HIV Transplant Case Report, Transplant Outcomes in Clinical Trials, and Organ Availability in High Risk Donors Katya Prakash 03/15/2019 UCSD HIV & Global Health Rounds

2. HOPE-ING FOR A
FIGHTING CHANCE: HIV
Organ Transplantation
KATYA PRAKASH, MD
INFECTIOUS DISEASES FELLOW PGY5

3. Financial Disclosures
I have no disclosures

4. 1985:State Law
Restricts
recovery of
HIV+ organs
2013 Hope Act
signed into law
2010 South
Africa
publishes study
HIV-to-HIV
transplantation
2015
Procurement
and txp of HIV+
organs to HIV+
recipients
begins
1981:CDC
documents
first cases of
AIDS
2008:1st big
study regarding
KT/LT in HIV+
recipients from
HIV- donors

5. Objectives
Epidemiology of HIV patients with ESRD/ESLD awaiting transplantation
Outcomes of HIV patients awaiting organ transplantation
Transplant Success in HIV positive individuals (HIV negative donors)
Literature regarding HIV-to-HIV transplantation
Introduction to the HOPE Act and its implications
Future directions and considerations for HIV-to-HIV transplantation

6. Life Expectancy
for PLWH

7. Epidemiology of ESRD
It is estimated that 660,000 people in the US are affected by ESRD
Of these 468,000 are dialysis patients, 94,740 are awaiting transplantation
Research estimates that about 1.5% of those with ESRD live with HIV (~10,000)
In 2012, ~1,500 HIV+ patients were on the waitlist for kidney transplant

8. Epidemiology of ESLD
Studies estimate that about 633,323 patients in the US have Cirrhosis
13,375 are currently awaiting transplantation
Liver failure is the #1 non-AIDS related cause of death in HIV patients
Research estimates about 1% of liver txp candidates have HIV
(~130)

11. Objectives
Epidemiology of HIV patients with ESRD/ESLD awaiting transplantation
Outcomes of HIV patients awaiting organ transplantation
Transplant Success in HIV positive individuals (HIV negative donors)
Literature regarding HIV-to-HIV transplantation
Introduction to the HOPE Act and its implications
Future directions and considerations for HIV-to-HIV transplantation

12. HIV+ individuals
have poor
outcomes on
dialysis
2002 Ahuja et al used US renal
data system (USRDS) database
to determine survival of HIV
dialysis patients
6179 with HIV. 99% with
HIVAN
Overall Survival on iHD
improving
Age, sex, race, dialysis
modality did not play a role
1 YR Survival
1990 – 38%
1997- 54%
2000- 74%

13. Survival rates in HIV- however much higher than HIV+
12 month survival in HIV+ 58% vs 87% in HIV-
Ahuja TS, Grady J, Khan S, Am Soc Nephrol 13: 1889-1893, 2002

14. ESLD Outcomes of HIV+ vs HIV-
58 HIV+ patients with ESLD were prospectively compared to HIV- between 1997 and 2002. Factoring for MELD:
◦ 15 (25.9%) underwent OLT in HIV+ vs 860 (63.3%) in HIV-
◦ 21 (48.8%) died before OLT vs 211 (15.5%) in HIV-
Cumulative survival post initial evaluation among HIV+ is 880d (2.5yr) vs 1427d (4yr) for HIV-
Those who died in the HIV+ group did not differ from those who didn’t by HIV progression, HCV status or MELD
57% of deaths were due to infection/sepsis
Ragni MV et al, Liver Transplantation November 2005

15. Objectives
Epidemiology of HIV patients with ESRD/ESLD awaiting transplantation
Outcomes of HIV patients awaiting organ transplantation
Transplant Success in HIV positive individuals (HIV negative donors)
Literature regarding HIV-to-HIV transplantation
Introduction to the HOPE Act and its implications
Future directions and considerations for HIV-to-HIV transplantation

16. Transplant Success in HIV Recipients (w/ HIV-
Donors)
Funded by National Institute of Allergy and Infectious Diseases
(NIAID)
150 HIV-infected kidney transplants at 19 US centers were followed
for 3 years compared to Scientific Registry of Transplant Recipients
(SRTR)
All Recipients had CD4>200, HIV VL <50 and on HAART for at least 16
weeks
25% HIVAN
25% HTN
Stock et al, Outcomes of Kidney Transplantation in HIV-Infected Recipients, NEJM 2010

17. 1yr Survival HIV+ 94.6% vs HIV- 96.2%
11 patients died: none due to HIV/OI
13 graft failures, 5 due to chronic rejection

