therapy in chronic hepatitis B Dr Grace Lai-Hung Wong MBChB (Hons, - - PowerPoint PPT Presentation

New perspective of anti-viral therapy in chronic hepatitis B

Dr Grace Lai-Hung Wong

MBChB (Hons, CUHK), MD (CUHK), MRCP, FHKCP, FHKAM (Medicine)

Associate Professor Institute of Digestive Disease Department of Medicine and Therapeutics The Chinese University of Hong Kong

International Symposium on Hepatology 2012 & 25th Annual Scientific Meeting

What’s New?

Evolving treatment guidelines in Hepatitis B

2001 2005 2007 2004 2006 2008 2003 2000 2009 2011 2012

APASL AASLD KASL US Treatment Algorithm APASL AASLD US Treatment Algorithm APASL US Treatment Algorithm AASLD EASL APASL

APASL 2012 EASL 2012

EASL AASLD

APASL guideline 2012

Recommendation 5 - Which drug or strategy

• Nucleos(t)ide analogs (NA)-naïve patients can be treated with

IFNa (IB), Peg IFN (IA), ETV (IA), TDF (IA), ADV (IB), LdT (IB) or LAM (IB). Thymosin-a can also be used (IB).

• ETV or TDF is the preferred NA

Liaw et al. Hepatol Internat 2012

APASL 2012

ETV or TDF is the preferred NA

Because of the high antiviral potency, low resistance profile

Drug resistance of different NAs

Ayoub and Keeffe. Aliment Pharmacol Ther 2011

No data

Low genetic barrier High genetic barrier

0 0 up to 6 years

data from AASLD 2012

Long-term efficacy of entecavir in trial setting

Chang TT, et al. Hepatology 2010

* Five patients who remained on treatment at the Year 5 visit had missing PCR values (Non-completer = missing).

Proportion of patients with HBV DNA <300 copies/mL, %

55%

Year 1

83%

Year 2

89%

Year 3

67% 236/354

Year 4

91% 80/146 116/140 116/131 98/108

Year 5

88/94* 94%

Year 1 ETV-022

20 40 60 80 100

HBeAg(+) ETV long-term cohort (ETV-022ETV-901)

99 72 20 40 60 80 100 98 46 20 40 60 80 100

Long-term efficacy of entecavir in real-life setting

Week 48 viral load and 3-year outcomes

Maintained viral suppression at 3 years, %

HBeAg-positive (N = 160) HBeAg-negative (N = 280)

HBV DNA <20 IU/ml ≥ 20IU/ml at week 48

94/96

Wong GL, et al. Aliment Pharmacol Ther2012

30/64 226/228 37/52

<20 IU/ml ≥ 20 IU/ml

2 20 40 60 80 100 0/96 1/64

Entecavir resistance at 3 years, %

<20 IU/ml ≥ 20 IU/ml

20 40 60 80 100 0/228 0/52

<20 IU/ml ≥ 20 IU/ml HBV DNA at week 48 < 20 IU/ml achieved in 324/440 (74%) patients Only 1/116 (0.9%) developed drug resistance even HBV DNA at week 48 ≥ 20 IU/ml

Low resistance with entecavir in real-life cohorts

• 1. Buti M, et al. Eur J Gastroenterol Hepatol 2012. 2. Zoutendijk et al. Hepatology 2011.
• 3. Lampertico P, et al. Curr Hepatitis Rep 2012. 4. Wong GL, et al. Aliment Pharmacol Ther 2012.

No resistance has been observed up to 1 year (n = 190)

ORIENTE study1

No resistance has been documented up to 3 years (n = 333)

VIRGIL (naïve)2

One patient (0.2%) developed ETV resistance in 3 years (n = 440)

Hong Kong study4

One patient (0.2%) developed ETV resistance over 42 months (n = 418)

Italian cohort3

* Up to 7 years Range: 3–7 years Median time: 280 weeks1†

Chang TT, et al. Hepatology 2010

Liver fibrosis improved with long-term ETV

Ishak fibrosis score Missing 1 2 3 4 5 6 n=57

Patients, n

10 20 30 40 50 60

Baseline Week 48 Long term*

† In the randomized controlled studies, patients received 0.5 mg ETV. In the 901 rollover study, patients received 1 mg ETV.

