Could antiviral therapy reduce the incidence of HCC in patients with chronic hepatitis B? Hong You Beijing Friendship Hospital

Transcription

1 Could antiviral therapy reduce the incidence of HCC in patients with chronic hepatitis B? Hong You Beijing Friendship Hospital

2 Main Content Part 1 Natural progression history of hepatitis B disease and epidemiology and risk factors of HCC Part 2 Effective long-term treatment of nucleoside (nucleotide) drugs could reduce the development and recurrence risk of HBV-related liver cancer Effective long-term antiviral therapy can reduce the incidence of HCC in patients with chronic hepatitis B Effective antiviral therapy can reduce the incidence of HCC recurrence in patients with HBV-related HCC Part 3 Antiviral therapy with nucleoside (nucleotide) drugs could significantly reduce, but can't completely eliminate the risk of HCC 2

3 Natural history of hepatitis B disease progression Acute HBV infection 5-year incidence: 8%~2% 4 Annual incidence 3%~6% 1 HCC Chronic HBV infection Chronic Hepatitis B Liver cirrhosis 35 million patients with chronic hepatitis B infection globally 1 3% of liver cirrhosis and 53% of HCC are associated with chronic HBV infection 2 21, cases of liver transplant each year 3 Chronic liver failure Liver transplant 1. Chinese Society of Hepatology, Chinese Society of Infectious Diseases, Chinese Medical Association. The Guideline of Prevention and Treatment for Chronic Hepatitis B (21 Version) Chinese Journal of Hepatology 211; 5: Ashley Brown et al. Expert Rev Gastroenterol Hepatol. 212 Apr;6(2):

4 Epidemiology of HBV-related HCC HCC is the fifth most common cancer, the third most common cause of death worldwide 1,2 Approximately 5% of the global HCC cases is associated with HBV infection. 3 In HBV-epidemic regions (Southeast Asia, Sub-Saharan Africa), as high as 78% of HCC cases is associated with HBV infection 3,4 Approximately 25% of untreated CHB patients will experience HCC 1 There is a higher incidence of HBV-related HCC in cirrhotic patients 5 5-year cumulative incidence of HCC in patients with chronic HBV infection 5 East Asia Inactive carriers CHB without cirrhosis CHB with compensated cirrhosis 1% 3% 17% Europe.1% 1% 1% 1.Tan YJ, et al. World J Gastroenterol 211;17: European Association For The Study Of The Liver. Hepatol 212;57: Ngyuen VT, et al. J Viral Hepat 29;16: Wong CH, et al. Biomedical Imaging Intervention Journal 26;2:e7. 4

5 Risk factors for HBV-related HCC Risk factors for HBV-related HCC Viral factors Host factors Environmental factors Continuous HBeAg positive Elderly Alcoholic Continuous high load of HBV DNA Mutation of HBV core promoter HBV genotype C Male Asian Liver cirrhosis Continuous high ALT level Aflatoxin Smoking Co-infection of HDV and HCV Family history of HCC Diabetes mellitus Resistance can lead to an increased risk of HCC Antiviral therapy with nucleoside (nucleotide) drugs could significantly reduce, but can t completely eliminate the risk of HCC (especially in patients with liver cirrhosis ) Lok AS,et al.j Gastroenterol Hepatol 211;26:

6 Main Content Part 1 Natural progression history of hepatitis B disease and epidemiology and risk factors of HCC Part 2 Part 3 Effective long-term treatment of nucleoside (nucleotide) drugs could reduce the development and recurrence risk of HBV-related liver cancer Effective long-term antiviral therapy can reduce the incidence of HCC in patients with chronic hepatitis B Effective antiviral therapy can reduce the incidence of HCC recurrence in patients with HBV-related HCC Antiviral therapy with nucleoside (nucleotide) drugs could significantly reduce, but can't completely eliminate the risk of HCC 6

7 Sustained viral suppression may delay disease progression The proportion of patients with disease progression Placebo (n = 215) ITT population Lamivudine (n = 436) Placebo Lamivudine 21% p = % Time to disease progression (months) Disease progression: liver decompensation, HCC, or death Liaw YF, et al. N Engl J Med. 24;351:

8 Kumada s study: effects of treatment with nucleoside (nucleotide) drugs (NUC) on incidence of HCC A retrospective single-center cohort study in Ogaki Hospital, Japan 785 CHB patients (enrolled into HCC monitoring project ) The primary outcome: HCC incidence Follow-up period: until the development of HCC or December, 211 NUC treatment 148 patients received treatment (NUC treatment >1 year before NUC detection) 117 matched patients ETV 61% 15% 24% LVD LVD+ADV Propensity score match* Non-NUC traetment 637 patients were followed 117 matched patients * Propensity score match includes age, gender, HBV DNA, HBeAg status, platelet counting and ALT. NUC is not approved in Japan, or refused by patients Kumada, T. et al. J Hepatol, 212, doi: 8

9 Kumada s study: NUC treatment reduces the incidence of HCC The cumulative incidence of HCC (%) Cox proportional hazard model: HR.28 (95% CI.13.62) P= % 2.7% 26.% 3.3% 3.3% Non-NUC treatment 4.% NUC treatment* Year Pts. at risk NUC treatment Non-NUC treatment NAs antiviral therapy including ETV could achieve the benefit of HCC risk reduction Kumada, T. et al. J Hepatol, 212, doi: 9

10 Long-term ETV treatment can reduce the incidence rate of HCC in patients with chronic hepatitis B A retrospective study in Japan involving 217 patients with chronic hepatitis B (at least 6 months of HBsAg positive) analyzed the data from the 5-year follow-up period. - ETV group: Treatment-naive patients with chronic hepatitis B treated with.5mg ETV n=472, after propensity score match n=316 - Control group: , Chronic hepatitis B patients without NA treatment n=1143, after propensity score match n=316 - LAM group: Chronic hepatitis B patients treated by LAM and matched with ETV group n=492,after propensity score match n=182 Complete cohort PS matched cohort* ETV (N=472) Control (N=1143) P ETV (N=316) Control (N=316) Age (mean, years) < Gender (n) Cirrhosis (n/%) 116 (25) 195 (17).1 79 (25) 85 (29).324 HBV genotype (n/%) A B C D Other / deletion 12 (3) 66 (14) 344 (73) () 5 (11) 41 (4) 188 (16) 791 (69) 1 (1) 122 (1) <.1 8 (3) 49 (16) 225 (71) 34 (11) 9 (3) 5 (16) 226 (72) 31 (1) HBeAg(+) 219 (46) 398 (35) < (43) 133 (42).936 HBV DNA (log 1 copies/ml) < ALT (IU/L) 7 33 < P.843 *Differences in baseline characteristics is eliminated by propensity score match of age, gender, presence of cirrhosis, HBeAg status, HBV DNA, AST, ALT, γgtp, bilirubin, albumin, and platelet count. Tetsuya Hosaka, et al. Hepatology. 212 Dec 5. doi: 1.12/hep

11 Long- term ETV treatment can reduce the incidence rate of HCC in patients with chronic hepatitis B 5 The cumulative incidence of HCC (%) Pts. at risk Figure 1. The cumulative incidence rate of HCC Log-rank test: P <.1 4.%.7% 7.2 % 1.2% 1.% 2.5% 13.7% 3.7% Control (n=316) ETV (n=316) Treatment period (Years) ET V Contro316 l The cumulative incidence of HCC progression (%) Pts. at risk Figure 2. The cumulative incidence rate of HCC in patients with liver cirrhosis ETV vs control (P <.1) ETV vs LAM (P <.43) 11.4% 4.8% 2.6% 2.9% 12.2% 4.3% Treatment period (Years) 28.5% 19.7% 38.9% 22.2% 7.% 7.% ETV LAM Control Control LAM ETV Compared with the control group, ETV treatment can reduce the 5-year risk of HCC by more than 6% In cirrhotic patients, cumulative incidence of HCC was significantly lower in ETV 11

