Should Organs from Hepatitis C-Positive Donors Be Used in Hepatitis C-Negative Recipients for Liver Transplantation? - AASLD
←
→
Page content transcription
If your browser does not render page correctly, please read the page content below
REVIEW ARTICLE SELZNER AND BERENGUER
Should Organs from Hepatitis
C-Positive Donors Be Used in
Hepatitis C-Negative Recipients
for Liver Transplantation?
Nazia Selzner1 and Marina Berenguer2
1
Multiorgan Transplant Program, University of Toronto, Toronto, Canada and 2Liver Transplantation and Hepatology Unit, La
Fe University Hospital, Universidad de Valencia, Valencia, Spain
Given the scarcity of donated organs and the frequency of death on the waiting list, strategies that could improve the avail-
able supply of high-quality liver grafts are much needed. Direct-acting antiviral agent (DAA) regimens have proved to be
highly effective to treat hepatitis C virus (HCV), even in the setting of posttransplantation. The question arises as to
whether transplant communities should consider the utilization of HCV-positive donors into HCV-negative recipients. This
review summarizes risk of transmission, treatment options with success rate, and ethical considerations for usage of HCV-
positive donors.
Liver Transplantation 24 831–840 2018 AASLD.
Received September 13, 2017; accepted March 10, 2018.
Liver transplantation (LT) is the preferred therapy superior compared with similar patients without
for most patients with end-stage organ failure transplantation. As outcomes of LT have improved,
because survival of liver transplant recipients is the number of patients listed for deceased donor
transplantation has increased dramatically over the
years, resulting in a growing gap between individuals
Abbreviations: Ab, antibody; ASTS, American Society of Transplan- awaiting LT and the number of organs available for
tation; DAA, direct-acting antiviral agent; CNTRP, Canadian transplant. As a consequence, the transplant com-
National Transplant Research Program; ELISA, enzyme-linked
immunosorbent assay; FHF, fulminant hepatic failure; GZREBR, munity has been continuously aiming to develop
grazoprevir/elbasvir; HCV, hepatitis C virus; HCV D1, HCV-pos- strategies to overcome organ shortage. These strate-
itive donor; HCV R1, HCV-positive recipient; HCV R-, HCV- gies include expansion of the deceased donor pool
negative recipient; IDU, injection drug users; IRD, increased risk
donor; LT, liver transplantation; NAT, nucleic acid testing; NS5A,
through utilization of marginal grafts such as fatty
nonstructural protein 5A; OCI, occult HCV infection; OPTN, Organ livers, donation after circulatory death, or through
Procurement and Transplantation Network; PBMC, peripheral blood development of live donor LT. Another strategy is
mononuclear cells; PEG/Riba, pegylated interferon and ribavirin; the use of potential deceased donors who have been
PHS, Public Health Services; POD1, postoperative day 1; PWID,
people who inject drugs; RAS, resistance-associated substitutions; identified as being at increased risk for transmission
SVR, sustained virologic response. of specific infectious pathogens such as hepatitis C
virus (HCV) based on defined demographic and
Address reprint requests to Nazia Selzner, M.D., Ph.D., Multi-Organ
behavioral characteristics or, rarely, use of donors
Transplant Program, University of Toronto, University Health
Network, University of Toronto, 585 University Avenue, 11 PMB with known HCV infection. Although emerging
178, Toronto, ON M5G 2N2. Telephone: 11-416-340-4800, ext. data seems to indicate that the use of a liver from
5884; FAX: 416-340-5321; E-mail: nazia.selzner@uhn.ca an HCV-positive donor (HCV D1) in an HCV-
C 2018 by the American Association for the Study of Liver
Copyright V positive recipient (HCV R1) is safe, especially with
Diseases. the advances in HCV treatment, the transplant
View this article online at wileyonlinelibrary.com. community seems reluctant to consider these organs
for HCV-negative recipients (HCV R-). This
DOI 10.1002/lt.25072
review summarizes risk of transmission, treatment
Potential conflict of interest: Nothing to report. options with success rate, and ethical considerations
for usage of HCV D1.
