When did hpv enter China?

In recent years, a series of breakthroughs have been made in the etiological study of cervical cancer: in the early 1980s, Harald Zur Hausen, a German virologist, first put forward the hypothesis that human papillomavirus (HPV) infection is closely related to cervical cancer [1], and later confirmed that HPV infection is the main cause of cervical cancer [2]. 1995, IRAC seminar confirmed that human papillomavirus infection is a necessary condition for cervical cancer. Human papillomavirus [3] can be detected in 99.7% of cervical cancer lesions, with a relative risk of 250 and an attributable risk percentage (ARP) of over 98%. People who are not infected with human papillomavirus will hardly develop cervical cancer (negative predictive value > 99%). A newly published 6-year follow-up study of women with different HPV status at baseline shows that the risk of cervical precancerous lesions in women with HPV positive at baseline and 6-year follow-up status is 167 times that of women without HPV infection. The risk of precancerous lesions in women infected with human papillomavirus at baseline is 52 times higher than that in women not infected with human papillomavirus [4], which fully confirms Hausen's hypothesis and confirms that human papillomavirus is the necessary cause of cervical cancer. The revelation of the necessary causes of cervical cancer made Hausen one of the winners of the 2008 Nobel Prize in Medicine, which promoted the revolutionary innovation of screening cervical cancer through human papillomavirus detection, and even promoted the advent of cervical cancer vaccine that can prevent human papillomavirus infection, opening a new chapter in cervical cancer prevention and treatment.

1 main types of high-risk human papillomavirus in cervical cancer in China In recent years, scholars have actively explored the dominant types of human papillomavirus in cervical cancer patients in China. Due to the diversity of experimental methods, regional differences and the complexity of sample sources, the research results are different: some scholars think that 16, 58, 52 or 33 is very important in Asian population [5,6], and some scholars think that human papillomavirus -63 is very important.

In 2007, a meta-analysis of the distribution of HPV types among women in China showed that HPV 16, 18, 58, 52 and 3 1 were the most common in ICC (the combined infection rate of HPV-1618 was 69. The accuracy of meta-analysis depends on the original research, but the results are still limited because it is difficult to unify. In 2007, China Academy of Medical Sciences conducted a national multi-center study in 19 hospitals in seven different regions of China. The central laboratory used the highly sensitive SPF 10 LiPA technology to detect the human papillomavirus type in cervical cancer tissues, and finally determined the distribution of human papillomavirus type in Chinese mainland.

This study confirmed that human papillomavirus-16, 1 8, 3 15 2 and 5 8 are the most common squamous cell carcinoma tissues.

Accounting for 76.7%, 7.8%, 3.2%, 2.2% and 2.2% respectively; In CIN 2/3, human papillomavirus-16, 58, 3 1, 52, 18 were the most common, accounting for 68.7%, 12.5%, 7.4%, 6.5% and 3.3% respectively.

2 Research and development of cervical cancer vaccine and its global application At present, two kinds of HPV preventive vaccines have been successfully developed internationally: bivalent vaccine against HPV-16/ 18 and tetravalent vaccine against HPV-6/116/65433. According to the distribution of HPV types, effective HPV vaccines containing HPV-16 and 18 can prevent 84.5% of cervical cancer and 72% of high-grade cervical precancerous lesions in China.

