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Clinical stage molecule PT150 is a modulator of glucocorticoid and androgen receptors with antiviral activity against SARS-CoV-2

Theise, Neil D; Arment, Anthony R; Chakravarty, Dimple; Gregg, John M H; Jacobson, Ira M; Jung, Kie Hoon; Nair, Sujit S; Tewari, Ashutosh K; Thurston, Archie W; Van Drie, John; Westover, Jonna B
PT150 is a clinical-stage molecule, taken orally, with a strong safety profile having completed Phase 1 and Phase 2 clinical trials for its original use as an antidepressant. It has an active IND for COVID-19. Antiviral activities have been found for PT150 and other members of its class in a variety of virus families; thus, it was now tested against SARS-CoV-2 in human bronchial epithelial lining cells and showed effective 90% inhibitory antiviral concentration (EC90) of 5.55 µM. PT150 is a member of an extended platform of novel glucocorticoid receptor (GR) and androgen receptor (AR) modulating molecules. In vivo, their predominant net effect is one of systemic glucocorticoid antagonism, but they also show direct downregulation of AR and minor GR agonism at the cellular level. We hypothesize that anti-SARS-CoV-2 activity depends in part on this AR downregulation through diminished TMPRSS2 expression and modulation of ACE2 activity. Given that hypercortisolemia is now suggested to be a significant co-factor for COVID-19 progression, we also postulate an additive role for its potent immunomodulatory effects through systemic antagonism of cortisol.
PMID: 33305659
ISSN: 1551-4005
CID: 4735512

Prevalence of Chronic Hepatitis B Virus Infection in the United States

Lim, Joseph K; Nguyen, Mindie H; Kim, W Ray; Gish, Robert; Perumalswami, Ponni; Jacobson, Ira M
Chronic hepatitis B virus (HBV) infection represents a major global health problem, affecting an estimated 257-291 million persons worldwide and is associated with substantial morbidity and mortality because of clinical complications, such as liver cirrhosis and hepatocellular carcinoma. Despite existing resources for vaccination, screening, and treatment, the burden of chronic HBV remains significant within the United States (US). Both the World Health Organization (WHO) and US Department of Health and Human Services (DHHS) have articulated formal hepatitis elimination plans, although an updated assessment of the epidemiology and prevalence of chronic HBV is needed to inform these initiatives. The Chronic Liver Disease Foundation (CLDF), a nonprofit 501(c)(3) educational organization dedicated to raising awareness of liver disease, partnered with a panel of leading US hepatologists to conduct an updated literature review to develop a contemporary HBV prevalence range estimate. Panel members researched and evaluated the peer-reviewed literature on HBV prevalence and, in May 2019, discussed their findings during a live HBV epidemiology workshop. The panel proposed an overall estimated prevalence for chronic HBV infection in the US of 1.59 million persons (range 1.25-2.49 million). This review provides a summary of the workshop findings and conclusions, which may serve to inform future initiatives focused on HBV screening and prevention in the US.
PMID: 32483003
ISSN: 1572-0241
CID: 4480922

Clinical assessment for high-risk patients with non-alcoholic fatty liver disease in primary care and diabetology practices

Younossi, Zobair M; Corey, Kathleen E; Alkhouri, Naim; Noureddin, Mazen; Jacobson, Ira; Lam, Brian; Clement, Stephen; Basu, Rita; Gordon, Stuart; Ravendhra, Natarajan; Puri, Puneet; Rinella, Mary; Scudera, Peter; Singal, Ashwani K; Henry, Linda
BACKGROUND:Primary care practitioners (PCPs) and diabetologists are at the frontline of potentially encountering patients with NASH. Identification of those at high risk for adverse outcomes is important. AIM/OBJECTIVE:To provide practical guidance to providers on how to identify these patients and link them to specialty care. METHODS:US members of the Global Council on NASH evaluated the evidence about NASH and non-invasive tests and developed a simple algorithm to identify high-risk NASH patients for diabetologists and primary care providers. These tools can assist frontline providers in decision-making and referral to gastroenterology/hepatology practices for additional assessments. RESULTS:The presence of NASH-related advanced fibrosis is an independent predictor of adverse outcomes. These patients with NASH are considered high risk and referral to specialists is warranted. Given that staging of fibrosis requires a liver biopsy, non-invasive tests for fibrosis would be preferred. Consensus recommendation from the group is to risk-stratify patients based on metabolic risk factors using the FIB-4 as the initial non-invasive test due to its simplicity and ease of use. A FIB-4 score ≥1.3 can be used for further assessment and linkage to specialty care where additional technology to assess liver stiffness or serum fibrosis test will be available. CONCLUSION/CONCLUSIONS:Due to the growing burden of NAFLD and NASH, PCPs and diabetologists are faced with increased patient encounters in their clinical practices necessitating referral decisions. To assist in identifying high-risk NASH patients requiring specialty care, we provide a simple and easy to use algorithm.
PMID: 32598051
ISSN: 1365-2036
CID: 4526802

