Coinfection with Hepatitis B and HIV Chia C. Wang Assistant Professor of Medicine AIDS Clinical Conference February 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: distribution.html. Accessed June 1, 2004.

Worldwide prevalence of hepatitis and HIV

Progression to adverse clinical sequelae in HIV-negative individuals Chronic hepatitis Cirrhosis 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 DNA 1 Lower rates of spontaneous HBeAg seroconversion 1 Increased rates of liver-related mortality 2 1.Hadler S, et al. J Infect Dis 1991;163: Thio CL, Lancet 2002;360:

Multicenter AIDS Cohort Study 1 1.Thio CL, Lancet 2002;360: 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 StagesAgeAgHBV DNA copies/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 StagesAgeAgHBV DNA copies/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 StagesAgeAgHBV DNA copies/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 StagesAgeAgHBV DNA copies/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 StagesAgeAgHBV DNA copies/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 StagesAgeAgHBV DNA copies/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 therapy StageEndpoint Resolved hepatitis BNo therapy Inactive hepatitis BNo therapy Chronic eAg positive hepatitis B eAg seroconversion (development of eAb) Chronic eAg negative hepatitis B Durable HBV DNA suppression Occult hepatitis BDurable HBV DNA suppression

Rates of HBeAg seroconversion Occurs at a rate of 8-12% yearly 1 With treatment, rate is increased to 15-27% 1 HBeAg loss has been associated with decreased rates of progression to cirrhosis or hepatocellular carcinoma 2 1.Lok ASF, McMahon BJ. Chronic hepatitis B. Hepatology. 2001;34(6): 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:

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:

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

Development of HCC was associated with viral load

LamivudineAdefovirEntecavirTelbivudinePeg-Infn HBV DNA loss40%21%67%60%25% eAg seroconversion16%12%21%22%27%/32% HBsAg loss<1%0003% ALT normalization41%48%68%77%39% Histologic improvement 49%53%72%65%38% Response durability50-80%90%69%80%100% Resistance rate19%,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

LamivudineAdefovirEntecavirTelbivudinePeg-Infn HBV DNA loss40%21%67%60%25% eAg seroconversion16%12%21%22%27%/32% HBsAg loss<1%0003% ALT normalization41%48%68%77%39% Histologic improvement 49%53%72%65%38% Response durability50-80%90%69%80%100% Resistance rate19%,49%, 64% 0,3%,11%, 18%,29% 3% (N) 16% (E) 4%, 22%0% Rx in HBeAg positive

LamivudineAdefovirEntecavirTelbivudinePeg-Infn HBV DNA loss40%21%67%60%25% eAg seroconversion16%12%21%22%27%/32% HBsAg loss<1%0003% ALT normalization41%48%68%77%39% Histologic improvement 49%53%72%65%38% Response durability50-80%90%69%80%100% Resistance rate19%,49%, 64% 0,3%,11%, 18%,29% 3% (N) 16% (E) 4%, 22%0% Rx in HBeAg positive

LamivudineAdefovirEntecavirTelbivudinePeg-Infn HBV DNA loss40%21%67%60%25% eAg seroconversion16%12%21%22%27%/32% HBsAg loss<1%0003% ALT normalization41%48%68%77%39% Histologic improvement 49%53%72%65%38% Response durability50-80%90%69%80%100% Resistance rate19%,49%, 64%, 70% 0,3%,11%, 18%,29% 3% (N) 16% (E) 4%, 22%0% Rx in HBeAg positive

HBV Therapy Activity against HIVNo activity against HIV lamivudineadefovir (10 mg dose) tenofovirentecavir emtricitabinetelbivudine 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 motif M204I YMDD motif M204V YMDD motif L180M N236TA181V/TrtI169, rtT184, rtS202, rtM250 lamivudineXXX entecavir*XXX telbivudineX adefovir**XX * 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 HBV DNA (log 10 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-treatmentFollow-up HBV DNA Levels Over Time Mean HBV DNA (log 10 cp/mL) -4.48* PEGASYS ® + placebo lamivudine + lamivudine PEGASYS ® HBeAg serocon EOT = 27%; EOF = 32% HBeAg serocon EOT = 24%; EOF = 27% HBeAg serocon EOT = 20%; EOF = 19% Lau et al AASLD

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 > % if CD4 between from Tenaldi et al, Clin Inf Dis 2004’38:

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 , an intensive schedule is recommended 1 : Months 0, 1, 2, and 6-12 If no response a new cycle with 40 ug (double dose) 1 Soriano et al, AIDS 2005, 19:

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)