Recently, some scholars have summarized some clinical trials of the two vaccines. The results showed that for women who were not infected with human papillomavirus, the two vaccines showed long-term high efficiency in preventing cervical precancerous lesions and cervical cancer (> 95%), and the tetravalent vaccine also had good preventive effect on genital lesions caused by related human papillomavirus (100%). For women who have been infected with the target human papillomavirus, this vaccine can significantly reduce the incidence of cytological abnormalities. The two vaccines showed high seroconversion rate (100%) in all age groups, and the titer of neutralizing antibody was more than 8 times higher than that of naturally infected antibody after 5 years. The antibody reaction of bivalent vaccine with AS04 as adjuvant against human papillomavirus-16/ 18 was higher than that of tetravalent vaccine with aluminum salt as adjuvant, and the bridging immunogenicity of the other two vaccines was studied. Agorastos summarized all the safety data of the global clinical trials of the two vaccines (n > 60000). The analysis results showed that the injection sites of the two vaccines may have mild and short-term local reactions (erythema, pain or swelling), and the incidence rate of the vaccine group was higher than that of their respective control groups, but there was no report of related death after the vaccination of human papillomavirus [13]. Although pregnant women have not observed serious consequences after accidental inoculation of any HPV vaccine, and it has been confirmed that lactating women can be vaccinated with tetravalent HPV vaccine, due to the limitation of data, pregnant women, HIV-positive children and other acute patients are still not recommended to be vaccinated with HPV vaccine. In addition, because the incidence of syncope and venous thrombosis is slightly higher in young women after vaccination, it is recommended that adolescent women observe 15 minutes after vaccination.

The efficiency of the two vaccines is exciting, and they have been listed in 80 ~ 100 countries around the world. According to the results of immune bridging test, some countries have approved vaccines for adolescent girls, young women (9-26 years old), adolescent boys (9-15 years old) and even middle-aged women (under 45 years old), with nearly 30 countries. In addition, the safety monitoring data after the marketing of vaccines also showed that about 40 million vaccines were inoculated with the two vaccines, and local minor adverse reactions or systemic symptoms were more acceptable than other vaccines, and no deaths directly related to vaccines occurred. Therefore, the World Health Organization (WHO), Centers for Disease Control (CDC) and European Medical Institutions (EMEA) all think that HPV vaccine is safe and effective, and its vaccination should be actively promoted in developed or developing countries around the world [13].

3 Challenges and Opportunities of Vaccine Application in China At present, vaccines have been approved for use in Hong Kong, Macao and Taiwan; At the same time, in view of the high efficiency and safety of HPV vaccine in the world, Chinese mainland is actively carrying out phase III clinical trials, so as to get the approval of the FDA as soon as possible and make it available as soon as possible. It is worth noting that in the process of applying HPV vaccine, Fuzheng Department should avoid repeating the mistakes of hepatitis B vaccine, so that women in China can enjoy this great achievement of mankind as soon as possible.

Similar to cervical cancer, China is also one of the countries with the heaviest burden of hepatitis B in the world. It took a long time for hepatitis B vaccine to be introduced into China and spread to the whole people. When 1992 hepatitis B virus (HBV) vaccine was first brought into the national planned immunization management, the vaccination coverage rate was not high due to the limited vaccine supply channels, low public awareness and high vaccine cost. 1999 survey showed that the vaccination rate of school-age children under 12 months was only 70.7% [14]. With the increasing burden of hepatitis B in China and the gradual emergence of the global immune effect of HBV vaccine, Zhengzhou, China has raised public awareness of HBV infection and the importance of preventive immunization through health education programs. With the further help and guidance of non-Zhengzhou organizations such as the Global Alliance for Vaccines and Immunization, in 2005, the state undertook all the expenses of HBV vaccine and included it in the Expanded Programme on Immunization, which made a key step for China to overcome hepatitis B, but we should also pay attention to the differences between the two. Although China's "Guidelines for the Prevention and Treatment of Chronic Hepatitis B" has recommended HBV vaccine as the most important measure to reduce the burden of severe liver cancer in rural areas, the main reason for recommending HBV vaccine in infants is that its infection mostly occurs in childhood, and the promotion of HBV vaccine in China is based on fighting HBV infection rather than directly preventing liver cancer; As the world's first vaccine against cancer, how to define its appropriate target population and how to incorporate it into China's current immunization program and cancer control program is facing severe challenges. At the same time, it will also provide an example for the future application plan of other vaccines being developed, such as the human immunodeficiency virus (HIV) vaccine.

Specifically, the application of HPV vaccine in China needs to face the following challenges.

