Preface.
The continuous replication of hepatitis B virus in the liver has the potential to make hepatitis B patients go through three stages: hepatitis, cirrhosis and liver cancer. Therefore, treating hepatitis B, delaying cirrhosis and reducing the occurrence of liver cancer requires a holistic view. In the panorama of hepatitis B treatment, cirrhosis is the end stage of the development of slow hepatitis B. At this stage, how to delay the disease progression and reduce the occurrence of liver cancer is a topic of great concern to all hepatitis B friends. We have invited Prof. Wang Yuming, Deputy Director of the Chinese Society of Infectious Diseases, Department of Infection, Southwest Hospital of the Third Military Medical University, to talk about the treatment of hepatitis B cirrhosis.
Part I:Hepatitis B virus is the root cause of hepatitis B cirrhosis, antiviral treatment should be started early
Prof. Yu-Ming Wang.
In China, the basic cause of cirrhosis is hepatitis B virus infection. We are a big hepatitis country, we have about one tenth of the population with hepatitis B in the past, and after these hepatitis B experience inflammation, they often have different degrees of fibrosis and cirrhosis, which is still relatively common. There are many patients in the hepatitis stage, in the cirrhosis stage, and even some to the liver failure stage, including HCC, is the occurrence of liver cancer of this situation, these patients often virus still exists, so later on a very important study, which is done in Taiwan called a review study. it this study is through a large number of groups, through 13 years later, it was found that disease progression This study is through a large number of groups, through 13 years later, it was found that the disease progression is related to the virus, at the same time, cirrhosis is related to the virus, cancer is also related to the virus, and finally seems to be related to the virus is very obvious.
With the hepatitis B virus, you are actually prone to the trilogy of hepatitis, cirrhosis and liver cancer.
In the past, it was thought that once cirrhosis was formed, it was impossible to reverse it, but through later antiviral treatment, especially the earliest drug called lamivudine, lamivudine was the first to do an international study of 4006 in patients with cirrhosis, that is, through antiviral treatment, will the patient be able to change his state of cirrhosis, and the results were very clear. The results were very clear.
The disease progression in the drug group (lamivudine) was reduced, his histology was improved, the inflammatory response was reduced, there was a reversal of cirrhosis, and the carcinoma was reduced, and then it was thought that the importance of this viral factor was disproved by antiviral therapy.
Part I Summary.
1: The hepatitis B virus has an amazing ability to replicate, producing between 10 to 12 and 10 to 13 “offspring” per day. If the hepatitis B virus is not suppressed, hepatitis B virus replication will cause slow hepatitis B to progress to cirrhosis or even liver cancer. Therefore, viral replication is the root cause of liver cirrhosis.
2: The role of antiviral drugs is to inhibit the replication of hepatitis B virus, so whether it is slow hepatitis B or cirrhosis, the root of the treatment is to inhibit viral replication, in order to delay the progress of the disease to the greatest extent possible, to reduce the occurrence of cirrhosis, liver cancer, especially cirrhosis patients, to start antiviral treatment as early as possible.
The second part: cirrhosis is already in the late stage of hepatitis B development, which is extremely harmful
Chronic hepatitis B is a gradual development process, of course, we have also talked about, some patients may, a major blow, a one-time this great blow, he is enough to lead to a cirrhosis, but in fact, there are many patients he is a relatively slow result. So in this sense, we say, what is the relationship between slow hepatitis B and cirrhosis, liver failure and cancer? In fact, inflammation is the basis, and it always starts with inflammation, and when this inflammation starts, the repair is incomplete, so it is often the fibrous connective tissue that replaces the liver, so it gradually and gradually fibrosis, we call it sclerosis. Generally speaking, small nodules tend to be slightly less inflammatory each time, while large nodules may be a large mass of necrosis, or sub-large mass of necrosis, more intense, on this basis, there is a very easy problem of human repair, that is, the repair process occurs in error, and this error will easily lead to cancer.
In short, it causes this cancer through a series of pathological and physiological processes, so this trilogy of hepatitis, cirrhosis and liver cancer is called one and the same.
What is the percentage of chronic hepatitis B that progresses to cirrhosis each year?
If our methods are more advanced, we can find that there are more patients with liver fibrosis and cirrhosis than we thought by using some other methods other than clinical, especially like fiber scan and liver biopsy. Probably I estimate that the rate is probably more than 10% per year, depending on the age of course. For example, if we say that there are many patients between the ages of 10 and 20 who do not develop the disease, then this figure is a bit high for them, while for people in their 50s and 60s, the figure will exceed our 10% figure.
Liver cirrhosis is divided into two stages: compensated and decompensated.
