Hepatitis B flare is a common complication of chronic hepatitis B and is defined as an increase in HBV viral load associated with abnormal alanine aminotransferases (ALT), the consensus being an ALT level ≥5 times the upper limit of normal. The immunopathogenesis is related to induction of inflammatory cells and cytokines by the rise in HBV DNA. There are multiple causes of flares, and they carry the risk of progression to hepatic decompensation and acute-on-chronic liver failure (ACLF) with associated mortality, potentially requiring liver transplantation. Initial assessment should exclude other causes of liver dysfunction and determine severity and prognosis. General prognostic models of ACLF are useful but the COSSH-ACLF II score is specific to HBV. Early initiation of nucleos(t)ide analogues is crucial, even in severe HBV flares; it can reduce mortality by 73.6%. Once jaundice and coagulopathy occur, salvage by antivirals is challenging, and liver transplantation should be considered. However, many patients may not be suitable candidates for transplant or donor livers may not be available, as is common in Asia. Recently, there has been increasing evidence of the benefits of adjunctive therapies such as corticosteroids and plasma exchange, but there are associated risks and these approaches should be considered rescue therapies in severe HBV flares or ACLF. Liver transplant is the ultimate intervention when these other strategies fail. In summary, HBV flares are clinically serious events that can lead to hepatic decompensation, ACLF, and the need for a donor liver; however, strategies for rescue should be considered before liver transplantation.
Acute hepatitis E virus (HEV) infection is typically self-limiting and has a favourable prognosis. However, certain populations such as patients with pre-existing chronic liver disease may experience severe manifestations, including progression to acute-on-chronic liver failure (ACLF). Among viral hepatitis types, hepatitis A, E, and B are major causes of ACLF. Active screening and early diagnosis of HEV infection in patients with cirrhosis, especially those who develop ACLF, can improve management and enable timely antiviral therapy. Preventive measures, including HEV vaccination for high-risk groups, could reduce the morbidity and mortality associated with hepatitis E.
Citations
Citations to this article as recorded by
Virus de la hepatitis E: un problema de salud pública emergente María Teresa Pérez-Gracia, Lara Martínez-Celdrán, Clara Más-Comes Medicina Clínica.2026; 166(2): 107286. CrossRef
Shellfish as a Potential Source of Hepatitis E Virus: Epidemiological Evidence, Biological Plausibility, and Research Gaps Hiroaki Okamoto Viruses.2026; 18(2): 220. CrossRef
Hepatitis E virus: An emerging public health problem María Teresa Pérez-Gracia, Lara Martínez-Celdrán, Clara Más-Comes Medicina Clínica (English Edition).2026; 166(2): 107286. CrossRef
Clinical characteristics of hospitalized patients with hepatitis E virus infection in Poland: a multi-centre retrospective study Anna Parfieniuk-Kowerda, Jerzy Jaroszewicz, Piotr Grabarczyk, Dorota Zarebska-Michaluk, Katarzyna Sikorska, Anna Piekarska, Aleksandra Berkan-Kawinska, Dorota Kozielewicz, Małgorzata Pawlowska, Monika Pazgan-Simon, Barbara Sobala-Szczygiel, Piotr Zielinsk Advances in Medical Sciences.2026; 71(1): 75. CrossRef
