Chasing the Gold Medal As mentioned earlier, the clever hepatitis B virus, transformed into cccDNA, hides in the nucleus of liver cells, where no drug can remove it completely, only inhibit its activity. “The amount of hepatitis B virus cccDNA in the nucleus of liver cells is very stable, and there are often only a dozen to several dozen copies in each infected liver cell.” Professor Wu Shanming, chief physician of the Shanghai Public Health Clinical Center, told this reporter, “To measure such a low level of DNA, one can only use a liver biopsy plus PCR, which is very troublesome, and therefore serological indicators are often used in the clinic to estimate the activity of the hepatitis B virus.” Serologic indicators measure protein (antigen and antibody) content, and the testing method is mature and highly accurate. In fact, the earliest diagnosis of hepatitis B was the hepatitis B surface antigen, commonly known as “Aus-Antibody”. Later, American scientists invented the “Hepatitis B triple system” on the basis of the surface antigen, E antigen and core antigen, as well as the corresponding three kinds of antibodies. Only because the core antigen can not be detected in the blood, only the core antibody can be detected, so only five clinical tests, which is often referred to as “Hepatitis B two halves”. Chronic hepatitis B patients like Xiaohong must know these five data well, because they represent the status of the hepatitis B virus in the body. “The criteria about the endpoints of hepatitis B treatment are always evolving.” Shanming Wu said, “It used to be thought that all that was needed was to suppress the replication of the hepatitis B virus, and then it was realized that E antigen seroconversion had to be done if the patient was not to relapse after stopping treatment. Then later it was realized that hepatitis B surface antigen conversion was also an attainable higher goal.” In the world of hepatitis B research, there is a saying “gold, silver and bronze medals”, which graphically explains Prof. Wu’s theory. The so-called “bronze medal” refers to the suppression of viral DNA replication, and nucleoside analogs are the best way to achieve this goal. In this annual meeting of American Liver Diseases, some scientists reported that the level of Hepatitis B DNA in a patient’s blood is the best indicator for judging the outcome of a patient’s treatment, and that if the Hepatitis B DNA can be maintained at a very low level, the patient’s probability of developing cirrhosis or liver cancer in the future will also be very low. However, the problem is that the replication of viral DNA is difficult to be permanently suppressed and often rebounds, which gives rise to the term “silver medal”. The term “silver medal” refers to the disappearance of the hepatitis B E antigen (conversion) and the appearance of E antibodies (conversion). The E antigen is a protein located on the inside of the shell of the hepatitis B virus, and E antigen positivity indicates that the replication of the hepatitis B virus is still active, which was the case for Xiaohong before she was treated with interferon. Prof. Wu Shanming told this reporter that if a patient does not achieve E antigen serological conversion, the likelihood of relapse after stopping the drug is around 80%, but if the patient achieves E antigen serological conversion through treatment, then the probability of relapse drops to 20%. Thus, this silver medal has become the goal that all E antigen positive (“big three suns”) patients are desperately pursuing. It is here that long-acting interferon shows its strength. The results of international multi-center randomized controlled clinical trials show that for E antigen positive patients, the probability of E antigen seroconversion after 48 weeks of treatment with Pyroxene and 24 weeks of discontinuation of the drug is 32%, which is better than Lamivudine’s 20%, and also better than ordinary interferon’s 25%. What is more valuable is that patients treated with interferon continue to improve after stopping the drug. The results of long-term clinical trials conducted in Europe and the United States have shown that the incidence of E antigen serologic conversion in hepatitis B patients treated with interferon can rise to more than 50% 2 years after stopping the drug. “Interferon is not only anti-viral, but also has an immunomodulatory effect, so the potential of the patient’s immune system is mobilized after treatment with interferon, and it can still continue to function and inhibit viral replication after stopping the drug.” Prof. Wu Shanming said, “Therefore, I think E antigen positive patients can stop taking the drug once they have achieved E antigen seroconversion and consolidate for another six months or so. They can basically live like normal people, except for the need for a regular physical examination.” Prof. Bonino agrees. In his opinion, the immune system of E antigen-converted patients has been driven up by interferon and can be treated without further treatment. However, these people still have to have regular medical checkups because after all, there is still the possibility of recurrence. Hong’s mother was still not satisfied with this, she decided to let Hong to get the “gold medal”, that is, the surface antigen serological conversion. “The medical community used to think that it was impossible to get a ‘gold medal’ in hepatitis B treatment.” says Chen Crescent. Crescent Chen said, “Since the availability of long-acting interferon, we have found that getting the ‘gold medal’ is no longer an unattainable goal.” Surface antigen conversion is called the “gold medal” because it is now recognized as the best outcome of hepatitis B treatment. Patients who have undergone surface antigen conversion have surface antibodies in their blood. This is a protective antibody, and the purpose of hepatitis B vaccination in healthy people is to produce surface antibodies in the blood of the vaccinated person. The presence of such antibodies means that the body develops immunity against the hepatitis B virus, which will no longer be able to replicate. “Although I’m not 100 percent sure, if a patient’s surface antigen is converted, then he no longer needs treatment or a medical checkup.” Bonino said, “No patient with hepatitis B who has relapsed after surface antigen conversion has yet been identified, and they can be said to have been cured.” Michael Manns, a world-renowned hepatitis B expert and professor at Hannover Medical School in Germany, speaking at this year’s Liver Disease Congress, pointed out that the process of using hepatitis B cccDNA as a template for the production of the surface antigen is independent of the replication process of the hepatitis B virus, which means that the titer of the surface antigen is directly correlated with the amount of cccDNA, and it’s the most reliable cccDNA content serologic marker. If the surface antigen turns negative, it means that the number of hepatocytes infected with cccDNA has dropped to a very low level, and the activity of cccDNA is completely inhibited, and no new hepatitis B virus will be produced. In this way, the newly produced liver cells will be completely healthy and they will gradually replace the old and dead infected liver cells until the last infected liver cell is replaced by a healthy one. At that point, hepatitis B is completely cured. In this battle for the “gold medal”, long-acting interferon shows a greater advantage. A number of international studies have shown that if nucleoside analogs are used alone, the percentage of patients getting the “gold medal” is only about 1%, which is roughly comparable to the conversion rate of surface antigen produced by patients spontaneously. If treated with long-acting interferon, the conversion rate is 3% after one course of treatment, 6% after one year of drug withdrawal and 11% after two years of follow-up, which means that 1/10 of the patients with hepatitis B have achieved clinical cure in four years after one course of interferon treatment and got the “gold medal”. Xiaohong is one of them. Unlike the foreign cases, Xiaohong insisted on injecting long-acting interferon for 2.5 years and continued to do so even after her E antigen became negative. In Bonino’s opinion, such a long period of interferon treatment is somewhat redundant. He believes that for E antigen positive patients, as long as the treatment is until the E antigen conversion has occurred, and then consolidated for 3 months, the drug can be discontinued, allowing the patient’s immune system to complete the remaining tasks by itself. If Xiaohong tolerates interferon well, there is not much difference between the two treatment ideas, but from an economic point of view, there is a difference of at least 70,000 RMB between the two methods.