HIV and transplant: obstacles and opportunities

Transcription

1 HIV and transplant: obstacles and opportunities Christine Durand, M.D. 18 de abril de 2013, XI Conferência Brasil Johns Hopkins University em HIV/AIDS

2 Outline Part 1: Solid organ transplant (SOT) Part 2: Bone marrow transplant (BMT) Clinical management BMT: Implications for HIV cure?

3 Kidney and liver transplant and HIV Epidemiology and indications Outcomes: kidney and liver transplant Highly active antiretroviral therapy (HAART)

4 Epidemiology: Living longer, getting older Shiels et al. J NCI. 2011

5 Changing patterns of mortality: Non-AIDS related ART Cohort Collaboration. CID

6 Chronic kidney disease in HIV infection HIV-associated nephropathy Hepatitis associated nephropathy Antiretroviral toxicity TDF, IDV, ATV Hypertension, diabetes, hyperlipidemia Atta et al. HIV Med

7 Chronic kidney disease in HIV infection HIV-associated nephropathy Focal segmental glomerulosclerosis Hepatitis associated nephropathy Antiretroviral toxicity TDF, IDV, ATV Hypertension, diabetes, hyperlipidemia HIV-positive patients Younger Hepatitis C (HCV) Less diabetes Atta et al. HIV Med

8 Liver disease in HIV infection Hepatitis C (HCV) Hepatitis B Alcohol Non-alcoholic steatohepatitis

9 Indications for transplant therapy When to refer? Kidney: patients on dialysis Liver: evidence of decompensated disease, MELD score > 16 What is the prognosis after transplant? Outcomes?

10 The evidence

11 Kidney transplant 150 patients CD4 > 200, VL < 50 Median age 46 70% African American, 80% male 25% HIV-associated nephropathy 25% hypertension 9% diabetes Stock PG et al. NEJM 2010;363:

12 Kidney transplant overall survival HIV+ > 65 years 1 yr: 95% 92% 3 yr: 88% 79.5% Stock PG et al. NEJM 2010;363:

13 Kidney transplant overall survival HIV+ > 65 years 1 yr: 95% 92% 3 yr: 88% 79.5% No difference Stock PG et al. NEJM 2010;363:

14 Kidney transplant graft survival HIV+ > 65 years 1 yr: 90% 88% 3 yr: 74% 74% Stock PG et al. NEJM 2010;363:

15 Kidney transplant graft survival HIV+ > 65 years 1 yr: 90% 88% 3 yr: 74% 74% No difference Stock PG et al. NEJM 2010;363:

16 Kidney transplant graft rejection HIV+ > 65 years 1 yr: 31% 12% 3 yr: 41% Stock PG et al. NEJM 2010;363:

17 Kidney transplant graft rejection HIV+ > 65 years 1 yr: 31% 12% 3 yr: 41% 3 fold increase! Stock PG et al. NEJM 2010;363:

18 Liver transplant -overall survival Spanish study HIV+/HCV+ HCV+ 5 yr: 54% 71% US study HIV+/HCV+ HCV+ 3 yr: 60% 79% Miro et al. Am J of Trans 2012;12: Terrault et al. Liver Transp 2012;18:

19 Liver transplant -overall survival Spanish study HIV+/HCV+ HCV+ 5 yr: 54% 71% Significantly lower US study HIV+/HCV+ HCV+ 3 yr: 60% 79% Miro et al. Am J of Trans 2012;12: Terrault et al. Liver Transp 2012;18:

20 Liver transplant graft survival Spanish study HIV+/HCV+ HCV+ 5 yr: 45% 64% US study HIV+/HCV+ HCV+ 3 yr: 53% 74% Miro et al. Am J of Trans 2012;12: Terrault et al. Liver Transp 2012;18:

21 Liver transplant graft survival Spanish study HIV+/HCV+ HCV+ 5 yr: 45% 64% Significantly lower US study HIV+/HCV+ HCV+ 3 yr: 53% 74% Miro et al. Am J of Trans 2012;12: Terrault et al. Liver Transp 2012;18:

22 Low risk HCV+/HIV+ Donor HCV negative BMI > 21 No combined kidney transplant Outcome High risk N = 25 Low risk N = 64 Survival (3 y) 29% 72% Graft survival (3 y) 20% 65% Terrault et al. Liver Transp 2012;18:

23 Low risk HCV+/HIV+ Donor HCV negative BMI > 21 No combined kidney transplant No difference Outcome High risk N = 25 Low risk N = 64 HCV+ only Survival (3 y) 29% 72% 79% Graft survival (3 y) 20% 65% 74% Terrault et al. Liver Transp 2012;18:

24 Low risk HCV+/HIV+ HCV genotype MELD Experience of hospital 5 year survival HIV+/HCV+ HCV+ 54% 71% Miro et al. Am J of Trans 2012;12:

25 Low risk HCV+/HIV+ HCV genotype MELD Experience of hospital No difference 5 year survival HIV+/HCV+ low high HCV+ 54% 69% 17% 71% Miro et al. Am J of Trans 2012;12:

26 HIV-specific criteria for organ transplant Kidney Liver CD4 > 200 HIV RNA undetectable

27 HIV-specific criteria for organ transplant CD4 > 200 Kidney HIV RNA undetectable CD4 > 100 Liver Predicted ability to control viremia

28 HIV-specific criteria for organ transplant CD4 > 200 Kidney HIV RNA undetectable Liver CD4 > 100 Predicted ability to control viremia Low risk? BMI > 21 Lower MELD HCV negative donor Single organ transplant

29 After transplant. Immunosuppressants and HAART INDUCTION MAINTENANCE Anti-thymocyteglobulin IL2 receptor blocker: Basiliximab, daclizumab Calcineurin inhibitor: cyclosporine, tacrolimus Mycophenolate mofetil Steroids OR Sirolimus

30 Interactions with ritonavir-boosted PIs Inhibit P450 enzyme system PIs Atazanavir Darunavir Indinavir Lopinavir Nelfinavir Ritonavir Saquinavir Tipranavir Calcineurin inhibitor (CNIs): cyclosporine, tacrolimus Requires infrequent, low doses of immunosuppressants

31 Interactions with ritonavir-boosted PIs Inhibit P450 enzyme system PIs Atazanavir Darunavir Indinavir Lopinavir Nelfinavir Ritonavir Saquinavir Tipranavir Calcineurin inhibitor (CNIs): cyclosporine, tacrolimus Requires infrequent, low doses of immunosuppressants Low immunosuppressants levels Reason for increased graft rejection? > 50% of patients on PIs in trials

32 Interactions with ritonavir-boosted PIs Inhibit P450 enzyme system PIs Atazanavir Darunavir Indinavir Lopinavir Nelfinavir Ritonavir Saquinavir Tipranavir Calcineurin inhibitor (CNIs): cyclosporine, tacrolimus Requires infrequent, low doses of CNIs Non-PI based HAART regimens Raltegravir, maraviroc, NNRTIs

33 Conclusions: Part 1 HIV infection is NOTa contraindication to kidney and liver transplant Well controlled HIV Liver transplant lower risk : REFER EARLY Higher rates of graft rejection Avoid protease inhibitors

34 Bone marrow transplant and HIV Hematologic malignancy in HIV Types of BMT Outcomes in the era of HAART Prospects for HIV cure

35 Cancer in HIV-infected patients % of patients who will get any cancer % of patients who will die due to cancer % of patients who will get hematologic malignancy 40% 30% 10%

36 Hematologic malignancy and HIV Non-Hodgkin s lymphoma AIDS defining cancer Hodgkin s lymphoma Non-AIDS defining, increasing incidence? Acute leukemia Increased risk

37 Bone marrow transplant (BMT) Autologous: SELF (AutoBMT) Relapsed lymphoma Good outcomes in HAART era

38 Bone marrow transplant (BMT) Autologous: SELF (AutoBMT) Relapsed lymphoma Good outcomes in HAART era Allogeneic: OTHER (AlloBMT) Leukemia, salvage therapy for lymphoma, primary refractory lymphoma

