How to use pegylated Interferon for Chronic Hepatitis B in 215 Teerha Piratvisuth NKC Institute of Gastroenterology and Hepatology Prince of Songkla University, Thailand
ASIAN-PACIFIC CLINICAL PRACTICE GUIDELINES ON THE MANAGEMENT OF HEPATITIS B:215 UPDATE GOALS AND END POINTS OF THERAPY Ideal end-point in HBeAg positive &negative is sustained off-therapy HBsAg loss with or without seroconversion to anti-hbs Sustained off-therapy virological response in HBeAg positive [with anti-hbe serovoncrsion] and HBeAg ve patients is a satisfactory end point. If sustained off-therapy response not achievable,then maintained virological remission(undetectable HBV DNA) under antiviral therapy is the nest most desirable end point APASL Guideline 2115. available at http://www.ihepa.com:888/pc/detail/13722..
Maximizing PegIFN treatment response through proper selection of the patients
Baseline predictors of response to pegylated interferon Baseline factors HBeAg-positive patients HBeAg-negative patients Serum HBV-DNA Lower HBV-DNA level Lower HBV-DNA level Serum ALT Higher ALT level Higher ALT level HBV genotype A>D and B> C B/C > D Quantitative HBsAg Lower HBsAg level Decline in HBsAg level Quantitative HBeAg Low HBeAg level HBV mutant Controversial Controversial IL28B polymorphisms Controversial Controversial Note: ALT, alanine aminotransferase; HBV, hepatitis B virus; HBsAg, hepatitis B surface antigen; HBeAg, hepatitis B e antigen Charatcharoenwitthaya P,Piratvisuth T. Curr Hepatitis Rep. 213;12:165-173.
Patients (%) Favourable baseline characteristics HBeAg seroconversion 24 weeks after the end of PegIFN alfa treatment 6 1 log 1 HBV DNA >1 log 1 HBV DNA 52% 4 32% 36% 28% 2 22% 12% 18/56 2/17 22/61 1/45 13/25 8/29 Low Medium High *According to baseline levels of ALT and HBV DNA. ALT: High >5 x ULN; Med >2 5 x ULN; Low 2 x ULN [8% Confidence Intervals] ALT Piratvisuth et al. Hepatol Int. 28
Response 6 months post-treatment (%) Response 6 months post-treatment (%) Baseline HBsAg and response to PegIFN treatment in HBeAg-positive CHB Phase 3 study NEPTUNE study (18/48) 6 5 4 37% 32% 6 5 4 5% 32% 3 2 1 21% 3 2 1 6% HBsAg level at baseline (IU/mL) <5 5 5, >5, N=126 N=276 N=16 <5 5 5, >5, N=5 N=59 N=18
A predictive tool for selecting HBeAg-positive CHB patients who have a high probability of HBV DNA suppression and HBeAg seroconversion with PegIFN alfa Baseline Scoring system for predictive baseline characteristics Predictive baseline characteristics for each individual patient were assigned points, which were summed to provide a score ranging from to 8, with higher scores indicating a higher chance of response Characteristic Score Sex: Male Female 1 HBV genotype: Non-A A 2 ALT ratio: x ULN <1.5 1.5 <4 1 4 2 HBsAg, IU/mL: 2 <2 1 HBV DNA, log 1 IU/mL: 1 8 <1 1 Abstract: 1886 <8 Chan H. 2 et al, AASLD 214
Predictive tool for selecting HBeAg-positive CHB patients who have a high probability of HBV DNA suppression and HBeAg seroconversion with PegIFN Results Predictive score 1 n/n 2/43 3/43 3/43 5 7 7 Response by baseline prediction score 48 weeks post-treatment 2 3 38/26 6/26 49/26 18 24 29 Combined response HBeAg seroconversion HBV DNA 2 IU/mL 4 43/131 61/131 49/131 33 37 47 5 2/52 31/52 25/52 38 48 6 6 7/11 9/11 8/11 64 73 82 1 2 3 4 5 6 7 8 9 1 Abstract: 1886 Patients (%) Chan H. et al, AASLD 214
BL predictive tool for selecting HBeAg-negative CHB pts who have a high probability of achieving sustained immune control with PegIFN alfa Scoring system for predictive baseline characteristics Predictive baseline characteristics for each individual patient were assigned points, which were summed to provide a score ranging from to 6, with higher scores indicating a higher chance of SIC and SR Characteristic Score HBV genotype: C 1 Non-C Age, years: >45 3 45 1 <3 2 HBsAg, IU/mL: 35 1 <35 1 <1 2 ALT ratio, x ULN: 5 1 <5 Abstract: 1885 Lampertico P et al, AASLD 214