Global Temporal Trends and Projections of Acute Hepatitis E Epidemiology for Adults 65 Years and Older from 1990 to 2021: Global Burden of Disease 2021 Based Study Shuangshuang Ma, Qingling Wang, Junjie Lin, Yufeng Gao Tropical Medicine and Infectious Disease.2026; 11(3): 82. CrossRef
Cholinesterase and the association between hepatic steatosis and liver fibrosis in patients with prior hepatitis E Ziteng Wang, Zhe Yu, Wen An, Herui Wei, Jing Luo, Mengqi Li, Lingling He, Jiali Ma, Fan Xiao, Lijuan Sun, Qi Gao, Hui Zhong, Hongshan Wei European Journal of Medical Research.2026;[Epub] CrossRef
Hepatitis E Virus Infection as a Trigger of Hepatic Decompensation: A Single‐Center Prospective and Cross‐Sectional Study From Rosario, Argentina Julián Acosta, Alceo Galimberti, Fernando Bessone, Hugo Tanno, Daniela Gardiol, María Virginia Reggiardo, Ana Laura Cavatorta Journal of Medical Virology.2026;[Epub] CrossRef
Nationwide Detection and Molecular Characterization of Hepatitis E Virus RNA in Retail Pork Meat in Japan Masaharu Takahashi, Manri Kawakami, Yukihiro Sato, Tatsunori Nakano, Jun Inoue, Junichi Koyama, Hitoshi Mizuo, Tomoya Koda, Kazumi Yamasaki, Hiroshi Okano, Akio Miyasaka, Shunji Watanabe, Norio Isoda, Tomofumi Takagi, Shinji Fujiwara, Hiroshi Ohnishi, Put Viruses.2026; 18(6): 621. CrossRef
Acute HEV Infection Is a Relevant Cause of Decompensation and ACLF in Patients With Liver Cirrhosis Katja Dinkelborg, Christian Niehaus, Birgit Bremer, Christine Wundes, Anja Tiede, Natalie Petruch, Katja Deterding, Anke R. M. Kraft, Björn Hartleben, Markus Cornberg, Heiner Wedemeyer, Patrick Behrendt, Benjamin Maasoumy Liver International.2026;[Epub] CrossRef
Conjugated bilirubin reduces hepatitis E virus infectivity by modulating immunometabolic processes Javier Orozco-Cordoba, Julio Y Anaya-Covarrubias, Minerva D Santiago, Diego Zamora, Sonia Roman, Arturo Panduro, Julio César Carrero, Nora A Fierro Journal of Leukocyte Biology.2026;[Epub] CrossRef
Clinical Guidelines for Hepatitis E Vaccination in India: An Expert Panel Consensus Report on the Recombinant Hepatitis E Vaccine, HEV 239 Mohammad Sultan Khuroo, Naira S. Khuroo Pathogens.2026; 15(8): 783. CrossRef
Virale Hepatitiden – Update Michael Steckstor, Ali E. Canbay Gastroenterologie up2date.2026; 22(03): 233. CrossRef
Hospital Admissions for Hepatitis A and E in Spain: Nationwide Trends and In‐Hospital Outcomes Mario Martín‐Portugués, Jorge Esteban‐Sampedro, Alejandro Muñoz‐Serrano, Natalia Vicente‐López, Patricia Mills‐Sánchez, Laura Dorado‐Doblado, Carmen de Mendoza, Vicente Soriano, Víctor Moreno‐Torres Journal of Medical Virology.2026;[Epub] CrossRef
Efficacy and safety of mesenchymal stem cell therapy in acute on chronic liver failure: a systematic review and meta-analysis of randomized controlled clinical trials Wenming Lu, Longxiang Yan, Lulu Peng, Xuesong Wang, Xingkun Tang, Jing Du, Jing Lin, Zhengwei Zou, Lincai Li, Junsong Ye, Lin Zhou Stem Cell Research & Therapy.2025;[Epub] CrossRef
Hepatitis A and E Viruses Are Important Agents of Acute Severe Hepatitis in Asia: A Narrative Review Reina Sasaki-Tanaka, Tatsuo Kanda, Takeshi Yokoo, Hiroyuki Abe, Kazunao Hayashi, Akira Sakamaki, Hiroteru Kamimura, Shuji Terai Pathogens.2025; 14(5): 454. CrossRef
The role of bacterial outer membrane vesicles in inflammatory response of acute-on-chronic liver failure Xiaojing Qin, Shuang Wang, Zhanyao Yan, Ninghui Zhao, Jia Yao Frontiers in Microbiology.2025;[Epub] CrossRef
Ribavirina como tratamiento de hepatitis E aguda grave sobre hepatopatía crónica: experiencia clínica Alba Rabadán Mata, María Dolores Antón Conejero, José María Paredes Arquiola Medicina Clínica.2025; 165(6): 107187. CrossRef
