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Solid Organ Transplantation in HIV Recipients in the HAART Era

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'A fairly positive clinical picture of HIV infection in transplant recipients is ... Pre-therapy: CBC, liver, renal, TSH, lipids, CXR, EKG ... – PowerPoint PPT presentation

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Title: Solid Organ Transplantation in HIV Recipients in the HAART Era


1
Solid Organ Transplantationin HIV Recipientsin
the HAART Era
Michelle Roland, MD November, 2003
2
1994 Publication from France
  • A fairly positive clinical picture of HIV
    infection in transplant recipients is emerging
    after our review of 11 patients. Guidelines are
    needed to promote a more consistent approach in
    this situation. Pending a consensus, the
    indications for and against liver transplantation
    in HIV-seropositive patients must be carefully
    weighed on a case-by-case basis.

Bouscarat et al. CID 1994 19 854-9
3
Why Now?
  • 1) HAART-associated improvements
  • ? mortality
  • ? opportunistic infection incidence
  • ? hospitalization rates
  • 2) Immunosuppressant drugs may have anti-HIV
    properties (direct, through immune mechanisms or
    by potentiating ARV drugs)
  • Cyclosporine (neoral)
  • mycophenalate mofetil (cellcept)

4
Should All HIV Patients With ESRD Be Excluded
From Transplantation?
  • 1998 U.S. Transplant Center Response Rate
  • 149/248 (60)
  • Is HIV testing required for prospective
    recipients?
  • Would a patient who refuses HIV testing
  • be considered for transplantation?
  • Would an HIV-infected ESRD pt be considered
  • for cadaveric transplantation?
  • Would an HIV-infected ESRD pt be considered
  • for living donor transplantation?

YES
NO
UNSURE
--
--
100
12
84
4
9
88
3
5
91
4
Spital. Transplantation, May 15, 1998
5
Published Pre-HAART Experience
  • Baseline characteristics and outcomes poorly
    defined (e.g. CD4 counts, OI s)
  • Small, anecdotal experiences with varied results
  • Does not take into consideration
  • advances in OI prophylaxis
  • improved anti-rejection therapies
  • improved antiretroviral therapies

6
Published Reports in HAART-Era
7
Other Centers Offering Transplants
  • Many U.S.
  • Canada
  • Germany
  • Spain
  • Netherlands
  • Switzerland
  • UK
  • India
  • Argentina

8
Solid Organ Transplantation in HIV-Infected
Recipients A Review of 53 Cases in the
HAART-Era
  • M. Roland et al (13 centers)
  • International AIDS Conference 2002

9
Background
  • Prospective pilot multi-site transitional study
    will evaluate
  • 1. Effect of immunosuppression on survival and
    HIV disease
  • 2. Effect of HIV on graft survival
  • 3. Drug interactions between PI/NNRTI and
    immunosuppressives
  • Many participating centers transplanted patients
    prior to the study

10
Methods
  • Prospective analysis of enrolled subjects
  • Retrospective review of recipients at study
    centers
  • Eligible subjects
  • No opportunistic infection history
  • CD4 gt 200 kidney gt100 liver
  • HIV RNA lt 50 kidney, liver or intolerant of ARVs
    in liver
  • but post-transplant suppression predicted
  • Ineligible subjects
  • Did not meet 1 or more criteria above

11
Results
  • 45 Eligible Subjects
  • 26 kidney recipients
  • 19 liver recipients
  • 8 Ineligible Subjects
  • HIV RNA gt 50 (K) or low CD4
  • history of OI/ON
  • undiagnosed HIV
  • altered mental status

12
Demographics
  • Gender
  • Kidney 92 male
  • Liver 95 male
  • Age
  • Kidney median 45
  • Liver median 43
  • Ethnicity
  • Kidney 54 AA 42 Caucasian 4 Asian
  • Liver 79 Cauc 11 Hispanic 5 AA 5 Asian

13
Results Baseline HIV Labs
  • CD4 T Cell Counts
  • median range
  • Kidney 441 (200 - 1054)
  • Liver 280 (103 - 973)
  • HIV-1 RNA
  • median range
  • Liver lt50 (lt50 - 115,776)

