Navigating the New Treatment Landscape Outline Interpretation of HBV Serologic Tests The Hepatitis B Virus Goals of Therapy When and What to Start The Guidelines New Treatment Options Choosing Among Good Options ID: 816231
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Slide1
Evolving Options for HBV Therapy:
Navigating the New Treatment Landscape
Slide2Outline
Interpretation of HBV Serologic Tests
The Hepatitis B Virus
Goals of Therapy
When and What to Start: The Guidelines
New Treatment Options
Choosing Among Good Options
Slide3Slide4Interpretation of Hepatitis B test results
Slide5Acute HBV Infection
Infection is by blood-borne, sexual, or vertical exposure to HBV.
Infection kinetics are slow.
Long lag period (weeks) before infection becomes detectable
Infection eventually involves up to 100% of the hepatocytes.
Resolution of acute infection occurs in 2 phases.
Non-cytolytic: host cytokines clear ~90% of the virus
Cytolytic: CD8+ive T-cells kill residual infected cells
HBsAb’s block new rounds of infection (immunity)
Best marker of resolution in loss of HBsAg and viral DNA in serumAcute HBV pathology occurs during the cytolytic phase of clearance.
Disease is primarily immune-mediatedClearance is unlikely to ever be absolute.
Trace levels of virus persist in liver and/or lymphocytes following “clearance”
Clinical relevance of virus that persists in resolved patients is low
Slide6Chronic HBV Infection
Failure to clear an acute infection leads to chronic infection.
Immune status and age of the patient govern outcome of acute infection.
HBV appears to induce partial immune tolerance to itself.
Chronic infection persists for the life of the patient.
Disease is due to immune attack on infected cells.
HBV replicates constantly during chronic infection.
There is no virological
“latency” for HBV.
Viral titers can be below detection by clinical assays, but the blood remains infectious.
Understanding why immune responses clear HBV in some and not in others is key research goal in finding a cure of HBV infection.
Slide7Hepatitis B Virus (HBV)
The only human
hepadnavirus
(
HEPA
totrophic
DNA
VIRUSes)
Enveloped partially dsDNA virus
Replicates by reverse transcription performed by virally encoded polymerase called “P”
Can infect human, chimps, and orangutans
Chronically infects 350-400 million people worldwide (~ 5-6% of world population)
~1.2 million people in USA with chronic HBV infection
~1800 deaths/year in USA
The leading cause of virally-induced liver failure and liver cancer world-wide
Slide8Hepatitis B Virus (HBV)
The only human
hepadnavirus
(
HEPA
totrophic
DNA VIRUSes)
Enveloped partially dsDNA virusReplicates by reverse transcription performed by virally encoded polymerase called “
P”Can infect human, chimps, and orangutans
Chronically infects 350-400 million people worldwide (~ 5-6% of world population)~1.2 million people in USA with chronic HBV infection~1800 deaths/year in USA
The leading cause of virally-induced liver failure and liver cancer world-wide
Slide9Cure as a Goal of Therapy
Actual cure
True cure = all traces of HBV gone from the liver (like HCV)
VERY difficult (if not impossible)
cccDNA
Functional cure
Use the markers of pts who do well:
HBsAg loss (ideally with anti-HBs)
Possibly sustained off-treatment inactive disease without HBsAg loss (HBeAg negative, DNA undetectable, normal ALT, normal histology)
Cure not so simple . . . reasons lie in the virology
Slide10HEPATITIS B VIRUS (HBV)
Virion
has a lipid envelope, studded with glycoproteins (
HBsAg
), surrounding a protein capsid (
“
Dane particle
”
)
The genome is partially double-stranded circular DNA
Makes 2 types of
subviral particles
~20 nm spheres and long tubes
Contain host lipid and
HBsAg
Slide11Hepatitis B Virus (HBV)
Virion has a lipid envelope, studded with glycoproteins (HBsAg), surrounding a protein capsid (
“
Dane particle
”
)
The genome is partially double-stranded circular DNA
Makes 2 types of subviral particles
~20 nm spheres and long tubesContain host lipid and HBsAg
Slide12Hepatitis B Virus (HBV)
Replication cycle
Entry by receptor binding followed by membrane fusion in endocytic vesicle
Partially dsDNA genome is
“
repaired
”
to nuclear cccDNAmRNAs transcribed from cccDNA in nucleus
Proteins translated in the cytoplasmPregenomic RNA and Pol are encapsidated by HBcAg (cont.)
