Yves BENHAMOU

Management of Patients with HIV/HBV Co-infection

Yves Benhamou

Hepatology Department

Groupe Hospitalier Pitié Salpétrière

Paris, France

Influence of HIV on HBVHIV in HBsAg positive patients (compared to HBV mono-

infected):

– Increases the risk of chronicity after HBV contamination

– Reduces the seroconversion rate to anti-HBe

– Increases reactivation rate

– Increases HBV replication

– Accelerates fibrosis progression

– Increases the risk of liver decompensation, HCC and liver deathBodsworth, JID 1989 ; Hadler, JID 1991 ; Krogsgaard, Hepatology 1987 ; Bodsworth, JID 1989 ; Gilson, AIDS 1997. Piroth, J Hepatol 2002

Vogel Cancer Res 1991; Corallini Cncer Res 1993 ; Altavilla Am J Pathol 2000 ; Bodsworth, JID 1989 ; Mills, Gastroenterol 1990 ; Goldin, J Clin Pathol 1990 ;Gilson, AIDS 1997 ; Thio, Lancet 2002. RR 8.3 (4.8-14.3) ; Di Martino, Gastroenterol 2002 ; Colin : Hepatol 1999 ; Di Martino, Gastroenterol ;

Perillo, Ann Int Med 1986 ; McDonald, J Hepatol 1987 ; Colin, Hepatology 1999 ; Gilson, AIDS 1997

HIV/CHB CoinfectionInfluence of HAART

• Increases duration of CHB by improving survival

• Increases the risk of ALT flares related to – Immune restoration– Hepatotoxicity

• (Severe) reactivation– Low CD4– ARV discontinuation– LAM resistance

• Inhibition of HBV replication associated with histological improvement (LAM, FTC, TDF)

• LAM reduces liver decompensation

?

Proia et al. Am J Med 2000. Wit et al. JID 2002. Benhamou et al. J Hepatol 2005. Bruno et al. Gastroenerol 2002. Bonacini et al. Gastroenterol 2002. Puoti et al. Antiviral Ther 2004. Gouskos AIDS 2004

HIV negativeN=504

HIV positiveN=164

P

Median ALTALT< 2xULN (%)

50 (45-56)26.7

57 (47-74)29.1

NS

HBeAg + (%) 49.9 78.8% <.0001

LAM-R HBV (%) 17.1 34.8% <.0001

HBVDNA> 6 log (%) 37.8 62.1% <.0001

Liver biopsy*

Fibrosis (median)- Cirrhosis (%)

Inflammation (median)- A2/3 (%)

N=469

1 (1-2)16

130.1

N=54

2 (2-2)29.6%

134.7

<.0001

<.0001

Assessed by the METAVIR scoring system.

HBsAg+ vs HBsAg+/HIVGHPS cohort

Benhamou et al CROI 2005

Liver Mortality Rate (per 1000 PY)MACS

0

2

4

6

8

10

12

14

16

HIV-/HBV- HIV-/HBV+ HIV+/HBV- HIV+/HBV-

Thio et al. Lancet 2004

0

0.25

0.50

0.75

1

0 75 150 225 300

Follow up (months)

Pro

po

rtio

n o

f p

atie

nts

fre

e

Of

live

r d

eco

mp

ensa

tio

nHIV – (n=504)

HIV + (n=164)

P=0.004

Liver decompensation in HBsAg+

Benhamou et al. CROI 2005

Anti-HBV therapy

• Objective: Decrease liver inflammation and fibrosis progression

• Criteria for anti-HBV initiation:– HBV DNA

• AgHBe+ > 20 000 UI/ml HBeAg+/- > 2000 UI/mL• AgHBe- > 2000 UI/ml

Alberti A et al. J Hepatol. 2005

– Histology• METAVIR A≥2 or F≥2

Thresholds based on HBV mono-infected knowledgeMay be used in HIV/HBV co-infected patients

Alberti A et al. J Hepatol. 2005

HIV/HBV: Treatment

Licensed for Treatment of CHB

• Lamivudine

• Adefovir dipivoxil

• Entecavir

• IFN/Pegylated IFN

Licensed for Treatment of HIV Only with Demonstrated Anti-HBV Activity

• Tenofovir DF

• Emtricitabine

Author(Yr.)Author(Yr.) n. Tx n. Tx n. Controlsn. ControlsHoofnagle(88)Hoofnagle(88) 1010 4 4Brook (89)Brook (89) 1616 6 6Brook (89)Brook (89) 6 6 9 9Pol (92)Pol (92) 1616 1414Wong (95)Wong (95) 1313 1313

