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

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Presentation on theme: "HIV Transplant Investigators Meeting: Introduction and Welcome Nancy Bridges, NIH Peter Stock, UCSF Michelle Roland, UCSF 8:00 – 8:10."— Presentation transcript:

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

2 Meeting Objectives 8:10 – 8:20 Michelle Roland 1) Administrative Issues 2) Protocol Review 3) Policy 4) Other

3 Objectives: Administrative Issues 1) U01 and “Terms and Conditions of Award” 2) Subcontracts: IRB and regulatory issues 3) Site visits pre-start up 4) Steering and Operations Committee; Publications and Presentations Subcommittee 5) Data Management 6) Adverse Events Reporting

4 Objectives: Protocol Issues 1)Study Aims 2)Inclusion and Exclusion Criteria 3)Schedule of Events and “Sub-Study Clusters” 4)Medication Regimens and Drug Interactions Immunosuppressants, ARVs, and Prophylaxis 5)Clinical Issues HCV, HBV, and Rejection 6)Stopping Rules

5 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)

6 Budget 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”)

7 Subcontract Requirements Milestone #1, first 15 Centers will get initial funding  IRB Approvals to Natasha Tomilin  Regulatory Documents to Natasha Tomilin n 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 1) Primary Aims 2) 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 1) Steering Committee 2) Operations Committee

25

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 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

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: :55 Don Stablein 1) Study Design and Control Groups 2) Sample Size 3) 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 Hypotheses One 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 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 1) Inclusion Criteria 2) Exclusion Criteria 3) 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 Are Unable 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

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.

53 Schedule 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

54 Years: Year 0 Year 1 Years 2 & 3 every 3 m 1 every 6 m 2 Years 4 & 5 every 6 m Weeks: Screen Day 0 Week CLINICAL Documentation of HIV infection X Informed Consent X Symptom & Medical Review plus Physical Exam X9X9 XXXXXXXXXXXXXXX1X1 X PPD 3 XXXX2X2 X Vaccination Review (Pneumovax, Hepatitis A and B) X Cervical PAP 4 X Pregnancy Test X9X9 X RADIOLOGY CXR X MRI head 5 Clinical and Radiology

55 Years: Year 0 Year 1 Years 2 & 3 every 3 m 1 every 6 m 2 Years 4 & 5 every 6 m Weeks: ScreenDay 0Week SAFETY LABS CBC-diff X9X9 XXXXXXXXXXXXXXX1X1 X Renal/Electrolytes X9X9 XXXXXXXXXXXXXXX1X1 X LFTs X9X9 XXXXXXXXXXXXXXX1X1 X Lipase XXXXXXXXXXXX1X1 X LDHXXXXXXXXX1X1 X Fasting Lipid Panel (Chol, LDL, HDL, TGL)XXXX2X2 X Phosphate (PO4) 6 XXXXXXXXXXXXXXXX2X2 X Urinalysis XXXXY2Y5 Immunosuppressant levels XXXXXXXXXXXXXX1X1 X Lactate Monitoring (if on HCV therapy)X9X9 XXXXXXXXXXXXXXX3X3 X3X3 Laboratory

56 Years: Year 0 Year 1 Years 2 & 3 every 3 m 1 every 6 m 2 Years 4 & 5 every 6 m Weeks: Screen Day 0 Week HIV LABS CD4+/CD8+ T-cell countXXXXXXXXXXXX1X1 X HIV-1 RNA (bDNA or PCR)XXXXXXXXXXXX1X1 X RPR/VDRL 7 X9X9 XXX2X2 X Toxoplasmosis Quantitative 7 XXXX2X2 X G6PDX 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 Ab 7 XXXXX2X2 X HepBSAg 7 XXXXX2X2 X HepBSAb 7 XXXXX2X2 X HepB core Ab 7 XXXXX2X2 X HCV Ab 7 XXXXX2X2 X EBV Ab 7 XXXXX2X2 X

57 “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

58 “Clusters”

