Hepatitis B Drug Use "Butterfly Change": Nucleosides Become The Mainstream, Chinese And Foreign Pharmaceutical Enterprises Go Hand In Hand

July 28 is World Hepatitis Day. Hepatitis is inflammation of the liver, the most common cause of which is viral infection. Hepatitis A, B, C, D and E viruses are the most concerned, because they cause a huge burden of disease, and may cause mass epidemic.

Among them, hepatitis B virus is very contagious and transmitted by blood. In recent years, with the improvement of hepatitis B vaccine coverage rate of newborns, the prevalence of hepatitis B in children in China has decreased significantly. However, patients with hepatitis B virus infection, in a short period of time will not cause great damage to health, and when the onset, often has developed into chronic hepatitis B, treatment is difficult, and the prognosis is poor. Sun Xiaohui, an associate professor of the Department of economics of Sun Yat sen University, said that he hopes to become a doctor of hepatitis B in the 21st century

At present, the market demand of hepatitis B drugs in China is huge, and will maintain a high growth trend in the future. According to global data, in 2020, the market scale of hepatitis B drugs in China will reach 20 billion yuan and 30 billion yuan in the long term. Among them, the hospital market is the main channel for drug sales of liver diseases, with a market share of about 80%.

Hepatitis B medication "butterfly change"

At present, chronic hepatitis B patients need long-term medication to achieve clinical cure.

The so-called cure in clinical medicine refers to the end point of hepatitis B treatment. According to the new edition of the guidelines for the prevention and treatment of chronic hepatitis B, the end points of hepatitis B treatment can be divided into three directions, including the basic end point, the ideal end point and the satisfactory end point.

Patients with HBsAg, or those with persistent HBsAg seroconversion, are defined as those with persistent HBsAg conversion. The satisfactory end point was that patients with HBeAg positive achieved sustained virological response and normalization of alt, accompanied by HBeAg seroconversion; HBeAg negative patients achieved sustained virological response and ALT normalization after withdrawal. During a long-term period, when the response to HBV is not sustained (e.g. after a long-term cessation of treatment, it is defined as the inability to maintain a baseline response).

According to the guidelines for the prevention and treatment of chronic hepatitis B, hepatitis B treatment drugs are mainly divided into two categories: interferon (IFN), including common IFN - α and long-acting IFN - α; nucleoside (acid) drugs, mainly including nucleic acid analogues such as lamivudine and entecavir, and nucleotide analogues such as adefovir Dipivoxil and tenofovir dipivoxil.

In 1992, FDA approved the first IFN - α - 2b for the treatment of chronic hepatitis B. In 2001, long-term IFN - α was approved for listing. In 2005, pegylated IFN - α 2A became the only pegylated interferon approved by the United States, China and the European Union for the treatment of chronic hepatitis B.

Among the nucleoside (acid) anti hepatitis B drugs, lamivudine (heptin, GlaxoSmithKline) was approved by FDA in 1998 and became the first nucleotide analogue for hepatitis B treatment in the world. Since then, Gilead's adefovir dipivoxil was approved as the first anti hepatitis B nucleotide drug in 2008, and Bristol Squibb's entecavir was listed one after another. At present, a number of drugs are on sale.

The side effects of interferon used in the treatment of chronic hepatitis B are relatively large, and nucleoside (acid) drugs are more commonly used in clinic. However, the 2017 edition of EASL guidelines for the diagnosis and treatment of hepatitis B has clearer recommendations on the use of nucleotide drugs and more explicit recommendations on the treatment course and early withdrawal standard of pegylated interferon, which also leads to the decline of interferon drugs in the hepatitis B treatment market year by year. Therefore, although stilbene drugs such as pirocin and perphene can still occupy a certain market share, the sales volume is also in the Gradually decrease.

