X X. Sirolimus CellCept Cyclosporine NEED FOR LIVER TRANSPLANTATION IN HIV + POPULATION. Solid Organ Transplantation in HIV+ Recipients 1

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1 Liver and Kidney Transplantation in HIV+ Recipients UCSF TRANSPLANT CONFERENCE 21 Peter Stock MD PhD Laurie Carlson RN University of California San Francisco Why Now? HAART-associated improvements: decreased mortality decreased incidence of opportunistic infections decreased hospitalization rates Immunosuppressives may have anti-hiv effects cyclosporine, MMF, rapamycin Better prophylaxis for opportunistic infections NEED FOR LIVER TRANSPLANTATION IN HIV + POPULATION X X X Sirolimus CellCept Cyclosporine 75,-1.5 million people infected with HIV with 4, new cases added each year. Life expectancy is high Prevalence of HCV coinfection is high (3%) Prevalence of HBV coinfection is 1% Progression to cirrhosis is rapid in coinfected pt Liver disease has become a major cause of death in people infected with HIV Solid Organ Transplantation in HIV+ Recipients 1

2 Epidemiology of CKD due to HIV. Between approx 8 new patients a year report HIVAN as the cause of CKD to the USRDS. 9% of those cases were reported by people of African descent. Currently in the US, HIVAN is the most common cause of renal failure among people with HIV and is the 3 rd most common cause of ESRD in African Americans between the age of 2-6years. (Cosgrove et al, 2). NIH TRIAL WEST San Francisco, CA University of California, SF (K, L, Peds K, Peds L) Los Angeles, CA Cedars-Sinai (L) 15 Kidney and 125 Liver Transplants MID-WEST Chicago, IL University of Chicago (K, L, Peds K, Peds L) Rush University (K, L) Northwestern (K, L) Cincinnati, OH University of Cincinnati (K, L) Cleveland, OH Cleveland Clinic (K, L) SOUTHEAST Atlanta. GA Emory University (K) Charlottesville, VA University of Virginia (K,L) Miami, FL University of Miami (K) New Orleans, LA Tulane (K, L, Peds K, Peds L) NORTHEAST Baltimore, MD Johns Hopkins (K,L) University of Maryland (K) Boston, MA Beth Israel Deaconess Medical Center (K, L) New York, NY Mt. Sinai School of Medicine (K, L, Peds K) Columbia University (L, Peds L) Philadelphia, PA Drexel University (L) University of Pennsylvania (K, L) Pittsburgh, PA University of Pittsburgh (K, L) Washington, D.C. Washington Hospital Center (K) Georgetown Medical Center (K, L) Specific Aims To evaluate the impact of kidney and liver transplantation, and post-transplant immunosuppression, on HIV disease progression and markers of immune function and activity. Pharmacodynamic Interactions and Medical Complexity Triple Immunosuppression to Prevent Graft Rejection To evaluate the impact of HIV infection on graft function and survival. To describe the pharmacokinetic interactions between immunosuppressive agents and the antiretroviral agents. Highly Active Antiretroviral Therapy Solid Organ Transplantation in HIV+ Recipients 2

3 Subject Selection Criteria CD4+ T-cell count > 2 for kidney recipients and > 1 for liver recipients HIV RNA undetectable. Liver recipients who are unable to tolerate ARVs but in whom full post- transplant virologic suppression is predicted. Opportunistic complication history excluded until protocol revision in April 22 to allow most OIs with continued exclusion of PML, cryptosporidiosis and visceral KS. (One subject with a history of pulmonary KS is included.) Immunosuppression and Rejection Management Initial immunosuppression included cyclosporine or tacrolimus +/- mycophenolate mofetil (MMF), in combination with steroids. Daclizumab use was allowed. Rejections managed with a steroid pulse, changing calcineurin inhibitors or doses doses, and/or adding sirolimus and/or thymoglobulin. Antiretrovirals and OI Prophylaxis Antiretroviral management: all ARVs were allowed. AZT and D4T use was minimized due to in vitro data showing antiretroviral antagonism with MMF. DDI = Don t Do It HIV and transplant prophylaxis: standard prophylaxis was employed for PCP, CMV, MAC and candida. UOI Kidney Transplant Baseline Characteristics N = 15 8% male 28% white, 68% black Average age = 46 (range: 9-72) 24% with history of AIDS-related OIs 19% HCV+ Solid Organ Transplantation in HIV+ Recipients 3

