HCV and HBV co-infections

Sanjay BhaganiRoyal Free Hospital

LondonEACS Advanced Course 2008

Causes of Liver Disease in HIV Infection

Mortality of HIV-infected patients in France (GERMIVIC Study Group)

0

5

10

15

20

Per

cen

tag

e

1995(n=17,487)

1997(n=26,497)

2001(n=25,178)

2003(n=20,940)

Overall mortality AIDS-assoc. Mortality Liver disease assoc. mortality

Rosenthal et al. AASLD 2004; Abstract 572.

40 million

40 million

175 million175

million

HIVHIVHCVHCV

Overlapping HCV & HIV Epidemics

10 million

10 million

25% of HIV

Reports of acute HCV in HIV+ MSM across Europe

Danta et al. AIDS 2007; 21: 983-991. Gambotti et al. Euro Surveill 2005; 10: 115-117. Ghosn et al. Sex Transm Infect 2006; 82: 458-460 ; 40: 41-46. Serpaggi et al. AIDS 2006; 20: 233-240.Vogel M et al. J Viral Hepat 2005; 12: 207-211

Risk Factors for Acute HCV in MSM

Group SexSexual practice

Drug practice

High-risk practices

Internet

Shared implements

‘Club drugs’

STIDanta et al, AIDS 2007

Phylogenetic Tree Constructed from Analysis of Paired Samples (red) Compared with Genebank Samples (black)

Jones et al. CROI 2008;Oral Abstract 64LB.

Is HCV Viraemia after SVR Following Initial Infection Re-infection or Relapse?

Effect of HIV/HCV co-infection on Effect of HIV/HCV co-infection on hepatic fibrosis progression hepatic fibrosis progression (Benhamou et al

1999)

0

0.5

1

1.5

2

2.5

3

3.5

4

10 20 30 40

HIV + Matched controls Simulated controls

Fibrosis progression influenced by• CD4 cell count (< 200 cells/microlitre)• Age at infection ( > 25 years)• Male sex• Alcohol consumption ( > 50g/d)

Fibro

sis

gra

de

HIV-HCV

Alcohol

HBV

Haemochromatosis

HCV

Steatosis BMI>25

2PBC0.00

0.17

0.33

0.50

0.67

0.83

1.00

0 20 40 60 80

Haza

rd f

un

ctio

n

4682 patients

Poynard, T. et al., (2003) A comparison of fibrosis progression in chronic liver disease. Journal of Hepatology 38:257-265

Age in years

Progression to cirrhosis

HIV/HCV - Cirrhosis and survival

Pineda et al. Hepatology 2005

A) Overall-Mortality

Observation time[days]]

500040003000200010000

Cu

mu

lati

ve s

urv

ival

1,1

,9

,7

,5

,3

P<0.0001

Patients with HAART

Patients with ART

untreated Patients

6000

Patients under observation:HAART-group: 93 79 33 - - - ART-group: 55 46 30 15 9 1Untreated-group: 137 94 49 37 32 27

6000500040003000200010000

1,1

,9

,7

,5

,3

B) Liver-related-Mortality

P<0.018

Patients with HAART

Patients with ART untreated Patients

Overall and Liver-related Mortality - effect of HAART

Qurishi N et al. Lancet, 2004

Cu

mu

lati

ve s

urv

ival

Observation time[days]]

Patients under observation:HAART-group: 93 79 33 - - - ART-group: 55 46 30 15 9 1Untreated-group: 137 94 49 37 32 27

% LEE by co-infection status

1. Benhamou Y, Mats V, Walcak D. Systemic overview of HAART associated liver enzyme elevations in patients infected with HIV and co-infected with HCV. CROI 2006;#88

Interactions were not significant between drug CLASS and CO (p=0.800)

N arms 11 7 4 12 9 3 14 10 4 11 6 5 5 3 2 53 35 18 N patients 581 1242 2705 2038 1055 7621 244 737 2321 630 572 4504 337 505 384 1408 483 3117

