HIV and HBV/HCV coinfectionand liver transplantation:

ResultsJean-Charles Duclos-Vallée

CENTRE HEPATO-BILIAIREHÔPITAL PAUL BROUSSE

VILLEJUIF

HIV Coinfection Shortens the Survival of Patients with HCV Decompensated Cirrhosis

MedianMedian survivalsurvival = 16 = 16 monthsmonths

Pineda et al. Pineda et al. HepatologyHepatology 20052005

Surv

ival

Surv

ival

prob

abili

typr

obab

ility

335511111919303046467575180180HIV positiveHIV positive

99626213313320820831331342942961961910371037HIV HIV negativenegative

NN°° atat riskrisk

ProbabilityProbability ofof patient patient survivalsurvivalaccordingaccording to HIV to HIV serostatusserostatus

44%44%61%61%74%74%HIVHIV--

25%25%40%40%54%54%HIV+HIV+

55--yearyear22--yearyear11--yearyearSurvivalSurvival

0 10 20 30 40 50 60 700.0

0.2

0.4

0.6

0.8

1.0

HIV negative

HIV positive

Months

Liver Transplantation in Adults Coinfected with HIV under HAART

Preliminary ExperiencePrachalias et al. Transplantation 2001

Liver Transplantation in Adults Coinfected with HIV under HAART

Preliminary ExperiencePrachalias et al. Transplantation 2001

Alive(4 months)

NANB5

Alive(24 months)

HBV4

Died (6 months)

HCV3

Died(15 months)

HCV2

Died (25 months)

HCV1

OutcomePost LT

DiagnosisPatients

LIVER TRANSPLANTATION IN HIV-HCV PATIENTSPittsburgh and Miami (1997-2001)

AliveNov 200115AliveOct 200114AliveJan 200113AliveOct 200012

CR/HCV Died (570 days)Mar199910

Acute CRDied (12 days)Jan 19999AliveDec 19988AliveSept 19977AliveMay 20016

CauseOutcomeOLT datePatient

Neff et al. Liver Transpl 2003

LIVER TRANSPLANTATION IN HIV-HBV PATIENTSPittsburgh and Miami (1997-2001)

AliveNov 200115AliveOct 200114AliveJan 200113AliveOct 200012

CR/HCV Died (570 days)Mar199910

Acute CRDied (12 days)Jan 19999AliveDec 19988AliveSept 19977AliveMay 20016

CauseOutcomeOLT datePatient

Neff et al. Liver Transpl 2003

PRETRANSPLANT INCLUSION AND EXCLUSION CRITERIA

Inclusion:

HIV viral load -Limited or no opportunistic

complicationsCD4+ > 250/mL for the past 6 monthsHistory of compliance with medical

protocol

Exclusion:

Ongoing opportunistic infection or cancer

History of any neoplasm except hepatocellular carcinoma

Paul Brousse ExperienceNovember 2000 - October 2005

Paul Brousse ExperienceNovember 2000 - October 2005

n = 41patients transplanted

HBV Cirrhosis n=6

(Delta coinfection: n=2)(HCC: n=1)

HCV Cirrhosis

n=34(HCC: n=3)

Fulminant Hepatitis: n=1

8 patients died

HCV recurrence and mitochondrial toxicity: n=5Acute pancreatitis: n=1

Pancreatic adenocarcinoma: n=1Cerebral hemorrhage: n=1

Paul Brousse ExperienceNovember 2000 - October 2005

Paul Brousse ExperienceNovember 2000 - October 2005

n = 41patients transplanted

0

1

2

3

4

5

6

7

8

9

D0 D15 M1 M3 M6 M12 M18 M24 M36

post LT

HCV RNA log10

HCV viral recurrenceHCV viral load

HCV viral recurrenceHCV viral load

5,6

5,8

6

6,2

6,4

6,6

6,8

Viral load at 6 months

6. 8 ± 0.4

6. 0 ± 1

P=0.03

Co-infectedMonoinfected

HCV viral recurrenceSeverity of fibrosisJanuary 1999 - June 2004

n= 23 HIV/HCV +

HCV viral recurrenceSeverity of fibrosisJanuary 1999 - June 2004

n= 23 HIV/HCV +

0

5

10

15

20

25

30

35

F=3

%

5/2322%

3/2313%

F=4

Rate of Fibrosis between M12 and M16= Time from LT/Metavir F

0

0,20,4

0,60,8

1

1,2

1,4

1,6

Coinfected(n=23)

Monoinfected (n=44)

