Try a new search

Format these results:

Searched for:

person:parkj02

Total Results:

61


Long-term open-label vebicorvir for chronic HBV infection: Safety and off-treatment responses

Yuen, Man-Fung; Fung, Scott; Ma, Xiaoli; Nguyen, Tuan T; Hassanein, Tarek; Hann, Hie-Won; Elkhashab, Magdy; Nahass, Ronald G; Park, James S; Jacobson, Ira M; Ayoub, Walid S; Han, Steven-Huy; Gane, Edward J; Zomorodi, Katie; Yan, Ran; Ma, Julie; Knox, Steven J; Stamm, Luisa M; Bonacini, Maurizio; Weilert, Frank; Ramji, Alnoor; Bennett, Michael; Ravendhran, Natarajan; Chan, Sing; Dieterich, Douglas T; Kwo, Paul Yien; Schiff, Eugene R; Bae, Ho S; Lalezari, Jacob; Agarwal, Kosh; Sulkowski, Mark S
BACKGROUND & AIMS/UNASSIGNED:The investigational first-generation core inhibitor vebicorvir (VBR) demonstrated safety and antiviral activity over 24 weeks in two phase IIa studies in patients with chronic HBV infection. In this long-term extension study, patients received open-label VBR with nucleos(t)ide reverse transcriptase inhibitors (NrtIs). METHODS/UNASSIGNED:Patients in this study (NCT03780543) previously received VBR + NrtI or placebo + NrtI in parent studies 201 (NCT03576066) or 202 (NCT03577171). After receiving VBR + NrtI for ≥52 weeks, stopping criteria (based on the treatment history and hepatitis B e antigen status in the parent studies) were applied, and patients either discontinued both VBR + NrtI, discontinued VBR only, or continued both VBR + NrtI. The primary efficacy endpoint was the proportion of patients with HBV DNA <20 IU/ml at 24 weeks off treatment. RESULTS/UNASSIGNED:Ninety-two patients entered the extension study and received VBR + NrtI. Long-term VBR + NrtI treatment led to continued suppression of HBV nucleic acids and, to a lesser extent, HBV antigens. Forty-three patients met criteria to discontinue VBR + NrtI, with no patients achieving the primary endpoint; the majority of virologic rebound occurred ≥4 weeks off treatment. Treatment was generally well tolerated, with few discontinuations due to adverse events (AEs). There were no deaths. Most AEs and laboratory abnormalities were related to elevations in alanine aminotransferase and occurred during the off-treatment or NrtI-restart phases. No drug-drug interactions between VBR + NrtI and no cases of treatment-emergent resistance among patients who adhered to treatment were observed. CONCLUSIONS/UNASSIGNED:Long-term VBR + NrtI was safe and resulted in continued reductions in HBV nucleic acids following completion of the 24-week parent studies. Following treatment discontinuation, virologic relapse was observed in all patients. This first-generation core inhibitor administered with NrtI for at least 52 weeks was not sufficient for HBV cure. CLINICAL TRIAL NUMBER/UNASSIGNED:NCT03780543. IMPACT AND IMPLICATIONS/UNASSIGNED:Approved treatments for chronic hepatitis B virus infection (cHBV) suppress viral replication, but viral rebound is almost always observed after treatment discontinuation, highlighting an unmet need for improved therapies with finite treatment duration producing greater therapeutic responses that can be sustained off treatment. First-generation core inhibitors, such as vebicorvir, have mechanisms of action orthogonal to standard-of-care therapies that deeply suppress HBV viral replication during treatment; however, to date, durable virologic responses have not been observed after treatment discontinuation. The results reported here will help researchers with the design and interpretation of future studies investigating core inhibitors as possible components of finite treatment regimens for patients with cHBV. It is possible that next-generation core inhibitors with enhanced potency may produce deeper and more durable antiviral activity than first-generation agents, including vebicorvir.
PMCID:10951643
PMID: 38510983
ISSN: 2589-5559
CID: 5640662

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

Successful Treatment of Tenofovir Alafenamide-Induced Lactic Acidosis: A Case Report