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

Machine learning identifies histologic features associated with regression of cirrhosis in treatment for chronic hepatitis B [Meeting Abstract]

Juyal, D; Shukla, C; Pokkalla, H; Taylor, A; Zevallos, O; Resnick, M; Montalto, M; Beck, A; Wapinski, I; Marcellin, P; Flaherty, J F; Suri, V; Gaggar, A; Subramanian, M; Jacobson, I; Gane, E; Buti, M
Background and aims: Machine learning (ML) may facilitate interpretation of histologic changes associated with treatment of chronic hepatitis B virus (HBV) infection. We developed ML models that identify and quantify histologic features in a clinical study of HBV patients receiving antiviral therapy.
Method(s): ML models were developed using H&E histology images from 330 patients enrolled in registrational studies for tenofovir disoproxil fumarate for HBV (GS-US-174-0102, GS-US-174-0103). Histological improvement and regression of cirrhosis were assessed by a central pathologist at baseline (BL) and weeks 48 and 240 according to the Ishak/Knodell necroinflammatory scoring and Ishak fibrosis staging systems. Images were split into training (N = 1090) and testing sets (N = 1061). Models were trained using the PathAI research platform (Boston, MA) to identify inflamed regions and immune cells (lymphocytes and plasma cells) using annotations from 40 board-certified pathologists. Additional annotations of steatosis and ballooning from previous models were included in training. Slide-level, quantitative ML features were computed and correlated with pathologist scores to assess accuracy. Regression analysis was performed to determine associations of ML features at BL and changes from BL with cirrhosis regression at week 240. Results were generated using the testing image set.
Result(s): ML % area of portal inflammation correlated strongly with Ishak portal inflammation scores (rho = 0.643; p < 0.001) and ML % area of interface inflammation correlated strongly with Ishak periportal necrosis scores (rho = 0.716; p < 0.001). Of the 48 patients in the testing set with cirrhosis at BL, 36 patients (75%) no longer had cirrhosis at week 240. Lower ML % area of steatosis (Figure) and greater ML % area of lobular inflammation at BL were predictive of cirrhosis regression (p = 0.006, p = 0.047, respectively), indicating the presence of underlying fatty liver in those who do not resolve cirrhosis. Change from baseline in ML % area of portal and lobular inflammation as well as change in lymphocyte density correlated with regression of cirrhosis at week 240 (p = 0.010, p = 0.026, p = 0.031 respectively). [Figure presented]
Conclusion(s): An ML approach accurately classified histopathologic features in H&E images from HBV clinical trial biopsies. ML features at BL and changes in ML features with treatment were significant associated with cirrhosis regression. An ML approach for evaluating liver histology in patients with HBV can provide mechanistic insight into both HBV disease pathogenesis and cirrhosis regression.
ISSN: 1600-0641
CID: 4781822

Non-invasive tests of fibrosis and risk of liver-related complications: observations following successful sofosbuvir-based treatment in patients with HCV cirrhosis [Meeting Abstract]

