Transcript No Slide Title

HIV Transplant Investigators Meeting:
Introduction and Welcome
8:00 – 8:10

Nancy Bridges, NIH

Peter Stock, UCSF

Michelle Roland, UCSF
Meeting Objectives
8:10 – 8:20
Michelle Roland
1)
Administrative Issues
2)
Protocol Review
3)
Policy
4)
Other
Objectives: Administrative Issues
1)
U01 and “Terms and Conditions of Award”
2)
Subcontracts: IRB and regulatory issues
3)
Site visits pre-start up
4)
Steering and Operations Committee; Publications and
Presentations Subcommittee
5)
Data Management
6)
Adverse Events Reporting
Objectives: Protocol Issues
1) Study Aims
2) Inclusion and Exclusion Criteria
3) Schedule of Events and “Sub-Study Clusters”
4) Medication Regimens and Drug Interactions
• Immunosuppressants, ARVs, and
Prophylaxis
5) Clinical Issues
• HCV, HBV, and Rejection
6) Stopping Rules
Meeting Objectives:
Policy and Other Issues
1)
2)
3)
4)
5)
6)
7)
Publications and Media Policy
Reimbursement
Donor Consent
Complete Good Clinical Practices (GCP) Training
Resources on the EMMES Study Website
Community Advisory Board
Coordinator Meeting Tomorrow
•
•
•
•
More GPC training
Data entry
Specimen shipping and tracking
Anal HPV swabs and follow-up (UCSF, U Maryland, Mt. Sinai liver, Columbia,
Cedars-Sinai)
Budget and Regulatory Issues
8:20 – 8:30
Michelle Roland
1)
2)
Regulatory Documents to NIH
3)
4)
IRB Approvals
Site Visits Pre-Start Up
Subcontract Conditions (“Milestones”)
Subcontract Requirements


Milestone #1, first 15 Centers will get initial funding

IRB Approvals to Natasha Tomilin

Regulatory Documents to Natasha Tomilin
Milestone #2, to renew subcontract, must demonstrate
productivity (screening, enrollment and
transplantation), data quality and regulatory adherence.

These factors will be reviewed approximately every 6 months
from the time of initial funding.

Concerns will be communicated as soon as identified
Good Clinical Practices Training
8:30 – 10:00
Barbara Pennington
Study Aims
10:15 – 10:25
Peter Stock
1)
2)
Primary Aims
Secondary Aims
Specific Aims

2 hypothesis-driven aims
 Patient survival
 Graft survival

4 exploratory aims
Primary Aim 1:
Evaluate 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.
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 >65 year old normative group was selected because it is
relatively common (7% of livers) and represents many organ
failure causes.
 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.
Primary Aim 2:
Evaluate 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.
Graft survival in HBV/HCV co-infection
Hypothesis 2: HIV+ liver transplant recipients coinfected 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.
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.
Secondary Aim 1:
Explore the impact of post-transplant
immunosuppression on changes in
CD4+ T cell counts and HIV-1 RNA
levels.
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.
Secondary Aim 2:
Explore the impact of post-transplant
immunosuppression on the hostresponse to viral co-pathogens,
including hepatitis B and C, the human
herpesviruses (CMV, EBV, HHV-6, HHV8) and HPV.
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 posttransplant.
Secondary Aim 3:
Explore the impact of HIV
infection on the alloimmune
response and rejection rates.
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.
Secondary Aim 4:
Explore the pharmacokinetic
interactions between
immunosuppressive agents and the
hepatically metabolized
antiretroviral agents.
Committees
10:25 – 10:40
Michelle Roland
1)
2)
Steering Committee
Operations Committee
Steering Committee Key Responsibilities

Approve protocol and any subsequent changes

Approve the design and implementation of all adjunct studies

Facilitate the conduct and monitoring of the main trial and
adjunct studies

Interpret study data: safety and endpoint

Oversee reporting of study results

Recommend the addition or removal of sites participating in
the study based upon completion of “milestones”
Implementation and Performance

The main trial and adjunct studies will be implemented with
approval of the Steering Committee and the NIAID Program
Officer

Sites will be required to accept and implement the protocol and
procedures approved by the Steering Committee
 Q6 month investigator meeting to consider protocol revisions

SC will oversee mechanisms for assessing the performance of
each institution, with particular attention to:
 accrual of adequate numbers of eligible subjects
 timely submission and quality of required data
 conscientious observance of protocol requirements
Protocol Exemptions/Violations

No exemptions to inclusion/exclusion criteria for
enrollment.

Protocol violations should be driven by patient care
needs.
 Minimize as much as possible
 Report to IRB and NIH
 Will be reviewed by Steering Committee for possible
protocol modification

Use of investigational agents must be approved by
steering committee (MOP)
Current Members

Peter Stock and Michelle Roland

Don Stablein: Senior Biostatistician

2 Independent investigators: To Be Named

Robert Zackin and Debi Surlas: Community Representatives

2

Nancy Bridges: DAIT Medical Officer

Larry Fox: DAIDS Medical Officer

1

1, 2
Daniella Livnat: NIAID Program Officer
John Fung and 1, 2 Margaret Ragni University of Pittsburgh
Timothy Pruett, University of Virginia
1
Rotate yearly
2 Non-voting members
Operations Committee

Monthly teleconference

Review safety reports (AE/SAE)

Monitor site performance (accrual, follow-up, and
withdrawal)

Review protection of Human Subjects in research

Address unanticipated problems

Make recommendations concerning the protocol and
study performance to the Steering Committee for
approval
Current Members

