HIV Transplant Investigators Meeting:Introduction and Welcome

HIV Transplant Investigators Meeting:Introduction and Welcome

Nancy Bridges, NIH

Peter Stock, UCSF

Michelle Roland, UCSF

8:00 – 8:10

Meeting ObjectivesMeeting Objectives

8:10 – 8:20

Michelle Roland

1) Administrative Issues

2) Protocol Review

3) Policy

4) Other

Objectives: Administrative IssuesObjectives: 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 IssuesObjectives: 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

Meeting Objectives: Policy and Other Issues

1) Publications and Media Policy

2) Reimbursement

3) Donor Consent

4) Complete Good Clinical Practices (GCP) Training

5) Resources on the EMMES Study Website

6) Community Advisory Board

7) 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 IssuesBudget and Regulatory Issues

8:20 – 8:30

Michelle Roland

1) IRB Approvals

2) Regulatory Documents to NIH

3) Site Visits Pre-Start Up

4) Subcontract Conditions (“Milestones”)

Subcontract RequirementsSubcontract 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 TrainingGood Clinical Practices Training

8:30 – 10:00

Barbara Pennington

Study AimsStudy Aims

10:15 – 10:25

Peter Stock

1) Primary Aims

2) Secondary Aims

Specific AimsSpecific Aims

2 hypothesis-driven aims Patient survival

Graft survival

4 exploratory aims

Primary Aim 1:

Evaluate the impact of immunosuppression on patient survival

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

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

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

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.

Graft survival in HIVANGraft 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.

Secondary Aim 1:

Explore the impact of post-transplant immunosuppression on changes in CD4+ T cell counts and HIV-1 RNA levels.

RationaleRationale

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 host-response to viral co-pathogens, including hepatitis B and C, the human herpesviruses (CMV, EBV, HHV-6, HHV-8) and HPV.

Secondary Aim 2:

Explore 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.

RationaleRationale

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.

Secondary Aim 3:

Explore the impact of HIV infection on the alloimmune response and rejection rates.

Secondary Aim 3:

Explore the impact of HIV infection on the alloimmune response and rejection rates.

RationaleRationale

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.

Secondary Aim 4:

Explore the pharmacokinetic interactions between immunosuppressive agents and the hepatically metabolized antiretroviral agents.

Committees Committees

10:25 – 10:40

Michelle Roland

1) Steering Committee

2) Operations Committee

Steering Committee Key Responsibilities

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 PerformanceImplementation 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/ViolationsProtocol 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 MembersCurrent Members

Peter Stock and Michelle Roland

Don Stablein: Senior Biostatistician

2 Independent investigators: To Be Named

Robert Zackin and Debi Surlas: Community Representatives

2 Daniella Livnat: NIAID Program Officer

Nancy Bridges: DAIT Medical Officer

Larry Fox: DAIDS Medical Officer

1 John Fung and 1, 2 Margaret Ragni University of Pittsburgh

1, 2 Timothy Pruett, University of Virginia 1 Rotate yearly2 Non-voting members

Operations CommitteeOperations 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 MembersCurrent 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 RulesStopping Rules

10:40 - 10:55

Don Stablein

1) Study Design and Control Groups

2) Sample Size

3) Monitoring

Design SummaryDesign Summary

Protocol contains separate single arm evaluations of kidney transplant

liver transplant

Dual Primary Endpoints patient survival

graft survival (death is an event)

Sample SizeSample 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 HypothesesDeveloping 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 group- older (>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 HypothesesOne Year Event Rates

Null and Alternative HypothesesOne 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 MonitoringDSMB 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

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

Kidney Graft Survival

Liver Survival Liver Graft Survival

Targeted 1-Year Rate

.88 .83 .82 .78

True 1-Year Rate .85 0.1 0 0 0 .80 1.4 0 0 0 .75 16.1 1.6 0.5 0 .70 56.8 16.4 6.2 1.1 .65 89.5 51.4 29.5 8.7 .60 98.5 84.7 63.7 32.9 .55 99.9 97.6 89.4 66.7 Mean 1-Year Estimate For Terminated Studies

0.596

0.561

0.535

0.504

Other Safety MonitoringOther 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 CriteriaInclusion and Exclusion Criteria

10:55 – 11:10

Michelle Roland

1) Inclusion Criteria

2) Exclusion Criteria

3) Narrower Selection Criteria

Key Inclusion CriteriaKey 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

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 AreUnable to Tolerate ARV Therapy

Liver Subjects Who AreUnable to Tolerate ARV Therapy

May have detectable viral load if the study HIV clinician confidently predicts HIV suppression post-transplant 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 UseARV 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 HistoryOI 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 EnrollmentSpecific 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 EnrollmentSpecific OI Requirements for Enrollment CNS Toxoplasmosis (“Toxo”)

MRI without active disease

Kaposi’s Sarcoma (“KS”) 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 InfectionsMycobacterial Infections

Mycobacterium tuberculosis (TB) Completed standard treatment course

Mycobacterium kansasii Completed standard treatment course

Mycobacterium avium complex (MAC) Completion of 12 months of MAC therapy AND negative

MAC blood culture

Key Exclusion Criteria: OIs 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: NeoplasmsExclusion 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 CandidatesHCV Co-Infected Kidney Candidates

Biopsy-documented cirrhosis requires listing for combined liver and kidney transplant.