In this compensated stage, some patients may have liver spider nevus, dull face, obvious loss of energy, some patients may be a little thin, etc., or we may find some changes of liver cirrhosis through some objective examinations. In the decompensated stage, any of the indications of decompensation appear, including possible upper respiratory tract bleeding, ascites formation, bilateral lower limb edema, decreased urination, and hepatic encephalopathy, which we call decompensation. Often spontaneous peritonitis, which also occurs more often on the basis of decompensation, is divided into these two main stages. Generally speaking, decompensation is the clinical appearance of cirrhosis is more obvious, and the disease is relatively heavy.
As for the compensated stage, the conversion to decompensated about every year depends mainly on whether the patient has an attack or not. If we take antiviral treatment before, let’s say 11 years ago, we know that lamivudine was marketed 11 or 12 years ago, before it was marketed in 1999, probably a patient occurs from compensated to decompensated process, the occurrence rate is still relatively high, at least may reach about 20% of such a state, onset of disease every year. Therefore, the study found that after 5 years of antiviral treatment for compensated cirrhosis, the majority of these patients can be safe after taking lamivudine. On the contrary, it was found that more than 80% of the patients who did not take the drug could develop and die, and less than 20% of the patients who took the drug could develop and die, which seems to be very important for the antiviral treatment to contain the virus and prevent it from developing further, and to prevent the patient from going from the compensated stage to decompensation.
Once decompensation occurs, the patient should be more than 80% in 5 years, which is very high, and eventually is a path of no return. But then again, after the antiviral treatment, the world has now reached a consensus that history can be rewritten. This rewriting of history, the survival rate of this patient can be doubled, disease progression is significantly reduced by more than double such a level, the occurrence of HCC (hepatocellular carcinoma) is also reduced, the possibility of its subsequent occurrence of serious illness is significantly reduced
Summary.
1: In general, if chronic viral hepatitis B is not effectively controlled in a timely manner, it will gradually progress to cirrhosis. Epidemiological surveys show that patients with chronic hepatitis B can develop cirrhosis in 5-10 years. Approximately 12-25% of patients with chronic viral hepatitis B progress to compensated cirrhosis every 5 years.
2: About 20-23% of patients with compensated cirrhosis progress to decompensated cirrhosis every 5 years, and about 6-15% of these patients progress to liver cancer every 5 years. The annual mortality rate for decompensated cirrhosis, also known as end-stage liver disease, can be as high as 20-57%.”
What are the dangers of cirrhosis?
That is, for hepatitis B, probably all our patients are afraid of what? About one fear is cirrhosis; we are of course talking about decompensated cirrhosis in this place, and the second fear is liver cancer. Loss of compensation can be said to be a source of all evils, and cirrhosis can be said to be a source of all evils, and if it is the source of all evils, then ultimately traced to the virus. However, it the performance of this virus it led to hepatitis, and then the occurrence of cirrhosis, cirrhosis is compensated at the beginning, the problem is not too big, this is generally a lot of patients do not know, then to the back, for example, we talk about Chen Yifei, Chen Yifei we all know he was busy a day, he did not know what disease he had, boom a gastrointestinal hemorrhage, itself can kill him, so this The source of all evil brings a lot of problems to people. I have written about many aspects of this complication in the past, cirrhosis can be recurrent for a long time some hepatic encephalopathy, can be complicated by many serious infections, because the liver barrier function is reduced, this serious infection is very easy to occur, and is it recurrent, recurrent type, spontaneous peritonitis is also very common, can occur gastrointestinal bleeding, just like Chen Yifei, but also can occur some other Some liver-related complications of various kinds can occur. Then cancer is also, itself liver failure can also lead to death, so it is a variety of complications.
Summary.
1: Early cirrhosis is not obvious harm, most symptoms are mild and generally do not affect the normal life and work of patients. However, late cirrhosis harms are serious, there will be a series of different degrees of portal hypertension and liver dysfunction, and even life-threatening, cirrhosis harms are mainly manifested in the systemic, digestive, complications and several other aspects.
2: Among them, the incidence of hepatic encephalopathy caused by decompensated cirrhosis is 84%, the incidence of esophagogastric fundic variceal bleeding is 50%, the incidence of ascites within 5 years is 30%, the incidence of hepatorenal syndrome within 5 years is 40%, and the incidence of hepatocellular carcinoma among cirrhotic patients is 3%-6% every year.
Part III: Three keys to the treatment of cirrhosis of the liver in hepatitis B
Key 1: Cirrhosis is the end stage of slow hepatitis B, with a high incidence of complications and greater harm, and a significant number of patients may be converted into liver cancer. Anti-viral therapy is the key to delaying disease progression
Professor Wang Yuming.
