Professor Massimo Puoti

Transcription

1 Five Nations Conference on HIV and Hepatitis in partnership with Professor Massimo Puoti Universita of Brescia, Italy Massimo Puoti Dept. of Infectious Diseases AO Ospedale Niguarda Cà Granda Milan, Italy Liver Transplantation in HIV infected population 1

2 Disclosures Massimo Puoti acted in a consultancy capacity for Abbvie, BMS, Boehringer Ingelheim, Janssen, GSK, ViiV, Gilead Sciences, MSD as a speaker at company-sponsored events for Abbvie, BMS, Boehringer Ingelheim, Janssen, Gilead Sciences, GSK, ViiV, Roche Diagnostics, MSD, Beckman, During this lecture data on not licensed products and on off label use of licensed products will be discussed Liver transplantation in HIV infected population Rationale cart reduction in mortality due to HIV disease 1 Liver disease major cause of death in PLHIV 2 Mortality in HCV/HIV similar to pre-cart era 3 1. Lancet 2008, 372: Weber R et al. HIV Med ;14: Puoti M. et al. Hepatology. 2013;57:4-6. 2

3 Liver Transplantation in the HIV infected population Pre Transplant Issues Selection criteria Access to transplant in the HIV infected population Management of the waiting list Donor selection Post transplant issues Results Results by indications HBV HCV HCC NRH Special problems in the HIV infected population Rejection and immmunosuppressive treatment cart Post transplant infections Renal failure Surgical complications Re-Transplantation Liver Transplantation in the HIV infected population Pre Transplant Issues Selection criteria Access to transplant in the HIV infected population Management of the waiting list Donor selection Post transplant issues Results Results by indications HBV HCV HCC NRH Special problems in the HIV infected population Rejection and immmunosuppressive treatment cart Post transplant infections Renal failure Surgical complications Re-Transplantation 3

4 HIV criteria for LT in HIV-infected patients in Europe expert opinion not validated in proper studies Previous AIDS defining events: Opportunistic Infections Spain 1 France 2 Italy 3 UK 4 Germany 5 Some* Some* None in the previous year** None after HAART-induced immune reconstitution Some Neoplasms None None Few Not defined CD4 cell count/mm3 - No previous OIs >100 Case by case >200 & > 100 ìf decomp cirrhosis >200 & > 100 ìf PH >100 - Previous OIs >200 >200 >200 >200 >200 Plasma HIV-1 RNA viral load <50 copies/ml on HAART# Yes Yes Yes Yes *In Spain and France, patients with previous TB, PjP, OC can be evaluated for LT; **In Italy, excluded those with PML, cryptosp., MDR systemic fungal infections,; Patients < 100 CD4 not excluded in France (case by case evaluation); #If HIvRNA detectable, post-lt suppression with HAART should be predicted in all patients. 1. Miro J et al. Enferm Infecc Microbiol Clin 2005, 23: Duclos Valle et al. Hepatology 2008, 47: Grossi PA Curr Opin Organ Transplant 2012, 17: O Grady JG HIV Med 2005, 6 Suppl 2: Anadol E et al. AIDS Res & Treatm 2012; ACCESSIBILITY TO LIVER TRANSPLANTATION FOR HIV/HCV COINFECTED PATIENTS WITH END STAGE LIVER DISEASE: THE FRENCH PROSPECTIVE MULTICENTER ANRS HC EP 25 PRETHEVIC COHORT PRETHEVIC 92 pa ents 68 DC 24 HCC 10 pa ents LT ques on non asked 12 pa ents sans indica on greffe 70 pa ents avec indica on de greffe 7 pa ents died 1 pa ent died 19 pa ents died 34 pa ents contraindicated for LT 23 DC 11 HCC 36 pa ents non contraindicated for LT 7 pa ents died 3 pa ents died 1 DC 2 HCC 3 pa ents dropped off the WL 26 pts registered on the wai ng list 18 DC 8 HCC 5 pa ents died 14 pa ents transplanted 3 pa ents died 9 DC 5 HCC Ostos M et al AAASLD 2014; Abstract # 698 4

