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Hepatitis B virus (HBV) infection is a serious global public health problem, it is estimated that there are about 70 million cases of chronic HBV infection in China, including 20 million to 30 million patients with chronic hepatitis B (CHB) [1].
During the 30th anniversary conference of the Hepatology Branch of the Chinese Medical Association and the 2022 Annual Conference of the Hepatology Branch of the Chinese Medical Association, Yimaitong invited Professor Wu Chao of Gulou Hospital Affiliated to Nanjing University School of Medicine to share
the treatment status and prospects of CHB patients.
Professor Wu Chao
Chief physician, professor and doctoral supervisor of the Department of Infectious Diseases, Drum Tower Hospital, Nanjing University School of Medicine
Chairman of the Infectious Diseases Branch of Jiangsu Medical Association
Member of Infectious Diseases and Hepatology Branch of Chinese Medical Association
Director, Institute of Virology and Infectious Diseases, Nanjing University
Member of the American and European Association of Hepatology (AASLD) (EASL).
Member of the European Society for Clinical Microbiology and Infectious Diseases (ESCMID).
As the first person in charge, he undertakes 4 major projects of the National Natural Science Foundation of China and major projects, sub-projects of major national infectious diseases projects and 8 provincial and ministerial scientific research projects
He has published more than 150 academic papers by the first and corresponding authors, including more than 150 papers included in SCI, with a cumulative impact factor of 1120.
879 and a single highest impact factor of 71.
421, including Lancet Infect Dis, JAMA Network Open, J Hepatol, Hepatology, Am J Gastroenterol, Aliment Pharmacol Ther, etc.
Among them, 3 papers were selected as ESI highly cited papers
.
He is an editorial board member and contributing reviewer
for more than 10 SCI journals.
Professor Wu Chao: With the progress of hepatitis B diagnosis and treatment for more than 20 years, we have a deeper and more comprehensive understanding of the diagnosis and treatment of hepatitis B, and have achieved very remarkable results, but there are still the following difficulties in the diagnosis and treatment of CHB patients in China: First, the diagnosis and treatment rate of CHB in China is 90% from the "CHB diagnosis rate by 2030" proposed by the World Health Organization , treatment rate to reach 80%" The goal is far
from the same.
Recent data show that the diagnosis rate of CHB in China is only 22%, and the treatment rate is only about
15%.
The reasons for the low diagnosis rate include: (1) the fear of hepatitis B in the general population and the misdiagnosis of hepatitis B carriers in the past, so that most patients do not take the initiative to go to the hospital for regular examination; (2) The public does not pay enough attention to hepatitis B screening, and due to the existence of "stigma", surface antigen screening
will not be carried out in entry/enrollment physical examination.
So we are now calling for more testing and higher detection rates
.
China's large population, coupled with the current promotion of expanded indications, means that at least 60 million CHB patients need treatment
.
Second, there is still great controversy about the indications for the treatment of CHB in clinical practice
.
The domestic 2019 guideline recommendations and the expert consensus on expanding the indications for CHB treatment in 2022 have put forward new suggestions for the treatment standards of hepatitis B, but there are still some problems to be solved, such as the therapeutic threshold of transaminases, the treatment criteria of HBV DNA, whether to treat the immune tolerance period, and how to treat inactive carriers
.
Third, the issue of
"ideas".
First, the concept of doctors, although the current specialist doctors have gradually paid attention to CHB treatment, the treatment concept is more advanced, the treatment intention is stronger, but many non-specialist doctors still have a large lack of understanding of the treatment of CHB, this cognitive impairment mainly comes from the traditional concept, that hepatitis B has no specific drugs, treatment or not, resulting in many patients can not be treated
in time.
In addition, many doctors and patients do not have enough trust in CHB treatment drugs, such as believing that they cannot stop the drug, need lifelong treatment, or there will be drug resistance problems, and current drugs are difficult to clear cccDNA
.
Therefore, the treatment of CHB patients in China still faces great challenges and problems
.
With the advancement of medical level, the CHB treatment plan has been continuously optimized, and many new drugs
under development have emerged.
Could you please introduce the current progress in the treatment of CHB and new drug research?
Professor Wu Chao: In recent years, the research and development of new drugs has made rapid progress, and the development of new drugs by CHB is exciting
.
There are two broad categories of treatment options for CHB: nucleoside (acid) analogues and interferons
.
