Global research explores hepatitis B treatment path
Hepatitis B virus (HBV) infection is an important cause of liver cirrhosis and liver cancer. Humans have been studying HBV for many years, and vaccines for suppressing viruses have already been on the market. Although the method of curing hepatitis B has not been found, as the article published in Science recently focused on the treatment of hepatitis B, the current drug candidate Almost every point in the complex life cycle of HBV has been targeted.
"Copy template" increases the difficulty of treatment
The Global Hepatitis Report 2017 published by WHO shows that about 325 million people worldwide are infected with chronic hepatitis B virus or hepatitis C virus. At present, WHO has listed viral hepatitis as one of the major threats to global public health.
"Although the number of new infections of hepatitis B is decreasing with the widespread vaccination of hepatitis B vaccine among children in China, the number of deaths due to chronic HBV infection is still increasing, and the situation of hepatitis B prevention and control in China remains Severe." Zheng Sujun, chief physician of the Department of Hepatology, Beijing You'an Hospital, Capital Medical University, told the Journal of the Chinese Academy of Sciences.
Unlike hepatitis C virus, which is only found in the cytoplasm and can be cured after it is cleared, there is a replication template in the nucleus of the hepatitis B virus, covalently closed circular DNA (cccDNA), which can continuously produce small viruses.
"Even if the HBV antigen antibody index has not been detected in the human body, the influence of hepatitis B virus on the human body still exists due to the latent cccDNA. At the same time, the level of cccDNA in the liver cells of patients is extremely low, and the traditional molecular biological methods are not only difficult to detect, Moreover, it is impossible to accurately locate infected tissue cells. These characteristics of hepatitis B virus determine its refractoryness," said Chen Xulin, a researcher at the Wuhan Institute of Virology, Chinese Academy of Sciences.
At present, the treatment of hepatitis B is a combination of antiviral and immunopotentiating agents, including two antiviral drugs, one is a nucleoside (acid) analog and the other is an interferon.
"Nuclear (acid) analogues are highly effective in inhibiting hepatitis B virus DNA, but require long-term medication and may cause drug resistance, and the recurrence rate is high after discontinuation; long-acting interferon is relatively fixed but exists The price is high, the adverse reactions are many, and the inhibitory effect on viral DNA is still unsatisfactory. "Zheng Sujun said, "The current antiviral drugs can not completely eliminate the hepatitis B virus in most cases, that is, they cannot completely cure hepatitis B. Although antiviral therapy can effectively reduce the incidence of liver cirrhosis and liver cancer, some patients with cirrhosis may still develop liver cancer."
Potential target prompt cure
Many researchers believe that hepatitis B virus infection will not be completely cured if cccDNA is not eliminated. Recent in-depth studies of the complex life cycle of the virus have provided new potential targets for antiviral.
Chen Xulin said that there are six major international researches on hepatitis B treatment, including viral assembly and nucleocapsid inhibitors, surface antigen secretion inhibitors, viral envelope inhibitors, cccDNA inhibitors, HBV entry inhibitors, and RNAi drugs against viral mRNA. These drugs act on different stages of viral infection, and as research progresses, the hope of curing hepatitis B is growing.
In the life cycle of HBV, from infection to new virus generation, almost every known step is the target of at least one new drug. In addition, researchers have devised some new immunomodulators to produce specific beneficial responses or to suppress harmful reactions. Many researchers suspect that, like HIV, combination therapy that attacks the virus from different angles is ultimately most likely to succeed.
According to incomplete statistics, nearly 50 potential treatments are currently under development, either directly attacking different stages of the viral life cycle or enhancing the host's immunity. More than 30 drugs have been found in human trials, three times that of the past 10 years.
Gilead is working on a similar anti-hepatitis B virus weapon. "This is by far the biggest project in virology," said John McHutchison, chief scientific officer of the company. "If someone wants to cure hepatitis B, Gilead is willing to help."
The study found that the drug works well in woodchucks and can reduce cccDNA to undetectable levels. The drug is currently in phase II clinical trials.
Eugene Schiff, a liver expert at the University of Miami in Florida, said: "A few years ago, they said that it is impossible to remove cccDNA. Now we have seen the dawn of clearing cccDNA. If we can cure hepatitis B patients and continue to vaccinate people who are not infected with hepatitis B, We can eradicate this disease."
The effect of research on drugs is facing challenges
The researchers found that it was a daunting task to prove whether any treatment could significantly deplete cccDNA. Direct monitoring of cccDNA means multiple painful liver biopsies in patients. Current clinical trials indirectly assess the efficacy of drugs by measuring the effects of drugs on HBsAg levels and viral load in the blood.
This situation may change if a relatively painless and simple fine needle aspirate the liver to capture enough tissue. Mala Maini, an immunologist at University College London in the UK, used a fine needle aspiration method to assess the liver's extensive immune response to hepatitis B virus. She is currently working with hepatologist Fabien Zoulim of the University of Lyon in France to analyze whether this technique is suitable for cccDNA studies.
The researchers say that in contrast to the growing interest of drug developers in the hepatitis B virus, the National Institutes of Health (NIH) spent only $44 million on hepatitis B virus this year, and a few of them were used for "discovery research." ".
Anthony Fauci, director of the NIH Bethesda National Institute of Allergy and Infectious Diseases, agrees with this approach, saying that when some treatments make some progress, we will invest more research funding.
"At present, international research on the treatment of hepatitis B has taken a big step. In addition to catching up, studying the contribution of traditional Chinese medicine to hepatitis B treatment may provide a new way for researchers in China." Chen Xulin said. (trainee reporter Bu Ye)
Chinese Journal of Science (2018-12-06 3rd Edition International)
Source: Chinese Journal of Science
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