18. Graft Survival is
comparable to
an older HIV-
population
1 yr GS:
HIV+ 90.4% vs HIV-
92.5%
3 yr GS:
HIV+ 73.7% vs HIV-
82.8%

19. HIV Progression
post transplant
CD4: by 3 years the median change from baseline -50mm3
VL:
68% never had a detectable VL post transplant
48 (32%) who did, of these 29 had only one detectable level
Peak viral load was 3270
OI:
2 new cases of cutaneous KS
1 case of PJP
1 case of cryptosporidiosis
Renal: 2 new HIV-nephropathy diagnosis

20. Higher Rejection
Rates in HIV+
compare to HIV-
recipients
49/150 (33%) recipients had acute
rejection
1 yr Cumulative Rejection 31% vs
12.3% in SRTR (1/2 were steroid
unresponsive)
Multivariate analysis showed the
following were protective against
rejection
1. Higher Tacrolimus Trough
Levels
2. Living Donors
3. Higher Post-txp CD4

21. Evaluating outcomes for all HIV+ KTs
Locke et al examined long-term patient and graft survival
◦ 510 HIV+ vs 94,948 HIV- controls
Locke et al, J Am Soc Nephrol. 2015

23. Evaluating
outcomes for all
HIV+ LTs
Locke et al examined long-term patient
and graft survival between 2002-2011
◦ 180 HIV+ vs 34,020 HIV- controls
Factors associated with increased
risk of graft death
◦ Coinfection with HCV
◦ Coinfection with HBV
◦ AA race
Controlling for factors above HIV+
have lower GS and PS than HIV-
Locke et al, Transplantation 2016

24. Cumulative viremia associated with liver fibrosis

25. What did we learn from HIV- Donor Organ
Transplantation into HIV+ Recipients?
HIV+ Recipients have similar outcomes to HIV- KT Recipients
◦ Patient Survival in similar in HIV+ and HIV- Recipients
◦ Graft Survival in lower in HIV+/HCV+ coinfected patients but not in HIV+/HCV-
and HIV-/HCV- matched controls
Since 2008 (introduction of integrase inhibitors?), HIV+ Recipients have
had similar outcomes to HIV- LT Recipients
Unfortunately despite success in transplantation, HIV infected patients are
dying on the waitlist

26. Objectives
Epidemiology of HIV patients with ESRD/ESLD awaiting transplantation
Outcomes of HIV patients awaiting organ transplantation
Transplant Success in HIV positive individuals (HIV negative donors)
Literature regarding HIV-to-HIV transplantation
Introduction to the HOPE Act and its implications
Future directions and considerations for HIV-to-HIV transplantation

27. South Africa – Where it all began

28. A Brief History
Dialysis machines are limited resource in SA therefore HIV is
an absolute contraindication to receiving iHD
HIV was also a contraindication to transplantation in SA
Elmi Muller a transplant surgeon led a study that evaluated 4
HIV+ recipients with ESRD, suppressed on ARV with no Ois
who had no access to iHD or HIV- donor transplant. She
transplanted them with HIV+ organs and showed good
outcomes at 1 year follow up

29. Promising results in HIV+ to HIV+ Renal
Transplants
MULLER ET AL, NEJM 2015
Prospective,
nonrandomized study
conducted 2008-2014
27 recipients
Recipients: HIV+ with
CD4>/= 200 and UD VL
Donors: HIVDD who were
ART naïve or on first-line
ART with UD VL
Immunosuppression:
• Induction: with rabbit
antithymocyte globulin
• Maintenance: prednisone,
MMF and tacrolimus
ARVs + ppx
• NNRTIs
• Bactrim daily
• Isoniazid daily
• Valganciclovir for 1st 3 months

30. Methodology Details
Exclusion of donors:
1. Sepsis
2. Active TB
3. WHO stage 4 HIV disease
4. Abnormal renal function (based on Cr and proteinuria)
Exclusion of recipients
1. ARV < 3months
2. History of any OI that suggested a diagnosis of AIDS

31. Patient and
Graft survival
2/27 had delayed graft function
- 1 patient had severe acute antibody
mediated rejection
Survival
1yr – 84% (CI 62-94)
3yr – 84%
5yr – 74% (CI 74-98)
Graft survival
1yr 93% (CI 74-98)
3 yr 84%
5 yr 84% (CI 55-95)

