Optimising therapy in chronic hepatitis B: Switch or add treatment

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1 Optimising therapy in chronic hepatitis B: Switch or add treatment Teerha Piratvisuth NKC Institute of Gastroenterology and Hepatology Prince of Songkla University,Thailand

2 NA + NA

3 Percent with resistance Viral Resistance at 2 Years vs. Antiviral Effect at Week 24 HBeAg Positive HBeAg Negative Telbivudine n = Serum HBV DNA Level at Week Lamivudine 2 5 <QL Q - 3L >4 <QL Q - 3L > Liaw YF. et al. Gastroenterology 09;136:

4 GLOBE Results based on the baseline and early virological response HBeAg Positive Patients HBeAg Negative Patients 89% PCR Negative Week 104 N=51/57 91% PCR Negative Week 104 N=76/86 Baseline HBV DNA <9 Log 10, ALT 2 x ULN N=80 71% of Telbivudine Treated Patients Achieve PCR Negativity ( 300 copies/ml) at Week 24 N=57/80 52% Seroconversion Week 104 N=25/48 Baseline HBV DNA <7 Log 10, N=91 95% of Telbivudine Treated Patients Achieve PCR Negativity ( 300 copies/ml) at Week 24 N=86/91 83% ALT normalization Week 104 N=57/69 1.8% Resistance Week 104 N=1/57 2.3% Resistance Week 104 N=2/86 Zeuzem S, et al. J Hepatology

5 The Roadmap Concept Start treatment Week 24 Complete response PCR negative Partial response 60 to <2,000 IU/mL or 300 to <10,000 copies/ml Inadequate response 2,000 IU/mL or 10,000 copies/ml Continue Add another drug without cross resistance, or continue monitor every 3 months Add a more potent drug Keeffe E,Piratvisuth T. et al. Clinical Gastroenterology and Hepatology 07;5:

6 Telbivudine Roadmap Strategy Prospectively Investigated in Study CLDT600A2410 Early decision 24 Screening 6 weeks prior to baseline Key Inclusion Criteria Male or female, 18 years of age Documented HBeAg-positive chronic hepatitis B Serum HBV DNA level 5 log 10 copies/ml at screening Elevated serum ALT level ( x ULN) at screening Evidence of chronic liver inflammation Telbivudine, N=105 Week 0 24 weeks 300 copies/ml Telbivudine + Tenofovir Week <300 copies/ml Telbivudine Week Off-treatment Follow-up Week Off-treatment Follow-up Week For patients with cirrhosis, clinically and biochemically compatible with compensated liver disease Piratvisuth T, et al. PLoS One 13; 8(2): e54279.

7 % of patients Road Map: HBeAg/HBsAg Response Rates at Weeks 52 and 104 Week 52, N=100 Week 104, N= HBeAg clearance HBeAg seroconversion HBsAg clearance HBsAg seroconversion Piratvisuth T, et al. PLoS One 13; 8(2): e54279.

8 Tenofovir in ADV nonresponders 1 Stratified by lamivudine experience (< vs 12 wks) and screening HBeAg status (positive vs negative) Wk 48 (current analysis) Wk 168 Patients receiving adefovir for chronic HBV infection with HBV DNA > 1,000 cps/ml after treatment > 24 upto 96 weeks (N = 105) Tenofovir 300 mg QD* (n = 53) Fixed-Dose Emtricitabine/Tenofovir 0/300 mg QD (n = 52) *If HBV DNA 400 copies/ml at or after Wk 24, patients could add emtricitabine (as open-label, fixed-dose emtricitabine/tenofovir) for 12 wks or discontinue study and start commercially available HBV treatment. Berg T, et al. Gastroenterology. 10;139:

9 HBV DNA < 400 copies/ml (%) Tenofovir in ADV nonresponders : Virological response 100 Tenofovir (n = 52) Emtricitabine/tenofovir (n = 53) Wk 24 Wk 48 (Intent to Treat) Berg T, et al. Gastroenterology. 10;139:

