How Old is HBV?

• HBV associated with humans for >1,000 years but no definitive evidence

• Recent evidence establishes ≥500 years

• Naturally mummified body of a Korean child found virtually intact

• Laparoscopy: Large organ in RUQ and biopsies sent for pathology and HBV DNA testing

– HBV DNA genotype C isolated from the liver

– Pathology: Appeared to be normal liver

Klein A, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 925.

Viral Characteristics

HIV HBV HCV

Virus type RNA Retrovirus DNA Hepadenovirus RNA Flavivirus

Eradication possible with therapy? No—Latent reservoirs No-cccDNA

Yes—Sustained virologic response (cure)

Viral targets Mainly CD4+ cells Hepatocytes Hepatocytes

Variants HIV 1 and 2 8 genotypes A-H 6 genotypes 1-6

Pathogenesis Damage to host immune system

Host immune response

Host immune response

Hepatitis B is 50 to 100 times more infectious than HIVUnlike HIV, it can live outside the body in dried blood for longer than a week

World Health Organization. Hepatitis B. http://www.who.int/mediacentre/factsheets/fs204/en/. Accessed November 7, 2007; Block TM, et al. Clin Liver Dis. 2007;11:685-706; Krogstad P. Semin Pediatr Infect Dis. 2003;14:258-268;

Penin F. Clin Liver Dis. 2003;7:1-21; Lauer GM, Walker BD. N Engl J Med. 2001;345:41-52.

World Health Organization. Hepatitis B. http://www.who.int/mediacentre/factsheets/fs204/en/. Accessed November 7, 2007; Block TM, et al. Clin Liver Dis. 2007;11:685-706; Krogstad P. Semin Pediatr Infect Dis. 2003;14:258-268;

Penin F. Clin Liver Dis. 2003;7:1-21; Lauer GM, Walker BD. N Engl J Med. 2001;345:41-52.

Nucleoside Analogues in HBV

HBV- Global health problem 250m people worldwideMax prevalence in Asia Pacific and Subsaharan

AfricaHBV: Vaccination : 179 countries

Chronic carriers at risk

Normal Aminotransferase Levels and Risk of Mortality from Liver Diseases

Kim HC et al. Kim HC et al. BMJBMJ 2004; 328:983 2004; 328:983

1.01.0

2.92.9

9.59.5

19.219.2

30.030.0

59.059.0

NormalNormal

ElevatedElevated

Korea Medical Insurance Corporation 94,533 men; 47,522 women

35-59 yrs old Relative risk for liver mortality compared with AST and ALT <20 IU/l

7 Taiwanese townships aged 30–65 years

(n=89,293)

Baseline HBsAg+(n=9800)

Baseline HBV DNA(n=3851)

Follow-up analysisfor cirrhosis/HCC

(n=3774)

Viral Load Predicts Disease Progression:The REVEAL Study

Risk Evaluation of Viremia Elevation & Associated Liver Disease

Prospective, multicenter, observational cohort study

Chen CJ. JAMA. 2006;295:65-73.

1991-19921991-1992RecruitmentRecruitment

June 2004: June 2004: 43,993 PYs follow-up43,993 PYs follow-up

• 24% PCR neg

• 85% HBeAg(-)

• 94% ALT<45 IU/L

• 98% non-cirrhotic (on Ultrasound)

00.0

0.1

0.2

0.3

0.4

0.5

0.6

1 2 3 4 5 6 7 8 9 10Year of follow-up

Cum

ulati

ve H

azar

d of

Liv

er

Dis

ease

HBeAg(+) HBV DNA ≥104

HBeAg(-) HBV DNA ≥104

HBeAg(-) HBV DNA <104

Progression from Chronic Hepatitis to Cirrhosis with normal ALT

Chen JD, et al. 43rd EASL; Milan, Italy; April 23-27, 2008. Abstract 644.

Chronic HBV

• Primary aim of treatment : progression of disease progression to cirrhosis, decompensation and HCC

• HBV DNA: Strongest predictor of HCCReveal study

Hongkong study: 8 yrs follow up

HCC risk calculators

GuidelineHBeAg + HBeAg-

HBV DNA

copies/mL

ALT

U/L

HBV DNA

copies/mL

ALT

U/L

US Algorithm 2008* ≥105>ULN or

(+) biopsy≥104

>ULN or

(+) biopsy

EASL 2008/9 ≥104 > ULN ≥104 > ULN

APASL 2008 ≥105 >2x ULN ≥105 >2x ULN

AASLD 2007/9 ≥105>2x ULN or

(+) biopsy≥105

>2x ULN or

(+) biopsy

Treatment Criteria for Chronic Hepatitis B

Chronic HBV Treatment:Simplified Flow Chart

Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936-962.

HBeAg Positive

Treat

Monitor

HBeAg Negative

HBV DNA >20,000 IU/mL HBV DNA >2,000 IU/mL

Normal ALT

Liver Biopsy

Abnormal Histology

Elevated ALT

ALT Evaluation

IU/mL to copies/mL conversion: Versant HBV DNA 3.0 (bDNA): 1 IU/mL=5.2 copies/mL. Cobas Amplicor HBV monitor: 1 IU/mL=5.6 copies/mL.