0

10

20

30

40

NNRTI PI Mixed BPI NRTI Overall

Drug Class

% P

atie

nts

wit

h L

EE

All Patients HCV Co-inf HIV Only

Treating HCV in HIV-infected patients

• HAART treated HIV patients live longer

• Faster progression to liver cirrhosis

• Increased mortality due to end stage liver disease

• Higher risk of hepatotoxicity following treatment with ART drugs

• Risk of hepatotoxicity reduced with successful HCV erradication

Response to PegIFN and Ribavirin in Response to PegIFN and Ribavirin in HIV/HCV co-infected patientsHIV/HCV co-infected patients

0102030405060708090

Overall SR G2/3 G1/4

Acute HCV/HIV: Overall virological responses:

64%

74%71%

66%

42%

RVR w12(pcr- ) w12(EVR) EOT SVR

133 = 56 89 95 99 853rd Int HIV/Hepatitis co-infection meeting, Paris 2007

Predictors of response

Host

Acute infectionYounger ageLack of stage 3/4 fibrosisEthnicityLow BMILack of hepatic steatosisHigh CD4 %Lack of insulin resistance

Virus

Genotypes 2/3Low viral loads

Gt 1 (n = 150)

34

162729

Gt 2/3 (n = 78)

47

7362 69

APRICOT: Baseline CD4+ Count and Efficacy of Peg-IFN alpha-

2a Plus RBV• Retrospective analysis of HIV/HCV-coinfected patients treated with

peg-IFN alpha-2a + RBV in APRICOT

• SVR rates analyzed in overall population and within genotypes according to baseline CD4+ cell count quartiles (Q1-Q4)

• Rate of SVR varied according to CD4+ cell percentage quartile in genotype 1 but not in genotypes 2/3

Dieterich D, et al. ICAAC 2006. Abstract H-1888.

0

20

40

60

80

100

Pts

Wit

h S

VR

(%

)

Q4 (32.1% to 69.3%)

Q1 (2.5% to 19%)

Q2 (19.1% to 25.0%)

Q3 (25.0% to 32.1%)

APRICOT: SVR rates according APRICOT: SVR rates according to exposureto exposure

Genotype 1 recipients of peginterferon alfa-2a plus ribavirin

39%

SV

R r

ate

(%

)S

VR

rate

(%

)

≥80/80/80exposure

0

10

20

30

40

50

11%

<80/80/80exposure*

62

29%

Allpatients

n = 176

114

*Patients violated the rule if ≥1 of the three targets were not achieved Opravil M, et al. 45th ICAAC 2005; Abstract

2038

Why lower response rates to anti-HCV therapy in HIV+ patients?

• Use of lower doses of RBV in most trials

• More advanced fibrosis grade

• Higher rate of steatosis (NRTIs, PIs)

• Unfavourable baseline HCV virological features

• Higher discontinuation due to side effects

• Lower initial HCV-RNA clearance

• Higher relapse rates

Viral Dynamic response to interferon and Viral Dynamic response to interferon and ribavirinribavirin

Pawlotsky Hepatology 2002; 32(4)

Does RVR predict response?(week 4 undetectable HCV

RNA)• APRICOT

– PPV 82%– NPV 79%

• RIBAVIC– PPV 97.5%– NPV 81.3%

• PRESCO– Lack of RVR independent

predictor of relapse

• Crespo M et al.– G3 patients with RVR low

rates of relapse with 24 weeks of therapy

• ROMANCE– G2/3 patients without RVR

need longer Rx (48 weeks)

APRICOT: week 12 – genotype 1 ≥2 log10 drop HCV RNA

● Genotype 1 patients (n=176)

SVR: n=50

PPV=45%

No SVR: n=60 (55%)

SVR: n=1 (2%)

No SVR: n=65

NPV=98%

n=66(37%)

n=110(63%)

Yes

No

Torriani F, et al. 45th ICAAC 2005; Abstract 1024

≥2 log10 drop or undetectable

HCV RNA

How can we maximise How can we maximise response to therapy?response to therapy?