Peter Stock and Michelle Roland

Daniella Livnat: NIAID Program Officer

Nancy Bridges: DAIT Medical Officer

Larry Fox: DAIDS Medical Officer

Natasha Tomilin: NIAID Project Manager

Laurie Carlson: UCSF Study Coordinator

Rodney Rogers: UCSF Project Manager

Don Stablein: Senior Biostatistician
Stopping Rules
10:40 - 10:55
Don Stablein
1)
Study Design and Control Groups
2)
3)
Sample Size
Monitoring
Design Summary

Protocol contains separate single arm evaluations of
 kidney transplant
 liver transplant

Dual Primary Endpoints
 patient survival
 graft survival (death is an event)
Sample Size

150 Kidney

125 Liver

3 Year accrual period

Developed using a Sequential Probability Ratio Test
with 95% power for the specified hypotheses of 1 year
patient survival
Developing the Hypotheses

Anticipate patients may not do as well as average, but
believe results will be similar to other high risk patients

Choose null using national data for a high risk groupolder (>64 year old) patients
 older patients have co-morbidities
 transplants are common
 outcome data are available

Choose alternative using common delta (difference) for
both endpoints within organ
Null and Alternative Hypotheses
One Year Event Rates
θ0
θ1
1. Monitoring Patient Survival after a kidney transplant
88%
76%
2. Monitoring Graft Survival after a kidney transplant
83%
71%
3. Monitoring Patient Survival after a liver transplant
82%
67%
4. Monitoring Graft Survival after a liver transplant
78%
63%
DSMB Monitoring

Construct upper confidence limit with 1-tailed
significance level of .0001 every 6 months.

Recommend stopping if the targeted national
value is not within the interval
Operating Characteristics for Stopping Guidelines Using Semi-Annual Confidence
Limits with .0001 1- Sided Significance Level.
% of Trials Recommended for Stopping Prior to Completing 3 Year Accrual Period, 2000 replicates per
cell
Kidney
Survival
Targeted 1-Year .88
Rate
True 1-Year Rate
.85
0.1
.80
1.4
.75
16.1
.70
56.8
.65
89.5
.60
98.5
.55
99.9
Mean 1-Year
Estimate For
Terminated
Studies
0.596
Kidney Graft
Survival
.83
Liver Survival
.82
Liver Graft
Survival
.78
0
0
1.6
16.4
51.4
84.7
97.6
0
0
0.5
6.2
29.5
63.7
89.4
0
0
0
1.1
8.7
32.9
66.7
0.561
0.535
0.504
Other Safety Monitoring

Serious Adverse Events: daily to co-PIs and NIH
Medical Officers

HIV Progression Alert Levels: daily report to
Operations Committee
 Viral Load: new onset detectable or >/= 1 log increase
 CD4 Count: 25% decline w/o rejection therapy

Other Adverse Events: monthly

Long term graft and patient survival
Inclusion and Exclusion Criteria
10:55 – 11:10
Michelle Roland
3)
1)
Inclusion Criteria
2)
Exclusion Criteria
Narrower Selection Criteria
Key Inclusion Criteria

Age > 1 year old at Pediatric sites
 UCSF (L/K), University of Chicago (L), Mt. Sinai (K),
Columbia (L)
 At non-pediatric sites: age >18

CD4+ T-cell count for past 6 months
 Kidney >/= 200
 Liver >/=100 OR >/= 200 if there is a history of protocol
allowed opportunistic complication
 Use of IL-2 or GM-CSF in the prior six months to increase
CD4 counts is an exclusion
Viral Load Must Be Undetectable for
Subjects on ARV Therapy

< 50 with Amplicor Monitor Ultrasensitive PCR or

< 75 with bDNA Versant version 3.0

If other assays are used, co-PI will define cut-off

Intermittent elevations to 1000 copies/mL, if not
persistent on more than 2 sequential measures and
followed by undetectable levels, are permitted
Liver Subjects Who Are
Unable to Tolerate ARV Therapy

May have detectable viral load if the study HIV
clinician confidently predicts HIV suppression posttransplant
 Based on ARV history, viral load while on ARVs, adherence,
and available resistance tests

If there is significant doubt about the ability to
suppress viral replication post-transplant, the patient
should not be enrolled
ARV Use

Kidney patients and liver patients currently using
antiretrovirals must be on stable ARV regimen for at
least 3 months prior to entry
OR

Be able to maintain a persistently (always)
undetectable HIV-1 RNA level without ARVs
 This criteria accounts for the very rare long-term non-progressor with no
history of detectable HIV RNA
OI History

Per site policy, a history of the following opportunistic
infections or neoplasms may be allowed if subjects
have received “appropriate acute and maintenance
therapy and have no evidence of active disease.”

Medical record documentation should be provided by
the primary medical provider whenever possible.
Specific OI Requirements for Enrollment

Cryptococcal meningitis
 Requires negative serum CRAG

Cytomegalovirus retinitis (“CMV”)
 No active disease on optho exam. Presence of an
intraocular implant does not imply active disease.