12 In HCC patients at high risk, the largest decrease of the incidence of HCC has occured in patients receiving ETV treatment The cumulative incidence of HCC (%) The number of patients at risk *Log-rank test 1. Hosaka T, et al. Hepatology, 212 Dec 5. doi: 1.12/hep [Epub ahead of print]. 2. Yang HI, et al. Lancet Oncol 211; 12: Yuen MF, et al. J Hepatol 29; 5: Wong VWS, et al. J Clin Oncol 21; 28: year cumulative incidence rate of HCC(%) 1 Risk Score Risk n ETV Control P* Yang HI Yuen MF 29 3 Wong VWS 21 4 E ETV Control P = %.6% 1.5% 1.5%.2%.4%.5%.5% Low High Low High Low Middle High ETV Control Year The cumulative incidence of HCC (%) F Pts. at risk ETV Control P =.62 1.% 2.7% % % 1.6% 6.9% % % Control ETV Year The cumulative incidence of HCC (%) Pts. at risk G ETV Control P <.1 1.1% 4.5% 19.% 8.% < % 8.% 33.3% 8.% ETV Year Control 12

13 Real-Life Study in Taiwan: C-TEAM interim report: ETV long-term treatment a significant reduction of disease progression (HCC) risk in patients with cirrhosis A multi-center study in Taiwan, 666 patients with cirrhosis receiving ETV monotherapy; 621 patients without treatment as the control group. In ETV group, the mean time of follow-up period was 2.7 years; in control group, the mean time of follow-up period was 9.1 years. During the 2.7 years of follow-up, 2.4% of patients in ETV group developed HCC; while it was 5.2% in control group (P=.9) 2.7 years of ETV monotherapy reduced the risk of HCC by 59% in patients with cirrhosis Su TH, et al. 64th AASLD meeting, Nov 1-5, Washington DC, USA. Poster

14 Main Content Part 1 Natural progression history of hepatitis B disease and epidemiology and risk factors of HCC Part 2 Effective long-term treatment of nucleoside (nucleotide) drugs could reduce the development and recurrence risk of HBV-related Part 3 liver cancer Effective long-term antiviral therapy can reduce the incidence of HCC in patients with chronic hepatitis B Effective antiviral therapy can reduce the incidence of HCC recurrence in patients with HBV-related HCC The impact of resistance on incidence of HBVrelated HCC 14

15 Wu s study: the impact of nucleoside (nucleotide) drugs on the recurrence of HCC A prospective, national cohort study (23-21) in Taiwan * All newly diagnosed HCC patients who underwent liver resection The primary outcome: HCC recurrence > 3 months after resection +/- NUC treatment Effective hepatic resection for patients with newly diagnosis of HBV related HCC N= 4569 Non-NUC treatment N=451 NUC treatment (duration 9 days) N=518 NUC combination treatment: combination treatment with nucleoside (nucleotide). *Data from the Taiwan s National Health Insurance (NHI) Research Database (representing >99% of Taiwan total population). Those who had accepted antiviral therapy for more than 3 months before surgery were excluded. Wu, CY, et al. JAMA, 212 Nov 14;38(18): LdT NUC combination treatment 15

16 Nucleoside (nucleotide) drugs reduced the recurrence risk of HCC Recurrence of HCC 6 5 The cumulative incidence rate of HCC (%) P<.1 Untreated Treated (56% ETV monotherapy) 54.6%* 45.6%* Follow up (years) Pts. at risk Untreated Treated *In multivariate group, due to the high incidence of liver cirrhosis in the treatment cohort, the difference of absolute recurrence rate is less than that of HR recurrence (.67; see the next slide) Wu, CY, et al. JAMA, 212 Nov 14;38(18):

17 Treatment with nucleoside (nucleotide) drugs reduced the risk of death Overall mortality rate 6 P=.2 Cumulative overall mortality (%) Untreated Treated 42.4% 29.% Pts. at risk Untreated Treated Follow up (years) Conclusion: Patients with HCC who underwent liver resection and received NUC treatment (56% received ETV monotherapy) had significantly reduced recurrence rate of HCC and improved overall survival rate. Considering the baseline viral load, NUC treatment may have greater impact on the risk of HCC recurrence. Wu, CY, et al. JAMA, 212 Nov 14;38(18):

18 Lee's study: effects of ETV treatment on recurrence of HCC A prospective, single-center cohort study (27 211) in Korea Objective: to investigate whether ETV will increase the risk of HCC recurrence Patients HBV-related cirrhosis, Child-Pugh level A Newly diagnosed HCC, Phase I Who accepted radiofrequency ablation (RFA) treatment Non-NUC treatment N=58 NUC monotherapy starts between 3 months before and after RFA treatment ETV N=29 Other NUCs N=19 Lee D, et al. AASLD 212; abstract