Zidovudine: impact on HCV treatment

HB decrease by week 4

3.14

1.96

0

1

2

3

ZDV No ZDV

HB

lo

ss (

g/d

l)

RBV dose reduction by week 4

52%

20%

0%

20%

40%

60%

ZDV No ZDVP

atie

nts

wit

h R

BV

dec

reas

e

Alvarez D et al. 12th Conference on Retroviruses and Opportunistic Infections (Abstract #: P-192). Boston, MA USA, February 22–25, 2005

Interactions between RBV & nucleoside analogues

AZT ddI d4T

anemia hepatic pancreatitis weight

decomp. & lactic acidosis loss

mitochondrial DNA synthesis lactate

Blanco et al. NEJM 2002; 347: 1287

Abacavir and SVR

Vispo et al, 3rd Int. HIV/hepatitis Conference, Paris 2007. Abs 46

Study Design

n=389

Study weeks0 96724824 60 84

Peg

-IFN

+ R

BV

1000-1

200 m

g/d

ay

12 36

Follow-up

G2,3

G1,4

G1,4

G2,3

Follow-up

Follow-up

Follow-up

Only patients who achieved EVR (>2 log drop in HCV-RNA at week 12) continued treatment.

N=192

N=45

N=96

N=56

PRESCO

Importance of weight-based Ribavirin(1000mg <75kg/1200mg >75kg)

Soriano, et al. AIDS 2007. 21: 1073-89

Treatment of Chronic Treatment of Chronic HCVHCV

Extending TherapyExtending Therapy

6152

32

45

0

20

40

60

80

48 72

Weeks of Treatment

% H

CV

RN

A (

-)

EOT

SVR

Extending the duration of therapy reduced relapse from 47% to 13%

Sanchez-Tapias et al. AASLD 2004. Abstract 126.

Results (On Treatment analysis)

56

15(8%)

36(80%)

9(16%)

Voluntary withdrawals (64) 4(4%)

Short arm

Extended arm

PRESCO

192 45 96No. of patients (389)

31%

53%

67%

82%

G 1/4

G 2/3

5924

4664

p=0.004

p=0.04

Adapted from Manns MP et al. Nat Rev Drug Discovery. 2007;6:991-1000.

New oral small molecule ARVs in development for the treatment of HCV

Drug name Drug class Preclinical Phase I Phase II Phase III

MK-0608 (Merck)

R7128 (Pharmasset & Roche)

NIM811 (Novartis)

ITMN-191 (InterMune & Roche)

MK-7009 (Merck)

BI12202 (Boehringer)

R1626 (Roche)

DEBIO-025 (Debiopharm)

BI 1220 (Boehringer)

Telaprevir (Vertex Pharmaceuticals)

Boceprevir (Schering-Plough)

TMC435350 (Tibotec & Medivir)

Nucleoside polymerase inhibitor

Nucleoside polymerase inhibitor

Cyclophilin inhibitor

Protease inhibitor

Protease inhibitor

Protease inhibitor

Nucleoside polymerase inhibitor

Cyclophilin inhibitor

Nucleosite polymerase inhibitor

Protease inhibitor

Protease inhibitor

Protease inhibitor

X

X

X

X

X

X

X

X

X

X

X

X

X

TELAPREVIR: PROVE 2SVR

2) S261. Dusheiko et al .Treatment of chronic hepatitis C with telaprevir in combination with peginterferon alfa 2a with or without ribavirin: further interim

analysis results of the PROVE2 study. J Hepatology 2008; 48 (suppl)

Take home messages:• HIV/HCV co-infection is common• Increasing incidence of acute HCV• ESLD major cause of morbidity/mortality• Early HAART beneficial

– Avoid d-thymidine analogues/AZT

• Treat HCV with PegIFN and Ribavirin– Best results if HCV treated in the acute phase– Maximal doses of Ribavirin (1000/1200mg)– Avoid AZT, d4T and DDI, – ?Avoid Abcavir– EPO and G-CSF – avoid dose reductions

Take home messages:• Duration of therapy individualised

– Genotype– Pre-Rx viral load– Fibrosis stage– RVR/EVR

• No role for maintenance low-dose IFN• Give some thought to hepatic steatosis

• New anti-HCV drugs (STAT-Cs!) will be available in the future…

• …be careful out there….!!!

