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
Author/Country/Year Liver Kidney Heart
Calabrese/U.S./2003 -- -- 1
Sugawara/Japan/2003 1 -- --
Nowak/Sweden/2003 4 -- --
Samuel/France/2003 9 -- --
Tolan/UK/2001 1 -- --
Roland/Transplantation/2003 19 26 --
Stock/Transplantation/2003 4 (10) 10 (14) --
Neff/Liver Transplantation/2003 16 -- --
Ragni/JID/In Press 23 -- --
Prachalis/United Kingdom/2001 5 (12) -- --
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.

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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

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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.