10 Response at week 168 Tenofovir ± FTC in patients with persistent viraemia on ADV (study 016) % TDF FTC/TDF HBV DNA <400 cps/ml HBeAg loss HBeAg seroconversion 53 6 HBsAg loss Berg T, et al Gastroenterology 10;139:17-17 Manns M et al., APASL 11 #PS

11 Role of Interferon in patients on long term Nucleoside therapy

12 Theoretical background : NA and IFN combination therapy Different mechanism of action NAs has little or no effect on intrahepatic cccdna High HBV DNA load is associated with an inefficient T Cell response to HBV-related antigen Moraleda G. et al. J Virol Dandri M. et al. Hepatology 00. Chisari FU. et al Annu Rev Immunol Boni C. et al Hepatology. 01.

13 Sequential therapy with entecavir and PegIFN in CHB with high HBV DNA Induction ETV 0.5 mg/day 12 weeks Association ETV 0.5 mg/day + PEG-IFN alfa-2a 180 μg/week 12 weeks Maintenance PEG-IFN alfa-2a 180 μg/week 36 weeks Stopping rule at 12 weeks of PEG-IFN <0.5 Log qhbsag decline and < 2 Log HBV DNA decline ETV alone Boglione L. et al. J Viral Hepatitis 13; ; e11-19.

14 Sequential therapy with Entecavir and PegIFN in CHB with high HBV DNA % 60% 10% 80% 30% 76.9% 15% csvr psvr HBeAg seroconversion Sequential PegIFN monotherapy (history control) % 0% HBsAg seroconversion csvr: complete sustained virological response, HBV DNA < IU/mL 24 week after EOT psvr: partial SVR, HBV DNA <2,000 IU/mL and ALT normalization 24 weeks after EOT Boglione L. et al. J Viral Hepatitis 13; ; e11-19.

15 Sequential therapy with Adefovir dipivoxil and PegIFN alfa-2a for HBeAg-negative patients Week 100 ADV PegIFN alfa-2a 180 mcg weekly genotype D 45% % 40 % 0 SVR 24 csvr 24 SVR 24: HBV DNA < 10,000 cps/ml 24 weeks post-treatment csvr 24: HBV DNA < 70 cps/ml 24 weeks post-treatment Moucari R. et al. J Viral Hepatitis ;

16 Patients with HBeAg seroconversion (%) PegIFN: response in patients who failed prior LAM therapy 48 weeks PegIFN 12 weeks PEG + LAM then 12 weeks of PEG alone HBsAg clearance in 9% of patients 31% 39% p = ns 31% HBsAg seroconversion in 13% of patients 31% 30 Naïve LAM-R 10 23/58 36/91 25/81 5/16 0 PegaLAM cohort 1 Chinese study 2 Chinese data 3 1. Piratvisuth T et al. (APASL 06) J Gastroenterol Hepatol 06; 21 (Suppl 1): A32. Abstract Xu DZ et al. (EASL 08) J Hepatology 08; 48 (Suppl 2): S266. Abstract Shi XF et al. (APASL 07) Hepatol Int 07; 1: 18. Abstract O-90.

17 Add-on Peg-IFNα + long-term NA enhances HBeAg and HBsAg decline 11 patients with stable HBV DNA suppression (< 0 IU/mL)* with long-term NA treatment (five ETV/six TDF ± LAM/FTC) Five patients received 24 weeks of Peg-IFNα-2b add-on treatment Six patients continued NA monotherapy 48 weeks of follow up *Patients remained HBeAg+ve with elevated HBsAg. Arends P, et al. EASL 13

18 Patients who received Peg-IFN add-on therapy had greater decline of HBeAg levels Follow up [weeks] Peg-IFNα addition (n = 5) Peg-IFNα treatment EOT = end of treatment. Arends P, et al. EASL 13.

