TH in HIV in Spain

1
Spanish Cohort of HIV-Infected Patients with
Orthotopic Liver Transplantation (OLT)
Evaluation of 116 Cases in the Highly Active
Antiretroviral (HAART) Era (2002-07).
FIPSE-GESIDA Working Group Investigators
2
End-Stage Liver Disease (ESLD) Magnitude of the
Problem in Spain
No. cases
Estimated No. Patients

• HIV-infected patients
• HCV co-infection
• HBV co-infection
• Liver cirrhosis
• - Child-Pugh B stage
• - Child-Pugh C stage

- 55 5 8 27 7
140,000 77,000 7,000 6,720 1,814 470
OLT candidates
17
1,142
Hamers FF. Lancet. 2004 36483
GESIDA/FIPSE. EIMC. 200523340.
3
OLT in Spanish HIV-1-infected patients in the
HAART era (2002-07) OBJECTIVES
1) To describe the clinical characteristics and
the evolution of 116 Spanish HIV-1-infected
patients who underwent liver transplantation
(OLT) between 2002 and 2007. 2) To know 4-year
survival among HCVHIV- and HCV-HIV-coinfected
patients. 3) To identify prognostic factors of
survival. 4) To know the rate of SVR among
treated pts.
4
OLT in Spanish HIV-1-infected patients in the
HAART era (2002-07) PATIENTS METHODS

• Prospective study of all HIV-1-infected patients
  who underwent OLT in Spain between 2002 and 2007.
  
• HIV (stage, CD4 cell count, plasma HIV-1 RNA
  viral load, ART), liver disease (etiology, stage)
  and OLT characteristics at baseline and after OLT
  were collected using an standardized CRF.
• Each site used the same immunosuppressive
  regimens prophylaxis protocols as for their
  HIV-negative patients.
• Cohort study. Descriptive analysis.

5
OLT in Spanish HIV-1-infected patients in the
HAART era (2002-07) OLT INCLUSION CRITERIA

• Liver criteria the same as for the non-HIV-1
  infected population.
• HIV criteria
• No previous C events (CDC, 1993) except some OIs
  (TB, PCP, Can),
• Pre-OLT CD4 cell count 100 cells/mm3 (or 200
  cells/mm3 in pts with OIs) and
• Undetectable plasma RNA HIV-1 viral load on HAART
  or detectable plasma viral load off HAART with
  post-transplant suppression predicted.
• Drug abuse A) No heroin or cocaine abuse for 2
  years B) No alcohol abuse for 6 months.

6
Rx of HIV-infected patients with recurrent HCV
after OLT with PEG-INFRBV ANTI-HCV TREATMENT (I)

• Indication for anti-HCV treatment ALT elevation,
  positive serum HCV RNA viral load (VL), and
  histological evidence of HCV recurrence.
• Treatment regimens Pegylated interferon
  (PEG-INF) ?2a (Pegasys sc 180 µg wk) or PEG-INF
  ?2b (Peg-Intron sc 1.5 µg/kg wk) plus Ribavirin
  (RBV)(Rebetol 400-1000 mg/day) for 48 wks.
• Doses were reduced according to tolerance and
  laboratory abnormalities.
• G-CSF or Erythro/Darbepoetin were given when
  necessary.

7
Rx of HIV-infected patients with recurrent HCV
after OLT with PEG-INFRBV ANTI-HCV TREATMENT
(II)

• Definitions
• - Early virological response (EVR) ? 2 log
  of HCV RNA viral load (VL) at 12 wks
• - End-of-treatment response (ETR) negative
  HCV RNA VL at 48 wks and
• - Sustained VR (SVR) negative HCV RNA VL 24
  wks after the end of treatment.
• Cohort study. Descriptive analysis.
• Responses were evaluated by ITT (NCF) analysis.

8
Spanish Cohort of OLT in HIV-infected patients
(FIPSE OLT-HIV-05 / GESIDA 45-05 )(2002-08)
9
OLT in Spanish HIV-infected patients in the HAART
era (2002-07) (N116)
0.5
1.5
1.8
3.0
3.0
1.5
4 patients had retransplantation OLT in
HIV-infected recipients/OLT in general population
ratio.
10
OLT in Spanish HIV-1-infected patients in the
HAART era (2002-07) Outcome of patients who did
not meet the HIV inclusion criteria (N4)
F-U Mo. 37 22 10 10
Age / Gender 42/M 42/M 51/M 41/F
Outcome Alive Alive Alive Alive
Case 0108 1003 1311 1607
Reason CD4 OI OI CD4 OI CD4
Etiology HCV HCV HCV HCV
OI MAC disease Toxoplasmosis.
11
OLT in Spanish HIV-1-infected patients in the
HAART era (2002-07) Demographics (N112)

• Male gender
• Age (years)
• HIV risk factor
• Former i.v. drug abuse
• Sexual
• Hemophilia
• Other
• Race Caucasian

