Hepatitis virus infection, especially chronic infection with hepatitis B virus (HBV) and hepatitis C virus (HCV), is a serious issue to global public health.
Although the prevalence of HBsAg in the general population has been declined dramatically in China due to universal HBV vaccination in newborns, chronic hepatitis B and hepatitis C are still the main causes of cirrhosis and hepatocellular carcinoma (HCC) that are responsible for a high rate of morbidity and mortality.1,2 HBV- and HCV-related end-stage liver disease are also the leading indications of liver transplantation in China.3
In the last 2 decades, the introduction and acceptance of good clinical practice (GCP) and evidence-based medicine (EBM) have led to substantial progress in the treatment of viral hepatitis in China. These advances are mainly reflected in the field of clinical research where an increasing number of randomized controlled trials (RCTs) have been carried out, and the publication and educational promotion of clinical guidelines on HBV and HCV management made available.
MORE MULTICENTER RCTS HAVE BEEN IMPLEMENTED IN CHINA
In 1999 the Ministry of Health of the People's Republic of China issued the national GCP guideline which adopted the major principles of the World Health Organization (WHO) and the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) GCP guidelines; since then the quality of design and implementation of clinical trials have been greatly improved. RCTs are rightly seen by the Chinese medical community and regulatory authority as the key means to evaluate the safety and efficacy of new treatments and interventions. There are now an increasing number of randomized trials being undertaken and published, which provide the cornerstone of evidence-based medicine in current clinical practice.
In May 2007 the World Health Organization International Clinical Trial Registry Platform (WHO ICTRP) was formally launched. The Australian and New Zealand Clinical Trials Registry (ACTR), ClinicalTrials.gov of the National Library of Medicine (United States) and the International Standard Randomized Controlled Trial Number Register (ICRCTN), and United Kingdom were certified as the first three Primary Registers. In June 2007 the national clinical trial register sponsored by Ministry of Health, the Chinese Clinical Trial Register (ChiCTR), was accepted as the fourth WHO ICTRP Primary Register.4
ChiCTR provides services that include register for trials, consultation for trial design, central randomization for an allocation sequence, peer review for draft articles and training for peer reviewers. Since June 2007, 17 RCTs for hepatitis treatment have been registered and this demonstrates the ever growing number and improving quality of clinical trials of hepatitis treatment in the mainland of China.
In the new era of antiviral therapy Chinese investigators have been involved in the clinical development of new anti-HBV agents and have contributed greatly in recruiting patients for clinical trials of lamivudine,5,6 adefovir dipivoxil,7 entecavir,8 telbivudine9 and pegylated interferon α-2a.10,11 Notably, they participate in the telbivudine GLOBE study12,13 and the phase III trial of PEG-interferon α-2a in chronic hepatitis B (CHB).14,15 These international, as well as national clinical trials, unsurprisingly have contributed greatly to the clinical evidence for hepatitis B management in the last 10 years.
MORE AND MORE INTERNATIONAL PUBLICATIONS HAVE BEEN AUTHORED BY CHINESE HEPATOLOGISTS
From January 1990 to September 2009, there were 448 PubMed indexed papers on viral hepatitis treatment published in English by authors from the mainland of China. Among them, 132 papers are clinical trails about hepatitis treatment in China. Totally, 74 out of 132 papers are RCT compliance (about 56.1%). There were nine papers published between January 1990 and December 1999 that increased to 65 papers published from January 2000 to August 2009. Obviously, the number of international publication has grown since the year 2000. Most importantly, the quality of methods of clinical studies are improving and more articles are published in the medical journals with higher impact factors; including Hepatology,7,9Gastroenterology13 and New England Journal of Medicine.12,14,15
CHINESE HBV AND HCV GUIDELINES RAISE THE STANDARD OF CARE
In the mainland of China hepatitis patients are treated by either hepatologists or physicians of infectious diseases. To establish a practical protocol for the prevention and treatment of patients with viral hepatitis, the Chinese Society of Infectious Diseases published “The Protocol for Prevention and Treatment of Viral Hepatitis” in 1979. The document had been revised several times since then and the last edition was published in September 2000.16 It has played an active role in the prevention and treatment of viral hepatitis in China.
