HIV Transplant Investigators Meeting: Introduction and Welcome

1. HIV Transplant Investigators Meeting:Introduction and Welcome 8:00 – 8:10 • Nancy Bridges, NIH • Peter Stock, UCSF • Michelle Roland, UCSF

2. Meeting Objectives 8:10 – 8:20 Michelle Roland • Administrative Issues • Protocol Review • Policy • Other

3. Objectives: Administrative Issues • U01 and “Terms and Conditions of Award” • Subcontracts: IRB and regulatory issues • Site visits pre-start up • Steering and Operations Committee; Publications and Presentations Subcommittee • Data Management • Adverse Events Reporting

4. Objectives: Protocol Issues • Study Aims • Inclusion and Exclusion Criteria • Schedule of Events and “Sub-Study Clusters” • Medication Regimens and Drug Interactions • Immunosuppressants, ARVs, and Prophylaxis • Clinical Issues • HCV, HBV, and Rejection • Stopping Rules

5. Meeting Objectives: Policy and Other Issues • 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)

6. Budget and Regulatory Issues 8:20 – 8:30 Michelle Roland • IRB Approvals • Regulatory Documents to NIH • Site Visits Pre-Start Up • Subcontract Conditions (“Milestones”)

7. 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

8. Good Clinical Practices Training 8:30 – 10:00 Barbara Pennington

9. Study Aims 10:15 – 10:25 Peter Stock • Primary Aims • Secondary Aims

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

11. 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.

12. 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.

13. 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.

14. 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.

15. 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.

16. 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.

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

18. 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.

19. 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.

20. Rationale • The combination of immunosuppression and HIV could alter viral activation and/or host immune control of viruses that are associated with the development of clinically significant disease post-transplant.

21. Secondary Aim 3:Explore the impact of HIV infection on the alloimmune response and rejection rates.

22. 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.

23. Secondary Aim 4:Explore the pharmacokinetic interactions between immunosuppressive agents and the hepatically metabolized antiretroviral agents.

24. Committees 10:25 – 10:40 Michelle Roland • Steering Committee • Operations Committee

26. 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”

27. 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

28. 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)

29. 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 Daniella Livnat: NIAID Program Officer • Nancy Bridges: DAIT Medical Officer • Larry Fox: DAIDS Medical Officer • 1John Fung and 1, 2Margaret Ragni University of Pittsburgh • 1, 2Timothy Pruett, University of Virginia 1 Rotate yearly 2 Non-voting members

30. 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

31. 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

32. Stopping Rules 10:40 - 10:55 Don Stablein • Study Design and Control Groups • Sample Size • Monitoring

33. Design Summary • Protocol contains separate single arm evaluations of • kidney transplant • liver transplant • Dual Primary Endpoints • patient survival • graft survival (death is an event)

34. 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

35. 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 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

36. Null and Alternative HypothesesOne Year Event Rates

37. 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

38. 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

39. 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

40. Inclusion and Exclusion Criteria 10:55 – 11:10 Michelle Roland • Inclusion Criteria • Exclusion Criteria • Narrower Selection Criteria

41. 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

42. 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

43. 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

44. 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

45. 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.

46. 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.)

47. Specific 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.

48. Mycobacterial 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

49. 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).

50. 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