4 No Significant HIV disease progression 1-Year Patient and Graft Survival and Comparison to HIV neg. HIV RNA generally suppressed 1 1 CD4+ T-cell counts relatively stable 1 1 case of candida esophagitis 1 1 case of cryptosporidiosis 1 1 case of presumptive PCP 2 2 cases of de novo cutaneous KS 2 2 cases of HIVAN post-txtx % PATIENT SURVIVAL SRTR (general) HIV-TR SRTR (>65yrs) % GRAFT SURVIVAL SRTR (general) HIV-TR SRTR (>65yrs) RISKS FOR GRAFT LOSS IN A MULTIFACTORIAL PROPORTIONAL HAZARDS MODEL REJECTION STATUS THYMOGLOBULIN INDUCTION DECEASED DONOR Time to First Rejection % REJECTION Kidney (HTR) Kidney (UNOS) Solid Organ Transplantation in HIV+ Recipients 4

5 egfr by Rejection Status 14 RISKS FOR REJECTION IN A MULTIFACTORIAL PROPORTIONAL HAZARDS MODEL 12 p=.3 p=.3 p=.11 egfr Use of CSA (versus tacrolimus) Deceased donor (versus living donor) Non-rejection Rejectio n Year CNI DRUG LEVELS ARE THEY SUFFICIENT? FOR CSA, THE MEDIAN (IQR) TROUGH LEVEL AT ONE MONTH WAS 171 FOR THE FIRST HALF OF ACCRUAL PERIOD, AND 234 FOR THE SECOND HALF FOR TAC, THE MEDIAN (IQR) TROUGH LEVEL AT ONE MONTH WAS 8.6 FOR THE FIRST HALF OF THE ACCRUAL PERIOD, AND 9.4 FOR THE SECOND HALF 27% (15% OF CSA GROUP AND 31% OF TACROLIMUS GROUP) WERE RECEIVING OTHER THAN DAILY DOSES N 36 MEDIAN 485 CD4 /ul CD4 Cell Counts Thymoglobulin No Thymoglobulin box clipped N 62 MEDIAN 462 CD4 /ul boxes clipped Solid Organ Transplantation in HIV+ Recipients 5

6 Thymoglobulin Utilization in Kidney Transplant Patients: use in Induction (1 st week) Subjects who received thymoglobulin therapy in the first week had about twice as many serious infections per follow-up year compared with subjects who did not (p =.2) Time to event curves for rejection were not significantly different between subjects who used thymo in the first week and those without. The % of subjects with steroid resistant initial rejection was 23% in thymo group and 18% in non- thymo group Drug Interactions Cyclosporine, tacrolimus & sirolimus dosing low with PI and PI+NNRTI typical to high with NNRTI PI and NNRTI levels affected but remain within adequate treatment ranges Factors Affecting the Liver in HIV Preliminary HBV Analysis HBV HAV HCV Immune Reconstitution Opportunistic Infections Nucleoside Analogues EtoH/IVDU NNRTI Protease Inhibitors HCV Treatment Diabetes Dyslipidemia 22 HBV/HIV co-infected subjects antivirals: tenofovir +lamivudine or emtricitabine Hepatitis B Immune Globulin (HBIG) 1, units anhepatic phase, daily x 6; monthly x 1 year; HBIG dose to maintain anti-hbs titers >2 IU/L 2 HBV mono-infected controls Coffin et al AJT 21, in press Solid Organ Transplantation in HIV+ Recipients 6