14
Results Outcomes
  • Median follow-up 314 days (3 - 1696)
  • Deaths 2 kidney 4 liver
  • Kidney ischemic bowel/ enterococcal sepsis (6
    mos) chronic allograft nephropathy --gt staph
    sepsis 2 mos after return to dialysis
  • Liver recurrent HCV (15 mos) rejection after PI
    discontinued (1.5 yrs) post-op pancreatitis
    rhizopus cavernous sinus thrombosis (gt 4.5 yrs)
  • Opportunistic Complications
  • 1 liver 1 kidney
  • - CMV esophagitis
  • - candida esophagitis

15
Results Outcomes
  • CD4 T cell counts
  • Kidney 436 ( 3 - 975)
  • Liver 218 (110 - 992)
  • HIV-1 RNA
  • Kidney lt 50 (lt 50 - 533)
  • Liver lt 50 (lt 50 - 9600)
  • Re-transplantation 1 L (small for size)
  • Additional graft loss 3 kidney (rejection x 2
    thrombosis)
  • Total rejection 38 kidney 21 liver

16
Outcomes Ineligible Subjects
  • Undiagnosed HIV death (MAC PML)
  • Altered MS death (PML)
  • --------------------------------------------------
    -------------------------
  • HIV RNA gt 50 (Kidney) lt50 (1) lt 400 (2) gt 50
    (1)
  • Low CD4 stable 76 --gt 195
  • History of OI/ON
  • (PCP CMV KS CMV) no recurrence at
  • 19 and 6 months

17
Conclusions
  • Patient survival similar to UNOS data at 1 year
  • 92 all kidney subjects UNOS 94.8
    cadaver/97.6 living
  • 91 1 year (N 11)
  • 79 all liver subjects UNOS 87.9
  • 92 1 year (N 12)
  • Graft survival similar to UNOS data at 1 year
  • 85 all kidney subjects UNOS 89.4
    cadaver/94.5 living
  • 71 1 year (N 14)
  • 79 all liver subjects UNOS 81.4
  • 83 1 year (N 12)

18
Conclusions Continued
  • No significant HIV disease progression in
    selected pts
  • Stable CD4 T-cell counts
  • Suppressed HIV-1 RNA
  • Only 2 OI s - could be due to HIV or
    immunosuppression
  • There is HIV progression with advanced disease

19
Updated UCSF Data3/00 9/03
  • 24 HIV-infected transplant recipients
  • 14 kidney, 9 liver, 1 liver-kidney
  • 4 (17) with OI history
  • CMV, MAC, TB, crypto, KS
  • HCV co-infection
  • 4 (29) kidney and 4 (40) liver

20
Key FindingsMedian Follow-Up 480 days (8-1254)
  • 2 deaths liver recipient with recurrent HCV
    (same) and kidney recipient with unknown
    pulmonary dz (new)
  • Same 2 OIs and 1 case pulmonary aspergillus
  • Rejection 10 (71) kidney recipients and 1 liver
    recipients when PI stopped
  • Graft loss 1 kidney from rejection 1 liver
    re-transplant
  • Recurrent HCV 2 liver, no kidney
  • CD4 407 (104 973)? 255 (8 902)
  • HIV RNA lt 75 (lt 75 9600)

21
Special Clinical Considerations
  • Co-Infections
  • Hepatitis B and C
  • HPV
  • HHV8
  • Immunosuppression-Related Issues
  • Rejection
  • Possible anti-HIV activity
  • Drug Interactions

22
Hepatitis B
  • Re-infection rapid and fatal without virologic
    control
  • Used to be a contraindication for liver
    transplant
  • Standard of care HBIg and lamivudine
  • Lamivudine resistant HBV common in HIV
  • Will these patients have poorer outcome?
  • Adefovir, tenofovir (and other drugs in
    development)
  • Management challenges to reduce HIV/HBV resistance