3. 1 target population research shows that girls who are not infected with HPV get the highest income from HPV vaccination, and sexual behavior is a direct risk factor for HPV infection, so girls who have never had sexual behavior become the first target population for HPV vaccination. Globally, girls aged 9 ~ 13 will be the appropriate target population [15]. At present, the preliminary data analysis of the age of women's first sexual behavior in China shows that the first sexual behavior of young women in China generally occurs at the age of 18 [16]. Therefore, the recommended vaccination age in China will be a little later than the international recommended age, ranging from 13 to 15. As an ancient civilization, China has a relatively conservative cultural tradition. Vaccinating young girls in China with such a vaccine can prevent cancer and reproductive diseases caused by sexually transmitted infections, which may be a sensitive topic, especially in rural areas with heavy disease burden. Relatively conservative thoughts and the lack of medical and health system make many rural women develop from early precancerous lesions to late lesions without knowing it. Immunization is expected to be an effective means to balance urban and rural health resources. For girls in junior and senior high schools of this age, we can rely on the Department of Sexual and Reproductive Health, which has rich experience in school health education and the transmission and exchange of sensitive information, which is conducive to the development of human papillomavirus immunization planning based on schools, and at the same time, the establishment of vaccine application strategies for off-campus girls based on community service stations and rural health centers.

3.2 Publicity and Education A population-based study investigated the knowledge of HPV vaccine among women aged 65,438+04 ~ 59 in China (n = 6024). Only 15% women have heard of human papillomavirus, about 50% women think that human papillomavirus is related to cervical cancer, and more than 80% women are willing to vaccinate themselves and support their daughters to vaccinate human papillomavirus. Another study shows that 67% of women don't think they are at risk of contracting human papillomavirus; 65% people think that vaccination will not affect whether they will get cervical cancer in the future; 55% women are worried about the quality and safety of vaccines, and 36% women do not fully understand the adverse effects of human papillomavirus infection; 98% of women prefer to know vaccine-related information through medical staff [18].

These results show that: through media publicity in recent years, women in China have a preliminary understanding of HPV vaccine, but they still need to be further strengthened; Women are more inclined to believe the information obtained from medical care. Therefore, it is very beneficial to make a general public education and communication plan about human papillomavirus, cervical cancer and other human papillomavirus-related cancers and diseases. The medical and health system can go into schools and disseminate information about human papillomavirus and the role and limitations of vaccines to students through health promotion lectures and publicity columns. The state should also cooperate with macro-control science, immunization, cancer control and sexual and reproductive health departments to provide supplementary information on HPV vaccine from a social perspective, coordinate their respective tasks and responsibilities, and balance the expectations and concerns of different stakeholders.

3.3 Price and Payment System A recent survey shows that [17, 18]: 79% of women in China want to pay for all or part of the vaccine, and about 70% of them are willing to pay up to $8. At present, it costs about $300 to buy three shots of vaccine in developed countries. Although there is a market price difference between developed and developing countries, the price of HPV vaccine in developing countries has not yet been determined, but we can speculate that if the vaccine is overpriced, the price will become the biggest obstacle to its wide application in China. At present, the adoption of TierPrice is considered as a powerful measure to accelerate the accessibility of vaccines: vaccines can be provided to countries suitable for GAVI at cost; For middle-income countries, gradient pricing can be used to reduce vaccine prices, and vaccine prices can also be reduced by improving product production efficiency or product localization. Due to China's special national conditions, it is feasible to adopt self-funded vaccines (such as influenza vaccines) in China's planned immunization program. First, the HPV vaccine is managed in a unified and standardized way through the Centers for Disease Control and Planned Immunization. On the premise of ensuring the safe supply of vaccines, priority should be given to some people to obtain HPV vaccines through market sales. With the popularization and application of HPV vaccine, it will eventually be included in the national immunization plan, so as to shorten the time lag between the formal registration and launch of products and people's access to medical care as much as possible. In addition, on the basis of global gradient pricing, China can try to form a tripartite cost-sharing mechanism of payment, medical insurance and individuals, and adopt different proportions of Medicaid programs for different income groups. For example, policy support is given to remote areas such as ethnic minorities, and the state bears the full cost of HPV vaccine; Implement high subsidies or even free plans for high-risk key protection groups; Form a national financial gradient proportional subsidy payment system for high, middle and low income groups from low to high, and gradually make HPV vaccine an affordable health product for ordinary people, so that the people can benefit as soon as possible.