A subset of patients with low levels of surface antigen can be clinically cured
after treatment with nucleoside (acid) analogues and then optimized treatment regimens.
For example, the "(Everest) Project" project now carried out in China enables such patients to obtain rapid clinical cure
through long-acting interferon optimization.
There is also the exploration
of special populations.
The first child, many studies in China, such as Professor Wang Fusheng, are trying to optimize the treatment of children in the early stage, and allow children (including children in the immune tolerance period) to obtain rapid viral clearance
through interferon/nucleoside (acid) analogues.
In patients in the second pregnancy, rapid initiation therapy can bring better treatment
results in this group of people during the perinatal period or after delivery.
The third "small three yang" patients, that is, the immune control period, can achieve better benefits through interferon combined with nucleoside (acid) analogue treatment, but the effective rate and overall cure rate vary from person to person, and the data obtained by different research centers are different, and multi-center, prospective research is needed to further expand and explore
.
New drug research and development is mainly divided into two categories
.
The first category: direct-acting antiviral drugs, which prevent hepatitis B virus from entering hepatocytes, directly target gene expression of cccDNA or HBV, and inhibit nucleocapsid assembly and surface antigen release
.
The second category is host-specific drugs, whose main role is to improve the host's immune system (including innate immunity and adaptive immunity).
At present, there are about 100 new drugs under development, and there are more than 60 kinds of potential drugs, of which several drugs are progressing rapidly
.
The first of the direct-acting antivirals is a modulator
of allosteric core proteins.
It is an antiviral drug targeting the core protein, mainly by changing the conformation of the core protein to interfere with the nucleocapsid assembly, which in turn affects the assembly and reverse transcription of viral molecules, and ultimately inhibits HBV replication
.
For example, the preliminary results of the phase II clinical study of JNJ-56136379 show that it can inhibit HBV DNA and RNA at the same time, and also has a certain inhibitory effect
on surface antigens.
Core protein allosteric modulators may be more effective in combination with other agents
.
The second is targeting viral mRNA, including two classes of drugs
, RNA interference and antisense oligonucleotides.
Among them, GSK3228836 (Bepirovirsen) performed well, and has begun phase III clinical studies, and its phase II results show that GSK3228836 shows good control of surface antigen and hepatitis B virus as a whole
.
The third is surface antigen inhibitors, most commonly nucleic acid polymers, which inhibit the secretion
of indicated antigens, mainly by blocking the assembly of intracellular subviral particles.
The phase II study of REP2139/2165 developed by NAP Replicor showed that the triple treatment with interferon, long-acting interferon and nucleoside (acid) analogues had a better effect on reducing surface antigen, and there was no viral rebound during follow-up, and such drugs will have good prospects
.
The fourth is HBV entry inhibitors, which target the viral entry step
by acting as an HBV entry receptor, that is, sodium taurocholate co-transports polypeptides.
At present, Bulevirtide, which treats hepatitis D, has been marketed in Europe, and research on hepatitis B is also in a good state, and phase II results show that its combination with interferon can reduce surface antigens
.
The drug is also worth looking forward to
.
The research and development of the above new drugs has shown a good momentum, and the phase III clinical study of GSK3228836 has been carried out in China, hoping to achieve success and put into use in patients as soon as possible
.
The second category is drugs
that regulate immunity.
Drugs that target innate immunity are mainly toll-like receptor agonists, and Gilead has developed a small molecule agonist against toll-like receptor 8, and its phase II clinical study has shown that a subset of human surface antigen can decline by more than 1 log
.
In addition, the study of the innate immune agonist SB9200 developed by Spring Bank in the United States showed that it could reduce HBV DNA load and surface antigen levels, but patients experienced serious adverse reactions later in the study and they terminated the study
.
The other is the immune checkpoint inhibitor for adaptive immunity, among which the subcutaneous injection of anti-PD-1/PD-L1 antibody ASC22 developed in China is relatively rapid, which can lead to a dose-dependent decrease of surface antigen and shows better safety and tolerability
.
The drug is also currently in phase II
.
In addition, there are many therapeutic vaccines, monoclonal antibodies, which are still in phase I or phase II clinical trials
.
At present, many companies around the world have multiple pipelines in the research and development of new hepatitis B drugs, and almost all new drugs under development require combination therapy, and more new drugs will enter phase III clinical studies
in the future for different viral replication cycles and different targets.
