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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.