23
Hepatitis C
  • A common co-infection
  • Relatively poor outcomes in HIV negative
    recipients
  • Accelerated natural history in context of HIV
  • Variable post-transplant experience across sites
  • Ragni in press suggests similar outcomes to HIV
    negative

24
Hepatitis C Infection Multi-site Analysis
  • Co-Infection is common
  • Kidney 11 (42)
  • Liver 13 (68)
  • Recurrence/Complications
  • Kidney No HCV complications
  • Liver 1 death due to HCV

25
Treatment of HCV Liver Recipients When?
  • HCV treatment will not be initiated preemptively
    post-transplant
  • No data to suggest that HCV RNA clearance rates
    are higher
  • Minimize drug interactions and toxicity in the
    early post-transplant period
  • HCV treatment will be initiated if biopsy shows
    severe or progressive recurrent HCV disease
  • HAI scoregt 8 and/or fibrosis stage gt2 are
    considered indications for treatment by most
    transplant physicians but the decision to treat
    will ultimately be determined by the treating
    physician.

26
Biopsies in HCV Liver Recipients When to Do?
Who Reads?
  • Protocol biopsies 6 and 12 months post
    transplant, then annually
  • And at any time as clinically indicated
  • Treatment decisions based upon local pathologist
    reading
  • For outcomes determinations, biopsies will be
    read by a central pathologist and will be scored
    using the Ishak version of  Knodell

27
HCV Treatment Regimen
  • Peg-INF or standard INF plus ribavirin.
  • Not altered based upon prior INF experience or
    genotype.
  • Peg-INF a-2b 1.0-1.5 ug/kg or Peg-INF a-2a 180 ug
    weekly
  • Start at half dose
  • Increase to full-dose in 2 weeks if blood counts
    are acceptable
  • Ribavirin 200 mg PO BID x 2 weeks, then 400 mg PO
    BID x 2 weeks if tolerated, then 10-13 mg-kg as
    divided dose if tolerated.
  • Transplant patients have renal clearance issues
    that make increasing ribavirin dose too high
    and/or too quickly result in drug-limiting
    anemia. Thus, ribavirin should be titrated up
    slowly as tolerated.

28
Monitoring on HCV Treatment
  • Pre-therapy CBC, liver, renal, TSH, lipids,
    CXR, EKG
  • Months 1-2 post-therapy initiation weekly
    CBC
  • Months 3, 6, 9, 12 post-therapy initiation TSH
  • HCV RNA all HCV co-infected patients have
    baseline, month 3, 6, 12 and years 2 and 5.
  • Subjects receiving HCV therapy have additional
    HCV RNA at 2, 6 and 12 months post-therapy
    initiation.
  • Depression screen monthly for first 3 months,
    then every 3 months.
  • Patients should be provided with 24-hour clinical
    contact number for adverse effect notification.

29
Length of Treatment
  • 12 month minimum. At 12 months, response will be
    determined by measurement of HCV RNA (if
    quantitative negative, will do qualitative),
    AST/ALT and liver histology.
  • Types of Response and Actions
  • HCV RNA negative at 6 and 12 months stop
    treatment
  • HCV RNA positive but liver histology improved
    stop treatment. Consider re-initiation of
    therapy if disease activity (histology,
    biochemical) increases.
  • HCV RNA positive but liver histology unchanged or
    worse Continue treatment for another 12 months
    (or consider for experimental therapies).

30
Marrow-Supportive Therapy
  • Erythropoietin
  • Start when hemoglobin is lt10g/dl.
  • Dose 40,000 IU subcutaneously weekly.
  • If hemoglobin decreases below 8.0 g/dL,
    discontinue ribavirin until gt10 g/dL (women) or
    gt12 g/dL (males) on erythropoietin. If ribavirin
    is restarted, use 50 of the dose used when
    ribavirin was discontinued.
  • G-CSF
  • Start when ANC is lt1,000/mm3.
  • Dose 300 ug twice weekly. If subsequent trough
    ANC gt3000/mm3, reduce dose to 150 ug twice weekly
    or 300 ug once weekly. Continued until the end
    of treatment.