Ribavirin as a treatment for severe acute hepatitis E on chronic liver disease: Clinical experience Alba Rabadán Mata, María Dolores Antón Conejero, José María Paredes Arquiola Medicina Clínica (English Edition).2025; 165(6): 107187. CrossRef
The current standard of care for patients with chronic hepatitis C virus (HCV) infection is a combination of direct-acting antiviral agents (DAAs). Most HCV patients treated with these drugs achieve viral elimination, but 1% to 15% fail to attain this objective. Treatment failures are usually related to relapse, and less often to on-treatment viral breakthrough. HCV drug resistant associated substitutions are detected in most patients who do not eliminate the virus. The risk of developing these variants depends on host- and virus-related factors, the properties of the drugs used, and the treatment strategies applied. Patients who carry Resistant Associated Substitutions (RASs) may not obtain benefits from treatment, and are at a risk of disease progression. Whether HCV RASs persist depends on their type: NS3-4A variants often disappear gradually after DAA therapy is stopped, whereas NS5A variants tend to persist for more than 2 years. The best way to prevent emergence of resistant variants is to eliminate the virus at the first treatment using highly potent DAAs with genetic barriers to resistance. For those who fail an NS5A inhibitor, deferral of treatment is recommended pending the availability of additional data if they do not have cirrhosis or reasons for urgent re-treatment. If re-treatment is needed, the most commonly used strategy is sofosbuvir as backbone therapy plus a drug from a class other than that previously used, for 24 weeks. Unless it is contraindicated, weight-based ribavirin should also be added. If available, nucleotide-based (eg, sofosbuvir) triple or quadruple DAA regimens may be considered. The optimal treatment for patients who fail an NS5A inhibitor and those with multidrug-resistant variants remains to be defined, and research efforts should continue to focus on treatment for these patients.
Effectiveness and safety of SOF/VEL containing rescue therapy in treating chronic HCV-GT4 patients previously failed NS5A inhibitors-based DAAs Heba Omar, Mohammed Hamdy Abdel Maksoud, Ahmed A. Goma, Essam A. Hassan, Nancy Abdalla Atta, Mahmoud Khalil, Mohamed Soliman Hegazy, Samy Zaky, Gamal Esmat Egyptian Liver Journal.2024;[Epub] CrossRef
High efficacy and safety of direct‐acting antivirals for the treatment of chronic hepatitis C: A cohort study conducted in Vietnam Thong Duy Vo, Van Thi Thu Bui, Huong Tu Lam, Quynh Thi Huong Bui Pharmacology Research & Perspectives.2024;[Epub] CrossRef
Is there a connection between neurocognitive profile in treatment naïve non-cirrhotic HCV patients and level of systemic inflammation? Maja Ružić, Natalija Rajić, Željka Nikolašević, Aleksandar Spasić, Maria Pete, Vojislava Bugarski Ignjatović Journal of NeuroVirology.2023; 29(6): 723. CrossRef
Fatores associados à adesão ao tratamento da hepatite C: revisão integrativa Layla Tatiane Côco, Giovanni Faria Silva, Fernando Gomes Romeiro, Ana Teresa de Abreu Ramos Cerqueira Ciência & Saúde Coletiva.2022; 27(4): 1359. CrossRef
Direct-acting antiviral retreatment patterns for hepatitis C Shaquib Al Hasan, Daniel G Dauner, Abhijeet Rajpurohit, Joel F Farley Journal of Managed Care & Specialty Pharmacy.2022; 28(10): 1100. CrossRef