59 Years:Year 0 Year 1 Years 2 & 3 Years 4 & 5 Weeks:Screen Day 0 Week Co-Pathogen CFC (McCune) Cytokine Flow CytometryXXXXY2Y5 Co-Pathogen CTL (Brander) Co-Pathogen ELISPOT XXXXY2Y5 HHV8 (Martin) HHV8 AbXXXXY2Y5 HHV8 Viral Load (plasma)XXXXY2Y5 HHV8 PBMC Associated Viral LoadXXXXY2Y5 HHV8 Saliva Viral LoadXXXXY2Y5 Herpes Viruses (Rinaldo) TaqMan Viral Load (CMV, HHV6, EBV) XXXXXXXXXXXY2Y5 NASBA (CMV pp67) assayXXXXXXXXXXXY2Y5 RT-PCR (5 EBV RNAs) assayXXXXXXXXXXXY2Y5 Transplant Immunology (Stock) – UCSF real time, others stored) MLCXXXXY2Y5 Donor tissue or bloodX Cluster 1 Sub-Studies: Co-Pathogen Virology/Immunology; Transplant Immunology

60 Years:Year 0 Year 1 Years 2 & 3Years 4 & 5 Weeks: ScreenWeek Pharmacokinetics (Benet) (UCSF ONLY) PI/NNRTI/CSA pKXXXXXY2 Urine toxicologyX X XXXY2 pGP PhenotypeX HPV (Palefsky) Anal PAP 1 X Specimen Storage Fresh blood shipped to BBI 3 XX XXXY2Y5 Cluster 1 Continued: pK and HPV

61 Years:Year 0 Year 1 Years 2 & 3 Years 4 & 5 Weeks:ScreenDay 0 Week Co-Pathogen CFC (McCune) Cytokine Flow CytometryXXXXY2Y5 Co-Pathogen CTL (Brander) Co-Pathogen ELISPOTXXXXY2Y5 HHV8 (Martin) HHV8 AbXXXXY2Y5 HHV8 Viral Load (plasma)XXXXY2Y5 HHV8 PBMC Associated Viral Load XXXXY2Y5 HHV8 Saliva Viral LoadXXXXY2Y5 Herpes Viruses (Rinaldo) TaqMan Viral Load (CMV, HHV6, EBV) XXXXXXXXXXXY2Y5 NASBA (CMV pp67) assayXXXXXXXXXXXY2Y5 RT-PCR (5 EBV RNAs) assayXXXXXXXXXXXY2Y5 Specimen Storage Fresh blood shipped to BBI 1 X X XXXY2Y5 Cluster 2 Sub-Studies: Co-Pathogen Virology/Immunology

62 Years:Year 0 Year 1 Years 2 & 3 Years 4 & 5 Weeks:Screen Day 0 Week HIVAN (Klotman) Biopsy Tissue 1 X HPV (Palefsky) – liver patients only Anal PAPX Specimen Storage Fresh blood shipped to BBI 1 X X XXXY2Y5 Cluster 3 Sub-Studies: HIVAN, HPV

63 Years:Year 0 Year 1 Years 2 & 3 Years 4 & 5 Weeks:Screen Day 0 Week HPV (Palefsky) – Columbia only- Anal PAP 1 X Specimen Storage Fresh blood shipped to BBIX X XXXY2Y5 Cluster 4 Sub-Studies: HPV

64 HCV + Subjects: Virology and Immunology Years:Year 0 Year 1 Years 2 & 3 Years 4 & 5 Weeks:ScreenDay 0 Week HCV (Oldach) Biopsy (protocol mandated biopsies) 1 X HCV RNA 2 XXXXY2Y5 HCV GenotypeX HCV QuasispeciesXXXXY2Y5 HCV Ab-RIBAX CTL (Brander) HCV Elispot XXXXY2Y5 CFC (McCune) Cytokine Flow CytometryXXXXY2Y5 General Abdominal CTX 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.