REVIEW ARTICLE | 831SELZNER AND BERENGUER LIVER TRANSPLANTATION, June 2018
Risk of Transmission of carry no risk of transmission of HCV because these
donors have no residual virus and are considered safe to
HCV Based on Donor’s be used for transplantation in HCV R-.(7) However, the
risk of HCV transmission is not null despite a negative
Serology After LT NAT and serology testing, especially for increased risk
donors (IRDs). Suryaprasad et al. reported a case series
The risk of transmission of HCV via solid organ or tis-
of 3 organ donors with evidence of active injection drug
sue transplantation has been recognized for decades.(1) use up to the time of the event leading to their death and
Worldwide Organ Procurement and Transplantation undetectable NAT at the time of initial evaluation.(8) A
agencies recommend that all donors should be rou- total of 8 of 12 (67%) recipients from these 3 donors
tinely screened to identify HCV infection by serology acquired a donor-derived HCV infection. Subsequent
testing. In the past, the use of HCV D1 grafts were retrospective testing of stored splenocytes or lymphocytes
limited to patients suffering life-threatening diseases collected during organ procurement detected HCV
(such as fulminant hepatic failure [FHF]) or more RNA confirming transmission of infection posttrans-
recently for recipients infected with HCV. plantation.(8) More recently, Bari et al.(9) reported a 16%
HCV positivity is generally defined as a donor who risk of HCV transmission after LT from donors who
has a positive antibody (Ab) to HCV. In addition, were HCV-antibody positive and serum NAT-negative
despite negative serology testing, some donors with to antibody negative recipients. In their prospective
high-risk behavioral characteristics may be at risk for cohort study, 25 HCV-negative liver transplant recipi-
transmitting HCV because of the window period, which ents transplanted were transplanted with HCV-positive
is the time between infection and detection by a specific IRDs. IRDs were defined as donors that meet the Public
testing method.(2) Nucleic acid testing (NAT) assay, Health Services (PHS) criteria for increased risk of infec-
which detects the presence of HCV viral RNA in tion transmission and were anti-HCV–positive and
donor’s blood is recommended for these high-risk HCV NAT-negative (nonviremic). All these recipients
donors. Compared with serology testing, NAT assays underwent NAT testing post-LT. HCV disease trans-
significantly reduce the window period between infec- mission occurred in 4 recipients (16%) by 3 months
tion and detection of HCV from 70 days to 3-5 days. post-LT, predominantly in females (3/4), 1 with a prior
The development of NAT, which provides a more accu- history of HCV/HIV coinfection who had undergone
rate assessment of HCV transmission, has led to rede- successful HCV treatment 2 years prior to LT. Three of
fining the term “HCV-positive donor” by the American these patients were treated with direct-acting antiviral
Society of Transplantation (ASTS) consensus confer- agents (DAAs). One has finished the course of treat-
ence.(3) An HCV seropositive donor who is NAT- ment and is at the end of treatment response while 2
negative (nonviremic) indicates a spontaneously cleared others are still under treatment. This report raises the
or successfully treated infection. Approximately 10%- question whether the NAT results were false-negative
25% of HCV-infected patients will spontaneously clear at the time of testing or if the virus was reactivated
the virus without treatment.(4,5) Other donors may clear post-LT in the setting of immunosuppression.
the virus with treatment, a circumstance which is likely The residual risk of HCV infection from IRDs with
to increase substantially in the near future given the high negative serologic screening has been estimated to
efficacy rates achieved with new antiviral therapies. An range from 0.3 (donors with hemophilia) to 301 (intra-
HCV-seropositive donor who is NAT-positive (viremic) venous drug users) per 10,000 donors.(10) Similarly,
indicates active infection and poses a high risk for disease the Canadian Society for Transplantation and the
transmission. Similarly, an HCV-seronegative donor Canadian National Transplant Research Program
with detectable RNA generally indicates acute infection (CNTRP) reported a residual risk of HCV infection
(within the past 2 months) and high risk for infection ranging between 1.4 to 41 per 10,000 donors, based on
transmission. An analysis of data from the United Net- the window period of both enzyme-linked immuno-
work for Organ Sharing found that over a 2-year period sorbent assay (ELISA) and NAT.(11) The risk of
(2015-2016), 1.8% of all donors in the United States transmission expressed in ratio was lowest (1:7100) in
were HCV Ab-positive and NAT-negative, while 4.2% donors with percutaneous injury resulting in HCV
were both Ab-positive and NAT-positive.(6) exposure through blood and highest in intravenous
In contrast to HCV seropositive donors with active drug use donors (1:245). Of note, these risk estimates
viremia, undetectable HCV-RNA donors theoretically are derived not from organ donors, but from living
832 | REVIEW ARTICLELIVER TRANSPLANTATION, Vol. 24, No. 6, 2018 SELZNER AND BERENGUER
TABLE 1. Advantages and Disadvantages of Utilizing HCV-Positive Donors for HCV-Negative Recipients
Advantage Disadvantage
- Increase pool of currently available donors - 100% risk of transmission of HCV for recipients
- Decrease wait-time mortality for very sick recipients - High cost of DAA
(FHF, high MELD >30) - Limited access to DAA regimens
- Potentially younger donors without other comorbidities - Requirement for preapproval by drug companies or insurance companies*
- DAA regimens have a very high rate of cure - Possible interaction between DAA regimens and immunosuppression
- Similar longterm graft and patient outcome - Ethical/society barrier
than HCV-negative donors *only for countries where insurance companies cover the costs
persons in whom behavioral risk is known. The actual promises wider acceptance of HCV D1. Newer regi-
risk in deceased donors may in fact be lower and will mens have now demonstrated an almost complete clear-
depend on additional factors, such as likelihood of ance of virus including difficult-to-treat genotypes(3)
recent high-risk behavior and length of hospitalization especially for HCV naive patients, with few or no
before donation, with risk generally decreasing as dura- adverse effects.