Virologic response during ETV is not influenced by severity of liver disease

48 96 144 25 50 75 100 No cirrhosis n=274 Cirrhosis n=89 Decompensated cirrhosis n=9 P=0.62 Time (weeks) Patients with virologic response (%)

Zoutendijk R, et al. Gut 2012

Virologic response: HBV DNA <80 IU/mL

Virologic response is associated with a lower probability of disease progression

Remained significant when correcting for age or MELD score

48 96 144 10 20 30

No virologic response Virologic response (<80 IU/mL)

P=0.05 Hazard rate (HR): 0.29, 95% CI 0.08–1.00 Time at risk (weeks) Probability of event (%)

Zoutendijk R, et al. Gut 2012

Efficacy of 48 weeks ETV in LAM/LdT-experienced

HBeAg(–) patients

* Among patients with quantifiable HBV DNA or ALT test results at baseline and Week 48, con-completer = missing.

† The majority of patients who achieved HBV <50 IU/ml also achieved HBV DNA <12 IU/mL.

86 20 40 60 80 100 82 75 20 40 60 80 100 Proportion of patients (%) HBV DNA <50 IU/mL*

78/95 54/63

ALT <1xULN†

74/99

HBV DNA <12 IU/mL*

Hou JL, et al. APASL 2011

Efficacy of 48 weeks ETV in ADV-experienced patients

74 20 40 60 80 100 57 95 62 20 40 60 80 100 Proportion of patients, %

65/115 54/63

ALT <1xULN

85/138 20/21

HBV DNA <50 IU/mL HBeAg(+) HBeAg(–) All

16% of HBeAg(+) patients experienced HBeAg loss; 12% seroconverted

Hou JL, et al. APASL 2011

• ETV was analysed for 43 of 51 ADV-experienced (+LAM experienced in

29 [67%]) patients who were directly switched to ETV

• One (2.3%) patient experienced virological breakthrough and developed genotypic

ETV resistance

Long-term efficacy of ETV in ADV-experienced patients

Zoutendijk, et al. EASL 2011

Median ADV treatment duration was 18 (3–55) months. Adjusted estimated survival curve for the cumulative probability of achieving virological response. For ADV-naïve, ADV- experienced patients and ADV-resistant patients. Based on a Cox’s model for mean values of baseline HBV DNA, ALT, HBeAg status and previous LAM exposure and resistance.

Long-term efficacy of tenofovir in trial setting

Marcellin, P, et al. AASLD 2011; Oral #238

Pre-treatment Liver Biopsy

RANDOMIZATION

2:1

Tenofovir DF 300 mg N=250 & N=176 Adefovir Dipivoxil 10 mg N=125 & N=90 Year 1 Liver Biopsy1 Year 1 Week 72 Year 8 Year 8 Tenofovir DF 300 mg Tenofovir DF 300 mg Year 3 N=235 N=154 N=112 N=84 Year 5/ Week 240 Liver Biopsy

• At Week 72, patients with HBV DNA ≥ 400 copies/mL had the option at

the discretion of the investigator to add emtricitabine (FTC)

• Retention rate at Week 240: 81% for HBeAg-, 70% for HBeAg+

Study 102 (HBeAg- Patients) and 103 (HBeAg+ Patients)

Long-term efficacy of tenofovir in trial setting

Weeks on Study Proportion of Subjects (%)

0 8 16 24 32 40 48 56 64 72 80 88 96 108 120 132 144 156 168 180 192 204 216 228 240 100 90 80 70 60 50 40 30 20 10