19 HBsAg decline [log10 IU/mL] HBsAg decline was more profound in patients who received Peg-IFN add-on Follow up (weeks) Peg-IFNα treatment NA monotherapy (n = 6) Peg-IFN α addition (n = 5) EOT = end of treatment. HBsAg loss was not observed Arends P, et al. EASL 13

20 Adding PegIFN alfa-2a on NAs therapy in HBeAg-positive CHB patients who have achieved virological responses Patient population Non-random classification N = 75 HBeAg+ve CHB patients who had achieved undetectable HBV DNA with at least 1 year of NA therapy without seroconverting Combination therapy with NAs plus Peg-IFNα-2a 180 µg/week Monotherapy group remaining on NA therapy 9 ETV+Peg-IFNα-2a 8 ADV+Peg-IFNα-2a 1 ETV+ADV+Peg- IFNα-2a 1 LAM 35 ETV 19 ADV 2 LAM No baseline difference between treatment groups (sex, age, ALT, qhbsag, qhbeag, prior NA treatment duration) Li Q. et al. EASL 13

21 HBeAg seroconversion Adding PegIFN alfa-2a on NAs therapy improves HBeAg seroconversion in HBeAg-positive CHB patients who have achieved virological responses* * Undetectable HBV DNA with at least 1 years of NA therapy but remained HBeAg positive 40% NA (n=56) PegIFN + NA (n=19) 36.8% 36.8% 36.8% 36.8% 30% % 10% 0% 0 0% p =0.002 p <0.001 p =0.004 p = % 15.8% 10.5% 10.5% 0 8.9% 0 3.6% 00% week 12 week 24 week 36 week 48 Li Q. et al. EASL 13

22 Mean HBsAg [log10 IU/mL] Adding PegIFN alfa-2a on NAs therapy improves qhbsag decline in HBeAgpositive CHB patients who have achieved virological responses* * Undetectable HBV DNA with at least 1 years of NA therapy but remained HBeAg positive 4.0 NA (n=56) PegIFN + NA (n=19) log 10 IU/mL p< log 10 IU/mL Weeks of therapy HBsAg seroconversion in 2 patients with combination therapy No difference between 2 groups in AE rate Li Q. et al. EASL 13

23 Improved serological response by additional PegIFN in NAs treated CHB NA treated CHB HBV DNA <1,000 cps/ml Obvious decline of HBsAg 16 pts 5 ve+ Additional PegIFN NA 48 wks * 16 pts 6 ve+ NA 48 wks % 60 50% % 0 0% 0% Continuous HBsAg decline HBeAg seroconversion HBsAg < 10 IU/mL Wu Z. et al. AASLD 12.

24 Response at week 48 Switched to Peg IFN therapy in ETV treated CHB patients HBeAg-positive ETV > 96 weeks HBV DNA < 500 copies/ml HBeAg < 50 PEIU/mL. No HBeAg seroconversion 27 pts 30 pts PegIFN alfa-2a 180 mcg weekly 48 weeks ETV 12 wks ETV 48 weeks P<0.05 P< % 37% P> HBeAg clearance 16.7% 13.3% HBeAg seroconversion 7.4% 0% HBsAg clearance Chen XF. EASL 13.

25 OSST Study, 0 Chineses HBeAg-positive CHB HBV DNA 10 3 copies/ml HBeAg <100 PEIU/mL ETV 0.5 mg QD (N=0) ~ 9 36 months Switch to Peg-IFNα-2a 180 μg/week for 48 weeks ETV 0.5 mg QD for 8 weeks (n=100) ETV 0.5 mg QD for 48 weeks (n=100) Randomized, multicenter, open-label study Primary endpoint: HBeAg seroconversion at end of treatment (Week 48) Secondary endpoint: HBsAg loss at week 48 Ning Q, et al. Hepatology 12; 56 (Suppl.1): 35 88A.