Among nucleotide drugs, lamivudine and adefovir dipivoxil, which were introduced early, have been gradually withdrawn from the first-line treatment due to their safety and tolerance limitations, and their market share has gradually decreased. In recent years, entecavir and tenofovir fumarate have been used as the first-line drugs in the treatment of hepatitis B in Japan, the United States, Canada and other countries. Tenofovir and entecavir have been selling more than US $1 billion in 2014-2017, occupying a huge market share.

Similar to the foreign market, nucleoside (acid) type hepatitis B drugs account for about 80% of the hepatitis B drug market in China, and gradually become the mainstream drug for the treatment of hepatitis B. The product concentration of nucleotide drugs market is high, mainly entecavir, adefovir dipivoxil, lamivudine and tenovir. Although telbivudine, lamivudine and adefovir dipivoxil still occupy a certain market share, the sales have declined.

In 2016, the sales volume of vecaterine was 0.87 billion yuan, which was far ahead of other drugs in the market share of RMB 0.87 billion. Adefovir dipivoxil was followed by adefovir dipivoxil, with a sales volume of 2.419 billion yuan in 2016, with a market share of 17.55%. Although adefovir dipivoxil is the first-line anti hepatitis B drug with entecavir, its scale is far behind entecavir. Although the market share of tenofovir is not high at present, it has a promising prospect as a first-line drug for the treatment of hepatitis B. especially after the expiration of Viread patent of Gilead, several generic drugs such as Chengdu Beite, Fujian guangshengtang pharmaceutical and Zhengda Tianqing have been listed, forming a situation of joint struggle between Chinese and foreign enterprises.

A doctor in the relevant department who did not want to be named told the reporter of the 21st century economic report that interferons need injection, fixed course of treatment, high cost and low compliance, while nucleosides are oral drugs, usually one capsule a day, with relatively high compliance, and nucleoside drugs have better antiviral effect, so they have become the main force of anti viral treatment for hepatitis B.

However, with the deepening and promotion of the reform of public hospitals and the gradual expansion of the drug market for chronic diseases in retail pharmacies, retail pharmacy terminals are expected to usher in new development opportunities in the future.

Hepatitis B medication dilemma

In November 2018, the pilot work of centralized drug procurement and use organized by the state was officially launched. Public medical institutions in 4 municipalities directly under the central government and 7 sub provincial cities were selected as the main body of centralized procurement. The demand and strength were gathered to improve the negotiation and negotiation ability, so as to realize the significant "water jump" of drug price.

As soon as the policy was issued, the pharmaceutical industry was greatly affected. In the pilot project of centralized purchase, entecavir reduced the price by 90%, and the price of 0.5mg of entecavir was reduced from 10.55 yuan to only 0.62 yuan per tablet of Zhengda Tianqing, the bid winning enterprise. As the mainstream drug for prevention and treatment of hepatitis B, the price of entecavir decreased by a cliff.

On the other hand, current antiviral drugs, including nucleoside (acid) analogues and interferon, can only control the generation of hepatitis B virus, but can not eliminate the hepatitis B virus in the nucleus of hepatocytes. At present, the important goal that can be achieved is functional cure, which is commonly known as "turning Yin". Researchers all over the world are trying to develop the targets and pathways of new generation anti HBV drugs. At present, there are mainly direct and indirect antiviral methods.

Among them, hepatitis B and hepatitis C can make hundreds of millions of people suffer from chronic diseases. China is a high prevalence area of hepatitis B virus infection. The positive rate of HBsAg in the general population is 9.09%. It is estimated that 70 million people have been infected. Once the disease occurs, the annual treatment cost of each person is nearly 10000 yuan, which is not affordable for every patient.

In addition, there are also doctors to the 21st century economic report reporter frankly, clinical hepatitis B patients have a long-term latent problem, because the symptoms are not obvious. At the same time, hepatitis B treatment also has a certain degree of medical insurance reimbursement problem, leading to some patients screening results out also do not treat. In addition, because of the serious discrimination against hepatitis B patients in society, hepatitis B detection is not allowed in the entry physical examination, which is not conducive to disease prevention and control.

?