Professor Guangxiang (George) Luo discusses recent advances in antiviral drug development and hepatitis B immunization which hold great promise for achieving the WHO goal of eliminating viral hepatitis by 2030.
The World Health Organization (WHO) has called for the elimination of viral hepatitis as a public health threat by 2030. This has inspired the scientific community, pharmaceutical industry, and government agencies to explore various strategies to achieve this ambitious goal in the next 15 years. The elimination of hepatitis B virus (HBV) infection in particular, was a topic of two recent meetings I attended. On April 27-28 the United States’ National Institutes of Health convened an NIH Workshop on Cures for Chronic Hepatitis B. A month later, I participated in a strategic discussion on prevention of HBV infection in China (organized by Professor Jidong Jia and Professor Hui Zhuang).
Of the five causative agents of viral hepatitis (hepatitis A, B, C, D, and E), HBV and HCV infections pose the most serious health problems, chronically infecting about 400 million people worldwide. HBV and HCV infections are also responsible for 80% of hepatocellular carcinoma (HCC) and result in more than a million deaths each year around the world. HBV vaccines can effectively prevent both hepatitis B and D and significantly reduce the rate of HCC. Although there is no HCV vaccine, the newly approved direct acting antivirals can cure the vast majority (>95%) of hepatitis C. The most significant challenge for eradicating hepatitis C is identifying HCV-infected individuals and providing them with treatment. To cure hepatitis B, the biggest challenge for eradication is how to eliminate the covalently closed circular DNA (cccDNA) of HBV, which is responsible for viral persistence. The existing antiviral regimens with interferon (IFN) and/or nucleoside/nucleotide analogs (NAs) can effectively suppress HBV replication, but do not significantly affect HBV cccDNA levels. There are also IFN non-responders. NAs can lead to the appearance of drug-resistant mutants. It has proven extremely difficult so far to eliminate HBV cccDNA by manipulating the host immune system or using existing antiviral drugs.
At the NIH workshop in April, there was intense debate on the question of whether the eradication of HBV cccDNA should be viewed as a criterion for a cure of chronic hepatitis B. In general, it is accepted that the disappearance of HBsAg and its seroconversion to HBsAb in the blood of hepatitis B patients are considered as markers of a ‘functional’ cure. However, the current standard antiviral therapies are not sufficient for a ‘complete’ cure of chronic hepatitis B. Additional novel drugs are urgently needed in order to eliminate chronic HBV infection. Several recent studies suggest two novel targets for new classes of inhibitors. The HBx protein has been shown to promote HBV replication by targeting the cellular Smc5/6 complex for degradation. The Smc5/6 complex acts as a restriction factor of HBV transcription. It is conceivable that inhibition of HBx protein may result in suppression of HBV transcription and replication. The HBc protein may be an even more desirable target, as it plays important roles in multiple steps of the HBV life cycle, including viral capsid and virion assembly, regulation of cccDNA formation, and possibly cccDNA transcription and persistence. Several pharmaceutical companies have already identified potent small molecule HBc inhibitors and preclinical and clinical studies have shown promising results. Future development and approval of HBc-specific antiviral drugs will significantly accelerate the elimination of chronic hepatitis B. Additionally, a number of biological therapeutics are in preclinical evaluation and development, including immune modulators (e.g., TLR and RIG-I agonists), antibodies (e.g. anti-PD1/PD-L1), small interfering RNAs (siRNAs), and CRISPR/Cas-mediated knockout of HBV cccDNA. These biological agents are still in their early stages of development. It is too early to tell whether the biological therapies will be safe and/or effective to treat HBV infection. It is anticipated that the elimination of chronic hepatitis B requires a combination of several drugs targeting different viral and cellular factors.
An HBV vaccine has contributed immensely to the successful prevention of HBV infection, which is exemplified by the remarkable decrease of HBV prevalence in China. China has been the epicenter of HBV infection with a prevalence rate of nearly 10% prior to the implementation of a national HBV immunization program in 1992. Although newborns were required to receive HBV vaccination within 24 hours after birth, its coverage rate was only about 22% in 1992. After several amendments of the national immunization program with inclusion of free vaccines, HBV vaccination coverage has climbed up to 99% of all newborns in 2014. The HBV prevalence rate dropped from 10% in 1992 to less than 1% in 2014 among children under the age of 15. Over the same time period, HCC morbidity has reduced by more than 10 times among 10-19 year olds [The Global Burden of Liver Disease: The Major Impact of China and The 2016 Annual Report of Medical Science and Technology Development in China (pdf in Chinese)]. Extending from this enormous success in HBV vaccination among children, China has decided to provide HBV vaccination to high-risk groups of adults such as healthcare professionals. In addition, China has developed new policies and strategies to prevent iatrogenic HBV spread, including the use of disposable needles, screening of blood donors for HBV DNA, effective disinfection of medical instruments and consumables, and the expansion of antiviral therapy to cover more chronic hepatitis B patients. The implementation of these comprehensive measures has reduced chronic hepatitis B cases by 40 million and lowered cirrhosis and HCC incidents by 7.5 million (pdf in Chinese). These great achievements can be duplicated in other developing countries if their governments are committed to the WHO goal of eliminating viral hepatitis by 2030.
In summary, it is feasible to eliminate chronic hepatitis B given the current advances in the discovery and development of novel antiviral drugs and scale-up of HBV vaccination. The key toward the elimination of hepatitis B lies in the commitment of WHO member State governments in their investments in basic and translational biomedical research and implementation and reinforcement of universal HBV immunization. Scientists, the pharmaceutical industry, and governments should work together to find a cure for hepatitis B, as they have done so successfully for hepatitis C.
Acknowledgments: I want to thank Drs. Rajen Koshy (NIAID/NIH), Jim J.-H. Ou (USC) and Jianming Hu (Pennsylvania State University) for critical reading and Prof. Hui Zhuang (Peking University Health Science Center) for suggestions and sharing information.
Guangxiang (George) Luo is a Professor in the Department of Microbiology, The University of Alabama at Birmingham School of Medicine and The Peking University Health Science Center. Email: firstname.lastname@example.org or email@example.com
Featured Image Caption: Hepatocellular carcinoma
Featured Image Credit: Ed Uthman, MD, wikimedia commons