Long-term Results of Pegylated Interferon alfa-2a and Tenofovir for Hepatitis B

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1 Long-term Results of Pegylated Interferon alfa-2a and Tenofovir for Hepatitis B Patrick Marcellin Viral Hepatitis Research Center Hôpital Beaujon, University of Paris France

2 OBJECTIVES OF THERAPY IN CHRONIC HEPATITIS B - Inhibit viral replication - Decrease liver necro-inflammation - Stop fibrosis progression (regression?) - Prevent cirrhosis - Prevent complications - Prevent HCC - Prevent mortality

3 HBsAg SEROCONVERSION: THE CHAMPION AMONG ENDPOINTS HBsAg Seroconversion HBV DNA Suppression 1 HBeAg Seroconversion 3 2 By courtesy of Anna Lok

4 HBsAg AND THE RISK OF HCC HBV progression and HCC in 11,893 men in Taiwan HBsAg HBeAg ALT Relative Risk normal elevated normal elevated normal elevated 19 Yang et al. NEJM 22

5 Cumulative Incidence of HBsAg Seroconversion INCIDENCE OF HBsAg LOSS ACCORDING TO RESPONSE TO IFN (HBe seroconversion) 1,,8,6,4,2 Response : 64% p<.1 Non response : 17%, Time (Years) Moucari et al. J Hepatol 29

6 OUTCOME (1 years) AFTER IFN THERAPY HBsAg+ HBsAg- HCC : 6 Ascitis : 5 Hemorrhage: Transplantation: Mortality (HCC): 4 Moucari et al. J Hepatol 29

7 Two Strategies to Treat Hepatitis B PEG-IFN Sustained response after a finite duration of treatment NAs Maintained response on treatment with complete supression of replication to avoid resistance EASL Clinical Practice Guidelines. J Hepatol 29

8 Long Term Effects of Therapy of Hepatitis B with Pegylated Interferon and Tenofovir? Durability of response HBs clearance and seroconversion Resistance (NUCs) Safety

9 Long-term results of pegylated interferon alfa-2a Two Studies: HBeAg-positive*: no long term follow-up HBeAg-negative**: long term follow-up *Lau et al. NEJM 25 **Marcellin et al. NEJM 24

10 PEG-IFN -2a in HBeAg-negative disease: Study design PEG-IFN -2a 18 μg qw + placebo qd Initial study* Long-term (LT) study** N=537 PEG ± LAM N=23 PEG-IFN -2a 18 μg qw + 1 mg lam qd Lamivudine 1 mg qd 48 weeks EOT (week 48) 6 months post-eot 5 years post-eot *Marcellin et al. NEJM 24 **Marcellin et al. Gastroenterology 29 **Marcellin et al. APASL and EASL 29

11 Patients (%) Response to PEG IFN 2a ± lamivudine 5 years post treatment PEGASYS ± lamivudine (n=23) % 12 ALT normal HBV DNA <1, copies HBV DNA <4 copies HBsAg clearance Marcellin et al. Gastroenterology 29 Marcellin et al. EASL 29

12 Patients (%) HBsAg clearance over time N=23 treated with PEG-IFN -2a ± lamivudine % 6% 9% 11% 12% 2 N=11 N=14 N=2 N=25 N= Marcellin et al. EASL 29 3 Years post-treatment % had anti-hbs

13 Use of HBsAg quantification to identify sustained responders Can quantitative HBsAg be used to identify at an early stage of treatment who is likely to achieve sustained response?

