1. HIV and HCV coinfection in solid organ transplantation
Christine Durand, MD
Associate Professor of Medicine and Oncology
Johns Hopkins University, School of Medicine
7th International Congress on Infections & Transplantation

2. Disclosures
Research grants from Abbvie, GlaxoSmithKline and grant review committee for Gilead

3. Outline Historical outcomes HIV/HCV transplant recipients
HCV treatment in co-infected transplant recipients
New frontier: HCV+ donors for HCV- recipients

4. Outline Historical outcomes HIV/HCV transplant recipients
HCV treatment in co-infected transplant recipients
New frontier: HCV+ donors for HCV- recipients

5. NIH: HIV+ kidney transplant
Patient survival
1 yr: %
3 yr: %
4 yr: %
Graft survival
1 yr: 90%
3 yr: 77%
4 yr: 70%
Stock PG/Roland M et al NEJM 2010;363:
Roland M et al AIDS 2016.

6. NIH HIV TR: subgroup HIV/HCV
HIV > 65 years
1 yr: % 92%
3 yr: % 79.5%
HIV+/HCV+ HIV+
1 yr: 86% 94% p=.09
Stock PG et al. NEJM 2010; 363:
4 year follow-up
Hazard of death for HCV/HIV = (p = .19)
Roland M et al AIDS 2016.

7. US national registry data: kidney
514 HIV+ KT recipients in SRTR,
Matched 1:10 HIV- (race, age, sex, BMI, PRA, ATG, steroids, donor age, CIT) A
89%
5 yrs
78%
64%
P=0.1
10 yrs
HIV+ vs matched HIV-
Locke JE/Segev. JASN, 2015

8. US national registry data: kidney
514 HIV+ KT recipients in SRTR,
Matched 1:10 HIV- (race, age, sex, BMI, PRA, ATG, steroids, donor age, CIT) A B
89%
5 yrs
78%
64%
P=0.1
10 yrs
79%
67%
5 yrs
P=.007
56%
29%
10 yrs
P=.002
HIV+ vs matched HIV-
HIV+/HCV+ vs matched HCV+
Locke JE/Segev. JASN, 2015

9. HIV/HCV liver transplant (LT)
US NIH study
HIV+/HCV+ n=89
Terrault et al. Liver Transp 2012;18:
Spanish study
HIV+/HCV+ n=84
Miro et al. Am J of Trans 2012;12:

10. HIV/HCV liver transplant (LT)
US NIH study
HIV+/HCV+ HCV+
3 yr: % %
Spanish study
HIV+/HCV+ HCV+
5 yr: % %

11. US national registry data: liver
N =180 LT recipients 1:10 matched HIV – controls
HIV+/HCV-, HIV+/HCV+, HIV-/HCV+, HIV-/HCV-
Locke JE, Durand CM, Segev DL. Transplantation, 2016.

12. Historically inferior outcomes with HIV/HCV co-infection

13. Outline Historical outcomes HIV/HCV transplant recipients
HCV treatment in co-infected transplant recipients
New frontier: HCV+ donors for HCV- recipients

14. hcvguidelines.org

15. Direct Acting Antiviral (DAA)
DAA trials in transplant recipients
Study
Study Design
Patient Population
Direct Acting Antiviral (DAA)
Genotype
SVR
MAGELLAN-2
Reau et al, 2018
Phase 3, open label, multicenter trial
N=20
Liver and kidney recipients
GLE/PIB
x 12 weeks
1-6
12 weeks: 99% 
Colombo et al, 2016
Randomized, phase 2, open label, multicenter trial
N=114
Kidney recipients
LDV/SOF
x 12 or 24 weeks
1 or 4
12 weeks: 100%
24 weeks: 100%
Saxena et al, 2017
Retrospective, multicenter, longitudinal treatment cohort
N=443
LDV/SOF ± ribavirin
SOF/DAC ± ribavirin
OMB/ PAR/r + DAS ± ribavirin 
12 weeks: 
Liver: 96.6%
Kidney: 94.5%
SLK: 90.9%
Reau N, et al. Hepatology 2018.
Colombo M,et al. Ann of Int Med
Saxena V et al, Hepatology. 2017
TXP: Transplant
SVR: Sustained virologic response