Proposed optimal duration of HCV therapy in HCV/HIV-coinfected patients.

W4 W12 W24 W48 W72

HCV-RNAneg

HCV-RNApos

> 2 log dropin HCV-RNA

< 2 log dropin HCV-RNA

HCV-RNAneg

HCV-RNApos

G2/3

G1/4

Stop

Stop

G2/3

G1/4

24 weekstherapy *

48 weekstherapy

72 weekstherapy

* In patients with baseline low viral load and minimal liver fibrosis.

EACS Guidelines 2008

40 million

40 million

400 million400

million

HIVHIVHBVHBV

HBsAg+

Overlapping HBV & HIV Epidemics

4 million

4 million

5–15% of HIV

HBsAg Prevalence

≥8% – High 2–7% – Intermediate

<2% – Low

Geographic Distribution of Chronic HBV Infection

Hepatitis B Disease Progression

Acute Infection

Chronic Infection Cirrhosis Death

1. Torresi, J, Locarnini, S. Gastroenterology. 2000.2. Fattovich, G, Giustina, G, Schalm, SW, et al. Hepatology. 1995.3. Moyer, LA, Mast, EE. Am J Prev Med. 1994.4. Perrillo, R, et al. Hepatology. 2001.

5%-10% of chronic HBV-infected individuals1

Liver Failure (Decompensation)

30% of chronic HBV-infected individuals1

• >90% of infected children progress to chronic disease

• <5% of infected immunocompetent adults progress to chronic disease1 23% of

patients decompensate within 5 years of developing cirrhosis 3

Liver Cancer (HCC)

Chronic HBV is the 6th leading cause of liver transplantation in the US 4

Liver Transplantati

on

Clearance

Phases of chronic HBV InfectionPhases of chronic HBV Infection

• Immune tolerant phase– High levels of HBV DNA– Very little inflammation

• Chronic hepatitis– HBeAg positive

• High levels HBV DNA, inflammation/progressive fibrosis– HBeAg negative

• Low levels HBV DNA, progressive inflammation and fibrosis

• Inactive HbsAg carrier state (non replicative phase)– HBeAg negative, low/absent HBV DNA, no

inflammation/fibrosis

Emergence of the e-negativeEmergence of the e-negativePrecore MutantPrecore Mutant

HBeAg+

HBV-DNA (mutant)

HBeAg / anti-HBe Anti-HBe+

HBV-DNA (wild)

Transaminases

Chronic hepatitismild

Chronic moderate tosevere hepatitis

Cirrhosis & hepato-cellular carcinoma

HBV tolerance HBV wild-typeclearance

Continued HBVprecore mutant

replication

0 5 10 15 20 YearsYears

Carman WF et al Viral Hepatitis. Scientific Basis and Clinical Management. NY: Churchill Livingstone; 1993:121.

Geographical distribution of HBV genotypes A to H

North Europe& USA - A

Mediterranean basin -D

AfricaE & DE & D

IndiaAA

Rare types:

F – Latin America

G –France, USA

H –Mexico,Latin America

Far EastB & C

Hepatitis B SerologyIsolated HBcAb+

• HIV negative– 50% true positive HBcAb– <2% with detectable serum HBV DNA

• HIV positive– 60-90% true positive HepBcAb– Many with detectable HBV DNA (~15% at RFH)– ~40% with necro-inflammation on liver biopsy

• Isolated anti-HBc more common in HIV/HCV• Implications for 3TC based HAART and

vaccination strategies

Hofer, Euro J Clinical Micro 1998. Ghandi, CID. June 15, 2003. Nebya, BHIVA 2006

HIV/HBV Coinfection• Increased incidence of chronic HBV in HIV+

patients (Lazizi JID 1988). Will vary greatly with subpopulation

• HIV+ pts 3-6x more likely to develop chronic HBV than HIV- (Bodsworth JID 1991)

• HBeAg and HBV DNA higher levels in HIV+ but AST/ALT lower (Perillo 1986)

• Increased hepatic fibrosis• Decreased spontaneous seroconversion (Krogsgaard

1987) or seroreversion of prior HBV infection with loss of anti-HBs and return of HBsAG (Waite AIDS 1988)

• Atypical serologies: anti-HBc may indicate chronic infection (Hofer 1998)

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

* Adjusted for age, sex, cigarette smoking, and alcohol consumption.

