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Coinfection with Hepatitis B and HIV
Chia C. WangAssistant Professor of Medicine
AIDS Clinical ConferenceFebruary 20, 2007
Outline
• Epidemiology and Natural history• Endpoints of therapy• Therapeutic options• Resistance• Hepatocellular carcinoma• Hepatitis B vaccination
8% - High
2-7% - Intermediate
<2% - Low
Areas with high rates of hepatitis B
1 World Health Organization. Hepatitis B. Available at: http://www.who.int/emc-documents/hepatitis/docs/whocdscsrlyo20022/disease/world_distribution.html. Accessed June 1, 2004.
Worldwide prevalence of hepatitis and HIV
Infection Worldwide U.S. HIV 31 million 860,000
Hepatitis B (chronic) 300 million 1 million
Hepatitis C (chronic) 170 million 4 million
Progression to adverse clinical sequelae in HIV-negative individuals
Chronic hepatitisCirrhosis
and/or liver cancer
20%
Epidemiology of HBV in HIV-infected individuals
• Reported prevalence has ranged from 6-13%• ~ 4 million individuals worldwide with
HIV/HBV coinfection • Lower prevalence than 20-80% reported for
HCV
Genotypes in hepatitis B
Natural history of HBV in HIV-coinfected patients
• Higher levels of HBV DNA1
• Lower rates of spontaneous HBeAg seroconversion1
• Increased rates of liver-related mortality2
1. Hadler S, et al. J Infect Dis 1991;163:454-4592. Thio CL, Lancet 2002;360:1921-1926
Multicenter AIDS Cohort Study1
1. Thio CL, Lancet 2002;360:1921-1926. Longitudinal follow-up study of 5293 MSM in Baltimore, Chicago, Pittsburgh, LA. Men were followed from study entry to death, last time seen, or March 30, 2000 (whichever first: median followup 10.5 years). Total 1648 deaths, with 62 liver-related deaths.
Staging of Hepatitis B Infection
Stage
Resolved hepatitis B
Inactive hepatitis B
Chronic eAg positive hepatitis B
Chronic eAg negative hepatitis B
Occult hepatitis B
Staging of Hepatitis B Infection
Stage sAg eAg HBV DNAcopies/ml
Resolved hepatitis B -
Inactive hepatitis B +
Chronic eAg positive hepatitis B
+
Chronic eAg negative hepatitis B
+
Occult hepatitis B -
Staging of Hepatitis B Infection
Stage sAg eAg HBV DNAcopies/ml
Resolved hepatitis B - -
Inactive hepatitis B + -
Chronic eAg positive hepatitis B
+ +
Chronic eAg negative hepatitis B
+ -
Occult hepatitis B - -
Staging of Hepatitis B Infection
Stage sAg eAg HBV DNAcopies/ml
Resolved hepatitis B - -
Inactive hepatitis B + -
Chronic eAg positive hepatitis B
+ +
Chronic eAg negative hepatitis B
+ -
Occult hepatitis B - -
Staging of Hepatitis B Infection
Stage sAg eAg HBV DNAcopies/ml
Resolved hepatitis B - - neg-low
Inactive hepatitis B + - <10,000
Chronic eAg positive hepatitis B
+ + >10,000
Chronic eAg negative hepatitis B
+ - >10,000
Occult hepatitis B - - >10,000
Staging of Hepatitis B Infection
Stage sAg eAg HBV DNAcopies/ml
Resolved hepatitis B - - neg-low
Inactive hepatitis B + - <10,000
Chronic eAg positive hepatitis B
+ + >10,000
Chronic eAg negative hepatitis B
+ - >10,000
Occult hepatitis B - - >10,000
Staging of Hepatitis B Infection
Stage sAg eAg HBV DNAcopies/ml
Resolved hepatitis B - - neg-low
Inactive hepatitis B + - <10,000
Chronic eAg positive hepatitis B
+ + >10,000
Chronic eAg negative hepatitis B
+ - >10,000
Occult hepatitis B - - >10,000
Endpoints of therapyStage Endpoint
Resolved hepatitis B No therapy
Inactive hepatitis B No therapy
Chronic eAg positive hepatitis B
eAg seroconversion (development of eAb)
Chronic eAg negative hepatitis B
Durable HBV DNA suppression
Occult hepatitis B Durable HBV DNA suppression
Rates of HBeAg seroconversion
• Occurs at a rate of 8-12% yearly1
• With treatment, rate is increased to 15-27%1
• HBeAg loss has been associated with decreased rates of progression to cirrhosis or hepatocellular carcinoma2
1. Lok ASF, McMahon BJ. Chronic hepatitis B. Hepatology. 2001;34(6):1225-41. 2. Niederau C, Heintges T, Lange S, et al. Long-term follow-up of HBeAg-positive patients treated with interferon alfa for
chronic hepatitis B. N Engl J Med. 1996;334:1422-1427.