BL predictive tool for selecting HBeAg-negative CHB pts who have a high probability of achieving sustained immune control with PegIFN alfa Results (SIC/SR rates by BL score) Predictive score n N SIC: HBV DNA <2 IU/mL SR: HBV DNA <2 IU/mL and normal ALT 1 12 12 9 12 12 9 2 3 37 128 31 128 29 24 4 26 33 2 33 61 79 2 4 6 8 1 Patients (%) Abstract: 1885 Lampertico P et al, AASLD 214
Maximizing PegIFN treatment response through on-treatment predictors
On-treatment predictors of response to pegylated interferon On-treatment Predictors Serum HBV-DNA HBeAg-positive patients Treatment success: <2, IU/mL at week 12 of treatment (PPV: 54 %) Treatment failure: >2 1 8 IU/mL at week 24 of treatment (NPV: 86 %) HBeAg-negative patients Treatment success: <63 IU/mL at week 24 of treatment (PPV: 42 %) Treatment failure: >63 IU/mL at week 24 of treatment (NPV: 94 %) Serum ALT Host induced ALT flare Host induced ALT flare Quantitative HBsAg Quantitative HBeAg Treatment success: <15 IU/mL at week 12 of treatment (PPV: ~58 %) Treatment failure: >2, IU/mL at week 24 of treatment (NPV: 97 %) Treatment success: 1 at week 12 of treatment (PPV: 63 %) Treatment failure: 1 at week 24 of treatment (NPV: 9 %) Treatment success: >.5 log1 or >1 % decline at week 12 of treatment (PPV: 47 %-89 %) Treatment failure: no decline at week 12 of treatment (NPV: 71 %-97 %) Note: ALT, alanine aminotransferase; HBsAg, hepatitis B surface antigen; HBeAg, hepatitis B e antigen; PPV, positive predictive value; NPV, negative predictive value Charatcharoenwitthaya P,Piratvisuth T. Curr Hepatitis Rep. 213;12:165-173.
HBeAg-positive CHB
Patients achieving response* (%) On-treatment ALT flares predict response to PEGIFN alfa-2a therapy PEGIFN -2b PEGIFN -2a 1 9 8 7 6 5 58% 44% 4 3 2 2% 1 Host induced N=24 Virus induced N=25 Host induced N=18 % Virus induced N=1 Flink et al. Gut 25; Piratvisuth et al. ILC 26
Mean HBeAg reduction ALT flare during PegIFN therapy in HBeAg-positive CHB 2 1-1 P<.1 -.25 logs -2-3 -4-3.24 logs Host-induced flare Virus-induced flare Patients achieving a decline HBsAg of >.5 log IU/ml within 4 weeks after ALT flare had HBsAg loss 64% (7/11) Sonneveld M. et al. CID. 213; 56: 1-5.
Treatment response according to on-treatment HBsAg levels in HBeAg-positive treated with PegIFN alfa-2a ± LAM P =.2172 P =.183 9 223 96 9 223 96 9 223 96 36 211 52 36 211 52 36 211 52 Piratvisuth T. et al. Hepatol Int 211.
Proportion of patients with lower HBsAg levels increases over time Week 12 <15 IU/mL 23% N=9/399 Week 24 <15 IU/mL 34% N=136/399 Week 12 <2, IU/mL Week 24 <2, IU/mL 78% N=313/399 87% N=347/399 Piratvisuth etal. APASL 211
HBeAg seroconversion 6 months post-treatment (%) NEPTUNE: Combining ALT levels and on-treatment HBsAg levels Increases the response rate to PegIFN HBsAg levels at Week 12 8 7 6 68 <15 IU/mL 15-2, IU/mL >2, IU/mL 5 46 45 4 3 31 2 1 5/11 9/29 1 2 x ULN 13/19 13/29 >2 x ULN ALT at screening Liaw et al. Hepatology 211
HBeAg seroconversion 6 months post-treatment (%) HBeAg seroconversion 6 months post-treatment (%) Low on-treatment HBsAg levels are associated with higher rates of response HBeAg-positive patients treated with PEGASYS ± lamivudine for 48 weeks 6 5 57% Week 12 Week 24 6 5 54% 4 3 2 1 Low (<15) 32% Medium (15 2,) HBsAg at week 12 (IU/mL) 16% 51/9 72/223 14/86 High (>2,) 4 3 2 1 Low (<15) 26% Medium (15 2,) HBsAg at week 24 (IU/mL) 15% 74/136 55/211 8/52 High (>2,) Phase 3 study P<.1 for <15 IU/mL vs higher levels P<.1 for <15 IU/mL vs higher levels Piratvisuth T. et al. Hepatol Int 211.
