Is there a need for combination treatment? Yes!

Transcription

1 C Hep Meeting Berlin Is there a need for combination treatment? Yes! Florian van Bömmel University Hospital Leipzig Hepatology Section Germany

2 Most patients respond to monotherapy with entecavir or tenofovir

3 - however, response can be decreased by HBV resistance OptiB Response to TDF monotherapy by baseline ADV resistance Patients % 100 ADV Rs SORs* 80 67% 61% 60 55% 55% 45% 40 37% 27% 20 p<0.05 NS 85% 81% 94% 0 0% Baseline All Patients ADV Rs SORs Weeks Levrero M, et al. EASL 2011; Poster #732. *suboptimal responders

4 Background: Currently available HBV polymerase inhibitors and HBV resistance mutations EASL Clinical Practice Guideline CHB. J Hepatol. 2009;50: HBV variant Resistant against Lamivudin Telbivudin Entecavir Adefovir Tenofovir Wildtyp S S S S S M204I R R I S S L180M + M204V R R I S S A181T/V I S S R S N236T S S S R I L180M + M204V/I ± I169T ± V173L ± M250V L180M + M204V/I ± T184G ± S202I/G R R R S S R R R S S EASL Clinical Practice Guideline CHB. J Hepatol. 2009;50:

5 Efficacy of TDF monotherapy against different resistance mutations HBV DNA < 400 cop/ml p< months patients under observation (n): ADV resistance LAM resistance ADV=adefovir dipivoxil LAM=lamivudine no genotypic resistance van Bömmel et al., Hepatology 2010

6 Response to ETV monotherapy in patients with resistance to ADV 100 ADV naive ADV experienced without development of ADV resistance ADV experienced with ADV resistant mutations at baseline % Cumulated response P = NS Nucleos(t)ide naive patients n=104 Patients previously treated with ADV n=42 Median duration (months) 19 [2 55] Treatment month Reijnders J et al. J Hepatol 2010

7 Why combination treatment? combination treatment may be needed in patients with drug resistance and incomplete response to monotherapy

8 What about pretreated patients with incomplete response to second/third line treatment?

9 Response to third line entecavir monotherapy in patients with previous failure to lamivudine and adefovir treatment Entecavir 1 mg/day Herber A, et al. DGVS 2011

10 Incomplete response to TDF monotherapy acording to baseline adefovir resistance mutations an Australian perspective Patterson S J et al. Gut 2011;60:

11 HBV DNA level and incidence of HCC R.E.V.E.A.L. HBV Study Chen et al; JAMA 2006

12 Combination treatment can be effective to induce complete response in patients with residual viremia Patients with HBV DNA > 400 cp/ml (n=9) TDF 245 mg monotherapy ADV resistance (N236T or/and A181T/V) at start of TDF HBV wildtype at start of TDF HBV DNA log 10 copies/ml lower limit of detection TDF 245 mg + lamivudine 100 mg months of treatment van Bömmel et al., AASLD 2009

13 Why combination treatment? Combination of nucleos(t)die analogues is safe and effective, also in patients with advanced fibrosis

14 Combination treatment is safe and effective

15 Petersen J et al JHepatol;56:

16 Petersen J et al JHepatol;56:

17 Probability of HBV DNA Below LLoD (<80 IU/ml) Petersen, J et al Jhepatol;56:

18 ETV 110: Study Design Dosing x 100 weeks ETV 0.5 mg, once daily (N = 182) * ETV 0.5 mg + TDF 300 mg, once daily (N = 197) * Further anti-hbv therapy at discretion of investigator up to 24 weeks follow-up Baseline Week 96 Primary endpoint Randomized, open-label, Phase IIIb trial NA-naïve CHB, HBeAg(-) patients capped at 30% *Modified intent-to-treat (ITT) population: received at least one dose of study medication Lok, AS, et al. AASLD 2011; Oral #223.

19 HBV DNA <50 IU/mL at Week 96 in HBeAg(+) Patients: By Baseline HBV DNA Stratum Difference 16.8% (95% CI 2.9, 30.7) All HBeAg(+) B/L HBV DNA B/L HBV DNA <10 8 IU/mL 10 8 IU/mL Number of patients: Lok, AS, et al. AASLD 2011; Oral # Non-completer = failure

20 Why combination treatment? combination treatment with NUCs and pegylated interferon alpha may increase the rate of HBsAg loss

21 10.8% HBsAg loss after 4 years of tenofovir: cumulative probability Study HBeAg+ve patients 10.8% Cumulative probability* function estimate N= Adapted from Heathcote EJ, et al. AASLD 2010; Poster #477. TDF-TDF Weeks Cumulative probability* of seroconversion to anti-hbs: 7.7% *Kaplan-Meier

22 Rapid and continuous decline of HBsAg observed in patients with HBsAg loss: Study 103 HBeAg+ve: HBsAg loss vs. NO loss Median HBsAg (lu/ml) 1,000, ,000 10,000 1, No HBsAg Loss: Genotype A Genotype B HBsAg Loss: Genotype A Genotype B Genotype C Genotype D Genotype D TDF-TDF arm Weeks 1. Adapted from Marcellin P, et al. EASL 2011; Poster #740.

23 OSST-Study: Add-On PegIFN may reduce HBsAg in NUC responders Q. Ning et al., AASLD 2011

24 Q. Ning et al., AASLD 2011

25 OSST-Study: Serologic Response Q. Ning et al., AASLD 2011

26 OSST-Study: Serologic Response Q. Ning et al., AASLD 2011

27 OSST-Study: Reduktion of HBsAg levels Q. Ning et al., AASLD 2011

28 Why combination treatment? not big evidence, but: are there pathogenic HBV variante beeing selected during treatment? Can combination treatment possibly prevent selection of pathogenic HBV variants?

29 Resistance mutations may become increasingly selected although HBV replication decreases a) 8 TDF TDF + LAM HBV DNA log 10 copies/ml lower limit of detection months % HBV variants 50 WT N236T 0 A181T+N236T van Bömmel et al, Antiviral Therapy 2012

30 HBsAg mutations: selected by NUCs and cancerogenous? Tenofovir, Lamivudine, Adefovir, Telbivudine, Clevudine A181T Polymerase gene Reverse transcriptase Terminal Protein Spacer RNAse H G F A B C D E Surface gene PreS1 Pre S2 S W172* L M S Surface proteins Surface proteins X ER lumen/virion surface membrane Cytosol/virion interior Transactivation and HCC? Warner N, et al. Hepatology 2008

31 Truncated s antigens may accumulate in the hepatocytes HBVwt HBV172* 1:1 mixture of both. Surface proteins are shown as brown staining. Cell nuclei are stained in blue. Warner N, et al. Hepatology 2008

32 Pre S Mutations and Long Term Outcome 141 HBeAg negative patients Progression to Cirrhosis Followed up for at least 36 months Incidence of Pre S mutation at baseline 27/141 (19.1%) Chen et al, Gastroenterology 2007

33 Increased HCC risk in patients with prior LAM resistance Papatheodoridis GV et al, J Hepatol 2010

34 Conclusion Monotherapy with nucleos(t)ide analogues is safe and very effective in the majority of cases However, some patients with previous resistance to nucleos(t)ide analogues may show resistance or incomplete response to following treatments with nucleos(t)ide analogues and may require combination treatment (especially patients with cirrhosis/advanced fibrosis) Combination treatment with pegylated interferon may increase HbsAg loss rates in future treatment regimes (ongoing studies) It needs to be investigated if pathogenic HBV mutations can be selected by monotherapy with nucleos(t)ide analogues in multiresistant patients (not prooven! ongoing research)