tion of hospitalization increases. Nevertheless, PHS For treatment naive HCV genotype 1, 2, 3, 4, 5, and
guidelines have recommended NAT screening for 6 infection, a fixed-dose combination of 12 weeks of
HCV in addition to mandated serology for high-risk sofosbuvir (400 mg) and velpatasvir (100 mg) has been
donors both in the United States and Canada. In reported to have an overall sustained virologic response
donors with no identified risk factors, there is insuffi- (SVR) rate of 99% in the 624 patients included in
cient evidence to recommend routine NAT, as the ASTRAL I, II, and III studies.(13) Of the 328 genotype
benefits of NAT may not outweigh the disadvantages 1 patients included, 323 achieved SVR with no differ-
of NAT, especially when false-positive results can lead ence observed by HCV subtype (98% 1a and 99% 1b).
to loss of donor organs.(12) SVR rate for genotypes 2, 3, and 4 naive patients were
99%, 98%, and 100%, respectively in the above study.
A fixed dosage of elbasvir (50 mg) and grazoprevir
Should HCV D1 Be (100 mg) for 12 weeks was associated with a SVR rate
Offered for of 99% in a multicenter phase III study (C-EDGE trial)
enrolling over 131 patients infected with HCV genotype
Transplantation? 1b.(14) Similarly excellent SVR results have also been
reported for treatment of HCV genotype 1, naive
Thus far, the notion of D1, R- transplantation for patients with other combinations of DAA regimens
HCV has been deemed inconceivable due to accelerated such as ledipasvir/sofosbuvir. Several recent case reports
risk of HCV disease progression and cirrhosis develop- have reported on efficacy of these combinations for treat-
ment in some recipients and the failure of previous ment of donor-derived HCV infection in HCV-
HCV therapy regimens to fully control the virus. It was negative recipients including in cases of transmission
considered that patient’s graft function and survival from nonviremic donors.(9,15) Therefore, it is generally
could be significantly compromised by HCV infection accepted that HCV infection, even newly acquired in a
based on the above. With a wait-list mortality ranging previously negative recipient, is now curable in almost all
between 15% and 30% in some Western countries and instances, provided there is access to the new DAAs.
the increased efficacy and tolerability of new oral antivi- DAA regimens have also been successfully utilized
rals against HCV, the question arises whether transplant perioperatively for prevention of graft contamination by
communities should consider the utilization of HCV HCV. Levitsky et al. reported an 88% SVR rate follow-
D1 into HCV R- in order to decrease wait-list mortal- ing a 4-week course of combined ledipasvir–sofosbuvir
ity and increase the number of transplants (Table 1). in 16 HCV genotype 1 patients. These patients
received a single dose of ledipasvir (90 mg)–sofosbuvir
(400 mg) the day of transplantation and once daily for
Success Rate of New HCV 4 weeks postoperatively.(16) Although adverse events
Regimens were reported in 88% of the patients, no patients dis-
continued treatment due to adverse events, and no
The advent of DAAs has now paved the road for well- death or graft loss was reported in this study. Only 1
tolerated and efficacious treatment of HCV and patient with 3 nonstructural protein 5A (NS5A)
REVIEW ARTICLE | 833SELZNER AND BERENGUER LIVER TRANSPLANTATION, June 2018
resistance-associated substitution (RAS) at baseline had based regimens. Furthermore, in contrast to the viruses
a virological relapse. This patient had a response to an resistant to NS3-4A protease inhibitors, which disap-
additional 12 weeks of therapy, suggesting that baseline pear from peripheral blood in a few weeks to months,
resistance testing may help with guiding the length of NS5A inhibitor–resistant viruses persist for years and
treatment. Similar perioperative approaches may be may impair the results of retreatment. For these
considered in the future with the newer DAA regimens patients, retreatment options with the combination of
to prevent graft contamination when using HCV vire- multiple DAA or longer length of treatment are avail-
mic donors in HCV R-. able. As such, ASTS consensus conference recom-
Cholestatic hepatitis is a severe but rare (approximately mended that the potential for genotype conversion and
10%) form of HCV recurrence post-LT. This aggressive presence of RAS should be considered but not contrain-
form of disease recurrence usually results in rapid graft dicate the use of HCV-viremic donors.
loss. Treatment of cholestatic hepatitis remains challeng- Based on all of the above, at present, utilization of
ing, and the optimal antiviral therapy is yet to be deter- HCV D1 for R- can only be considered safely within
mined. Successful treatment with new oral DAA well-defined clinical studies with preapproval for HCV
regimens post-LT for cholestatic hepatitis has been anec- treatment immediately posttransplantation.
dotally reported. Currently, no cases of cholestatic hepati-
tis have yet been reported in the recipients of a HCV-
positive donor graft, but by analogy to the HCV-positive HCV D1 in Recipients of
recipients one may estimate a risk of 10% cholestatic hep-
atitis. This risk warrants NAT testing in recipients of
Nonhepatic Solid Organ
HCV-positive donors and initiating antiviral therapy Transplant
immediately following detection of HCV RNA.