5 Evaluated: 98 pts AO Niguarda Ca Granda Milano Evaluation of PLHIV referred for LT Jan 2012 Nov 2014 Etiologies in 98 pts Not included: 53 pts Listed: 13 pts 2 in WL 1 died on WL 1 HCC progression on WL death 9 transplanted : 1 death 1 Re-transplantation 7% Reason for exclusion On follow up: 32 pts 6 (22%) HCC 26 DC median MELD 12 Pre-OLT survival in HIV+ ESLD Cumulative survival following initial evaluation 880 vs days p=0.035 After adjustment for baseline CD4 count and detectability of HIV RNA, the risk of waiting list mortality increased by 20% for each unit increase in MELD from baseline No MELD exceptions regarding HIV infection per se. Waiting list mortality associated with lower CD4 count 5

6 Liver transplantation for HCC HIV+ vs HIV-: data from waiting list RF + TACE: 8/21 HIV+ (38%) vs. 15/65 HIV- (23% p=0.18) TACE 5/21 HIV+ (23%) vs 23/65 HIV- (25% p=0.83) Dropout rate on list : HIV+ 5/21, (23%) vs HIV- 7/65, (10%), P = DO for tumour progression in 4/5 HIV+ and 5/7 HIV- Monthly rise in AFP >15 main predictor of DO on the waiting list : 8 /11 DO 72% ( 4/5 HIV+ 80% & 4/6, 67% HIV-) vs. 16/63 (80%) transplanted (4 /11, 36% HIV+ 6 12/52, 23%) Vibert E et al Hepatology 2010 Donor selection HCV/HIV coinfected have poorer outcomes with 1,2 : Older donors as for HCV+/HIV especially if the recipient has high MELD Anti HCV positive donors 1 Consider matching between donor age recipient MELD Avoid anti HCV + donors 1.Terrault NA et al Liver Transpl 2012, 18: Miro MJ Am J Transplant 2012, 12:

7 Liver Transplantation in the HIV infected population Pre Transplant Issues Selection criteria Access to transplant in the HIV infected population Management of the waiting list Donor selection Post transplant issues Results Results by indications HBV HCV HCC NRH Special problems in the HIV infected population Rejection and immmunosuppressive treatment cart Post transplant infections Renal failure Surgical complications Re-Transplantation International cohorts & case series meta-analysis Survival estimates post liver transplantation 15 cohort studies ( 686 pts.) e 49 case series (226 pts) 1. Cooper et al. AIDS

8 International cohorts and case series meta-analysis 15 cohort studies ( 686 pts.) e 49 case series (226 pts) 12 months survival : 84.4% [95% CI: %] 1) HBV coinfection : OR 8.28 (95% CI ) 2) HIV RNA <50 cp/ml: OR 2.89 (95% CI ) 3) HCV coinfection: OR [0.23, 95%confidence interval (CI) ], but AOR [0.54 (95% CI )]. 1. Cooper et al. AIDS 2011 Ref. Summary of outcomes post orthotopic liver transplant in hepatitis B virus/human immunodeficiency virus co-infection Study period Country n Median FU (mo) Survival Coffin CS et USA % 1 yr al 1 85% 3 yr Graft survival 85% 1 yr 85% 3 yr Comments 50% HBVDNA+ pre OLt Tateo M et France % 100% 1 HCV, 2 al 2 HDV, 4 HDV HCV Anadol E et Germany % 1yr al 3 80% 5 yr Schreibman USA 8 NR 75% 1yr I et al 4 75% 3 yr Norris S et UK % 1 al 5 yr All /57 (89%) 1 yr 33/40 (82%) 3 yr 8/10 (80%) 5 yr NR NR NR 2 HCV 1 FHF 1. Coffin CS et al. Am J Transplant 2010; 10: ; 2. Tateo M et al AIDS 2009; 23: ; 3. Anadol E et al. AIDS Res Treat 2012; 2012: ,3. 4. Schreibman I, Transplantation 2007; 84: Norris S et al. Liver Transpl 2004; 10:

