Mutazioni di HBV in corso di trattamento; quale approccio

Marco Lagget

UODU Gastroenterologia ed Epatologia AOU San Giovanni Battista di Torino

Mutazioni di HBV in corso di trattamento; quale approccio

razionale?

^Prevenire

Interpretare

Trattare

^Prevenire

1) Timing

Indication to Treatment is an Integrated Decision

LIVER DISEASE STAGE

PATIENT PROFILE

HBVDNA LEVELS

PREVENTION OF

HBV DRUGS RESISTANCE INDICATION

TO TREATMENT

EASL 2009, Stresa 1-2

EASL

Stresa 1

Anni

Anti-HBe+

HBV DNA < 2000 UI/ml ALT < UNL

Portatore inattivo (PCI)

Risposta

Durante il trattamento

Perdita HBsAg

Follow-up (mesi/anni)

IFN (S2)/ NUC (S3)

Long-term: trattamento “soppressivo”

HBV DNA < 200 UI/ml Prtatore inattivo (PCI)

NUC (s)

Perdita HBsAg

Short-term: trattamento “curativo”

Preventire: 2) strategie terapeutiche

Nucleoside analogue

Trade name Company Dosage €*

2007

- Lamivudine - Entecavir - Telbivudine - Emtricitabine

ZEFFIX

BARACLUDE SEBIVO*

EMTRIVA ^

100 mg/die 0.5mg/1mg/die

600 mg/die 200 mg/die

89 670 693 266

Nucleotide analogue

- Adefovir Dipivoxil

- Tenofovir Disopr. Fum.

HEPSERA VIREAD

10 mg/die 300 mg/die

705 415

Nucleoside+nucleotide analogue

- Emtricitabine + Tenofovir Disopr. Fum.

TRUVADA ^ 200 mg+

300 mg/die

713

Prevenire: 3) scelta del farmaco

^

*www.farmacieitaliane.it

HBeAg-Positive naive Patients 48 weeks

0%0%

10%10%

20%20%

30%

30%

40%

40%

50%50%

60%

60%

70%70%

80%80%

90%90%

100%100%

PEG

PEG--IFNIFN LAM LAM

ADV ADV

ETV ETV LdT

LdT TDF TDF

PEG

PEG--IFNIFN LAM LAM

ADV ADV

ETV ETV LdT

LdT TDF TDF

PEG

PEG-IFN-IFN LAM LAM

ADV ADV

ETV ETV LdT

LdT TDF TDF

HBeHBeseroconversionseroconversion Undetectable HBV DNAUndetectable HBV DNA Normal ALTNormal ALT

30%30%

22%

22%

12%

12%

22%22% 26%26%

21%

21% 25%25%

39%

39%

21%21%

67%67%

60%60%

74%74%

39%39%

66%

66%

48%48%

68%68%

77%

77%

69%

69%

EASL 2009

Dec. 2008 Jan. 2009

58%

Mean HBV DNA: 10.26 (ETV) vs 9.88 (ADV) Logs

76%

Mean HBV DNA: 8.64 (TNF) vs 8.88 (ADV) Logs

Entecavir

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

0 20 40 60 80 100

P ro p o rt io n o f P a ti e n ts ( % ) H B V D N A < 3 0 0 c o p ie s /m L

55%

Year 1

83%

Year 2

89%

Year 3

67%

n = 236/354

Year 4 91%

80/146 116/140 116/131 98/108

Year 5

88/94^a

94%

Year 1

ETV-022

a 5 patients who remained on treatment at the Year 5 visit had missing PCR values (NC=M)

Han, AASLD 2008

Entecavir

Risposta in pazienti HBeAg+

(naïve, 5 anni)‏‏‏‏

HBV DNA Suppression

0 2 4 6 8 10 12

0 Year 1 Year 2 Year 3 Year 4 Year 5

Mean HBV DNA (log 10copies/mL)

300 copies/mL

n = 146 146 140 131 108 94^a

a 5 patients who remained on treatment at the Year 5 visit had missing PCR values (NC=M)

HBeAg(+) ETV Long-term Cohort (ETV-022 ETV-901)

HBV DNA suppression

Han, AASLD 2008

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

Han, AASLD 2008

Good, no renal disfunction

Safety

Lactic acidosis (LA) and NUC

HBeAg-Negative naive Patients 48 weeks

0%0%

10%10%

20%20%

30%

30%

40%

40%

50%50%

60%

60%

70%70%

80%80%

90%90%

100%100%

PEG

PEG--IFNIFN LAM LAM

ADV ADV

ETV ETV LdT

LdT TDF TDF

PEG

PEG--IFNIFN LAM LAM

ADV ADV

ETV ETV LdT

LdT TDF TDF

Undetectable HBV DNA

Undetectable HBV DNA Normal ALTNormal ALT

63%63%

72%72%

51%

51%

90%90% 88%88% 92%92%

38%

38%

74%

74% 72%72%

78%78%

74%74% 77%77%

EASL 2009

3-yr ETV in HBeAg-negative Re-Treatment cohort Virological response

n= 93/99 4/99 56/95 79/95 84/90 72/77 67/74 54/57^‡ EOD^† Baseline Wk 12 Wk 24 Wk 48 Wk 72 Wk 96 Wk 144