Unfortunately, access to DAA regimens remains Utilizing HCV D1 grafts in negative recipients has
limited, expensive, and, in some countries, insurance only been reported in 1 series from the University of
companies refuse to cover the cost of treatment for this Pennsylvania.(20) This group recently reported their
indication. Of note, some of the new DAA regimens experience in 10 recipients who received kidneys from
including sofosbuvir/velpatasvir, elbasvir/grazoprevir, HCV1 genotype 1 donors as part of a single-center,
and glecaprevir/pibrentasvir have not yet been institutional-approved protocol. All recipients had
approved for use in post-LT in the United States. Fur- HCV-detectable RNA viral loads ranging from less
thermore, interaction between these drugs and immu- than 15 IU per milliliter (detectable but unquantifiable)
nosuppressive regimens is still a concern especially for to 193,000 IU per milliliter at day 3 posttransplantation
regimens that use protease inhibitors. However, recent and were treated with elbasvir/grazoprevir as per their
small clinical trials in the setting of liver and kidney protocol. All recipients achieved a 100% SVR at week
transplantation have shown the safety of some of these 12 posttreatment with acceptable graft function at 6
regimens without requirement for dose adjustment of months follow-up.(21) Similarly, Durand et al. (18)
baseline immunosuppression regimens.(17-19) Clearly, recently reported their experience in the use of HCV
larger prospective studies with newer pangenotypic D1 kidneys in HCV-negative recipients with preemp-
DAAs are required to assess the safety of these drugs. tive DAA treatment in a pilot trial. Eight donors with
Pertinent considerations regarding the donor and detectable HCV RNA were transplanted to respective
recipient virus are genotype and presence of RAS. HCV-negative recipients. All recipients received a sin-
While genotype 1 remains the predominant strain of gle dose of grazoprevir/elbasvir (GZR-EBR) pretrans-
virus in the United States, this pattern may change over plant and daily for 12 weeks posttransplant. Sofosbuvir
time, especially due to genotype changes within the was added when genotype 2 or 3 was identified in the
people who inject drugs (PWID) population. Finally, donor. Of the 8 recipients, 4 had detectable HCV RNA
despite an overall high rate of virological cure achieved on postoperative day 1 (POD1) but not at later time
with DAAs, HCV resistance to DAAs in some patients points while 4 recipients never had HCV RNA
results in failure of achieving SVR. The presence of viral detected. One recipient has completed GZR-EBR with
variants resistant to NS5A inhibitors at baseline is asso- no HCV RNA detected posttreatment. Although pre-
ciated with lower rates of virological cure in certain liminary, these pilot studies on transplantation of
groups of patients, such as those with genotype 1a or 3 HCV-positive kidney into HCV-negative recipients,
HCV, and prior nonresponders to pegylated interferon- within the frame of a well-defined protocol with access
834 | REVIEW ARTICLELIVER TRANSPLANTATION, Vol. 24, No. 6, 2018 SELZNER AND BERENGUER
to treatment, suggests that this is a potentially important Unfortunately, most studies evaluating fibrosis pro-
strategy to increase the donor pool associated with gression from HCV D1 lack protocol liver biopsies
excellent allograft function with a cure of HCV and were performed in an era where antiviral therapies
infection. were seldom successful. In a multicenter study of 99
recipients of HCV D1 grafts, the unadjusted 1-year
and 3-year rates of advanced fibrosis were significantly
HCV-Positive Donors in higher for recipients of HCV D1 grafts (14% and
Recipients of Liver Grafts 48%) versus HCV D- grafts (7% and 33%, P 5
0.01).(24) Similarly, in a small series of 29 HCV recipi-
In LT, no studies have yet been reported on the use of ents with matched biopsies, those who received grafts
HCV D1 grafts in HCV R-, and only a few anecdotal from HCV D1 had significantly more fibrosis over
cases are known worldwide, mostly within the setting the same period of follow-up indicating a faster rate of
of acute liver failure and for the purpose of life-saving progression compared with recipients of HCV D-.(25)
surgery. As the liver is the major reservoir of HCV and It is important to highlight that these studies are
the main site of HCV replication, transmission of the reports from an era when antiviral therapy was intro-
infection is almost 100% and the quality of HCV1 duced after the establishment of moderate fibrosis
grafts and the degree of fibrosis at time of transplanta- (often >stage 2) and the response rate to antiviral regi-
tion remain fundamental questions to address before men was low resulting in progression of fibrosis.
utilizing such grafts. Whether or not fibrosis progresses similarly in the set-
A recent report of 70 liver biopsies of HCV Ab1 ting of early administration of antiviral therapy post-
patients with undetectable HCV RNA showed that transplantation remains unclear. Future studies with
only 7% of patients had a normal liver compared with longer term follow-up should address this point.
