1 HIV, Transplantation, and HOPE Using Research to Drive Local & National Policy Jayme E. Locke, MD, MPH, FACS Assistant Professor of Surgery Scientist, UAB Center for AIDS Research Director, Transplant Analytics, Informatics, and Quality

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3 HIV Epidemic in the United States Prevalence and Mortality

4 HIV and Life Expectancy Changing TrendsAdditional years of life expected for a 20-year old, HIV-infected individual receiving treatment Life Expectancy 1999 ~ 55 years 2007 ~ 67 years NA_ACCORD, International Epidemiologic Database to Evaluate AIDS. The Wall Street Journal, October 11, 2012.

5 HIV and Chronic Disease Changing TrendsNA_ACCORD, International Epidemiologic Database to Evaluate AIDS. The Wall Street Journal, October 11, 2012.

6 HIV Epidemic & The Deep SOUTHHIV epidemic is shifting from cities, such as NY and San Francisco, to the rural South South is home to 37% of the nation’s population Accounts for 50% of new HIV diagnoses each year Accounts for 46% of new AIDS cases each year Among females, African American women represent 74% of HIV/AIDS cases reported Similar nationally with the estimated rate of new HIV infections 15x higher among African American women

7 Chronic Kidney Disease & HIV-infection>1% of the dialysis population is infected HIV-associated nephropathy (HIVAN) is now the leading cause of kidney failure in African Americans 14 fold increase in prevalence of ESRD in HIV+ individuals between (Kucirka, ATC 2015 plenary)

8 Higher Mortality on Dialysis among HIV-infectedTrullas et al. J AIDS

9 Transplant Outcomes – NIH Clinical TrialThe evidence that we have to date comes from a single prospective multicenter trial knows as the Multisite study. It was performed at 21 transplant centers across the country, including Johns Hopkins, between , and looked at both kidney and liver transplants in this patient population. Stock PG, Barin B, Murphy B, et al. Outcomes from kidney transplantation in HIV-infected recipients. NEJM 2010, 363:

10 Kidney Transplant – Patient SurvivalHIV > 65 years 1 yr: % 92% 3 yr: % 79.5% 5 yr: % 64.7% HIV better outcomes than > 65yr olds Let’s look at the major outcomes compared to outcomes in an older kidney transplant population US Registry of Scientific Transplant Recipients, which would be considered another higher risk group. In the Kaplan Meier estimator figures, all TR are shown in red, HIV infected patients from the study are shown as a black dotted line and older KTR recipients are shown in blue. And at 1 year was 95% and at 3 years was 88%, this was similar to OS at 92% and 79.5% in older KTR. Stock PG, Barin B, Murphy B, et al. Outcomes from kidney transplantation in HIV-infected recipients. NEJM 2010, 363:

11 Kidney Transplant – Graft SurvivalHIV > 65 years 1 yr: % 88% 3 yr: % 74% 5 yr: % 59% HIV better outcomes than > 65yr olds Graft survival also looked similar between the 2 groups, with 90% graft survival at 1 year in HIV infected TR and 74% at 3 years, the same as older TR. Stock PG, Barin B, Murphy B, et al. Outcomes from kidney transplantation in HIV-infected recipients. NEJM 2010, 363:

12 Kidney Transplant – Graft RejectionHIV 31% 12.3% Stock PG, Barin B, Murphy B, et al. Outcomes from kidney transplantation in HIV-infected recipients. NEJM 2010, 363:

13 Barriers to Kidney Transplantation High Rates of Acute RejectionStudies have documented acute rejection rates as high as 52% at 1-year Lowest reported rate ~13%  still more than twice the incidence among the non-HIV infected kidney transplant population Etiology of higher rejection rates remains elusive Tendency to limit immunosuppression in this already immunocompromised patient population Reluctance to use lymphocyte depleting agents for induction because these agents severely deplete CD4+ counts for months Drug interactions resulting in altered exposure to maintenance immunosuppressants and lower therapeutic levels may be responsible Locke JE, James N, Mehta S, et al. Induction immunosuppression and the risk of acute rejection in HIV-infected kidney transplant recipients. Transplantation 2014; 97:

14 Barriers to Kidney Transplantation Potential Etiologies for High Rates of Acute Rejection1. Tendency to limit immunosuppression Locke JE, James N, Mehta S, et al. Induction immunosuppression and the risk of acute rejection in HIV-infected kidney transplant recipients. Transplantation 2014; 97:

15 Barriers to Kidney Transplantation Potential Etiologies for High Rates of Acute Rejection2. Reluctance to use lymophocyte depleting agents Median change in the CD4+ T-cell count from baseline to 1-year after transplantation was significantly greater in patients who received early induction therapy with antithymocyte globulin therapy Patients who received antithymocyte globulin therapy in the first week had 2x as many serious infections per follow-up year (0.9 vs. 0.4, p=0.002) Stock PG, Barin B, Murphy B, et al. Outcomes from kidney transplantation in HIV-infected recipients. NEJM 2010, 363:

16 Barriers to Kidney Transplantation Potential Etiologies for High Rates of Acute Rejection3. Drug interactions resulting in altered exposure to immunosuppressants Stock PG, et al. NEJM 2010 Pharmacokinetic curve of tacrolimus in HIV patients receiving protease inhibitors does not show the normal peak-and-trough pattern Resembles a flat line with half-life of up to 20 days secondary to strong inhibition of CYP3A Trough levels of tacrolimus in patients receiving protease inhibitors should be higher to achieve AUCs equal to patients not on protease inhibitors 17.5 ng/mL at 1-month 10 ng/mL at 1-year Van Maarseveen EM, van Zuilen AD, Mudrikova T. Correspondence NEJM 2010.

17 Immunosuppression Regimen & Risk of Acute Rejection at 1-yearSRTR Kidney-only recipients HIV-infected recipients [n=516] Immunosuppression Induction: none, anti-thymocyte globulin, anti-interleukin 2, and alemtuzumab Maintenance: other, CNI-based, sirolimus-based Analysis Design Modified multivariate Poisson regression Cox proportional hazard Matched case-control analysis among recipients induced with ATG Outcome Measures Acute rejection within the first post-transplant year Patient and Death-censored graft survival Locke JE, James N, Mehta S, et al. Induction immunosuppression and the risk of acute rejection in HIV-infected kidney transplant recipients. Transplantation 2014; 97:

18 Lower Risk of Acute Rejection at 1-year with ATG Induction among HIV-infected RecipientsLocke JE, James N, Mehta S, et al. Induction immunosuppression and the risk of acute rejection in HIV-infected kidney transplant recipients. Transplantation 2014; 97:

19 No Difference in Risk of Acute Rejection among ATG Induced HIV+ & HIV- RecipientsMatched Control analysis among HIV-infected and non-HIV infected anti-thymocyte globulin induced kidney transplant recipients Progressive radius matching (1:1) Donor Factors  type (living or deceased) Recipient Factors  age, race PRA, number HLA mismatches, h/o previous transplant, HCV Locke JE, James N, Mehta S, et al. Induction immunosuppression and the risk of acute rejection in HIV-infected kidney transplant recipients. Transplantation 2014; 97: .

20 No Difference in Graft Survival (DCGS) among ATG Induced HIV+ & HIV- RecipientsHIV-infected 91.7% (84-95) non-HIV infected 94.2% (88-97) Risk of graft loss HR 1.54 95%CI P=0.26 Locke JE, James N, Mehta S, et al. Induction immunosuppression and the risk of acute rejection in HIV-infected kidney transplant recipients. Transplantation 2014; 97:

21 No Difference in Patient Survival among ATG Induced HIV+ & HIV- RecipientsHIV-infected 98% (92-99) non-HIV infected 96.6% (91-98) Risk of graft loss HR 1.08 95%CI P=0.87 Locke JE, James N, Mehta S, et al. Induction immunosuppression and the risk of acute rejection in HIV-infected kidney transplant recipients. Transplantation 2014; 97:

22 HIV, Immunosuppression, and Infection315 HIV+ KT recipients, SRTR and Medicare, Serious infections using hospitalization codes Hospitalization days Patient survival, graft rejection Kucirka L, Locke JE, et al. American Journal of Transplantation 2016, accepted for publication.

