Outline. New Frontiers in Solid Organ Transplantation and HIV Infection. Learning Objectives

Transcription

1 New Frontiers in Solid Organ Transplantation and HIV Infection Christine Durand, MD Assistant Professor of Medicine and Oncology Johns Hopkins University School of Medicine Baltimore, MD Learning Objectives After attending this presentation, learners will be able to: Recognize which HIV+ patients are appropriate candidates for referral for transplant Modify antiretroviral therapy in order to minimize interactions with transplant immunosuppression Discuss the pros and cons of treating hepatitis C infection in transplant candidates Outline Growing need for transplant Outcomes: kidney and liver transplant Management challenges: HCV, rejection, drug interactions, transplant infections HIV to HIV transplantation: HOPE in Action

2 Kidney disease in HIV infection 10-30% prevalence of chronic kidney disease HIV-associated nephropathy, hepatitis B/C associated nephropathy Antiretroviral toxicity Hypertension, diabetes, cardiovascular About 1.5% of individuals on dialysis More than 10,000 HIV+ individuals on dialysis Lucas G/Kalayjian R. CID 2014; SRTR data Liver disease in HIV infection Hepatitis B, C Alcoholic and non-alcoholic fatty liver disease 13% of all deaths due to liver disease Smith/Lundgren. DAD study group. Lancet High mortality for those with HIV and ESRD US N = 10, year survival HIV- vs HIV+ 63% vs. 23% HIV+: dx of HIV-associated nephropathy SRTR/USRDS data

3 High mortality for those with HIV and ESLD Mortality on liver wait-list At one yr HIV+ 36% vs HIV- 15% Ragni M/Fung J. Liver Transplantation Less access to transplant At one yr HIV+ 36% transplanted vs HIV- 47% Subramanian A/Ragni M. Gastroenterology Outline Growing need for transplant Outcomes: kidney and liver transplant Management challenges: HCV, rejection, drug interactions, transplant infections HIV to HIV transplantation: HOPE in Action NIH TR Study: HIV+ kidney transplant N = 150 CD4 > 200, VL < 50 Median age: 46 Black: 70% Male: 80% HIV-AN: 25% Hypertension: 25% Diabetes: 9% Stock PG/Roland M et al NEJM 2010;363:

4 NIH TR Study: HIV+ kidney transplant Patient survival 1 yr: 95% 3 yr: 91% Graft survival 1 yr: 90% 3 yr: 77% Stock PG/Roland M et al NEJM 2010;363: NIH TR Study: HIV+ kidney transplant Patient survival 1 yr: 95% 3 yr: 91% 4 yr: 89% Graft survival 1 yr: 90% 3 yr: 77% 4 yr: 70% Roland M et al AIDS SRTR: HIV+ kidney transplant, long term outcomes Kidney N = 514 Matched HIV- 1:10 Race, age, sex, BMI, PRA, induction, steroids, donor age, cold ischemia time Patient and graft survival through 10 years Locke JE/Segev DL. JASN, 2015.

5 SRTR: HIV+ kidney transplant, long term outcomes A Kidney N = 514 Matched HIV- Patient survival HIV+ HIV- 5 yr: 89% 89% 10 yr: 64% 78% p=.10 Locke JE/Segev DL. JASN, NIH: HIV+/HCV+ liver transplant HIV/HCV HCV N = 89 N = 325 CD4 > 100 VL any allowed* Terrault et al. Liver Transp 2012;18: NIH: HIV+/HCV+ liver transplant HIV/HCV HCV N = 89 N = 325 CD4 > 100 VL any allowed* Median age: 49 White: 65% Male: 75% Liver cancer: 35% Decompensated liver disease: 65% Terrault et al. Liver Transp 2012;18:

6 NIH: HIV+/HCV+ liver transplant HIV/HCV HCV N = 89 N = 235 Patient survival 1 yr: 76% 92% 3 yr: 60% 79% Graft survival 1 yr: 72% 88% 3 yr: 53% 74% Terrault et al. Liver Transp 2012;18: Outline Growing need for transplant Outcomes: kidney and liver transplant Management challenges: HCV, rejection, drug interactions, transplant infections HIV to HIV transplantation: HOPE in Action HCV Treatment in Transplant DAAs are effective, well-tolerated with minimal drug interactions Patients on dialysis: cure rates % Transplant recipients: cure rates % Treatment experienced, cirrhotic patients: lower

7 HCV Treatment in Transplant Pre or Post? Benefits Risks HCV Treatment in Transplant Pre or Post? Benefits Prevent progression of liver disease Prevent HCV complications e.g fibrosing cholestatic hepatitis or immune complex glomerulonephritis Risks Exclude HCV+ donors: impact on wait time Harder to cure in patients with cirrhosis If relapse, risk of RAS HCV variants HCV Treatment in Transplant Pre or Post? What s the answer in practice? No guidelines Strongly consider waiting for kidney transplant candidates For low MELD liver candidates, consider treating For high MELD liver candidates, consider waiting

