Hepatitis B: From control to cureAuthor links open overlay panelJia-HorngKaoabaDepartment of Internal Medicine, Hepatitis Research Center, and Department of Medical Research, National Taiwan University Hospital, Taipei, TaiwanbGraduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
Received 22 July 2018, Accepted 23 August 2018, Available online 7 September 2018.
https://doi.org/10.1016/j.jfma.2018.08.020Get rights and content
Open Access funded by Formosan Medical Association
Under a Creative Commons license
Although hepatitis B virus (HBV) has been discovered for more than half a century with the availability of effective hepatitis B vaccines for over 3 decades, chronic HBV infection continues to be a major global health problem.1 It is estimated that there still exist 257 million HBsAg-positive individuals worldwide.2 Several host, viral, and external factors are identified to predict the progression of liver disease to cirrhosis, hepatic decompensation, and hepatocellular carcinoma (HCC) in patients with chronic HBV infection.3 Recent data suggested quantification of hepatitis B surface antigen (HBsAg), hepatitis B core-related antigen (HBcrAg), HBV mutants and antibodies to hepatitis B core antigen (anti-HBc) may serve as useful tools to define inactive vs. active HBV carriers and to guide anti-viral therapy.4, 5, 6, 7 Nowadays, HBV-related disease progression can be controlled by effective treatment but a cure for chronic hepatitis B (CHB) remains a challenge.8 Currently approved antiviral agents for CHB therapy include direct antiviral nucleos(t)ide analogues (NUC) and immune modulatory interferon (IFN). Long-term NUC therapy profoundly suppress HBV replication through inhibition of viral reverse transcriptase/polymerase. However, viral relapse frequently occurs after discontinuation of NA in both HBeAg-positive and –negative CHB patients, primarily because of the persistence of intranuclear HBV covalently closed circular DNA (cccDNA). In contrast, despite IFN has dual effects of direct inhibition of viral replication and indirect enhancement of host immunity against the virus, the overall viral response to a finite duration of interferon therapy is far from satisfactory.9 Like other infectious agents, successful HBV infection is composed of three components: an infection source, a susceptible host, and an established route of transmission. Thus, to reach the goal of eliminating HBV infection, both preventive strategies and effective treatment of HBV infection are essential.10 First, interruption of HBV transmission routes is the most cost-effective way to reduce the global burden of HBV infection. Combination of hepatitis B immunoglobulin (HBIg) and hepatitis B vaccine as immunoprophylaxis in newborns has been shown to remarkably reduce the rate of mother-to-child transmission (MTCT). However, the implementation of immunoprophylaxis has a failure rate of 10–30% in infants born to mothers with an HBV DNA level of more than 200,000 IU/mL.11 To overcome the gap, a short-term tenofovir therapy for highly viremic pregnant mothers has been implemented as the standard of care to prevent HBV transmission.10, 111 Second, treating those who are already infected with HBV would decrease the risk of transmission to others and the development of long-term disastrous clinical outcomes. From now on, HBsAg loss with or without the gain of anti-HBs has been recognized as a “functional cure” for HBV and serves as an ideal treatment endpoint.12 Nevertheless, it is rare to achieve this ultimate goal by using current treatment modalities. To this end, several novel strategies to clear HBsAg have been proposed. Among them, killing of HBV-infected hepatocytes via cytotoxic T cell (CTL) induced by immunotherapy is the most promising one. Although HBV-specific CTL response is vigorous and multi-specific during acute HBV infection, it is usually weak or even undetectable during CHB stage.13 An ideal immune-therapeutic strategy should combine profound suppression of viral replication to prevent uninfected hepatocytes from HBV infection, which can be achieved by existing NUC treatment or novel direct antiviral agents (DAA) with different modes of action, and restoration of HBV-specific CTL response to clear the infected hepatocytes, which can be partially enhanced by host targeting agents (HTA).12 In summary, despite effective immunoprophylaxis and anti-HBV treatment, chronic HBV infection may remain a major threat in different parts of the world for a long time. Challenges ahead for the global control of HBV infection include the suboptimal coverage of universal vaccination in developing countries, a large number of chronic carriers are undiagnosed and many patients have limited access to treatments in highly endemic areas.11 All these barriers need to be overcome to eradicate HBV infection. Furthermore, an effective and simple treatment strategy should be implemented to reach the goal of HBV cure by 2030 (see Fig. 1).2  Figure 1. Discovery, prevention, treatment and cure of hepatitis B. Hepatitis B surface antigen (HBsAg) was discovered in 1965 by Dr. Blumberg. The universal HBV vaccination program was firstly launched in Taiwan since 1986, which successfully prevents viral transmission and disease progression. The introduction of Interferon (interferon-alfa-2b, and pegylated interferon-alfa-2a) and nucleos(t)ide analogues (lamivudine, adefovir dipivoxil, entecavir, telbivudine, tenofovir disoproxil fumarate, and tenofovir alafenamide) indirectly or directly suppress HBV replication. Novel agents (direct acting antivirals and host targeting agents) and combination strategies for HBV cure are undergoing phase 1 and 2 clinical trials. Hopefully, the global control of hepatitis B will be achieved by the year of 2030.
| 
发表于 2018-9-12 16:36
