22 February 213 Treatment of chronic hepatitis B 213 update Pietro Lampertico 1st Gastroenterology Unit Fondazione IRCCS Cà Granda - Ospedale Maggiore Policlinico Università di Milano
EASL 212 Clinical Practice Guidelines: What is long-term treatment success in CHB and how do we achieve it?...to improve quality of life and survival by preventing progression of the disease to cirrhosis, decompensated cirrhosis, end-stage liver disease, hepatocellular carcinoma (HCC) and death This goal can be achieved if HBV replication can be suppressed in a sustained manner. Then, the accompanying reduction in histological activity of CHB lessens the risk of cirrhosis and decreases the risk of HCC, particularly in non-cirrhotic patients European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Management of chronic hepatitis B virus infection. J Hepatol. (212), http://dx.doi.org/1.116/j.jhep.212.2.1.
Different patterns of HBV suppression Ideal end-point: sustained off-therapy HBsAg clearance with/without seroconversion Satisfactory end-point: sustained off-therapy virological and biochemical response Desirable end-point: maintained virological remission (undetectable HBV DNA by a sensitive PCR assay) EASL HBV Guidelines, J Hepatol 212
Peg-IFN
Peg-IFN α-2a (4 KD) provides sustained immune control that increases post-therapy Increase in HBeAg seroconversion 1 year post-treatment among 271 patients with HBeAg+ve CHB treated with Peg-IFN α-2a (4 KD) e+ Patients with HBeAg seroconversion (%) 5 4 3 2 1 27% 32% 42% 72/271 87/271 EOT Post-treatment (6 months) 73/172* Post-treatment (1 year) * Results from an observational follow-up study Lau GKK, et al. N Engl J Med 25; 352: 2682; Lau GKK, et al. 41st EASL 26: Abstract 5.
Peg-IFN α-2a (4 KD) demonstrates sustained immune control up to 5 years e- 23 patients with HBeAg ve CHB treated with Peg-IFN α-2a (4 KD) ± LAM 5 Patients with a durable response 5 years post-treatment Patients with HBV DNA 1 copies/ml (%) 4 3 2 1 31% 88% 72/23 Post-treatment (1 year)) Patients who achieved HBV DNA 1, copies/ml at Year 1 post-treatment who maintained that response up to year 5 (N=36/41*) * Based on an analysis of patients with available data at 1 and 5 year post-treatment follow-up assessments Piratvisuth T, et al. 2th APASL 21: Abstract 21.
Sustained immune control with Peg-IFN α-2a (4 KD) leads to HBsAg clearance e- 23 patients with HBeAg ve CHB treated with Peg-IFN α-2a (4 KD) ± LAM 5 Patients with HBsAg clearance at 5 years post-treatment Patients with HBV DNA 1 copies/ml (%) 4 3 2 1 31% 28% 72/23 Post-treatment (1 year)) In the registration study involving 375 HBeAg-ve patients, % of HBeAg-ve patients experienced loss of HBsAg with up to 4 years of TDF treatment * All 72 patients had 5-year post-treatment follow-up HBsAg data Piratvisuth T, et al. 2th APASL 21: Abstract 21. Marcellin P, et al. 46 th EASL 211: Poster 74.
S-Collate cohort study Study design and data collection overview A multicenter, prospective, non-interventional real-life cohort study enrolling HBeAg positive and negative patients Pre-therapy Peg-IFNα-2a 18 µg/week (dosing and duration in accordance with local label) Follow-up 24 * 12* 24* 36* 48*.5* 1* 2* 3* Study weeks Post treatment years APASL 212 * Time points when data will be collected as per standard of care Marcellin, Chen et al, APASL 212
How can we improve PEG-IFN efficacy? de-novo combination therapy duration of therapy pre-treatment predictors of response on-treatment predictors of response
De-novo combo therapy for HBeAg neg CHB? (randomized controlled trials) Peg-IFN + LAM vs Peg-IFN 1,2 Peg-IFN + ADV vs Peg-IFN 3 Peg-IFN + RBV vs Peg-IFN 4 1) Marcellin P et al, NEJM 24 2) Lampertico P et al, Gut 212 3) Piccolo P et al, Antiv Therapy 29 4) Rijckborst V. et al, Am J Gastroenterology 21
De-novo combo therapy for HBeAg neg CHB? (randomized controlled trials) Peg-IFN + LAM vs Peg-IFN 1,2 Peg-IFN + ADV vs Peg-IFN 3 Peg-IFN + RBV vs Peg-IFN 4 1) Marcellin P et al, NEJM 24 2) Lampertico P et al, Gut 212 3) Piccolo P et al, Antiv Therapy 29 4) Rijckborst V. et al, Am J Gastroenterology 21