Slide13Hepatitis B Virus (HBV)
Replication cycle (cont.)
Reverse transcription occurs in the cytoplasm
Virions from by budding of the capsids into the ER to acquire envelope and HBsAg
Virions are released non-cytolytically by secretion
cccDNA pools are maintained by
“
recycling” new genomes back to the nucleus
Slide14HEPATITIS B VIRUS (HBV)
Replication cycle
Entry by receptor binding followed by membrane fusion in
endocytic
vesicle
Partially
dsDNA
genome is
“
repaired
” to nuclear cccDNA
mRNAs transcribed from cccDNA
in nucleus
Proteins translated in the cytoplasm
Pregenomic
RNA and Pol are
encapsidated
by
HBcAg
(cont.)
Slide15HEPATITIS B VIRUS (HBV)
Replication cycle (cont.)
Reverse transcription occurs in the cytoplasm
Virions
from by budding of the capsids into the ER to acquire envelope and
HBsAg
Virions
are released non-
cytolytically
by secretioncccDNA pools are maintained by
“recycling” new genomes back to the nucleus
Slide16Potent HBV DNA Suppression With Nucleos(t)ide Therapy
Long-term therapy with potent nucleos(t)ides leads to suppression in almost all pts
Yr
HBeAg positive
HBeAg negative
Long-term ETV
[1]
Pts With Suppressed
HBV DNA (%)
0
20
40
60
80
100
236/
354
67
55
n/N =
1
80/
146
116/
140
116/
131
98/
108
88/
94*
83
89
91
94
1
2
3
4
5
*5 additional pts who remained on treatment at the Yr 5 visit had missing HBV DNA measurements.
1. Chang TT, et al. Hepatology. 2010;51:422-430. 2. Marcellin P, et al. N Engl J Med 2008; 359:2442-2455. 3. Marcellin P, et al. Lancet. 2013;381:468-75. 4. Buti M, et al. Dig Dis Sci. 2015;60:1457-1464.
Long-term TDF
Pts With Suppressed
HBV DNA (%)
1
[2]
]
5
[3]
7
[4]
99
99
271/
273
159/
160
97
99
292/
295
170/
175
83
97
233/
241
0
20
40
60
80
100
Slide credit:
clinicaloptions.com
Yr
Blinded
Open labe
l
133/
160
n/N =
Slide17HBV Therapy Reduces Risk of Disease Progression
Prospective cohort study in pts with HBV and first-onset complications of decompensated cirrhosis (N = 707) treated predominantly with lamivudine (n = 203) or entecavir (n = 198)
Antiviral therapy improved transplant-free survival over mean follow-up of 49 mos
(
P
= .0098 vs untreated)
Jang JW, et al. Hepatology. 2015;61:1809-1820.
Nonresponders
included pts with HBV rebound or genotypic resistance, primary nonresponse, NE due to early event (death, LT, LTFU).
Treated, responder (n = 245)
Treated, nonresponder* (n = 178)
Untreated (n = 284)
P
< .0003
LT-
Free Survival (%)
Mos
0
84
12
24
36
48
60
72
100
80
60
40
20
0
Slide credit:
clinicaloptions.com
Slide18Need for
Long-term Therapy
Slide190
20
40
60
80
100
Is Long-term HBV Therapy Required?
Systematic review of stopping nucleos(t)ide therapy in HBeAg-negative
(n = 967) and HBeAg-positive (n = 733) pts
Papatheodoridis GV, et al. Hepatol. 2016;63:1481-1492.