84 (75) 43 (3946) 82 (73) 19 (17) 5 (4) 6
(5) 110 (98)
Median (IQR)
12
OLT in Spanish HIV-1-infected patients in the
HAART era (2002-07) Liver disease
characteristics (N112)
92 (82) 1 (1) 19 (17) 15 (13) 45 (40) 46
(41) 14 1118

• Liver cirrhosis etiology
• HCV
• HBV
• HCVHBV
• Child-Pugh stage (WL)
• A
• B
• C
• MELD (WL) (median IQR)

25 patients (22) had a hepatocellular carcinoma
(HCC) HCV genotypes 1/4 in 73 (65) genotypes
2/3 in 25 (22) 4 other genotypes 5 cases had
a non-typable genotype and no data in 5 cases
Delta co-infection in nine cases.
13
OLT in Spanish HIV-1-infected patients in the
HAART era (2002-07) ART characteristics before
OLT (N112)

• ART regimens
• Efavirenz-based ART
• PI-based ART
• 3/4 NRTI
• Other combinations
• CD4 count (cel./mm3)
• CV

43 (39) 36 (32) 11 (10) 21 (19) 276
(182402) 106 (95)
Abacavir-based ART Median (IQR).
14
OLT in Spanish HIV-1-infected patients in the
HAART era (2002-07) Donor Characteristics (N108)
Age (yr.) Male Gender Etiology of death -
Craneal traumatism - Stroke - Other Marginal
donors Cold isquemia (min)
52 (4068) 68 (61) 33 (29) 49 (44) 22
(20) 15 (13) 334 (250 480)
Median (IQR).
15
OLT in Spanish HIV-1-infected patients in the
HAART era (2002-07) OLT Characteristics (N112)

• Time on waiting list (mo.)
• Type of liver
• Cadaveric
• Living-donor
• Blood transfusion (Units)
• Follow-up (mo.)

4 (2-7) 99 1 4 (17) 18 (8-29)
Median (IQR).
16
OLT in Spanish HIV-1-infected patients in the
HAART era (2002-07) Post-Operative Outcome
(N112)

• Hospitalization stay (days)
• Surgical complications
• Biliary fistula
• Hepatic artery
• Surgical wound infection
• - Other complications
• Re-transplantation
• - PGF
• Arterial thrombosis
• HCV recurrence

21 (16 37) 48 (43) 13 9 3 36 4
(4) 2 1 1
Median (IQR).
17
OLT in Spanish HIV-1-infected patients in the
HAART era (2002-07) Mortality (N32 29)

• Early mortality (
• Post-op. complications
• Severe cholestatic HCV hepatitis
• Other
• Late mortality (6 mo.)
• Graft ELSD HCV reinfection
• Chronic rejection
• Other

9 (28) 4 2 3 23 (72) 11 4 8
Massive variceal bleeding, lactic acidosis
mitochondrial toxicity and CMV disease 1 case
each. MOF (2), OI (2), Cancer
(2), mucormicosis (1) and lactic acidosis
mitochondrial toxicity (1).
18
OLT in Spanish HIV-1-infected patients in the
HAART era (2002-07) Patient Survival (N83)
88 (78-93)
72 (60-81)
65 (51-75)
65 (51-75)
Patients at risk
83
70
37
21
14
Survival analysis was performed including only
patients underwent OLT between 2002 and 2006 and
followed until December 31st, 2007.
19
4-year survival after OLT comparing 82 HIV-pos.
and 1,489 HIV-neg. HCV-positive OLT recipients
(2002-06).
P.5306
HIV
HIV -
Years
Patients at risk
HIV -
120
1489
1085
763
492
298
HIV
83
2
70
37
20
14
20
OLT in Spanish HIV-1-infected patients in the
HAART era (2002-07) Acute Rejection, 37 patients
(33)
Acute Rejection
- Cyclosporine A (N33) Prednisone, or
IL-2 Ra, or Prednisone plus MMF -
Tacrolimus (N66) Prednisone, or
Prednisone MMF Prednisone IL-2 Ra
MMF or IL-2 Ra
13 11 9 36 8 4 18
45
26
Basiliximab (Simulect) MMF Mycophenolate
mophetil p0.068
21
OLT in Spanish HIV-1-infected patients in the
HAART era (2002-07) Infections after OLT (N112)
Type of infections
180 days
0-30
31-180
Viral PCP Bacterial Mycobacterial
(TB) Fungal Other Total
16 1 24 - 1 4 48
9 - 7 - 6 - 22
5 - 3 2 5 2 17
22
OLT in Spanish HIV-1-infected patients in the
HAART era (2002-07) B and C events after OLT
(N112)

• B events
• - Oral candidiasis
• C events
• Disseminated M. tuberculosis
• CMV disease
• Esophageal candidiasis
• Disseminated Herpes simplex
• Pneumocystis jiroveci pneumonia

3 (2.5) 3 7 (6) 2 2 1 1 1
23
OLT in Spanish HIV-1-infected patients in the
HAART era (2002-07) ART characteristics after
OLT (N112)
Antiretroviral therapy was started 9 (519) days
after liver transplantation.