Cobas TaqMman 48 HBV: 1 IU/mL=5.8 copies/mL.

Indications of treatment

• Moderate to severe liver disease- h/p ALT/HBV DNA levels

• AASLD/ EASL/APASL guidelines• But

• Advanced age,• Extrahepatic manifestations,• Family history of cirrhosis• HBV treatment with help of biomarkers• Fiborscan

Antiviral agents

1982

HBV Vaccine

1985

INF

2005

Peg INF

Enticavir

2006

Telbivudine

2008

Tenofovir

Oral Drugs with Anti-HBV Activity - 2015

Nucleoside Analogs: Lamivudine

EntecavirTelbivudineEmtricitabine

Nucleotide Analogs Adefovir DipivoxilTenofovir Disoproxil

‡

First Line Treatment Options Have The Lowest Resistance Rates

Lowest Rate of

Resistance

Lamivudine 65% to 70% at 4 to 5 years

Telbivudine 25% in HBeAg-positive patients11% in HBeAg-negative patients

at 2 years

Adefovir dipivoxil29% at 5 years

Entecavir*in the absence of prior lamivudine resistance

(1.25% at 5 years)

*Patients with LAM resistance have a 51% rate of novel mutations after 5 years of entecavir therapy

Tenofovir DFin treatment

naïve patients (0% at 2 years)

Highest Rate of

Resistance

US Treatment Algorithm – Resistance Profile

Keeffe, E, et al. Clinical Gastroenterology and Hepatology 2008;doi: 10.1016/j.cgh.2008.08.021 (e-pub).

New Preferred First-Line Treatment Options

• Based on superior efficacy, tolerability, and favorable resistance, the new preferred Oral first-line treatments are: – Tenofovir DF*

– Entecavir

US Treatment Algorithm and EASL Guidelines - Treatment Options

+Tenofovir DF should replace adefovir dipivoxil as a first-line drug in previously untreated patients with HBeAg-positive and HBeAg -negative disease

Keeffe, E, et al. Clinical Gastroenterology and Hepatology 2008;doi: 10.1016/j.cgh.2008.08.021 (e-pub).EASL Clinical Practice Guidelines (update, in press); access: www.easl.ch/PDF/cpg/EASL_HBV_CPGs.pdf, 11.14.08

Mechanisms of action of NUCS

• Suppress HBV DNA by targeting the HBV DNA polymerase (a reverse transcriptase) and thus intervene the replication of HBV DNA

0102030405060708090

PEG-INF LAM ADV ETV LdT TDF

Rates of Undetectable HBV DNA and Normal ALT in HBeAg+ Patients

0

1020

30

40

5060

70

80

PEG-INF LAM ADV ETV LdT TDF

24%

39%

21%

67%60%

74%

39%

66%

48%

68% 69%77%

Undetectable HBV DNA Normal Range ALT

Rates of undetectable HBV DNA and normal range ALT at one year of therapy with:pegylated interferon alpha 21 (PEG_INF), lamivudine (LAM), adefovir (ADV), entecavir (ETV),

and tenofovir DF (TDF) in HBeAg positive patients with CHB in randomized clinical trails. These trials used different HBV DNA assays and they were not head-to-head comparisons for all the drugs.

EASL Clinical Practice Guidelines (update, in press); access: www.easl.ch/PDF/cpg/EASL_HBV_CPGs.pdf, 11.14.08

Rates of Undetectable HBV DNA and Normal ALT in HBeAg– Patients

0

20

40

60

80

100

PEG-INF LAM ADV ETV LdT TDF0

102030405060708090

PEG-INF LAM ADV ETV LdT TDF

63%72%

51%

90% 88% 91%

38%

74% 72%78%

74% 77%

Undetectable HBV DNA Normal Range ALT

Rates of undetectable HBV DNA and normal range ALT at one year of therapy with:pegylated interferon alpha 21 (PEG_INF), lamivudine (LAM), adefovir (ADV), entecavir (ETV),

and tenofovir DF (TDF) in HBeAg negative patients with CHB in randomized clinical trails. These trials used different HBV DNA assays and they were not head-to-head comparisons for all the drugs.

EASL Clinical Practice Guidelines (update, in press); access: www.easl.ch/PDF/cpg/EASL_HBV_CPGs.pdf, 11.14.08

Summary: AASLD Guidelines for Management of Antiviral-Resistant HBV

Resistance Rescue Therapy

LamivudineTelbivudine

Add adefovir or tenofovir DFSwitch to: Emtricitabine + tenofovir DF (fixed-dose combination) Entecavir (risk of entecavir resistance)

Adefovir Add lamivudineSwitch to: Emtricitabine + tenofovir DF (fixed-dose combination) Entecavir (if no prior lamivudine resistance)

Entecavir Add adefovir or tenofovir DF

Multidrug Multidrug resistance to lamivudine + adefovir: Consider emtricitabine + tenofovir DF (fixed-dose combination), tenofovir DF, entecavirMultidrug resistance to lamivudine + entecavir: Consider tenofovir DF or emtricitabine + tenofovir DF (fixed-dose combination)

Lok AS, et al. Hepatology. 2007;46:254-265.