23 HIV, Immunosuppression, and InfectionATG Anti-IL2 No induction Any Infection 52.8% 53% 57% AIDS-Defining 9.4% 12% 10% CMV 3.8% 7.5% Pneumonia 5.7% 14% C. Difficile 1.9% 4.7% Sepsis 15% 13% 19% UTI 38% 33% 32% Kucirka L, Locke JE, et al. American Journal of Transplantation 2016, accepted for publication.

24 Infection common > 50% first year (AIDS-defining ~10%) Neither ATG or IL2 associated with higher infection risk ATG associated with lower risk of CMV, CDI, pneumonia Kucirka L, Locke JE, et al. American Journal of Transplantation 2016, accepted for publication.

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26 Concerns Remain . . . What About Long-term Outcomes?Mono-infected HIV outcomes similar to matched HIV- counterfactuals

27 Concerns Remain . . . What About Long-term Outcomes?Co-infected HIV outcomes worse than matched HIV-/HCV+ counterfactuals

28 Kidney Transplantation and Survival Benefit What about HIV+ Waitlist Candidates?Ojo AO, et al. J Am Soc Nephrol. 2001;12:

29 Novel data linkage – SRTR data and IMS pharmacy HIV-infection Status NOT Captured at Waitlisting How do we study HIV+ waitlist candidates? Novel data linkage – SRTR data and IMS pharmacy Candidates who filled >1 antiretroviral medication unique to HIV treatment were identified Candidates were followed from the later of date of waitlisting or first known HIV medication fill Simultaneous listings were collapsed Time-to-event survival analyses were performed using Cox proportional hazards modeling Locke JE et. al. Annals of Surgery 2016, accepted for publication.

30 Transplant vs. Dialysis among HIV+ Is transplant associated with a survival benefit?Characteristic Hazard Ratio 95% Confidence Interval p-value Transplant (ref, waitlist) 1-year 0.47 < 0.001 3-year 0.36 5-year 0.21 Age, per 10 years 1.30 Race (ref, white) Black 0.61 0.005 Hispanic 0.43 0.003 Asian-American/PI 0.48 0.32 Other 0.13 Diabetes (ref, none) Type 1 2.30 0.03 Type 2 1.70 0.02 0.85 Primary payer (ref, Medicaid) Medicare 0.74 Private/self 0.58 Albumin 0.81 0.06 Dialysis, per 10 years 2.00 Willingness to accept HCV+ donor 1Model adjusted for: Transplant (Y/N), days post-transplant, age at listing, race, gender, ABO type, angina or coronary artery disease, BMI, cerebrovascular disease, diabetes type, drug-treated COPD, education level, malignancy, medical condition, peptic ulcer, physical capacity, primary payer type, total albumin, working for income, primary diagnosis, time on dialysis, PRA level, prior solid-organ transplant, prior kidney transplant, willingness to accept an HCV+ kidney Locke JE et. al. Annals of Surgery 2016, accepted for publication.

31 Living donor transplant 1-year (vs. waitlist) 0.15 0.03-0.72 0.02 Characteristic Hazard Ratio 95% Confidence Interval p-value Living donor transplant 1-year (vs. waitlist) 0.15 0.02 3-year (vs. waitlist) 0.13 0.01 5-year (vs. waitlist) 0.18 0.03 Deceased donor transplant 0.53 0.002 0.44 0.23 < 0.001 Age, per 10 years 1.30 0.006 Race (ref, white) Black 0.59 Hispanic 0.42 Asian-American/PI 0.54 0.40 Other 0.21 Diabetes (ref, none) Type 1 2.30 Type 2 1.70 0.84 0.58 Primary payer (ref, Medicaid) Medicare 0.75 Private/self 0.60 0.90 0.83 Albumin 0.81 0.07 Dialysis, per 10 years 1.90 Willingness to accept HCV+ donor 2.20 1Model adjusted for: Transplant (Y/N), days post-transplant, age at listing, race, gender, ABO type, angina or coronary artery disease, BMI, cerebrovascular disease, diabetes type, drug-treated COPD, education level, malignancy, medical condition, peptic ulcer, physical capacity, primary payer type, total albumin, working for income, primary diagnosis, time on dialysis, PRA level, prior solid-organ transplant, prior kidney transplant, willingness to accept an HCV+ kidney Locke JE et. al. Annals of Surgery 2016, accepted for publication.

