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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

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

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

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

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

Safety of Patients with Hepatitis C Virus Treated with Glecaprevir/Pibrentasvir from Clinical Trials and Real-World Cohorts

Forns, Xavier; Feld, Jordan J; Dylla, Douglas E; Pol, Stanislas; Chayama, Kazuaki; Hou, Jinlin; Heo, Jeong; Lampertico, Pietro; Brown, Ashley; Bondin, Mark; Tatsch, Fernando; Burroughs, Margaret; Marcinak, John; Zhang, Zhenzhen; Emmett, Amanda; Gordon, Stuart C; Jacobson, Ira M
INTRODUCTION/BACKGROUND:More than 70 million people are estimated to be infected with hepatitis C virus (HCV) globally. If left untreated, HCV infection can lead to complications such as extensive liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Evolution of treatments has resulted in highly effective and well-tolerated all-oral direct-acting antivirals. The pangenotypic regimen of glecaprevir/pibrentasvir is approved for treating HCV for patients without cirrhosis or with compensated cirrhosis (CC). Guidelines have evolved to simplify treatment to enable non-specialists to manage and treat HCV-infected patients. Simultaneously, such treatment algorithms provide guidance on the pretreatment identification of small subsets of patients who may require specialist treatment and long-term follow-up for advanced liver disease, including those at risk of developing HCC. This study describes the safety profile of glecaprevir/pibrentasvir in patients identified using previously described noninvasive laboratory measures who may be eligible for treatment by non-liver specialists. METHODS:This post hoc analysis of glecaprevir/pibrentasvir in patients, identified by noninvasive laboratory measures, intended to exclude patients with advanced liver disease and severe renal impairment, who can be managed within non-liver specialist settings. Patients were included from clinical trials and real-world studies of glecaprevir/pibrentasvir for HCV treatment. Baseline demographics, clinical characteristics, and safety assessments, including adverse events and laboratory abnormalities, were summarized. RESULTS:Data across these large-scale studies confirm that glecaprevir/pibrentasvir is well tolerated across different patient populations, with fewer than 0.1% of patients experiencing a serious adverse event related to treatment drugs, and few patients developing HCC during or after treatment. CONCLUSION/CONCLUSIONS:The safety profile of glecaprevir/pibrentasvir enhances the confidence of non-liver specialists to treat the majority of HCV-infected patients, and provides an opportunity to expand the treater pool, potentially increasing diagnosis and treatment rates for HCV, contributing to elimination of HCV.
PMID: 34021887
ISSN: 1865-8652
CID: 4894932

Comparison of Non-Tumoral Portal Vein Thrombosis Management in Cirrhotic Patients: TIPS Versus Anticoagulation Versus No Treatment

Zhan, Chenyang; Prabhu, Vinay; Kang, Stella K; Li, Clayton; Zhu, Yuli; Kim, Sooah; Olsen, Sonja; Jacobson, Ira M; Dagher, Nabil N; Carney, Brendan; Hickey, Ryan M; Taslakian, Bedros
BACKGROUND:There is a lack of consensus in optimal management of portal vein thrombosis (PVT) in patients with cirrhosis. The purpose of this study is to compare the safety and thrombosis burden change for cirrhotic patients with non-tumoral PVT managed by transjugular intrahepatic portosystemic shunt (TIPS) only, anticoagulation only, or no treatment. METHODS:This single-center retrospective study evaluated 52 patients with cirrhosis and non-tumoral PVT managed by TIPS only (14), anticoagulation only (11), or no treatment (27). The demographic, clinical, and imaging data for patients were collected. The portomesenteric thrombosis burden and liver function tests at early follow-up (6-9 months) and late follow-up (9-16 months) were compared to the baseline. Adverse events including bleeding and encephalopathy were recorded. RESULTS:= 0.007). No bleeding complications attributable to anticoagulation were observed. CONCLUSION/CONCLUSIONS:TIPS decreased portomesenteric thrombus burden compared to anticoagulation or no treatment for cirrhotic patients with PVT. Both TIPS and anticoagulation were safe therapies.
PMID: 34073236
ISSN: 2077-0383
CID: 4891422

The case for simplifying and using absolute targets for viral hepatitis elimination goals

