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 • Administrative Issues • Protocol Review • Policy • Other
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
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
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)
Budget and Regulatory Issues 8:20 – 8:30 Michelle Roland • IRB Approvals • Regulatory Documents to NIH • 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 • 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 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 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 host-response to viral co-pathogens, including hepatitis B and C, the human herpesviruses (CMV, EBV, HHV-6, HHV-8) 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 post-transplant.
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 • 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 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
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 • Study Design and Control Groups • 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 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
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
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 • Inclusion Criteria • 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 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 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”) • 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 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 • 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