Mutazioni di HBV in corso di trattamento; quale approccio razionale?

Transcription

1 Mutazioni di HBV in corso di trattamento; quale approccio razionale? Prevenire Interpretare Trattare Marco Lagget UODU Gastroenterologia ed Epatologia AOU San Giovanni Battista di Torino

2 Prevenire 1) Timing

3 Indication to Treatment is an Integrated Decision LIVER DISEASE STAGE HBVDNA LEVELS INDICATION TO TREATMENT PATIENT PROFILE PREVENTION OF HBV DRUGS RESISTANCE EASL 2009, Stresa 1-2

4 EASL Stresa 1

5 Preventire: 2) strategie terapeutiche Short-term: trattamento curativo IFN (S2)/ NUC (S3) Follow-up (mesi/anni) Risposta Durante il trattamento Anti-HBe+ HBV DNA < 2000 UI/ml ALT < UNL Portatore inattivo (PCI) Perdita HBsAg NUC (s) Long-term: trattamento soppressivo HBV DNA < 200 UI/ml Prtatore inattivo (PCI) Perdita HBsAg Anni

6 Prevenire: 3) scelta del farmaco Nucleoside analogue - Lamivudine - Entecavir - Telbivudine - Emtricitabine Trade name Company Dosage * 2007 ZEFFIX 100 mg/die 89 BARACLUDE 0.5mg/1mg/die 670 SEBIVO* 600 mg/die 693 EMTRIVA ^ 200 mg/die 266 Nucleotide analogue - Adefovir Dipivoxil HEPSERA 10 mg/die Tenofovir Disopr. Fum. VIREAD 300 mg/die 415 Nucleoside+nucleotide analogue - Emtricitabine + TRUVADA ^ 200 mg+ 713 Tenofovir Disopr. Fum. 300 mg/die ^ Drug approved for HIV *

7 HBeAg-Positive naive Patients 48 weeks HBe seroconversion Undetectable HBV DNA Normal ALT 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 30% 22% 12% 22% 26% 21% 25% 39% 21% 67% 60% 74% 39% 66% 48% 68% 77% 69% 0% PEG-IFN LAM ADV ETV LdT TDF PEG-IFN LAM ADV ETV LdT TDF PEG-IFN LAM ADV ETV LdT TDF EASL 2009

8 Dec Mean HBV DNA: 8.64 (TNF) vs 8.88 (ADV) Logs Jan Mean HBV DNA: (ETV) vs 9.88 (ADV) Logs 76% 58%

9 Entecavir

10 ( LAM ) HBeAg seroconversion: 31% (ETV) vs 26%

11 Entecavir Risposta in pazienti HBeAg+ ( anni (naïve, 5 ETV-022 HBeAg(+) ETV Long-term Cohort (ETV-022 ETV-901) Proportion of Patients (%) HBV DNA <300 copies/ml Year 1 67% Year 1 55% Year 2 83% Year 3 89% Year 4 91% Year 5 94% 0 n = 236/354 80/ / /131 98/108 88/94 a a 5 patients who remained on treatment at the Year 5 visit had missing PCR values (NC=M) Han, AASLD 2008

12 HBV DNA suppression HBeAg(+) ETV Long-term Cohort (ETV-022 ETV-901) Mean HBV DNA (log 10 copies/ml) copies/ml HBV DNA Suppression 0 0 Year 1 Year 2 Year 3 Year 4 Year 5 n = a a 5 patients who remained on treatment at the Year 5 visit had missing PCR values (NC=M) Han, AASLD 2008

13 Resistance Analysis One (0.7%) of the 146 patients in this cohort had ETV resistance (Year 3). This patient also experienced virologic breakthrough Among the 47 patients who discontinued ETV prior to the Year 5 visit, 10 patients (7%) had HBV DNA 300 copies/ml at the last on-treatment measurement Genotypic analysis showed that none had evidence of genotypic ETVr Safety Good, no renal disfunction Han, AASLD 2008

14 Lactic acidosis (LA) and NUC

15 HBeAg-Negative naive Patients 48 weeks Undetectable HBV DNA Normal ALT 100% 90% 80% 70% 60% 50% 40% 63% 72% 51% 90% 92% 88% 38% 78% 77% 74% 72% 74% 30% 20% 10% 0% PEG-IFN LAM ADV ETV LdT TDF PEG-IFN LAM ADV ETV LdT TDF EASL 2009

16 3-yr ETV in HBeAg-negative Re-Treatment cohort Virological response ETV-027 ETV-901 Proportion of patients (%) HBV DNA <300 copies/ml % Off-treatment >60 days 93% 94% 95% 91% 83% 59% 4% EOD Baseline Wk 12 Wk 24 Wk 48 Wk 72 Wk 96 Wk 144 n= 93/99 4/99 56/95 79/95 84/90 72/77 67/74 54/57 EOD= end-of-dosing 10 patients who remained on treatment at the Week 144 of ETV-901 visit had missing PCR samples Shouval, AASLD 2008

