HIV AND TRANSPLANTATION

1. HIV AND TRANSPLANTATION LOUIS M. SLOAN, M.D. MARCH 27, 2008

2. HIV and Transplantation • In general, patients with HIV have been excluded from organ transplantation • Exclusion has been based on several major concerns • Immunosuppressant medications increasing further risks of opportunistic infections, morbidity and death • Acceleration of AIDS progression • Scarce organs going to HIV patients who may have a worse prognosis than an HIV - patient

3. HIV and Transplantation • In 1997, survey of renal transplant centers in USA, vast majority would not transplant an HIV patient who otherwise was a good candidate • Now, as a result of improved outcomes in both transplantation and HIV therapy, increased transplantation in HIV patients occurring • More effective prophylaxis have reduced OI’S • HAART has changed the face of HIV since 1996

4. HIV and HAART • HAART = Highly Active Anti Retroviral Therapy • Survival with HAART therapy is now considered similar to other chronic diseases; however, given the prolonged survival, these patients are now facing others diseases such as ESLD and ESRD

5. Survival Benefits of HIV Therapy • Greatly exceeds that achieved by many other chronic diseases • Non- small cell lung cancer – 7 months • Adjuvant chemo for breast cancer – 29 mnths • Post MI care – 50 months • BMT for Hodgkins disease 92 months • HAART - >14 years

6. HIV • Because of common routes of transmission, HIV patients are commonly coinfected with Hepatitis C and Hepatitis B (30% and 10%) respectively • ESRD is also an increasing problem with estimates around 5% • HIV associated nephropathy (HIVAN) • HUS • IgA nephropathy

7. Increasing Mortality in HIV • HAART has decreased HIV associated mortality • Because of increased longevity, other comorbidities have assumed greater importance • HIV modifies natural history of HCV infection and accelerates disease • ESLD now leading cause of death among HIV patients at many institutions • HCV • ETOH abuse • Hep B • Hepatotoxic medications

8. ESRD in HIV • HIVAN has become 3rd leading cause of ESRD in the African American population • HIV survival on HD @ 1 & 2 years reported at 58 and 41% • According to US Renal Data System, 1 year death rate ~32.7% in HIV patients maintained on HD

9. ISSUES IN TRANSPLANTATION • Immunosuppressant therapy • Ethical considerations • Economics • Survival benefits • Safety

10. Immunosuppressants • Initially thought to be contraindicated in HIV infected patients • Multiple studies have shown many immunosuppressants have documented antiretroviral properties(CYA, tacrolimus, sirolimus, MMF) • Multiple drug interactions with HAART and immunosuppressants which need to be managed closely

11. Stock Study • Effect of immunosuppression on HIV progression • HIV viral load remained undetectable in all patients maintained on HAART • CD4 counts dropped immediately after transplant then rebounded within several weeks • Thymoglobulin caused a decrease in CD4 with very slow rebound • No AIDS defining opportunistic infections • Some severe infections occurred after treatment with thymoglobulin and should be used cautiously

12. Stock Study - Rejection • Some increased rejection in the kidney transplant thought to be secondary to dysregulated immune system with HIV- this study did not use induction therapy • In liver transplants, recurrent disease rather than rejection was the significant problem • Stock - Transplantation 2003

13. Survival in Liver Transplants • Cumulative survival in HIV patients comparable to HIV – at 12, 24 and 36 months • Survival poorer among subjects with post transplant HAART intolerance or Hep C • More rapid demise of the coinfected HIV transplant candidate observed on waiting lists as the MELD score did not accurately predict outcome in the HIV patient subset Ragni – Liver Transplant 2005

14. Mortality in the HIV Pretransplant Patient • Increased number of patients that succumbed to sepsis – related death • Thought to be secondary to multiple immunologic and metabolic insults present in the coinfected patient with liver disease • Impaired detoxification of the impaired liver • Hepatotoxicity of some HAART regimens

15. Liver Transplant in HIV • Favorable outcomes overall • Despite increased incidence of lamivudine resistance, hep B virus has been easily controlled in the HIV posttransplant • Multicenter analysis suggests survival similar to the general transplant population; trend towards poorer survival in the Hep C coinfected patient – similar to that of HIV(-) coinfected – Ragni JID 2003

16. Liver Transplantation in HIV • Early referral of the HIV coinfected patient • Synchronized medical management between hepatologist and HIV physician essential • Additional allocation of MELD points for the coinfected patient or pursuit of alternative sources of donor livers that could facilitate earlier transplantation • Living donors • “high risk infectious “ donor (serology negative for viral infection but risky behavior for HIV) Stock - Liver Transplantation 2005