300 - < 104 104 - 105

HBV DNA copies/mL

105 - 106

All Participants(n = 3582)

*

RR * (95% CI)

*P < .001

6.55.6

2.51.4

0

2

4

6

8

10

12

14

> 106

*

*

HBeAg(-), Normal ALT(n = 2923)

300 - < 104 104 - 105 > 106

HBV DNA copies/mL

105 - 106

6.65.6

2.51.4

*P < .001

*

*

*

0

2

4

6

8

10

12

14

Level of HBV DNA (PCR-assays) at entry & progression to cirrhosis in population-based cohort studies

3582 HBsAg untreated asian carriersmean follow-up 11 yrs → 365 patients newly diagnosed with

cirrhosis

Iloeje UH, Gastroenterology 2006; 130: 678-686

HBV-DNA viral load (> 104 cp/ml) strongest predictor of progression to cirrhosis independent of ALT and HBeAg status

HBV-DNA levels (> 104 cp/ml) strong predictor of HCC, independent of HBeAg, ALT and cirrhosis

Entire cohort (N = 3653)

HBV-DNA (cp/ml) RR

< 3001.0-9.9 x 10 4

1.0-9.9 x 10 5

> 1.0 x 10 6

1.02.36.66.1

Subcohort (N = 2925)

HBV-DNA (cp/ml) RR

< 3001.0-9.9 x 10 4

1.0-9.9 x 10 5

> 1.0 x 10 6

1.04.5

11.317.7

•Population based cohort study of HBsAg asian carriers, mean follow-up= 11.4

Chen CJ et al JAMA 2006;295:65-73

13.5 %

7.9 %

0.9 %

0.7 %

3.1 %

>6log

5-6log

4-5log <4log

Level of HBV DNA (PCR-assays) at entry & risk of HCC

HBeAg (), Normal ALT,

No cirrhosis at entry (n = 2925)>6log

5-6log

4-5log

<4log

14.9%

12.1%

3.5%

1.3% 1.3%

Entire cohort (n = 3653)

How?

Restoring immune control

• Type I interferons– Interferon-alpha– Pegylated interferon-

alpha-2a

• ?others

Viral replication suppression with antivirals

• Lamivudine• Adefovir• Entecavir• (Tenofovir)• (FTC)• Telbivudine• (Clevudine)

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

HB

V D

NA

(lo

g1

0 cop

ies/m

l)

- 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 negativeHBeAg negative

3/33*3/33*

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

HIV/HBV LAM-RADV

Tenofovir for HBV - Gilead Study 903 HIV/HBV Coinfected Patients

Mean Change from Baseline in HBV DNA (95% CI)

TDF+LAM+EFV: 5d4T+LAM+EFV: 6

5 6

5 6

4 5

5 6

Ch

ang

e F

rom

Bas

elin

e in

log

10 H

BV

-DN

A

(co

pie

s/m

L)

-8

-7

-6

-5

-4

-3

-2

-1

0

WeeksBL 12 24 36 48

-2.95

-4.70

TDF+LAM+EFV

d4T+LAM+EFV

Cooper D. 10th CROI, Boston MA, February 10-14, 2003, Abstract # 825

Similar (better?) Anti-HBV Activity of Tenofovir compared to Adefovir in

Coinfected Patients• Interim data from ACTG A5127: HBV/HIV-1 coinfected pts

– HBV DNA ≥ 100,000 – Stable antiretroviral therapy; HIV-1 RNA ≤ 10,000

• Reduction in HBV DNA with tenofovir noninferior to adefovir

Peters M, et al. CROI 2006 Abstract 124.

HB

V D

NA

(lo

g1

0)

0

2

4

6

8

10

0 20 40 60 80 90

Weeks

48

AdefovirTenofovir DF

GLOBE: Year 1 Results of Telbivudine (LdT) for Chronic Hepatitis B

Lai et al. AASLD;2005. Abstract LB01.

