HIV Transplant Investigators Meeting: Introduction and Welcome

1
HIV Transplant Investigators MeetingIntroduction
and Welcome
800 810

• Nancy Bridges, NIH
• Peter Stock, UCSF
• Michelle Roland, UCSF

2
Meeting Objectives

• 810 820
• 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

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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

• 820 830
• 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

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Good Clinical Practices Training

• 830 1000
• Barbara Pennington

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Study Aims

• 1015 1025
• Peter Stock
• Primary Aims
• Secondary Aims

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Specific Aims

• 2 hypothesis-driven aims
• Patient survival
• Graft survival
• 4 exploratory aims

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Primary Aim 1Evaluate the impact of
immunosuppression on patient survival

• Hypothesis Liver and kidney transplant
  recipients will have survival rates comparable to
  other patient groups without HIV infection that
  are currently considered acceptable transplant
  candidates.

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 gt65 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 2Evaluate the impact of HIV
infection and HAART on graft survival

• Hypothesis 1 HIV liver and kidney transplant
  recipients will have graft survival rates
  comparable to other patient groups without HIV
  infection that are currently considered
  acceptable candidates.

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.
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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 2Explore the impact of
post-transplant immunosuppression on the
host-response to viral co-pathogens, including
hepatitis B and C, the human herpesviruses (CMV,
EBV, HHV-6, HHV-8) and HPV.
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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 3Explore 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 4Explore the pharmacokinetic
interactions between immunosuppressive agents and
the hepatically metabolized antiretroviral agents.
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Committees

• 1025 1040
• Michelle Roland
• Steering Committee
• Operations Committee

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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

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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

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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)

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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
• 1 John Fung and 1, 2 Margaret Ragni University of
  Pittsburgh
• 1, 2 Timothy Pruett, University of Virginia

1 Rotate yearly 2 Non-voting members
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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

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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

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Stopping Rules

• 1040 - 1055
• Don Stablein
• Study Design and Control Groups
• Sample Size
• Monitoring

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Design Summary

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

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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

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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 (gt64 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

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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

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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
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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 gt/ 1 log
  increase
• CD4 Count 25 decline w/o rejection therapy
• Other Adverse Events monthly
• Long term graft and patient survival

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Inclusion and Exclusion Criteria

• 1055 1110
• Michelle Roland
• Inclusion Criteria
• Exclusion Criteria
• Narrower Selection Criteria

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Key Inclusion Criteria

• Age gt 1 year old at Pediatric sites
• UCSF (L/K), University of Chicago (L), Mt. Sinai
  (K), Columbia (L)
• At non-pediatric sites age gt18
• CD4 T-cell count for past 6 months
• Kidney gt/ 200
• Liver gt/100 OR gt/ 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

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Viral Load Must Be Undetectable for Subjects on
ARV Therapy

• lt 50 with Amplicor Monitor Ultrasensitive PCR or
• lt 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

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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.

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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
• Kaposis 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.

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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

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Key Exclusion Criteria OIs

• Progressive Mulitfocal Leukoencephalopathy (PML)
• Chronic Cryptosporidiosis (gt 1 month duration)
• Pulmonary Coccidiodomycosis will be treated per
  local site policy in HIV negative transplant
  candidates (generally 5-year disease-free
  interval).

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Exclusion Criteria Neoplasms

• Lymphoma (Burkitts, immunoblastic or CNS)
• Any other neoplasm except
• cutaneous kaposis 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

51
HCV 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

52
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.

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Schedule of Events

• 1110 1125
• Michelle Roland
• Clinical, Radiology, Laboratory (Safety, HIV,
  Screening Serology)
• Clusters/Sub-Studies
• HCV and HBV co-Infected Subjects

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Clinical and Radiology
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Laboratory
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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

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Clusters
59
Cluster 1 Sub-Studies Co-Pathogen
Virology/Immunology Transplant Immunology
60
Cluster 1 Continued pK and HPV
61
Cluster 2 Sub-Studies Co-Pathogen
Virology/Immunology
62
Cluster 3 Sub-Studies HIVAN, HPV
63
Cluster 4 Sub-Studies HPV
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HCV Subjects Virology and Immunology
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.

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HBV Subjects Virology

66
Questions and Answers

• 1125 1145

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Immunosuppressives

• 1230 1245
• Peter Stock
• Calcineurin Inhibitors
• CellCept
• Steroids
• Acute and Chronic Rejection

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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

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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.

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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.

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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)

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Antiretrovirals and Resistance

• 1245 100
• Michelle Roland
• General Management Principals
• Responding to New Detectable Viral Load
• Resistance Testing

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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

74
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 pos,
  there is no vomiting, and there are no tests
  anticipated that will require an NPO period.

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

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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

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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 gt 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

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Prophylaxis

• 100 115
• Michelle Roland
• Transplant-Specific
• HIV-Specific
• Special Issues in Subjects with an OI History
  (Recommendations from the MOP)

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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)

80
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).

81
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

82
CMV Primary Prophylaxis

• Per Site Practice

83
CMV Secondary Prophylaxis

• CD4 cut-off 100 to start and gt/ 200 x 6
  months to discontinue.
• Preferred valcyte QD
• Alternative oral ganciclovir TID

84
MAC Primary Prophylaxis

• CD4 T-cell count 75 to start and gt/ 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.