26 Demographic or baseline characteristic Peg-IFNα-2a (n=97*) ETV (n=100* ) Males, n (%) 78 (80.4) 87 (87.0) Age, years, mean (SD) 33.2 (8.2) 33.2 (8.9) Asian race, n (%) 97 (100) 100 (100) Body mass index, kg/m 2, mean (SD) 22.9 (2.7) 22.9 (2.9) Duration of previous treatment with ETV, months, mean (SD) 19.7 (8.2).4 (8.4) HBsAg, log 10 IU/mL, mean (SD) 3.3 (0.5) 3.3 (0.5) HBV DNA by PCR, log 10 copies/ml, mean (SD) 3.0 (0.1) 3.0 (0.0) ALT, U/L, mean (SD) 27.5 (21.3) 24.2 (13.6) HBeAg, PEIU/mL, mean (SD) 15.6 (48.0) 7.5 (19.9) HBeAg loss, n (%) 54 (55.7) 52 (52.0) * Patients who received at least one dose of study drug Two patients had received adefovir prior to initial ETV therapy Peg-IFNα-2a; n=93; ETV; n=95 SD = standard deviation Ning Q, et al. Hepatology 12; 56 (Suppl.1): 35 88A.

27 HBsAg decline significantly greater in responders than non-responders in Peg-IFNα-2a arm Mean quantitative HBsAg (log 10 IU/mL) Peg-IFNα-2a responders Peg-IFNα-2a non-responders ETV responders ETV non-responders P = * P = * No. of patients (responders/non-responders) Weeks Peg-IFNα-2a 13/80 15/79 15/76 15/72 13/70 ETV 6/89 6/91 6/91 6/88 6/86 *P value for responders versus nonresponders at Week 48 Ning Q, et al. Hepatology 12; 56 (Suppl.1): 35 88A.

28 Response rates at week 48 (%) Response rates at Week 48 ofpeg-ifnα-2a: ITT population Peg-IFNα-2a (n=97) 100 P < ETV (n=100) n/n P = P = * P = * /97 90/100 15/97 6/100 9/97 4/97 HBV DNA HBeAg seroconversion HBsAg loss <1000 copies/ml HBsAg seroconversion * Fisher Exact test, other p-values are using Chi-Squared Test Updated data from time of abstract submission ITT = intention-to-treat Ning Q, et al. Hepatology 12; 56 (Suppl.1): 35 88A.

29 Patients (%) HBsAg < 1,500 IU/mL at baseline is a predictor of HBeAg seroconversion at Week 48 HBeAg seroconversion HBsAg loss 35% 30% 33.3 P = P = % % P = P = % 10% 5% 0% /9 2/34 2/12 3/29 4/ /12 1/29 HBeAg-ve HBeAg+ve HBeAg-ve HBeAg+ve Baseline HBeAg status while patients on ETV BaselineHBsAg < 1500 IU/mL Baseline HBsAg >1500 IU/mL Ning Q, et al. APASL 13.

30 Patients (%) HBsAg at Weeks 12 and 24 predicts response to Peg-IFNα-2a therapy at Week % 80% HBeAg seroconversion HBsAg loss P < P < % 40% 23.1 % % 6/9 <0 6/ <1499 3/59 > /9 <0 1/ <1499 1/59 > 1500 Week 12 HBsAg (IU/mL) HBsAg < 0 IU/mL at Week 12 provides optimal prediction of HBeAg seroconversion (PPV = 67%) and HBsAg loss (PPV = 78%) at Week 48 Ning Q, et al. APASL 13.

31 Conclusions : Switch or add-on more potent non-cross resistant agent is recommended in patients treated with lamivudine or telbivudine with detectable HBV DNA at week 24 Switch to tenofovir should be consider in patients with suboptimal response to adefovir therapy Add-on or switch to PegIFN in patients on long-term NA may provide better sustained response Further study to confirm the benefit and to identify the optimal strategy is needed

32 Thank you