17. “MARGINAL ORGANS” in HIV • Would expect poorer graft function and survival rates and therefore mitigate toward a poorer outcome • Increased need for more immunosuppression secondary to increased acute rejection in a group of patients we want to minimize immune suppressing drugs • Despite >50% of HIV patients receiving “marginal kidneys” at transplant, 1 & 2 year survival > 85% and 82% - Kumar Kidney International 2005

18. SAFETY • Risk of needlestick injury • As of 2000, only 56 reported cases documented of HIV seroconversion temporally associated with occupational exposure despite thousands of exposures

19. SAFETY • Average risk of HIV transmission is ~0.3% after percutaneous exposure • Increase risk of seroconversion with device contaminated with blood or deep injection • Decreased viral load of source patient decreases risk of transmission • Suture needles not implicated as source of seroconversion in prospective studies • Risk of seroconversion for HCV ~1.8% • Risk of seroconversion for HBsAg ~ 22-31%

20. SAFETY • Review recipients antiretroviral history prior to transplant and consider postexposure prophylaxis if necessary • Surgical team education of the need for immediate administration of prophylaxis in the event of significant exposure • HIV clinician available at all times and to support transplant staff thru 28 day postexposure therapy period

21. Economics • Reimbursement by third-party payers for experimental procedures is not assured • No Medicare rules preclude transplantation in the HIV population • Study investigators believe that private and public insurance will cover the costs of the transplant

22. Ethics • No prospective studies were performed in patients with diabetes or HCV prior to considering these groups for transplantation, but now it is routine to offer organs to these patients despite evidence of diminished post transplant survival rates

23. ETHICAL QUESTIONS • Does transplantation benefit the HIV patient? • Would organ transplantation benefit other patients more than an HIV patient?

24. Ethical Questions • In an article by Qiu, these questions were considered • Study involved identifying all pairs of duplicated kidneys from same donors transplanted to one HIV + patient and 1 HIV- patient • 1997 – 2004 reported through UNOS

25. Qiu Study • Demographics • Post transplant regimen • Graft survival • Patient survival

26. Qiu Study • HIV group slightly younger 49 vs. 52.3 y/o • Peak PRA lower in HIV group 5.1 vs. 15.6 • HCV+ similar in both groups – 28.9 vs. 31.6 • Higher trend toward sirolimus use in HIV group • Serum Cr slightly higher @ 1,3,5 yrs although not statistically significant

27. Results • Graft survival – 5 year posttransplant survival at 76.1 vs. 65.1 in HIV – patient • Patient survival – 5 year posttransplant for HIV + 91.3 vs. 87.3 • Qiu , Transplantation 2006

28. Study Results • Growing body of evidence that survival in HIV transplantation is equivalent to the non-HIV patient • Kumar, et al. followed 40 HIV + renal transplants from 2001 – 2004 and showed 1 -2 yr graft survival rates similar to other high risk populations receiving kidney transplants • Majority of these transplants were from “marginal donors’ based on UNOS criteria

29. Ethical Questions • Does transplantation benefit the HIV patient? • Does the graft benefit another patient more? • Based on multiple studies, it appears that transplantation benefits both patient groups equally and this ethical concern should not exist • No difference in survival rates has been shown in the HIV patient with either “marginal organs” or using same donor transplants

30. Criteria for Transplantation • Standard criteria for transplantation • Special HIV criteria • Undetectable viral load > 3 months on stable regimen • CD4 count >200 or 14% • No history of untreatable OI’s or opportunistic neoplasms (PML, Burkitt’s lymphoma)

31. HIV Solid Organ Transplant Multi-Site Study • 20 sites participating in HIV transplantation • Liver, kidney transplantation in both adults and pediatrics • Sites include UCSF, Cedars-Sinai, Johns Hopkins, Univ. of Pittsburgh, Emory, etc… • >150 patients transplanted since 2002, anticipate 275 subjects total • NIH supported

32. Multi Center Trial • Questions to be answered • Opportunistic infection risk • HIV viral load • Hep C and liver transplantation • Hep C and kidney transplantation

33. CONCLUSIONS • HIV patients should be considered no different than any other patient who may have higher transplant risks than an average patient such as an African American, highly sensitized, diabetic or older patient • Reluctance to transplant patients with HIV is no longer justified • UNOS policy statement (HIV) “…should not necessarily be excluded from candidacy for organ transplantation”

34. POSITION STATEMENT • “Transplantation in HIV patients should be analogous to transplantation in patients with other chronic illnesses”

35. Why Should We Transplant HIV Patients? • Premiere transplant center – BUMC • Growing body of evidence suggests comparable survival rates in solid organ transplant patients • ID service committed to help care for the HIV patient as well as available for exposure issues • It is the right thing to do !

36. References