Title: Solid Organ Transplantation in HIV Recipients in the HAART Era
1Solid Organ Transplantationin HIV Recipientsin
the HAART Era
Michelle Roland, MD November, 2003
21994 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
3Why 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)
-
4Should 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
5Published 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
6Published 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) -- --
7Other Centers Offering Transplants
- Many U.S.
- Canada
- Germany
- Spain
- Netherlands
- Switzerland
- UK
- India
- Argentina
8Solid 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
9Background
- 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
10Methods
- 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
11Results
- 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
12Demographics
- 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
13Results 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)
14Results 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
15Results 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
16Outcomes 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
17Conclusions
- 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)
18Conclusions 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
19Updated 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
20Key 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)
21Special Clinical Considerations
- Co-Infections
- Hepatitis B and C
- HPV
- HHV8
- Immunosuppression-Related Issues
- Rejection
- Possible anti-HIV activity
- Drug Interactions
22Hepatitis 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
23Hepatitis 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
24Hepatitis 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
-
25Treatment 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.
26Biopsies 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
27HCV 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.
28Monitoring 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.
29Length 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.
31HPV
- 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
32HHV8
- 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
33Rejection
- 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
3439 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
35HIV 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
36Immunosuppressant 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).
37Other 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
38Pharmacology 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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44Drug 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
45NIH-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
46Overview 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).
47Specific Aims
- 2 hypothesis-driven aims
- Patient survival
- Graft survival
- 4 exploratory aims
48Primary 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.
49Control 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.
51Primary 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.
52Graft 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.
53Graft 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.
54Secondary Aim 1 Explore the impact of
post-transplant immunosuppression on changes in
CD4 T cell counts and HIV-1 RNA levels.
55Rationale
- 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.
56Secondary 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.
57Rationale
- 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.
58Secondary Aim 3Explore the impact of HIV
infection on the alloimmune response and
rejection rates.
59Rationale
- 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.
60Secondary Aim 4Explore the pharmacokinetic
interactions between immunosuppressive agents and
the hepatically metabolized antiretroviral agents.
61Donors in Pilot Multi-Site Study
- Kidney
- Cadaveric 54
- Living 27
- High Risk 19
- Liver
- Cadaveric 79
- Living 16
- High Risk 5
62Donor 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.
63Of 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.