ETV-027 ETV-901

Off-treatment >60 days

4%

59%

83%

93% 94%

91% 95%

94%

0 20 40 60 80 100

† 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

P ro p o rt io n o f p a ti e n ts ( % ) H B V D N A < 3 0 0 c o p ie s /m L

Tenofovir

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+ 8.64 LOG

Mean HBV DNA HBeAg- 6.86 LOG

RANDOMIZATION 2:1

T e n o f o v i r 3 0 0 m g

A d e f o v i r 1 0 m g

O p e n - l a b e l

W e e k 4 8 L i v e r B i o p s y P r e - t r e a t m e n t

L i v e r B i o p s y

D o u b l e B li n d

W e e k 9 6 T e n o f o v i r 3 0 0 m g

T e n o f o v i r 3 0 0 m g

Y e a r 2 Y e a r 1

W e e k 7 2* W e e k 3 8 4

Y e a r 8

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

Patients with HBV DNA <400 copies/mL (95% CI) (ITT)

Percentage (%)

0 10 20 30 40 50 60 70 80 90 100

Weeks on Study

0 8 16 24 32 40 48 56 64 72 80 88 96

89%

91% _P=0.672

Randomized Double Blind Open Label

18% LAM Exp:

93%

96%

250

TDF-TDF N= 250250 245245245 243243243 248248248 247247247 242242242 243243243 234234234 125

ADV-TDF N= 125125 125125125 124124124 120120120 123123123 123123123 122122122 122122122

Marcellin, P, AASLD 2008

0 8 16 24 32 40 48 56 64 72 80 88 96 0

10 20 30 40 50 60 70 80 90 100

Patients With HBV DNA <400 copies/mL (95% CI) (ITT)

Randomized Double Blind Open Label

165 86

78%

78%

164 87 168

89 171

90 172

88 170

88 174

89 176

90 TDF-TDF

ADV-TDF n=

n=

P=0.801

Weeks in Study

Percentage (%)

Heathcote J, AASLD 2008

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

Prevenzione: 4) aderenza ai criteri di risposta

Primary non-response

Virological response

Undetectable HBV DNA by real-time PCR assay (<10-15 IU/mL) within 48 weeks of therapy

Partial virological response

Decrease of HBV DNA of more than 1 log₁₀ 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)‏‏‏‏

Virological breakthrough

HBV resistance to NUCs

Selection of HBV variants with amino acid substitutions that confer reduced susceptibility to the administered NUC(s)‏‏‏‏

EASL 2009

0 00 0 5 55 5 10 1010 10 151515 15 20 2020 20 252525 25 30 3030 30 35 3535 35 404040 40

<QL

<QL<QL

<QL QL-3 logQL-3 logQL-3 logQL-3 log 3-4 log3-4 log3-4 log3-4 log >4 log>4 log>4 log>4 log LdT

LdT LdT

LdT LAMLAMLAMLAM

00 00 1010 1010 2020 2020 30 30 30 30 40 40 40 40 50 50 50 50

<3 log

<3 log

<3 log

<3 log >3 log>3 log>3 log>3 log ADV

ADVADV ADV

Partial virologic response to NUCs and risk of resistance (%)‏‏‏‏

6%

49%

39%

0% 1%

6%

13%

7%

25%

20%

HBV DNA at week 24 HBV DNA at week 48

Lai et al AASLD 2005 Hadziyannis et al, Gastroenterology 2006 Resistance rate %

Terapia di prima linea

con analoghi nucleos(t)idici

Risposta virologica parziale (PVR)‏‏‏‏

24 settimane

48 settimane

HBeAg+

Anti-HBe+

56%

20%

69%

29% 37%

10*% 8^%

87%

33*% 24^%

LDT LAM ADV ETV TNF

% P V R

100

50

0

HBeAg+

Anti-HBe+

* 6% 72w ^ 1-9 % 72w

^ 22% 72w

* 16% 72w

Prevenzione: 4) aderenza ai criteri di risposta

Primary non-response

Virological response

Undetectable HBV DNA by real-time PCR assay (<10-15 IU/mL) within 48 weeks of therapy

Partial virological response

Decrease of HBV DNA of more than 1 log₁₀ 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)‏‏‏‏

Virological breakthrough

HBV resistance to NUCs

Selection of HBV variants with amino acid substitutions that confer reduced susceptibility to the administered NUC(s)‏‏‏‏

EASL 2009

Cumulative Incidence

of HBV Resistance in naive patients

10%10%

20%20%

30%30%

40%40%

50%50%

60%60%

70%70%

80%80%

90%90%

100%100%

24%

24%

38%

38%

49%49%

67%

67%

70%

70%

0%0%

3%3%

11%

11%

18%18%

29%

29%

0.5%0.5%

1.2%1.2%

1.2%1.2%

1.2%1.2%

4%

4%

22%22%

0%0%

LAMLAM ADVADV ETVETV LdTLdT TDFTDF

0.2%

0.2% 0%0%

Year 1 Year 1 Year 2 Year 2 Year 3 Year 3 Year 4 Year 4 Year 5 Year 5

EASL 2009

Long-Term Treatment with NUCs

suppressive strategy

 Indicated in

• HBeAg-positive patients who did not achieve an HBe seroconversion

• HBeAg-negative patients

 The most potent drugs with the optimal resistance profile should be used as first-line monotherapies:

• Tenofovir

• Entecavir

EASL 2009

Interpretare

Keefee, J Vir Hep 2009

Marzano, 2007

Trattare la resistenza:

Switch-to o Add-on

Add-on vs switch-to strategy in 588 e-CHB LAM-R patients (3y)‏‏‏‏

0 20 40 60 80 100

ADV+LAM ADV mono

% P a ti e n ts w it h H B V D N A < 3 l o g c p /m l

59%

74%

P<0.001

Lampertico & Marzano, AASLD 2006

Add-on vs. switch-to strategy

in 42 LAM-R patients (HBV DNA > 5 Logs)‏‏‏‏

0 20 40 60 80 100

ADV+LAM (21) ADV mono

(21)‏‏‏‏

% P a ti e n ts w it h H B V D N A < 3 l o g c p /m l

38%

81%

P<0.05

Gaia & Marzano, J Hepatol 2008

0 5 10 15 20 25 30 35 40

ADV mono (n=265)

ADV+LAM (n=272)
30%

6%

Patients with ADV-R

(%)

P<0.05 A randomized controlled study

Add-on versus switch-to ADV in LAM-R HBeAg- CHB (ADV resistance)‏‏‏‏

Lampertico & Marzano AASLD 2006

Lamivudine-Refractory Cohort (HBeAg+): Cumulative Probability of ETV Resistance Through 5 Years

C u m u la ti v e P ro b a b il it y ( % )

1

N=187

2 2

N=146 N=146

3 3

N=80 N=80

4 4

N=53 N=53

0%

25%

50%

75%

100%

6 1

41

11

27 15

36

46

5 5

N=33 N=33

43 51

Years Years

• 72/187 (39%) achieved HBV DNA < 300 c/mL;

• 3/72 (4%) had subsequent genotypic ETV resistance

ETVrETVr == LVDrLVDr (M204V ±(M204V ± L180M) + T184, S202 and/or M250 substitutionsL180M) + T184, S202 and/or M250 substitutions ETVrETVr + Virologic Breakthrough (≥+ Virologic Breakthrough (≥1 log increase from nadir)1 log increase from nadir)

Detection of Mutations Associated With Resistance to Nucleos(t)ide Analogues in Patients With HBV Infection During Treatment With

Tenofovir

Van Bommel, AASLD 2008

P r o b a b i li t y o f A c h i e v i n g H B V D N A l e v e l s < 4 0 0 c o p i e s / m L w i t h T e n o f o v i r M o n o t h e r a p y i n H B V - m o n o i n f e c t e d

P a t i e n t s A c c o r d i n g t o t h e P r e s e n c e o f R e s i s t a n t V a r i a n t s

0 6 1 2 1 8 2 4

W t L V D - R A D V - R

2 0 2 2 6

1 7 1 8 6

1 5 1 2 5

1 0 9 4 2 0

2 2 6

m o n t h s 0 . 0

0 . 2 0 . 4 0 . 6 0 . 8 1 . 0

P < 0 .0 0 0 1

P a t i e n t s u n d e r o b s e r v a t i o n

K a p la n - M e ie r A n a ly s is ; P < 0 .0 0 0 1 , lo g r a n k . W t: w ild t y 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

Years of treatment ⁽¹⁾

Virologicalresponse 1 2 3 4

(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⁾ 0 0 0 0

Genotypic ADV-R ⁽⁴⁾ 0 0 0 0

rtA181T⁽⁵⁾ 1 (0.7%) 1 (0.9%) 1 (1.3%) 0

Lampertico et al, Gastroenterology 2007

(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

Add-on strategy

3-4 yrs ADV+LAM treatment in 145 LAM-R pts:

virological response and ADV resistance

16 12

8 4

0 1,0

,8

,6

,4

,2

0,0

%

Months

p< 0,0001 p<0,05

>5 log HBV DNA 4-5 log HBV DNA

< 4 log HBV DNA

Early vs late treatment in LAM-R patients

Cumulative virologic response by baseline viremia in 52 subjects

Uni and Multivariate analysis:

Basal HBV DNA load ( p<0.001,RR3.8,CI 95% 1.7-8.6) and HBeAg+ (p<0.01, RR 3.6, CI 95% status 1.2-10.6) 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

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

Kitrinos Km et al., AASLD 2009 (434)‏

Management of HBV Resistance

Lamivudine resistance _ Add tenofovir

Telbivudine resistance _ Add tenofovir*

Entecavir resistance _ Add tenofovir*

Adefovir resistance

 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

Tenofovir resistance**

 Do genotyping and phenotyping in an expert lab to determine the cross-resistance profile

 Add entecavir*, telbivudine*, lamivudine or switch to Truvada

*the long-term safety of these combinations is unknown

**not seen so far

EASL 2009

Nucleoside Nucleotide

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 cross- resistance

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