Summary of Year 1 Results With Telbivudine

Outcome HBeAg-Positive Patients

HBeAg-Negative Patients

LdT, %(n = 458)

LAM, %(n = 463)

LdT, %(n = 222)

LAM, %(n = 224)

Undetectable HBV DNA• Week 52• Week 76

75*75* (n =

163)

6758 (n =

165)

88*84* (n =

68)

7167 (n = 67)

Virologic breakthrough by Week 48

3* 10 2* 9

Normalized ALT• Week 52• Week 76

7778* (n =

163)

7568 (n =

165)

7476 (n =

68)

7964 (n = 67)

Fibrosis decline by Wk 52 68 61 59 46

HBeAg seroconversion by Week 76

41* (n = 100)

26 (n = 93) N/A N/A*P < .05 vs lamivudine.

Potent Anti-HBV Activity From Addition of Entecavir to Continued 3TC in Coinfection

• ETV-038: HBV/HIV coinfected pts– HBV DNA ≥ 100,000, HBeAg+

or -, HBsAg+, compensated – HIV RNA < 400 for ≥ 12 weeks – 3TC-containing HAART for ≥ 24

weeks or YMDD mutation, no other agent with anti-HBV activity

• Entecavir (1 mg QD) vs placebo added to continued 3TC for 24 wks

• 84% ETV had HBV DNA < 400 or 2 log reduction by Week 24

• No difference in AEs

• RT sequencing for mutations M204V/I, L180M (3TC mutations) and T184, S202 and M259 (ETV mutations) at baseline and at week 48

Pessoa W, et al. CROI 2005, Abstract 123, Colonno et al, CROI 2006, Abstract 832

5117

4616

4816

n =n =

4916

*P < .0001

-3.66

-5

-4

-3

-2

-1

0

1

0 2 12 24

+0.11

*

*

*

Weeks

PlaceboEntecavir

Mean

HB

V D

NA

by P

CR

(l

og

10)

03

11

18

28

38

19

42

50

18

37

52

63

78

0

10

20

30

40

50

60

70

80

% P

atie

nts

Clinical lamivudine resistance (phenotypic resistance)

1

Detection of lamivudine-resistant mutations (genotypic resistance)

2 3 4 5years

Adefovir-resistance

(van Bömmel F, Mihm U, Jung C, Berg T. AASLD 2003Locarnini S et al EASL 2005, Abstract 36)

(Hadziyannis S et al. AASLD 2005 Abstract LB14)

Resistance development – Nucleos(t)ides

Comparative Incidence of HBV Resistance in Patients Treated with ADV or LAM

1. Benhamou Y. et al., Lancet (2001) 358:718-7232. Qi, et al., EASL 2004, Apr 16, 2004, Berlin 3. Lai C.L., et al., Clinical Infectious Diseases (2003) 36:6874. Benhamou Y et al. Hepatology 1999; 30:1302-6 * Year 4 resistance rate for ADV not yet

available

Inci

den

ce o

f Re

sist

an

ce

ADV1,2,*

(N236T or A181V)LAM3

(YMDD )LAM4

(YMDD in HIV/HBV)

0%

24%

2%

42%47%

3.9%

53%

70%

90%

0%

20%

40%

60%

80%

100%

year 1 year 2 year 3 year 4

Resistance Mutations Associated with Viral Breakthrough in Patients on

Treatment

Locarnini S et al. Antivir Ther 2004;9:679–93.

V214A/Q215S

V84M/S85A

A181V/T

M250V

L180M

T184G/S

S202IN236T

M204/I

LAM

ADV

ETV

LdT

FTC

Selection of LAM-Resistant Mutants Affects Future Treatment Options

Envelope changesPolymerase changes

Ag–Ab binding [IC50 (μg/ml)]

Wild type Wild type 1.09HBIG escape sG145R Anti-viral drug resistant sE164D sW196S sI195M sM198I sE164D/I195M

rtW153G

rtV173LrtM204IrtM204VrtV207IrtV173/rtL180/rtM204V

>55.0

14.868.295.2612.5

54.53

Cooley L et al. AIDS 2003;17:1649–57.