Extending treatment duration with pegifn alfa-2a in HBeAg-positive disease N=31 patients with partial response to pegifn alfa-2a at week 48 HBV DNA suppression <1 5 copies/ml without HBeAg seroconversion Received either: Further 24 weeks of pegifn alfa-2a (= extension group) No further treatment Jiang et al. data on file
Extended treatment is associated with better virological response at week 72 Extension group Follow-up group 1% 8% P=.14 81% 6% 53% P=.43 4% 2% 38% P=.23 19% % HBV DNA undetectable HBeAg seroconversion % % HBsAg loss Jiang et al. data on file
Excluded: n=96 Pooled analysis Other HBV genotypes: n=17 Missing HBsAg levels: n=38 No available outcome: n=41 Patients in database: N=899 PegIFN alfa-2a phase 3 study: n=542 HBV 99-1 study: n=221 NEPTUNE study: n=136 Patients analyzed: n=83 Response: n=182 (23%) HBsAg loss: n=39 (5%) Sonneveld M, Piratvisuth T.AASLD 212
Percentage of patients Percentage of patients HBsAg level is superior to decline at week 24 HBsAg level HBsAg decline 6 5 46 p<.1 <15 IU/mL (n=253) 15 2 IU/mL (n=373) >2 IU/mL (n=162) 6 5 Decline (n=649) No decline (n=139) 4 4 p=.1 3 3 25 2 16 15 p<.1 2 12 p=.3 1 3 1 6 HBeAg loss with HBV DNA <2 IU/mL HBsAg loss HBeAg loss with HBV DNA <2 IU/mL HBsAg loss HBsAg >2, IU/mL at week 24 provides NPV 97% >> stopping rule in all HBV genotypes
HBeAg-negative CHB
Patients with HBsAg Clearance (%) Patients with HBV DNA <2 IU/mL (%) HBsAg decline at week 12 or week 24 of treatment is associated sustained response at 1 and 5 years post PegIFN treatment in HBeAg-negative CHB 6 5 4 3 47.2 HBsAg decline at week 12 (log 1 IU/mL) > 1% < 1% p =.3 41.5 p =.5 43.3 HBsAg decline at week 24 (log 1 IU/mL) > 1% < 1% p =.4 35.8 p =.2 2 1 16.4 13.4 13.2 13.2 P-values: Mantel-Haenszel Chi-Square. 3 25 2 1 year post-treatment 5 years post-treatment 1 year post-treatment 5 years post-treatment HBsAg decline at week 12 (log 1 IU/mL) > 1% < 1% p =.161 HBsAg decline at week 24 (log 1 IU/mL) > 1% < 1% 22.6 22.4 p <.1 15 p =.484 p =.26 1 9.4 7.5 9 5 P-values: Mantel-Haenszel Chi-Square. 1.5 1 year post-treatment 3.8 5 years post-treatment 1 year post-treatment 5 years post-treatment Marcellin P, et al. Hepatol Int 213; 7: 88-97
SVR rates at week 24 HBsAg levels at week 48 (EOT) predict SVR 127 HBeAg-negative patients treated with Peg-IFNalfa2a for 48 weeks 1 88% All genotypes 8 6 4 36% 2 14/16 <1 4/11 11-1 2% 7/35 11-1 13% 6/48 11-5 HBsAg levels at week 48 % >5 (/17) HBsAg loss at 3 years: 52% in HBsAg <1 IU/ml vs 2% in HBsAg >1 UI/ml SVR: HBV DNA <4 cp Brunetto et al. Hepatology 29
Patients with HBV DNA <2, IU/ml % Extended PegIFN alfa-2a treatment in HBeAg-negative CHB 35 3 25 2 15 1 p=.39 p=.3 28.8 28.8 21.6 11.8 5 48 Weeks (n = 51) 96 Weeks (n = 52) 11 15 6 15 24 week 48 week Post-treatment time point Lampertico P. et al. Gut. 213; 62: 29-298.
HBV DNA <2, IU/mL. HBsAg clearance rate (%) Response rate (%) Extended Peginterferon Alfa-2a Therapy in Chinese Patients With HBeAg-Negative Chronic Hepatitis B Standard therapy group, 48wks Extended therapy group, 72 wks p=.54 p=.23* 1 9 8 7 6 5 4 3 2 1 EOT 68.4 9.5 24 wks 48 wks p=.27* 6.5 83.3 1 9 8 7 6 5 4 3 2 1 p=.118 EOT p=.17* p=.9* 1.5 33.3 24 wks 48 wks 1.5 35.7 1 9 8 7 6 5 4 3 2 1 p=.4* p=.13* p=.1* EOT 24 wks 48 wks Posttreatment Posttreatment Posttreatment Posttreatment Posttreatment Posttreatment Response rate was defined as HBsAg level less than 1, IU/ml and HBV DNA less than 2, IU/ml. Chen X, et al. J Med Virol. 214 ; 86: 175-1713.