32. Morbidity and Mortality:
Deaths: 5
1.Acute pancreatitis
2.MI
3.2 died of infection – one
recurrent UTI and one invasive
aspergillosis
4.Pulmonary squamous cell
carcinoma 5 years post
transplant
Allograft Rejection: 5
1. Rejection rates of 8% at 1 year
and 22% at 3 years
2. 2 patients had graft failure
◦ Severe Ab mediated rejection
◦ Chronic scarring and fibrosis of graft
2 years post txp

33. Progression of HIV and its comorbidities
CD4
Median T cell count decreased to 179 within 1 year of transplant (expected with ATG)
Median T cell count was upto 386 by 3 years post transplant
Viral Load
All recipients had suppressed VL prior to surgery and remained suppressed in follow up
Histologic
3/27 patients had features typical of early HIV-associated nephropathy on routine renal biopsy (not
present on initial donor biopsy, none progressed to clinically significant renal dysfunction)

34. How did SA cohort differ?
1. Race
2. Causes of renal disease
3. ART: NNRTIs and PI (after 2 years
all PI were transitioned to NNRTI
due to CIN seen on renal biopsy)
4. Transmitted resistance is low
(~5%)

35. ARTs and
Immunosuppression
PI: Ritonavir an inhibitor of the cytochrome p450 enzyme system
decreases metabolism of tacrolimus
• Muller et al found higher rates of CIN on renal biopsy
• 2017 American Transplant Congress Abstract: retrospective review of
all KTs in HIV+ patients by ART. Patient were matched age, race, HCV
status, causes of ESRD, immunosuppression.
• PIs were associated with 1.8 fold increased risk of graft loss and 1.9
fold increased risk of death
Shelton B et al Am J Transplant. 2017.
Muller et al, NEJM 2015

36. UK Case Report:
Recipient: VL suppressed, CD4 >200 for at least 6 months.
A. Diabetic Nephropathy. He was on Abacavir, Lamivudine, Darunavir/Ritonavir
B. HIV Nephropathy. On Lamivudine, Darunavir/Ritonavir, Dolutegravir
Donor:VL suppressed for 6 months, CD4>200, no ARV resistance
Recipient A had acute rejection and delayed graft function but recovered. Both have good graft
function 2 years later. Both are virologically suppressed. No Ois. No fall in CD4
Nolan et al, Clinical Kidney Journal, 2018

37. Switzerland – Case Report of LT
Recipient:
A. Diagnosed in 1987, ART experienced, CD4 nadir of 78 but VL suppressed with CD4 300-400.
On Rilpivirine, Tenofovir and Emtricitabine
B. HBV+ (VL<20), HCV+ genotype 4 (RNA <15), HDV+ (VL>108) on pegylated interferon, MELD 9
Donor:
A. Diagnosed in 1989, ART experienced on tenofovir, emtricitabine, dolutegravir. At time of
death VL suppressed with CD4 400
Post transplant: Tenofovir, Emtricitabine and Rilpivirine + Raltegravir and SQ Enfuvirtide (cover
donor’s genotype
All VL remained UD 5 months post transplant
Calmy et al, American Journal of Transplantation 2016

38. Objectives
Epidemiology of HIV patients with ESRD/ESLD awaiting transplantation
Outcomes of HIV patients awaiting organ transplantation
Transplant Success in HIV positive individuals (HIV negative donors)
Literature regarding HIV-to-HIV transplantation
Introduction to the HOPE Act and its implications
Future directions and considerations for HIV-to-HIV transplantation

39. HOPE ACT:
November 21,
2013
HIV ORGAN POLICY EQUITY ACT

40. What is the HOPE Act?
Calls for the development and publication of research criteria relating to
transplantation of HIV positive organs into HIV positive individuals.
The deliverables to be met by November 21, 2015:
◦ The OPTN must revise standards for the recovery and transplantation of organs
from HIV positive donors in
◦ The Secretary of HHS must develop and publish criteria for research relating to
transplantation of organs from donors infected with HIV into individuals who are
infected with HIV before receiving such organs.

41. Implications of HOPE Act?
Boyarsky et al: Using Nationwide Inpatient Sample data (NIS), HIV Research
Network (HIVRN) and the United Network for Organ Sharing (UNOS) between
2005-2008
◦ NIS: Estimated 534 (range 481-652) potential HIVDD of whom 250 were potential multiorgan,
221 were liver-only, 63 were kidney-only donors
◦ HIVRN: Estimated 494 (range 441-533) potential HIVDD/yr
Richterman et al: retrospective chart review of all HIV+ deaths in 6 large clinics in
Philadelphia from 2009-2014 to estimate how many deceased HIV+ patients may
qualify as donors if HOPE act took affect
◦ Estimated 365 potential HIVDD (VL suppressed, CD4>200) = 192 kidneys and 247 livers annually
Boyarsky et al, American Jounral of Transplantation. 2011
Richterman et al, American Journal of Transplantation 2015

