of advanced liver disease in clinical and real-world cohorts

Feld, Jordan J; Forns, Xavier; Dylla, Douglas E; Kumada, Hiromitsu; de Ledinghen, Victor; Wei, Lai; Brown, Robert S; Flisiak, Robert; Lampertico, Pietro; Thabut, Dominique; Bondin, Mark; Tatsch, Fernando; Burroughs, Margaret; Marcinak, John; Zhang, Zhenzhen; Emmett, Amanda; Jacobson, Ira M
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.
PMID: 36036117
ISSN: 1365-2893
CID: 5337542

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

Expert Panel Consensus on Clinical Assertion Statements Describing Noninvasive Tools for Diagnosing Nonalcoholic Steatohepatitis

Jacobson, Ira M; Wong, Vincent Wai-Sun; Castera, Laurent; Anstee, Quentin M; Noureddin, Mazen; Cusi, Kenneth; Harrison, Stephen A; Bugianesi, Elisabetta; Younossi, Zobair M
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.
PMID: 36251413
ISSN: 1539-2031
CID: 5360242


Verbinnen, T; Jezorwski, J; Biermer, M; Shukla, U; Augustyns, I; Jacobson, I; Yuen, M -F; De, Meyer S; Lenz, O
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
ISSN: 1527-3350
CID: 5379662

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

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

An Evidence-based Practical Guide to Vaccination for Hepatitis B Virus

Jacobson, Ira M; Brown, Robert S; McMahon, Brian J; Perrillo, Robert P; Gish, Robert
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.
PMID: 35389923
ISSN: 1539-2031
CID: 5204992

Biliary Tract Injury in Patients With COVID-19: A Review of the Current Literature

Faruqui, Saamia; Shanbhogue, Krishna; Jacobson, Ira M
Multiple studies and extensive clinical experience have shown that COVID-19 can impact the hepatobiliary system, with most reports describing primarily hepatocellular injury with elevations of aspartate aminotransferase and alanine aminotransferase. In addition to hepatocellular injury, recent literature has described a pattern of severe biliary tract injury resulting in patients with COVID-19. This novel syndrome, termed COVID-19 cholangiopathy, may have severe consequences for affected patients. This article will examine the literature describing this novel entity, its relationship to secondary sclerosing cholangitis, clinical outcomes, and proposed mechanisms underlying this form of biliary injury.
PMID: 36397771
ISSN: 1554-7914
CID: 5384972

Letter to the editor: Both universal screening and vaccination are essential components of a multipronged approach to hepatitis B elimination [Letter]

Pan, Calvin Q; Jacobson, Ira M; Martin, Paul; Kwo, Paul; Lim, Joseph; Han, Steven-Huy B; Hu, Ke-Qin; Ahn, Joseph; Tong, Myron J
PMID: 35092080
ISSN: 1527-3350
CID: 5155002

High Sustained Virologic Response Rates of Glecaprevir/Pibrentasvir in Patients With Dosing Interruption or Suboptimal Adherence

Zamor, Philippe J; Brown, Ashley; Dylla, Douglas E; Dillon, John F; Luetkemeyer, Anne F; Feld, Jordan J; Mutimer, David; Ghalib, Reem; Crown, Eric; Lovell, Sandra S; Hu, Yiran; Moreno, Christophe; Nelson, David R; Colombo, Massimo; Papatheodoridis, Georgios; Rockstroh, Juergen K; Skoien, Richard; Lawitz, Eric; Jacobson, Ira M
INTRODUCTION:Pangenotypic, all-oral direct-acting antivirals, such as glecaprevir/pibrentasvir (G/P), are recommended for treatment of hepatitis C virus (HCV) infection. Concerns exist about the impact on efficacy in patients with suboptimal adherence, particularly with shorter treatment durations. These post hoc analyses evaluated adherence (based on pill count) in patients prescribed 8- or 12-week G/P, the impact of nonadherence on sustained virologic response at post-treatment week 12 (SVR12), factors associated with nonadherence, and efficacy in patients interrupting G/P treatment. METHODS:Data were pooled from 10 phase 3 clinical trials of treatment-naive patients with HCV genotype 1-6 without cirrhosis/with compensated cirrhosis (treatment adherence analysis) and 13 phase 3 clinical trials of all patients with HCV (interruption analysis). RESULTS:Among 2,149 patients included, overall mean adherence was 99.4%. Over the treatment duration, adherence decreased (weeks 0-4: 100%; weeks 5-8: 98.3%; and weeks 9-12: 97.1%) and the percentage of patients with ≥80% or ≥90% adherence declined. SVR12 rate in the intention-to-treat (ITT) population was 97.7% (modified ITT SVR12 99.3%) and remained high in nonadherent patients in the modified ITT population (<90%: 94.4%-100%; <80%: 83.3%-100%). Psychiatric disorders were associated with <80% adherence, and shorter treatment duration was associated with ≥80% adherence. Among 2,902 patients in the interruption analysis, 33 (1.1%) had a G/P treatment interruption of ≥1 day, with an SVR12 rate of 93.9% (31/33). No virologic failures occurred. DISCUSSION:These findings support the impact of treatment duration on adherence rates and further reinforce the concept of "treatment forgiveness" with direct-acting antivirals.
PMID: 34465693
ISSN: 1572-0241
CID: 5011252