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Hiv‐positive‐to‐hiv‐positive liver transplantation

American Journal of Transplantation 2016; XX: 1–6 Copyright 2016 The American Society of Transplantation Wiley Periodicals Inc.
and the American Society of Transplant Surgeons doi: 10.1111/ajt.13824 A. Calmy1,*,†, C. van Delden2,†, E. Giostra3, C. Junet4, L. Rubbia Brandt5, S. Yerly6,J.-P. Chave7, C. Samer8, L. Elkrief3, J. Vionnet9 Concerns about donor-derived human immunodeficiency and T. Berney3 on behalf of the Swiss HIV and virus (HIV) transmission have excluded HIV-positive Swiss Transplant Cohort Studies patients from organ donation lists in most countries. Thisleads to the loss of an estimated 356 potential organ donors per year in the United States (1). HIV-positive solid HIV Unit, Geneva University Hospitals, Geneva, organ transplant candidates remain disadvantaged on wait- 2Transplant Infectious Diseases Unit, Geneva University ing lists with an increased risk of death, particularly in HIV- Hospitals, Geneva, Switzerland hepatitis C virus (HCV)–coinfected individuals with liver 3Division of Transplantation, Geneva University Hospitals, disease (2–4). Despite a higher relative risk of experiencing Geneva, Switzerland graft failure compared to HIV-negative controls, HIV status 4Private Practice, Geneva, Switzerland was not associated with an increased risk of death in a 5Division of Pathology, Geneva University Hospitals, cohort of solid organ transplant recipients in the United Geneva, Switzerland States (5). The concern that transplantation of organs from 6Virology Laboratory, Geneva University Hospitals, HIV-positive donors might harm transplant recipients Geneva, Switzerland remains. Indeed, transmission of a new HIV strain to an Private Practice, Lausanne, Switzerland 8Division of Clinical Pharmacology and Toxicology, immunosuppressed HIV-positive recipient could poten- Geneva University Hospitals, Geneva, Switzerland tially lead to uncontrolled viral replication, immune dysreg- 9Division of Gastroenterology and Division of ulation, and opportunistic infections (4,6). So far, reports Transplantation, CHUV, Lausanne, Switzerland on the transplant of HIV-positive organs have been limited *Corresponding author: Alexandra Calmy, to kidney transplantation in South Africa from treatment- naive or first-line antiretroviral therapy (ART)–treated HIV- †Both authors contributed equally to the manuscript.
positive donors to HIV-positive recipients (7). The SwissFederal Act on Transplantation and its bylaws has allowed Most countries exclude human immunodeficiency transplantation from HIV-positive donors to HIV-positive virus (HIV)-positive patients from organ donation recipients since July 2007 (Data S1, Document 1) (8,9).
because of concerns regarding donor-derived HIV Similarly, the HIV Organ Policy Equity (HOPE) act passed transmission. The Swiss Federal Act on Transplanta- by the United States Congress in November 2013 legal- tion has allowed organ transplantation between HIV- ized such transplants, but only in the setting of an positive donors and recipients since 2007. We report approved research protocol (10). From 2008 to 2014, 569 the successful liver transplantation from an HIV- HIV-positive individuals died in Switzerland, with liver- positive donor to an HIV-positive recipient. Both donor related deaths accounting for nearly 14% of all reported and recipient had been treated for many years withantiretroviral therapy and harbored multidrug-resistant deaths (11). During this period of time, 14 HIV-positive viruses. Five months after transplantation, HIV viremia individuals benefited from a liver transplant (LT) from remains undetectable. This observation supports the HIV-negative donors (Franziska Sch€ oni-Affolter, personal inclusion of appropriate HIV-positive donors for trans- communication). We report the first documented case of plants specifically allocated to HIV-positive recipients.
successful LT between an ART-experienced HIV-positivedonor and recipient.