85
MAC Secondary Prophylaxis

• CD4 cut-off 75 to start and gt/ 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.

86
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

87
Toxoplasmosis Secondary Prophylaxis

• CD4 cut-off lt/ 200 to start gt 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.

88
Cryptococosis Primary Prophylaxis

• None Recommended

89
Cryptococcosis Secondary Prophylaxis

• CD4 cut-off lt/ 200 to start gt 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.

90
Histoplasmosis Primary Prophylaxis

• None Recommended

91
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

92
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

93
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.

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Anticipated Drug Interactions/Dosing

• 115 130
• Laurie Carlson
• Protease Inhibitors and Calcineurin Inhibitors
• NNRTIs

95
Dosing of Protease Inhibitors with Calcineurin
Inhibitors
96
Dosing of NNRTIs with Calcineurin Inhibitors
97
Dosing of PI NNRTIs Combinations with
Calcineurin Inhibitors
98
Dosing of Antiretrovirals with Sirolimus
99
Factors Influencing Dosing

• Graft function
• Initiation of ARV therapy post transplant
• Tenofovir and renal insufficiency
• Side effects
• Education

100
Questions and Answers

• 130 145

101
HCV Co-Infected Patients

• 200 220
• Peter Stock
• Liver Patients
• Kidney Patients

102
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 scoregt 8 and/or fibrosis stage gt2 are
  considered indications for treatment by most
  transplant physicians but the decision to treat
  will ultimately be determined by the treating
  physician.

103
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

104
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.

105
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.

106
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).

107
Marrow-Supportive Therapy

• Erythropoietin
• Start when hemoglobin is lt10g/dl.
• Dose 40,000 IU subcutaneously weekly.
• If hemoglobin decreases below 8.0 g/dL,
  discontinue ribavirin until gt10 g/dL (women) or
  gt12 g/dL (males) on erythropoietin. If ribavirin
  is restarted, use 50 of the dose used when
  ribavirin was discontinued.
• G-CSF
• Start when ANC is lt1,000/mm3.
• Dose 300 ug twice weekly. If subsequent trough
  ANC gt3000/mm3, reduce dose to 150 ug twice weekly
  or 300 ug once weekly. Continued until the end
  of treatment.

108
Pre-Transplant Treatment of HCV Kidney
Candidates When?

• Pre-transplant therapy with interferon/peg-interfe
  ron 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 gt50 for this subgroup.

109
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

110
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 gt2 ULN for gt/ 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

111
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.

112
Monitoring on HCV Treatment

• Same as in liver recipients

113
Length of HCV TreatmentPre-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.

114
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.

115
Marrow-Supportive Therapy

• EPO and G-CSF as for liver recipients

116
HBV Co-Infected Patients

• 220 230
• Peter Stock
• Liver Patients
• Kidney Patients

117
Biopsies Liver and Kidney Recipients

• No protocol-mandated biopsies
• Biopsies should be obtained if
• AST or ALT gt 1.5 ULN
• Any HBV virological breakthrough
• Suspicion of drug hepatotoxicity

118
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)

119
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

120
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.

121
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 gt 1.5 ULN) and every 3 months.

122
Treatment Guidelinesfor Kidney Recipients
Post-Transplant

• If patient has stage 3 or 4 fibrosis, antiviral
  therapy should be continued indefinitely
• For patients with lt/ 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)

123
Treatment Guidelinesfor Kidney Recipients
Restarting HBV Therapy

• Restart HBV therapy and continue indefinitely if
  AST or ALT increase to gt 1.5 ULN and HBV DNA gt
  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)

124
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 gt 1.5 ULN) and that HBSAg and HBSAb be
  followed monthly

125
Rejection

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• Peter Stock
• Management
• Definitions

126
Acute and Chronic Rejection

• A biopsy will be performed in all cases of
  suspected rejection
• Therapy may be initiated lt/ one day prior to the
  results of the biopsy if clinically indicated.
• Treatment for gt 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.

127
Definition of Rejection

• Kidney (NIH CCTT Definition)
• Type I mononuclear infiltrate in gt 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.

128
Questions and Answers

• 245 310

129
Adverse Event Reporting

• 310 325
• Natasha Tomlin
• TBD

130
Data Management

• 325 345
• Craig Lazar
• TBD

131
Website Modifications

• Updated sample letter requesting reimbursement
• Updated PDFs for relevant studies
• Updated contact list of experienced folks willing
  to help

132
Publication and Media Policy

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• Michelle Roland
• Membership
• Roles

133
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 its chair

134
PPSC 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)

135
Reimbursement Considerations

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• Peter Stock, Cheryl Janov

136
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

137
Website

• Sample letters to insurers
• Supporting articles to include with coverage
  request

138
IRB Re Experimental

• The procedure is not experimental
• The population/context is

139
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

140
Community Advisory Board

• 410 420
• Michelle Roland, Debi Surlas and Robert Zackin
• TBD

141
Closing Discussion

• 420 500

142
Parking Lot Issues from SC

• Pre-eligible consent/enrollment for outcomes
• Specimen request review process