PEGASYS in HBeAg-positive disease: Dose and duration are important e+ NEPTUNE study N=136 N=136 N=136 N=14 PEGASYS 18 µg PEGASYS 9 µg 48 PEGASYS 18 µg PEGASYS 9 µg Follow-up Follow-up 24 48 Follow-up Follow-up 72 HBeAg seroconversion 6 months posttreatment 4 3 2 1 36% 26% 23% 14% 9/24 18/24 9/48 18/48 Highest sustained response with 18 µg and 48 weeks confirms Phase 3 study Liaw et al. Hepatology 211
Extending PEGASYS in HBeAg-negative disease reduces relapse: PegBeLiver study e- 96% genotype D 4 HBV DNA <2 IU/mL HBsAg clearance N=51 PEGASYS 18 Follow-up 3 29% N=52 PEGASYS 18 PEGASYS 135 48 96 Study weeks Follow-up 114 2 1 12% 6% 48 96 48 96 Duration of therapy (weeks) Extending therapy can increase response rate in genotype D patients Lampertico et al. GUT 212 %
Peg-IFN for HBeAg positive CHB Influence of precore and core mutations 6 Week 78 (n=263) e+ Percentage of patients 5 4 3 2 43 P=.372 37 P<.1 34 13 P<.1 21 18 Wild type PC/BCP mutants P<.1 1 HBeAg loss Combined Response* 5 HBVDNA <8 IU/mL 2 HBsAg loss * HBeAg loss and HBV DNA<1, copies/ml Sonneveld et al. Hepatology 212
IL28B polymorphisms in PEG-IFN treated HBeAg-pos patients with CHB A review Favourable IL28B genotype % Patients with HBeAg seroconversion 6 months off-therapy 1 8 6 4 2 26% TT P=NS 25% Non-TT 54% P=.5 35% 2% AA AG GG Unfavourable IL28B genotype P=.3 29% TT 51% Non-TT (rs899917) (rs1298275) (rs899917) Taiwan (n=115) Europe-Asia (n=25) China (n=512) Lampertico and Liaw, GUT 212
IL28B polymorphims (86) in 11 IFN treated HBeAg-negative patients with CHB 1 OR: 2.99 (1.24-7.21) p=.1 CC CT/TT % Patients with response 8 6 4 2 69% 45% OR: 3.72 (1.19-11.5) p=.2 31% 13% OR: 3.63 (1.5-12.5) p=.4 29% 13% End of treatment response Sustained response HBsAg clearance Lampertico et al, Hepatology 212
Clinical significance of HBsAg level: An additional marker of CHB 1: 27 HBV DNA (virions) virions qhbsag + defective particles HBV replication HBV replication cccdna transcription/ mrna translation Serum HBV DNA: a marker of HBV replication Serum HBsAg: a marker of transcriptionally active cccdna* Brunetto. J Hepatol 21
Response-guided therapy (RGT) using HBsAg levels in Peg-IFN-treated patients: early stopping rules* HBeAg-positive HBeAg-negative (geno D) Week 12: - No decline of HBsAg (A,D) - HBsAg >2, IU/mL (B,C) Week 12: - No decline in HBsAg + <2 log decline in HBV DNA Week 24: - HBsAg >2, IU/ml (A,B,C,D) * 97-1% Negative Predictive Values Sonneveld et al. Hepatology 21 Piratvisuth et al. APASL 21 Liaw et al. Hepatology 211 Sonneveld et al., AASLD 212 Rijckborst et al. Hepatology 21 Rijckborst / Lampertico et al. J Hepatol 212
Response-guided therapy (RGT) using HBsAg levels in Peg-IFN-treated patients: early stopping rules* HBeAg-positive HBeAg-negative (geno D) Week 12: - No decline of HBsAg (A,D) - HBsAg >2, IU/mL (B,C) Week 12: - No decline in HBsAg + <2 log decline in HBV DNA Week 24: - HBsAg >2, IU/ml (A,B,C,D) * 97-1% Negative Predictive Values Sonneveld et al. Hepatology 21 Piratvisuth et al. APASL 21 Liaw et al. Hepatology 211 Sonneveld et al., AASLD 212 Rijckborst et al. Hepatology 21 Rijckborst / Lampertico et al. J Hepatol 212
NUC
Incidence of Resistance in NUC-naïve Patients *Collation of currently available data not from head-to-head studies 8 1 st generation 67 7 6 Patients (%) 4 2 24 38 49 2 nd generation 29 18 17 3 rd generation 11 3 4.5 1.2?.2 1.2 1.2 LAM ADV LDT ETV TDF adapted from EASL HBV Guidelines, J Hepatol 212
3-yr ETV in HBeAg-neg CHB - Re-Treatment cohort Virological response ETV-27 ETV-91 Proportion of patients (%) HBV DNA <3 copies/ml 1 8 6 4 2 94% Off-treatment >6 days 4% 59% 83% 93% 94% 91% 95% EOD Baseline Wk 12 Wk 24 Wk 48 Wk 72 Wk 96 Wk 144 n= 93/99 4/99 56/95 79/95 84/9 72/77 67/74 54/57 EOD= end-of-dosing 1 patients who remained on treatment at the Week 144 of ETV-91 visit had missing PCR samples D. Shouval et al, J Hepatol 29