Envelope/Polymerase Mutations and the Antigen/Antibody Binding Capacity in Genotype A and D HBV/HIV Co-infected Subjects (n=9) with LAM Resistance

Anti-HIV activity of entecavir

• 17 HIV/HBV coinfected pts (10 naïve, 7 treatment-experienced from US and Australia) who received entecavir (ETV) monotherapy for HBV therapy.

• ETV monotherapy results in clinically-significant reduction in plasma HIV-RNA in the majority but not all pts, and can select for the M184V mutation even in naive pts

• HIV/HBV co-infected individuals should not receive ETV monotherapySelection of M184V following ETV tx

0

10

20

30

40

50

60

70ART naïve

Total

Median time to M184V 148 days 98 days

% w

ith

M18

4V

3/7

3/5

6/12ART experienced

Risk factor p value

Total duration on ETV 0.05

Magnitude of HBV-DNA reduction on ETV

0.04

HIV-RNA pre-ETV therapy 0.87

HBV-DNA pre-ETV therapy 0.69

Nadir CD4+ count 0.201. Audsley J, et al. 15th CROI, Boston 2008, No.63

Univariate analysis for selection of M184V

Conclusion: • TDF/3TC superior to 3TC alone but not TDF in HBV naïve • No benefit continuing 3TC in experienced HBV viraemic patients• No difference between adding or switching TDF

TDF vs TDF/3TC vs 3TCin drug-naïve HIV/HBV

coinfected

3TC - Naive

P=0.045vs. 3TC

N = 10 11 6

1. Nelson M, et al. A 48 week study of tenofovir or lamivudine or a combination of tenofovir and lamivudine for the treatment of chronic hepatitis B in HIV/HBV co-infected individuals. 13th CROI. Denver, CO, February 5-8, 2006; Abst. 831.

-6

-5

-4

-3

-2

-1

0BL 24 weeks

TDF 3TC TDF/3TC

LdT

FTC

Anti HBV Drugs in HIV Infection

TDF

ADF

ETVETV in LAMexp

LAM

Genetic Barrier

Pot

ency

No anti-HIV activity

Anti-HIV activity

IFN

Cumulative toxicity with ART (AZT, ddI)Cumulative toxicity with ART (AZT, ddI) 1 Log HIVRNA1 Log HIVRNA

CD4 counts = %CD4 counts = %

Partial Anti-HIVActivityM184V accumulation

Treatment Algorithm: Patients with Compensated Liver Disease and No indication for HIV therapy (CD4

count > 350/µl)

• No treatment

• Monitor every 6–12 months

• Monitor ALT every 3-12 months

• Consider biopsyand treat if disease

present***

• PEG IFN**** (favorable response factors are: HBeAg+ -

HBV Genotype A – elevated ALT and low HBV-DNA)

• Telbivudine (if HBV-DNA ist still detectable at week 24

add adefovir to minimize resistance development risk)

• Adefovor and telbivudine de novo therapy

• Early HAART initiation including Tenofovir+3TC/FTC

ALT Elevated

ALT Normal

HBV DNA2,000 IU/mL

HBV DNA<2,000 IU/mL**

HIV/HBV*

Soriano V, et al. 4th IAS, Sydney 2007, #MoBS104; Benhamou Y, 3rd International Workshop on HIV and hepatitis coinfection, Paris 2007

Immediate indication for HIV treatment

HBV-DNA

> 2000 IU/mlHBV-DNA

< 2000 IU/ml

HAART includingTDF + 3TC or FTC

Substitute one NRTI byTenofovir or add

Tenofovir*

Patients without HBV associated 3TC

resistance

Patients with cirrhosis

ECC Statement J Hepatol 2005

Patients with HBV associated 3TC

resistance

HAART regimen of choice

HAART includingTDF + 3TC or FTC

Management and therapeutic options in HIV-HBV co-infected patients with an indication of anti-HIV therapy

*if feasible and appropriate from the perspective of maintaining HIV suppression

Refer patient for liver transplantation evaluation if liver decompensation

occurs