As the understanding of hepatitis B and C has increased and new evidence on treatment accumulated, the expectations of the evidence-based guidelines increased. To meet this demand, the Chinese Society of Hepatology, together with her sister society, the Chinese Society of Infectious Diseases decided to prepare clinical guidelines on the management of hepatitis B and hepatitis C. After extensive discussion and intensive revision the first evidence-based guideline on the prevention and management of chronic hepatitis C was published in the Chinese language in 2004.17 Soon after that the guideline on prevention and treatment of chronic hepatitis B was published in the Chinese language in 200518 and in English in 2007.19
These two guidelines give a comprehensive yet concise description on the virology, epidemiology, natural history and prevention, as well as diagnosis and management of hepatitis C and B. Recommendations for the initial evaluation of patients, the choice and duration of antiviral therapy and the follow-up protocols are made with the grade of evidence being rated.
Hepatitis educational programs in China
In 2002, the Chinese Foundation for Hepatitis Prevention and Control sponsored a hepatitis B education and vaccination program to prevent mother-to-child transmission. This educational program successfully increased the awareness of hepatitis B vaccination in rural areas and improved the training of local health care workers.
To promote judicial use of HBV and HCV guidelines the Chinese Society of Hepatology and the Chinese Society of Infectious Diseases jointly initiated a series of educational activities. A panel of highly selected speakers gave well-prepared talks on the key points of the HBV guideline in 25 major cities across China, which reached more than 100 million people nationwide. According to the post-event evaluations, this academic lecture-tour has greatly improved the awareness and the standard of care of antiviral therapy. To fulfill the educational demand of physicians who practice in smaller cities, a 36-city lecture-tour was carried out in early 2007.20 In response to growing new clinical evidence the update of the HBV guidelines will be finished by the end of this year.
Mtshali, director for SECURE THE FUTURE® (a philanthropy program sponsored by Bristol-Myers Squibb Foundation) in southern Africa, said: “China currently has a well-developed health network functioning throughout the country. Integrating chronic hepatitis B training, education and treatment into that primary care system will help overcome significant barriers to hepatitis education and prevention in China.”21
China has achieved a great achievement in prevention and control of viral hepatitis. The seroepidemiological survey on HBV infection conducted in 2006 showed that HBsAg carrier rate was decrease from 9.75% in 1992 to 7.18% in the overall population. However, the further decrease of the HBV prevalence and better management of existing chronic infection of HBV and HCV are still enormous challenges; not only to the Chinese medical community but also to the government and the whole of society.
To meet this challenge, in 2008 the Chinese government funded several important projects on the prevention and management of viral hepatitis B in the package of the 11th 5-year Plan Key Scientific Research Projects. No doubt, this vast input into clinical research will yield fruitful results in terms of the better understanding of the natural history of chronic HBV and HCV infection and optimization of the care of the patients.
1. Jia JD. Hepatitis B in China: from Guideline to Practice. Virologica Sinica 2008; 23: 152-155.
2. Benson AB 3rd, Abrams TA, Ben-Josef E, Bloomston PM, Botha JF, Clary BM, et al. NCCN clinical practice guidelines in oncology: hepatobiliary cancers. J Natl Compr Canc Netw 2009; 7: 350-391.
3. Marcellin P. Hepatitis B and hepatitis C in 2009. Liver Int 2009; 29 Suppl 1: s1-s8.
4. Wu TX, Li YP, Li J, Liu GJ. A milestone for clinical trials: establishment of a global clinical trial registration system. Chinese Clinical Trial Register, MOH Chinese Evidence-Based Medicine Centre, Chinese Cochrane Centre, INCLEN CERTC in West China Hospital, Sichuan University. (Accessed on October 2000 at http://www.chictr.org/Upload/milestone.pdf
5. Xu WM, Cui YT, Wang L, Yang H, Liang ZQ, Li XM, et al. Lamivudine in late pregnancy to prevent perinatal transmission of hepatitis B virus infection: a multicentre, randomized, double-blind, placebo-controlled study. J Viral Hepat 2009; 16: 94-103.