Histoplasmosis
 Must be on or restart secondary prophylaxis regardless of
CD4 count. (Will be modified if the USPHS/IDSA Guidelines
re discontinuation of secondary OI prophylaxis change.)
Specific OI Requirements for Enrollment

CNS Toxoplasmosis (“Toxo”)


Kaposi’s Sarcoma (“KS”)


MRI without active disease
Clinical and radiologic evidence of complete remission with
immune reconstitution. No residual cutaneous lesions and
negative chest CT scan
HIV Encephalopathy (“HIV Dementia”)

Resolved on HAART with marked improvement in mental
status and increased CD4+ T-cell count and no evidence of
progression of CNS disease AND are otherwise considered
eligible from a functional standpoint.
Mycobacterial Infections

Mycobacterium tuberculosis (TB)


Mycobacterium kansasii


Completed standard treatment course
Completed standard treatment course
Mycobacterium avium complex (MAC)

Completion of 12 months of MAC therapy AND negative
MAC blood culture
Key Exclusion Criteria: OIs

Progressive Mulitfocal Leukoencephalopathy (PML)

Chronic Cryptosporidiosis (> 1 month duration)

Pulmonary Coccidiodomycosis will be treated per local
site policy in HIV negative transplant candidates
(generally 5-year disease-free interval).
Exclusion Criteria: Neoplasms

Lymphoma (Burkitt’s, immunoblastic or CNS)

Any other neoplasm except:
 cutaneous kaposi’s sarcoma
 in situ anogenital carcinoma
 adequately treated basal or squamous cell carcinoma of the
skin
 solid tumors treated with curative therapy and disease free
for more than 5 years
 hepatocellular carcinoma in liver candidates
HCV Co-Infected Kidney Candidates

Biopsy-documented cirrhosis requires
combined liver and kidney transplant.
listing
for

Exceptions will be made when sequential rather than
simultaneous transplant is appropriate, eg:
 ineligible for liver transplant due to medical contraindications
such as severe cardiopulmonary disease
 stable, compensated cirrhosis deemed by the investigator to
not necessitate transplant at this time
“Narrower Selection Criteria”

Final decisions with regard to the application of
narrower selection criteria with regard to pretransplant viral load and history of opportunistic
complications are the prerogative of the individual
sites. However, individual sites may not enroll
patients who are outside the bounds of the inclusion
criteria.
Schedule of Events
11:10 – 11:25
Michelle Roland
1)
Clinical, Radiology, Laboratory (Safety, HIV,
Screening Serology)
2)
3)
Clusters/Sub-Studies
HCV and HBV co-Infected Subjects
Clinical and Radiology
Years:
Weeks:
Year
0
Screen
Years
2&3
Year
1
Years
4&5
every 3 m1
every 6 m2
every 6 m
Day
0
Week
1
2
4
6
8
1
0
1
2
1
6
2
0
26
3
6
4
4
5
2
53-156
157-260
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X1
X
X
X2
X
CLINICAL
Documentation of HIV infection
X
Informed Consent
X
Symptom & Medical Review plus Physical Exam
X9
PPD 3
X
Vaccination Review
(Pneumovax, Hepatitis A and B)
X
Cervical PAP4
X
Pregnancy Test
X9
RADIOLOGY
CXR
MRI head 5
X
X
X
Laboratory
Years:
Weeks:
Year
0
Years
2&3
Year
1
Years
4&5
every 3 m1
every 6 m2
every 6 m
Screen
Day 0
Week 1
2
4
6
8
10
12
16
20
26
36
44
52
53-156
157-260
CBC-diff
X9
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X1
X
Renal/Electrolytes
X9
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X1
X
LFTs
X9
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X1
X
Lipase
X
X
X
X
X
X
X
X
X
X
X
X1
X
LDH
X
X
X
X
X
X
X1
X
Fasting Lipid Panel (Chol, LDL, HDL, TGL)
X
X
X2
X
Phosphate (PO4)6
X
X
X2
X
Urinalysis
X
X
Y2
Y5
SAFETY LABS
X9
X
X
X
X
X
X
X
X
X
X
X
X
X
Immunosuppressant levels
Lactate Monitoring (if on HCV therapy)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X3
X3
Years:
Year
0
Screen
Day
0
CD4+/CD8+ T-cell count
X
HIV-1 RNA (bDNA or PCR)
X
RPR/VDRL7
X9
Toxoplasmosis Quantitative7
X
G6PD
X
Weeks:
Years
2&3
Year
1
Week
1
2
4
6
8
X
X
X
X
X
X
X
X
1
0
1
2
1
6
Years
4&5
every 3 m1
every 6 m2
every 6 m
2
0
2
6
3
6
4
4
5
2
53-156
157-260
X
X
X
X
X
X
X1
X
X
X
X
X
X
X
X1
X
X
X
X2
X
X
X
X2
X
HIV LABS
MAC-Blood (monthly when CD4 <75)
MAC-Sputum (monthly when CD4 <75)
Urine histoplasmosis antigen (If histo history and CD4 <
200)
CSF JC virus (see protocol)
X
General Serology
CMV Ab7
X
X
X
X
X2
X
HepBSAg7
X
X
X
X
X2
X
HepBSAb7
X
X
X
X
X2
X
HepB core Ab7
X
X
X
X
X2
X
HCV Ab7
X
X
X
X
X2
X
EBV Ab7
X
X
X
X
X2
X
“Clusters”

An administrative tool to distribute the “burden” of
additional lab studies among sites/subjects

