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Slide #1 CL Thio, MD. Presented at RWCA Clinical Update, August 2006. Optimizing Hepatitis B Virus Treatment in HIV-Infected Individuals Chloe L. Thio,

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Presentation on theme: "Slide #1 CL Thio, MD. Presented at RWCA Clinical Update, August 2006. Optimizing Hepatitis B Virus Treatment in HIV-Infected Individuals Chloe L. Thio,"— Presentation transcript:

1 Slide #1 CL Thio, MD. Presented at RWCA Clinical Update, August 2006. Optimizing Hepatitis B Virus Treatment in HIV-Infected Individuals Chloe L. Thio, MD Associate Professor of Medicine The Johns Hopkins University The International AIDS Society–USA

2 Slide #2 CL Thio, MD. Presented at RWCA Clinical Update, August 2006. Natural History HBsAg HBV DNA HBeAg/anti-HBe ALT/hepatitis Immune state Clinical Exposure Tolerance Incubation (wks-years) HBeAg+ Active Symptoms (wks:self- limited or years:chronic) Anti-HBe+ Non-replicative Inactive carrier (may last lifetime- risk of reactivation) Reactivation Minimal HBsAg+HBsAg-

3 Slide #3 CL Thio, MD. Presented at RWCA Clinical Update, August 2006. Hepatitis B Virus – Replication Uncoating Nuclear import Repair Transcription Translation HBsAg Positive strand synthesis Assembly & budding ER Removal of pregenome Negative strand synthesis Encapsidation cccDNA 5’ 3’ 3.5 kb RNA Viral entry 2.4/2.1 kb RNA Export Viral accessory proteins: HBeAg and HBX CL Thio, MD. Presented at RWCA Clinical Update, August 2006.

4 Slide #4 CL Thio, MD. Presented at RWCA Clinical Update, August 2006. Classification of Hepatitis B Acute IgM anti-HBc Chronic HBsAg > 6 months Vaccine recipient Anti-HBs only Past infection Anti-HBs and anti-HBc

5 Slide #5 CL Thio, MD. Presented at RWCA Clinical Update, August 2006. Classification of Chronic Hepatitis B Chronic (HBsAg > 6 mo) HBeAg pos with active hepatitis ALT > 2x HBV DNA >10 5 Liver histology HBeAg neg with active hepatitis ALT > 2x HBV DNA >10 4 Liver histology HBeAg neg healthy carrier ALT <2x No HBV DNA No liver lesions

6 Slide #6 CL Thio, MD. Presented at RWCA Clinical Update, August 2006. Why treat HBV in HIV-infected persons Co-infection is common-10% of HIV- infected More rapid progression of liver disease Increased risk of liver-related mortality Increased risk of HAART-related hepatotoxicity ?Immune reconstitution syndrome

7 Slide #7 CL Thio, MD. Presented at RWCA Clinical Update, August 2006. Increased Liver Mortality in HIV- HBV co-infected men: MACS 5293 men (326 HBsAg+ baseline) followed 10.5 years RR of liver death 18.7 in coinfected vs. only HBsAg+ 0.0 0.8 1.7 14.2 Thio et al, Lancet 2002

8 Slide #8 CL Thio, MD. Presented at RWCA Clinical Update, August 2006. Available therapies for HBV FDA approved Lamivudine* Adefovir dipivoxil Pegylated-interferon*-not tested in HIV+ Entecavir Available but not FDA approved Emtricitabine* Tenofovir disoproxil fumarate* *active against HIV

9 Slide #9 CL Thio, MD. Presented at RWCA Clinical Update, August 2006. Adefovir dipivoxil for treatment of LMV-R HBV in HIV infected persons Observational cohort (n=35) receiving 10 mg ADV. 31 persons at 48 weeks and 29 at 144 weeks. Benhamou et al, J Hepatol 2006

10 Slide #10 CL Thio, MD. Presented at RWCA Clinical Update, August 2006. ACTG A5127:TDF vs adefovir for HBV in HIV coinfection Double-blind, placebo- controlled study of ADF (10 mg) vs TDF (300 mg) Patients on stable HAART; n=52 HBV DNA >100,000 c/mL HIV RNA <10,000 c/mL Early termination when endpoints met Peters M, et al. 12th CROI, Boston 2005, #124 Mean change in HBV DNA from BL n ADFTDFDiffLower CI ITT52–3.12–4.030.91–0.498 Mod. ITT47–3.35–4.461.11–0.090 AT41–3.48–4.761.280.180 Serum HBV DNA DAVG 48 (log 10 c/mL) DAVG: time-weighted average change from baseline

11 Slide #11 CL Thio, MD. Presented at RWCA Clinical Update, August 2006. Entecavir Double-blind placebo controlled study of ETV vs. continuing LMV in LMV-R CHB for 24 wks 68 HIV-HBV patients Mean HBV DNA 9.13 log copies/ml Mean HIV RNA 2 log copies/ml ETV n=51 LMV N=17 HBV DNA <300 cp/ml (%) 60 Mean Δ HBV DNA (log cp/ml) -3.65+0.11 ALT nl (%)348

12 Slide #12 CL Thio, MD. Presented at RWCA Clinical Update, August 2006. Years on therapy Drug resistant HBV (%) Development of LMV and ADV Resistant HBV Emergence of resistance is clinically evident with elevation in ALT/AST In US, 90% of coinfected persons with h/o LMV use

13 Slide #13 CL Thio, MD. Presented at RWCA Clinical Update, August 2006. Cross-resistance of Drug-Resistant HBV 1. Chin et al. AAC 2001; 45:2495. 4. Levine et al. AAC 2002; 46:2525. 2. Angus et al. Gastroenterology 2004; 125:297. 5. Tenny et al. AAC 2004 (in press). 3. Ono-Nita et al. AAC 2002; 46:2602. Lamivudine LMV 1 Adefovir PMEA 2 Clevudine L-FMAU 1,3 Telbivudine L-dT 4 Entecavir ETV 4,5 HBV Fold Resistance Wild-type11111 LMV-R 1.70.5>120121 >1060.7>12023630 >1050.2>12013330 ADV-R 2-61-5NA 3-87-104.72.40.67 ETV-R >1,0001.0NA>100>1,000 2.0NA>1,000

14 Slide #14 CL Thio, MD. Presented at RWCA Clinical Update, August 2006. Strategies to treat HBV and not HIV Use agents that are not active against HIV to prevent development of drug- resistant HIV Pegylated-interferon-alfa –HBeAg+, genotype A, elevated ALT Entecavir Adefovir ?combination entecavir+ adefovir

15 Slide #15 CL Thio, MD. Presented at RWCA Clinical Update, August 2006. Strategies to treat HBV and HIV All of the following should be used with HAART LMV naive –First line: TDF plus LMV/FTC (emtricitabine) –Other considerations Entecavir +/- TDF PEG-IFN LMV experienced –First line: Add TDF to LMV –Other considerations Entecavir 1.0 mg- resistance with LMV-R HBV Add ADV

16 Slide #16 CL Thio, MD. Presented at RWCA Clinical Update, August 2006. Summary Treatment of HBV should be considered in HIV-infected persons. Resistance occurs but rates vary. –Cross-resistance also occurs Treatment plan is individualized based on need for HIV treatment and prior LMV therapy. Prevent emergence of drug-resistant HBV and HIV. More potent agents are needed. Combination therapy needs further investigation.


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