7 Patient Survival: HBV HBV Recurrence & Viremia HBV HBV-HIV No recurrent HBsAg No histologic recurrence Median follow-up 3.5 years P=.9 *No deaths due to recurrent HBV 53% detectable HBV DNA post-transplanttransplant Mean HBV DNA 18 IU/ml (range 2-79 IU/ml) More frequent in patients with detectable HBV DNA pre-transplant and those with prior treated acute rejection No persistently detectable HBV DNA HBV Conclusions Short-term term patient and graft survival in HBV/HIV co-infected recipients similar to HBV mono-infected Recurrent HBV prevented with HBIG and antivirals Low level viremia in ~ half supports the long-term use of combined HBIG plus antivirals HBIG may be particularly important to prevent virologic breakthrough due to antiviral drug resistance Liver Transplant Graft Survival % GRAFT SURVIVAL by HCV Status HCV- HCV Solid Organ Transplantation in HIV+ Recipients 7

8 Preliminary HCV Analysis Patient Survival: HCV 1 HCV-HIV HIV co-infected (n=81) vs HCV mono- infected (n=213) Controls: HCV mono-infected recipients matched on study site; single vs dual organ transplant; HCC Predictors of patient and graft survival % PATIENT SURVIVAL P=.1 P=.1 2 HCV-HIV Coinfected HCV Monoinfected P= Terrault et al, 29 AASLD HCV mono-infected N=135 N=67 N=22 HCV-HIV co-infected N=46 N=28 N=14 % GRAFT SURVIVAL Graft Survival: HCV P=.1 P=.1 HCV-HIV Coinfected HCV Monoinfected HCV mono-infected N=128 N=67 N=21 HCV-HIV co-infected N=43 N=26 N=13 Graft Failure: HCV-HIV co-infected Predictor Multivariate Analysis Hazard Ratio (95% CI) P value Dual Kidney-Liver 5.5 (1.8, 16.9).3 HCV+ Donor 4.5 (1.8,11.2).1 BMI at Listing < (1., 7.3).5 Treated Acute Rejection 2.9 (1.2, 7.).2 Solid Organ Transplantation in HIV+ Recipients 8

9 Time to First Acute Rejection Acute Rejection % REJECTION HCV-HIV Coinfected HCV Monoinfected 5% of AR episodes occurred 21 days of LT HCV mono-infected: N=16 N=52 N=17 HCV-HIV co-infected: N=31 N=14 N=7 Acute rejection rates 2-fold higher in co- infected Treated acute rejection independent predictor of: Graft loss in all recipients/co-infected infected patients Severe HCV recurrence HCV outcomes and implications for patient selection HCV/HIV Liver Transplantation Clearance of HCV UCSF Experience 19/3 doing well Patient and graft survival in HCV-HIV HIV co- infected transplant recipients are lower but acceptable Not due to HIV-related complications Outcomes may be improved by: Restricting to BMI >21; no dual kidney transplant Avoiding use of livers from anti-hcv+ donors Better management of acute rejection 3 spontaneous clearers 9 treated with interferon/ ribavirin 7 have not required treatment 6 have cleared virus and have sustained response 1 have cleared virus and still on treatment 2 non-responders Solid Organ Transplantation in HIV+ Recipients 9

10 What influences the 5% of HIV/HCV recipients with better long term survival? - What are the optimal HAART regimens, immunosuppressive regimens, HCV treatment protocols? - Can we do a better job with patient selection? Does MELD serve the co-infected patients well? Immunologic Questions Enhanced rejection T T cell maturation/activation following immune reconsitituion(flow) Pre-sensitization via HIV infection (MLR) Cross-reactivity reactivity between donor- and pathogen- reactive T cells (cross-reactivity reactivity assay) Better HCV clearance Cross-reactivity reactivity between donor- and pathogen- reactive T cells (cross-reactivity reactivity assay) Slide #39 HPV Natural history of treated HIV disease Effective HAART reduces but does not normalize the level of inflammation, T cell activation and microbial translocation HPV-related cervical and anorectal disease, already accelerated in people with HIV infection, may be exacerbated by post-transplant transplant immunosuppression. Preliminary experience at UCSF: common, with progression, but not obviously more aggressive than in non-transplant population First case anal CA in situ post-txtx Volberding and Deeks, Lancet 21 Solid Organ Transplantation in HIV+ Recipients 1