31
HPV
  • HVP-related cervical and anorectal disease,
    already accelerated in people with HIV infection,
    may be exacerbated by post-transplant
    immunosuppression.
  • Preliminary experience at UCSF common, with
    progression, but not obviously more aggressive
    than in non-transplant population

32
HHV8
  • HHV8-related disease, particularly KS, may be
    exacerbated or reactivated by post-transplant
    immunosuppression.
  • 1 UCSF kidney recipient and 1 heart transplant
    (NEJM) in recipients with KS history no
    recurrence yet.
  • No new KS yet.
  • Raises issues re antibody screening, viral load
    monitoring, etc. that will be evaluated in
    current study

33
Rejection
  • 38 rejection in multi-site study
  • Complications associated with rejection therapy
  • 1 episode staph aureus endocarditis
  • 1 influenza pneumonia with hospitalization
  • Reversible DM on prednisone and tacrolimus x 2
  • Toxic tacrolimus levels x 2 (dosing error)
  • Toxic sirolimus levels x 1

34
39 y/o Female 8 Years S/P OLT For Fulminant
Hepatic Failure
  • 7/93 OLT for Hepatitis B
  • 1/94 Diagnosed with Hepatitis C and HIV
  • Immunosuppression ? 2 HIV dx
  • ? FK triggered rejection episode
  • Rejection tx with steroid bolus, FK
  • 1996 started 3TC, d4T
  • 1996-2000
  • No detectable HIV or HCV RNA
  • No opportunistic infections
  • Normal LFTs

35
HIV RNA in UCSF Subjects
  • HIV RNA levels remained undetectable in
  • Most patients when on ARV therapy (few blips)
  • In patients with delayed graft function whose
    ARVs were held for 1 - 2 weeks
  • HIV RNA rebound was not immediate and levels
    remained relatively low (maximum 45,741
    copies/mL) in 1 liver transplant patient who
    required 4 ARV treatment interruptions

36
Immunosuppressant Drugs May Have Antiviral
Activity
  • ARV treatment interruptions have resulted in
    minimal and delayed HIV rebound, suggesting that
    one or more of the immunosuppressive drugs
    (including MMF and cyclosporine) may have
    antiviral activity (direct or immune mediated).

37
Other Complications
  • Infectious
  • staph endocarditis, cholangitis and fungal
    sepsis,
  • influenza PNA, bacterial PNA, wound infections,
    epididymitis, oral candida, asx CMV viremia
  • Metabolic
  • Diabetes, hyperlipidemia, hip fracture
  • Neoplastic
  • Anal dysplasia, skin squamous cell CA, Bowens
    disease
  • Other
  • Drug toxicity (prograf, sirolimus), MI, bowel
    obstruction

38
Pharmacology Studies
  • 12 - 24 hour pharmacokinetic evaluation of
  • immunosuppressant, PI, and NNRTI concentrations
  • pre-transplant
  • Weeks 2 and 12, month 6, and years 1, 2 and 5
  • When there is a change in ARVs, immunosuppressant
    drugs, or the development of an opportunistic
    infection

39
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44
Drug Levels
  • Cyclosporine doses have been low in those onPIs
    and typical in those on NNRTIs to achieve
    adequate plasma levels and immunosuppression
  • Tacrolimus and sirolimus are similar
  • PI and NNRTI levels have been affected but have
    largely remain within adequate treatment ranges.
  • Unclear how to respond to these data from a
    clinical perspective

45
NIH-Funded Clinical TrialKidney and Liver
Transplantation in HIV-Infected Patients at 16
U.S. Transplant Centers
  • PI Peter Stock
  • Co-PI Michelle Roland
  • University of California, San Francisco

46
Overview of Study Design
  • Prospective, multi-center cohort study of 275
    HIV transplant recipients who are followed for
    two to five years.
  • 150 kidney and 125 liver recipients
  • Central hypothesis HIV liver and kidney
    transplant recipients will have patient and graft
    survival rates comparable to other patient groups
    without HIV infection that are currently
    considered acceptable transplant candidates (e.g
    gt age 65).