1.5 ±1.4

0.8 ± 0.5

P=0.03

M4, M6, M16,M20, M21Post LT

M24, M24,M18

Post LT

Fibrosing cholestasis Hepatitis n=1

M24Post LT

HCV viral recurrenceEffect of Antiviral TherapyHCV viral recurrence

Effect of Antiviral Therapy

10/14 (71%)3/13 (23%)Virological response

14/44 (32 %)13/22 (59 %)Pegylated interferon a 2-b + ribavirin

Monoinfected patients

Co-infected patients

Secondary effect of anti-HCV therapy

Anti Anti HCV HCV therapy wastherapy wasstopped stopped in 5 patientsin 5 patients

•• Pancreatitis Pancreatitis : n = 1: n = 1•• Lethal lactic acidosis Lethal lactic acidosis : n = 1: n = 1

•• Intense Intense Asthenia Asthenia : n = 3: n = 3

13/22 (59%) treated

Mitochondrial toxicityMicrovesicular steatosis

Microvesicular steatosis range (10%-50%)

observed in 8/19 (42%) patients

Mitochondrial toxicityComparison of Liver mtDNA

in HIV+/HCV+ Patients and HIV Negative Controls

Mitochondrial toxicityComparison of Liver mtDNA

in HIV+/HCV+ Patients and HIV Negative Controls

Liver mt DNA (copies number/ng total DNA)

Patients

19 5235(203207-611111)

p=0.01

HIV-/HCV+(1 year post LT)

(n=8)

26 511 (5817-143010)

HIV+/HCV+ (n=5)

Duclos-Vallee J Hepatol 2005

IV complexActivity

0<<4 nmol/min/mg

In 6/7 patientsstudied

CD4 Count and HIV viral load During the Post-LT Course

n=7

Cells/mm3

0

200

400

600

800

1000

1200

0 5 10 15 20

Log 10

0

1

2

3

4

5

6

7

0 5 10 15 20months

Bacterial and opportunistic infections

Bacterial and opportunistic infections

Coinfected Patients

3/23(13%)

p=0.03

Monoinfected Patients

16/44(36%)

Bacterial infection

Coinfected Patients

Oesophagal candidosis:

n=1

Monoinfected Patients

P. Carinii: n=2Syst.

Candidosis: n=2

Opportunistic infections

Drug InteractionIn HIV Liver Transplant Patients

Teicher et al. Submitted

0

100

200

300

400

500

600

Alone + ARV

NUCLPVLPVLPVLPVEFVEFV

Tacr

olim

us o

ral c

lear

ance

-ml/m

in

+ LPV/RTV ⇒ Tacrolimus

0.5mg / 10 or 15 days

Figure 1A

0

0.2

0.4

0.6

0.8

1

0 1 2 3 4 5

HIV-HCV+

HIV+HCV+

Survival analysisSurvival analysis

2-year survival:`

HIV+/HCV (n=23): 72%HIV-/HCV (n=44): 92%Log rank p=0.07

1.0

0.8

0.6

0.4

0.2

0.0

0 6 12 18 24 30 36 48 60

HCV+/HIV-/OLTXHCV+/HIV+/OLTX

p = 0.06

57%

80%

Months since OLTX

Prop

ortio

n su

rviv

ing

Survival of Transplanted Monoinfected HCV (4062 Unos) and Coinfected HCV-HIV (15)

RagniRagni M et al, J Infect Dis, 2003;188:1412M et al, J Infect Dis, 2003;188:1412––2020

Liver Transplantation In HIV-HBV Patientsn=5

HBIg+Lam+Tenof.

HBIg+Lam+Tenof.

HBIg+Lam+Tenof.

HBIg+Lam+Tenof.

HBIg+Lam+Tenof.Post LT HBV therapy

WellM12GREY.

WellM12MONG.

WellM24BON.

WellM31MAH.

WellM36ALE.Clinical status Follow-up Patients

ConclusionsConclusions

• Feasible• HBV-HIV: Excellent• HCV-HIV: Difficult

– Mitochondrial toxicity»Avoid DDI, D4T, AZT»Change HAART if microvesicular steatosis

– HCV recurence»Early Antiviral therapy

A Multidisciplinary Approach A Multidisciplinary Approach

Centre Hépato-Biliaire

D CastaingD SamuelR Adam

D AzoulayC FerayF SalibaP Ichai

B RocheT AntoniniM GigouC Danet

E PasdeloupC Tanguy

G BerthelotNurses …

Virology UnitAM Roque-Afonso

V MackiewiczE Dussaix

Pathology UnitM SebaghMP BraletC Guettier

Department of Infectious DiseasesE Teicher

D Vittecoq

Biochemistry UnitC Jardel

A Lombès

Department of AnesthesiologyC JosseA Mirand

MC Gillon