Abbreviations: ART, antiretroviral therapy; CDC, Cen-ters for Disease Control and Prevention; HBIG, hep-atitis B immunoglobulins; HBV, hepatitis B virus;HCV, hepatitis C virus; HDV, hepatitis D virus; HIV, human immunodeficiency virus; HOPE, HIV OrganPolicy Equity; LT, liver transplant; MELD, Models for End-Stage Liver Disease; RT, reverse transcriptase; A 53-year-old HIV-positive man was offered a liver from SHCS, Swiss HIV Cohort Study a brain death deceased HIV-positive donor in October2015 in Switzerland. He was diagnosed HIV-positive sec- Received 01 April 2016, revised 08 April 2016 ondary to intravenous drug abuse in 1987 with a Centers accepted for publication 09 April 2016 for Disease Control and Prevention (CDC) stage B3 (herpes zoster) and a CD4 cell count nadir 78 cells/mm3.
core antigen positive, with undetectable HBV DNA vire- Initial treatment consisted of zidovudine and zalcitabine mia under tenofovir therapy. Seroconversion from hepati- in 1992, followed in 1997 by a combination of indinavir, tis B envelope antigen (HBeAg) to anti-HBe occurred in stavudine, and lamivudine until a virological escape and a 2010. A replicative hepatitis D virus (HDV) infection (7.3 M184V mutation were identified in 2001. Following a E+8 copies/mL) with sustained hepatic cytolysis occurred in 2011. Pegylated interferon was initiated but stopped between 2001 and 2002, he resumed an ART of aba- after four doses because of adverse drug reactions. At cavir, efavirenz, and didanosine (switched in 2003 to the time of pretransplant evaluation, the Child-Pugh tenofovir) late in 2002. Since 2003, HIV-RNA levels have score was B7 and the Model for End-Stage Liver Disease remained below the threshold of detectability (50 copies/ (MELD) score was 9. The patient was registered on the mL) with a stable CD4 cell count between 300 and waiting list in November 2014. Clinical condition and liver 400 cells/mm3. In 2013, a combination of rilpivirine, teno- function tests rapidly declined thereafter, with poorly fovir, and emtricitabine was initiated (Figure 1). Chronic controlled ascites and recurring episodes of encephalopa- hepatitis C virus (HCV) genotype 4 coinfection was diag- thy. In June 2015, the Child-Pugh score had increased to nosed in 1997 with a positive HCV RNA viremia that C10, but the MELD score remained low (11). Given this became undetectable in 2004 without specific therapy.
particular situation, he was granted a nonstandard MELD Hepatitis B virus (HBV) serological status was hepatitis B exception for incapacitating encephalopathy and refrac- surface antigen positive, antibodies to the hepatitis B tory ascites. Both a liver biopsy and explant examination Figure 1: Clinical timeline of the HIV-positive liver transplant recipient. Shown are key dates from 1987 throughout January2016 (5 months after LT) regarding the human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis D virus (HDV), and hep-atitis C virus (HCV) infections, in terms of diagnosis and therapies. HIV, human immunodeficiency virus; LT, liver transplant; MMF,mycophenolate mofetil; AntiHBs, antibodies to the hepatitis B surface antigen.
American Journal of Transplantation 2016; XX: 1–6 HIV+ to HIV+ Liver Transplantation confirmed the diagnosis of cirrhosis on HBV/HDV-related modified to nevirapine, boosted lopinavir, and abacavir.
chronic hepatitis of moderate inflammatory activity (Data Thereafter, his HIV-RNA viremia remained below the S1, Document 2A–C).