Hepatitis C Resistance-Associated Substitutions Among People Who Inject Drugs Treated With Direct-Acting Antiviral-Containing Regimens Matthew J Akiyama, Lindsey Riback, Jacqueline D Reeves, Yolanda S Lie, Linda Agyemang, Brianna L Norton, Julia H Arnsten, Alain H Litwin Open Forum Infectious Diseases.2021;[Epub] CrossRef
Positive predictive value of sustained virologic response 4 weeks posttreatment for achieving sustained virologic response 12 weeks posttreatment in patients receiving glecaprevir/pibrentasvir in Phase 2 and 3 clinical trials Edward Gane, Victor de Ledinghen, Douglas E. Dylla, Giuliano Rizzardini, Mitchell L. Shiffman, Stephen T. Barclay, Jose Luis Calleja, Zhenyi Xue, Margaret Burroughs, Julio A. Gutierrez Journal of Viral Hepatitis.2021; 28(11): 1635. CrossRef
Effectiveness of retreatment with ombitasvir/paritaprevir/ritonavir and dasabuvir+sofosbuvir+ribavirin in patients with chronic hepatitis C, subtype 1b, and cirrhosis, who failed previous treatment with first‐ and second‐generation NS5A inhibitors Sergii V. Fedorchenko, Tatiana Martynovych, Zhanna Klimenko, Iryna Solianyk Journal of Medical Virology.2021; 93(8): 4975. CrossRef
Provider Perceptions of Hepatitis C Treatment Adherence and Initiation Grace Zhang, Krupa Patel, Akshata Moghe, Andrea Reid, Marina Serper, Linda Calgaro, Sandra Gibson, Susan Zickmund, Obaid Shaikh, Shari Rogal Digestive Diseases and Sciences.2020; 65(5): 1324. CrossRef
Long-chain fatty acyl-coenzyme A suppresses hepatitis C virus infection by targeting virion-bound lipoproteins Xinlei Li, Jinqian Li, Yetong Feng, Hua Cai, Yi-Ping Li, Tao Peng Antiviral Research.2020; 177: 104734. CrossRef
Simple predictors of nonresponse to direct-acting antivirals in chronic hepatitis C patients Hend Ibrahim Shousha, Yasmin Saad, Doa’a A. Saleh, Hosam Dabes, Magdy Alserafy, Yehia ElShazly, Mohamed Said European Journal of Gastroenterology & Hepatology.2020; 32(8): 1017. CrossRef
Real‐world safety and effectiveness of retreatment of Egyptian chronic hepatitis C patients not responding to NS5A inhibitor‐based therapies Monkez M. Yousif, Hussien Ahmed, Hany M. Elsadek, Ali M. shendi, Tamer M. Gouda, Islam A. Elsayed, Mohamed A. Gendia, Mahmoud M. Magdy, Nevin F. lbrahim, Ayman M. E. M. Sadek, Ayman M. Zaki, Hamdy Shafeik, Mahmoud H. Zahran Journal of Viral Hepatitis.2020; 27(11): 1190. CrossRef
Treatment of chronic HCV infection with DAAs in Rio de Janeiro/Brazil: SVR rates and baseline resistance analyses in NS5A and NS5B genes Vanessa D. Costa, Carlos E. Brandão-Mello, Estevão P. Nunes, Pedro Guilherme Corôa dos Santos Silva, Lia Laura Lewis Ximenez de Souza Rodrigues, Elisabeth Lampe, Francisco Campello do Amaral Mello, Tatsuo Kanda PLOS ONE.2019; 14(5): e0216327. CrossRef
New Direct-Acting Antivirals for the Treatment of Patients With Hepatitis C Virus Infection: A Systematic Review of Randomized Controlled Trials Valentina Pecoraro, Rita Banzi, Elisabetta Cariani, Johanna Chester, Erica Villa, Roberto D'Amico, Vittorio Bertele', Tommaso Trenti Journal of Clinical and Experimental Hepatology.2019; 9(4): 522. CrossRef
Tolerability and effectiveness of generic direct‐acting antiviral drugs in eradication of hepatitis C genotype 4 among Egyptian patients Sameh A. Lashen, Mohammed M. Shamseya, Marwa A. Madkour, Galal A. Aboufarrag Liver International.2019; 39(5): 835. CrossRef