9 Patient survival after transplantation in HCV/HIVcoinfected and HCV monoinfected liver recipients in France 1, Spain 2, and the United States Duclos-Vallee JC Hepatology 2008, 47: Miro MJ Am J Transplant 2012, 12: Terrault NA et al Liver Transpl 2012, 18: Predictive factors of mortality in HCV/HIV-coinfected liver recipients in the French 1, Spanish 2, and US cohorts 3 Cohort Variable HIV/HCV & HCV HIV/HCV French Cohort Spanish Cohort US Cohort HIV-1 infection 1.91 ( ) MELD score (1-unit increase) 1.08 ( ) Donor age 1.04 ( ) HIV-1 infection 2.20 ( ) N.A. HCV genotype ( ( ) Donor risk index 3.03 ( ) 9.48 ( ) Negative plasma HCV RNA viral load 0.23 ( ) 0.14 ( ) HIV-1 infection 2.3 ( ) NA BMI at listing < ( ) Combined kidney-liver transplant 3.8 ( ) Anti-HCV positive donor 2.5 ( ) Donor age (by decade) 1.3 ( ). 1. Duclos-Vallee JC Hepatology 2008, 47: Miro MJ Am J Transplant 2012, 12: Terrault NA et al Liver Transpl 2012, 18:

10 Rapid progression of recurrence of Hepatitis C in the liver graft t in PLHIV HIV(+)/HCV(+) Patients without progression to a fibrosis score F2 HIV(+)/HCV(+) vs HIV(-)/HCV(+) Duclos-Vallèe, Hepatology, vol 47 (2) , 2008 Fibrosing Cholestatic Hepatitis in HIV/HCV 10

11 SVR to IFN based therapies for post OLT recurrence of Hepatitis C in PLHIV Author year (country) HCV G1/4 HCV G3 Duclos-Vallee C (France) Duclos Vallee C (france) Castells L (Spain) Terrault N et al (USA) Antonini T et al (France) PEG IFN + RBV PEG IFN+ PI PEGIFN + RBV 1/13 (8%) 2/6 (33%) 4/36 (10% 5/56 (9%) 10/17 (59%) 3/31 (10%) 2/6 (33%) 3/7 (43%) ALL 13/136 (10%) 3/7 (43%) 14/29 (48%) 1. Duclos-Vallee C et al. Hepatology 2008; 47: Duclos-Vallee C et al Liver Transpl 2011, 6: S8. 3. Castells L et al 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), Denver, CO, USA. September 10-13, Abstract # H-1532b. 4. Terrault N et al. Am J Transplant 2014, 14; Antonini TM et al. AIDS in press Survival after anti-hcv therapy according to treatment response 92% (57%-99%) 81% (41%-95%) 83% (68%-91%) 33% (16%-52%) P<0.01 Miro JM et al. CROI Boston, MA. Abs

12 Treatment options if Sofosbuvir, Simeprevir and Daclatasvir are available PegIFNα + ribavirin + sofosbuvir 12 weeks PegIFNα + ribavirin + simeprevir PegIFNα + ribavirin + daclatasvir Sofosbuvir + ribavirin 12 weeks +RGT 12/36 12 weeks weeks Sofosbuvir + simeprevir (± ribavirin) 12 weeks Sofosbuvir + daclatasvir (± ribavirin) weeks Courtesy from JM Pawlotsky: EASL 2014; available on Anti HCV Tx in patients with compensated cirrhosis on the transplant list Regimen PR + SOFO 12 w PR + SIME w PR + DAC 24 w SOFO + R w SOFO + DAC + R w SOFO + SIME + R w HCV Genotype 1&4 2 3 Not indicated in HCV G1a Q80K+ Not indicated in HCV G1a For 24 weeks For 16 weeks in experienced For 24 weeks 1 st choice; 2 nd choice; 3 rd choice EASL Recommendations on Treatment of Hepatitis C