92% with presence of inflammation and 82% with sig- Finally, longterm graft and patient survival with
nificant injuries including a fibrosis stage >2.(22) HCV1 organs remains controversial. Part of the con-
Immune-staining analysis of liver tissues from HCV troversies may be explained by the type and success
RNA negative patients showed expanded portal tracts, rate of HCV treatment regimens and whether or not
with significantly fewer CD41 and more CD81 cells patients received pegylated interferon and ribavirin
than in healthy controls similar to HCV RNA positive (PEG/Riba) as opposed to new DAA regimens. A
cases for these parameters. The authors speculated that European multicenter matched case-control analysis
the presence of a CD81 rich inflammatory infiltrate compared graft and patient survival between recipients
suggests an ongoing immune response in the liver of 63 HCV D1 matched with 63 HCV D-.(26) Of
despite clearance of HCV RNA. Similarly, although note, only grafts with a preperfusion liver biopsy show-
highly uncommon, occult HCV infection (OCI) ing a fibrosis stage not greater than 1 were used in this
defined as detectable HCV RNA in either liver tissue or study. In comparing overall patient and graft survival,
peripheral blood mononuclear cells (PBMC) despite there was no statistically significant difference between
repeatedly undetectable levels of HCV RNA in serum the 2 groups, but recurrence of HCV tended to be
has also been reported in patients who have spontane- more rapid in the group of patients who received
ously cleared the virus or achieved SVR. Recently, HCV1 grafts. Analyzing UNOS data on the use of
Elmasry et al. examined the occurrence of OCI in 5 out HCV D1, Cholankeril et al. reported a lower 1-year
of 129 HCV-positive liver transplant recipients who and 5-year posttransplant survival in HCV R-, com-
achieved SVR after therapy with DAAs but had persis- pared with the recipients transplanted with HCV D-
tently elevated transaminases.(23) HCV RNA was grafts or with HCV R1 transplanted with HCV D1
detected in these 5 patients either in the liver, PBMC, grafts.(27) The authors pointed out that almost half of
or both compartments. Although a relationship between the transplants with HCV D1 into negative recipients
residual HCV RNA and liver test abnormalities and/ or were performed in the last 2 years of the study period
histologic changes in some patients who achieve SVR is (2013-2014) with improved 1-year survival compared
still not well established, this report warrants larger clin- with HCV D-, raising the possibility that the donor
ical studies to assess the relevance of OCI posttrans- pool can be expanded in the future. Northup et al. had
plantation of HCV1 grafts and its clinical impact. also analyzed UNOS data of 19,496 HCV R1 of
Another concern with HCV1 liver grafts is the risk whom 934 received grafts from HCV D1.(28) The
of progression of fibrosis posttransplantation. hazard ratio for death was similar for HCV R1/HCV
REVIEW ARTICLE | 835SELZNER AND BERENGUER LIVER TRANSPLANTATION, June 2018
D- compared with HCV R1/HCV D1 donor (1.176 Assuming a prevalence of 30%-70% HCV-positivity
versus 1.165, P 5 0.91) in their study. In contrast, a among IDUs, this increase may be the reason of the
recent study of more than 30,000 HCV LT recipients, recent shift in the use of HCV D1 in the United
of which 1,900 received a graft from HCV D1, showed States.