detection limit with a stable CD4 cell count around400 cells/mm3. In 2011, he was started on raltegravir, modified for dolutegravir 15 days prior to his death, in The donor was a 75-year-old man who died of a cerebel- conjunction with tenofovir and emtricitabine. Following lar hemorrhage. He was diagnosed HIV-positive in 1989 information by his primary care physician that Swiss law (transmission route–bisexual contacts; CDC stage C3 allowed him to donate his organs to HIV-positive recipi- [cryptosporidiosis, esophageal candidiasis, herpes zos- ents, he provided written explicit consent for organ dona- ter]). His ART consisted initially of zidovudine, lamivu- tion in September 2015 (Data S1, Document 3). At the dine, and indinavir started in the setting of detected time of donation his laboratory values (including white multiple resistance mutations in 1996. Due to a virologi- blood cell count, liver and kidney function tests) were cal failure and the presence of mutations associated with normal; CD4 cell count was 298 cells/mm3 (21%) and drug resistance in 2002 (Figure 2), his drug regimen was HIV-RNA below the detection level of 40 copies/mL.
Figure 2: Genotypic HIV resistance of the HIV-positive liver donor. Shown are genotypic resistance obtained through population-based sequencing of the full protease gene and codons 28–225 of the reverse transcriptase gene interpreted according to the ANRSalgorithm 2015 version 25 ) (22). No further determinations of HIV resistance were performed due tocontinuous viral suppression. HIV, human immunodeficiency virus; ANRS, Agence Nationale de Recherche sur le Sida et les h American Journal of Transplantation 2016; XX: 1–6 Liver transplantation patient and graft survival (74% and 84% with censoring A transplant infectious diseases physician informed the for death with function, respectively) were similar to recipient candidate about potential virus transmission and those in HIV-positive recipients of an HIV-negative organ.
the requirements to adapt his anti-HIV therapy due to dif- In this study, however, both donors and recipients were ferent viral resistances. The patient accepted the risk and highly selected. To reduce the risk of resistant-virus signed an informed consent for liver transplantation (Data transmission, donors were either ART-na€ıve or had taken S1, Document 4). No ethical clearance was necessary only first-line ART, while CD4 T cell counts of at least due to the permissive law in Switzerland. A donor per- 200/mm3 and undetectable plasma HIV RNA levels were operative liver biopsy identified a macrovesicular steato- prerequisites in potential recipients taking ART for at sis of minimal extent (less than 10%) on frozen section least 3 months. In addition there has been a recent histology and mild portal inflammation, not contraindicat- report (March 2016) in the news media of a liver and a ing the organ donation (Data S1, Document 2D). We kidney transplant performed in Baltimore from an HIV+ were unable to detect HIV-RNA by polymerase chain donor to HIV+ recipients.
reaction performed on cells extracted from formalin-fixedparaffin-embedded donor liver tissue despite adequate The present report is original in many ways. Both donor and recipient had been seropositive for roughly 30 years, showed immediate function, and no surgical or medical had been treated with several ART regimens, and had complications occurred. The transplant serostatus was negative viral assays for HIV at the time of transplanta- the following: cytomegalovirus D+/R tion. Both harbored HIV strains with resistance mutations negative recipient), toxoplasmosis D+/R+, Epstein-Barr on the reverse transcriptase (RT) gene, which were non- D+/R+. He received a standard, steroid-free identical. Thus, to decrease the risk that the transplanted liver would transmit a viral strain with distinct mutations, induction, as well as tacrolimus and mycophenolate mofe- we adapted the recipient's pretransplant suppressive til. To prevent HBV recurrence, hepatitis B immunoglobu- ART to the donor's HIV genotype by adding an integrase lins (HBIG) were infused during the transplant surgery.
inhibitor and a short course of enfuvirtide. This strategyhas thus far proven successful; at 5 months, HIV viremia Posttransplant care remains suppressed below the threshold of detection of Rilpivirine/tenofovir/emtricitabine were restarted on Day 2 20 copies/mL. At this point, there is no indication that posttransplant, together with raltegravir and subcuta- immunosuppressive therapy has enabled an increase in neous enfuvirtide to cover for the donor's HIV resistance HIV pathogenicity and thus potentiated its spread, as genotypes. The patient was discharged on posttransplant previously feared (6).