High rate of relapse to active disease
Low rate of HBsAg loss…long-term therapy required
Slide credit:
clinicaloptions.com
Pooled HBsAg Loss: 1.7% (50/693)
Durable biochemical remission: 57% (394/687)
Pts in Virologic Remission (%)
64
0
20
40
60
80
100
44
31
30
6
12
24
36
HBeAg-negative
73
63
53
52
6
12
24
36
HBeAg-positive
Months
After Nucleos(t)ide Discontinuation
Pooled HBsAg Loss: 1.0% (17/341)
Durable biochemical remission: 76% (268/403)
Months
After Nucleos(t)ide Discontinuation
Slide20Long-term Oral HBV Therapy is Highly Effective
Suppresses HBV DNA
[1,2]
Normalizes ALT
[2,3]
Prevents fibrosis progression
[3,4]
Promotes fibrosis regression, even in cirrhosis
[4]
Prevents and even reverses hepatic decompensation
[1]Reduces, but does not eliminate, the risk of HCC
[1,5]Long-term therapy is effective . . . but low rates of HBsAg loss
[6]
1. Lim YS, et al. Gastroenterology. 2014;147:152-161.2. Chang TT, et al. Hepatology. 2010;51:422-430.
3. Zoutendijk R, et al. Gut. 2013;62:760-765. 4. Marcellin P, et al. Lancet. 2013;381:468-475.
5. Papatheodoridis GV, et al. J Hepatol. 2015;62:363-370. 6. Papatheodoridis GV, et al. Hepatol. 2016;63:1481-1492.
Slide credit:
clinicaloptions.com
Slide21Long-term Oral HBV Therapy: Downsides
Toxicity
Potential for renal, bone complications with TDF
Resistance
High with lamivudine (not preferred by guidelines)
[1]
Very low with entecavir—unless already LAM resistant
[2]
None with TDF in clinical trials (similar expected with TAF)
[3]Cost
Adherence
1.
Hadziyannis
SJ, et al. Hepatology. 2000 ;32:847-51. 2. Gish SR, et al. Gastroenterology. 2007;133:1437-44. 3.
Buti M, et al. Dig Dis Sci. 2015;60:1457-1464.
Slide credit:
clinicaloptions.com
Slide22When and What to Start
Slide23Guidelines: When to Start HBV Therapy
Guidelines
HBeAg Positive
HBeAg Negative
HBV DNA, IU/mL
ALT
Liver
Disease
HBV DNA, IU/mL
ALT
Liver
Disease
AASLD
[1]
> 20,000
≥ 2 x ULN
N/A
≥ 2000
≥ 2 x ULN
N/A
N/A
N/A
Cirrhosis
N/A
N/A
Cirrhosis
1. Terrault NA, et al. Hepatology. 2016;63:261-283.
Slide credit:
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Continue indefinitely in HBeAg-negative pts with cirrhosis
Slide24Guidelines
HBeAg Positive
HBeAg Negative
HBV DNA, IU/mL
ALT
Liver
Disease
HBV DNA, IU/mL
ALT
Liver
Disease
AASLD
[1]
> 20,000
≥ 2 x ULN
N/A
≥ 2000
≥ 2 x ULN
N/A
N/A
N/A
Cirrhosis
N/A
N/A
Cirrhosis
EASL
[2]
> 2000
> ULN*
Moderate inflammation
or fibrosis*
> 2000
> ULN*
Moderate inflammation or fibrosis*
> 20,000
> 2 x ULN
N/A
> 20,000
> 2 x ULN
N/A
1.
Terrault
NA, et al. Hepatology. 2016;63:261-283.
2. EASL. J Hepatol. 2017;67:370-398.
*In pts with HBV DNA > 2000 IU/mL, treatment indicated if ALT > ULN and/or at least moderate fibrosis.
Slide credit:
clinicaloptions.com
Guidelines: When to Start HBV Therapy
Slide25Guidelines: What to Start as Initial HBV Therapy
Treatment
Preferred
[1,2]
Notes
Entecavir
Yes
High potency, high genetic barrier to resistance
Tenofovir alafenamide*
Yes
High potency, high genetic barrier to resistance
Tenofovir disoproxil fumarate
†
Yes
High potency, high genetic barrier to resistance
Peginterferon
Should only be considered as initial therapy for pts with mild/moderate CHB or selected pts with compensated cirrhosis (no portal hypertension)
Less safe in pts with cirrhosis,
contraindicated in pts with decompensated cirrhosis
Adefovir
No
Low genetic barrier to resistance
Lamivudine
No
Low genetic barrier to resistance
Telbivudine
No
Low genetic barrier to resistance
*AASLD guidelines not yet updated since approval of TAF.
†
Pts receiving TDF: monitor renal function, consider monitoring BMD in pts at risk.