Reddy, R; Muir, A; Naggie, S; Lawitz, E; Gane, E; CONWAY, B; Ruane, P; Younes, Z H; Chen, F; Camargo, M; Gaggar, A; Myers, R; Chokkalingam, A; Leggett, B; Panero, J L C; Agarwal, K; Jacobson, I; Mangia, A
Background and Aims: Noninvasive tests of fibrosis (NITs) are an alternative to liver biopsy for fibrosis staging and monitoring; however, associations between NITs and disease progression are poorly understood. Our aim was to evaluate the risk of liver-related complications according to baseline at enrolment (BL) and changes in the Enhanced Liver Fibrosis (ELF) test and liver stiffness by transient elastography (LS by TE) following sustained virologic response (SVR) in patients with HCV cirrhosis.
Method(s): Patients with pre-treatment HCV cirrhosis who achieved SVR with sofosbuvir (SOF)-based regimens were enrolled in an ongoing, prospective registry (NCT02292706). Patients underwent routine clinical and laboratory assessments, including semi-annual ELF testing and annual LS by TE. At BL, fibrosis stage was defined based on ELF (F0-F2, <9.8; F3, 9.8-11.3; F4, >11.3) and LS by TE (F0-F2, <9.6 kPa; F3, 9.6-12.5 kPa; F4,?>12.5 kPa). Changes at 48 weeks (improved, no change, worse) were defined based on ELF response (>=0.5 unit change from BL) and LS by TE response (>=25% change from BL). Associations between NITs and all-cause mortality, hepatocellular carcinoma (HCC), and total liver-related events (hepatic decompensation, transplantation, HCC, and liver-related death) were evaluated using Cox regression.
Result(s): We included 1,370 subjects with HCV Child-Pugh A cirrhosis (median 60 years of age, 32% female). At BL, median ELF was 9.8 (IQR 9.1, 10.7); 530 (39%) and 158 (12%) patients had ELF scores consistent with F3 and F4 fibrosis, respectively. Median LS by TE was 13.9 kPa (IQR 9.1, 21.3); 210 (15%) and 640 (47%) patients had LS by TE consistent with F3 and F4 fibrosis, respectively. After a median follow-up from BL of 144 weeks (IQR 119, 172), BL ELF and LS by TE class were associated with risks of all-cause mortality, HCC, and liver-related events (Table). Relative to BL F0-F2, significantly increased risks for all outcomes were observed for both F3 and F4 fibrosis defined by ELF, and F4 fibrosis defined by LS by TE. Worsening of ELF at 48 weeks was significantly associated with increased risk of all-cause mortality, while risks of HCC and total liver-related events were numerically, but non-significantly, higher for this group. In contrast, worsening of LS by TE at 48 weeks was not significantly associated with increased risks of the studied outcomes. Improvements in either measure were not associated with the risk of complications.
Conclusion(s): Following successful HCV therapy in patients with HCV-related cirrhosis, BL NITs are prognostic. Changes in NITs over 48 weeks may also be predictive of disease progression; however, further study is necessary following the accrual of additional follow-up time and events. This study is among the first to show an association between changes in liver fibrosis and changes in liver-associated morbidity and mortality in patients with compensated cirrhosis. [Figure presented]
ISSN: 1600-0641
CID: 4782872

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-positive chronic hepatitis B infection in a long-term extension study [Meeting Abstract]

Yuen, M -F; Agarwal, K; Ma, X; Nguyen, T; Schiff, E R; Hann, H -W; Dieterich, D; Nahass, R; Park, J; Chan, S; Han, S -H; Gane, E; Bennett, M; Alves, K; Zayed, H; Huang, Q; Colonno, R; Knox, S; Stamm, L; Bonacini, M; Jacobson, I; Ayoub, W; Weilert, F; Ravendhran, N; Ramji, A; Kwo, P; Elkhashab, M; Hassanein, T; Bae, H; Lalezari, J; Fung, S; Sulkowski, M
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.
ISSN: 1600-0641
CID: 4782892

Outcomes with Treatment with Glecaprevir/Pibrentasvir Following Heart Transplantation Utilizing Hepatitis C Viremic Donors