Day 22 receiving prophylactic valgancyclovir and trimetho-prim and sulfamethoxazole in addition to his immuno- Outcome in HIV/HBV-coinfected LT recipients is excel- suppression and ART. ART was modified 3 months after lent, and comparable to that of HBV-monoinfected transplantation to a fixed-dose combination of rilpivirine/ patients receiving combined HBIG and HBV antiviral ther- tenofovir/emtricitabine and dolutegravir. Rilpivirine plasma apy (12,13). Accordingly, our patient received HBIG with levels, measured at 6 days and 8 weeks after transplanta- tenofovir, and HBV viremia remained undetectable. In tion, were in the normal to lower therapeutic range (25th contrast, HIV–HCV coinfection is of concern in LT, with to 40th percentile) and decreased at weeks 15 and 18 increased risks of rejection and reduced graft and patient posttransplant to the 10th lower percentile (30 ng/mL).
survival, particularly when donors are 50 years of age or Plasma levels of dolutegravir were lower than expected older (14,15). In the present case, the recipient was coin- after a dose of 50 mg twice a day at weeks 15 and 18.
fected with HBV, HCV, and HDV, while the donor was Tacrolimus dosage was easily adjusted to maintain trough 75 years old. However, the risk of a poor outcome was levels in the desired range (8–15 ng/mL). HBV and HDV likely mitigated by the recipient's spontaneous clearance DNA, as well as HIV and HCV RNA, remained unde- of HCV viremia before LT and low MELD score. Indeed, tectable after transplantation (Figure 1). No rejection epi- the pre-LT MELD score was identified as the only predic- sode occurred during the 5-month follow-up period.
tor of survival in a French multicenter cohort of HIV–HCVcoinfected LT recipients (16). This has led experts toadvocate the use of HIV-positive organs to facilitate access to transplantation for those with lower MELDscores (16,17). Furthermore, an eventual HCV infection We report the first successful liver transplantation, to our recurrence in our recipient would very likely be controlled knowledge, from an HIV-positive donor to an HIV-positive with the newly available highly active anti-HCV agents.
recipient. So far, report of transplantation of organs from Despite long-standing exposure to multiple antiviral HIV-positive donors has been restricted to the descrip- drugs, the histology of the transplanted liver revealed tion of the outcome in 27 HIV-positive recipients who only minor macrovesicular steatosis. Furthermore, hep- received kidneys from HIV-positive donors in South atic function recovered rapidly after LT, lessening the Africa (7). Five years posttransplantation, both cumulative fear that the transplant might have suffered from drug- American Journal of Transplantation 2016; XX: 1–6 HIV+ to HIV+ Liver Transplantation induced damage. Longer follow-up is certainly needed to ensure both the virologic and functional safety of thisprocedure.
The authors of this manuscript have no conflicts of inter-est to disclose as described by the American Journal of Drug–drug interactions remain potentially challenging in HIV transplant recipients (18). Dolutegravir, rilpivirine, andtacrolimus are substrates of cytochrome P450 (CYP) 3A(19,20). Dolutegravir plasma levels were lower than expected in the recipient, and rilpivirine and tacrolimusplasma concentrations gradually decreased to the desired We thank Natalia Enriquez, Laurent Kaiser, and Roseline Ing for helpful dis- therapeutic range. No CYP3A inducer was included cussions, as well as Rosemary Sudan and Angela Huttner for editing the among the recipient's comedications that could explain manuscript. We also thank La Source Private Hospital for additional free the increased drug clearance and reduced plasma con- biological analyses. Members of the Swiss HIV Cohort Study (SHCS) centrations of CYP3A substrates. Donor genetic variabil- are as follows: V. Aubert, M. Battegay, E. Bernasconi, J. B€ ity could account for the phenotypic alterations observed Bucher, A. Calmy, M. Cavassini, G. Dollenmaier, M. Egger, L. Elzi, J. Fehr, J. Fellay, H. Furrer (Chairman, Clinical and Laboratory Committee), C.A.
in the recipient (21).