5-year TDF in HBeAg-negative patients with CHB HBV-DNA <4 cp/ml 1 9 On-Treatment Analysis (Observed; missing=excluded/addition of FTC = included) TDF 99% 99% Proportion of Subjects (%) 8 7 6 5 4 3 2 TDF ADV TDF-TDF ADV-TDF 1 8 16 24 32 4 48 56 64 72 8 88 96 18 12 132 144 156 168 18 192 24 216 228 24 Weeks on Study Marcellin P. et al.; AASLD 211
Management of HBV Resistance (Early rescue) DRUG RESCUE STRATEGY LAM, LDT, ETV Switch to TDF (or add ADV) ADV TDF* Switch to ETV (if LAM naive) Switch to TDF (if LAM resist and LVL) Combo: TDF + ETV (if LAM resist and HVL) Switch to ETV (if LAM naive) Add ETV (if LAM resistant) * Never described so far adapted from EASL HBV guidelines, J Hepatol 212
NUC therapy: secondary Endpoints HBeAg seroconversion rates increase (4% at year 5) HBsAg loss rates increase over time (-2% at year 5) Normal ALT levels in most patients (85%) Regression of fibrosis in most patients (year 5) No major safety issues up to 5 years Effective in compensated and decompensated cirrhotics
Real-world studies can add valuable additional insights to RCT data RCTs systematically exclude special populations patients with concurrent diseases, concurrent drug use, at age extremes, or are at risk of noncompliance Studying real-world populations gives valuable additional insights in heterogeneous populations http://www.fda.gov/safety/safetyofspeci ficproducts/ucm 18547.htm. (Accessed April 21).
5-year TDF treatment in patients with CHB Changes of fibrosis in cirrhotics Change from Baseline in Fibrosis Score -5-4 -3-2 -1 +1 +2 +3 +4 +5 74% of patients had cirrhosis reversed n = 14 n = 41 n = 15 n = 1 n = 24 n = 1 96 patients with cirrhosis (Ishak fibrosis score 5) had paired BL and Year 5 biopsies 74% (n=71) of patients had cirrhosis reversed (Ishak fibrosis score <5) at Year 5, and 73% (n= 7) had decreases of 2 points at Year 5; 25% (n=24) did not change Of 94 patients who did not add FTC, 73% had cirrhosis reversed; 26% showed no change Marcellin P et al, AASLD 211
Changes of esophageal varices (EV) in compensated cirrhotics treated with LAM±TDF for 1 years Overall, EV worsening rate per year:.9%* 1 F1 varices at baseline (n=27) 1 No varices at baseline (n=8) 8 8% 8 6 6 EV regression 4 4 2 EV progression 12% 12 24 36 48 6 72 84 96 18 12 Months 2 EV progression 12 24 36 48 6 72 84 96 18 12 8% 27 27 24 21 19 15 9 8 4 4 3 27 27 26 24 23 21 2 18 14 14 9 Patients at risk 8 8 78 78 74 67 62 56 45 39 33 * 6 of 7 progressors (86%) had either LMV-R and/or HCC Lampertico et al, submitted 213
HCC rates in NUC-naïve cirrhotic patients long-term responding to NUC 4 HCC per year (%) 3 2 1 1.5% 2.4% 2.5% 2.8% Liaw (24) Papatheod. (21) Papatheod. (211) Kurokawa (212) Num. of pts: 211 81 62 42 Drug: LAM LAM LAM LAM Study: RCT Review Retrosp. Retrosp. Follow-up: 3 yrs 2 yrs 6 yrs 5 yrs Aghemo A et al, J Hepatol 212
5-year complication-free survival in compensated cirrhotics treated with ETV 1 8 Decompensation HCC 1% 86% 6 4 HCC=17 HCC rate/year: 2.8% Decompensation rate/year: % 2 6 12 18 24 3 36 42 48 54 6 Months Patients at risk 155 153 149 145 135 125 115 15 92 58 2 * Kaplan-Meier estimates Lampertico P et al, AASLD 212
When to stop NUC therapy? Patient features EASL 212 guidelines HBeAg-positive A) confirmed anti-hbe seroconversion (and undectable HBV DNA) after at least 12 months of consolidation* B) confirmed HBsAg loss and anti-hbs seroconversion HBeAg-negative confirmed HBsAg loss and anti-hbs seroconversion Cirrhotics confirmed HBsAg loss and anti-hbs seroconversion *A proportion of patients who discontinue NUC therapy after anti-hbe seroconversion may require retreatment, since they fail to sustain their serological and/or virological response adapted from EASL HBV Guidelines, J Hepatol 212
Conclusions Short-term PEG-IFN therapy: 48-week course effective in 2-3% of patients qhbsag at week 12 as a stopping rule (97-1% NPV) Efficacy must be improved: - qhbsag, extension, genomics, combo with NUC Long-term NUC therapy: Long-term ETV or TDF monotherapy for most patients Very effective and no major safety signals over 5 years New stopping rules must be developed: - Serology (qhbsag) - Immunology - Genomics - Combo with peg-ifn or other immunomodulators