The conditions of this antiviral treatment for cirrhosis are not quite the same as our ordinary slow hepatitis B. The ordinary slow hepatitis B HBeAg positive and negative are set at 5 times 10 and 4 times 10 respectively, but for cirrhosis we can relax and relax a bit, let’s say, in HBeAg positive only 4 times 10, relaxed by 10 times, and HBeAg negative relaxed to 3 times 10. In addition, there is also decompensated cirrhosis, which is currently considered to be treated with antiviral therapy as long as the virus is detected. Compared with the general slow hepatitis B, these patients should be treated earlier if they can be treated, and the conditions should be relaxed for treatment, and long-term treatment should be carried out.
Professor Wang Yuming.
So these are the hints that if we target a relatively early stage of cirrhosis in a compensated state, after a long-term treatment, these patients may come off the cap of cirrhosis. This risk of his disease development can be greatly reduced, he can be a long-term treatment, even including cirrhosis, liver cancer of this situation is to prevent its further development, to prevent its development
Key 2: Long-term treatment is the key: must be ready for long-term treatment, can not easily stop the drug, and should choose their own long-term burden of antiviral drugs
Prof. Yu-Ming Wang.
Antiviral treatment for hepatitis B cirrhosis should be adhered to for a long time, and antiviral treatment, if we want to emphasize a long-term for these groups, to be early, and even to be used often, for a long time.
Patients with cirrhosis may be life-threatening to discontinue drugs at will, to carry out long-term treatment, this treatment, it is relatively best not to just stop the drug, because after discontinuing the drug there is a great danger in where? The first is that these patients’ liver reserve function is relatively poor, right? The second is that if the virus bounces back, the bounce is relatively fast, and the bounce may cause a process of severe disease, and this process of severe disease makes him an acute loss of compensation, and this loss of compensation is sometimes related to the life of the patient.
Long-term antiviral to choose cost-effective drugs
So let’s face it, let’s say we have four nucleoside analogues, and we have to calculate the relative expenditure, the cost effectiveness of lamivudine is still relatively good
Aside.
Among the four major classes of oral antiviral drugs currently on the market lamivudine, telbivudine, adefovir, and entecavir can all inhibit viral replication, but there is a big difference in price. The monthly cost of these four drugs is: lamivudine (Herceptin): about $470, adefovir (Haverix): about $550, telbivudine (Sulbivir): about $750, entecavir (Boludin). About 1200 yuan. More than 70% of hepatitis B patients in China have a monthly income of less than 3,000 yuan, so choosing a drug that they can afford to adhere to long-term treatment is the first thing that hepatitis B patients should consider. Hepatitis B treatment cannot be a quick fix, and switching to other drugs or stopping them in the middle of treatment due to excessive financial burden is most likely to lead to treatment failure and thus disease progression. Therefore, to adhere to the long-term antiviral, drug spending is important.
Key 3: drug safety is the key: cirrhosis is heavy, the drug safety requirements are very high, antiviral should be selected with good safety, less side effects of the drug
Professor Wang Yuming.
In some patients with decompensated cirrhosis, especially in cases where there is a significant increase in the severity of the disease, the internal environment is disturbed, and some patients may have increased lactate, and at this time, the use of entecavir is reported internationally that some patients may have a further increase in lactate, and in some patients, the kinase in his creatine called CK, in this case, some patients like telbivudine, in the use of drugs In this case, some patients, such as tiapifudin, should be careful when using the drugs, especially some patients he has to use cephalosporin, to use sometimes statin drugs it can cause CK increased, these aspects should also pay attention again.
However, relatively speaking, the safety of adefovir is not a big problem, mainly in terms of renal function, and often the incidence of this patient is relatively low, about 1%-3% of such a level, these patients relatively speaking the frequency of creatinine increase and its magnitude is relatively small, it should be said that it is still relatively small. Lamivudine should be considered relatively safe, and up to now the safety of lamivudine as a whole is still relatively high, so it can be used at times even in pregnancy.
Aside.
Lamivudine: the longest marketed, most widely used and most used, the 10-year results of the 4006 study confirmed the long-term safety of lamivudine in the treatment of patients with cirrhosis. the first patients who used lamivudine 10 years ago have directly benefited from long-term treatment, as some patients with early cirrhosis have even achieved complete reversal because of the ability to adhere to long-term treatment.
The safety of other oral antiviral drugs remains to be confirmed by more studies.
Summary.
For the three keys to the treatment of cirrhosis, experts concluded that the treatment of cirrhosis should focus on the principle of “three less”, that is, choose: 1) less cirrhosis, less liver cancer 2) less side effects 3) less costly antiviral drugs to adhere to long-term treatment, do not arbitrarily stop the drug.