14 Quantification of HBsAg: Stopping Rule Early Serological Response =.5 log at W12 ESR + PPV = 89 % 48 Patients treated with PEG IFN a2a ESR - NPV = 9 % Moucari et al. Hepatology 29

15 Mean decline from BL log 1 IU/mL HBsAg levels over time: HBeAg-negative study Baseline HBsAg levels were similar in all 3 arms ~3.4 log 1 IU/mL LAM Weeks PEG-IFN -2a + LAM PEG-IFN -2a Treatment period PEG N=59 PEG + LAM N=61 LAM N=44 For subsequent analyses the 2 PEG-IFN -2a-containing arms were pooled N=12

16 Mean decline from BL log 1 IU/mL HBsAg levels over time according to virologic response 5 years post-treatment Weeks HBV DNA >1, cp/ml HBsAg not cleared but HBV DNA 1, cp/ml HBsAg cleared Treatment period

17 Rate of response (%) Association between decline in HBsAg from BL to week 24 and sustained response 5 years post-treatment P=.78 HBsAg decline from BL to week 24 1% 56% of patients <1% 44% of patients 63% of these also cleared HBsAg P=.48 HBV DNA 1, copies/ml HBsAg clearance

18 Long-term results of PEG-IFN- 2a study: Summary PEG-IFN- 2a therapy can induce sustained virological response (25% at 5 years) 2/3 of sustained responders develop HBsAg loss Significant association between on-treatment HBsAg decline and sustained response On-treatment HBsAg quantification may help identify: Patients likely to benefit most from PEG-IFN -2a Those who may benefit from modification of treatment regimen or treatment strategy

19 Long-term results of Tenofovir Two Studies: HBeAg-positive*: long term follow-up HBeAg-negative*: long term follow-up *Marcellin and Heathcote et al. NEJM 28

20 RANDOMIZATION 2:1 HBeAg-Negative and HBeAg-Positive Study Design Double Blind Open-Label Tenofovir 3 mg Tenofovir 3 mg Adefovir 1 mg Pre-treatment Liver Biopsy Week 48 Liver Biopsy Week 72 Week 24 Week 144 Liver Biopsy Year 3 Week 384 Year 8 HBV DNA 4 copies/ml option to add emtricitabine (FTC) to TDF Patients Completing Year 3: 87% HBeAg Negative 8% HBeAg Positive Marcellin and Heathcote et al. NEJM 28

21 Percentage (%) % HBeAg-Negative Patients with HBV DNA <4 copies/ml (Long Term Evaluation) Randomized Double-Blind Weeks on Study Open-Label TDF 88% 88% 88% ADV-TDF 87% TDF-TDF 94% LAM-Ep Patients who added FTC were considered failures (N=3).

22 Percentage (%) % HBeAg-Negative Patients with HBV DNA <4 copies/ml (On-Treatment Analysis) Randomized Randomized Double-Blind Open-Label Open-Label TDF TDF Double-Blind Weeks on Study 1% ADV-TDF 99% TDF-TDF LAM-Exp: 1% Includes 3 patients who had HBV DNA <4 copies/ml at week 144 on FTC+TDF

23 Percentage (%) % HBeAg-Positive Patients with HBV DNA < 4 copies/ml (Long Term Evaluation) Randomized Double-Blind Open-Label TDF Weeks on Study 72% TDF-TDF 71% ADV-TDF Patients who added FTC were considered failures (N=31).

24 Percentage (%) % HBeAg-Positive Patients with HBV DNA < 4 copies/ml (On-Treatment Analysis) Randomized Double-Blind Randomized Double Blind Open Label TDF Open-Label TDF Weeks on Study 95% TDF-TDF 91% ADV-TDF Includes 17 patients across both treatment groups who had HBV DNA <4 copies/ml at week 144 on FTC+TDF

25 Mean (95% CI) ALT (U/L) Mean ALT (U/L) Over Time (HBeAg-Negative Patients) Randomized Double-Blind Open-Label TDF TDF-TDF ADV-TDF Randomized Double-Blind Open-Label TDF U/L 33 U/L Weeks on Study % ALT normalization: 73% TDF-TDF and 76% ADV-TDF 95% of patients with ALT >ULN had ALT values <2.5xULN ULN for females=34 U/L ULN for males=43 U/L ULN: females=34 U/L males=43 U/L