Sustained Immune control (%) HBsAg levels at week 48 is associated with sustained immune control 1 year post-treatment 1 8 6 48-week (n=37) 8 96-week (n=35) 4 2 25 26 11 1 2/8 8/1 2/19 5/19 1/1 <1 1-75 >75 HBsAg levels at week 48 17 1/6 Sustained immune control: HBV DNA <2 IU/mL 1 year post-treatment Lampertico P, et al. EASL 2112, Poster 524
Combining HBsAg and HBV DNA decline for early identification of non-response Analysis of 12 HBeAg-negative patients with available HBV DNA and HBsAg levels (8% genotype D) WEEK 12 12 HBeAgpatients ANY HBsAg decline No N=54 Yes N=48 HBV DNA decline (copies/ml) <2 log N=2 2 log N=34 <2 log N=2 2 log N=28 Sustained response* /2 (%) 8/34 (24%) 5/2 (25%) 11/28 (39%) *HBV DNA <1, copies/ml and ALT normal 6 months post-treatment Rijckborst et al. Hepatology 21
Response-guided therapy using HBsAg levels in Peg- IFN-treated patients: to identify good responders HBeAg positive HBeAg negative Week 12-24: - HBsAg <15 IU/ml Week 12-24 : - 1% decline HBsAg 47-57% Positive Predictive Values Piratvisuth T, et al. Hepatol Int.211 Liaw et al. Hepatology 211 Marcellin et al, Hepatol Int 213 Lampertico et al. EASL 212
Response-guided therapy (RGT) in Peg-IFNtreated 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., Hepatology 213 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) Sonneveld et al. Hepatology 21 Piratvisuth et al. APASL 21 Liaw et al. Hepatology 211 Sonneveld et al., Hepatology 213 * 97-1% Negative Predictive Values Rijckborst et al. Hepatology 21 Rijckborst / Lampertico et al. J Hepatol 212
Maximizing PegIFN treatment response in HBeAg+ve CHB HBeAg+ve CHB qhbsag at 24 weeks 1,5 IU/mL 1,5-2, IU/mL 2, IU/mL and 57% HBeAg seroconversion 48 weeks of Peg-IFN treatment* If the patient fails to achieve HBeAg seroconversion at 48 weeks 35% HBeAg seroconversion Extend treatment to 72 weeks Combined with/switch to NAs NAs = nucleos(t)ide analogs; qhbsag = quantified HBsAg.
Maximizing PegIFN treatment response in HBeAg-ve CHB HBeAg-ve CHB qhbsag at 24 weeks Decline >1 log IU/mL 43% SIC Decline < 1 log IU/mL 13% SIC qhbsag at 48 weeks < 1 IU/mL 48 weeks of Peg-IFN treatment* >1-1 IU/mL Extend treatment to72-96 weeks >75 IU/mL Switch to NAs Combined with/switch to NAs SR 88% SR 8%
To improve sustained off-therapy response with combination therapy
Long-term NAs therapy can not enhance durability of HBeAg loss/seroconversion Retrospectively study:57 patients who exhibited HBeAg loss/serocon-version by NAs(37 with lamivudine 1 mg /day and 2 with entecavir.5mg /day) and stopped the therapy after additional treatment Even more than 2 years additional therapy of lamivudine did not have the advantage in post-treatment relapse in the later periods of followup about 1-2 years additional therapy of entecavir might not be helpful in reducing post-treatment relapse >12 months <12 months Post-treatment relapse was defined as the reappearance of serum HBV DNA, and/or HBeAg in two consecutive tests Park Y,et al.apasl 214.Abstract 134.
Improved serological response by additional PegIFN in NAs treated CHB NA treated CHB HBV DNA <1, cps/ml Obvious decline of HBsAg 16 pts 5 ve+ Additional PegIFN NA 48 wks * 16 pts 6 ve+ NA 48 wks 1 8 75% 6 5% 4 31.3% 2 % % Continuous HBsAg decline HBeAg seroconversion HBsAg < 1 IU/mL Wu Z. et al. AASLD 212.