Part IV: The evolution of the treatment strategy for cirrhosis B. Currently, the optimal combination is preferred
Phase I: monotherapy + drug resistance after drug replacement
The first stage, some say, is the combination after resistance to monotherapy. That is, let’s say lamivudine initially it appears, then later after the emergence of drug resistance we add adefovir, and then the combination therapy. But in fact, during this period, because it was in 2005 when adefovir was launched, before that there was a lamivudine resistance, we did not have more strategies to carry out treatment, because when adefovir was not available, at that time, we continued to use the drug, thinking that after all, it suppressed the wild strain, then relatively speaking, this patient will not occur, rarely occurred loss of compensation. Later, it was found that this strategy is still not very good, especially once adefovir is on the market, this strategy does not exist anymore.
Phase II: monotherapy + combination after drug resistance
The second phase is after monotherapy, after drug resistance, the beginning is we are switching, the first phase is switching, that is, some, like I myself also said in the past, we are not theoretically, we first put it, we called overlapping use for three months, and then switch it over, but I quickly found that this strategy is problematic, because it is not enough time to act, the effect is not strong, so it After the occurrence of drug resistance a situation more, we soon changed, formed the so-called second stage, that is, after the resistance to monotherapy is a combination, we have to add drugs, not to change drugs but to add drugs
The third stage (the current stage): optimization of treatment or initial combination therapy
”So far, then the updated opinion out, is that one is a single drug an optimization of treatment, we may start with only one drug, this drug if used down everything is very good, not bad. But this optimization means that if the viral content is not too high, and if the transaminases are high, and if it is estimated that it is less resistant to drugs in the future, we use a single drug. Of course, some if the compensatory four nucleoside analogues can, relatively speaking, are selected according to the situation of each patient, after the occurrence of drug resistance, then this is to add drugs, is to optimize the treatment. The patients we select are relatively easy to obtain good results.
Then there is another situation is called the initial combination, the initial combination, the initial combination is the beginning of our two drugs, a nucleoside analogue and nucleotide analogues together for treatment, but this experience is currently more lamivudine plus adefovir, and other nucleoside analogues, like tipifudine, entecavir and then combined with adefovir to this experience is not too much Because of the cost effectiveness of the drug, we are using a combination of lamivudine and adefovir a little bit more.”
If we want to evaluate the efficacy, then definitely the initial combination is the best, followed by the addition of drugs, that is, after the resistance to add drugs, the worst is the change of drugs. Because of drug exchange, now the world’s guidelines have abandoned it, now no longer use this method, because it is considered that this kind of drug exchange it is easy to appear cross-resistance, so now it seems that we can accept is the main two strategies, if you want to use the effect is definitely the initial combination is better, plus drug this if we optimize the addition of drugs, I should say that the effect is also good, so now more consistent, in cirrhosis The same is true for cirrhosis, that is, if the initial combination of this effect is certainly the best, but the addition of drugs to the second, if the optimization of the addition of drugs this is a little better, basically this is such a state.
Part V: Summary
Through this expert forum, you have learned about the dangers and treatment points of cirrhosis, which is in the late stage of the hepatitis B treatment panorama, and please keep in mind the following points.
1. the replicative nature of the hepatitis B virus and its difficulty of removal are the fundamental causes of chronic hepatitis B and cirrhosis.
2. Anti-viral treatment is the key to slow down the disease progression, reduce transplantation and reduce the development of cirrhosis into liver cancer
3. Due to the characteristics of cirrhosis disease and the course of treatment, the principle of three less should be adhered to when choosing oral antiviral drugs for treatment, and the drugs that can maintain long-term treatment and clearly reduce disease progression and the occurrence of liver cancer should be chosen in terms of clinical efficacy, safety and economy.
4. The current treatment strategy for cirrhosis is based on optimizing the combination, and additional drugs are needed instead of changing drugs when drug resistance or poor response occurs.
Finally, Prof. Yuming Wang emphasized.
Finally, I would like to say that the most important thing for patients with chronic hepatitis B is that no matter which stage you are in, you should keep in mind one thing, because this virus is the source of all evils, so in this case you always have to go to a specialist, you always have to be monitored, and you always have to listen to the guidance of a specialist to carry out your series, we include this trilogy, the whole trilogy of hepatitis, cirrhosis and liver cancer treatment is to listen to the experts. And in this, no matter which step you take, if you find a good specialist, he will give you a good guidance and a treatment on the basis of the original one, so that you can achieve the maximum benefit with the minimum expense, not the other way around.
Thank you all!