Includes the site where the lab is

Loosely geographically located

Balance numbers to address aims

Total blood volumes/storage blood calculated by
cluster
“Clusters”
Cluster 1 Sub-Studies: Co-Pathogen
Virology/Immunology; Transplant Immunology
Years:
Year 0
Weeks:
Screen
Years
2&3
Years
4&5
52
53-156
157-260
Year
1
Day
0
Week
1
2
4
6
8
10
12
16
20
26
36
44
Co-Pathogen CFC (McCune)
Cytokine Flow Cytometry
X
X
X
X
Y2
Y5
X
X
X
X
Y2
Y5
HHV8 Ab
X
X
X
X
Y2
Y5
HHV8 Viral Load (plasma)
X
X
X
X
Y2
Y5
HHV8 PBMC Associated Viral Load
X
X
X
X
Y2
Y5
HHV8 Saliva Viral Load
X
X
X
X
Y2
Y5
Co-Pathogen CTL (Brander)
Co-Pathogen ELISPOT
HHV8 (Martin)
Herpes Viruses (Rinaldo)
TaqMan Viral Load (CMV, HHV6,
EBV)
X
X
X
X
X
X
X
X
X
X
X
Y2
Y5
NASBA (CMV pp67) assay
X
X
X
X
X
X
X
X
X
X
X
Y2
Y5
RT-PCR (5 EBV RNAs) assay
X
X
X
X
X
X
X
X
X
X
X
Y2
Y5
X
X
Y2
Y5
Transplant Immunology (Stock) – UCSF real time, others stored)
MLC
X
Donor tissue or blood
X
X
Cluster 1 Continued: pK and HPV
Years:
Weeks:
Year
1
Year 0
Screen
Week
1
2
4
6
8
10
12
16
20
26
36
44
52
Years 2 & 3
Years 4 & 5
53-156
157-260
Pharmacokinetics (Benet) (UCSF ONLY)
PI/NNRTI/CSA pK
X
X
X
X
X
Y2
Urine toxicology
X
X
X
X
X
Y2
Y2
Y5
pGP Phenotype
X
HPV (Palefsky)
Anal PAP1
X
Specimen Storage
Fresh blood shipped to BBI3
X
X
X
X
X
Cluster 2 Sub-Studies: Co-Pathogen
Virology/Immunology
Years:
Year 0
Weeks:
Screen
Years
2&3
Years
4&5
52
53156
157-260
Year
1
Day 0
Week
1
2
4
6
8
10
12
16
20
26
3
6
44
Co-Pathogen CFC (McCune)
Cytokine Flow Cytometry
X
X
X
X
Y2
Y5
X
X
X
X
Y2
Y5
HHV8 Ab
X
X
X
X
Y2
Y5
HHV8 Viral Load (plasma)
X
X
X
X
Y2
Y5
HHV8 PBMC Associated Viral
Load
X
X
X
X
Y2
Y5
HHV8 Saliva Viral Load
X
X
X
X
Y2
Y5
Co-Pathogen CTL (Brander)
Co-Pathogen ELISPOT
HHV8 (Martin)
Herpes Viruses (Rinaldo)
TaqMan Viral Load (CMV,
HHV6, EBV)
X
X
X
X
X
X
X
X
X
X
X
Y2
Y5
NASBA (CMV pp67) assay
X
X
X
X
X
X
X
X
X
X
X
Y2
Y5
RT-PCR (5 EBV RNAs) assay
X
X
X
X
X
X
X
X
X
X
X
Y2
Y5
X
X
X
X
Y2
Y5
Specimen Storage
Fresh blood shipped to BBI1
X
Cluster 3 Sub-Studies: HIVAN, HPV
Years:
Year 0
Weeks:
Screen
Year
1
Day
0
Week
1
2
4
6
8
10
12
16
20
26
36
44
Years 2
&3
Years 4
&5
52
53-156
157-260
X
Y2
Y5
HIVAN (Klotman)
Biopsy Tissue1
X
HPV (Palefsky) – liver patients only
Anal PAP
X
Specimen Storage
Fresh blood shipped to
BBI1
X
X
X
X
Cluster 4 Sub-Studies: HPV
Years:
Year 0
Weeks:
Screen
Year
1
Day
0
Week
1
2
4
6
8
10
12
16
20
26
36
44
Years
2&3
Years
4&5
52
53-156
157260
X
Y2
Y5
HPV (Palefsky) – Columbia only-
Anal PAP1
X
Specimen Storage
Fresh blood shipped to BBI
X
X
X
X
HCV + Subjects: Virology and Immunology
Years:
Year 0
Weeks:
Screen
Year
1
Day 0
Week
1
2
4
6
8
10
12
1
6
20
26
3
6
44
Years 2 &
3
Years 4 & 5
5
2
53-156
157-260
HCV (Oldach)
Biopsy (protocol mandated biopsies)1
X
HCV RNA2
X
HCV Genotype
X
HCV Quasispecies
X
HCV Ab-RIBA
X
X
X
X
Y2
Y5
X
X
X
Y2
Y5
X
X
X
X
Y2
Y5
X
X
X
X
Y2
Y5
CTL (Brander)
HCV Elispot
CFC (McCune)
Cytokine Flow Cytometry
General
Abdominal CT
X
1. Liver: biopsy at month 6 post transplant then annually. Kidney: biopsy at month 6, year 2.5, and year 5
if insurance is willing to cover.
2. Liver subjects receiving HCV therapy must have additional HCV RNA at 2, 6 and 12 months posttherapy initiation. Kidney subjects receiving HCV therapy must have additional HCV RNA at 3 and
12 months post-therapy initiation.
HBV + Subjects: Virology
Years:
Weeks:
Year
Year 0
Years 2 & 3
Years 4 & 5
52
53-156
157-260
1
Scree
n
Day
0
Week
1
2
4
6
8
10
12
16
20
26
36
44
HBV (Terrault)
Biopsy (NO protocol mandated biopsies)
X
HepBSAb
X
X
X
X
Y2
Y5
HepBSAg
X
X
X
X
Y2
Y5
HepB DNA
X
X
X
X
Y2
Y5
Anti HDV
X
X
X
X
Y2
Y5
Questions and Answers
11:25 – 11:45
Immunosuppressives
12:30 – 12:45
Peter Stock
1)
4)
Calcineurin Inhibitors
2)
CellCept
3)
Steroids
Acute and Chronic Rejection
Calcineurin Inhibitor
 Cyclosporine initial dose recommendations
• PI-containing regimen: 25 – 50 mg PO BID.
This also applies to combined PI-NNRTI-based regimens
• When used with a non-PI containing regimen: 200 – 450
mg PO BID (200 mg if on Nevirapine; 250 – 450 mg if on
Efavirenz)
 Tacrolimus initial dose recommendations
• PI-containing regimen: 1 mg PO once to twice per week.
This also applies to combined PI-NNRTI-based regimens
• When used with an non-PI-containing regimen: 1 - 2 mg
bid PO
CellCept (MMF) and Steroids
 Standard dosing (1000 mg PO BID) will be initiated in all
kidney and liver subjects.
 Dosing should be modified based on toxicity (neutropenia,
GI) and clinical judgment.
 MMF may be tapered in stable liver transplant recipients
after 6 months of therapy.
 Steroid induction, taper, and maintenance will be according
to local site practice.
Notes