[1]
Slide credit:
clinicaloptions.com
1. Terrault NA, et al. Hepatology. 2016;63:261-283. 2.
EASL. J Hepatol. 2017;67:370-398.
ETV, TDF, TAF have very favorable safety profiles
[2]
Slide260
84
12
24
36
48
60
72
Wong G L-H, et al. Hepatology. 2015;62:684-693.
Safety of Nucleos(t)ide Analogues in HBV
Observational study of n = 46,454 untreated vs n = 7046 pts treated with NAs, median follow-up of 4.9
yrs
Generally very good long-term safety . . . but individual pts
may have
toxicity
Untreated
NA treated
Weighted Cumulative Incidence of Renal Failure (%)
15
10
5
0
Follow-up (Mos)
0
84
12
24
36
48
60
72
Untreated
NA treated
Weighted Cumulative Incidence of All Fracture (%)
15
10
5
0
Follow-up (Mos)
Slide credit:
clinicaloptions.com
Renal
Bone
Slide27Current Options in 2018
Slide28Recommended
Nucleos
(t)ide Analogues for HBV
Slide credit:
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Nucleos(t)ide Analogue
Approval in HIV
Approval in CHB
QD Dose
Lowest CrCl Without Dose Adjustment (mL/min)
Entecavir
N/A
2005
0.5 mg
50
Tenofovir disoproxil fumarate
2001
2008
300 mg
50
(no dose recommendation at
< 10 without dialysis)
Tenofovir alafenamide
2015 (as part of fixed-dose combination with antiretrovirals)
2016
25 mg
15
(not recommended at < 15 in HBV
monoinfection
)
Entecavir [package insert]. 2017. Tenofovir disoproxil fumarate [package insert]. 2017. Tenofovir alafenamide [package insert]. 2017.
Slide29TAF vs TDF: Mechanism of Action
Arribas JR, et al. CROI 2017. Abstract 453. Duarte-Rojo A. Therap Adv Gastroenterol. 2010;3:107-119. Murakami E, et al. Antimicrob Agents Chemother. 2015;59:3563-3569. Tenofovir disoproxil fumarate [package insert]. 2017. Tenofovir alafenamide [package insert]. 2017.
Slide credit:
clinicaloptions.com
Renal tubular cell
Slide30TAF vs TDF in Chronic HBV Infection: Wk 96 Efficacy
HBV DNA:
TAF
noninferior
to TDF at
Wks
48 and 96 in both studies; no resistance found in any arm
ALT:
significantly greater rate of ALT normalization at Wk 96 with TAF vs TDF
HBeAg-positive pts:
higher rate of HBeAg seroconversion at Wk 96 vs Wk 48 with TDF or TAF[2]HBeAg-negative pts: minimal decline in HBsAg with TDF or TAF for (1 TAF-treated pt with GT A had HBsAg loss and seroconversion)
[1]
Slide credit:
clinicaloptions.com
*Adjusted for BL HBV DNA and PO antiviral treatment status.
1. Brunetto M, et al. EASL 2017. Abstract PS-042. 2.
Agarwal K, et al. EASL 2017. Abstract FRI-153.
HBV DNA
< 29 IU/mL at
Wk
96 (%)
100
80
60
40
20
0
TAF
TDF
90
91
257/
285
127/
140
Treatment difference (95% CI):
-0.6% (-7.0, 5.8),
P
= .84*
n/ N =
TAF
TDF
73
75
423/
581
218/
292
HBeAg Negative
[1]
HBeAg Positive
[2]
100
80
60
40
20
0
Treatment difference (95% CI):
-2.2% (-8.3, 3.9),
P
= .47*
Slide31Significantly smaller effect on spine BMD with TAF at Wk 48 and Wk 96 HBeAg-negative pts
[1]
TAF vs TDF in Chronic HBV Infection: Renal and Bone Outcomes
Slide credit:
clinicaloptions.com
1. Brunetto M, et al. EASL 2017. Abstract PS-042. 2. Agarwal K, et al. EASL 2017. Abstract FRI-153.
Similar results seen with HBeAg-positive pts
[2]
Significantly smaller effect on renal function with TAF at Wk 48 and Wk 96 in HBeAg-negative pts
[1]
Significantly smaller effect on spine BMD with TAF at
Wk
48 and
Wk
96
HBeAg
-negative pts[1]
Slide32Choosing Among Nucleos(t)ide Analogues
If no comorbidities (for most pts)
When to prioritize ETV over TAF
If less expensive (generic available)
Dosing guidelines for CrCl < 15 mL/min
When to prioritize TAF over ETV
Previous nucleoside exposure
[2]
Lamivudine with or without adefovir resistance
HIV/HBV coinfection
No dose adjustment for CrCl ≥ 15 mL/min
1. Terrault NA, et al. Hepatology. 2016;63:261-283. 2.
EASL. J Hepatol. 2017;67:370-398.
