Anna LOK. Management of Antiviral Resistant Hepatitis B Clinical Case Anna S. F. Lok University of Michigan Ann Arbor, MI, USA.

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

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og

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ies/

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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

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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

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<300

1010

HBV

DNA

(Cop

ies/

ml)

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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

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<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

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% o

f p

atie

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% o

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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

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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

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0 3 6 9 12 15 18 21 24 Months

% P

atie

nts

wit

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un

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ecta

ble

HB

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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

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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