16. DAAs recommendations in transplant

17. Direct Acting Antiviral (DAA)
Trials in HIV/HCV transplant recipients
Study
Study Design
Patient Population
Direct Acting Antiviral (DAA)
Genotype
SVR
Sawinski, 2017
Case series
N=6
Kidney recipients
LDV/SOF
x 12 weeks 1
100% 
Antonini, 2018
ANRS CO23
CUPILT
Multicenter prospective trial
N=29
Liver recipients
SOF/DAC ± ribavirin
LDV/SOF ± ribavirin
x 12 or 24 weeks
1, 3, 4
97%
Manzardo,
2018
FIPSE LT-HIV
Multicenter prospective cohort study
N=47
SIM/SOF ± ribavirin
SIM/DAC ± ribavirin
95%
Sawinski D, et al. Transplantation, 2017.
Antonini T ,et al. Transplantation, 2018.
Manzardo et al, Am J Transplant, 2017
SVR: Sustained virologic response

18. HIV/HCV co-infected individuals

19. HIV/HCV co-infected individuals

20. LDV/SOF SOF/VEL ELB/GRZ GLE/PIB SOF/VEL/VOX ATVr DRVr LPVr EFV RPV ETR
SOF=sofosbuvir; LDV=ledipasvir; VEL=velpatasvir; ELB GRZ=grazoprevir elbasvir; GLE PIB =glecaprevir pibrentasvir; VOX=voxilaprevir
LDV/SOF
SOF/VEL
ELB/GRZ
GLE/PIB
SOF/VEL/VOX
ATVr
DRVr
LPVr
EFV
RPV
ETR
RAL
EVGc
DTG
BIC
MVC
TDF
TAF
ATV=atazanavir; r=ritonavir; DRV=darunavir; LPV=lopinavir; EFV=efavirenz ; RPV=rilpivirine; ETR=etravirine; RAL=raltegravir; EVG=elvitegravir; c=cobicistat; DTG=dolutegravir; BIC=bictegravir; MVC=maraviroc; TDF= tenofovir disoproxil fumarate; TAF=tenofovir alafenamide fumarate;

21. PIs LDV/SOF SOF/VEL ELB/GRZ GLE/PIB SOF/VEL/VOX ATVr DRVr LPVr EFV RPV
SOF=sofosbuvir; LDV=ledipasvir; VEL=velpatasvir; ELB GRZ=grazoprevir elbasvir; GLE PIB =glecaprevir pibrentasvir; VOX=voxilaprevir
LDV/SOF
SOF/VEL
ELB/GRZ
GLE/PIB
SOF/VEL/VOX
ATVr
DRVr
LPVr
EFV
RPV
ETR
RAL
EVGc
DTG
BIC
MVC
TDF
TAF
PIs
ATV=atazanavir; r=ritonavir; DRV=darunavir; LPV=lopinavir; EFV=efavirenz ; RPV=rilpivirine; ETR=etravirine; RAL=raltegravir; EVG=elvitegravir; c=cobicistat; DTG=dolutegravir; BIC=bictegravir; MVC=maraviroc; TDF= tenofovir disoproxil fumarate; TAF=tenofovir alafenamide fumarate;