Fux, M. Gorgievski, H. G€ unthard (President, SHCS), D. Haerry (deputy of "Positive Council"), B. Hasse, H.H. Hirsch, M. Hoffmann, I. H€ The immunologic and virologic control produced by effec- lert, L. Kaiser, O. Keiser, T. Klimkait, R. Kouyos, H. Kovari, B. Ledergerber, tive ART in both donor and recipient was essential to the G. Martinetti, B. Martinez de Tejada, K. Metzner, N. M€ uller, D. Nadal, D.
success of this LT. With currently available antiretrovirals, Nicca, G. Pantaleo, A. Rauch (Chairman, Scientific Board), S. Regenass, M.
HIV-RNA can be rapidly suppressed in the vast majority Rickenbach (Head, Data Centre), C. Rudin (Chairman, Mother & Child Sub- of cases and should not be a major concern in the deci- study), F. Sch€ oni-Affolter, P. Schmid, J. Sch€ upbach, R. Speck, P. Tarr, A.
sion to proceed with transplantation.
Telenti, A. Trkola, P. Vernazza, R. Weber, S. Yerly. The data are gathered by the 5 Swiss university hospitals, 2 cantonal hospitals, 15 affiliated hospitals, Another issue could be the need to decide on the safety and 36 private physicians ).
The members of the Swiss Transplant Cohort Study (STCS) are as fol- of organ transplantation in the absence of adequate doc- lows: R. Achermann, P. Amico, J.-D. Aubert, P. Baumann, G. Beldi, C. Ben- umentation of the clinical history of both HIV+ donor and den, C. Berger, I. Binet, P.-Y. Bochud, E. Boely, H. Bucher, L. B€ recipient. This includes viral rebound episodes and geno- Carell, E. Catana, Y. Chalandon, S. de Geest, O. de Rougemont, M. Dicken- typic resistance, as well as potential active opportunistic mann, M. Duchosal, T. Fehr, S. Ferrari-Lacraz, C. Garzoni, P. Gasche Soc- infections and/or concurrent oncologic diseases. This cal, E. Giostra, D. Golshayan, D. Good, K. Hadaya, J. Halter, D. Heim, C.
may in certain situations impose limits to organ donation.
Hess, S. Hillinger, H.H. Hirsch, C. Hirzel, G. Hofbauer, U. Huynh-Do, F.
In Switzerland over 75% of all HIV+ patients, including Immer, R. Klaghofer, M. Koller (Head of the data center), B. Laesser, R.
both our donor and recipient, are included in the Swiss Lehmann, C. Lovis, O. Manuel, H.-P. Marti, P.Y. Martin, L. Martinolli, P.
HIV Cohort Study (SHCS), allowing precise documenta- Meylan (Head, Biological samples management group), P. Mohacsi, I. Mor- tion of all HIV-related events (22). Moreover in 2016, ard, P. Morel, U. Mueller, N.J. Mueller (Chairman Scientific Committee), H.
Mueller-McKenna (Head of local data management), A. M€ with the advent of potent ARTs, the vast majority of HIV ullhaupt, D. Nadal, M. Pascual (Executive office), J. Passweg, C. Piot strains can be successfully treated. In certain circum- Ziegler, J. Rick, E. Roosnek, A. Rosselet, S. Rothlin, F. Ruschitzka, U.
stances such as the absence of ART, HIV+ patients with Schanz, S. Schaub, C. Seiler, S. Stampf, J. Steiger (Head, Executive Office), active HIV viral replication may be considered as poten- G. Stirnimann, C. Toso, D. Tsinalis, C. van Delden (Executive office), J.-P.
tial donors.
Venetz, J. Villard, M. Wick (STCS coordinator), M. Wilhelm, P. Yerly.
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