Induction with an IL-2 receptor inhibitor (anti-CD25
antibody) may be utilized for kidney transplants, but no
induction will be used for liver transplants.

Immunosuppressant doses will be modified to obtain
routine trough levels standard for kidney and liver
transplants.

In the case of HIV disease progression,
immunosuppressive doses may be reduced to prevent
clinical decline.
Notes

The transplant team/study coordinator must be notified
of any change in immunosuppressive dosing because
there may be interactions with antiretroviral drug
dosing and visa versa.

Other agents to be used tx of acute and chronic
rejection
 Sirolimus
 Anti-lymphocyte preparations (Thymoglobulin)
Antiretrovirals and Resistance
12:45 – 1:00
Michelle Roland
1)
2)
General Management Principals
Responding to New Detectable Viral Load
3)
Resistance Testing
Avoiding the Development of ARV
Resistance

Effective viral suppression requires multiple ARVs

Viral resistance develops when the ARV regimen is
not potent enough
 Inadequate number of different drugs
 Inadequate dose of drug
 Inadequate dosing schedule (eg missed doses)

ARVs should be discontinued and restarted in entire
combinations, not parts of combinations
Resistance Development

HIV drug resistance can develop very quickly, within
days, for some drugs
 Lamivudine (lamivudine) and all the NNRTIs (efavirenz,
nevirapine)
 Cross resistance is a problem with all these drugs

In the post-op period, it is best to hold all ARVs until
the patient is able to take po’s, there is no vomiting,
and there are no tests anticipated that will require an
NPO period.
Managing HBV and HIV Therapy

In most cases, unless HIV drug resistance is already
present, HBV therapy should only be initiated in
combination with the full HIV ARV combination (except
HBIg)

This can be particularly complicated with pretransplant management in a patient with bad liver
disease in whom you want to avoid hepatotoxins.
New Detectable HIV Viral Load

May be true failure to control HIV replication and
harbinger of “breakthrough”

May be a “blip”

May be a false positive

Recommend repeat ASAP so if it is a true and
persistent positive, the pros and cons of modifying
ARV therapy to minimize resistance development can
be considered
Resistance Testing

HIV Physician will determine when to request in both screening
and follow-up period

2 types are available: genotypic and phenotypic

Main limitation is sensitivity
 Can only detect minority quasispecies > 20% of population
 Drug selection pressure drives proportion of quasispecies that will be
resistant versus wild type
 Reversion to wild type does not mean resistant virus is cleared
 Can use to rule drugs out, but not to rule them in

Second significant limitation is interpretation of
sequence/phenotype
Prophylaxis
1:00 – 1:15
Michelle Roland
1)
Transplant-Specific
2)
3)
HIV-Specific
Special Issues in Subjects with an OI History
(Recommendations from the MOP)
Primary Prophylaxis

Subject with no history of the disease

At risk due to defined CD4 reduction or transplantation

Standard prophylaxis recommendations

Usually one drug

Often discontinued when CD4 count is high enough
unless there is transplant associated risk (eg PCP)
Secondary Prophylaxis = Chronic
Maintenance Therapy

Subjects with a history of the disease

Secondary prophylaxis should be reinstituted:
 post- transplant for 1 month
 during treatment of acute rejection and for 1 month following
completion of rejection therapy
 if CD4 cell count drops below the defined level

Secondary prophylaxis should be discontinued when CD4+ T-cell count is
above the defined level for six months
 unless the patient is within one month of completion of therapy for a
rejection episode

These are often more intensive regimens than primary prophylaxis regimens
(eg usually 2 drugs).
Pneumocystis Carinii Pneumonia (PCP)

Primary and Secondary Prophylaxis are indicated in
all patients for life and should start immediately posttransplant.