19 In patients treated by ETV, HCC recurrence rate is lower than in those without NUC therapy HCC recurrence rate (%) Non-NUC treatment ETV Other NUCs Multivariate analysis The risk of HCC recurrence ETV vs Non-NUC treatment: OR.454 P=.15. Treatment-naive ETV Other NUCs Pts. at risk Follow up (months) ETV treatment after RFA could reduce the recurrence risk of HCC in patients with HCC; improve disease-free survival; and provide more potent anti-viral suppression compared with non-nuc treatment. Lee D, et al. AASLD 212; abstract

20 Main Content Part 1 Natural progression history of hepatitis B disease and epidemiology and risk factors of HCC Part 2 Effective long-term treatment of nucleoside (nucleotide) drugs could reduce the development and recurrence risk of HBV-related liver cancer Part 3 Effective long-term antiviral therapy can reduce the incidence of HCC in patients with chronic hepatitis B Effective antiviral therapy can reduce the incidence of HCC recurrence in patients with HBV-related HCC Antiviral therapy with nucleoside (nucleotide) drugs could significantly reduce, but can't completely eliminate the risk of HCC 2

21 Resistance reduces the long-term benefit of antiviral therapy Proportion of patients with disease progression(%) Placebo(n = 215) M24I/V mutation(n = 29, 49%) Wild-type(n = 221) 21% 13% 5% Time after random sampling (months) Adapted from Liaw. Semin Liver Dis 25; 25:447; Liaw et al. N Eng J Med 24; 351:

22 Resistance may lead to progression of HCC in patients with HBV-related cirrhosis A case-control study in Korea: 413 patients with HBV-related cirrhosis treated by lamivudine, 26 patients untreated The median follow-up period is 4.7 years. 47.6% of patients treated by lamivudine experienced virologic breakthrough P=.144 (Control group vs Lamivudine resistance group) P=.5 (Control group vs Sustained viral suppression group) Control group The incidence of HCC (%) Lamivudine resistance group Sustained viral suppression group Follow up (years) Eun JR et al. J Hepatol; 53:

23 Kobashi's study: Drug resistance may lead to increased risk of HCC A prospective study: 194 patients with CHB and 62 patients with liver cirrhosis were enrolled. Among them, 129 patients received ETV therapy and 127 patients received treatment with LVD. Follow-up period last for 4.25 years, with a total of 6 patients developing LVD resistance 1. The incidence rate of HCC (%) P= % 1.5% 3.2% 2.3% 22.7% Year 9.6% 42.% 26.5% LVDr LVDs Number of patients at risk LVDr LVDs Kobashi H, et al. Hepatology Research 211; 41:

24 Virological remission after salvage therapy could not reduce the risk of HCC in LAM-resistant patients The incidence of HCC after virologic response following salvage therapy in lamivudine resistant patients was analyzed by a meta-analysis: in the 14 patients without virological response, after 13 patients who developed HCC at the start of adefovir treatment being excluded, statistics data (8/91, 8.8% vs 19/32, 5.9%, p =.466) did not show any significant difference. There was no difference in the incidence of HCC regardless the efficacy of salvage therapy. The proportion of patients with HCC(%) Patient P<.1 Column 1 Without Nucleotide treatment 982/852 Lamivudine-resistant 32/91 Virological response Without virological response Papatheodoridis,GV,et al.j Hepatol 21;53:

25 Despite antiviral therapy, the risk of HCC is still higher in CHB patients than in patients of immune tolerance phase Cho et al, Gut 214, in press 25

26 Summary Occurrence of HCC is associated with HBV infection. Hepatic cirrhosis, high HBV DNA levels at baseline, sustained high viral load, high HBsAg levels are independent risk factors of HCC. For patients with chronic hepatitis B, sustained suppression of HBV replication by nucleoside (nucleotide) drugs can reduce the risk of HCC, especially for patients with hepatic cirrhosis. For HCC patients after operation, antiviral treatment with nucleoside (nucleotide) drugs can reduce or delay the recurrence of residual tumor in liver tissue, and improve disease-free survival rate Antiviral treatment with nucleoside (nucleotide) drugs could significantly reduce, but can't completely eliminate the risk of HCC 26

27 Thank you! 27