TDF-TDF 99% ADV-TDF 99%

HBeAg-positive patients: On-Treatment

Marcellin et al. AASLD 2012

HBeAg-negative patients: On-Treatment

Proportion of Subjects (%)

0 8 16 24 32 40 48 56 64 72 80 88 96 108 120 132 144 156 168 180 192 204 216 228 240 100 90 80 70 60 50 40 30 20 10

Weeks on Study

TDF-TDF 100% ADV-TDF 96%

No Resistance to TDF up to 6 years

288 288

Liver fibrosis regression with long-term TDF

• Patients with Ishak score ≤2: 39% at Baseline, 63% at Year 5
• Patients with Ishak score ≥4: 38% at Baseline, 12% at Year 5
• Patients with cirrhosis (Ishak score ≥5): 28% at Baseline, 8% at Year 5

Ishak Fibrosis Scores

Percentage of Patients

*Sign test

10 20 30 40 50 60 70 80 90 100 Baseline Y ear 1 Y ear 5 39% 38% 12%

P < 0.001 P < 0.001

63% 10 20 30 40 50 60 70 80 90 100 Baseline Y ear 1 Y ear 5 39% 38% 12%

P < 0.001 P < 0.001

63%

6 5 4 3 2 1 6 5 4 3 2 1

Gane et al. APASL 2012

Regression of cirrhosis with long-term TDF

• 28% (96/348) of patients with paired biopsies had cirrhosis at Baseline
• 74% (71/96) were no longer cirrhotic (Ishak score <5) at Year 5
• 5
• 4
• 3
• 2
• 1

1 2 3

n=15 n=41 n=14 n=1 n=24 n=1 73% of patients had ≥2 unit reduction

Change in Ishak Scores at Year 5 for Patients with Cirrhosis at Baseline

Gane et al. APASL 2012

Long-term efficacy of TDF in real-life setting

European Retrospective/prospective multicenter cohort study

271 272 Patients on follow-up 245 193 109

20 40 60 80 100 6

65

% patients with undetectable‡ HBV DNA 12

84 91

18

90

24

91

30

Patients at risk 61 45 20 55 32 6

20 40 60 80 100 6 12 18 24 30

33%

% patients with HBeAg seroconversion

Lampertico P, et al. AASLD 2011

HBeAg seroconversion: 15 patients** Month

Efficacy of TDF in Rx-experienced patients in real-life setting

The “Geminis” German Multicenter Observational Study

Petersen J, et al. EASL 2012

N = 400, FU up to 3 years Results of interim analysis at 1 year

** ** * * * ** ** * *

** ** * * * ** ** * *

HBV-DNA (IU/mL)

Baseline Month 3 Month 6 Month

< 20 < 200-20 < 2000-200 < 20.000-2000 < 200.000-20.000 < 2 Mio-200.000 < 20 Mio-2 Mio < 200 Mio-20 Mio ≥ 200 Mio

*

HBV-DNA (IU/mL)

Baseline Month 3 Month 6 Month

< 20 < 200-20 < 2000-200 < 20.000-2000 < 200.000-20.000 < 2 Mio-200.000 < 20 Mio-2 Mio < 200 Mio-20 Mio ≥ 200 Mio

*

HBV-DNA (IU/mL)

Baseline Month 3 Month 6 Month

< 20 < 200-20 < 2000-200 < 20.000-2000 < 200.000-20.000 < 2 Mio-200.000 < 20 Mio-2 Mio < 200 Mio-20 Mio ≥ 200 Mio

*

Baseline Month 3 Month 6 Month

< 20 < 200-20 < 2000-200 < 20.000-2000 < 200.000-20.000 < 2 Mio-200.000 < 20 Mio-2 Mio < 200 Mio-20 Mio ≥ 200 Mio

*

Treatment-naïve patients Treatment-experienced patients

Combining ETV and TDF?

