Case study: Chronic HBV infection Marion Peters University of California San Francisco 2009.

Case study: Chronic HBV infection

Marion Peters

University of California San Francisco

2009

HBV case

• 45 year old man admitted with fatigue, malaise and abdominal swelling in June 2003

• He was born in Greece, came to US age 14• His brother had a liver transplant for HBV

in 1998• On Examination: jaundice, ascites, no

muscle wasting, spider nevi

HBV Laboratory and Imaging

• Bilirubin 3.7, AST 129, ALT 106, albumin 2.4, PT 1.7, Ammonia 51, Creatinine 0.9

• MELD 19

• HBsAg and HBeAg positive

• HBV DNA 340,000 IU/mL

• AFP 741 mcg/L

• Acites: paracentesis WCC 183, albumin <1

How would you treat his HBV?

Blue Pegylated interferon for 48 week

Green Lamivudine 100 mg per day

Red Entecavir 0.5 mg per day

Yellow Tenofovir 300 mg per day/ Combo

How would you treat his HBV?

Blue Pegylated interferon for 48 week

Green Lamivudine 100 mg per day

Red Entecavir 0.5 mg per day

Yellow Tenofovir 300 mg per day/ Combo

HBV case-3

• June 2003 started lamivudine 100 mg daily– Well tolerated, lost ascites– Patient had improved liver function

• Listed for liver transplantation

• Ultrasound cirrhotic liver no masses

• CT quadruple phase no masses

Date AST Bili Albumin AFP HBVDNA6-03 160 3.7 2.5 741 340,000,000

11- 03 59 0.9 3.1 14 400,000

IU/mL

LAM

Date AST Bili Albumin AFP HBVDNA6-03 160 3.7 2.5 741 340,000,000

11- 03 59 0.9 3.1 14 400,000

2-04 74 1.3 2.9 193 500,000,000

IU/mL

LAM

What has occurred?

Blue LAM non response

Red LAM resistance

Green Non compliance

What has occurred?

Blue LAM non response

Red LAM resistance

Green Non compliance

n =

HBV DNA at Month 6 of LAM Predicts Later Risk of Resistance

N = 159 HBeAg-positive patientsMedian follow-up: 29.6 months

Yuen ME, et al. Hepatology. 2001;34:785-791.

Pat

ien

ts W

ith

Res

ista

nce

(%

)

813

32

64

0

20

40

60

80

100

≤ 2 ≤ 3 ≤ 4 > 4

Pat

ien

ts W

ith

Y

MD

D V

aria

nts

(%

)

HBV DNA at 6 Months (log10 copies/mL)

12 23 41 118

HBV status

• HBV Genotype A, HBeAg positive

• Polymerase mutations– L180M, +M204V– no precore mutations detected– No ADV mutations detected

• HIV negative• HDV negative

HBV: How would you treat his HBV now with LAM resistance?

Blue Switch to Adefovir/TDF

Red Switch to Entecavir 0.5 mg per day

Green Add Entecavir 0.5 mg per day

Yellow Add Adefovir/TDF

HBV: How would you treat his HBV now?

Blue Switch to Adefovir/TDF

Red Switch to Entecavir 0.5 mg per day

Green Add Entecavir 0.5 mg per day

Yellow Add Adefovir/TDF

Date AST Bili Albumin AFP HBVDNA6-03 160 3.7 2.5 741 340,000,000

11- 03 59 0.9 3.1 14 400,000

2-04 74 1.3 2.9 193 500,000,000

IU/mL

LAM

addADV

Date AST Bili Albumin AFP HBVDNA6-03 160 3.7 2.5 741 340,000,000

11- 03 59 0.9 3.1 14 400,000

2-04 74 1.3 2.9 193 500,000,000

5-04 69 1.5 3.0 169 320,000,000

IU/mL

LAM

addADV

What has occurred?

Blue ADV resistance

Red ADV primary non response

Green ADV suboptimal response

Yellow Non compliance

What has occurred?