Cumulative survival (until liver transplantation or death) among Interferon-treated patients (solid lines) and
untreated patients (dashed lines) compared to patients who did not lose HBeAg
Niederau C, Heintges T, Lange S, et al. Long-term follow-up of HBeAg-positive patients treated with interferon alfa for chronic hepatitis B. N Engl J Med. 1996;334:1422-1427.
HBV DNA suppression as an endpoint of therapy
• 3 recent papers have demonstrated that HBV DNA suppression may be an important therapeutic goal, regardless of seroconversion
• Conventional Wisdom• Chronic HBV does not need to be treated
unless liver enzymes are elevated, liver biopsy is abnormal, or both
• The cost/risk of treatment of HBV treatment do not outweigh the potential benefit in patients with low likelihood of HBeAg seroconversion
“Therapy should be reserved for patients who need to be treated, those with active liver disease exemplified by raised serum ALT and by clinical or histologic evidence or progressive disease, or both.”
Jay Hoofnagle, NEJM, March 9 2006
Development of HCC was associated with viral load
Lamivudine Adefovir Entecavir
Telbivudine
Peg-Infn
HBV DNA loss 40% 21% 67% 60% 25%
eAg seroconversion
16% 12% 21% 22% 27%/32%
HBsAg loss <1% 0 0 0 3%
ALT normalization 41% 48% 68% 77% 39%
Histologic improvement
49% 53% 72% 65% 38%
Response durability
50-80% 90% 69% 80% 100%
Resistance rate 19%,49%,64%
0,3%,11%,18%,29%
3% (N)16% (E)
4%, 22% 0%
Rx in HBeAg positive
New England Journal of Medicine, June 30, 2005
Lamivudine Adefovir Entecavir
Telbivudine
Peg-Infn
HBV DNA loss 40% 21% 67% 60% 25%
eAg seroconversion
16% 12% 21% 22% 27%/32%
HBsAg loss <1% 0 0 0 3%
ALT normalization 41% 48% 68% 77% 39%
Histologic improvement
49% 53% 72% 65% 38%
Response durability
50-80% 90% 69% 80% 100%
Resistance rate 19%,49%,64%
0,3%,11%,18%,29%
3% (N)16% (E)
4%, 22% 0%
Rx in HBeAg positive
Lamivudine Adefovir Entecavir
Telbivudine
Peg-Infn
HBV DNA loss 40% 21% 67% 60% 25%
eAg seroconversion
16% 12% 21% 22% 27%/32%
HBsAg loss <1% 0 0 0 3%
ALT normalization 41% 48% 68% 77% 39%
Histologic improvement
49% 53% 72% 65% 38%
Response durability
50-80% 90% 69% 80% 100%
Resistance rate 19%,49%,64%
0,3%,11%,18%,29%
3% (N)16% (E)
4%, 22% 0%
Rx in HBeAg positive
Lamivudine Adefovir Entecavir
Telbivudine
Peg-Infn
HBV DNA loss 40% 21% 67% 60% 25%
eAg seroconversion
16% 12% 21% 22% 27%/32%
HBsAg loss <1% 0 0 0 3%
ALT normalization 41% 48% 68% 77% 39%
Histologic improvement
49% 53% 72% 65% 38%
Response durability
50-80% 90% 69% 80% 100%
Resistance rate 19%,49%,64%, 70%
0,3%,11%,18%,29%
3% (N)16% (E)
4%, 22% 0%
Rx in HBeAg positive
HBV Therapy
Activity against HIV No activity against HIV
lamivudine adefovir (10 mg dose)
tenofovir entecavir
emtricitabine telbivudine
peg-interferon
Recommendations for HBV treatment in HIV patients NOT on
HAART• Pegylated interferon alpha 2a
• (CD4 count >500)• Entecavir• Adefovir (!)• not Telbivudine (induce M204I mutation)
Recommendations for HBV treatment in HIV patients on
HAART• Include in the regimen a drug that has
activity against HBV• If HBV DNA levels are high, use two drugs• Be cautious when discontinuing or
switching HAART• Hepatitis flares may occur with withdrawal of
hepatitis B treatment
Monitoring on therapy
24 week viral suppression From Lai et al, Gastroenterology 2005;129:528.