17 Tenofovir

18 2:1 RCTs HBeAg + (176 pts-5 LAM exp) and (250 pts-43 LAM exp) TNF vs HBeAg + (90 pts-1 LAM exp) and (125 pts-23 LAM exp) ADV for 48 weeks HBV DNA negative (< 400 cps/ml/69 IU/mL) Assay: TaqMan cut-off 29 IU/mL HBeAg+ 76% TNF and 13% ADV HBeAg- 93% TNF and 63% ADV (P<0.001) Mean HBV DNA HBeAg LOG Mean HBV DNA HBeAg LOG

19 Two Years Tenofovir Disoproxil Fumarate (TDF) Treatment and Adefovir Dipivoxil (ADV) (ITT) Switch Data in HBeAg+ (Heathcote J) and anti-hbe+ (Marcellin ( P Three years (HBeAg+ and anti-hbe+ ITT 81%; OTA 97%), Lee, AASLD 2009 D o u b l e B li n d Y e a r 1 O p e n - l a b e l Y e a r 2 Y e a r 8 RANDOMIZATION 2:1 T e n o f o v i r m g A d e f o v i r 1 0 m g T e n o f o v i r m g T e n o f o v i r m g P r e - t r e a t m e n t L i v e r B i o p s y W e e k 4 8 L i v e r B i o p s y W e e k 7 2 * W e e k 9 6 W e e k Patients With HBV DNA <400 copies/ml (95% CI) (ITT) Patients with HBV DNA <400 copies/ml (95% CI) (ITT) 100 TDF-TDF ADV-TDF Percentage (%) n= n= Randomized Double Blind Open Label Weeks in Study % 78% P=0.801 Percentage (%) Randomized Double Blind Weeks on Study Open Label TDF-TDF N= ADV-TDF N= % P= % 18% LAM Exp: 93% 96% Heathcote J, AASLD 2008 Marcellin, P, AASLD 2008

20 Resistance Surveillance Results No resistance up to 2 years of TDF mono-therapy No HBV pol/rt amino acid substitutions associated with TDF resistance were detected through 96 weeks of TDF monotherapy Safety Good, no renal disfunction

21 Prevenzione: 4) aderenza ai criteri di risposta Primary non-response Less than 1 log 10 IU/mL decrease in HBV DNA level from baseline at 3 months of therapy Virological response Partial virological response Virological breakthrough Undetectable HBV DNA by real-time PCR assay (<10-15 IU/mL) within 48 weeks of therapy Decrease of HBV DNA of more than 1 log 10 IU/mL but detectable HBV DNA by real-time PCR at 24 or 48 weeks of therapy (according to drug potency and genetic barrier to ( resistance Confirmed increase in HBV DNA level of more than 1 log 10 IU/mL compared to the nadir HBV resistance to NUCs Selection of HBV variants with amino acid substitutions that confer reduced ( NUC(s susceptibility to the administered EASL 2009

22 Partial virologic response to NUCs (%) and risk of resistance Resistance rate % LdT LAM 39% ADV 49% % 1% 6% 13% 7% 25% 20% % 0 <QL QL-3 log 3-4 log >4 log 0 <3 log >3 log HBV DNA at week 24 HBV DNA at week 48 Lai et al AASLD 2005 Hadziyannis et al, Gastroenterology 2006

23 Terapia di prima linea con analoghi nucleos(t)idici ( PVR ) Risposta virologica parziale settimane 48 settimane * 16% 72w ^ 22% 72w * 6% 72w ^ 1-9 % 72w HBeAg+ HBeAg+ % PVR % Anti-HBe+ 87% Anti-HBe+ 69% 20% 29% 33*% 24^% 37% 10*% 8^% LDT LAM ADV ETV TNF

24 Prevenzione: 4) aderenza ai criteri di risposta Primary non-response Less than 1 log 10 IU/mL decrease in HBV DNA level from baseline at 3 months of therapy Virological response Partial virological response Virological breakthrough Undetectable HBV DNA by real-time PCR assay (<10-15 IU/mL) within 48 weeks of therapy Decrease of HBV DNA of more than 1 log 10 IU/mL but detectable HBV DNA by real-time PCR at 24 or 48 weeks of therapy (according to drug potency and genetic barrier to ( resistance Confirmed increase in HBV DNA level of more than 1 log 10 IU/mL compared to the nadir HBV resistance to NUCs Selection of HBV variants with amino acid substitutions that confer reduced ( NUC(s susceptibility to the administered EASL 2009

25 Cumulative Incidence of HBV Resistance in naive patients 100% 90% Year 1 Year 2 80% 70% 70% 67% Year 3 Year 4 Year 5 60% 50% 49% 40% 38% 30% 20% 24% 18% 29% 22% 10% 0% LAM 3% 0% 11% ADV 0.5% 1.2% 4% 0.2% 1.2% 1.2% 0% ETV LdT TDF EASL 2009

26 Long-Term Treatment with NUCs suppressive strategy Indicated in HBeAg-positive patients who achieve an HBe seroconversion did not HBeAg-negative patients The most potent drugs with the optimal resistance profile should be used as first-line monotherapies: Tenofovir Entecavir EASL 2009