Blue ADV resistance

Red ADV primary non response

Green ADV suboptimal response

Yellow Non compliance

Nonresponse, Suboptimal Response, and Virologic

Breakthrough

Lok AS, et al. Hepatology. 2007;45:507-539.

1 log

Ch

ang

e in

HB

V D

NA

(lo

g10

IU

/mL

)

0

-1.0

-2.0

-3.0

-4.0

1.0

Nadir

Virologic breakthrough

Antiviral Drug

Months

60 12 18

Primary nonresponse

Suboptimal response

HBV DNA at Week 48 of ADV Predicts Risk of Resistance at Wk 144

Res

ista

nce

(%

)

1. Locarnini S, et al. EASL 2005. Abstract 36.2. Hadziyannis SJ, et al. Gastroenterology. 2006;131:1743-1751.

HBV DNA at Week 48 (log10copies/mL)

6

49

0

20

40

60

80

100

< 3 > 3

4

67

26

0

20

40

60

80

100

< 3 3-6 > 6

N = 114 patients, primarily HBeAg negative[1]

N = 124 patients, HBeAg

negative[2]

HBV-case: What would you do?

Blue Continue ADV

Red Add Tenofovir 300 mg

Green Change to TDF and ETV

Yellow Change to TDF and Lam/FTC

HBV-case: What would you do?

Blue Continue ADV

Red Add Tenofovir 300 mg

Green Change to TDF and ETV

Yellow Change to TDF and Lam/FTC

Date AST Bili Albumin AFP HBVDNA6-03 160 3.7 2.5 741 340,000,000

11- 03 59 0.9 3.1 14 400,000

2-04 74 1.3 2.9 193 500,000,000

5-04 69 1.5 3.0 169 320,000,000

8-04 68 1.8 3.4 42 15,400,000

11-04 67 1.0 3.7 16.2 19,200

5-06 52 1.1 4.0 8 518

5-07 28 1.0 4.4 2.9 undetectable

IU/mL

LAM

addADV

SwitchTo TDF+LAM

Adefovir monotherapy (Study 438: naive patients)

Adefovir + lamivudine (Studies 435 and 460i: lamivudine resistance*; Study 435: pre- and post-OLT; Study 460i: HIV/HBV)

Adefovir Resistance Not Observed With Lamivudine Combination Therapy

*2 patients enrolled in Study 435 initially received combination therapy with adefovir + lamivudine and subsequently selected adefovir resistance mutation N236T. However, they had switched to adefovir monotherapy at time when adefovir resistance mutation was detected.

Inci

den

ce o

f R

esis

tan

ce (

%)

0 0 3 0

11

0

19

30

0

20

40

60

Year 1 Year 2 Year 3 Year 4 Year 5

0

Lee YS, et al. Hepatology. 2006;43:1385-1391. Lampertico P, et al. AASLD 2006. Abstract LB5. Schiff E, et al. Liver Transpl. 2007;13:349-360. Hepsera [package insert].

Management of HBV

• Check response at 12 and 24 weeks• If no response switch• When virologic breakthrough occurs

– “Switch to” another drug– “Add on” another drug– “Switch to” and “add on” another drug

• Choice of second drug generally dictated by lack of cross-resistance

Combination therapy

• Sequential monotherapy with nucleos(t)ide analogues has led to HBV resistance

• Resistance has been low with combination therapy

• Peg IFN and LAM showed more HBV DNA suppression while on therapy, but lost after end of therapy, no increased HBeAg serconversion

• ADV and LAM/FTC less resistance but no increase in efficacy

Lampertico Gastro 2007; Yim HJ, et al. Hepatology. 2006:43:S173-181;Shaw T, et al. AASLD2007. Abstract 986; Schildgen O, et al. N Engl J Med. 2006;354:1807-1812; Reijnders JG, AASLD 2007. Abstract 951; Colonno R, et al. Hepatology. 2006;44:1656-1665.