42. Objectives
Epidemiology of HIV patients with ESRD/ESLD awaiting transplantation
Outcomes of HIV patients awaiting organ transplantation
Transplant Success in HIV positive individuals (HIV negative donors)
Literature regarding HIV-to-HIV transplantation
Introduction to the HOPE Act and its implications
Future directions and considerations for HIV-to-HIV transplantation

45. Study Design
Prospective trial comparing:
80 HIV+ transplant recipients of kidneys from HIV+ deceased
donors (HIV D+/R+)
80 HIV+ transplant recipients of kidneys from HIV- deceased
donors (HIV D-/R+)
Multicenter – 23 clinical sites
Funded by NIAID

46. Primary Endpoints
Time to a composite event of:
• All-cause mortality
• Graft failure
• Serious Adverse Events
• HIV breakthrough
• HIV virologic failure
• Opportunistic Infection

47. Secondary Endpoints:
•Clinical outcomes between HIV+ transplant recipients of
kidneys from HIV+ and HIV- donors.
•HIV-superinfection
•Changes in the HIV latent reservoir
•Ethical, and patient reported psychosocial outcomes.

48. Recipient Selection Criteria
18 years and older with documented HIV infections
CD4>200 for at least 16 weeks
VL < 50
No active OIs
BMI >21

49. HOPE in Action: Survey
Secondary Study evaluating HIV positive individuals opinion of the
HOPE act and perceptions regarding receiving at risk organs
Survey is being administered to any HIV infected individual, 18 years or
older on the organ transplantation waitlist (for lung, liver, kidney or
heart)
Hopefully this study allows us to advocate on behalf of our patients if
and when we try and make HIV+ organ procurements routine

50. Bibliography
The Antiretroviral Therapy Cohort Collaboration. Survival of HIV-positive patients starting antiretroviral therapy between 1996 and 2013; a collaborative analysis of cohort studies. The Lancet HIV, online publication 10 May 2017.
Boyarsky BJ, Durand CM, Palella FJ and Segev DL, Challenges and Clinical Decision-Making in HIV-to-HIV Transplantation: Insights from the HIV Literature, American Journal of Transplantation 2015; 15: 2023-2030
Haider G, Singh N, The Times, They are a-Changing: HOPE for HIV-to-HIV Organ Transplantation, Transplantation Sep 2017: Volume 101, Number 9: 1987-1995
Muller et al, HIV-positive-to-HIV-positive Kidney Transplantation - Results at 3 to 5 years, NEJM 2015; 372:613-20
Shelton B, Sawinski D, Reed R, MacLennan P, Mehta S, Locke J. Protease Inhibitor-Based Regimens Are Associated with Inferior Outcomes in HIV-Infected Kidney Transplant Recipients. Am J Transplant. 2017;17 (suppl 3).
Calmy et al, HIV Positive-to-HIV-Positive Liver Transplantation, American Journal of Transplantation 2016; 16: 2473-2478
Nolan et al, First UK case report of kidney transplantation from an HIV-infected deceased donor to two HIV-infected recipients, Clinical Kidney Journal, 2018, vol. 11
Richterman et al, As assessment of HIV-infected patients dying in care for deceased organdonation in a United States Urban Center, American Journal of Transplantation 2015; 15: 2105-2116
Boyarsky et al, Estimating the potenail pool of HIV-infected deceased organ donors in the United States, American Jounral of Transplantatation. 2011 June; 11(6):1209-1217
Ahuja TS, Grady J, Khan S, Changing Trends in the Survival of Dialysis Patients with Human Immunodeficiency Virus in the United States, J Am Soc Nephrol 13: 1889-1893, 2002
Stock PG et al, Outcomes of Kidney Transplantation in HIV-Infected Recipients, NEJM 2010; 363:2004-14
Locke et al, long term outcomes after liver transplantation among human immunodeficiency virus infected recipients, transplantation 2016 Jan;100(1): 141-6
Locke et al, A national study of outcomes among HIV-infected Kidney Transplant Recipients, J Am Soc Nephrol. 2015 Sep;26(9): 2222-9
Ragni MV et al, Pretransplant survival in shortening HIV-positive than HIV-negative subjects with end stage liver disease, Liver Transplantation November 2005 Vol 11, Nov 11, p1425-30

51. THANK YOU
Saima Aslam
Cathy Logan
Nancy Law
Randy Taplitz
Jill Blumenthal
Questions?