11 Pilot Study Progression to Cancer AIN 3 abnormal DRE 4/4 HHV8 HHV8-related disease, particularly KS, may be exacerbated or reactivated by post-transplant transplant immunosuppression. 1 UCSF kidney recipient and 1 heart transplant (NEJM) in recipients with KS history no recurrence yet. Three cases of de novo cutaneous KS all well controlled with rapamycin RESULTS OF KIDNEY PANCREAS TRANSLANTS (N=4) AND ISLET AFTER KIDNEY TX (N=2) IN HIV POSITIVE RECIPINTS 1% INSULIN FREE AND DIALYSIS INDEPENDENT FOLLOWING SPK (MEAN FOLLOW UP> 1 YR) UNDETECTABLE HIV AND STABLE CD4 COUNTS ALL PATIENTS RECEIVED THYMO INDUCTION BOTH ISLET RECIPIENTS REQUIRED 2 INFUSIONS SUMMARY There has been no significant HIV clinical, virologic nor immunologic disease progression in the immunosuppressed patients. There has been no evidence of impaired graft function due to HIV. Rejection rates unexpectedly high in renal transplant recipients (6%) Treatment with anti-t-cell depleting agents results in prolonged depletion of CD4 positive cells Solid Organ Transplantation in HIV+ Recipients 11

12 SUMMARY Recurrent hepatitis B controlled with lamivudine/adefovir therapy and monthly HBIg Recurrent HCV may be a significant problem, with an increased risk of morbidity and mortality HPV anal CA; HHV8 KS - problematic? HAART regimens including PI require major adjustments in CI dosing UCSF Tx Surgeons Nancy Ascher John Roberts Ryuataro Hirose Chris Freise Andrew Posselt Sandy Feng Sandy Mo Kang Tx Nephrologists Steve Tomlanovich Flavio Vincenti Brian Lee Allison Weber Acknowledgements UCSF Hepatologists Marion Peters Norah Terrault Tony Bass Montgomery Bissell Francis Yao Orin Fix Bilal Hameed HIVTR Study Team Michelle Roland Laurie Carlson Annette Klemme Rodney Rogers PK Sub-Study Les Benet Lynda Frassetto HPV Sub-Study Joel Palefsky Michael Berry HCV Immunology Christian Brander Florian Bihl David Oldach HHV8 Sub-Study Jeff Martin David Wojciechowski Practical Considerations Clinical Management of the HIV + Transplant Recipient Provider and Recipient Challenges Solid Organ Transplantation in HIV+ Recipients 12

13 Challenges Faced by Providers 1. Drug Interactions: 1. Interpreting Levels 2. Obtaining Levels 3. Changing meds/adjusting doses Coordination, Collaboration, Communication: 1. Multiple Providers 2. Shared Decision Making 3. Primary Decision Maker 4. Assess Pertinent Information 5. Patient Management without Direct Assessment 6. Negotiating Care Plan with Patient The Challenge of Living with HIV and an Organ Transplant Demands of living with chronic illness Building on Strengths demonstrated a survivor spirit skilled in managing complex medical regimen confronted mortality dealt with side effects & body changes that accompany a life threatening chronic illness family and community support active participants in health care Challenges Faced by All Transplant Recipients Lack of knowledge regarding the pre- transplant process long waiting period organ allocation process insufficient supply of organs fear of dying or becoming medically unacceptable prior to transplant Lack of understanding of the post transplant experience unmet expectations overestimating the benefits minimizing the new challenges Challenges Faced by the HIV+ Transplant Recipient Managing two complex, chronic conditions Participating in a pioneering study Emotional response to living with two chronic conditions Solid Organ Transplantation in HIV+ Recipients 13

14 Challenge: Physical Complications Multiple medications Managing and identifying side effects Potential drug interactions Challenge:Limited Experience, Limited Access Unknown outcomes Restricted assess to transplant Emotional, financial, and support issues relocating temporarily closer to transplant center Challenge: Psychiatric Situational Depression adjusting pre transplant expectations to post transplant realities Long Term Depression transplant didn t solve all their medical or psychosocial problems guilt Conclusion Living with a chronic illness can transform life in a positive way Personal transformation verses despair Acceptance of death leads to more meaningful living Freedom from conformity to social expectations Solid Organ Transplantation in HIV+ Recipients 14