that longterm mortality and graft loss were similar to Bowering et al. recently reported on a dramatic
those recipients transplanted with HCV D-.(29) Fur- increase in the use of the HCV D1 livers in HCV
thermore, short-term outcomes including being dis- R1. Using the Scientific Registry of Transplant
charged alive from the hospital, having a rejection Recipients, the authors identified 25,566 HCV R1
episode before discharge, and 1-year mortality, all from 2005 to 2015 and compared practices according
seemed to be lower in the recipients of a HCV1 graft, to the introduction of DAA therapies. The proportion
which the investigators attributed to overall lower of HCV R1 who received HCV1 livers increased
MELD score of the recipients of HCV D1 suggesting from 7% in 2010 to 17% in 2015. Compared with
a cautious use of HCV1 organs and careful selection of HCV- livers, HCV1 livers were 3 times more likely to
recipients of HCV D1. In contrast to the study by Bal- be discarded before 2010, compared with 1.7 times
larin et al., this study was limited by the lack of data on more likely after 2013.(32) A possible explanation for
viremia levels of both donors and recipients as well as the increase in utilization of HCV1 livers over recent
histological data of the grafts, which all may potentially years is a change in the HCV1 deceased donor popu-
contribute to posttransplant outcomes. lation. In their study, HCV1 liver donors used for
transplantation in the recent era were more likely to be
Estimates of the Potential younger and Caucasian, and less likely to have diabe-
tes, in contrast to what has been observed in the overall
Number of Organs from donor population over time.(33-35) Therefore, alongside
the improving quality of HCV D1, the declining
HCV1 Individuals quality of the overall donor pool may be an additional
driver of increasing physician confidence in accepting
Enthusiasm for HCV1 organ donation may depend
HCV1 livers. This unique shift among HCV1 liver
on the size of the potential organ pool. This pool con-
donors in the recent era may be related to the recent
sists of organs from donors who die of causes unrelated
rise in injection drug use overdose deaths and acute
to their HCV infection, but also of organs currently
HCV infections among young Caucasian individuals
being discarded due to false-positive serologic testing
for HCV in the donor. HCV infection is estimated to observed in the United States.(36,37)
In their analysis of the UNOS data from 2015-
affect 71 million people globally, which corresponds to
0.5%-1% of the total world population.(30) Based on 2016, Kling et al. reported a total of 280 actual
Organ Procurement and Transplantation Network liver donors with HCV Ab1NAT1. Using a propen-
(OPTN) data as of December 5, 2014, 4.4% of sity score-matched model, they estimated using
deceased donors with organs recovered for transplanta- Ab1NAT1 donors at the same rate as Ab-NAT-
tion in 2013 had a positive HCV Ab test. The preva- donors could result in 28 more livers per year.(6)
lence of HCV infection is even higher among injection
drug users (IDUs). The most recent surveys of active Tools for Assessment of
IDUs indicate that approximately one-third of young
(aged 18-30 years) IDUs are HCV1 compared with a HCV1 Grafts and Donor
higher prevalence of 70%-80% in older and former
IDUs. In the United States, since 2000, the rate of
Selection Prior to
deaths from drug overdoses has increased 137%,
including a 200% increase in the rate of overdose
Transplantation
deaths involving opioids (opioid pain relievers and her- Due to lack of consensus regarding selection of
oin).(31) As such, 1 out of every 11 organ donors in the HCV1 organs and easily available and reliable tools to
United States is someone who has died of a drug over- assess the grafts within the timeframe of allocation,
dose, according to recent government data. The num- many grafts are currently declined even in the new era
ber of drug users contributing to the organ pool has of highly effective DAA therapies. The evaluation of
increased by more than 50% over the last 5 years. HCV D1 requires a careful assessment of grafts for
836 | REVIEW ARTICLELIVER TRANSPLANTATION, Vol. 24, No. 6, 2018 SELZNER AND BERENGUER FIG. 1. Algorithm for use of HCV D1 grafts. the fibrosis stage. While grafts with advanced fibrosis Furthermore, more advanced fibrosis was observed in (stage 3-4) are evidently declined for transplantation, it HCV grafts from older donors (age >50 years) remains unclear whether grafts with moderate fibrosis compared with HCV grafts from younger donors (Stage 2) are acceptable or only grafts with stage 0-1 (
SELZNER AND BERENGUER LIVER TRANSPLANTATION, June 2018
has created an ethical imperative for transplant clini- to the consent for living donor LT is recommended.
cians to seek solutions for expanding transplant The discussion with the patient should be at the time
access. Increasing mortality of those individuals of listing and again at the time of offer. A standardized
whose health is worsening on the waiting list provides informed-consent process is recommended. Informed-
a strong rationale for the transplant community to consent processes should include explicit communica-
advocate for use of HCV viremic organs into nonvire- tion of the uncertainty about the HCV cure rate with
mic recipients. However, large clinical trials are posttransplantation treatment and the potential risks of
required to demonstrate that such practice is safe. In viral complications (Fig. 1).
the absence of guaranteed or delayed access to HCV
therapy, these organs should not be offered to non-
viremic recipients with lower MELD score. Recently Posttransplant Management
Chhatwal et al.(38) reported a modeling study to eval- and Surveillance
uate which HCV-negative patients (based on their
MELD score) would benefit from accepting an HCV No studies have yet assessed the surveillance and
viremic organ. They found that accepting any liver, optimal timing for treatment of liver transplant
regardless of HCV status, versus accepting only recipients with HCV D1. Recent ASTS consensus
HCV-negative livers resulted in an increase in life data on the use of HCV D1/NAT1 organs recom-
expectancy when MELD was 20, and the benefit mended development of clinical trials to assess the
was highest at MELD 28 (0.172 additional life- benefits of a perioperative treatment versus initiating
years). The clinical benefit was greater in UNOS therapy at first positive NAT testing in recipient
regions with higher HCV viremic donors, in other versus observation. Knowledge of donor genotype is
words, Region 1, 2, 3, 10, and 11. Further clinical important only if nonpangenotypic regimens are
studies based on such modeling studies are needed to considered for treatment post-LT. Testing for RAS
confirm the LT wait-list patients that may benefit prior to therapy should be considered before selec-
most from accepting HCV-positive donors. tion of the DAA regimen, although the clinical rel-
The potential to harm transplant recipients through evance is unclear.
