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

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

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

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

NIH: HIV+ kidney transplant Patient survival 1 yr: 95% 3 yr: 91% 4 yr: 89% Graft survival 1 yr: 90% 3 yr: 77% 4 yr: 70% Stock PG/Roland M et al NEJM 2010;363:2004-2014. Roland M et al AIDS 2016.

NIH HIV TR: subgroup HIV/HCV HIV+ > 65 years 1 yr: 95% 92% 3 yr: 91% 79.5% HIV+/HCV+ HIV+ 1 yr: 86% 94% p=.09 Stock PG et al. NEJM 2010; 363: 2004-2014. 4 year follow-up Hazard of death for HCV/HIV = 0.81.941 (p = .19) Roland M et al AIDS 2016.

US national registry data: kidney 514 HIV+ KT recipients in SRTR, 2002-2011 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

US national registry data: kidney 514 HIV+ KT recipients in SRTR, 2002-2011 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

HIV/HCV liver transplant (LT) US NIH study HIV+/HCV+ n=89 Terrault et al. Liver Transp 2012;18:716-726. Spanish study HIV+/HCV+ n=84 Miro et al. Am J of Trans 2012;12:1866-76.

HIV/HCV liver transplant (LT) US NIH study HIV+/HCV+ HCV+ 3 yr: 60% 79% Spanish study HIV+/HCV+ HCV+ 5 yr: 54% 71%

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.

Historically inferior outcomes with HIV/HCV co-infection

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

hcvguidelines.org

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. 2017. Saxena V et al, Hepatology. 2017 TXP: Transplant SVR: Sustained virologic response

DAAs recommendations in transplant

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

HIV/HCV co-infected individuals

HIV/HCV co-infected individuals

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;

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;

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;

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;

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

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

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

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?

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?

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

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

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

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

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

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

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

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 12-16 weeks No chronic HCV Median wait: 30 days 5 patients never viremic 10/10 no chronic HCV Durand/Desai Ann Intern Med 2018

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 12-16 weeks +/- RBV 9 patients cured, 1 died due acute rejection Reese/Goldberg AJT 2018

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 12-16 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

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

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

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

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

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

Thank you for your attention.