32 Kidney Transplantation is Associated with a Significant Survival Benefit among HIV+ CandidatesBenefit achieved 194 days post-transplant Locke JE et. al. Annals of Surgery 2016, accepted for publication.

33 Kidney Transplantation is Associated with a Significant Survival Benefit among HIV+ CandidatesLocke JE et. al. Annals of Surgery 2016, accepted for publication. .

34 Kidney Transplantation is Associated with a Significant Survival Benefit among Co-infected HIV+ Candidates Benefit achieved 392 days post-transplant Locke JE et. al. Annals of Surgery 2016, accepted for publication.

35 Can Increased Risk Associated with HCV Infection be Mitigated among HIV+ Candidates?YES!  1. Avoid high degrees of HLA mismatching 2. Antiviral therapy to eradicate HCV (early post-transplant referral) Locke JE et. al. American Journal of Transplantation 2016, accepted for publication.

36 New Guidelines on CKD and HIV

37 Guidelines on HIV and Transplant

38 Access to Kidney Transplantation among HIV+ Waitlist CandidatesRate per 100 PY HIV+ Candidates HIV- Candidates Waitlist Mortality 5.61 6.62 Transplantation 14.32 26.70 Likelihood of Transplantation Hazard Ratio 95% Confidence Interval P-value Overall 0.72 <0.001 Deceased Donor 0.87 0.07 Living Donor 0.53 Locke JE et. al. Journal of the American Society of Nephrology 2016, in submission.

39 Access to Kidney Transplantation among HIV+ Waitlist CandidatesLocke JE et. al. Journal of the American Society of Nephrology 2016, in submission.

40 The Supply and Demand Problem – Is there an alternative source of donors?Locke JE et. al. Annals of Surgery 2016, accepted for publication.

41 South African Experience – HIV to HIV KTPatient Survival 1-year 86% 3-year 73% Graft Survival 1-year 91% 3-year 81% Muller et al, 2010: 362(24):

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43 US National Organ Transplant Act (NOTA)Federal ban, 1984 “United Network for Organ Sharing Members shall not shall not knowingly participate in the procurement or transplantation of organs from donors who are known to be infected with HIV”

44 Data from two national registries 500-600 donors per year Likely to be an underestimate This has the potential to decrease wait-list time for both HIV infected and uninfected individuals alike. Boyarsky et al, Am J of Transplant; 2011: 11:

45 Estimating the HIV+ Donor Pool Preliminary Results from OPO SurveySurvey all 58 Organ Procurement Organizations Questions re: OPO referrals from local hospitals Number known to be HIV+ at the initial call Number discovered to be HIV+ during evaluation Estimates vs . quantitative records Attitudes re: HIV to HIV transplant Willingness to participate in our study Cash A et al ATC 2015 oral presentation.

46 Estimating the HIV+ Donor Pool Preliminary Results from OPO Survey32/58 surveys completed (55%) 31% (10/32) tracked HIVDD referrals Reported 442 HIVDD in 2013 Average of 44.2 HIVDD per year per OPO 69% (22/32) estimated HIVDD referrals Reported HIVDD in 2013 Average of 40.3 HIVDD per year per OPO Cash A et al ATC 2015 oral presentation.

