Slide #1

CL Thio, MD.Presented at RWCA Clinical Update, August 2006.

Optimizing Hepatitis B Virus Treatment in HIV-Infected

Individuals

Optimizing Hepatitis B Virus Treatment in HIV-Infected

IndividualsChloe L. Thio, MD

Associate Professor of Medicine

The Johns Hopkins University

The International AIDS Society–USA

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-

Slide #3

CL Thio, MD.Presented at RWCA Clinical Update, August 2006.

Hepatitis B Virus – ReplicationHepatitis B Virus – Replication

UncoatingUncoating

Nuclear import

Nuclear import

RepairRepair TranscriptionTranscription

TranslationTranslation

HBsAgHBsAg

Positive strand synthesis

Positive strand synthesis

Assembly & buddingAssembly & budding

ERER

Removal of pregenomeRemoval of pregenome

Negative strand synthesis

Negative strand synthesis

EncapsidationEncapsidation

cccDNAcccDNA

5’5’

5’5’

3’3’

3’3’

3.5 kb RNA3.5 kb RNA

Viral entryViral entry

2.4/2.1 kb RNA2.4/2.1 kb RNA

ExportExport

Viral accessory proteins:HBeAg and HBX

CL Thio, MD.Presented at RWCA Clinical Update, August 2006.

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

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 >105

Liver histology

HBeAg negwith active hepatitis

ALT > 2x

HBV DNA >104

Liver histology

HBeAg neg healthy carrier

ALT <2x

No HBV DNA

No liver lesions

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

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

2

4

6

8

10

12

14

16

Liv

er

MR

/10

00

PY

s

0.0 0.81.7

14.2

Thio et al, Lancet 2002

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

Slide #9

CL Thio, MD.Presented at RWCA Clinical Update, August 2006.

Adefovir dipivoxil for treatment of LMV-R HBV in HIV infected persons

68.6

5.7

14

27

4846

25

8.65.7

68

58

70

0

20

40

60

80

HBV DNA<1000 cp/ml

HBV DNA <200cp/ml

eAg loss HBeAg SC ALTnormalization

48 weeks 96 weeks 144 weeks 192 weeks

Observational cohort (n=35) receiving 10 mg ADV. 31 persons at 48 weeks and 29 at 144 weeks.

Benhamou et al, J Hepatol 2006

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 ADF TDF Diff Lower CI

ITT 52 –3.12 –4.03 0.91 –0.498

Mod. ITT 47 –3.35 –4.46 1.11 –0.090

AT 41 –3.48 –4.76 1.28 0.180

Serum HBV DNA DAVG48 (log10 c/mL)

DAVG: time-weighted average change from baseline

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 (%)

6 0

Mean Δ HBV DNA

(log cp/ml)

-3.65 +0.11

ALT nl (%) 34 8

Slide #12

CL Thio, MD.Presented at RWCA Clinical Update, August 2006.

0

25

50

75

100

1 2 3 4 5

LMV monoinfection

LMV HIV-HBV coinfection

ADV

Years on therapy

Dru

g r

esis

tan

t H

BV

(%

)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

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 LMV1

AdefovirPMEA2

ClevudineL-FMAU1,3

TelbivudineL-dT4

EntecavirETV4,5

HBVFold

ResistanceFold

ResistanceFold

ResistanceFold

ResistanceFold

Resistance

Wild-type 1 1 1 1 1

LMV-R

1.7 0.5 >120 12 1

>106 0.7 >120 236 30

>105 0.2 >120 133 30

ADV-R2-6 1-5 NA NA NA

3-8 7-10 4.7 2.4 0.67

ETV-R>1,000 1.0 NA >100 >1,000

>1,000 2.0 NA >1,000 >1,000

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

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

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.