Prevalence of baseline NS3 resistance-associated substitutions (RASs) on treatment with protease inhibitors in patients infected with HCV genotype 1 Vanessa Duarte Costa, Nathália Delvaux, Carlos Eduardo Brandão-Mello, Estevão Portela Nunes, Paulo Sérgio Fonseca de Sousa, Lia Laura Lewis Ximenez de Souza Rodrigues, Elisabeth Lampe, Francisco Campello do Amaral Mello Clinics and Research in Hepatology and Gastroenterology.2019; 43(6): 700. CrossRef
Resistance Mutations A30K and Y93N Associated with Treatment Failure with Sofosbuvir and Daclatasvir for Hepatitis C Virus Infection Non-Responder Patients: Case Reports Vanessa D. Costa, Patricia Pellegrini, Vivian Rotman, Ana Maria Pittella, Estevão P. Nunes, Barbara V. Lago, Elisabeth Lampe, Francisco C. A. Mello Viruses.2019; 11(11): 1004. CrossRef
Development of Duodenal Ulcers due to the Discontinuation of Proton Pump Inhibitors After the Induction of Sofosbuvir Plus Ledipasvir Therapy: A Report of Two Cases S. Miuma, H. Miyaaki, Y. Miyazoe, T. Suehiro, R. Sasaki, H. Shibata, N. Taura, K. Nakao Transplantation Proceedings.2018; 50(1): 222. CrossRef
Retreatment Efficacy of Sofosbuvir/Ombitasvir/Paritaprevir/Ritonavir + Ribavirin for Hepatitis C Virus Genotype 4 Patients Adel Abdel-Moneim, Alaa Aboud, Mohamed Abdel-Gabbar, Mohamed Zanaty, Mohamed Ramadan Digestive Diseases and Sciences.2018; 63(5): 1341. CrossRef
A sofosbuvir-based quadruple regimen is highly effective in HCV type 4-infected Egyptian patients with DAA treatment failure Adel Abdel-Moneim, Alaa Aboud, Mohamed Abdel-Gabbar, Mohamed I. Zanaty, Mohamed Ramadan Journal of Hepatology.2018; 68(6): 1313. CrossRef
The outcome of combined treatment with ombitasvir-paritaprevir-ritonavir, sofosbuvir with or without ribavirin as salvage therapy for Egyptian HCV experienced patients: A single center study Waleed Abdelfattah Ismail, Fady Maher Wadea Drug Discoveries & Therapeutics.2018; 12(6): 368. CrossRef
Interaction between Galectin-9/TIM-3 pathway and follicular helper CD4+ T cells contributes to viral persistence in chronic hepatitis C Ya Zhuo, Yi-Fu Zhang, Hong-Jie Wu, Lei Qin, Yan-Ping Wang, A-Min Liu, Xin-Hong Wang Biomedicine & Pharmacotherapy.2017; 94: 386. CrossRef
Treatment of Chronic Hepatitis C Patients Who Do Not Respond to Direct Acting Antivirals Jeong Han Kim The Korean Journal of Gastroenterology.2017; 70(2): 111. CrossRef
Concomitant proton pump inhibitor use does not reduce the efficacy of elbasvir/grazoprevir: A pooled analysis of 1,322 patients with hepatitis C infection Nancy Reau, Michael N. Robertson, Hwa‐Ping Feng, Luzelena Caro, Wendy W. Yeh, Bach‐Yen T. Nguyen, Janice Wahl, Eliav Barr, Peggy Hwang, Stephanie O. Klopfer Hepatology Communications.2017; 1(8): 757. CrossRef
Hepatitis C in sub-Saharan Africa: the current status and recommendations for achieving elimination by 2030 Mark W Sonderup, Mary Afihene, Reidwaan Ally, Betty Apica, Yaw Awuku, Lina Cunha, Geoffrey Dusheiko, Neliswa Gogela, Marie-Jeanne Lohouès-Kouacou, Phillip Lam, Olufunmilayo Lesi, Papa Saliou Mbaye, Emmanuel Musabeyezu, Betty Musau, Olesegun Ojo, John Rweg The Lancet Gastroenterology & Hepatology.2017; 2(12): 910. CrossRef
Retreatment Options Following HCV Direct-Acting Antiviral Failure Autumn Zuckerman, Cody A. Chastain, Susanna Naggie Current Treatment Options in Infectious Diseases.2017; 9(4): 389. CrossRef
Avasimibe: A novel hepatitis C virus inhibitor that targets the assembly of infectious viral particles Longbo Hu, Jinqian Li, Hua Cai, Wenxia Yao, Jing Xiao, Yi-Ping Li, Xiu Qiu, Huimin Xia, Tao Peng Antiviral Research.2017; 148: 5. CrossRef
First
Prev