Reyentovich, Alex; Gidea, Claudia G; Smith, Deane; Lonze, Bonnie; Kon, Zachary; Fargnoli, Anthony; Pavone, Jennifer; Rao, Shaline; Saraon, Tajinderpal; Lewis, Tyler; Qian, Yingzhi; Jacobson, Ira; Moazami, Nader
BACKGROUND:The use of direct acting antivirals (DAA) has expanded transplantation from hepatitis C viremic donors (HCV-VIR). Our team has conducted an open-label, prospective trial to assess outcomes transplanting HCV-viremic hearts. Glecaprevir/Pibrentasvir (GLE/PIB) was our sole DAA. METHODS:Serial quantitative hepatitis C virus (HCV) RNA PCR was obtained to assess HCV viral titers. Between January 2018 to June 2019, a total of 50 recipients were transplanted. Of these, 22/50 (44%) were from HCV-VIR, the remaining 28 from non-viremic (HCV NON-VIR) donors. An 8 week course of GLE/PIB was initiated at 1 week post-transplant. RESULTS:There was no difference in demographic or clinical parameters between groups. All 22 recipients of HCV-VIR transplants became viremic. GLE/PIB was effective in decreasing viremia to undetectable levels by 6 weeks post-transplant in all patients. The median time to first undetectable HCV quantitative PCR was (4.3 weeks, IQR: 4-5.7 weeks). All patients demonstrated sustained undetectable viral load through 1 year follow up. There was no difference in survival at one year between HCV NON-VIR 28/28: (100%) vs. HCV-VIR 21/22 (95%) recipients. CONCLUSIONS:Our center reports excellent outcomes in transplanting utilizing hearts from HCV-VIR donors. No effect on survival or co-morbidity was found. An 8 week GLE/PIB course was safe and effective when initiated approximately 1 week post-transplant.
PMID: 32441413
ISSN: 1399-0012
CID: 4444732

Hepatitis E Virus infection in the United States: Current understanding of the prevalence and significance in the liver transplant patient population and proposed diagnostic and treatment strategies

Whitsett, Maureen; Feldman, David M; Jacobson, Ira
Hepatitis E virus (HEV), of the family Herpeviridae, is a virus which infects nearly 20 million people per year throughout the world. HEV is most commonly transmitted via the fecal-oral route and has long been described as a virus which afflicts only those in resource-poor countries. However, HEV has been detected in numerous animal carriers, various food sources, and even in human blood products in resource-rich regions of the world. HEV is of importance in the transplant patient population, for its ability to cause chronic viral infection in these patients can lead to graft loss and cirrhosis. In this review, we discuss the current knowledge of HEV as it pertains to the liver transplant patient population and discuss diagnosis and treatment of this infection.
PMID: 32061053
ISSN: 1527-6473
CID: 4304712

Heterozygous alpha-1 antitrypsin deficiency potentiates liver fibrosis with other chronic liver diseases [Meeting Abstract]

Black, M; Whitsett, M; Jacobson, I; Suarez, Y; Theise, N
Background: Alpha-1 antitrypsin deficiency (AATD) arises from inherited autosomal co-dominant SERPINA1 mutations that lead to liver and lung disease. Clinical manifestations within the liver are variable and include chronic hepatitis, cirrhosis, and the development of hepatocellular carcinoma. While the risk of liver disease with homozygous AATD is established, the prevalence of clinically significant liver disease in heterozygotes is not well described. Accumulating evidence suggests that heterozygous AATD (HAATD) acts as a co-factor for other liver diseases, but little is known about its effect on pathologic fibrosis. We investigate the stage of liver fibrosis in patients with histologic evidence of HAATD compared to controls with a wide range of chronic liver diseases.
Design(s): Our database was retrospectively searched to obtain 23 liver biopsy and resection specimens with evidence of chronic liver disease and intracytoplasmic alpha1 anti-trypsin (AAT) globules stained by immunohistochemistry. The group with histologic evidence of possible HAATD was compared to control cases of liver biopsies obtained from patients with chronic liver disease without evidence of AAT globules. Clinicopathologic data included age, gender, race, genotype, chronic liver disease type (chronic cholestatic disease, fatty liver disease, Hepatitis B or C, auto-immune hepatitis, hemochromatosis, and unknown cause), liver disease stage, and clinical follow-up. Statistical analyses were performed to assess correlation between clinicopathologic variables and disease groups.
Result(s): Compared to controls, subjects in the HAATD cohort had a higher rate of stage 4 fibrosis (52.17% vs 21.67%, p = 0.017). The control specimens were relatively evenly distributed among stages 1-4 fibrosis (Table). Of the 7 HAATD patients who underwent subsequent genetic testing, 6 patients were found to have heterozygous SERPINA1 mutations (5 PI*MZ, 1 PI*SZ). There were no significant differences in age, race, or gender between control and HAATD groups. (Table presented)
Conclusion(s): Histologic and immunohistochemical evidence of AAT globules was associated with a higher stage of concurrent liver disease. These results add to the growing body of literature which suggests that HAATD may potentiate the progression of concurrent liver diseases. In addition, histologic and immunohistochemical evidence of AAT globules may be useful in the early diagnosis of HAATD
ISSN: 1530-0285
CID: 4472752