Sequential therapy with entecavir and PegIFN in CHB with high HBV DNA Induction ETV.5 mg/day 12 weeks Association ETV.5 mg/day + PEG-IFN alfa-2a 18 μg/week 12 weeks Maintenance PEG-IFN alfa-2a 18 μg/week 36 weeks Stopping rule at 12 weeks of PEG-IFN <.5 Log qhbsag decline and < 2 Log HBV DNA decline ETV alone Boglione L. et al. J Viral Hepatitis 213; 2; e11-19.
1 9 8 7 6 5 4 3 2 1 Sequential therapy with entecavir and PegIFN in CHB with high HBV DNA % 2 6% 1% 2 2 8% 3% 2 76.9% 15% csvr psvr HBeAg seroconversion Sequential 13 11 2 PegIFN monotherapy (history control) 2% HBsAg seroconversion csvr: complete sustained virological response, HBV DNA < 2 IU/mL 24 week after EOT psvr: partial SVR, HBV DNA <2, IU/mL and ALT normalization 24 weeks after EOT % Boglione L. et al. J Viral Hepatitis 213; 2; e11-19.
OSST Study, 2 Chineses HBeAg-positive CHB HBV DNA 1 3 copies/ml HBeAg <1 PEIU/mL ETV.5 mg QD (N=2) ~ 9 36 months Switch to Peg-IFNα-2a 18 μg/week for 48 weeks ETV.5 mg QD for 8 weeks (n=1) ETV.5 mg QD for 48 weeks (n=1) 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 212; 56 (Suppl.1): 35 88A.
Patients (%) HBsAg < 1,5 IU/mL at baseline is a predictor of HBeAg seroconversion at Week 48 HBeAg seroconversion HBsAg loss 35% 3% 33.3 P =.153 P =.113 25% 2% P =.6197 16.7 22.2 P =.22 16.7 15% 1% 5% % 1.3 5.9 6/9 2/34 2/12 3/29 4/18. 3.4 2/12 1/29 HBeAg-ve HBeAg+ve HBeAg-ve HBeAg+ve Baseline HBeAg status while patients on ETV BaselineHBsAg < 15 IU/mL Baseline HBsAg >15 IU/mL Ning Q, et al. Hepatology 214.
PegIFN and Tenofovir therapy in CH-B 74 patients 6% were HBeAg positive genotype C 43%, B 28%, D 21% Tenofovir + PegIFN for 48 week TDF+ PegIFN 16 weeks TDF til 48 weeks TDF monotherapy 12 weeks PegIFN monotherapy 48 weeks Marcellin P et al. AASLD 214.
HBeAg loss (%) HBeAg loss at EOT and 24 weeks post therapy 1 8 Week 48 Week 72 6 4 2 25.9% 29.6% 2% 24.8% 25.5% 13.2% 8.3% 12.8% TDF + Peg IFN 48 wk TDF + Peg IFN 16 wk combo Peg IFN 48 wk TDF mono Marcellin P et al. AASLD 214.
HBsAg loss (%) HBsAg loss at EOT and 24 weeks post therapy 3 TDF + PegIFN 48 week TDF + PegIFN 16 week TDF PegIFN 48 week TDF monotherapy 2 1 7.3 9. 2.8 2.8 2.8 2.8 Week 48 Week 72 Marcellin P et al. AASLD 214.
Extended treatment with PegIFN -2a (135 g) in combination with LAM or ADV for 96 wks in HBeAg-ve+ CHB 1 9 8 7 6 5 4 3 2 1 (%) 46.8 8.5 6.4 74.5 72.3 25.5 27.7 21.3 48 weeks 96 weeks 12 weeks HBeAg seroconversion HBsAg seroclearance HBsAg seroconversion 27.7 CAO ZH. et al. J Digestive Dis. 213; 14: 446-5.
96-week Peg-IFN -2a (135 g) with lamivudine or adefovir therapy in HBeAg positive CHB 1 9 % HBeAg seroconversion HBsAg seroclearance HBsAg seroconversion 8 7 75 7.8 73.9 73.9 6 5 4 3 2 1 5 43.5 33.3 29 33.3 25 21.7 21.7 21.7 17.4 12.5 8.3 4.3 4.3 48 weeks 96 weeks 12 weeks 48 weeks 96 weeks 12 weeks PegIFN + LAM (n = 24) PegIFN + ADV (n = 23) CAO ZH. et al. J Digestive Dis. 213; 14: 446-5.
Conclusions Finite duration of Peginterferon treatment is one of the first line therapy for chronic hepatitis B Currently, response guided-therapy through baseline and ontreatment predictors for maximizing sustained response is reasonably recommended PegIFN and NA combination may be a promising treatment strategy for improving sustained off-therapy response. However, further study to identify the optimal strategy is essential
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