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”“Narrower Selection Criteria”

Final decisions with regard to the application of narrower selection criteria with regard to pre-transplant 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 EventsSchedule of Events

11:10 – 11:25

Michelle Roland

1) Clinical, Radiology, Laboratory (Safety, HIV, Screening Serology)

2) Clusters/Sub-Studies

3) HCV and HBV co-Infected Subjects

Years:Year

0Year

1

Years 2 & 3

every 3 m1

every 6 m2

Years 4 & 5

every 6 m

Weeks: ScreenDay

0Week

12 4 6 8

10

12

16

20

2636

44

52

53-156 157-260

CLINICAL

Documentation of HIV infection X

Informed Consent X

Symptom & Medical Review plus Physical Exam X9 X X X X X X X X X X X X X X X1 X

PPD 3 X X X X2 X

Vaccination Review (Pneumovax, Hepatitis A and B)

X

Cervical PAP4 X

Pregnancy Test X9 X

RADIOLOGY

CXR X

MRI head 5

Clinical and RadiologyClinical and Radiology

Years:Year

0Year

1

Years 2 & 3

every 3 m1

every 6 m2

Years 4 & 5

every 6 m

Weeks: Screen Day 0 Week 1 2 4 6 8 10 12 16 20 26 36 44 52 53-156 157-260

SAFETY LABS

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 X X X1 X

Fasting Lipid Panel (Chol, LDL, HDL, TGL) X X X X2 X

Phosphate (PO4)6 X X X X X X X X X X X X X X X X2 X

Urinalysis X X X X Y2 Y5

Immunosuppressant levels X X X X X X X X X X X X X X1 X

Lactate Monitoring (if on HCV therapy) X9 X X X X X X X X X X X X X X X3 X3

LaboratoryLaboratory

Years:Year

0Year

1

Years 2 & 3

every 3 m1

every 6 m2

Years 4 & 5

every 6 m

Weeks: ScreenDay

0Week

12 4 6 8

10

12

16

20

26

36

44

52

53-156 157-260

HIV LABS

CD4+/CD8+ T-cell count X X X X X X X X X X X X1 X

HIV-1 RNA (bDNA or PCR) X X X X X X X X X X X X1 X

RPR/VDRL7 X9 X X X2 X

Toxoplasmosis Quantitative7 X X X X2 X

G6PD X

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”“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”“Clusters”

Years: Year 0Year

1

Years 2 & 3

Years 4 & 5

Weeks: ScreenDay

0Week

12 4 6 8 10 12 16 20 26 36 44 52 53-156 157-260

Co-Pathogen CFC (McCune)

Cytokine Flow Cytometry X X X X Y2 Y5

Co-Pathogen CTL (Brander)

Co-Pathogen ELISPOT X X X X Y2 Y5

HHV8 (Martin)

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

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

Transplant Immunology (Stock) – UCSF real time, others stored)

MLC X X X X Y2 Y5

Donor tissue or blood X

Cluster 1 Sub-Studies: Co-Pathogen Virology/Immunology; Transplant Immunology

Cluster 1 Sub-Studies: Co-Pathogen Virology/Immunology; Transplant Immunology

Years: Year 0Year

1Years 2 & 3 Years 4 & 5

Weeks:Screen Week

12 4 6 8 10 12 16 20 26 36 44 52 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

pGP Phenotype X

HPV (Palefsky)

Anal PAP1 X

Specimen Storage

Fresh blood shipped to BBI3 X X X X X Y2 Y5

Cluster 1 Continued: pK and HPV

Years: Year 0Year

1

Years 2 & 3

Years 4 & 5

Weeks: Screen Day 0Week

12 4 6 8 10 12 16 20 26

36

44 5253-156

157-260

Co-Pathogen CFC (McCune)

Cytokine Flow Cytometry X X X X Y2 Y5

Co-Pathogen CTL (Brander)

Co-Pathogen ELISPOT X X X X Y2 Y5

HHV8 (Martin)

