case study: chronic hbv infection marion peters university of california san francisco 2009
TRANSCRIPT
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Case study: Chronic HBV infection
Marion Peters
University of California San Francisco
2009
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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
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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
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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
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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
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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
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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
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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
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What has occurred?
Blue LAM non response
Red LAM resistance
Green Non compliance
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What has occurred?
Blue LAM non response
Red LAM resistance
Green Non compliance
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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
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HBV status
• HBV Genotype A, HBeAg positive
• Polymerase mutations– L180M, +M204V– no precore mutations detected– No ADV mutations detected
• HIV negative• HDV negative
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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
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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
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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
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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
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What has occurred?
Blue ADV resistance
Red ADV primary non response
Green ADV suboptimal response
Yellow Non compliance
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What has occurred?
Blue ADV resistance
Red ADV primary non response
Green ADV suboptimal response
Yellow Non compliance
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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
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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]
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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
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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
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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
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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].
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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
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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.