Antiviral Therapy for HBV/HCV in China: Clinical Perspective

Transcription

1 Antiviral Therapy for HBV/HCV in China: Clinical Perspective Jidong Jia, MD, PhD Beijing Friendship Hospital Capital Medical University Beijing, May 9, 2014

2 Outline Current status Challenges Opportunities

3 Current Status of CHB in China 1. Successful vaccination program since Protect equal right for education and employment (2010) 3. Amend reimbursement list (2010) 4. Update and promote clinical guidelines(2010) 5. National Major Research Project (2008-) 6. Long-term follow-up system: CR-HepB (2012) 7. LIFT Project-Liver Center of Excellence (2013)

4 Evolution of HBV Vaccination Programs in Mainland China 1 st Jan st Jan st Jun 2005 Routine infant HBV vaccinatio n, vaccine & service should be paid HBV vaccine integrated into EPI, service fee (~1 US$) should be paid HBV vaccine fully integrated into EPI for free HBV vaccine catch- up for children under 15 years Technical guideline for HBV vaccine in adults Courtesy of Professor Hui Zhuang

5 Declining HBsAg Prevalence in China (1979,1992 and 2006) 12,00 10,00 8,00 6,00 4,00 2,00 0,00 1~4 5~9 10~14 15~19 20~24 25~29 30~34 35~39 40~44 45~49 50~54 55~49 HBsAg (%) 1~4 0.96% 5~ % 15~ % Age Group (year) 1.Qu Z. An epidemiological study on the distribution of HBsAg and anti-hbs in China. Chine Journal of Microbiogy Immunology. 1986; Suppl(20-40). 2.Dai ZC, G.M. Q. Seroepidemiological Survey in Chinese population (part one), Beijing. Sci Tech Exp. 1996: Liang X, Bi S, Yang W, Wang L, Cui G, Cui F, et al. Epidemiological serosurvey of hepatitis B in China--declining HBV prevalence due to hepatitis B vaccination. Vaccine. 2009; 27(47):

6 Update and advocacy of Guideline for Prevention & Treatment of CHB in 2011

7 Recommendations from CHB guidelines 7 Guidelines Updated Recommendations for treatment-naïve CHB patients APASL EASL AASLD China ETV or TDF are the preferred NUCs for NUCnaïve CHB patients. LAM, ADV and LdT may only be used if more potent drugs with a high barrier to resistance are not available or appropriate. ETV and TDF are potent HBV inhibitors with a high barrier to resistance. Thus, they can be confidently used as first-line monotherapies. Treatment may be initiated with any of the seven approved antiviral medications, but peg-ifn-, TDF or ETV are preferred. If possible, drugs with high potency and low resistance should be chosen for NUC-naïve patients. 1.Lok ASF & McMahon BJ. AASLD practice guidelines. Chronic hepatitis B: Update Hepatology, 2009,50(3): Chinese Journal of Clinical Hepatology 2011, 27 (1): Liaw YF, et al. Hepatol Int, 2012, 6(3): EASL Clinical Practice Guidelines: J Hepatol 2012, 57:

8 Clinical Trials on HBV antiviral Therapy in China (English Publication) Papers

9 National Major Scientific Project Sponsored 4 large RCT studies N=1594 LdT (EFFORT study) PEG- IFN (EXCEL study) Lam (EXPLORE study) ETV (DRAGON study) 9

10 EFFORT study LdT(EFFORT) optimization LDT I-A: w24 if HBV DNA 300 copies/ml Add ADV I-B: W24 HBV DNA <300 copies/ml LDT montherapy Treatmentnaïve CHB SOC LDT Add ADV if viral breakthorugh 0 w 24 W52 w12 W104 Sun J, et al. Hepatology 2014; 59:

11 Study results 104-week Outcomes Median reduction of HBV DNA, log 10 copies/ml OPTIMIZE N = 300 MONO N = 299 P Value ALT Normalization, n (%) 234 (80.7) 232 (79.2) NS HBeAg Seroconversion, n (%) 71 (23.7) 66 (22.1) NS HBsAg Clearance, n (%) 2 (0.7) 2 (0.7) NS Virological Breakthrough, n (%) 18 (6.0) 91 (30.4) <0.001 Genotypic Resistance, n (%) 8* (2.7) 77 ** (25.8) <0.001 Sun J, et al. Hepatology 2014; 59:

12 REALM China Sub-study Study design 12 REALM study Randomized 1:1 Dosing ETV (0.5 mg, once daily) osoc (= LVD, ADV, or LdT) Baseline Wk 48 Wk 96 Wk 144 Wk 192 Wk 240 Inclusion criteria for present cohort: Enrolled at one of the 50 Chinese study sites of REALM study NUC naïve ADV, adefovir; LdT, telbivudine; LVD, lamivudine; osoc, other standard of care Hou JL, et al. APASL Abstract 245

13 REALM China Sub-study Patient Disposition at Week Randomized N=3546 Never treated n=7 Discontinued from originally prescribed therapy n=123 ETV n=1773 Treated n= 1766 Efficacy population* n=1724 osoc n=1773 Treated n=1760 Efficacy population* n=1720 Never treated n=13 Discontinued from originally prescribed therapy n=199 Discontinued from study n=109 Discontinued from study n=175 * Patients with decompensated liver disease or HCV co-infection were excluded from efficacy analyses. Remained on study but discontinued their randomized assigned regimen and were offered alternative anti-hbv therapy at discretion of investigator. osoc: other standard of care (ADV, LVD, LdT) Hou JL, et al. APASL Abstract 245

14 REALM China Sub-study Virologic Efficacy: All Patients 14 HBV DNA <50 IU/mL (%) Week ETV osoc Non-completer = missing analysis osoc: other standard of care (ADV, LVD, LdT) Hou JL, et al. APASL Abstract 245

15 Chinese EVOLVE Study 6 territories, 63 sites, ~200 investigators, 3435 pts 15 A 2-year Prospective and Observational Study To Evaluate the Effectiveness of Nucleos(t)ide Analogs (NUC) Therapy Among CHB Patients Naive to NUC in Real World Practice at Hospitals in Tier 2 Cities in China Started from December 2012 Enrollments: as of end of March 2014, totally 3,431 patients have been enrolled, the target number is 3,435.

16 建立中国乙肝随访与临床科研平台 China Registry- Hepatitis B(CR-HepB) 16 Up to Jan 15, 2014,24205 cases inputted, follow-up times

17 LIFT Project-Liver Center of Excellence Publication of standardized approach for liver disease management in 2013

18 Challenges in the treatment of CHB in China High disease burden Accessibility & affordability to treatment Insufficient reimbursement for rural residents Inadequate therapy-first line therapy not first

19 The Estimated Hepatitis B Infections by diseases classification in China, 2010 Classification Proportion (%) Estimated in 2010(million) Seroclearance HBV Carrier Chronic Hepatitis B Cirrhosis HCC Total Courtesy of Dr FQ Cui

20 Total Economic Burden of CHB-Related Diseases in Beijing and Guangzhou 北京和广州慢性乙肝相关疾病经济负担及经济指数 每例患者花费 (US$) Cost per case/yr 10,000 9,000 8,000 7,000 6,000 5,000 4,000 3,000 2,000 1, CHB 慢性乙肝 2722 Com cirr 代偿性肝硬化 4611 Dec cirr 失代偿性肝硬化 北京 6615 HCC 肝细胞癌 Beijing Family 家庭年收入 income/yr Per capita 人均 GDP 直接医疗费用 直接非医疗费用 间接经济负担 ~8000 ~ * 1452 慢性乙肝 Hu M & Chen W. value in health, 2009 Direct medical cost Direct nonmedical cost Indirect cost CHB 2065 Com cirr 代偿性肝硬化 4290 Dec cirr 失代偿性肝硬化 肝细胞癌 广州 6054 HCC Guangzhou 9145 * Family 家庭年收入 income/yr Per capita 人均 GDP GDP 4

21 Proportion of CHB Patients Receiving Antiviral Therapy Yes, 19% No, 81% Study on knowledge of 452 patients with CHB from 6 cities of China, Chinese Society of Hepatology & Chinese Society of Infectious Diseases, 2004

22 Factors Associated with not Receiving Antiviral Treatment for CHB Patients % Cost Side effect Not recomm Other drugs Data from 115 physicians active in treatment of CHB, China Medical Tribune, 2005.