47
Specific Aims
  • 2 hypothesis-driven aims
  • Patient survival
  • Graft survival
  • 4 exploratory aims

48
Primary Aim 1Evaluate the impact of
immunosuppression on patient survival
  • Hypothesis Liver and kidney transplant
    recipients will have survival rates comparable to
    other patient groups without HIV infection that
    are currently considered acceptable transplant
    candidates.

49
Control Groups
  • We anticipate, as with older subjects, that
    transplantation of HIV patients is an acceptable
    but high risk procedure.
  • We expect survival may be less than that of age
    matched controls but that results should be
    similar to those seen in other poor prognosis
    groups (e.g. diabetics, hospitalized patients,
    etc).
  • The gt65 year old normative group was selected
    because it is relatively common (7 of livers)
    and represents many organ failure causes.

50
  • Also age-race-donor source-matched controls from
    the national registry.
  • The effect of transplantation on mortality will
    be examined by comparing the mortality rate of
    subjects awaiting transplant to those receiving
    an allograft.

51
Primary Aim 2Evaluate the impact of HIV
infection and HAART on graft survival
  • Hypothesis 1 HIV liver and kidney transplant
    recipients will have graft survival rates
    comparable to other patient groups without HIV
    infection that are currently considered
    acceptable candidates.

52
Graft survival in HBV/HCV co-infection
  • Hypothesis 2 HIV liver transplant recipients
    co-infected with hepatitis B or C will have graft
    survival comparable to other patient groups with
    the same viral hepatitis infections but without
    HIV infection that are currently considered
    acceptable candidates.

53
Graft survival in HIVAN
  • Hypothesis 3 HIV kidney transplant recipients
    with HIV nephropathy (HIVAN) will have recurrence
    of HIVAN resulting in impaired renal function and
    graft survival despite the use of HAART.

54
Secondary Aim 1 Explore the impact of
post-transplant immunosuppression on changes in
CD4 T cell counts and HIV-1 RNA levels.
55
Rationale
  • Immunosuppression may accelerate HIV disease
    progression, resulting in declines in CD4 T-cell
    counts, increased rates of infectious and
    neoplastic opportunistic complications, and HIV-1
    RNA breakthrough on HAART. Such acceleration may
    be mediated through viral and/or host immunologic
    pathways.
  • Alternatively, immunosuppression may result in
    depletion of HIV-1 reservoirs or reductions in
    viral rebound and improved HIV-related outcomes.

56
Secondary Aim 2Explore the impact of
post-transplant immunosuppression on the
host-response to viral co-pathogens, including
hepatitis B and C, the human herpesviruses (CMV,
EBV, HHV-6, HHV-8) and HPV.
57
Rationale
  • The combination of immunosuppression and HIV
    could alter viral activation and/or host immune
    control of viruses that are associated with the
    development of clinically significant disease
    post-transplant.

58
Secondary Aim 3Explore the impact of HIV
infection on the alloimmune response and
rejection rates.
59
Rationale
  • HIV transplant recipients may have perturbations
    of the immune system that influence the immune
    response to solid organ allografts that may have
    implications for immunosuppression requirements.

60
Secondary Aim 4Explore the pharmacokinetic
interactions between immunosuppressive agents and
the hepatically metabolized antiretroviral agents.
61
Donors in Pilot Multi-Site Study
  • Kidney
  • Cadaveric 54
  • Living 27
  • High Risk 19
  • Liver
  • Cadaveric 79
  • Living 16
  • High Risk 5

62
Donor Issues
  • High risk donors are currently being considered
    at many transplant centers.
  • The safety of accepting HIV positive donors for
    HIV positive recipients is unknown, as the
    question of the prevalence and clinical impact
    of super-infection remains unknown.

63
Of particular concern in the management of
HIV-infected transplant recipients
  • The need for a multi-disciplinary health care
    team to participate actively in patient
    monitoring and management, with excellent
    communication among team members. This is
    particularly important relative to medication
    changes and evaluation of symptoms and lab
    abnormalies.
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