Transcript HBV DNA levels and long

On-treatment management for
chronic hepatitis B (CHB) in patients
receiving oral antiviral therapy
Byung-Ho Kim
Kyung Hee University School of Medicine
2009. 9. 1.
Oral nucleos(t)ides (NUCs) for CHB
Agents
Type
Lamivudine
Clevudine
Abbreviations
LAM
Nucleoside
analogue
CLV
Telbivudine
TLV
Entecavir
ETV
Adefovir dipivoxil
Tenofovir disoproxil
fumarate
Acyclic
nucleotide
analogue
ADV
TDF
Importance of serum HBV DNA
levels in clinical outcomes of
patients with CHB
REVEAL study: HBV DNA levels and
long-term outcomes (11.4 years)
Viral Load at Baseline (copies/mL)
20
< 300 (Undetectable)
300-9,999
100,000-999,999
 1 Million
Cumulative incidence
of HCC (n = 3653)
14.89%
15
12.17%
12
10,000-99,999
Relative risk of
LC (n = 3482)
10.6%
9.7%
10
8
6
10
HR=2.3
3.6%
4
5
3.57%
1.30% 1.37%
0
Chen CJ, et al. JAMA. 2006;295:65.
2.0%
2
1.0%
0
Iloeje UH, et al. Gastroenterology 2006;130:678.
Past HBV viral load as predictor of
mortality and morbidity from HCC and
CLD in a prospective study (11 years)
Chen G, et al. Am J Gastroenterol 2006;101:1797.
Impact of treatment-induced viral
suppression on clinical outcomes
Time to disease progression
Percentage with disease progression
ITT population
Lamivudine, n=436
Placebo, n=215
17.7%
Placebo
P=0.001
7.8%
Lamivudine
Time to disease progression (months)
Liaw et al, N Engl J Med, 2004
Time to diagnosis of HCC
Percentage with diagnosis
Lamivudine, n=436
Placebo, n=215
7.4%
Placebo
P=0.047
Lamivudine
3.9%
Time to diagnosis (months)
Excluding 5 cases in year 1: HR=0.47; P=0.052
Liaw et al, N Engl J Med, 2004
Summary on importance of serum
HBV DNA level in clinical outcomes
1. A serum HBV DNA level ≥ 4 log10
copies/mL is a strong risk factor for
disease progression and HCC.
2. Sustained HBV eradication may be the
important factor to determine therapeutic
outcomes.
Limited efficacy of current NUCs
• Weak antiviral potency
– ADV < LAM < TLV < ETV < TDF
• Long-term treatment is required.
• Drug resistance
– Frequent with LAM
– Less frequent with ADV and TLV
– Rare with ETV and TDF
Rates of undetectable HBV DNA
at 1 year of NUCs therapy
HBeAg (+) patients
HBeAg (-) patients
not head-to-head comparisons
EASL guidelines. J Hepatol 2009;50:227
Incidence/Probability of
Resistance Substitutions (%)
Rates of drug-resistance in
treatment-naïve patients
100
90
70
80
70
60
42
50
40
30
20
10
0
70
53
24
29
0
<1
1
3
<1
2
<<1
3
18
11
<1
4
<1
5
Lamivudine
Adefovir in HBeAg (-)
Entecavir
Duration of Therapy (Years)
Entecavir: Gish RG, et al. Gastroenterology 2007;133:1437
Adefovir: Hadziyannis S, et al. Gastroenterology 2006;131:1743
ETV resistance in HBeAg-positive
patients with LAM-resistance
Cumulative Probability (%)
100%
ETVr = LAMr (M204V ± L180M) +
T184, S202 and/or M250 substitutions
ETVr + Virologic Breakthrough
75%
46
50%
36
25%
6
0%
51
41
43
27
15 11
1
1 yr
(n=187)
2 yr
(n=146)
3 yr
(n=80)
• 72/187 (39%) achieved HBV DNA < 300 copies/mL
• 3/72 (4%) had subsequent genotypic ETV resistance
4 yr
(n=53)
5 yr
(n=33)
Tenney et al, APASL 2008
Time to disease progression by mutant
status during LAM treatment
Percentage with disease progression
25
Placebo (n=215)
21%
YMDDm (n=209) (49%)
20
Wild Type (n=221)
Placebo
15
13%
YMDD
10
5%
5
Wild type
0
0
6
12
18
24
30
36
Time after randomisation (months)
Liaw et al, N Engl J Med, 2004
On-treatment monitoring for
predicting therapeutic outcomes
during early treatment period
From month 6 onward during LAM tx, HBV
PCR negativity was predictive of HBeAg loss
PPV 54%
NPV 100%
Zöllner B, et al. J Med Vriol 2001;65:659.
HBV load & resistance during LAM
therapy
PPV 100%
NPV 53%
Zöllner B, et al. J Med Vriol 2001;65:659.