Durability of response

LAM: HBeAg –VE : 50% relapse with 6m of cessation of treatment

ADV: 46% relapse with 5 years

ETV : 29% to 53% after cessation of treatment

50% - sustained HBeAg seroconversion off treatment

Role of quantitative HBsAg

• HBsAg quantitative correlates with CCC DNA only in HBeAg +ve patients and not in HBeAg –ve patients

• True inactive carriers HBV DNA <2000IU/ml with HBsAg quantitative <1000IU/ml

• HBeAg –ve patient HBV DNA 2000 IU/ml and HBsAg <100 IU/ml.

• Good chance of spontaneous clearance

GS-103: HBsAg Loss/seroconversion Occurred only in HBV Genotypes A + D

• At week 48, HBsAg loss occurred in 3.2% with TDF and 0% with ADV (p=0.02)

• 14 patients (6%) lost HBsAg by year 2 on TDF– 9 TDF-TDF and 5 ADV-TDF– 11/14 HBsAb seroconversion

• TDF induced loss of HBsAg in Caucasian patients infected with genotype A or D virus

GenotypeHBsAg Clearance at

Year 2 n/N (%)

A 8/67 (12%)

B 0/35 (0%)

C 0/69 (0%)

D 6/90 (7%)

Heathcote EJ, et al. 44th EASL; Copenhagen, Denmark; April 22-26, 2009; Abst. 909.

Impact of HBV Genotype on treatment response

• No relation with HBeAg seroconversion or HBV DNA decline respond.

Oral Antivirals Reduce the Incidence of HCC in Patients with HBV-related Liver Cirrhosis

Eun, J. et al, AASLD 2007, Abstract #961.

Control, n=111

Treated, n=111

Mean follow-up 4.4 for treated, 5.4 for untreated

Annual incidence rate of 1.02% Tx. vs. 6.0% non-Tx. patients/year

* (Log-rank, p=0.003)

5%*

33%

Impact of NA treatment on HCC

• Well documented for LAM /ADV only

• Prospective study: LAM vs Placebo 651 CHB patients

• Results 3.9% Vs 74% (LJAM etal. NEJM 2004)

• Enticavir/ TDF: Regression of fiborsis/ cirrhosis/ documented ? HCC reduction

Impact of NA treatment on hepatic decompensation

Lam : 32M : 50% reduction in rate of hepatic decompensation

A significant proportion of patients taken off OLT list

NA treatment after LT

• Entecavir monotherapy 91% HBsAg loss

98.8% undetectable HBV DNA after LT after a mean follow up of 53 months

Fung et al AJ Gastroentrol 2013

NA on Immunosuppresed State and Immune restoration

• Reactivation of HBV replication and decompensation reported in 20-50% of CHB patients

• Poor outcome on those with high viral load and underlying established cirrhosis

Pregnancy Category

Tenofovir DF Category B

Telbivudine Category B

Lamivudine Category C

Entecavir Category C

Adefovir Category C

• There is a considerable body of safety data in pregnant HIV-positive women who have received TDF and/or LAM or FTC

US Treatment Algorithm and EASL Guidelines - Treatment Options

Keeffe, E, et al. Clinical Gastroenterology and Hepatology 2008;doi: 10.1016/j.cgh.2008.08.021 (e-pub).EASL Clinical Practice Guidelines (update, in press); access: www.easl.ch/PDF/cpg/EASL_HBV_CPGs.pdf, 11.14.08

Strategies to improve treatment efficacy – Denovo combination treatment

• TDF + ETV better than either along if HBVDNA > 108 IU/ml in HBeAg +ve patients

Lok AS(Gastroenterol 2012)

• Road Map therapy -only for TDV patients

NEWER NAS

• Prodrug of Tenofovir better lymphoid distribution

• Lesser renal and bone toxicities

• Besifovir : Acyclic nucleotide phosphonate : as good as ETV/ TDF

Tenofovir Alafenamide 25mg

Future NA development

• Viral entry inhibitors• Acylated peptides derived from the large HBV

envelop protein block viral entry• Use preS1 peptides• Small interfering RNA produce strong and

persistent antiHBV activity• Block interaction between HBeAg and HBsAg• Some HBV Gerome Oligonuclitides induce Robust

expression of INF by plasmocytosed cells.

Conclusion

• NAS- New era of HBV treatment• Reduce hepatic decompensation and HCC• Infrequent side effects/ ease administration• 1st Generation : Viral resistance• 2nd Generation: ETV : 1.2% ( 5 years)

TDF: 0% ( 6 years)• Combination treatment for HBV DNA>10 8 log• ? What to do for suboptimal responders• ?RGT

Future Perspectives

• Indefinite treatment : major drawback

• ? Peg INF + TDF – RCT on

• ? Peg INF after HBeAg seroconversion

• Tenofovir Alafenamide, Besifovir : Newer NAS/entry inhibitors/smrnas

39

HBsAg