65 HBV + Subjects: Virology Years:Year 0 Year 1 Years 2 & 3Years 4 & 5 Weeks: Scree n Day 0 Week HBV (Terrault) Biopsy (NO protocol mandated biopsies)X HepBSAbXXXXY2Y5 HepBSAgXXXXY2Y5 HepB DNAXXXXY2Y5 Anti HDVXXXXY2Y5

66 Questions and Answers 11:25 – 11:45

67 Immunosuppressives 12:30 – 12:45 Peter Stock 1) Calcineurin Inhibitors 2) CellCept 3) Steroids 4) Acute and Chronic Rejection

68 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: mg bid PO

69 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.

70 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.

71 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)

72 Antiretrovirals and Resistance 12:45 – 1:00 Michelle Roland 1) General Management Principals 2) Responding to New Detectable Viral Load 3) Resistance Testing

73 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 po’s, there is no vomiting, and there are no tests anticipated that will require an NPO period.

75 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.

76 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

77 Resistance Testing HIV Physician will determine when to request in both screening and follow-up period 2 types are available: genotypic and phenotypic Main limitation is sensitivity  Can only detect minority quasispecies > 20% of population  Drug selection pressure drives proportion of quasispecies that will be resistant versus wild type  Reversion to wild type does not mean resistant virus is cleared  Can use to rule drugs out, but not to rule them in Second significant limitation is interpretation of sequence/phenotype

78 Prophylaxis 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)

79 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 >/= 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 >/= 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 >/= 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: 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: 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.

94 Anticipated Drug Interactions/Dosing 1:15 – 1:30 Laurie Carlson 1) Protease Inhibitors and Calcineurin Inhibitors 2) 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 1:30 – 1:45

101 HCV Co-Infected Patients 2:00 – 2:20 Peter Stock 1) Liver Patients 2) 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 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.

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 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 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 <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.

108 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.

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 >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

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 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 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.

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 2:20 – 2:30 Peter Stock 1) Liver Patients 2) Kidney Patients

117 Biopsies: Liver and Kidney Recipients No protocol-mandated biopsies Biopsies should be obtained if:  AST or ALT > 1.5 ULN  Any HBV virological breakthrough  Suspicion of drug hepatotoxicity

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 > 1.5 ULN) and every 3 months.

122 Treatment Guidelines for Kidney Recipients: Post-Transplant If patient has stage 3 or 4 fibrosis, antiviral therapy should be continued indefinitely For patients with

123 Treatment Guidelines for Kidney Recipients: Restarting HBV Therapy Restart HBV therapy and continue indefinitely if AST or ALT increase to > 1.5 ULN and HBV DNA > 105 copies/mL after treatment is stopped. Additionally, give HBV antiviral therapy whenever a patient receives treatment for rejection; continue for at least 4 months; stop only when:  Normal liver enzymes  Minimal (5 mg QD or QOD) or no prednisone  No recent change in IMS (stable for preceding 3 months)

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 > 1.5 ULN) and that HBSAg and HBSAb be followed monthly

125 Rejection 2:30 – 2:45 Peter Stock 1) Management 2) Definitions

126 Acute and Chronic Rejection A biopsy will be performed in all cases of suspected rejection  Therapy may be initiated 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 > 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 2:45 – 3:10

129 Adverse Event Reporting 3:10 – 3:25 Natasha Tomlin 1) TBD

130 Data Management 3:25 – 3:45 Craig Lazar 1) 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 3:45 – 3:55 Michelle Roland 1. Membership 2. 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 it’s chair

134 PPSC Roles Specific roles and procedures to be determined by PPSC Guiding principles: “Old Ideas”“New Ideas” Multi-SiteStudy Aim PIConcept Sheet (encouraged) Single SiteConcept SheetNone Required (discouraged)(requested)

135 Reimbursement Considerations 3:55 – 4:10 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 4:10 – 4:20 Michelle Roland, Debi Surlas and Robert Zackin 1) TBD

141 Closing Discussion 4:20 – 5:00

142 “Parking Lot” Issues from SC Pre-eligible consent/enrollment for outcomes Specimen request review process


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