Monitoring on therapy (some experts)
• Based on GLOBE trial data, maximize early viral suppression at 24 weeks
• Goal=1 log decrease every 3 months
• Undetectable viral load should occur at some point during therapy if no eAg seroconversion
Resistance to nucleoside analogues
YMDD motifM204I
YMDD motif
M204V
YMDD motif
L180M
N236T
A181V/T
rtI169, rtT184, rtS202, rtM250
lamivudine
X X X
entecavir* X X X
telbivudine
X
adefovir** X X
*resistance occurs via two-hit mechanism with initial selection of M204 V/I mutation followed by amino acid substitutions at one of the rt-sites. In vitro studies showed that the mutations at positions 169,184,202, or 250 on their own have minimal effect on susceptibility to entecavir, but susceptibility is decreased by 10 to 250-fold when one of these mutations is present with lamivudine-resistant mutations, and by >500-fold when two or more entecavir-resistant mutations are present with lamivudine resistance mutations.**The N237 T mutation has been shown to be susceptible to lamivudine and entecavir in vitro, but the A181V mutation has reduced susceptibility to both lamivudine and entecavir in vitro, but remains sensitive to tenofovir
Manifestations of Antiviral Resistance
0
8
6
4
2
HB
V D
NA
(lo
g1
0 IU
/ml)
Antiviral Treatment
Virologic rebound
Genotypic resistance
Biochemical breakthrough
Hepatitis flare
Years
3210
ALT
viral load
Comparison of antiviral responses at 48 weeks of ADV therapy according to emergence of ADV-resistant
mutations in LAM-Resistant patients
from Lee et al, Hepatology June, 2006.
On-treatment Follow-up
HBV DNA Levels Over Time M
ean
HB
V D
NA
(lo
g1
0 c
p/m
L)
-4.48*
-7.18
-5.81
-1.95
-2.39
-2.61
PEGASYS®
+ placebo
lamivudine
+ lamivudinePEGASYS®
HBeAg seroconEOT = 27%; EOF = 32%
HBeAg seroconEOT = 24%; EOF = 27%
HBeAg seroconEOT = 20%; EOF = 19%
Lau et al AASLD 2004
2
4
6
8
10
12
0 6 12 18 24 30 36 42 48 54 60 66 72
Evidence that combination therapy may slow resistance
• 29 HIV/HBV patients with documented lamivudine resistance
• All were treated with adefovir 10 mg daily
• None developed resistance to adefovir after 144 weeks (2.8 years)
• All maintained lamivudine resistance• Only 25% developed HBV DNA below
the level of detection (200 copies/ml) from Benhamou et al, Journal of Hepatology 44 (2006) 62-7.
Conclusions, hepatitis B treatment in HIV-coinfected
patients• Include emtricitabine and tenofovir in
HAART regimen if possible• If previously treated with lamivudine &
emtricitabine and with high viral load, likely underlying lamivudine resistance, consider including entecavir (particularly if no response in first 6 months of treatment)
• Goal of therapy is DNA suppression <10,000 copies/ml, or eAg seroconversion
• Telbivudine likely not useful if underlying lamivudine resistance
B-yond
Future management of hepatitis B
• Baseline genotyping on all patients• Resistance monitoring (?every 6
months) in treated patients
Two more things . . .
• HBV vaccination• Hepatocellular carcinoma
screening
Hepatitis B vaccination response rates
• 87% if CD4 count > 500• 33% if CD4 between 200-500
from Tenaldi et al, Clin Inf Dis 2004’38:1478-1484.
Hepatitis B vaccination
• Hepatitis B vaccination should be given when CD4 count > 200 cells/ul
• Otherwise HAART should be given first and then HBV vaccination given
• If CD4 between 200-500, an intensive schedule is recommended1:
• Months 0, 1, 2, and 6-12• If no response a new cycle with 40 ug
(double dose)
1Soriano et al, AIDS 2005, 19:221-240.
Liver Cancer
Hepatocellular carcinoma in patients with chronic hepatitis B
Chronic HBV
infection
HCC
Death
Cirrhosis
Decompensated cirrhosis
Hepatocellular carcinoma in patients with chronic hepatitis C
Chronic HCV
infection
HCC
Death
Cirrhosis
Decompensated cirrhosis
How to screen?
Why AFP should not be used as a screening test
Cutoff = 20 ng/ml
Using an AFP cutoff on 20 ng/ml
• Sensitivity = 60%• 40% of cancers would be missed• False positive rate very high• Positive predictive value = 41.5%• The chance that a positive test
would actually predict the presence of a tumor would be only 41.5%!!
Using an AFP cutoff on 200 ng/ml
• Lower false positive rate• But sensitivity only 22%
AASLD conclusions for screening tests
• The best test for HCC surveillance is ultrasound
• AFP should not be used alone unless ultrasound is not available
• Surveillance interval should be 6-12 months (most experts use 6 months, no data to support this practice)