47 Estimating the HIV+ Donor Pool Preliminary Results from OPO Survey2013 HIV+ Referrals (Known) CADN 39 DCTC 62 FLUF 70 IAOP 3 LAOP 50 MNOP 5 NJTO 97 NYRT 58 VATB 55 WIUW HIV+ Referrals (Estimate) ALOB 112.5 CAGS 7.5 FLFH 100 MOMA 5 TNMS 38 TXSB 43 UTOP 2.5 WALC 42 WIDN 12 Cash A et al ATC 2015 oral presentation.

48 Estimating the HIV+ Donor Pool Preliminary Results from OPO SurveyProjected 2435 HIV+ referrals in 2013 Cash A et al ATC 2015 oral presentation.

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51 HOPE Act Signed into Law – November 21, 2013Mandate for research on the use of HIV-infected diseased donors (HIVDD) Guidelines for research in November 2015 Specifically, develop and publish criteria for the conduct of research relating to transplantation of organs from donors infected with HIV to HIV+ end-stage patients I pulled a few headlines regarding the HOPE Act should you want to position this paper with respect to that.

52 Implementation of the HOPE ActImplementation Date – November 21, 2015 Revise the section of the OPTN Final Rule that presently requires the OPTN to adopt and use standards to prevent the recovery of HIV-infected organs OPTN must revise standards of quality for acquisition and transportation of donated organs infected with HIV – must begin concurrently with above

53 OPTN Final Rule Amended – May 8, 2015https://www.federalregister.gov/articles/2015/05/08/ /organ-procurement-and-transplantation-implementation-of-the-hiv-organ-policy-equity-act

54 Beyond Research Consortia Does Experience Matter?SRTR, , n = 499 HIV+ KT recipients Experience measures Participation in NIH Multi-site Trial Volume of HIV+ KT at center (> 5 advanced) Transplant and ART era ( , ) Impact on outcomes Cox proportional hazards models for risk of graft loss and risk of patient death Sandwich estimator used to account for within center clustering Models adjusted for: donor age and type; recipient age, race, HCV, and prior KT; immunosuppression regimen; transplant year Locke JE et al. Am J of Transplantation, 2015: in press.

55 Beyond Research Consortia Does Experience Matter?NIH Protocol Cities San Francisco Chicago New York Boston Philadelphia Pittsburgh Baltimore Charlottesville Atlanda Miami New Orleans Center Volume Early / Advanced (6 or more HIV+ transplants) Transplant Era Introduction of Integrase Inhibitors 2004 2007 2008 2011 Locke JE et al. Am J of Transplantation, 2015; 15(8):

56 3-fold increase in the number of transplants since 2004 2.6-fold increase at NIH-study centers 3.4-fold increase at non-NIH study centers Locke JE et al. Am J of Transplantation, 2015; 15(8):

57 Center-level Experience & Risk of Graft LossHazard Ratio Confidence Interval P-value Transplant era 1.00 0.62 0.02 Center volume Early (first 5) Advanced (≥6) 1.05 0.82 NIH study participation Non-study NIH-study 1.08 0.71 Recipient Characteristics Black race 1.20 0.32 HCV+ 1.94 < 0.001 EPTS ≤ 20 0.65 CNI maintenance 0.50 ATG induction 1.15 0.56 Donor Characteristics KDPI ≤ 20 0.67 0.04 Locke JE et al. Am J of Transplantation, 2015; 15(8):

58 Center-level Experience & Risk of Patient DeathHazard Ratio Confidence Interval P-value Transplant era 1.00 0.59 0.01 Center volume Early (first 5) Advanced (≥6) 0.93 0.76 NIH study participation Non-study NIH-study 1.13 0.63 Recipient Characteristics Black race 0.68 0.09 HCV+ 2.60 < 0.001 EPTS ≤ 20 0.28 CNI maintenance 0.65 ATG induction 1.09 0.78 Donor Characteristics KDPI ≤ 20 0.74 0.21 Locke JE et al. Am J of Transplantation, 2015; 15(8):

59 38% lower risk of graft failure41% lower risk of death Adjusted for transplant era, center volume, NIH-study participation, recipient race, HCV status, immunosuppression regimen, estimated post transplant survival score (EPT, and donor kidney donor profile index (KDPI) Locke JE et al. Am J of Transplantation, 2015; 15(8):