23 NUCs Treatment Regimens for CHB ---Real Clinical Practice in China Chronic hepatitis B patients: 20 ~ 30 million cases Antiviral treatment:1,850,000 cases TCM and others:550, 000 cases Telbivudine 100,000 cases Interferon (Peg-IFN,IFN) 300,000 cases Entecavir 300,000 cases Domestic Adefovir dipivoxil products(2) 150,000 cases each Adefovir dipivoxil 350,000 cases Lamivudine 500,000 cases TCM 500,000 CASES Others 50,000 cases JL Hou, et al. Journal of Viral Hepatitis, 2010,17: Treatment survey for 2, 500 chronic hepatitis B patients in 12 first and second tier cities in 2008.

24 Inadequate use of NAs in clinical practice

25 Projection of HBV antiviral market Patients on treatment (Million) 25

26 Current Status of CHC in China 1. Declining prevalence of HCV infection 2. Release & promote clinical guidelines 3. Amend reimbursement list 4. National Major Research Project

27 Anti-HCV Prevalence in China in 1992 and 2006 Anti-HCV (%) age(yr) Chen YS,et al. Chin J Epidemiol 2011;32:888-91

28 Prevalence of HCV genotypes in China (CCgenos) 13% 3.90% 27.0% 5.4% 0.9% 黑龙江 48.10% 35.10% 新疆 0 西藏自治区 青海 32.7% 四川 5.4% 宁夏 4.1% 3.1% 甘肃陕西 重庆 内蒙古 山西 河南 湖北 北京 61.3% 河北 17.5% 山东 安徽 55.1% 1.6% 江苏 浙江 辽宁 6.3% 上海 吉林 3.2% 天津 71.4% 29.4% 4.8% 8.9% 3.5% 53.4% 19.6% 云南 26.1% 5 1% 贵州 13.0% 广西 4.3% 海南 湖南 37.0% 广东 香港 江西 福建 台湾省 Genotype 1 Genotype 1 mixed Genotype 2 Genotype 3 Genotype 6 National Wide Rao H, et al. J Gastroenterol Hepatol. 2014;29:

29 Distribution of IL28B host genotype in China IL28B Genotype (rs ) CC CT TT Rao H, et al. J Gastroenterol Hepatol. 2014;29:

30 Clinical Trials on HCV antiviral Therapy in China (English Publication)

31 HCV cohorts and clinical studies in China N=2000 十一五丙肝临床研究 十一五丙肝延长研究 Follow-up =1200 Difficult to treat CHC=800 HCV natural history TN=400 Relapsers=120 Nonresponder s=80 Generic IFN=200 SVR 24W Relapse pridictors Novel diagnostic tech Long-term outcomes Efficacy predictors 31 Courtesy of Prof L Wei 31

32 Difficult-to-treat HCV achieves SVR of 8.7% with tailored PEGIFN+RIB therapy Genotype 1b or HVL(HCV RNA 4 10^5 IU/ml) Treatment naive N=438 cevr Peg-IFN-α-2a 180µg/wk +RBV 48W f/u 24 W A PEGIFN +RBV Peg-IFN-α-2a 180µg/wk +RBV 72W F/u 24W B No-cEVR (stop if NVR ) Peg-IFN-α-2a 180µg/wk +RBV 96 W C F/u 24W 0 12 W 24W 48 W 72 W 96 W 120W 32 randomization cevr:hcv RNA<15 IU/ml at wk 12 Courtesy of Prof L Wei

33 Optimized therapy with PEFIFN+RIV yields an overall SVR of 78.7% in TN CHC 100,0% 90,0% 80,0% 78,7% 70,0% 60,0% 64,2% 50,0% 40,0% 30,0% 20,0% 10,0% 0,0% SVR 9,70% 7,9% Relapse SVR Relapse PP Set =338 ITT set = Courtesy of Prof L Wei

34 Challenges in the treatment of CHC in China High diseases burden Accessibility & affordability to treatment High disease burden and Insufficient reimbursement for rural residents

35 Reported HCV cases is increasing China CDC

36 Importance of expanding testing and treatment to impact the global prevalence of HCV infection Thomas DL. Nature Med 2013, 19:850-8

37 HBV &HCV treatment opportunities in China Highly effective drugs for CHB (ETV and TDF) are registered in China DAAs trials for HCV are under way Public health CHB treatment program provides an opportunity for significant price reduction TDF negotiated at RMB 113/month for the HIV public health program (RMB 1,470/ month for CHB) Public health approach embedded in the health reform would open new opportunities for price reduction of antiviral drugs to meet the targets of Universal Health Care Coverage

38 WHO WPRO Informal Technical Meeting Manila, April 1-2, 2014

39 Acknowledgement