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

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

Specimen Storage

Fresh blood shipped to BBI1 X X X X X Y2 Y5

Cluster 2 Sub-Studies: Co-Pathogen Virology/Immunology

Cluster 2 Sub-Studies: Co-Pathogen Virology/Immunology

Years: Year 0Year

1Years 2

& 3Years 4

& 5

Weeks: ScreenDay

0Week

12 4 6 8 10 12 16 20 26 36 44 52 53-156 157-260

HIVAN (Klotman)

Biopsy Tissue1 X

HPV (Palefsky) – liver patients only

Anal PAP X

Specimen Storage

Fresh blood shipped to BBI1 X X X X X Y2 Y5

Cluster 3 Sub-Studies: HIVAN, HPVCluster 3 Sub-Studies: HIVAN, HPV

Years: Year 0Year

1Years 2 & 3

Years 4 & 5

Weeks: ScreenDay

0Week

12 4 6 8 10 12 16 20 26 36 44 52 53-156

157-260

HPV (Palefsky) – Columbia only-

Anal PAP1 X

Specimen Storage

Fresh blood shipped to BBI X X X X X Y2 Y5

Cluster 4 Sub-Studies: HPVCluster 4 Sub-Studies: HPV

HCV + Subjects: Virology and ImmunologyHCV + Subjects: Virology and Immunology

Years: Year 0Year

1Years 2 &

3Years 4 & 5

Weeks: Screen Day 0Week

12 4 6 8 10 12 16 20 26 36 44

52

53-156 157-260

HCV (Oldach)

Biopsy (protocol mandated biopsies)1 X

HCV RNA2 X X X X Y2 Y5

HCV Genotype X

HCV Quasispecies X X X X Y2 Y5

HCV Ab-RIBA X

CTL (Brander)

HCV Elispot X X X X Y2 Y5

CFC (McCune)

Cytokine Flow Cytometry X X X X Y2 Y5

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 post-therapy initiation. Kidney subjects receiving HCV therapy must have additional HCV RNA at 3 and 12 months post-therapy initiation.

HBV + Subjects: VirologyHBV + Subjects: Virology

Years: Year 0Year

1Years 2 & 3 Years 4 & 5

Weeks:Scree

nDay

0Week

12 4 6 8 10 12 16 20 26 36 44 52 53-156 157-260

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 AnswersQuestions and Answers

11:25 – 11:45

ImmunosuppressivesImmunosuppressives

12:30 – 12:45

Peter Stock

1) Calcineurin Inhibitors

2) CellCept

3) Steroids

4) Acute and Chronic Rejection

Calcineurin Inhibitor 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 SteroidsCellCept (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 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 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 ResistanceAntiretrovirals and Resistance

12:45 – 1:00

Michelle Roland

1) General Management Principals

2) Responding to New Detectable Viral Load

3) Resistance Testing

Avoiding the Development of ARV Resistance

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 DevelopmentResistance 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 TherapyManaging 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 pre-transplant management in a patient with bad liver disease in whom you want to avoid hepatotoxins.

New Detectable HIV Viral LoadNew 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 TestingResistance 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

ProphylaxisProphylaxis

1:00 – 1:15

Michelle Roland

1) Transplant-Specific

2) HIV-Specific

3) Special Issues in Subjects with an OI History (Recommendations from the MOP)

Primary ProphylaxisPrimary 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

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)Pneumocystis Carinii Pneumonia (PCP)

Primary and Secondary Prophylaxis are indicated in all patients for life and should start immediately post-transplant.

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 ProphylaxisCMV Primary Prophylaxis

Per Site Practice

CMV Secondary ProphylaxisCMV Secondary Prophylaxis

CD4 cut-off: ≤ 100 to start and >/= 200 x 6 months to discontinue.

Preferred: valcyte QD

Alternative: oral ganciclovir TID

MAC Primary ProphylaxisMAC 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 ProphylaxisMAC 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 ProphylaxisToxoplasmosis 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 ProphylaxisToxoplasmosis 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 ProphylaxisCryptococosis Primary Prophylaxis

None Recommended

Cryptococcosis Secondary ProphylaxisCryptococcosis 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 ProphylaxisHistoplasmosis Primary Prophylaxis

None Recommended

Histoplasmosis Secondary ProphylaxisHistoplasmosis 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

CandidiasisCandidiasis

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 ProphylaxisEBV 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/DosingAnticipated Drug Interactions/Dosing

