Post on 15-Jan-2016
Anna LOK
Management of Antiviral Resistant Hepatitis B
Clinical Case
Anna S. F. Lok
University of Michigan
Ann Arbor, MI, USA
Clinical Case
• M/25, born in Taiwan, moved to USA 3 yr ago, single, attending graduate school
• 3/02 – incidental mild increase in ALT
• No past history of acute hepatitis or jaundice
• Denied risk factors for hepatitis B
• FH: uncle diagnosed liver cancer at age 55, mother and 1 brother HBV+
• PE: Normal
M/25, asymptomatic
• LFT normal except for ALT 46 IU/L (N <40), AST 34 (N <35)
• CBC, PT, AFP – normal
• HBsAg+, HBeAg+
• HBV DNA 8.7 log10 c/mL
• US: normal liver size and texture, spleen not enlarged
M/25, perinatal infection, HBeAg+
• Repeat labs 1 month later: ALT 42 IU/L (N <40), HBV DNA 9.4 log10 c/mL
• Gastroenterologist concerned, HBV DNA doubled!!, ALT still increase, particularly by “new” standard
• Liver biopsy recommended but patient declined
• Treatment recommended: HBeAg+, high HBV DNA, abnormal ALT, family history of HCC
• Only approved therapies then: standard IFN and lamivudine
M/25, HBeAg+, ALT mild increase
• 6/02 - Lamivudine started, HBV DNA 9.4 log
• 9/02 - HBV DNA 5.8 log
• 12/02 – HBV DNA 4.5 log, ALT 29, HBeAg+
• 7/03 – ALT 31, AFP 7.1, HBV DNA not tested
• Patient graduated and relocated
M/25, Lamivudine breakthrough after 20 months
• 2/04 – severe fatigue
ALT 237 IU/L, bil 0.9 mg/dL, INR 1.0
HBeAg+, HBV DNA 8.7 log10 c/mL
M/25, HBeAg+, HBV DNA 9 log, ALT mild increase, lamivudine breakthrough after
20 months. What would you do at this time?
A) Stop lamivudine and observe
B) Continue lamivudine and observe
C) Stop lamivudine and switch to adefovir
D) Continue lamivudine and add adefovir
E) Stop lamivudine and switch to entecavir
Lamivudine breakthrough, switched to Adefovir monotherapy in 3/04
• 3/04 – Patient advised to stop lamivudine and switch to adefovir
• 9/04 – HBV DNA decreased from 8.7 to 6.4 log10 c/mL
• 4/05 – HBV DNA 5.2 log10 c/mL
Lamivudine breakthrough, switched to Adefovir monotherapy, HBV DNA 5 log after
13 monthsWhat would you now do?
A) Increase dose of adefovir to 20 mg
B) Add lamivudine
C) Add entecavir
D) Add interferon
E) Switch to tenofovir
Lamivudine breakthrough, switched to Adefovir monotherapy in 3/04
• 11/05 – HBV DNA 5.9 log10 c/mL, ALT 27
• 2/06 – HBV DNA 6.5 log10 c/mL, ALT 39 IU/mL, no symptoms
– rtN236T mutation detected
Lamivudine breakthrough in 2/04 Adefovir breakthrough in 2/06
What to do now?
A) Stop treatment and observe
B) Add lamivudine
C) Add entecavir
D) Switch to Truvada: combination of emtricitabine + tenofovir
E) Add interferon
Figure 1. Sequential monotherapy leading to sequential antiviral resistance
0
1
2
3
4
5
6
7
8
9
3 9 3 9 3 9 3 9
HB
V D
NA
(L
og
10
cop
ies/
ml)
2002 2003 2004 2005 2006
AL
T
(IU/L
)
300
0
200
100
LAMIVUDINEADEFOVIR
ALT
HBV DNA
Management of Antiviral-Resistant HBV
• How often should patients be monitored during antiviral therapy?
• Should all patients with breakthrough infection be tested for resistance mutation?
• When should rescue therapy be implemented?
• Which is the most appropriate rescue therapy?
How often should patients be monitored during nucleos/tide analogue therapy?
• Quantitative HBV DNA by PCR assay and ALT (LFT)– Q 3 months – ideally
– Q 1 month – initially, in patients with severe flare or decompensation
– Q 6 months – minimum frequency
• HBeAg in those initially positive– Month 12, then every 6-12 months
• HBsAg in those HBeAg negative– Month 12, then yearly
Why is it necessary to monitor patients so frequently?
