Long-Term Anti-HBV Therapy
Considerations
Adrian M. Di Bisceglie, MD, FACP
Badeeh A. & Catherine V. Bander Chair in Internal Medicine
Chairman and Professor of Internal Medicine
Chief of Hepatology
Saint Louis University School of Medicine
St. Louis, Missouri
Tram T. Tran, MD
Associate Professor of Medicine
University of California, Los Angeles School of Medicine
Medical Director
Liver Transplantation
Comprehensive Transplant Center
Cedars-Sinai Medical Center
Los Angeles, California
Recommended Duration of
Nucleos(t)ide Analog Therapy
Source
Recommended Duration
HBeAg-Positive Patients
HBeAg-Negative Patients
Package inserts1,2
Optimal duration of therapy is unknown
Optimal duration of therapy is
unknown
AASLD guidelines3
Continue at least 6 months after anti-HBe
seroconversion with HBV DNA
undetectable
Continue until HBsAg clearance
Continue 12 months after HBeAg
seroconversion as long as HBV DNA
levels are decreasing and until the HBV
DNA levels are undetectable
Continue long-term
US Algorithm guidelines4
In patients who undergo HBeAg
seroconversion but who still have
detectable but stable HBV DNA levels,
continue treatment for 6 months; then
document seroconversion again and
consider stopping treatment in patients
without cirrhosis.
1. Baraclude [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2010. 2. Viread [package insert]. Foster City,
CA: Gilead Sciences, Inc.; 2011. 3. Lok AS, et al. Hepatology. 2009;50:1-36. 4. Keeffe EB, et al. Clin Gastroenterol Hepatol.
2008;6:1315-1341.
Responses to Anti-HBV Therapies in TreatmentNaive HBsAg(+) Patients Treated for 1 Year
Drug
HBV DNA
Loss
HBeAg
Loss
HBeAg
Seroconversion
HBsAg
Loss
Durability*
25%
30%/34%†
27%/32%†
3%
NA
40%–44%
17%–32%
16%–21%
1%
50%–80%
Adefovir
21%
24%
12%
0%
90%
Entecavir
67%
22%
21%
2%
69%
Tenofovir
76%
NA
21%
3%
NA
PEG IFN
Lamivudine
*Lamivudine and entecavir – no or short consolidation; adefovir and tenofovir – consolidation for most
patients. †Results for week 48 end of treatment/week 72 (24 weeks posttreatment).
Abbreviation: NA, not available.
Lok AS, et al. Hepatology. 2009;50:1-36.
Responses to Anti-HBV Therapies in TreatmentNaive HBsAg(-) Patients Treated for 1 Year
Drug
HBV DNA
Loss
Durability
63%
~20%
60%–73%
<10%
Adefovir
51%
~5%
Entecavir
90%
3%
Tenofovir
93%
NA
PEG IFN
Lamivudine
Abbreviation: NA, not available.
Lok AS, et al. Hepatology. 2009;50:1-36.
Tenofovir—Regression of Hepatic Fibrosis
After 5 Years
•
Treatment-naive HBeAg(+) or
HBeAg(-) patients treated with
tenofovir 300 mg/day (N = 641)
348 had paired baseline and
5-year biopsies evaluated by
Ishak fibrosis score
– 98% had undetectable HBV DNA
at year 5
•
•
•
98% had improved or no
worsening of fibrosis
74% of cirrhotic patients no longer
had cirrhosis at year 5
Conclusion: Long-term tenofovir
treatment stabilizes or improves
fibrosis in most patients
(n = 10)(n = 126)(n = 79) (n = 37) (n = 19) (n = 77)
100%
No Change
Worsening
90%
80%
Percentage of Subjects
•
Improvement
Year 5 Response
70%
60%
50%
40%
30%
20%
10%
0%
1
2
3
4
5
6
Baseline Ishak Fibrosis Score
Graphic with permission from Marcellin P, et al. Paper presented at: 62nd AASLD; November 4-8,
Marcellin
P, et al.San
62nd Francisco,
AASLD; San Francisco,
November 4-8, 2011;
Abst. 1375.
2011;
CA.CA;
Hepatology.
2011;54:Abstract
1375.
Entecavir—Histologic Responses at
Week 48 and Long-Term
96
100
88
Patients (%)
80
Week 48
73
Long-term*
58
60
40
32
20
0
41/
56
55/
57
Histologic
Improvement
18/
56
50/
57
Ishak Score
≤1-Point Decrease
7
3/42
25/
43
Ishak Score
≤2-Point Decrease
*Median time on entecavir at time of long-term biopsy was 6 years (range, 3–7 years).
Chang TT, et al. Hepatology. 2010;52:886-893.
Adherence to Anti-HBV
Nucleos(t)ide Analogs
Adherence Rate
New Patients
Existing Patients
>95%
39.7%
46.1%
91%–95%
10.5%
9.3%
81%–90%
18.1%
18.5%
71%–80%
8.5%
10.5%
61%–70%
9%
6.1%
51%–60%
5%
3.9%
9.2%
5.6%
<50%
 Predictors of adherence
 Older than 45 years of age (P = .001)
 Receipt of adefovir or entecavir vs lamivudine (P <.001)
 Existing vs new patients (P = .002)
Chotiyaputta W, et al. J Hepatol. 2011;54:12-18.
Factors Associated with
Adherence Rate >90%
Factor
Age
Medication
Multivariate Analysis
Odds Ratio (95% CI)
≤45 years
0.82 (0.74–0.91)
>45 years
1.00
Lamivudine
0.66 (0.58–0.76)
Nonlamivudine
1.00
New/existing New
patient
Existing
Chotiyaputta W, et al. J Hepatol. 2011;54:12-18.
P-value
P = .001
P <.001
0.68 (0.53–0.86)
1.00
P = .002
Lamivudine vs Placebo—Clinical Endpoints
Drug
Disease
Progression
Child-Pugh
Increase
HCC
Lamivudine (n = 436)
7.8%
3.4%
3.9%
Placebo (n = 215)
17.7%
8.8%
7.4%
.001
.02
.047
P-value
Differences between groups for other endpoints were insignificant
• Renal insufficiency (lamivudine 0.5%; placebo 0%)
• Bleeding varices (lamivudine 0.5%; placebo 0%)
• Spontaneous bacterial peritonitis (lamivudine 0%; placebo 0%)
• Liver-related death (lamivudine 0%; placebo 0%)
Abbreviation: HCC, hepatocellular carcinoma.
Liaw YF, et al. N Engl J Med. 2004;351:1521-1531.