3.4 Health Economics Evaluation The data of several vaccine health economics models that have been completed abroad show that the older the girl who is vaccinated, the lower the cost-effectiveness ratio of the vaccine; The longer the immune efficacy is maintained, the wider the coverage of adolescent vaccination and the better the cost-effectiveness ratio; If the continuous immune efficacy of the vaccine is less than 10 years, screening will be better than vaccine replanting from the perspective of cost-effectiveness [19]. In view of the diversity of medical choices and the high cost of HPV vaccine, China should also establish a health economics prediction model suitable for China's national conditions to provide basic epidemiological data for the comprehensive application of HPV vaccine in China, so as to determine the health care needs, direct/indirect costs, potential short-term (impact on early pathological changes and screening) and long-term effects (impact on cancer, women and family productivity) and indirect benefits of HPV vaccine, and further guide the formulation of national financial expenditure and project plans.

3.5 The Best Combination of Vaccine and Screening In 2005, a population-based multicenter epidemiological survey of human papillomavirus infection and cervical cancer in China found that the average infection rate of carcinogenic human papillomavirus among women aged 65,438+05 ~ 54 in China was as high as 65,438+05.0% [20]. Based on this calculation, a large number of married women in China have been infected with human papillomavirus. If this group of people are vaccinated, the effect is not great. Therefore, in the next 20 to 30 years, screening will still be the main means to prevent cervical cancer in adult women.

Young girls are vaccinated with HPV vaccine to prevent new infections, and elderly women participate in early diagnosis and treatment of cervical diseases. The primary prevention (vaccination) and secondary prevention (disease screening) of cervical cancer prevention and treatment are combined. The plan is expected to be the best model for prevention and treatment of cervical cancer in China. China will also take the lead in selecting some areas to carry out the demonstration project of joint application of vaccination and disease screening (molecular diagnostic technology), and the results will set an example for the construction of comprehensive prevention and treatment system of cervical cancer in China in the future. In addition, considering the differences in incidence, health accessibility and economic level of cervical cancer in different regions of China, exploring the best combination scheme of cervical cancer vaccine and screening in rural and urban areas depends on the corresponding health economic evaluation and research on different combination schemes in the future.

3.6 Although the establishment of an effective monitoring and evaluation system belongs to the late stage of vaccine application, it is very important to consider how to evaluate it in the early stage of application. Monitoring can be divided into process monitoring and result monitoring. Process indicators need to be measured by routine monitoring system of national immunization program (including adverse event report); Results This index refers to the preventive effect of vaccine on cervical cancer. It is generally possible to prevent genital warts (tetravalent vaccine) or cervical abnormalities (precancerous lesions) by vaccines for early assessment. In addition, China urgently needs to establish a nationwide tumor registration system, comprehensively obtain the incidence and death data of cervical cancer in various regions of China through tumor registration points, and comprehensively monitor and evaluate the effect of vaccines and the burden of cervical cancer in China.

Historically, it often takes 15 ~ 20 years for new vaccines to be accepted and widely used in developing countries. HPV vaccine is the most wonderful step in the course of overcoming cancer, and its popularization and application in China as soon as possible is the key measure to control cervical cancer in China. After the launch of HPV vaccine in China, how to shorten the time lag between product launch and people's access to medical care, how to balance and combine primary prevention (vaccination), secondary prevention (precancerous screening, early diagnosis and treatment: cytology, VIA or human papillomavirus detection technology), cancer treatment, palliative treatment, cancer monitoring and other preventive measures, all need the guidance of national decision-making departments and the concerted efforts of immunization, cancer control, sexual and reproductive health departments. I hope that through the joint efforts of all walks of life, cervical cancer will become the first malignant tumor that human beings have overcome.