Therefore, we are full of confidence in the clinical cure of CHB, and the prospects are relatively optimistic, but it may take a while
longer.
Yimaitong: The management of CHB patients is still a hot and difficult topic at present, what challenges do we face? What are the future research directions? Tell us about your insights
.
Professor Wu Chao: First of all, we need to change our concepts, and recently Academician Zhuang Hui has repeatedly stressed that CHB needs "Test all and Treat all" - all testing and treatment
.
In the past, the treatment standards stipulated by major authoritative guidelines at home and abroad were strict, and only about 16%-20% of patients could receive treatment
if the previous standards were followed.
Recently, the American Society for the Study of Liver Disease has conducted several studies on the standard of treatment for CHBDiscussions, such as the suggestion by some experts: regardless of viral load and aminotransferase levels, treatment should be started as long as HBV DNA can be detected
.
According to this standard, treatment can cover 87% of the CHB population, which is relatively close to the WTO target
.
In addition, with the increase of evidence-based evidence, it has been found that the incidence of liver cancer in patients with "uncertain phase" CHB is much higher than that in patients
under treatment.
This is a new problem discovered in the past 20 years of nucleoside (acid) analogue therapy, which is the performance of experts in the field of CHB in summing up experience, and it is also one of
the prerequisites that experts believe must expand the indications for CHB treatment.
Moreover, from the perspective of transmission, if not treated, it is always in a positive state of virus carrier and HBV DNA, and it still has the ability to transmit, and treating a patient is to eliminate a source of infection, which cuts off the transmission route
.
And now that drug access has improved, with the long-term use of these drugs, the treatment benefit has also improved, reducing the risk of
liver cirrhosis and liver cancer.
Even immunotolerant patients can achieve high rates of HBV DNA suppression with treatment
.
Early treatment provides early benefit
.
Finally, combined with the experience of expanding the treatment indications of hepatitis C and HIV, more and more experts advocate "Test all and Treat all"
.
This requires awareness and widespread publicity
among all clinicians.
In addition to doctors, the mindset of people infected with hepatitis B also needs to change
.
In the past, many patients were not actively treated at a young age, and as they aged, serious complications
such as cirrhosis, liver cancer and even death began to appear.
At present, the treatment purpose of CHB is not only to pursue transaminase renormalization, HBV DNA conversion, surface antigen seroconversion, but also to prevent disease progression and reduce the occurrence
of liver cirrhosis and liver cancer.
We should not only focus on the disappearance of surface antigens and clinical cure, but more importantly, start treatment as soon as possible and benefit
from the treatment process.
The important prerequisite for improving treatment rates is to increase screening/diagnosis rates, which requires the joint efforts
of our industry associations, enterprises and government departments in the future.
Therefore, it is also called for hepatitis B surface antigen detection as a routine examination, and it is necessary to check due diligence and try to screen out hepatitis B patients, which is very beneficial
to future disease control, especially liver cirrhosis, liver cancer and other complications.
The final challenge is the management
of the patient from start to finish.
At present, there are still great deficiencies in the ability of continuous follow-up of CHB patients in China, and how to improve the follow-up compliance of patients and establish relevant measures to closely follow up and manage patients throughout the life cycle is a problem
that needs to be studied.
This requires our administrative departments, medical insurance departments, medical institutions, especially how to give full play to the close liaison and collaboration of tertiary medical institutions, including community medical care, which is the direction
we need to explore and work towards.
In fact, some administrative regions in China, such as Zhejiang and Hainan, under the leadership of the government, have carried out useful attempts
to coordinate screening and diagnosis and treatment management with regions.
With the support of various experts, our center has launched the "Pilot" project, mainly for patients in the uncertain stage, and for long-term observation
of such patients according to the latest guidelines.
At the same time, there are many experts in China who are doing the same type of prospective research, such as the "(Everest) Project" project led by Professor Gao Zhiliang, the "Starlight Project" led by Professor Chen Xinyue, etc.
, which are all prospective long-term observation studies for different CHB populations, in order to obtain more evidence and make more contributions
to the prevention and control of hepatitis B in China.
References: 1.
Chinese Medical Association, Journal of Chinese Medical Association, Chinese Medical Association General Practice Branch, et al.
Guidelines for the primary diagnosis and treatment of chronic hepatitis B (Practice Edition, 2020)[J].
Chinese Journal of General Practitioners, 2021,20(03):281-289