6. Yao G, Wang B, Cui Z, Yao J, Zeng M. A randomized double-blind placebo-controlled study of lamivudine in the treatment of patients with chronic hepatitis B virus infection. Chin Med J 1999; 112: 387-391.
7. Zeng M, Mao Y, Yao G, Wang H, Hou J, Wang Y, et al. A double-blind randomized trial of adefovir dipivoxil in Chinese subjects with HBeAg-positive chronic hepatitis B. Hepatology 2006; 44: 108-116.
8. Yao G, Chen C, Lu W, Ren H, Tan D, Wang Y, et al. Virologic, serologic, and biochemical outcomes through 2 years of treatment with entecavir and lamivudine in nucleoside-naïve Chinese patients with chronic hepatitis B: a randomized, multicenter study. Hepatol Int 2008; 2: 486-493.
9. Hou J, Yin YK, Xu D, Tan D, Niu J, Zhou X, et al. Telbivudine versus lamivudine in Chinese patients with chronic hepatitis B: Results at 1 year of a randomized, double-blind trial. Hepatology 2008; 47: 447-454.
10. Shi M, Wang RS, Zhang H, Zhu YF, Han B, Zhang Y, et al. Sequential treatment with lamivudine and interferon-alpha monotherapies in hepatitis B e antigen-negative Chinese patients and its suppression of lamivudine-resistant mutations. J Antimicrob Chemother 2006; 58: 1031-1035.
11. Zhao H, Kurbanov F, Wan MB, Yin YK, Niu JQ, Hou JL, et al. Genotype B and younger patient age associated with better response to low-dose therapy: a trial with pegylated/nonpegylated interferon-alpha-2b for hepatitis B e antigen-positive patients with chronic hepatitis B in China. Clin Infect Dis 2007; 44: 541-548.
12. Lai CL, Gane E, Liaw YF, Hsu CW, Thongsawat S, Wang Y, et al. Telbivudine versus lamivudine in patients with chronic hepatitis B. N Engl J Med 2007; 357: 2576-2588.
13. Liaw YF, Gane E, Leung N, Zeuzem S, Wang Y, Lai CL, et al. 2-Year GLOBE trial results: telbivudine Is superior to lamivudine in patients with chronic hepatitis B. Gastroenterology 2009; 136: 486-495.
14. Marcellin P, Lau GK, Bonino F, Farci P, Hadziyannis S, Jin R, et al. Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B. N Engl J Med 2004; 351: 1206-1217.
15. Lau GK, Piratvisuth T, Luo KX, Marcellin P, Thongsawat S, Cooksley G, et al. Peginterferon Alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B. N Engl J Med 2005; 352: 2682-2695.
16. Chinese Society of Infectious Diseases, Chinese Society of Hepatotogy. A protocol for the prevention and treatment of viral hepatitis. Chin Med J 2001; 40: 62-68.
17. Chinese Society of Hepatology and Chinese Society of Infectious Diseases. Guideline of prevention and treatment of hepatitis C. Chin J Hepatol (Chin) 2004; 12: 194-198.
18. Chinese Society of Hepatology and Chinese Society of Infectious Diseases. Guideline on the prevention and treatment of chronic hepatitis B. Chin J Hepatol (Chin) 2005; 13: 881-891.
19. Chinese Society of Hepatology and Chinese Society of Infectious Diseases. Guideline on prevention and treatment of chronic hepatitis B in China (2005). Chin Med J 2007; 120: 2159-2173.
20. Jia JD, Zhuang H. A winning war against hepatitis B virus infection in China. Chin Med J 2007; 120: 2157-2158.
21. The Bristol-Myers Squibb Foundation Combats Chronic Hepatitis B in Asia. (Accessed on November 13, 2007 at http://www.businesswire.com/news/bms/20090202005953/en