Download Virology, Epidemiology, and Natural History of HIV and HCV Infections

What About Alcohol?
Chance Of Getting
Cirrhosis
Non-Drinker
Hepatitis C Non-Drinker
Drinker Without Hepatitis C
Drinker With Hepatitis C
Coinfection peg-IFN/RBV
Treatment Studies: Summary
Study
ACTG
A5071
APRICOT RIBAVIC
SVR % for 27%
GT 1
40%
27%
D/C Rate 12%
due to AEs
15%
31%
Low and High HCV RNA:
APRICOT
%SVR
Low HCV RNA High HCV RNA
(< 800,000)
(>800,000)
Gentoype 1
62%
18%
Genotype 2,3
62%
65%
Transmissibility through
contaminated injections
• HBV
30%
• HCV
3%
• HIV
0.3%
Hepatitis B Virus
• Member of Hepadnaviridae that primarily infects
liver cells
• Known carcinogen
• 100 times more infectious than HIV
• 10 times more infectious than HCV
Geographic Distribution of Chronic HBV Infection
HBV Genotypes
F
D
A
D
A,B,C,D
C
C
D
D
E
D
Bj
Ba
F
F
A
A,B,C,D
 This is an oversimplification as populations are not static…
Chronic HBV: Clinical Features
• Symptoms
– General: fatigue, anorexia, arthralgia, nausea
– Advanced: ascites, edema, bleeding GE varices, bruising, enlarged
spleen, jaundice, spider nevi, muscle wasting
• Symptoms may not correlate with liver biopsy findings
HBV DNA
HBsAg
HBeAg
ALT (U/L)
+
+
+/–
Normal to 
Anti-HBc (IgM) and Anti-HBs will also be negative for patients with chronic hepatitis B.
Dienstag, et al. In: Harrison’s Principles of Internal Medicine, 15th ed. Chap 297.
Mahoney. Clin Microbiol Rev. 1999;12:351-366.
McMahon. Semin Liver Dis. 2004;24:17-21.
CDC. Epidemiology and Prevention of Vaccine-Preventable Diseases. Atkinson W, et al, eds. 9th ed. 2006.
Natural Progression of CHB
15%–40% of CHB patients may experience disease progression
Liver
Cancer
(HCC)
5%–10%
10%–15% in 5 yr
Chronic
Infection
30%
Cirrhosis
Liver
Transplantation
Death
23% in 5 yr
Acute flare
Liver
Failure
Adapted from: Fattovich, et al. Gastroenterology. 2004;127:S35-S50. Torresi, et al. Gastroenterology. 2000;118:S83S103. Fattovich, et al. Hepatology. 1995;21:77-82. Perrillo, et al. Hepatology. 2001;33:424-432.
Influence of HBV on HIV
CONFLICTING DATA
• Increased rate of HIV progression to AIDS? 1
• No change in progression? 2
• Cohort studies suggest that HBV does not
appear to influence the progression of HIV.
Ref : 1.Eskild A, Magnus P, et al. Hepatitis B antibodies in HIV-infected homosexual
men are associated with more rapid progression to AIDS. Aids 1992:6:571-4
2. Diamondsstone LS, Blakly SA, et al. Prognostic factors for all-cause mortality among
hemophiliacs infected with human immunodeficiency virus. Am J Epidemiol
1995:142:304-13
Influence of HIV on HBV
• Lower rates of clearance of HBeAg
• Increased serum HBV DNA viral load 1
• Reactivation of hepatitis in asymptomatic
carriers
• Increased liver injury
• Faster fibrosis cirrhosis and HCC
• Higher mortality and morbidity
Ref: 1. Perillo RP, Regenstein FG, et al. Chronic hepatitis B in asymptomatic homosexual men with
antibody to the human immunodeficiency virus. Ann Intern Med 1986:105:382-3
HIV Co-infection Increases the Risk of
End-Stage-Liver-Disease (ESLD) due to HBV
• MACS, 4,967 men
– HIV, 47%
– HBV, 6% (n=326)
– HIV/HBV, 4.3% (n=213)
• HIV/HBV: 17-fold
higher risk of liver
death compared to
HBV alone
Liver Mortaility by HIV
and HBV Status
14.1
15
10
5
0
0.8
1.7
No HIV
or HBV
HBV
only
HIV
only
0
• Alcohol and low CD4
even increase the risk
Thio C et al. Lancet 2002;360:9349.