• To enable early detection of treatment failure
– Primary treatment failure (primary nonresponse)
– Secondary treatment failure (breakthrough)
• To enable timely adjustment of treatment
– To prevent death and liver failure due to hepatitis flares associated with emergence of drug resistance
– To ensure better response through early institution of rescue therapy in patients with drug resistance
– To decrease the risk of drug resistance by adjusting treatment in patients with primary nonresponse
Primary Treatment Failure or Primary Non Response
• Definition: Serum HBV DNA decrease by <2 log and to a level >4 log10 IU/mL after 6 months of treatment
• Estimated frequency (using >4 log10 copies/mL at week 24) – Adefovir ~30-50% Lamivudine 10-35%– Telbivudine 8-30% Entecavir 5-10%
• Consequences:– Lower rates of response at year 1 and 2– Higher rates of drug resistance
Entecavir vs. Lamivudine Treatment of
Nucleoside-Naϊve Patients
1011
109
108
107
106
105
104
103
102
<300
1010
HBV
DNA
(Cop
ies/
ml)
0 24 36 48 0 24 36 48
Treatment (Weeks)
N = 324 316 296 314 311 302 285 297
1011
109
108
107
106
105
104
103
102
<300
1010
HBV
DNA
(Cop
ies/
ml)
0 24 36 48 0 24 36 48
Treatment (Weeks)
N = 324 316 296 314 311 302 285 297
HBeAg+ patients
Lai CL, NEJM 2006; 354:1010-20
HBeAg- patients
1011
109
108
107
106
105
104
103
102
<200
1010
HBV
DNA
(Cop
ies/
ml)
0 24 36 48 0 24 36 48Treatment (Weeks)
N = 352 331 326 341 354 322 305 324
1011
109
108
107
106
105
104
103
102
<200
1010
HBV
DNA
(Cop
ies/
ml)
0 24 36 48 0 24 36 48Treatment (Weeks)
N = 352 331 326 341 354 322 305 324
Chang T, NEJM 2006; 354:1001-10
Week 24 HBV DNA Level is Predictive of Response to Telbivudine or Lamivudine at 2 years
0
10
20
30
40
50
60
70
80
90
0
10
20
30
40
50
60
70
80
90
% o
f p
atie
nts
% o
f p
atie
nts
HBeAg seroconversion ALT normalization PCR negative
PCR neg <3 3-4 >4 PCR neg <3 3-4 >4
HBV DNA at wk 24 (log10 copies /ml)
Di Bisceglie A, AASLD 2006, Abstract 112
HBeAg+ HBeAg-
Better viral suppression reduces the risk of genotypic resistance
LamivudineResistance (median 29 mos)vs. wk 24 HBV DNA
AdefovirResistance at wk 144 vs. wk 48 HBV DNA
% R
esis
tan
ce
8 %13 %
32 %
64 %
4 %
26 %
67 %
Wk 24 HBV DNA (log10 c/ml)
N = 159 HBeAg+ patients
Yuen M, Hepatology 2001; 34:785
< ND 3-6 >6< ND > 4< 4< 3
Wk 48 HBV DNA (log10 c/ml) N = 114, primarily HBeAg- patients
Locarnini S, J Hepatol 2005; 42(Suppli 2):17
Should All Patients with Breakthrough Infection be Tested for Antiviral Resistant Mutations?
• Not all patients with breakthrough infection are confirmed to have resistant mutations
– ~70% in clinical trials, likely less in practice
• Rescue therapy can be tailored to pattern of resistant mutations
– More important in patients who had been exposed to sequential monotherapy
When Should Rescue Therapy be Initiated?