22. NNRTIs LDV/SOF SOF/VEL ELB/GRZ GLE/PIB SOF/VEL/VOX ATVr DRVr LPVr EFV
SOF=sofosbuvir; LDV=ledipasvir; VEL=velpatasvir; ELB GRZ=grazoprevir elbasvir; GLE PIB =glecaprevir pibrentasvir; VOX=voxilaprevir
LDV/SOF
SOF/VEL
ELB/GRZ
GLE/PIB
SOF/VEL/VOX
ATVr
DRVr
LPVr
EFV
RPV
ETR
RAL
EVGc
DTG
BIC
MVC
TDF
TAF
NNRTIs
ATV=atazanavir; r=ritonavir; DRV=darunavir; LPV=lopinavir; EFV=efavirenz ; RPV=rilpivirine; ETR=etravirine; RAL=raltegravir; EVG=elvitegravir; c=cobicistat; DTG=dolutegravir; BIC=bictegravir; MVC=maraviroc; TDF= tenofovir disoproxil fumarate; TAF=tenofovir alafenamide fumarate;

23. INSTIs LDV/SOF SOF/VEL ELB/GRZ GLE/PIB SOF/VEL/VOX ATVr DRVr LPVr EFV
SOF=sofosbuvir; LDV=ledipasvir; VEL=velpatasvir; ELB GRZ=grazoprevir elbasvir; GLE PIB =glecaprevir pibrentasvir; VOX=voxilaprevir
LDV/SOF
SOF/VEL
ELB/GRZ
GLE/PIB
SOF/VEL/VOX
ATVr
DRVr
LPVr
EFV
RPV
ETR
RAL
EVGc
DTG
BIC
MVC
TDF
TAF
INSTIs
ATV=atazanavir; r=ritonavir; DRV=darunavir; LPV=lopinavir; EFV=efavirenz ; RPV=rilpivirine; ETR=etravirine; RAL=raltegravir; EVG=elvitegravir; c=cobicistat; DTG=dolutegravir; BIC=bictegravir; MVC=maraviroc; TDF= tenofovir disoproxil fumarate; TAF=tenofovir alafenamide fumarate;

24. Not if to treat, but when to treat, that is the question….

25. DAAs in kidney transplant – pre or post?
Benefits
Excellent SVR rates
Prevent liver disease progression
Prevent post-transplant HCV complications: immune complex glomerulonephritis

26. DAAs in kidney transplant – pre or post?
Benefits
Harms
Exclude HCV+ donors
Longer wait time and mortality on dialysis
Excellent SVR rates
Prevent liver disease progression
Prevent post-transplant HCV complications: immune complex glomerulonephritis

28. DAAs in liver transplant – pre or post?
Benefits
Prevent post-transplant complications, e.g fibrosing cholestatic hepatitis C
Reduce death on waitlist
Improve MELD and clinical status on waitlist – delisting?

29. DAAs in liver transplant – pre or post?
Benefits
Harms
↓ SVR (< 90%) in decompensated cirrhosis
↑drug toxicity, tolerability
↓ MELD decrease transplant priority, ↑wait time
May limit HCV+ donor options
Prevent post-transplant complications, e.g fibrosing cholestatic hepatitis C
Reduce death on waitlist
Improve MELD and avoid the need for transplant?

30. hcvguidelines.org: recommend referral to liver transplant center for consideration

31. Outline Historical outcomes HIV/HCV transplant recipients
HCV treatment in co-infected transplant recipients
New frontier: HCV+ donors for HCV- recipients

32. Increasing number and quality of HCV+ donor organs over time
> 13% deceased donors in US opioid overdose death donors
Durand/Segev Ann of Intern Med 2018

33. Increasing number and quality of HCV+ donor organs over time
> 13% deceased donors in US opioid overdose death donors
Over 30% HCV Ab+ in 2017
Prevalence of HCV+ donors (antibody)
Durand/Segev Ann of Intern Med 2018

34. Increasing number and quality of HCV+ donor organs over time
> 13% deceased donors in US opioid overdose death donors
Over 30% HCV Ab+ in 2017
HCV Ab+ donors younger, fewer comorbidities
Transplants outcomes with overdose death donor organs same or better than trauma death donors
Prevalence of HCV+ donors (antibody)
Durand/Segev Ann of Intern Med 2018