HIV
and
HBV
When to Treat
• HBeAg +
• HBeAg –
HBV DNA (IU/mL)
20,000
2,000
1 IU/mL = 5 to 6 copies/mL
Treatment Options for CHB
Interferon
-alfa
Immunomodulatory action
Antigen
presenting cell
T helper cell
B cell
Cytotoxic T cell
Antiviral action
Natural killer cell
Antiviral action
Nucleoside/
nucleotide
analogues
Treatment Options
AVAILABLE DRUGS
• Nucleoside/ nucleotide analogues
– LAM(3TC), ADV, ETV, FTC, TDF
• Newer agents
TELBUVIDINE (LdT),CLEVUDINE, PREDOFOVIR
• Interferons
- conventional
-pegylated
Aims of Therapy for
HBeAg-positive CHB
• Short-term measurable ‘surrogate’ markers of
treatment efficacy
– recommended endpoint: HBeAg seroconversion1
– other endpoints: HBV DNA suppression, ALT normalisation
• Long-term goals
– prevent/stop/reduce
• liver necrosis
• progression to cirrhosis, decompensated cirrhosis or HCC
•
Ultimate goal
– HBsAg seroconversion
– prolong ‘event-free’ survival
1. Lok, McMahon. Hepatology 2004 (AASLD Guidelines)
Treatment of HBeAg-Negative
Chronic Hepatitis B
• With nucleotide/nucleoside analogs
• With interferons (conventional/pegylated)
Challenges Of Therapy
• Rational drug use
– Both require treatment
– Treat HBV alone or treat HIV alone
• Screening?
• Liver biopsy?
• Treatment complications and their
management
• Viral resistance
Lamivudine (LAM,3TC)
Monotherapy for HBV
• Resistance rates (HBV)
1st year
15 – 32%
2nd year
38%
3rd year
56%
4th year
67%
Emergence of mutants associated with
phenotypic resistance, viral breakthrough,
with frequent hepatic failure.
Adefovir (ADV)
Monotherapy for HBV
• Resistance rates (HBV)
• 70 HBeAg negative patients 5 years of therapy
with ADV
1 year 0%
2 years 3%
3 years 11%
4 years 18%
5 years 29%
Hadziyannis et al Hepatology 2005; 42:754
Entecavir versus Adefovir:
Mean HBV DNA Through Week 24
12
Entecavir (n=33)
Adefovir (n=32)
Mean HBV DNA by PCR
(log10 copies/mL)
10
8
6
*
4
2
log10(300) copies/mL
0
0
14
28
42
56
70
84
Days
*P<0.0001, primary efficacy endpoint.
Leung N, et al. 57th AASLD. Boston, 2006. Abstract 982.
91
98
112
126
140
154
168
Tenofovir vs Adefovir in HBeAg-Positive
Patients: HBV DNA <400 Copies/mL
100
Tenofovir DF (n=176)
Adefovir (n=90)
90
76%
Patients (%)
80
70
60
P<0.001
50
40
30
13%
20
10
0
0
4
8
12
16
20
24
28
Weeks on Study
ITT: missing=failure.
Heathcote EJ, et al. 58th AASLD. Boston, 2007. Abstract LB6.
92
32
36
40
44
48
Tenofovir vs Adefovir in HBeAg-Negative
Patients: HBV DNA <400 Copies/mL
93%
100
Tenofovir DF (n=250)
Adefovir (n=125)
90
P<0.001
Patients (%)
80
70
60
63%
50
40
30
20
10
0
0
4
8
12
16
20
24
28
Weeks on Study
ITT: missing=failure.
Marcellin P, et al. 58th AASLD. Boston, 2007. Abstract LB2.
93
32
36
40
44
48