All All 6161 4646

100100 1010 00 0,10,1 0,010,01

8,98,9

16 RCT IFN- vs placebo 837 HBsAg+ - 107 HIV+ included in 5 studies

HBe seroconversion/negativation : HIV+ vs HIV: – 0.38 (CI 0.06-0.7 P =.02)

IFN- in HBV /HIV co-infection

IFN Placebo

Puoti et al. personnal comm.

-3.5

-3

-2.5

-2

-1.5

-1

-0.5

0

0 4 8 12 20 28 36 44 52

Time in Weeks

Me

dia

n c

ha

ng

e in

log

HB

V D

NA

Lamivudine Placebo

Serum HBV DNA

Dore GJ, et al. J Infect Dis. 1999;180:607-613.

HIV/HBVLamivudine

-2.7 log10 copies/mL

0

50

100

150

200

250

300

Baseline 2 4 6 8 10 12

AL

T (

UI/L

)

HBV DNA >5x105 copies/mL at baseline

HBV DNA <5x105 copies/mL at baseline

P<0.05

Lamivudine therapy duration (months)

Changes in ALT (UI/mL) during lamivudine therapy

Y Benhamou et al. Ann Intern Med. 1996;125:705-712.

HIV/HBVLamivudine

Lo

g1

0 H

BV

DN

A

24 22 20 20 1733 33 33 33 3310 10 10 7 7

FTC HBV+HIVFTC HBV

d4T HBV+HIV

FTC is not licensed for the treatment of HBV.Raffi F. IAS Conference, July 13-16, 2003, Abstract # 215.

FTC HBV+HIV

d4T HBV+HIV

FTC in Chronic HBV (FTCB-102)

HIV/HBVFTC

4

5

6

7

8

9

10

0 12 24 36 48

ETV PBO

5.56

HB

V D

NA

(lo

g1

0 c

op

ies/

ml)

9.19

4.79

5.63

Weeks

RDZ double blinded phase All the patients: ETV 1.0 mg

HIV/HBV LAM-R: ETV

Pessoa et al. ICAAC 2005

Number of patients (%)

ETV

W24

ETV

W48

PBO

W24

PBO ETV

W48

ALT 5 (10) 2 (4) 0 (0) 2 (12)

AST 5 (10) 0 0 (0) 2(12)

Pessoa et al. ICAAC 2005

HIV/HBV LAM-R: ETV

ALT/AST flares (>3 x ULN) during ETV therapy

HB

V D

NA

(lo

g10 c

op

ies/

ml)

- 6.2 log10 c/ml p<0.001*

-7.0

-6.0

-5.0

-4.0

-3.0

-2.0

-1.0

0.0

0 24 48 72 96 120 144 168 192

ADV (weeks)

- 5.9 log10 c/ml p<0.001*

- 4.7 log10 c/ml P<0.001* - 5.5 log10 c/ml

p<0.001*

31 29 31 30 31 29 27†27n = 35

†27 patients remain on study

* p<0.001 Wilcoxon Sign Rank Test

Benhamou et al. Lancet. 2001;358: 718-23. & J Hepatol. 2006;44:62-7.

HBV DNA HBV DNA (< 2.6 log(< 2.6 log1010 copies/ml) copies/ml) 8/358/35

HBeAg negativationHBeAg negativation 3/33*3/33*

HBe seroconversion HBe seroconversion 2/33*2/33*

HIV/HBV LAM-RADV

Mean change from baseline (102.511.5 IU/L*) in serum ALT levels during ADV

40

75

110

145

180

Weeks of ADV

Se

rum

AL

T (

IU/m

L)

Bas. 12 24 36 48 60 72 84 88 92

P<0.001

Benhamou et al. Lancet. 2001;358: 718-23. & J Hepatol. 2006;44:62-7.

HIV/HBV LAM-RADV

Improvement in Fibrosis - METAVIR Score*

* Improvement defined as ≥1 point reduction ; ** Worsening defined as ≥ 1 point increase

Median METAVIR Fibrosis Score at Baseline = 2

Improved *

Worsened **

N = 15 12

33%50%

20% 8%

-30%

-10%

10%

30%

50%

70% Week 48 Week 192

Benhamou Y et al. J Hepatol. 2006;44:62-7.