8 Immunosuppression after transplant Anti-thymocyte globulin Kidney OR INDUCTION IL2 receptor blocker: Basiliximab, daclizumab Liver Steroids Immunosuppression after transplant Anti-thymocyte globulin Kidney OR Calcineurin inhibitors: cyclosporine, tacrolimus INDUCTION IL2 receptor blocker: Basiliximab, daclizumab MAINTENANCE OR Mycophenolate mofetil Steroids Liver Steroids mtor inhibitors: sirolimus, everolimus NIH: Rejection in HIV+ kidney transplant N = 150 HIV+ KT 1 yr: 31% 3 yr: 38% 3-4 fold higher risk Stock PG/Roland M et al NEJM 2010;363:

9 NIH and SRTR: rejection in HIV+ liver transplant NIH study: 39% at 3 yrs (> 50% acute cases in first few weeks) SRTR data: 18% at 1 yr Terrault et al. Liver Transp Locke JE/Segev DL. Transplantation, ART and immunosuppression interactions MAINTENANCE Calcineurin inhibitors: cyclosporine, tacrolimus Drug interactions? Pharmacoenhancers (ritonavir, cobicistat) To maintain safe troughs, very low and infrequent dosing (e.g. 0.5 mg tacrolimus/week), underexposure? AVOID CYP3A4 INHIBITORS SRTR: Rejection in HIV+ kidney transplant N = 516 HIV+ KT Rejection 1 yr: 15% HIV+ vs 8% HIV- 2 fold higher risk of rejection Lower in those who received ATG Locke/Segev. Transplantation. 2014;97:

10 Post-transplant infections: NIH TR kidney transplant Pre-transplant Prior history of an OI N = PCP 8 CMV 7 MAC 3 KS Post-transplant N = 13 4 Kaposi sarcoma 3 PCP 1 cryptosporidiosis 6 candida (esophagitis 5, bronchial 1) No recurrences in patients with OI history No survival difference with OI history Stock PG et al. NEJM 2010;363: Post-transplant infections: impact of induction therapy Infections common > 50% in first year Mostly UTI AIDS defining 10% Mostly CMV No difference by induction Trend towards fewer infections with ATG Kucirka L/Segev D. AJT Opportunistic infection prophylaxis HIV TR PCP prophylaxis Bactrim indefinite CMV prophylaxis valganciclovir duration depends on donor/recipient CMV status MAC, histoplasmosis etc depends on history, CD4 Transplant ID consultation pre-transplant

11 Outline Growing need for transplant Outcomes: kidney and liver transplant Management challenges: HCV, rejection, drug interactions, transplant infections HIV to HIV transplantation: HOPE in Action United States: HIV+ transplant over time HIV+ Kidney Transplant HIV+ Liver Transplant United States: organ shortage crisis 116,622 individuals on the waitlist In 2016: 9,975 deceased donors Novel donor sources are needed Decrease wait times for HIV+ and HIV-

12 South Africa: HIV D+/R+ kidney transplant Muller et al, NEJM 2010: 362: HIV Organ Policy Equity Act: 2013 signed into law Implementation of the HOPE Act: late 2015 Directs the Secretary to revise current regulations (specifically, 42 CFR 121.6) June 2015 Directs Secretary to publish research criteria relating to HIV+ to HIV+ transplant November 2015 Requires the OPTN to revise standards for the acquisition and transportation of donated HIV+ organs November 2015

13 Overarching goal of HOPE in Action Studies Learn if the use of HIV+ deceased donors in the is safe and effective Risks of HIV D+/R+ Transplant Biologic risks HIV superinfection HIV nephropathy Donor derived infections Rejection Jan 2016: JHU pilot protocol (NCT ) March 2016: first HOPE donor First in US HIV D+/R+ kidney and liver transplants

14 20 transplant centers with active HOPE studies NIH U01 Study: HIV+ deceased donor kidney transplant 19 US Transplant Centers Safety and efficacy Non-inferiority design Compare outcomes between HIV+ recipients of HIV+ donors and HIVdonors N = 160 (80 in each arm) Program Officer: Jonah Odim, MD PhD HIV-to-HIV Solid Organ Transplantation in the US: R34AI23023, U01AI Project Manager: Natasha Watson, MSN Trial Design HIV+ kidney or liver transplant candidates Standard clinical criteria for transplant *HIV specific criteria