Preferred Regimen: TMP-SMX DS or SS daily

Alternatives: TMP-SMX DS TIW, dapsone QD
(contraindicated if G6PD deficient), atovaquone QD
or aerosolized pentamidine monthly
CMV Primary Prophylaxis
 Per Site Practice
CMV Secondary Prophylaxis
 CD4 cut-off: ≤ 100 to start and >/= 200 x 6
months to discontinue.
 Preferred: valcyte QD
 Alternative: oral ganciclovir TID
MAC Primary Prophylaxis
 CD4+ T-cell count ≤ 75 to start and >/= 100 x 6
months to discontinue.
 Preferred: Azithromycin weekly
 Alternatives: clarithromycin BID (drug interactions
with immunosuppressive agents must be
considered). Because of the risk of rejection due to
drug interaction with calcinerin inhibitors, rifabutin
and rifampin should be avoided for prophylaxis
unless all other alternatives have been exhausted.
MAC Secondary Prophylaxis
 CD4 cut-off: ≤ 75 to start and >/= 100 x 6 months to
discontinue.
 Preferred: azithromycin QD plus ethambutol QD
plus leucovorin QD.
 Alternatives: replace azithromycin with clarithromycin BID
(drug interactions with immunosuppressive agents must be
considered). Because of the risk of rejection due to drug
interaction with calcinerin inhibitors, rifabutin and rifampin
should be avoided for prophylaxis unless all other
alternatives have been exhausted.
Toxoplasmosis Primary Prophylaxis
 Toxo IgG-positive subjects with CD4+ T-cell count ≤
200.
 Preferred: DS TMP-SMX QD
 Alternatives: SS TMP-SMX QD or atovaquone. If
on dapsone for PCP need to add + pyrimethamine
QD + leucovorin QD
Toxoplasmosis Secondary Prophylaxis
 CD4 cut-off: </= 200 to start; > 200 for 6 months to
discontinue
 Preferred: pyrimethamine QD plus sulfadiazine
QD plus leucovorin QD.
•
Separate PCP prophylaxis should be discontinued if this regimen is
used.
 Alternative: for patients who cannot tolerate sulfa
drugs pyrimethamine QD plus clindamycin QID.
•
PCP prophylaxis must be continued with this regimen.
Cryptococosis Primary Prophylaxis
 None Recommended
Cryptococcosis Secondary Prophylaxis

CD4 cut-off: </= 200 to start; > 200 for 6 months to discontinue

Preferred: fluconazole qD (200 mg)
 Severe toxicity from calcineurin inhibitors may result if daily fluconazole
(or another azole) is used
 The dose of calcineurin inhibitors should be reduced by 50%; sometimes
more significant dose reduction is required.
 Daily calcineurin inhibitor trough levels should be monitored during the
first week of therapy, or longer if necessary.
 Similar adjustments are required in the dosing of sirolimus and
tacrolimus.
Histoplasmosis Primary Prophylaxis
 None Recommended
Histoplasmosis Secondary Prophylaxis

Prophylaxis must be continued regardless of
CD4 count until DHHS guidelines are modified
to recommend a safe level for discontinuation

Preferred: itraconazole DD
Alternatives: high dose fluconazole (400 mg)
QD

 Severe toxicity from calcineurin inhibitors may
result if daily azoles are used
Candidiasis
 Per site practice, but fluconazole 100mg once per
week for 3 months, supplemented with Mycelex
troches, is highly recommended.
 Severe toxicity from calcineurin inhibitors may
result if daily fluconazole (or another azole) is used
 See previous recommendations for dose
adjustments
EBV Prophylaxis
 Indicated for EBV negative recipient
with positive donor.
 Regimen: IV ganciclovir QD while
hospitalized then, ganciclovir PO TID
x 1 year.
•
Patients should not be continued on acyclovir
if they are on ganciclovir.
Anticipated Drug Interactions/Dosing
1:15 – 1:30
Laurie Carlson
1)
Protease Inhibitors and Calcineurin Inhibitors
2)
NNRTIs
Dosing of Protease Inhibitors with
Calcineurin Inhibitors
Drug/ Protease Inhibitors
Initial dose of CSA
Maintenance dose of CSA
CsA trough
Kaletra
25 mg bid or qd
25 mg qd or qod
?
Nelfinavir
50-75 mg bid
25 mg bid
Avg 112 R 59-174
Indinavir
75-100 mg bid
75 bid (limited data)
Avg 125; R 74-175
Nelfinavir/Amprenavir
50 mg bid
25 mg in am and 50 mg in pm
Avg 103 R 95-109
Drug/ Protease Inhibitors
Initial dose of Prograf
Maintenance dose Prograf
FK trough
Kaletra
.5 mg bid
.5 mg qod
?
Nelfinavir
1 mg bid
.5 mg qd to .5 mg qod
3.6
Indinavir
ND
ND
Dosing of NNRTIs with Calcineurin
Inhibitors
Drug/ NNRTI
Initial dose of CSA
Maintenance dose of CSA
CsA trough
Nevirapine
200-250 mg bid
100-175 mg bid
Avg 122; R 45-195
Sustiva
350 -450 mg bid
250-400 mg bid
Avg 117, R84-182
Drug/ NNRTI
Initial dose of Prograf
Maintenance dose Prograf
FK trough
Nevirapine
3 mg bid
1.0-2 mg bid
Avg 6; R 3.1-9.8
Sustiva
ND
ND
Dosing of PI & NNRTIs Combinations
with Calcineurin Inhibitors
NNRTI/PI combo
Sustiva/ Amprenavir
Nelfinavir/Nevirapine
Initial dose of Prograf
1 mg bid
.5 bid
Maintenance dose Prograf
1.0 q am and .5 qpm
.5 mg qd- qod
FK trough
Avg 9.6; R 6.3-10.6
Avg 6; R 2-12
NNRTI/PI combo
Sustiva/ Amprenavir
Nelfinavir/Nevirapine
Indinavir/Nevirapine
Kaletra/Nevirapine
Initial dose of CSA
100 mg bid
25mg bid
150 mg bid
25 bid
Maintenance dose CSA
ND
25 mg qd -bid
100 mg bid
25 qd-qod
CsA trough
114-182
Avg 169 R 152-176
Avg 139 R 85-173
R 45-254; avg 129
Dosing of Antiretrovirals with Sirolimus
ARV
CI
Maintenance dose of Sirolimus
SRL trough
Nelfinavir
Nelfinavir/Sustiva
Kaletra/Nevirapine
Kaletra
Nelfinavir
Neoral 25 mg bid
Neoral 25 mg bid
Neoral 25 qod
None
None
1mg BIW
1 mg BIW
1 mg q week
1 mg BIW
1 mg qod
1.9
3.9
Factors Influencing Dosing