27 Interpretare Keefee, J Vir Hep 2009 Marzano, 2007

28 Trattare la resistenza: Switch-to o Add-on

29 Add-on vs switch-to strategy ( 3y ) in 588 e-chb LAM-R patients 100 % Patients with HBV DNA < 3 log cp/ml % P< % 0 ADV mono ADV+LAM Lampertico & Marzano, AASLD 2006

30 Add-on vs. switch-to strategy ( Logs in 42 LAM-R patients (HBV DNA > 5 % Patients with HBV DNA < 3 log cp/ml % ADV mono ( 21 ) P< % ADV+LAM (21) Gaia & Marzano, J Hepatol 2008

31 Add-on versus switch-to ADV in ( resistance LAM-R HBeAg- CHB (ADV Patients with ADV-R (%) A randomized controlled study 30% ADV mono (n=265) P<0.05 6% ADV+LAM (n=272) Lampertico & Marzano AASLD 2006

32 Lamivudine-Refractory Cohort (HBeAg+): Cumulative Probability of ETV Resistance Through 5 Years 100% ETVr = LVDr (M204V ± L180M) + T184, S202 and/or M250 substitutions ETVr + Virologic Breakthrough ( 1( 1 log increase from nadir) Cumulative Probability (%) 75% 50% 25% 0% Years N= N= N= N= N=33 72/187 (39%) achieved HBV DNA < 300 c/ml; 3/72 (4%) had subsequent genotypic ETV resistance

33

34 Detection of Mutations Associated With Resistance to Nucleos(t)ide Analogues in Patients With HBV Infection During Treatment With Tenofovir P r o b a b ilit y o f A c h ie v in g H B V D N A le v e ls < c o p ie s /m L w it h T e n o f o v ir M o n o t h e r a p y in H B V - m o n o in fe c t e d P a tie n t s A c c o r d in g t o t h e P r e s e n c e o f R e s is t a n t V a r ia n ts P < P a tie n ts u n d e r o b s e r v a tio n m o n th s W t L V D -R A D V -R K a p la n -M e ie r A n a ly s is ; P < , lo g ra n k. W t: w ild ty p e ; L V D : la m iv u d in e ; A D V : a d e fo v ir d ip iv o x il Van Bommel, AASLD 2008

35 Add-on strategy 3-4 yrs ADV+LAM treatment in 145 LAM-R pts: virological response and ADV resistance Years of treatment (1) Virologicalresponse (n=145) (n=112) (n=78) (n=39) HBV-DNA <35 cp/ml (2) 86 (61%) 78 (70%) 62 (79%) 32 (82%) Virologic breakthrough (3) Genotypic ADV-R (4) rta181t (5) 1 (0.7%) 1 (0.9%) 1 (1.3%) 0 (1) Median follow-up: 42 months (range 12-76) (2) TaqMan real time PCR assay, LLQ: 1.5 log copies/ml (3) > 1 log HBV-DNA compared to on treatment nadir, tested every 3 months (4) rtn236t and rta181v by INNOLiPA V2 assay (5) as a mixed viral population with rta181a Lampertico et al, Gastroenterology 2007

36 Early vs late treatment in LAM-R patients Cumulative virologic response by baseline viremia in 52 subjects 1,0 < 4 log HBV DNA %,8 4-5 log HBV DNA >5 log HBV DNA p<0,05 p< 0,0001,6,4,2 0, Months Uni and Multivariate analysis: Basal HBV DNA load ( p<0.001,rr3.8,ci 95% ) and HBeAg+ (p<0.01, RR 3.6, CI 95% status ) predicted VR. Basal ALT, age, sex, serum creatinine, stage of disease, therapeutic strategies: did not predict VR at univariate analysis. Gaia & Marzano, J Hepatol 2008

37 In vitro Tenofovir sensitivity of HBV populations from clinical specimens containing rta181t/v and or rt236t The presence of 50% of rta181t/v and/or N236T mutations did not have an impact of TNF susceptibility in an in vitro phenotypic assay ( 434 ) Kitrinos Km et al., AASLD 2009

38 Management of HBV Resistance Lamivudine resistance Add tenofovir Telbivudine resistance Add tenofovir* Entecavir resistance Adefovir resistance Tenofovir resistance** Add tenofovir* Switch to tenofovir and add a second drug If N236T, add lamivudine, entecavir* or telbivudine* or switch to Truvada If A181V/T, add entecavir* or switch to Truvada Do genotyping and phenotyping in an expert lab to determine the cross-resistance profile Add entecavir*, telbivudine*, lamivudine or switch to Truvada Nucleoside Nucleotide *the long-term safety of these combinations is unknown **not seen so far EASL 2009

39 2010 and more.challenge Partial Virological Response and Resistance Check for compliance Resistance surveillance and knowledge Patients receiving lamivudine, adefovir or telbivudine with a partial virological response at week 24: Either change to a more potent drug (tenofovir or ( entecavir Or add a more potent drug that does not share crossresistance Patients receiving tenofovir or entecavir with a partial virological response at week 48: Add the other drug in order to prevent resistance in the long term