Arnouk, Serena; Whitsett, Maureen; Papadopoulos, John; Stewart Lewis, Zoe; Dagher, Nabil N; Feldman, David M; Park, James S
Nucleoside or nucleotide analogues (NAs) have the potential to cause lactic acidosis by inhibiting DNA polymerase-γ of human mitochondria and impairing aerobic metabolism. Patients may be asymptomatic, have mild non-specific symptoms, or present in multisystem organ failure. There is a paucity of data to guide management of life-threatening lactic acidosis due to NA therapy. Here we describe a case of a 60-year old critically ill male with decompensated cirrhosis secondary to hepatitis B virus (HBV) infection who developed severe lactic acidosis (13.8 mmol/L) 2 days after initiation of tenofovir alafenamide (TAF). All other possible etiologies for the elevated lactate were ruled out. Lactic acidosis resolved rapidly with TAF discontinuation and supplementation with cofactors supporting mitochondrial oxidative phosphorylation, including coenzyme Q10, levocarnitine, riboflavin, and thiamine. This case highlights the ability of TAF to cause lactic acidosis early after therapy initiation, especially in susceptible hosts, and reviews the potential role for cofactor supplementation for drug-induced mitochondrial injury.
PMID: 35635046
ISSN: 1531-1937
CID: 5235822

Intrahepatic microbes govern liver immunity by programming NKT cells

Leinwand, Joshua C; Paul, Bidisha; Chen, Ruonan; Xu, Fangxi; Sierra, Maria A; Paluru, Madan M; Nanduri, Sumant; Alcantara Hirsch, Carolina G; Shadaloey, Sorin Aa; Yang, Fan; Adam, Salma A; Li, Qianhao; Bandel, Michelle; Gakhal, Inderdeep; Appiah, Lara; Guo, Yuqi; Vardhan, Mridula; Flaminio, Zia J; Grodman, Emilie R; Mermelstein, Ari; Wang, Wei; Diskin, Brian; Aykut, Berk; Khan, Mohammed; Werba, Gregor; Pushalkar, Smruti; McKinstry, Mia; Kluger, Zachary; Park, Jaimie J; Hsieh, Brandon; Dancel-Manning, Kristen; Liang, Feng-Xia; Park, James S; Saxena, Anjana; Li, Xin; Theise, Neil D; Saxena, Deepak; Miller, George
The gut microbiome shapes local and systemic immunity. The liver is presumed to be a protected sterile site. As such, a hepatic microbiome has not been examined. Here, we showed a liver microbiome in mice and humans that is distinct from the gut and is enriched in Proteobacteria. It undergoes dynamic alterations with age and is influenced by the environment and host physiology. Fecal microbial transfer experiments revealed that the liver microbiome is populated from the gut in a highly selective manner. Hepatic immunity is dependent on the microbiome, specifically Bacteroidetes species. Targeting Bacteroidetes with oral antibiotics reduced hepatic immune cells by ~90%, prevented APC maturation, and mitigated adaptive immunity. Mechanistically, our findings are consistent with presentation of Bacteroidetes-derived glycosphingolipids to NKT cells promoting CCL5 signaling, which drives hepatic leukocyte expansion and activation, among other possible host-microbe interactions. Collectively, we reveal a microbial - glycosphingolipid - NKT - CCL5 axis that underlies hepatic immunity.
PMID: 35175938
ISSN: 1558-8238
CID: 5163572

The importance of community and culture for the recruitment, engagement, and retention of Chinese American immigrants in health interventions

Tsai, William; Zhang, Liwei; Park, James S; Tan, Yi-Ling; Kwon, Simona C
Chinese Americans experience cancer health disparities throughout the entire cancer continuum. Yet, they remain underrepresented in health research in part due to barriers in recruitment, engagement, and retention. This paper describes the strategies that we devised, by drawing upon our experiences with conducting two culturally sensitive cancer intervention studies, to help researchers improve their recruitment and retention rates of Chinese Americans in health research and address the gap in knowledge on intervention research with this population. The first study assessed the efficacy, adoption, and impact of an intervention, delivered by community health workers, to improve adherence to recommended stomach cancer prevention guidelines for at-risk Chinese Americans. The second study evaluated the feasibility and preliminary efficacy of a culturally adapted version of the Expressive Helping intervention for Chinese American cancer patients and survivors. Our main recruitment strategies revolved around building community relationships, developing culturally sensitive materials, and establishing good first impressions with participants. Our main engagement and retention strategies focused on attending to cultural sensitivity, fostering relationships, and using technology. Harnessing the community's inherent strengths and prioritizing cultural understanding is crucial for culturally sensitive health research with Chinese Americans.
PMID: 33963414
ISSN: 1613-9860
CID: 4878132