Graft function

Initiation of ARV therapy post transplant

Tenofovir and renal insufficiency

Side effects

Education
Questions and Answers
1:30 – 1:45
HCV Co-Infected Patients
2:00 – 2:20
Peter Stock
1)
Liver Patients
2)
Kidney Patients
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 score> 8 and/or fibrosis stage >2 are considered indications
for treatment by most transplant physicians but the decision to
treat will ultimately be determined by the treating physician.
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
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.
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.
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).
Marrow-Supportive Therapy

Erythropoietin
 Start when hemoglobin is <10g/dl.
 Dose: 40,000 IU subcutaneously weekly.
 If hemoglobin decreases below 8.0 g/dL, discontinue
ribavirin until >10 g/dL (women) or >12 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 <1,000/mm3.
 Dose: 300 ug twice weekly. If subsequent trough ANC
>3000/mm3, reduce dose to 150 ug twice weekly or 300 ug
once weekly. Continued until the end of treatment.
Pre-Transplant Treatment of HCV +
Kidney Candidates: When?

Pre-transplant therapy with interferon/peg-interferon
will be considered in each patient but is not required.

Pre-transplant therapy is strongly recommended if:
 Biopsy shows stage stage 2 or greater disease
 All patients with non-1 genotypes, regardless of
stage of disease, since the viral clearance rates
with INF treatment are >50% for this subgroup.
Post-Transplant Treatment of HCV +
Kidney Recipients: When?

Advanced or progressive liver disease post-transplant
will be targeted for anti-HCV treatment

Post-transplantation therapy will be offered but not
required in the following circumstances:
 Biopsy evidence of progressive disease (increase in fibrosis
score)
 Any biopsy showing stage 3 or 4 disease
 Biopsy and clinical features of fibrosing cholestatic hepatitis
Biopsies in HCV + Kidney Recipients:
When to Do? Who Reads?

Pre-transplant: assess histological stage; rule out cirrhosis

Protocol biopsies: month 6, year 2.5, and year 5 (use GCRC)

At any time for clinical indications:



AST or ALT >2 ULN for >/= 3 months

significant change in AST, ALT, alkaline phosphatase or total bilirubin
from baseline in order to rule out concurrent conditions (e.g. drug
toxicity, biliary disease, fibrosing cholestatic hepatitis or other
progressive HCV disease).
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
HCV Treatment Regimen

Pre-transplant: Peg- INF or standard INF
 not altered based upon prior INF experience
 standard INF 3 million units three times weekly
 pegylated INF 1.0-1.5 ug/kg (peg-INF alfa-2b) weekly or 180
ug weekly (peg-INF alfa-2a).

Post-transplant: Peg-INF or standard INF plus
ribavirin.
Monitoring on HCV Treatment

Same as in liver recipients
Length of HCV Treatment:
Pre-Transplant


Minimum of 3 months
At 3 months, if a 2-log reduction in HCV RNA or HCV RNA
negative, continued for a total of 6 to 12 months (depending
upon genotype and stage of fibrosis).
 If the patient does not achieve at least a 2-log reduction in HCV RNA by
month 3 of treatment, the treatment will be discontinued.
Note: liver and combined kidney-liver candidates
will not be encouraged to treat HCV pre-transplant (as kidney
candidates are) as it is assumed that they have already
exhausted all medical therapy options for the treatment of HCV.
Length of Treatment Post-Transplant

12 months. HCV RNA at 3 and 12 months post-therapy (if
quantitative negative at 12 months, will do qualitative

Repeat biopsy following 12 months of treatment recommended
Types of Response and Actions:

HCV RNA negative at end of treatment: stop and observe for
relapse.

HCV RNA positive at end of treatment: stop and observe for
histological progression.

Consider re-initiation of therapy if histological activity or fibrosis
score increases.
Marrow-Supportive Therapy

EPO and G-CSF as for liver recipients
HBV Co-Infected Patients
2:20 – 2:30
Peter Stock
1)
2)
Liver Patients
Kidney Patients
Biopsies: Liver and Kidney Recipients

No protocol-mandated biopsies

Biopsies should be obtained if:
 AST or ALT > 1.5 ULN
 Any HBV virological breakthrough
 Suspicion of drug hepatotoxicity
Treatment Guidelines for Liver and Kidney
Candidates: Pre-Transplant

If lamivudine naïve, treat with lamivudine 150mg BID
 May use lamivudine plus adefovir or tenofovir


If lamivudine resistant, use tenofovir or adefovir plus
lamivudine
(Emtriva [FTC] has not been added to protocol yet)
Treatment Guidelines for Liver and Kidney
Recipients: Peri-Transplant

Continue lamivudine, adefovir
prescribed pre-transplant
or
tenofovir
as
 Adjust for renal function
 If unable to start HIV antiretroviral therapy post-transplant,
hold HBV antiviral medication until able to start HIV
antiretroviral therapy
Treatment Guidelines for Liver Recipients:
Peri-Transplant