• Detection of resistant mutations through surveillance program
– Impractical in practice
– Overall benefit not established, may consider for patients with decompensated cirrhosis or immunosuppressed patients
• Virologic breakthrough – HBV DNA increase by >1 log10 from nadir
– More effective
• Viral rebound – HBV DNA increase to >5 log10
– Not as effective
• Biochemical breakthrough – ALT increase
– Not as effective
• Hepatitis flare or hepatic decompensation
– May not reverse outcome
Manifestations of Antiviral ResistanceH
BV
DN
A (
Lo
g 1
0 IU
/ml)
BiochemicalBreakthrough
ULN
ViralBreakthrough
0 1 2 3
Years
Antiviral Treatment
0
2
4
6
8
Hepatitis Flare
Viral Rebound
GenotypicResistance
-1
Early Addition of Adefovir is More Effective in Patients with Lamivudine Resistance
Lampertico P, Hepatology 2005;42:1414
0
20
40
60
80
100
0 3 6 9 12 15 18 21 24 Months
% P
atie
nts
wit
h
un
det
ecta
ble
HB
V- D
NA
Virologic BT <6 log HBV-DNA
Virologic BT6-8 log HBV-DNA
Biochemical BT>8 log HBV DNA
p<0.0001
Patientsstill at risk
28 3 1
32 22 14 10 6
13 12 11 914
0 0 0
5
6 10
09 4
4
0
2
3
0
Choice of Rescue Therapy
Depends on knowledge of
• Prior therapy
• Pattern of resistant mutations
• In vitro data on susceptibility of mutants to other antiviral therapies and any cross-resistance
Location of Primary Antiviral-Resistant HBV Location of Primary Antiviral-Resistant HBV Mutations in the HBV Polymerase/RT DomainMutations in the HBV Polymerase/RT Domain
LAM Resistance rtA181T rtM204V/I/S
ADV Resistance rtA181T/V rtN236T
ETV Resistance* rtI169T rtT184S/A/I/L rtS202G/I rtM250I/V
L-dT Resistance rtM204I
* In association with LAM-resistant mutations
845 a.a.
Terminal Protein Spacer POL/RT RNaseH
A B C ED
1 183 349 (rt1) 692 (rt 344)
YMDDF__V__LLAQ__
I(G) II(F)
Selection of lamivudine-resistant mutations limits future treatment options
L18
0M
A18
1V/T
T18
4G/S
/A/C
S20
2G
M20
4V/1
N23
6T
M25
0V
LAM
FTC
LdT
ADV
ETV
In Vitro Cross-Resistance
LAM LdT ETV ADV TDF
M 204 I ┼┼┼┼ ┼┼┼ ? ┼ ┼
L 180M+
M 204 V
┼┼┼┼ ┼ ┼┼ ┼ ┼
A 181 T/V ┼┼ ┼┼ ┼ ┼┼ ?
N 236 T ┼ ┼ ┼ ┼┼ ┼┼
I 169+
M 250V*
┼┼┼┼ ┼┼┼┼ ┼┼┼┼ ┼ ┼
T 184G+
S202 I*
┼┼┼┼ ┼┼┼┼ ┼┼┼┼ ┼ ┼
* (+ L180M + M 204 V/I)
Management of Lamivudine- or Telbivudine- Resistant HBV
• Add Adefovir
• Add Tenofovir or Switch to Truvada (FTC+Tenofovir)
– Not yet approved for HBV
• Switch to Entecavir
– Response not as good as wild type HBV, increase risk of ETV resistance
• Switch to Adefovir
– Response not as good as add-on therapy (some studies), increase risk of ADV resistance
• Switch to Interferon
– Limited data
Lamivudine resistant HBV: Add-on Adefovir is less likely to be associated
with subsequent resistance to Adefovir
5/5(100%)
9/29(31%)
% patients switched to ADV
Fung et al, J Hepatol 2006; 44:283-90
p=0.01
0102030405060708090
100
ADV-R No ADV-R
5/55/5100%100%
9/299/2931%31%
Management of Adefovir-Resistant HBV
• Lamivudine-naïve patients
– Add Lamivudine: long-term efficacy unknown
– Switch to Truvada: limited data
– Add or switch to Entecavir: limited data
– Switch to IFN: no data
– Switch to Tenofovir: partial response
Management of Adefovir-Resistant HBV
• Lamivudine-experienced patients
– Add Lamivudine: long-term efficacy unknown
• Rapid re-emergence of LAM-resistant mutations reported
– Switch to Truvada: limited data
– Add or switch to Entecavir: limited data
• Possibility of subsequent ETV-resistance unknown
– Switch to IFN: no data
– Switch to Tenofovir: partial response
Management of Entecavir-Resistant HBV
• Add or switch to Adefovir
• Add or switch to Tenofovir
• Switch to IFN
Little or no data on all options
Prevention of Antiviral-resistant HBV
• Judicious use of antiviral treatment
• Initiate treatment with combination therapy – what agents to combine?
• Use most potent agent with highest genetic barrier to resistance
• Monitor viral response – switch therapy if response suboptimal
• Counsel on medication compliance
• Avoid sequential monotherapy
• Avoid cross-resistant drugs