The BE-LOW study (ETV-110)

Week 96 Primary endpoint Baseline Dosing x 100 weeks

RANDOMIZATION 1:1

ETV 0.5 mg + TDF 300 mg, once daily (N = 197) * ETV 0.5 mg, once daily (N = 182) *

Further anti-HBV therapy at discretion of investigator – up to 24 weeks follow-up

Randomized, open-label, Phase IIIb trial NA-naïve CHB, HBeAg(-) patients capped at 30%

Lok AS, et al. Gastroenterology 2012

HBeAg(+) HBeAg(-)

Combining ETV and TDF?

The BE-LOW study (ETV-110)

Lok, AS, et al. Gastroenterology 2012

ETV + TDF: no overall benefit c.f. ETV mono (low dose) May benefit in HBeAg(+) with baseline HBV DNA ≥ 108 IU/mL

Alternatives: high dose ETV or TDF monotherapy??

How about safety profile of ETV and TDF?

Asian patients are at risks of renal and bone problems

because of common comorbidities

American Heart Association. http://www.americanheart.org/. (Sep 2010). Dixon AN, et al. Diabetes and Vascular Dis Res 2006; 3:22–25. Li-Ng M, et al. Digest Liver Dis 2007;6:549–556. National Digestive Diseases Information Clearinghouse.http://digestive.niddk.nih.gov/ddiseases/pubs/lactoseintolerance/. (Sep 2010). National Osteoporosis Foundation. http://www.nof.org/osteoporosis/diseasefacts.htm. (Sep 2010).

a South Asian

Low Bone Mineral Density (BMD) Osteoporosis Diabetes Hypertensiona Low BMI

Asian Ethnicity

Long-term safety of TDF in real-life setting

• The proportion with GFR <50 mL/min remained stable over targeted renal

therapy (~3–4%)

• 11 (4%) patients had a decline in MDRD and required dose reduction or

discontinuation

Renal function Baseline creatinine, mg/dL* 0.90 (0.4–5.2) Year 2 creatinine, mg/dL* 0.90 (0.5–8.2) >0.5 mg/dL increase creatinine ~1% Low phosphorus (<2.0 mg/dL) ~1% Proteinuria (30 mg by dip stick) ~1% Other variables Dose changes due to AEs‡ 9 (3%) Drug discontinuations due to AEs§ 9 (3%) Renal related in 4%

Lampertico P, et al. AASLD 2011

Renal function in 160 patients treated with ETV or TDF

Gish R, et al. Clin Gastroenterol Hepatol 2012

ETV TDF 10 20 30 40 50

Serum creatinine increase > 0.2 mg/dL eGFR decrease > 20% Dose adjustment

29% 36% 5% 28% 35% 16% Risk factors: History of organ transplantation – adjusted OR = 6.74 Pre-existing renal insufficiency – adjusted OR = 10.96

Considerations in the prevention of drug-induced renal and bone problems

• Be aware of patient-related risk factors
• General measures to prevent nephrotoxicity

– Avoid nephrotoxic combinations – Adjust medication dosages based on renal function

• Tests to exclude both tubular and glomerular renal toxicity

– GFR and estimating equations can not detect tubular damage – Phosphate wasting, glycosuria, and proteinuria can be detected in patients with proximal tubular dysfunction

Naughton CA, et al. Am Fam Physician 2008;78:743–750; Essig M, et al. J Acquir Immune Defi Syndr 2007;46:256–258; Ishikawa M, et al. J Anesthesia 2001;15:49–52; Kinai E, et al. AIDS 2005;19:2031–2041; Kinai E, et al. Aids Res Human Retro 2009;25:387–394; Labarga P, et al. AIDS 2009;23:689–696; Woodward CLN, et al. HIV Medicine 2009;10:482–487.

Conclusions & Perspective

• ETV or TDF are the preferred NAs in chronic hepatitis B patients.
• High antiviral potency and low risk of drug resistance is

confirmed in both trial and real-life settings for ETV and TDF.

• Beware of renal and bone toxicity in long-term users.
• Perspective: more potent viral suppression, better clinical
• utcomes?