13 Anti HCV Tx in patients with decompensated cirrhosis on the transplant list Regimen Decomp. on LT list HCV Genotype 1&4 2 3 PR + SOFO 12 w PR + SIME 48 w PR + DAC 24 w SOFO + R w SOFO + DAC + R w SOFO + SIME + R w For 16 weeks in experienced For 24 weeks For weeks 1 st choice; 2 nd choice; EASL Recommendations on Treatment of Hepatitis C Post-Transplant Recurrent Hepatitis C Patients with post-transplant recurrence of HCV infection should be considered for therapy IFN-free treatment is recommended: HCV G1,3,4-4 Daclatasvir + Sofosbuvir + RBV x weeks HCV G1 & 4 Sofosbuvir + Simeprevir + RBV x 12 weeks HCV G1-4 Sofosbuvir + RBV x 24 weeks No dose adjustment is required for tacrolimus or cyclosporine with any of the available combinations 13

14 Pretransplant Sofosbuvir + Ribavirin to prevent recurrence of HCV infection after transplantation Patients with HCC meeting Milan criteria CPT < 7 MELD < pts were treated with Sofosbuvir + RBV for up to 48 weeks; 44 transplanted At transplant HCVRNA < LLOQ 93% Post transplant SVR 12 in 23/37 (62%) Viral recurrence n. 10 SAE 18% not related to Sofosbuvir Curry MP et al Gastroenterology 2014 in press 14

15 Brown Jr Rs et al AASLD

16 HARVONI SCHEDULE: EMA 16

17 Sofosbuvir + Ledipasvir SVR 12 in HCV G3 16/22 27/27 25/28 26/27 Gane EJ AASLD 2014 abstract # LB 17

18 DDI Studies With the AbbVie 3D Regimen: Therapeutic Drug Monitoring Recommended for Tacrolimus and Cyclosporine Interacting Drug Tacrolimus 0.5 mg Single-dose Recommendation The initial tacrolimus dose is recommended to be 0.5 mg/week to achieve a C 24 (trough) equivalent to prestudy levels over the first week of the study. Cyclosporine 30 mg Single-dose Total daily cyclosporine dose is recommended to be reduced to 1/5 th of the prestudy dose to achieve a C 24 (trough) equivalent to prestudy levels Therapeutic drug monitoring is being conducted in an ongoing Phase 2 study 36 18

19 Considerations in the Timing of Hepatitis C Virus Treatment in the Liver Transplant Setting Campos Varela I et al Clin Infect Dis 2014 in press Liver transplantation for PLHIV and HCC Platt HL et al AASLD 2014 abstract #

20 Liver transplantation for HCC in HIV + vs HIV- Vibert E et al Hepatology 2010 Lengthy Follow-up After Liver Transplantation for Nodular Regenerative Hyperplasia in Human Immunodeficiency Virus Infected Patients: Does the Disease Recur? 4 HIV-infected patients who underwent LT for severe portal hypertension secondary to NRH To prevent a recurrence, antiretroviral therapy was chosen to avoid drugs incriminated in liver vascular toxicity. All patients received effective ACT. However, one patient developed NRH after LT, without any sign of obliterative portal venopathy on GBs. De novo NRH after LT has been described whatever the indication for LT Appropriate long-term ACT and the performance of iterative GBs are indicated after LT in HIV-infected patients Sultanik P et al Transplantation 2012;96: e

21 Liver Transplantation in the HIV infected population Pre Transplant Issues Selection criteria Access to transplant in the HIV infected population Management of the waiting list Donor selection Post transplant issues Results Results by indications HBV HCV HCC NRH Special problems in the HIV infected population Rejection and immmunosuppressive treatment cart Post transplant infections Renal failure Surgical complications Re-Transplantation Acute Rejection 1 Acute rejection rates 2 fold higher in coinfected. Treated acute rejection independent predictor of: Graft loss Worse HCV recurrence 1. Stock P et al. HIV and the Liver Jackson Lake