35. But HCV+ organs remain underutilized 3/1/15-1/31/18
Slide courtesy of David Goldberg, OPTN data

36. HCV D+/R- kidney transplant THINKER: Transmit and Treat
HCV D+/R- KT
n=10, Genotype 1a Treatment initiated if transmission: 100%
Treated with GZR/EBR for 12 weeks
All patients cured
Median wait: 58 days
Goldberg/Reese NEJM 2017

37. HCV D+/R- kidney transplant EXPANDER: Prophylaxis
HCV D+/R- kidney transplant n= 10
Genotypes 1a, 2, 3, mixed
DAAs pre- and post-exposure prophylaxis
Prophylaxis GZR/EBR +/- SOF for weeks
No chronic HCV
Median wait: 30 days
5 patients never viremic
10/10 no chronic HCV
Durand/Desai Ann Intern Med 2018

38. HCV D+/R- trials in heart and lung
USHER – Transmit and Treat
n=10 heart transplants
Treatment initiated if transmission: 100% day 3
Treated with GZR/EBR for weeks +/- RBV
9 patients cured, 1 died due acute rejection
Reese/Goldberg AJT 2018

39. HCV D+/R- trials in heart and lung
USHER – Transmit and Treat
DONATE HCV – Post-prophylaxis
n=10 heart transplants
Treatment initiated if transmission: 100% day 3
Treated with GZR/EBR for weeks +/- RBV
9 patients cured, 1 died due acute rejection
n=36 lung, n=8 heart transplants
6 hours after transplant received post-exposure prophylaxis
Prophylaxis SOF/VEL for 4 weeks
No chronic HCV, increased rejection
Reese/Goldberg AJT 2018
Wooley/Baden NEJM 2019

40. Moving into clinical practice
Multiple observational studies of the “transmit and treat” approach
Schlendorf (Vanderbilt): 9 HCV D+/R- heart transplants1
Kwong (Stanford): 10 HCV D+/R- liver transplants2
Aslam (UCSD): 12 HCV D+/R- heart transplant3
Alonso (Utah): 10 HCV D+/R- liver transplants4
1. Schlendorf/Lindenfeld JHLT 2018
3. Aslam, abstract IHLTS 2018
2. Kwong/Kwo AJT 2018
4. Alonso, abstract ASTS 2017

41. Complications of HCV D+/R-
Some reports suggest increased allograft rejection1,2
HCV treatment failure
THINKER: n=1 viral breakthrough with initial therapy, required intensification of therapy and prolonged duration, cured
Toronto trial of HCV D+/R- lung transplant: 2/13 viral relapse, including severe case with fibrosing cholestatic HCV, on intensified treatment for prolonged duration, ongoing4
Long term outcomes
Logistical issues – insurance coverage of DAAs, administration via nasogastric tubes
1. Kwong/Kwo AJT 2018
3. Reese/Goldbert AJT 2018
2. Wooley/Baden NEJM 2019
4. Feld/Cyprel abstract AASLD 2018, updated data
personal communication

42. Remaining questions Prophylaxis vs Transmit and Treat
Prevent HCV related complications e.g. fibrosing cholestatic HCV, rejection
Avoid risk of transmission to others
Ensure recipients can take oral medications, stable renal function
More practical approach for obtaining DAAs from insurers

43. Remaining questions Prophylaxis vs Transmit and Treat
Prevent HCV related complications e.g. fibrosing cholestatic HCV, rejection
Avoid risk of transmission to others
Ensure recipients can take oral medications, stable renal function
More practical approach for obtaining DAAs from insurers
Clinical care vs Research only
Guaranteed access to DAAs
More rigorous consent process
Increased access to transplant
Standard with CMV, HBV, EBV

44. Conclusions
Historically, HIV/HCV recipients have inferior outcomes compared to mono-infected recipients
DAAs well tolerated and effective in this population…when to treat is the question?
Drug interactions are key – INSTIs and RPV generally safe or consider DAC/SOF as DAA
HCV D+/R- next frontier with several unknowns

45. Thank you for your attention.