60 What’s Next? How Do We Make HOPE a Reality?

61 What’s Next? How Do We Make HOPE a Reality?South Africa US Population 53 million 316 million Persons living with HIV 5.6 million 1.1 million HIV+ prevalence 17.8% 0.6% Predominant subtype C B Annual HIV+ deaths 310,000 17,000 Transmitted drug resistance < 5% 10-18% Transplant wait list 4300 123,992 Transplant per year 229 16,896

62 Biologic risks of HIV-to-HIV TransplantHIV superinfection Resistant virus X4 tropic virus Occult opportunistic infection transmission – CMV, HHV8/Kaposi sarcoma Recurrent HIV associated nephropathy

63 Feasibility Can we characterize HIV specific risks to potential recipients of HIV+ organs during the deceased donor “rapid decision making window”? What about HIV+ living kidney donors? Can we model risk? Using epidemiologic, medical history and laboratory data available at the time of donor evaluation Our group did the only study ( HIVDD per year) this is likely an underestimate

64 Lower risk of HIV superinfection and drug resistance Standard donor criteria plus positive HIV ELISA and/or NAT* Undetectable HIV (RNA <200 c/mL) Detectable HIV (RNA >200 c/mL) ART naïve No history of ART and undetectable drug levels Virologic failure Prescribed ART and/or detectable drug levels Lower risk of HIV superinfection and drug resistance Higher risk of HIV superinfection and drug resistance Lower risk donor Higher risk donor First line ART regimen R5 tropic virus Potential for PI Ritonavir -sparing regimen Higher CD4+ T cell count Second-line ART X4 tropic virus History of drug resistance Requires PI/Ritonavir-based regimen Lower CD4+ T cell count

65 Conclusions HIV-infected individuals are living longer and chronic diseases are now leading causes of death The South has the largest rate of growth in incident HIV cases HIV-infected individuals have higher rates of mortality on dialysis compared to their uninfected counterparts

66 Conclusions HIV-infected individuals can achieve excellent long-term outcomes after kidney transplantation Acute rejection can be minimized by proper use of induction immunosuppression Compared to dialysis, kidney transplantation is associated with a 79% or 4.76-fold reduction in risk for death among HIV+ ESRD patients HIV+ kidney transplant recipients achieve this benefit within 6 months post-transplant

67 Conclusions Outcomes after HIV+ kidney transplantation have improved over time Center volume and/or participation in a research consortium are not necessary to achieve excellent long-term outcomes These results support continued expansion of HIV+ kidney transplantation in the US

68 Conclusions HIV-to-HIV kidney transplantation is now legal and research consortia are being developed UAB is home to the largest number of HIV-infected individuals awaiting kidney transplantation Alabama OPO has more HIV+ donors than any other OPO in the US UAB’s time is now – HOPE will be realized

69 Acknowledgements UAB Center for AIDS ResearchMichael Saag, MD, Director UAB Outcomes Research Center Jayme E. Locke, MD, MPH, FACS, Director Derek DuBay, MD Surgery Faculty Stephen Gray, MD, MSc Jeremy Goodman, MD Carlton Young, MD Mark Deierhoi, MD Michael Hanaway, MD Devin Eckhoff, MD Jared White, MD Roslyn B. Mannon, MD Nephrology Faculty Robert Gaston, MD Shikha Mehta, MD Vineeta Kumar, MD Cliff Kew, MD Graham Towns, MD Song Ong, MD Medicine/Surgery Epidemiology Paul A. MacLennan, PhD Epidemiology Rhiannon D. Reed, MPH Brittany Shelton, MPH Hunter Hayles, MSc Computational Science Christopher Ray Medical Student Cole Crowson Burke Smith Grant Smith Devin Sun Turner Overton, MD ID Faculty Donna C. Porter, PhD CFAR Administrative Director Andy Westfall, MSc Biostatistician Mary Smile Program Coordinator Computational Science Graduate Students UAB Comprehensive Transplant Institute Robert Gaston, MD, Director Research Assistants