Median (Q1-Q3) HBV DNA in HBeAg+ (n=72)

Benhamou Y, et al. Hepatology. 2006;43:548-55.

HIV/HBVTDF

Months of TDF

*Roche Cobas Amplicor, LLQ 200 copies/mL

HIV/HBV: TDFRetrospective Analysis

TDF added to 3TC HBV LAM-R vs TDF+ 3TC first line

Mauss S. et al. EASL 2006

Coinfection HBV: TDF

TDF added to 3TC HBV LAM-R vs TDF+ 3TC first line

Mauss S. et al. EASL 2006

Coinfection HBV: TDFTDF added to 3TC HBV LAM-R vs TDF+ 3TC first line

Mauss S. et al. EASL 2006

Peters M et al. CROI 2005.

-7

-6

-5

-4

-3

-2

-1

0

0 12 24 36 48

ADVTDF

HB

V D

NA

(lo

g 10

c/m

L)*

ADV 25 24 23 20 18 17

TDF 27 26 23 18 17 18

HIV/HBVADV vs TDF

*Roche Cobas Amplicor, LLQ 200 copies/mL

PEG 2a + ADV in HIV/HBV LAM-R

0123456789

Baseline 12 24 48 72

Weeks

Seru

m H

BV D

NA (l

og

copi

es/m

L)

PEGASYS + ADV

0

20

40

60

80

100

Weeks

Seru

m A

LT (I

U/L)

PEGASYS + ADV

HBV DNA ALT

Benhamou Y et al. ADPEG Study Preliminary report

HBV resistance

Lai C et al. N Engl J Med 1998. Leung N et al. J Hepatol 1999. Chang T et al. Antiv Ther 2000. Benhamou Y et al. Hepatology 1999. Benhamou Y et al. Lancet 2001 and AADSL 2003. Data on file. NV-02B-003. Idenix.

HIV/HBV HIV/HBV HBV HBV

0

00

0

0

0

0

50

90

0

4%

024%

18

4%

9

19%24

38

49

67%

0

10

20

30

40

50

60

70

80

90

1

3

LMVFTC LdT ADV

LMV+LdT

ETVLMV

LMV+ADV

LMV+TDF

ETV +

LAM

Years

Patien

ts (%)

Patien

ts (%)

HIV/HBV: TDF Resistance ?

Sheldon J et al. Antiviral Ther. 2005

Management and therapeutic options in HBV/HIV

MONITOR

Normal ALT

Low HBV DNA*

MONITOR

METAVIR A≤1 F≤1 METAVIR A≥2 F≥2Treat HBV only

Evaluation of liver lesions

Elevated ALT

High HBV DNA*

HBeAg, HBV DNA

ALT

Patients with no indication for anti-HIV therapy

HBeAg – Treat HBV only

ADV + ETV or + LdT

HBeAg +ADV + ETV or + LdT

PEG IFN ?

* HBV DNA • HBeAg+ : >20,000 IU/mL• HBeAg-: >2000 IU/mL Alberti A et al. J Hepatol. 2005

• HBeAg+/- > 2000 UI/mL

Adapted from Alberti A et al. J Hepatol. 2005

Management and therapeutic options in HBV/HIV

* HBV DNA • HBeAg+ : >20,000 IU/mL• HBeAg-: >2000 IU/mL

• HBeAg +/- > 2000 IU/mL

Adapted from Alberti A et al. J Hepatol. 2005

Monitor HBV DNAMonitor liver function

Low HBV DNA*

Lamivudine-naive

ARV with TDF +FTC/lamivudine

Substitute 1 NRTIwith tenofovir or

add tenofovir

Lamivudine resistantHBV

High HBVDNA*

ARV withtenofovir +

FTC/lamivudine

Cirrhosis

Immediate indication for anti-HIV therapy

Any ARV

HBV/HIV Co-infected Patient

CHB

Non complianceHBV Resistance

Unsuccessful immunereaction

HBV «reactivation»

Hepatotoxicity Others

DrugAlcohol

HDV superinfectionConcurrent medications

Metabolic disorders…

Liver disease progression

3TC, TDF, FTC activity

Successful immunereaction

Control of HBVreplication

Improvement of liver lesions

Cirrhosis