26 Mean (95% CI) ALT (U/L) Mean ALT (U/L) Over Time (HBeAg-Positive Patients) Randomized Double-Blind Open-Label TDF TDF-TDF ADV-TDF U/L 37 U/L Weeks on Study % ALT normalisation: 83% TDF-TDF and 77% ADV-TDF 9% of patients with ALT>ULN had ALT values <2.5xULN ULN for females=34 U/L ULN for males=43 U/L

27 % Patients % Patients % Patients TDF-TDF with HBeAg Loss and Seroconversion HBeAg Loss HBeAg Seroconversion 35 34% % 23% 22% % 26% Year 1 Year 2 Year 3 Year 1 Year 2 Year 3

28 Cumulative Probability Function Estimate Cumulative Probability* of HBsAg Loss in the HBeAg-positive Study.1 Originally Randomized Treatment TDF ADV 8% in each group.5 Open Label TDF Weeks on Study *Kaplan-Meier 6% TDF-TDF and 7% ADV-TDF seroconverted to anti-hbs 14/2 patients with HBsAg loss discontinued treatment & entered treatment-free follow-up (mean 171 days)

29 Surveillance for Resistance Genotyping (HBV pol/rt) All patients at baseline All patients yearly if HBV DNA 4 copies/ml (69 IU/mL) All patients who discontinued TDF if HBV DNA 4 copies/ml Phenotyping (HBV pol/rt) Any patient post-baseline with: conserved site changes in pol/rt virologic breakthrough polymorphic site changes (> 1 patient)

30 Surveillance for Resistance No HBV pol/rt amino acid substitutions developed that were associated with TDF resistance

31 Summary of Cumulative Safety Data at 3 Years HBeAg Negative HBeAg Positive TDF-TDF ADV-TDF TDF-TDF ADV-TDF Study Drug-Related SAE 1 (<1%) 2 (1.3%) 2 (2.4%) Deaths Cholangiocellular carcinoma cervical cancer metastases nasopharyngeal carcinoma 2 (<1%) 1 (<1%) 1 (<1%) 1 (<1%) 1(<1%) G3 or G4 Laboratory 14% 15% 12.3% 15.5% Discontinue due to an AE HCC dizziness, fatigue, lack of concentration creatinine septic Shock 3 (1.2%) Confirmed phosphorus < 2mg/dL 2 (<1%) 1 (<1%) 1 (1%) Confirmed.5 mg/dl in creatinine 2 (2%) Confirmed creatinine clearance <5 ml/min

32 Mean Creatinine Serum Creatinine Over Time in HBeAg-Negative Patients Insert Plot when available TDF-TDF ADV-TDF Randomized Double-Blind Open-Label TDF Weeks on Study

33 Mean Creatinine Mean Creatinine Serum Creatinine Over Time in HBeAg-Positive Patients Insert Plot when available TDF-TDF ADV-TDF Randomized Double-Blind Weeks on on Study Open-Label TDF TDF N= ADV N=

34 Conclusions: Tenofovir 3 Years Results TDF demonstrated durable, potent antiviral activity 99% of HBeAg patients had HBV DNA <4 c/ml 95% of HBeAg+ patients had HBV DNA <4 c/ml Increasing HBsAg loss observed in HBeAg-positive patients Renal safety was good TDF was well tolerated No resistance to TDF developed through Week 144

35 AKNOWLEDGEMENTS Investigators from more than 1 centers from more than 5 countries More than 15 patients

36 Baseline Disease and Demographic Characteristics CHARACTERISTIC Study 12 (HBeAg ) TDF-TDF (N=25) ADV-TDF (N=125) Study 13 (HBeAg+) TDF-TDF (N=176) ADV-TDF (N=9) Mean Age (years) Race Caucasian Asian 64% 25% 65% 24% 52% 36% 51% 36% Male 77% 78% 68% 71% Prior lamivudine experience 17% 18% 5% 1% Mean HBV DNA (log1 copies/ml) Mean ALT (U/L) Mean Knodell necroinflam score Mean Knodell fibrosis score Knodell fibrosis score = 4 (cirrhosis) Viral Genotype % 2% 2% 21%