Cholangiopathy After Severe COVID-19: Clinical Features and Prognostic Implications

Faruqui, Saamia; Okoli, Fidelis C; Olsen, Sonja K; Feldman, David M; Kalia, Harmit S; Park, James S; Stanca, Carmen M; Figueroa Diaz, Viviana; Yuan, Sarah; Dagher, Nabil N; Sarkar, Suparna A; Theise, Neil D; Kim, Sooah; Shanbhogue, Krishna; Jacobson, Ira M
INTRODUCTION/BACKGROUND:Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 virus, is a predominantly respiratory tract infection with the capacity to affect multiple organ systems. Abnormal liver tests, mainly transaminase elevations, have been reported in hospitalized patients. We describe a syndrome of cholangiopathy in patients recovering from severe COVID-19 characterized by marked elevation in serum alkaline phosphatase (ALP) accompanied by evidence of bile duct injury on imaging. METHODS:We conducted a retrospective study of COVID-19 patients admitted to our institution from March 1, 2020, to August 15, 2020, on whom the hepatology service was consulted for abnormal liver tests. Bile duct injury was identified by abnormal liver tests with serum ALP > 3x upper limit of normal and abnormal findings on magnetic resonance cholangiopacreatography. Clinical, laboratory, radiological, and histological findings were recorded in a Research Electronic Data Capture database. RESULTS:Twelve patients were identified, 11 men and 1 woman, with a mean age of 58 years. Mean time from COVID-19 diagnosis to diagnosis of cholangiopathy was 118 days. Peak median serum alanine aminotransferase was 661 U/L and peak median serum ALP was 1855 U/L. Marked elevations of erythrocyte sedimentation rate, C-reactive protein, and D-dimers were common. Magnetic resonance cholangiopacreatography findings included beading of intrahepatic ducts (11/12, 92%), bile duct wall thickening with enhancement (7/12, 58%), and peribiliary diffusion high signal (10/12, 83%). Liver biopsy in 4 patients showed acute and/or chronic large duct obstruction without clear bile duct loss. Progressive biliary tract damage has been demonstrated radiographically. Five patients were referred for consideration of liver transplantation after experiencing persistent jaundice, hepatic insufficiency, and/or recurrent bacterial cholangitis. One patient underwent successful living donor liver transplantation. DISCUSSION/CONCLUSIONS:Cholangiopathy is a late complication of severe COVID-19 with the potential for progressive biliary injury and liver failure. Further studies are required to understand pathogenesis, natural history, and therapeutic interventions.
PMID: 33993134
ISSN: 1572-0241
CID: 4876442

Continuing Medical Education Questions: March 2021:Pregnancy Outcomes after Liver Transplantation: A Systematic Review and Meta-Analysis

Park, James S
Article Title: Pregnancy Outcomes after Liver Transplantation: A Systematic Review and Meta-Analysis.
PMID: 33657037
ISSN: 1572-0241
CID: 4835812

Liver tumor in gaucher's disease [Meeting Abstract]