• ART regimens
• Efavirenz-based ART
• PI-based ART
• 3/4 NRTI
• Other combinations

50 (50) 29 (29) 4 (4) 17 (17)
Abacavir-based ART Median (IQR).
24
OLT in Spanish HIV-1-infected patients in the
HAART era (2002-07) HIV cART after OLT (N112)
CD4 cells/µL Median (IQR)
Plasma HIV-1 RNA VL
Before OLT 3 mo (N92) 12 mo (N70) 24 mo
(N39) 36 mo (N23) 48 mo (N14)
95 93 94 92 95 93
276 (182402) 288 (193420) 309 (197424) 260
(197470) 262 (156500) 258 (156372)
25
Rx of HIV-infected patients with recurrent HCV
after OLT with PEG-INFRBV Anti-HCV Rx
Virological Response (N33)

• Six patients were treated before OLT without
  SVR. None of them had an SVR when Rx after OLT.
• Therapy with PEG-INFRBV was started a median
  (IQR) of 7 (511) months after OLT. ITT analysis
  (MF).

Genotype 1/4 N22 2 (9)

• - EVR
• - ETR
• SVR

13 (39) 10 (30) 7 (21)
Genotype 2/3 N11 5 (45)
EVR Early virological response ETR End of
therapy response SVR Sustained response.
26
Prognostic factors of mortality in Spanish
HCV-HIV coinfected LT recipients Univariate
Analysis of Mortality
Variable
HR (95CI)
P value
Donor age - of donor death - Other - Stroke ESLD
etiology - HCVHBV - HCV alone MELD (WL) (1
unit increase) Blood transfusion (1 unit increase)
1 2.06 (0.96 4.39) 1 2.40 (1.01 5.71) 1
2.30 (0.856.25) 1.07 (1.021.16) 1.22
(1.091.38)
.06 .04 .10 .01
Baseline CD4 count, HCV genotype, Child score,
type of HAART or immunosuppressive regimen, SAEs
and HCC were not associated with death.
27
Prognostic factors of mortality in Spanish
HCV-HIV coinfected LT recipients Univariate
Analysis of Mortality
Variable
HR (95CI)
P value
1 1.66 (0.773.58) 1 2.77 (1.116.89) 1 2.68
(1.225.88) 1 0.16 (0.021.20)
Rejection - No - Yes Post-OLT infection
- No - Yes Recurrence of cirrhosis (F4) -
No - Yes SVR to anti-HCV Rx (N33) - No
- Yes
.19 .03 .01 .03
Baseline CD4 count, HCV genotype, Child score,
type of HAART or immunosuppressive regimen, SAEs
and HCC were not associated with death.
28
OLT in Spanish HIV-1-infected patients in the
HAART era (2002-07) CONCLUSIONS

• The first case of OLT in Spain was performed in
  January 2002. Since then, 116 patients have been
  transplanted within the Spanish criteria at 17
  (77) sites.
• Most cases of OLT in Spain were due to
  HCV-infection in former i.v. drug users.
• HCV re-infection is the major cause of mortality
  after OLT (29).

29
OLT in Spanish HIV-1-infected patients in the
HAART era (2002-07) CONCLUSIONS

• HIV disease can be adequately controlled after
  OLT.
• Better donor selection and effective anti-HCV
  therapies could improve the outcome of HCV OLT in
  HIV-infected recipients.
• At present, OLT for selected HIV-1-infected
  patients is a safe and effective procedure with a
  short and mid-term survival that is comparable to
  the HIV-negative population.

30
OLT in HIV in Spain (FIPSE cohort) Research
Lines
- 5-year prognosis (HIV/-) Drs.
Miro/Rimola/Mahillo - Acute rejection. Drs.
Rafecas/Rimola/Fortún - Natural history
HCV(HIV/-) Drs. Valdivieso /Castells/de la
Torre - Rx of HCV reinfection Drs.
Castells/Valdivieso/delaTorre - Infections
Drs. Moreno/Fortun/Blanes - HIV cART (PK
interactions toxicity)Drs. Gonzalez/Miro/Miralle
s - Waiting list prognosis (HIV/-) Drs.
Rimola/Rafecas/de la Rosa
31
OLT in Spanish HIV-1-infected patients in the
HAART era (2002-07) ACKNOWLEDGEMENTS

• Fundación para la Investigación y Prevención del
  SIDA en España (FIPSE).- Grupo de Estudio de
  Sida (GESIDA/SEIMC).- Sociedad Española de
  Trasplante Hepático (SETH).- Grupo de Estudio de
  Infecciones en Trasplantados. (GESITRA/SEIMC).-
  Secretaria del Plan Nacional del Sida (SPNS) del
  Ministerio de Sanidad y Consumo (MSC).-
  Organización Nacional de Trasplante (ONT).Our
  patients.