HBV DNA level at week 24 is useful to
predict viral resistance during LAM therapy
• HBV DNA ≤103 copies/mL
– A 21% chance of the developing YMDD mutant
• HBV DNA >103 copies/mL
– 63%
Yuen, et al. Hepatology 2001;34:785.
Optimal cut-off HBV DNA levels for
prediction of excellent response during
5 years of LAM treatment
74 HBeAg (+) patients
Ideal response at 5 years: n=17 (23%)
Best cut-off levels
Week 4: 4.0 log copies/mL (AUC 0.89)
PPV 100%, NPV 83.8%
Week 16: 3.6 log copies/mL (AUC 0.94)
PPV 100%, NPV 87.7%
Yuen et al, Hepatology 2007;46;1695.
Early viral suppression of TLV vs LAM:
GLOBE study
Serum HBV DNA after 24 weeks of treatment
Lai et al, NEJM, 2007;357:2576.
Undetectable HBV DNA
by PCR (%)
Low HBV DNA levels at wk 24 predict
favorable 1-year efficacy outcomes
Serum HBV DNA level at week 24 (log10 copies/mL)
Low HBV DNA levels at wk 24 predict
favorable 1-year efficacy outcomes
HBeAg seroconversion in HBeAg (+) patients
Serum HBV DNA level at week 24 (log10 copies/mL)
Low HBV DNA levels at wk 24 predict
favorable 1-year efficacy outcomes
Resistance at week 48 (%)
Serum HBV DNA level at week 24 (log10 copies/mL)
Viral response to long-term ADV
monotherapy
n=76
VR: HBV DNA<3 log10 copies/mL
Reijnders JGP, et al, J Viral Hept 2009;16:113.
Virologic response to ADV can be assessed
at 24 weeks
Reijnders JGP, et al, J Viral Hept 2009;16:113.
HBV DNA levels at week 24 after switching
to ADV monotherapy predict an optimal
response in patient with LAM resistance
Area under the ROC curve
(n=43)
(n=30)
HBV DNA level at wk 12
HBV DNA level at wk 24
HBV DNA reduction from
the baseline at wk 12
HBV DNA reduction from
the baseline at wk 24
Shim, et al. 2009 APASL STC
Prediction of response at weeks 48 by HBV
DNA levels measured at week 24
HBV DNA cutoff level
(log10 copies/mL)
PV index
PPV
NPV
2.8
0.719
83.3%
88.6%
3.0
0.766
79.2%
97.4%
3.3
0.733
76.0%
97.3%
3.6
0.645
64.5%
100%
4.0
0.513
51.3%
100%
PV (predictive value) index means PPV plus NPV minus 1.
Shim, et al. 2009 APASL STC
On-treatment predictors for
ETV or TDF
• The 24-week on-treatment HBV DNA level
achieved in patients with LAM resistance
also may be predictive of long-term
outcomes and the eventual emergence of
resistance to this drug
Colonno, et al. Hepatology 2005;42(Suppl 1):573A.
2009 EASL definition of viral
response to NUCs
Virologic
breakthrough
HBV DNA (log10 IU/mL)
8
Primary
non-response
6
Partial VR
4
Virologic
response (VR)
2
0
12
24
36
48
Duration of treatment (wks)
EASL guidelines. J Hepatol 2009;50:227.
Factors related to primary non-response
• Host factors
– Compliance
– Enzyme polymorphism
• Viral factors
– High viral load
– Viral quasispecies with lower drug susceptibility
– Intrinsic mutation
• Drug-related factors
– Drug potency
• More frequent with ADV: 10-20%
• Rare with LAM, TLV, ETV or TDF: 1-3%
Summary
• Potent drugs with a high genetic barrier
should be used as first-line monotherapy.
• Early virological response is of value in
predicting likely long-term outcomes.
– Primary response to NUCs should be checked at
week 12 to modify management.
– Monitoring the serum HBV DNA level at week 24
may be crucial to maximize treatment outcomes.
Tailoring oral antiviral therapy
Primary non-response (PNR) at week 12
Responder
PNR
Compliance (+)
Continue tx
Change tx option
Compliance (-)
Education
Monitoring at week 24 for drugs with a low genetic
barrier or moderately potent drugs (LAM, TLV, ADF)
Complete VR
Incomplete VR
Continue tx
Change tx option
HBV treatment roadmap concept
Primary non-response (PNR) at week 12
PNR ()
PNR (+)
Compliance (+)
Continue tx
Change tx option
Compliance (-)
Education
Monitoring at week 24 for less potent drugs
CVR
PVR
IVR
Tailoring oral antiviral therapy at week 24
CVR
- Continued therapy
- Monitor every 6 months
Drugs with low genetic
barrier - add a second drug
with different resistant profile
If complete response at 48 weeks
- Continued therapy
PVR
IVR
- Switch to potent drug or
Add more potent drug
with no cross-resistance
- Monitor every 3 months
Drugs with high genetic barrier
or suboptimal potency – monitor
every 3 months beyond 48 weeks
If incomplete response at 48 weeks
- Add a more potent drug with no
cross-resistant profile