Abaalkhail, Faisal; Abbas, Zaigham; Abdallah, Ayat; Abrao Ferreira, Paulo; Abu Raddad, Laith Jamal; Adda, Danjuma; Agarwal, Kosh; Aghemo, Alessio; Ahmed, Aijaz; Al-Busafi, Said A; Al-Hamoudi, Waleed; Al-Kaabi, Saad; Al-Romaihi, Hamad; Aljarallah, Badr; AlNaamani, Khalid; Alqahtani, Saleh; Alswat, Khalid; Altraif, Ibrahim; Asselah, Tarik; Bacon, Bruce; Bessone, Fernando; Bizri, Abdul Rahman; Blach, Sarah; Block, Tim; Bonino, Ferruccio; Brandão-Mello, Carlos Eduardo; Brown, Kimberly; Bruggmann, Philip; Brunetto, Maurizia Rossana; Buti, Maria; Cabezas, Joaquín; Calleja, Jose Luis; Castro Batänjer, Erika; Chan, Henry Lik-Yuen; Chang, Henry; Chen, Chien-Jen; Christensen, Peer Brehm; Chuang, Wan-Long; Cisneros, Laura; Cohen, Chari; Colombo, Massimo; Conway, Brian; Cooper, Curtis; Craxi, Antonio; Crespo, Javier; Croes, Esther; Cryer, Donna; Cupertino de Barros, Fernando Passos; Derbala, Moutaz; Dillon, John; Doss, Wahid; Dou, Xiaoguang; Doyle, Joseph; Duberg, Ann-Sofi; Dugan, Ellen; Dunn, Rick; Dusheiko, Geoffrey; El Khayat, Hisham; El-Sayed, Manal H; Eshraghian, Ahad; Esmat, Gamal; Esteban Mur, Rafael; Ezzat, Sameera; Falconer, Karolin; Fassio, Eduardo; Ferrinho, Paulo; Flamm, Steven; Flisiak, Robert; Foster, Graham; Fung, James; García-Samaniego, Javier; Gish, Robert G; Gonçales, Fernando; Halota, Waldemar; Hamoudi, Waseem; Hassany, Mohamed; Hatzakis, Angelos; Hay, Susan; Himatt, Sayed; Hoepelman, I M; Hsu, Yao-Chun; Hui, Yee Tak; Hunyady, Bela; Jacobson, Ira; Janjua, Naveed; Janssen, Harry; Jarcuska, Peter; Kabagambe, Kenneth; Kanto, Tatsuya; Kao, Jia-Horng; Kaymakoglu, Sabahattin; Kershenobich, David; Khamis, Faryal; Kim, Do Young; Kim, Dong Joon; Kondili, Loreta A; Kottilil, Shyamasundaran; Kramvis, Anna; Kugelmas, Marcelo; Kurosaki, Masayuki; Lacombe, Karine; Lagging, Martin; Lao, Wai-Cheung; Lavanchy, Daniel; Lazarus, Jeffrey V; Lee, Alice; Lee, Samual S; Levy, Miriam; Liakina, Valentina; Lim, Young-Suk; Liu, Shuang; Maddrey, Willis; Malekzadeh, Reza; Marinho, Rui Tato; Mathur, Poonam; Maticic, Mojca; Mendes Correa, Maria Cassia; Mera, Jorge; Merat, Shahin; Mogawer, Sherif; Mohamed, Rosmawati; Mostafa, Ibrahim; Muellhaupt, Beat; Muljono, David; Nahum, Mendez Sanchez; Nawaz, Arif; Negro, Francesco; Ninburg, Michael; Ning, Qing; Ntiri-Reid, Boatemaa; Nymadawa, Pagbajabyn; Oevrehus, Anne; Ormeci, Necati; Orrego, Mauricio; Osman, Alaa; Oyunsuren, Tsendsuren; Pan, Calvin; Papaevangelou, Vassiliki; Papatheodoridis, George; Popping, Stephanie; Prasad, Papu; Prithiviputh, Rittoo; Qureshi, Huma; Ramji, Alnoor; Razavi, Homie; Razavi-Shearer, Devin; Razavi-Shearer, Kathryn; Reddy, Rajender; Remak, William; Richter, Clemens; Ridruejo, Ezequiel; Robaeys, Geert; Roberts, Lewis; Roberts, Stuart; Roudot-Thoraval, Françoise; Saab, Sammy; Said, Sanaa; Salamat, Amjad; Sanai, Faisal; Sanchez-Avila, Juan Francisco; Schiff, Eugene; Schinazi, Raymond; Sebastiani, Giada; Seguin-Devaux, Carole; Shanmugam, R P; Sharara, Ala; Shilton, Sonjelle; Shouval, Daniel; Sievert, William; Simonova, Marieta; Sohrabpour, Amir Ali; Sonderup, Mark; Soza, Alejandro; Steinfurth, Nancy; Sulkowski, Mark; Tan, Soek-Siam; Tanaka, Junko; Tashi, Dhondup; Thein, Hla-Hla; Thompson, Peyton; Tolmane, Ieva; Toy, Mehlika; Valantinas, Jonas; Van de Vijver, David; Vince, Adriana; Vélez-Möller, Patricia; Waked, Imam; Wang, Su; Wedemeyer, Heiner; Wendy Spearman, C; Wong, Vincent; Xie, Qing; Yamada, Seiji; Yang, Hwai-I; Yesmembetov, Kakharman; Yilmaz, Yusuf; Younossi, Zobair; Yu, Ming-Lung; Yuen, Man-Fung; Yurdaydin, Cihan; Yusuf, Aasim; Zekry, Amany; Zeuzem, Stefan
The 69th World Health Assembly endorsed the Global Health Sector Strategy for Viral Hepatitis, embracing a goal to eliminate hepatitis infection as a public health threat by 2030. This was followed by the World Health Organization's (WHO) global targets for the care and management of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. These announcements and targets were important in raising awareness and calling for action; however, tracking countries' progress towards these elimination goals has provided insights to the limitations of these targets. The existing targets compare a country's progress relative to its 2015 values, penalizing countries who started their programmes prior to 2015, countries with a young population, or countries with a low prevalence. We recommend that (1) WHO simplify the hepatitis elimination targets, (2) change to absolute targets and (3) allow countries to achieve these disease targets with their own service coverage initiatives that will have the maximum impact. The recommended targets are as follows: reduce HCV new chronic cases to ≤5 per 100 000, reduce HBV prevalence among 1-year-olds to ≤0.1%, reduce HBV and HCV mortality to ≤5 per 100 000, and demonstrate HBV and HCV year-to-year decrease in new HCV- and HBV-related HCC cases. The objective of our recommendations is not to lower expectations or diminish the hepatitis elimination standards, but to provide clearer targets that recognize the past and current elimination efforts by countries, help measure progress towards true elimination, and motivate other countries to follow suit.
PMID: 32979881
ISSN: 1365-2893
CID: 4679282

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