Slide credit:
clinicaloptions.com
If risk of or preexisting bone or renal disease, prioritize ETV or TAF
[2]
Age > 60 yrs
Bone disease
Chronic steroids or other meds that affect bone
History of fragility fracture
Osteoporosis
Renal abnormalities
eGFR < 60 mL/min/1.73 m
2
Albuminuria > 30 mg or moderate proteinuria
Low phosphate (< 2.5 mg/dL)
Hemodialysis
Monotherapy with ETV, TDF, or TAF
[1,2]
Slide33Chronic HBV Infection:
Management of Pts With NA Resistance
Slide credit:
clinicaloptions.com
Resistance
Switch Strategy
Add Strategy
Adefovir
Entecavir
[1]
Entecavir
[1]
Entecavir
Tenofovir*
[1,2]
Tenofovir (or emtricitabine/tenofovir*)
[1]
Lamivudine
Tenofovir*
[1,2]
Tenofovir (or emtricitabine/tenofovir*)
[1]
Telbivudine
Tenofovir*
[1,2]
Tenofovir
[1]
Multidrug
Tenofovir*
[1]
Tenofovir* + entecavir
[1,2]
*Includes either TDF or TAF in EASL guidelines; AASLD guidelines not yet updated since approval of TAF.
1. Terrault NA, et al. Hepatology. 2016;63:261-283. 2.
EASL. J Hepatol. 2017;67:370-398.
Slide34Entecavir
[2]
Tenofovir
Disoproxil Fumarate
[3]
Tenofovir
Alafenamide
[4]
Reduce dose if
CrCl
< 50 mL/min
Reduce dose if
CrCl
< 50 mL/min
No dose reduction if
CrCl
≥ 15 mL/min
No dose recommendation at
CrCl
< 10 mL/min without dialysis
Not recommended at
CrCl
< 15 mL/min
All pts receiving TDF should undergo periodic monitoring of renal function, including phosphate levels
[1]
Chronic HBV Infection: Management of Pts With Renal Impairment
Slide credit:
clinicaloptions.com
1. EASL
. J Hepatol. 2017;67:370-398. 2.
Entecavir [package insert]. 2017. 3. Tenofovir disoproxil fumarate [package insert]. 2017. 4. Tenofovir alafenamide [package insert]. 2017.
Slide35Should Patients Receiving TDF Switch to TAF?
Slide36Analysis of open-label extension data from 2 phase III trials in HBV-infected pts switching from TDF to TAF at
Wk
96
88% of pts achieved virologic suppression at Wk 96 (preswitch) and maintained to
Wk
120 (post switch)
Significantly higher proportion of pts achieved ALT normalization after switch to TAF
Chan HLY, et al. EASL 2017. Abstract PS-041.
Switch to TAF vs Continuing TDF in Chronic HBV Infection: Renal and Bone Outcomes
Slide credit:
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Slide37Conclusions: Current Treatment Landscape
In pts without comorbidities, 3 highly effective preferred options with high barrier to resistance: ETV, TAF, TDF
ETV and TAF useful for pts at risk of or with current renal impairment or bone toxicity
In such pts, consider ETV if
CrCl
< 15 mL/min, TAF if previous nucleoside exposure
Guidelines suggest useful to switch to TAF for pts with current toxicityEqually effective viral suppression with TAF as TDF with faster ALT improvement
Ongoing studies to better understand mechanism
Slide credit:
clinicaloptions.com
Slide38Summary
NA therapy is highly effective but not curative
HBV DNA suppressed but low HBsAg loss
Long-term therapy required
For most pts: ETV, TAF or TDF similar
TAF has similar efficacy with improved renal and bone safety compared with TDF
Slide39www.clinicaloptions.com/HBVlandscape
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