15 HIV+ candidate inclusion criteria No active opportunistic infections On effective ART with HIV RNA < 200 Kidney CD4 > 200 Liver CD4 > 100 Effective ART regimen anticipated Trial Design HIV+ kidney or liver transplant candidates Standard clinical criteria for transplant *HIV specific criteria UNOS organ offers per availability Natural randomization HIV D-/R+ HIV D+/R+ Trial Design HIV+ kidney or liver transplant candidates Standard clinical criteria for transplant *HIV specific criteria UNOS organ offers per availability Natural randomization HIV D-/R+ HIV D+/R+

16 HIV+ donor inclusion criteria No active opportunistic infections or cancer Any HIV VL or CD4 count is allowed but study team must describe effective post-transplant antiretroviral regimen for the recipient Per study investigators clinical judgement Trial Design HIV+ kidney or liver transplant candidates Standard clinical criteria for transplant *HIV specific criteria UNOS organ offers per availability Natural randomization HIV D-/R+ HIV D+/R+ HIV- donor inclusion criteria Per transplant center study investigator clinical judgement/ standard clinical criteria

17 Trial endpoints Primary endpoint Time to composite event of major transplant and HIV related complications Death, graft failure, rejection, AIDS, virologic failure Trial endpoints Secondary endpoints: Graft function HIV-associated renal disease Surgical complications Donor specific antibodies HIV viral load CD4 counts HIV superinfection Non AIDS infections Post-transplant malignancies Conclusions Survival benefit of transplant for HIV+ individuals with end stage organ disease Consider waiting to treat HCV until post transplant in some individuals Optimize ART (avoid strong CYP3A4 inhibitors) HIV+ donors may expand donor options

18 Medical/Surgery Christine Durand, MD Infectious Diseases Principal Investigators Dorry Segev, MD PhD Surgery Aaron Tobian, MD PhD Pathology Epidemiology and Biostatistics Mary Grace Bowring, MPH Lauren Kucirka, ScM PhD Xun Luo, MD MPH Allan Massie, PhD Richard Moore, MD PhD Larry Moulton, PhD Abi Muzaale, MD MHS Nephrology/Hepatology Mohammed Atta, MD Derek Fine, MD James Hamilton, MD Fizza Naqvi, MD Hamid Rabb, MD Clinical Study Operations Surgery Saad Anjum, BA Andrew Cameron, MD PhD Diane Brown, MSN Niraj Desai, MD Ayla Cash, MPH Jacqueline Garonzik-Wang, MD PhD Willa Cochran, NP Shane Ottman, MD Samantha Halpern, BA Benjamin Philosophe, MD PhD Edward JR Johnston, MPH Komal Kumar, MPH Virology and Immunology Oyinkansola Kusemiju, MPH Darin Ostrander, PhD Gilad Bismut, BS Sarah Rasmussen, BA Alyssa Martin, PhD Shanti Seaman, BA Alexandra Murray, BS Thomas Quinn, MD Andrew Redd, PhD Robert Siliciano, MD PhD Ethical, Legal, Social Issues Team Brianna Doby, BA Pathology Macey Henderson, JD PhD Serena Bagnasco, MD Jeremy Sugarman, MD William Clarke, MD PhD Albert Wu, MD Lysandra Voltaggio, MD UCSF Peter Chin-Hong, MD Rodney Rogers Peter Stock, MD PhD Columbia University Marcela Laurito, MD PhD Theresa Lukose, PharmD Marcus Pereira, MD Rush University Medical Center Mark Mall, RN Yoona Rhee, MD Carlos A.Q. Santos, MD Northwestern University Jane Charette, RN Sara Lake Lescano, MPH Valentina Stosor, MD Indiana University Oluwafisayo Adebiyi, MD Jeanne Chen, PharmD Icahn School of Medicine at Mount Sinai Sander Florman, MD Brandy Haydel, CCRC Shirish Huprikar, MD Susan Lerner, MD University of Alabama at Birmingham Emory University Medical/Surgery Yolanda Hogeland Elizabeth Ferry, RN Jayme Locke, MD Farzan Saeed Shikha Mehta, MD Nicole Turgeon, MD Darnell Mompoint-Williams, DNP Dasia Webster Drexel University Duke University Cynthia Gifford-Hollingsworth, DNP Kelly Stanly Dong Heun Lee, MD Cameron Wolfe, MBBS University of Maryland Yale University Maricar Malinis, MD Anthony Amoroso, MD Ricarda Tomlin, CCRP Amanda Bartosic Jonathan Bromberg, MD PhD Georgetown University Massachusetts General Hospital Matthew Cooper, MD Alexander Gilbert, Margaret Thomas, CCRC MD David Wojciechowski, DO University Takada of Pennsylvania Harris Weill Cornell Medical College Emily Blumberg, MD Thangamani Muthukumar, MD Susanna Nazarian, MD PhD Benjamin Samstein, MD Maryann Najdzinowicz Catherine Small, MD Deirdre Sawinski, MD