coinfection with hepatitis b and hiv chia c. wang assistant professor of medicine aids clinical...

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)