HCV transmission nonetheless remains a fundamental In summary, given the scarcity of donated organs
concern. However, it is now recognized that organ and the frequency of death on the waiting list, strate-
transplantation is inherently associated with potential gies that could improve the available supply of high-
risks including surgical complications, posttransplant quality organs are much needed. DAA regimens have
immunosuppression, and mortality. With the increas- proved to be highly effective to treat HCV, even in the
ing wait-list mortality, the higher mortality rate for setting of posttransplantation and immunosuppressed
patients with high MELD (>35 score), and the poten- patients, and they facilitate the decision to broader
tial to cure HCV infection with a success rate of 97% acceptance of HCV D1. However, the potential to
or higher, it is conceivable to consider offering HCV induce an infection raises ethical concerns and requires
D1 to selected negative recipients where the risk- a rigorous process of obtaining informed consent from
benefit outweighs ethical considerations. However, in potential recipients.
addition to concerns regarding cost and coverage of
HCV regimens and the risk of resistance to treatment,
the universal application of offering D1 organs to R- REFERENCES
remains hindered by a number of concerns including 1) Pereira BJ, Wright TL, Schmid CH, Levey AS. A controlled
patients’ willingness to accept these organs. study of hepatitis C transmission by organ transplantation. The
Consistent with the ethical requirement to respect New England Organ Bank Hepatitis C Study Group. Lancet
1995;345:484-487.
autonomy, the consent process is critical to ensure that 2) Ellingson K, Seem D, Nowicki M, Strong DM, Kuehnert MJ.
patients’ decisions are informed and voluntary. Factors Estimated risk of human immunodeficiency virus and hepatitis C
to consider include the decision-making capacity of virus infection among potential organ donors from 17 organ pro-
curement organizations in the United States. Am J Transplant
the individual, comprehension of the risks, benefits
2011;11:1201-1208.
and alternatives, and the voluntary nature of the deci- 3) Levitsky J, Formica RN, Bloom RD, Charlton M, Curry M,
sion. A multistep consent process including informa- Friedewald J, et al. The American Society of Transplantation
tion, education, meeting with various health care consensus conference on the use of hepatitis C viremic donors in
providers, and enough time for decision making similar
838 | REVIEW ARTICLELIVER TRANSPLANTATION, Vol. 24, No. 6, 2018 SELZNER AND BERENGUER
solid organ transplantation. Am J Transplant 2017;17:2790- 20) Goldberg DS, Abt PL, Blumberg EA, Van Deerlin VM, Levine
2802. M, Reddy KR, et al. Trial of Transplantation of HCV-infected
4) Villano SA, Vlahov D, Nelson KE, Cohn S, Thomas DL. Per- kidneys into uninfected recipients. N Engl J Med 2017;376:
sistence of viremia and the importance of long-term follow-up 2394-2395.
after acute hepatitis C infection. Hepatology. 1999;29:908-914. 21) Sawinski D, Patel N, Appolo B, Bloom R. Use of HCV1
5) Micallef JM, Kaldor JM, Dore GJ. Spontaneous viral clearance donors does not affect hcv clearance with directly acting antiviral
following acute hepatitis C infection: a systematic review of lon- therapy but shortens the wait time to kidney transplantation.
gitudinal studies. J Viral Hep 2006;13:34-41. Transplantation 2017;101:968-973.
6) Kling CE, Perkins JD, Landis CS, Limaye AP, Sibulesky L. 22) Hoare M, Gelson WT, Rushbrook SM, Curran MD, Woodall
Utilization of organs from donors according to hepatitis C anti- T, Coleman N, et al. Histological changes in HCV antibody-
body and nucleic acid testing status: time for change. Am J positive, HCV RNA-negative subjects suggest persistent virus
Transplant 2017;17:2863-2868. infection. Hepatology 2008;48:1737-1745.
7) Grebely J, Prins M, Hellard M, Cox AL, Osburn WO, Lauer 23) Elmasry S, Wadhwa S, Bang BR, Cook L, Chopra S, Kanel G,
G, et al. Hepatitis C virus clearance, reinfection, and persistence, et al. Detection of occult hepatitis C virus infection in patients
with insights from studies of injecting drug users: towards a vac- who achieved a sustained virologic response to direct-acting anti-
cine. Lancet Infect Dis 2012;12:408-414. viral agents for recurrent infection after liver transplantation.