22 EFFICACY OF ANTIRETROVIRAL THERAPY POST OLT Cooper C et al AIDS

23 Acquired hypogammaglobulinemia in HIV-positive subjects after liver transplantation Gregg S Transpl Infect Dis 2013: 15:

24 Post transplant Infectious complications in HCV/HIV Severe infections increased mortality (HR 2.9; 95%CI ) Risk factors for severe infections : - MELD > 15 (HR 3.50; 95%CI ) - Pre OLT AIDS event (HR 2.5; 95%CI ) Moreno et al. Liver Transpl Immunosuppressive regimens <> tacrolimus (HR 2.5, 95% CI ) Surgical complications post OLT in PLHIV Harbell J et al Surgery 2012; 152:

25 Retransplantation in PLHIV 14 pts (6% retransplantation rate) HCV- HCV+ Gastaca Am J Transpl 2012 Liver transplantation in HIV infected population Rationale cart reduction in mortality due to HIV disease 1 Liver disease major cause of death in PLHIV 2 Mortality in HCV/HIV similar to pre-cart era 3 Liver transplantation in selected HIV infected patients performed in most developed countries 4 Excellent results in liver diseases unrelated to HCV 4 Poorer survival in HCV/HIV coinfected patients 4 Should the transplant be offered to PLHIV and hepatitis C 4? New DAA game changer 5 1. Lancet 2008, 372: Weber R et al. HIV Med ;14: Puoti M. et al. Hepatology. 2013;57: O Grady JG LIVER TRANSPLANTATION 18: , Aghemo A Gastroenterology 2014 in press 25

26 Outcome and management of HCV/HIV coinfection preand post-liver transplantation. A 2015 Update: The TEN COMMANDMENTS 1. Coinfected patients should be referred for liver transplantation early after the first episode of hepatic decompensation 2. Avoid: the use of deceased donors aged >50 years. the use of HCV-positive donors combined liver and kidney transplantation. LT in patients with very low pre-transplant body mass index (<21 kg/m2). LT in centers with a low volume of LT in HIV-infected patients and no wellorganized multidisciplinary team. 3. Disease progression should be monitored with liver biopsy or hepatic elastography at least annually to assess for progression of fibrosis 4. Early anti-hcv therapy is indicated in patients with moderate or severe acute hepatitis, FCH, or rapid progression of fibrosis. 5. In order to minimize drug interactions that could potentially result in insufficient exposure to immunosuppressive agents (calcineurin inhibitors), PI-sparing ART should be prescribed if feasible. Miro JM et al. J Hepatology 2014 in press Outcome and management of HCV/HIV coinfection preand post-liver transplantation. A 2015 Update: The TEN COMMANDMENTS 6. If PIs are necessary to control HIV infection, strict and frequent monitoring of immunosuppressive drug levels is required to minimize the risk of rejection and toxicity 7. The best antiretroviral regimen in HCV/HIV-coinfected liver recipients is the combination of 2 NRTIs plus raltegravir in order to avoid PK interactions with immunosuppressive drugs and HCV Pis 8. HCV/HIV-coinfected patients with HCC who fulfill the Milan criteria should be considered for LT 9. HIV-infected patients with HCC should be considered for MELD exceptions according to local transplant policy 10. Given the poor outcomes recorded, HCV/HIV-coinfected patients with active HCV infection should not undergo relt, regardless of whether the indication for relt is related to HCV recurrence or not. Miro JM et al. J Hepatology 2014 in press 26

27 12/12/2014 Acknowledgments D. Back Liverpool UK M Ostos and C Duclos-Vallée - France N Brau USA AO Niguarda Ca Granda Transplant Department Chief L. De Carlis Giovanna Travi, Annamaria Pazzi and Maria Cristina Moioli Infectious Diseases Division AO Niguarda Ca Granda, Italy Italy in partnership with 21 27