Yakubov, S; Singh, K N; Golfeyz, S; Yunina, D; Rahmani, R; Tsirlin, Y; Mayer, I E; Park, J
INTRODUCTION: Gaucher disease (GD) is an autosomal recessive, lysosomal storage disorder that results from a deficiency of the glucocerebrosidase enzyme, which is involved in the breakdown of the glycosphingolipid glucocerebroside. We present a rare and unusual case of HCC in a patient with Gaucher disease who was found to have a 5 cm liver tumor. CASE DESCRIPTION/METHODS: 65 yo M with PMH Gaucher's disease Type 1 on enzyme replacement therapy, GERD, OSA on CPAP, IBS, Anxiety, Appendectomy, Left hip replacement, Right knee replacement, was referred for evaluation of a 5 cm liver tumor. Patient denied fevers, chills, abdominal pain, nausea, vomiting, diarrhea, constipation, or any other associated symptoms. He denied alcohol use, herbal use, recent travel or other toxic habits. Family history consisted of a brother was also carried a diagnosis of Gaucher's disease. On presentation, VS were within normal limits and complete physical examination was unremarkable. Laboratory testing revealed TB 0.9, AST 22, ALT 22, ALP 91, INR 1.0, Plt 258, AFP 4.5, CEA 3.6, Ca19-9 of 21. The rest of laboratory work up including hepatitis panel has been unremarkable. MRI Abd showed a 5 cm segment 6 arterially enhancing lesion concerning for HCC. Upper and lower endoscopy were unremarkable. Presently patient is scheduled for a liver tumor resection surgery. DISCUSSION: The prevalence of GD is approximately 1 in 57-75 thousand births worldwide but it's more prevalent in Ashkenazi Jewish descent in whom the incidence is 1 in 800 births. GD was first described by Phillippe Gaucher in 1882, and in the 1900's Epstein and later Brandy et al, further described the disease. GD has been classified into 3 Types depending on age and presence of neurological deficit. It can present with hepatic fibrosis, hepatosplenomegaly, liver cirrhosis, pulmonary hypertension, cardiac or vascular anomalies, neurologic disease, lymphoma, itchyosis, and can have bone involvement which is usually painful. GD primarily leads to hematologic malignancies with solid organ tumors not far behind. Specific risk factors in GD leading to HCC have not been fully defined, although splenectomy has been considered. Our non cirrhotic patient with a healthy lifestyle and no splenectomy was found to have HCC based on imaging, and other similar cases have been reported. Therefore, close monitoring and HCC screening should be considered in any patient with Gauchers disease
EMBASE:633658878
ISSN: 1572-0241
CID: 4720462

Unusual and rare presentation of hepatitis d [Meeting Abstract]

Yakubov, S; Singh, K N; Golfeyz, S; Yunina, D; Rahmani, R; Tsirlin, Y; Mayer, I E; Sun, K; Park, J
INTRODUCTION: Hepatitis D virus, also known as the 'Delta virus' is a defective virus that requires hepatitis B virus for infection. About 257-291 million people are chronically infected with HBV worldwide, and of those up to 20 million had experienced HDV infection. We present unusual case with histological, serological, virological evidences of chronically active HDV infection which was initially thought to be medication induced. CASE DESCRIPTION/METHODS: A 34 yo M with PMH of Chronic hepatitis B infection diagnosed in 2013 has been on Tenofovir Disoproxil Fumarate (TDF) x4 years. After getting switched from TDF to Tenofovir Alfenamide (TAF) he had a rise in LFTs; Bilirubin 0.2, AST 126, ALT 327. He denied alcohol use, herbal use, recent travel or other toxic habits. On presentation, VS were within normal limits and complete physical examination was unremarkable. Patient was switched from TAF to TDF as it was thought to be possibly contributing to his abnormal LFTs and a complete liver disease work up was obtained. Laboratory testing revealed TB 0.9, AST 134, ALT 386, ALP 49, INR 1.1, Hepatitis B sAg+, sAb-, eAg-, eAb-, HBV DNA non detected, HDV Ag-, HDV Ab+, HDV PCR 133,000. Ultrasound showed hepatic steatosis. Despite switching back to TDF his LFTs remained elevated. Therefore, liver biopsy was performed showing features of portal and lobular inflammation consistent with hepatitis B & D infection and fatty liver disease. He was started on Pegylated Interferon-alpha treatment, and post-treatment, his LFTs have normalized, AST-28, ALT-43, HDV PCR 1050 IU/ml. DISCUSSION: HDV is a single stranded RNA that is composed of an outer HBsAg lipoprotein envelope, inner ribonucleoprotein structure and is complexed with the HDV encoded antigen. It can present as either acute HBV-HDV coinfection, acute HDV superinfection of a chronic HBV carrier, or as chronic HDV infection. HDV infection causes more severe viral hepatitis, increases risk of developing cirrhosis and hepatocellular carcinoma in comparison to HBV monoinfection. Prevalence of HDV Ab is highest in Africa, Turkey, Mongolia, Moldova, sex workers, IV drug users, HCV, HIV, etc. Clinically HDV infection manifests from asymptomatic carrier state to acute liver failure. Diagnosis of HDV is done with serologic testing. INF-a has been the only proven antiviral treatment against HDV. SVR to therapy, which is measured as undetectable serum HDV RNA levels is at around 25%. Although rare HDV should part of a differential diagnosis in all patients with HBV infection
EMBASE:633658202
ISSN: 1572-0241
CID: 4720502