1:15 – 1:30

Laurie Carlson

1) Protease Inhibitors and Calcineurin Inhibitors

2) NNRTIs

Dosing of Protease Inhibitors with Calcineurin Inhibitors

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

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

Dosing of PI & NNRTIs Combinations with Calcineurin Inhibitors

NNRTI/PI combo Initial dose of Prograf Maintenance dose Prograf FK trough

Sustiva/ Amprenavir 1 mg bid 1.0 q am and .5 qpm Avg 9.6; R 6.3-10.6

Nelfinavir/Nevirapine .5 bid .5 mg qd- qod Avg 6; R 2-12

NNRTI/PI combo Initial dose of CSA Maintenance dose CSA CsA trough

Sustiva/ Amprenavir 100 mg bid ND 114-182

Nelfinavir/Nevirapine 25mg bid 25 mg qd -bid Avg 169 R 152-176

Indinavir/Nevirapine 150 mg bid 100 mg bid Avg 139 R 85-173

Kaletra/Nevirapine 25 bid 25 qd-qod R 45-254; avg 129

Dosing of Antiretrovirals with Sirolimus Dosing of Antiretrovirals with Sirolimus

ARV CI Maintenance dose of Sirolimus SRL trough

Nelfinavir Neoral 25 mg bid 1mg BIW Nelfinavir/Sustiva Neoral 25 mg bid 1 mg BIW Kaletra/Nevirapine Neoral 25 qod 1 mg q week Kaletra None 1 mg BIW 1.9 Nelfinavir None 1 mg qod 3.9

Factors Influencing DosingFactors Influencing Dosing

Graft function

Initiation of ARV therapy post transplant

Tenofovir and renal insufficiency

Side effects

Education

Questions and AnswersQuestions and Answers

1:30 – 1:45

HCV Co-Infected PatientsHCV Co-Infected Patients

2:00 – 2:20

Peter Stock

1) Liver Patients

2) Kidney Patients

Treatment of HCV + Liver Recipients: When?

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?

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 RegimenHCV 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 TreatmentMonitoring 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 TreatmentLength 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 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 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?

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?

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 RegimenHCV 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 TreatmentMonitoring on HCV Treatment

Same as in liver recipients

Length of HCV Treatment:Pre-Transplant

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-TransplantLength 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 TherapyMarrow-Supportive Therapy

EPO and G-CSF as for liver recipients

HBV Co-Infected PatientsHBV Co-Infected Patients

2:20 – 2:30

Peter Stock

1) Liver Patients

2) Kidney Patients

Biopsies: Liver and Kidney RecipientsBiopsies: 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

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

Treatment Guidelines for Liver and Kidney Recipients: Peri-Transplant

Continue lamivudine, adefovir or tenofovir as prescribed pre-transplant 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

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

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 Guidelinesfor Kidney Recipients: Post-Transplant

Treatment Guidelinesfor 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 Guidelinesfor Kidney Recipients:

Restarting HBV Therapy

Treatment Guidelinesfor 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

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

RejectionRejection

2:30 – 2:45

Peter Stock

1) Management

2) Definitions

Acute and Chronic RejectionAcute 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 RejectionDefinition 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 AnswersQuestions and Answers

2:45 – 3:10

Adverse Event ReportingAdverse Event Reporting

3:10 – 3:25

Natasha Tomlin

1) TBD

Data ManagementData Management

3:25 – 3:45

Craig Lazar

1) TBD

Website ModificationsWebsite Modifications

Updated sample letter requesting reimbursement

Updated PDFs for relevant studies

Updated contact list of experienced folks willing to help

Publication and Media PolicyPublication and Media Policy

3:45 – 3:55

Michelle Roland

1. Membership

2. Roles

PPSC MembershipPPSC 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 RolesPPSC Roles

Specific roles and procedures to be determined by PPSC

Guiding principles:

“Old Ideas” “New Ideas”

Multi-Site Study Aim PI Concept Sheet (encouraged)

Single Site Concept Sheet None Required(discouraged) (requested)

Reimbursement ConsiderationsReimbursement Considerations

3:55 – 4:10

Peter Stock, Cheryl Janov

Who Paid in Pilot Multi-Site Study?Who Paid in Pilot Multi-Site Study?

• Kidney recipients:• 69% Medicare

• 8% Medicaid

• 23% Private Insurers

• Liver recipients: • 10% Medicare

• 20% Medicaid

• 40% Private Insurers

• 30% CA Research Funds

WebsiteWebsite

Sample letters to insurers

Supporting articles to include with coverage request

IRB Re: ExperimentalIRB Re: Experimental

The procedure is not experimental

The population/context is

Donor ConsentDonor 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 BoardCommunity Advisory Board

4:10 – 4:20

Michelle Roland, Debi Surlas and Robert Zackin

1) TBD

Closing DiscussionClosing Discussion

4:20 – 5:00

“Parking Lot” Issues from SC“Parking Lot” Issues from SC

Pre-eligible consent/enrollment for outcomes

Specimen request review process