HBIg Dosing Schedule: 10,000 IU during the anhepatic phase
and on admission to ICU. 5,000 IU Q6 hours for days 1 and 2
post-op, and 10,000 IU daily for days 3 – 7 post-op. Check
HBsAg on day 2 and if positive, give 10,000 IU every 12 hours
until HbsAg negative.
If patient is HBV DNA detectable pre liver transplant, closer
monitoring of HBIG dosing is advised, especially if HBV
antivirals are on hold.
If HBV antivirals are held, check HbsAg daily and continue
5000 IU Q6 hours until HbsAg is negative, then 10,000 IU daily
for 7 days of treatment.
HBV Treatment Guidelines for Liver
Recipients: Post-Transplant

Continue HBV and HIV antiretrovirals indefinitely

HBIG
 10,000 IU monthly for 3 months, then
 5,000 IU for next 3 months, then
 2,500 IU (IM or IV) monthly thereafter, indefinitely


Monitor HBsbAg and anti-HBs titer monthly.
Monitor HBV DNA levels as clinically indicated (AST
or ALT > 1.5 ULN) and every 3 months.
Treatment Guidelines
for Kidney Recipients: Post-Transplant

If patient has stage 3 or 4 fibrosis, antiviral therapy
should be continued indefinitely

For patients with </= stage 2 fibrosis, antiviral therapy
can be stopped after 12 months if the following criteria
are met:
 Normal liver enzymes
 Minimal (5 mg QD or QOD) or no prednisone
 No recent change in immunosuppression (stable for
preceding 3 months)
Treatment Guidelines
for Kidney Recipients:
Restarting HBV Therapy

Restart HBV therapy and continue indefinitely if AST or ALT
increase to > 1.5 ULN and HBV DNA > 105 copies/mL after
treatment is stopped.

Additionally, give HBV antiviral therapy whenever a patient
receives treatment for rejection; continue for at least 4 months;
stop only when:
 Normal liver enzymes
 Minimal (5 mg QD or QOD) or no prednisone
 No recent change in IMS (stable for preceding 3 months)
Monitoring Guidelines:
Liver and Kidney Recipients

Pre-transplant : HBV DNA every 3 months

Peri-transplant : HBV DNA immediately pre-transplant.

Post-transplant : In addition to the protocol-mandated
labs, it is recommended for clinical management that
HBV DNA be followed every 3 months and as clinically
indicated (AST or ALT > 1.5 ULN) and that HBSAg
and HBSAb be followed monthly
Rejection
2:30 – 2:45
Peter Stock
1)
2)
Management
Definitions
Acute and Chronic Rejection

A biopsy will be performed in all cases of suspected rejection
 Therapy may be initiated </= one day prior to the results of the biopsy if
clinically indicated.
 Treatment for > 1 day, including increases in the dose of
immunosuppressive medications, cannot be sustained without a biopsy,
unless the managing physicians believe biopsy is unsafe.

Treatment of rejection episodes will be according to local site
practices and may include sirolimus.

OKT3 and polyclonal anti-lymphocyte preparations have
resulted in prolonged reduction in CD4+ counts in HIV infected
transplant recipients, and their use should be restricted to
treatment for severe rejection.
Definition of Rejection

Kidney (NIH CCTT Definition)
 Type I: mononuclear infiltrate in > or =5% of cortex, a total of at least
three tubules with tubulitis in 10 consecutive high-power fields from the
most severely affected areas, and at least two of the three following
features: edema, activated lymphocytes, or tubular injury.
 Type II: arterial, or arteriolar, endothelialitis with or without the preceding
features.
 Type III: arterial fibrinoid necrosis or transmural inflammation with or
without thrombosis, parenchymal necrosis, or hemorrhage.

Liver (Banff Criteria)
 Liver rejection will be defined by the Banff global grading scheme and
Banff rejection activity index.
Questions and Answers
2:45 – 3:10
Adverse Event Reporting
3:10 – 3:25
Natasha Tomlin
1)
TBD
Data Management
3:25 – 3:45
Craig Lazar
1)
TBD
Website Modifications

Updated sample letter requesting reimbursement

Updated PDFs for relevant studies

Updated contact list of experienced folks willing to
help
Publication and Media Policy
3:45 – 3:55
Michelle Roland
1.
Membership
2.
Roles
PPSC Membership

1 from each Clinical Site
 Balance transplant and HIV
 PI discuss with key personnel and elect

1 from each Lab Site

1 from CAB

Add expertise as needed for concepts

PPSC elects it’s chair
PPSC Roles

Specific roles and procedures to be determined by
PPSC

Guiding principles:
Multi-Site
“Old Ideas”
“New Ideas”
Study Aim PI
Concept Sheet
(encouraged)
Single Site
Concept Sheet
None Required
(discouraged)
(requested)
Reimbursement Considerations
3:55 – 4:10
Peter Stock, Cheryl Janov
Who Paid in Pilot Multi-Site Study?
• Kidney recipients:
• 69%
• 8%
• 23%
Medicare
Medicaid
Private Insurers
• Liver recipients:
•
•
•
•
10%
20%
40%
30%
Medicare
Medicaid
Private Insurers
CA Research Funds
Website

Sample letters to insurers

Supporting articles to include with coverage request
IRB Re: Experimental

The procedure is not experimental

The population/context is
Donor Consent

Required at each site

Must include disclosure of candidate HIV status prior
to invasive procedures in donor

Alternatives: cadaver donor, off-study transplant
Community Advisory Board
4:10 – 4:20
Michelle Roland, Debi Surlas and Robert Zackin
1)
TBD
Closing Discussion
4:20 – 5:00
“Parking Lot” Issues from SC

Pre-eligible consent/enrollment for outcomes

Specimen request review process