39 Allogeneic effect Graft versus tumor Graft versus host disease

40 BMT evolution MAXI transplant CHEMOTHERAPY KILL TUMOR TRANSPLANT RESCUE 40

41 BMT evolution MAXI transplant CHEMOTHERAPY KILL TUMOR TRANSPLANT RESCUE MINI transplant REDUCED INTENSITY CHEMOTHERAPY MAKE ROOM TRANSPLANT GRAFT KILLS TUMOR ALLOGENEIC EFFECT 41

42 Outcomes of allogeneic BMT and HIV Hutter et al, Clin Exp Immun, 2011.

43 Growing evidence for equal outcomes Durand CM, Ambinder RF, Biol Blood Marr Trans, 2012.

44 Implications for HIV cure?

45 The Berlin patient NY Times, 11/28/11

46 Obstacles to HIV cure

47 Obstacles to HIV cure Davey et al, PNAS, 1999.

48 HIV latent reservoir in resting memory CD4 + T cells

49 HIV latency in resting memory CD4+ T cells Establishment: A consequence of tropism for a cell type that oscillates between active and quiescent states

50 Frequency of Latently HIV Infected CD4+ Frequency (IUPM) T Cells as a Function of Time on HAART Time on HAART (years) - t ½ = 44.2 months 73.4 years Siliciano JD, Nat Med, 2003.

51 HIV reservoir eradicated NY Times, 11/28/11

52 The Berlin patient: clinical history Acute myeloid leukemia MAXI TRANSPLANT Chemotherapy (amsacrine, fludarabine, cytarabine, cyclophosphamide) Anti-thymocyte globulin, total body irradiation x 2 GENE THERAPY BMT from CCR5Δ32 donor

53 Berlin patient: treatment course Hutter, Sci World, 2011.

54 Mechanism of cure? Gene therapy Cytotoxic therapy Allogeneic effect

55 Clinical trials: gene therapy CCR5Δ32 Cannon et al, Curr Opin HIV/AIDS, 2011.

56 Mechanism of cure? Gene therapy Cytotoxic therapy Allogeneic effect Chemotherapy, irradiation direct killing of latently infected cells?

57 HIV latent reservoir size unchanged with chemotherapy for AIDS lymphoma

58 Mechanism of cure? Gene therapy Cytotoxic therapy Allogeneic effect

59 Allogeneic effect: graft versus HIV reservoir Recipient CD4+ T cell LTR LTR Donor CD8+ T cell Cell death

60 HIV cure and BMT Step 1: Eradicate reservoir Allogeneic effect Step 2: Protect donor cells from infection

61 Berlin patient: HIV resistant cells Donor CD4+ cell Recipient CD4+ T cell LTR LTR

62 HAART: protects donor cells HAART Donor CD4+ cell Recipient CD4+ T cell LTR LTR

63 Boston patients 1: Hodgkins, BMT in : Hodgkins, myelodysplasia, BMT in 2010 Reduced intensity chemotherapy: MINI Normal donors, CCR5 wild-type No evidence of HIV by best measures Henrich et al, JID 2013

64 Boston patients 1: Hodgkins, BMT in : Hodgkins, myelodysplasia, BMT in 2010 Reduced intensity chemotherapy: MINI Normal donors, CCR5 wild-type No evidence of HIV by best measures Test of cure: STOP HAART? Henrich et al, JID 2013

65 HIV cure and BMT Step 1: Eradicate reservoir Allogeneic effect Step 2: Protect donor cells from infection Maintain HAART

66 HIV cure and BMT Step 1: Eradicate reservoir Allogeneic effect Step 2: Protect donor cells from infection Maintain HAART Drug interactions ritonavir Intolerance of oral medications mucositis, nausea and vomiting

67 Conclusions: Part 2 Higher risk of heme malignancy BMT is safe and effective treatment for heme malignancy in HIV+ patients First HIV cure in setting of unique BMT Cure with standard BMT due to allogeneic effect?

68 Acknowledgements Robert Siliciano Rich Ambinder Charles Flexner Joel Gallant Paul Pham Transplant Oncology ID Group Kieren Marr Dennis Neofytos Shmuel Shoham Robin Avery