8) Suryaprasad A, Basavaraju SV, Hocevar SN, Theodoropoulos N, Gastroenterology 2017;152:550-553.e8.
Zuckerman RA, Hayden T, et al. Transmission of hepatitis C 24) Lai JC, O’Leary JG, Trotter JF, Verna EC, Brown RS, Jr.,
virus from organ donors despite nucleic acid test screening. Am J Stravitz RT, et al. Risk of advanced fibrosis with grafts from
Transplant 2015;15:1827-1835. hepatitis C antibody-positive donors: a multicenter cohort study.
9) Bari K, Luckett K, Kaiser T, Diwan T, Cuffy M, Schoech M, Liver Transpl 2012;18:532-538.
et al. Hepatitis C transmission from seropositive, nonviremic 25) Khapra AP, Agarwal K, Fiel MI, Kontorinis N, Hossain S,
donors to non-hepatitis C liver transplant recipients. Hepatology Emre S, et al. Impact of donor age on survival and fibrosis pro-
2018;67:1673-1682. gression in patients with hepatitis C undergoing liver transplan-
10) Kucirka LM, Sarathy H, Govindan P, Wolf JH, Ellison TA, tation using HCV1 allografts. Liver Transpl 2006;12:1496-
Hart LJ, et al. Risk of window period hepatitis-C infection in 1503.
high infectious risk donors: systematic review and meta-analysis. 26) Ballarin R, Cucchetti A, Spaggiari M, Montalti R, Di Benedetto
Am J Transplant 2011;11:1188-1200. F, Nadalin S, et al. Long-term follow-up and outcome of liver
11) CSTCNTRP increased risk donor working group. Guidance on transplantation from anti-hepatitis C virus-positive donors: a
the use of increased infectious risk donors for organ transplanta- European multicentric case-control study. Transplantation 2011;
tion. Transplantation. 2014;98:365-369. 91:1265-1272.
12) Humar A, Morris M, Blumberg E, Freeman R, Preiksaitis J, 27) Cholankeril G, Li AA, March KL, Yoo ER, Kim D, Snyder H,
Kiberd B, et al. Nucleic acid testing (NAT) of organ donors: is et al. Improved outcomes in HCV patients following liver trans-
the ‘best’ test the right test? A consensus conference report. Am plantation during the era of direct acting antiviral agents. Clin
J Transplant 2010;10:889-899. Gastroenterol Hepatol 2018;16:452-453.
13) Feld JJ, Jacobson IM, Hezode C, Asselah T, Ruane PJ, Gruener 28) Northup PG, Argo CK, Nguyen DT, McBride MA, Kumer SC,
N, et al. Sofosbuvir and velpatasvir for HCV genotype 1, 2, 4, 5, Schmitt TM, et al. Liver allografts from hepatitis C positive
and 6 infection. N Engl J Med 2015;373:2599-2607. donors can offer good outcomes in hepatitis C positive recipients:
14) Zeuzem S, Ghalib R, Reddy KR, Pockros PJ, Ben Ari Z, Zhao a US National Transplant Registry analysis. Transpl Int. 2010;
Y, et al. Grazoprevir-Elbasvir combination therapy for treatment- 23:1038-1044.
naive cirrhotic and noncirrhotic patients with chronic hepatitis C 29) Stepanova M, Sayiner M, de Avila L, Younoszai Z, Racila A,
virus genotype 1, 4, or 6 infection: a randomized trial. Annals Younossi ZM. Long-term outcomes of liver transplantation in
Intern Med 2015;163:1-13. patients with hepatitis C infection are not affected by HCV
15) Shah AP, Cameron A, Singh P, Frank AM, Fenkel JM. Suc- positivity of a donor. BMC Gastroenterol 2016;16:137.
cessful treatment of donor-derived hepatitis C viral infection in 30) World Health Organization. Hepatitis C. http://www.who.int/
three transplant recipients from a donor at increased risk for mediacentre/factsheets/fs164/en/ Accessed April 2018.
bloodborne pathogens. Transpl Infect Dis. 2017;19. doi: 31) Rudd RA, Aleshire N, Zibbell JE, Gladden RM. Increases
10.1111/tid.12660. in Drug and opioid overdose deaths--United States, 2000-
16) Levitsky J, Verna EC, O’Leary JG, Bzowej NH, Moonka DK, 2014. MMWR Morb Mortal Wkly Rep 2016;64:1378-
Hyland RH, et al. Perioperative ledipasvir-sofosbuvir for HCV 1382.
in liver-transplant recipients. N Engl J Med 2016;375:2106- 32) Bowring MG, Kucirka LM, Massie AB, Luo X, Cameron A,
2108. Sulkowski M, et al. Changes in utilization and discard of hepati-
17) Reau N, Kwo PY, Rhee S, Brown RS, Jr., Agarwal K, Angus P, tis C-infected donor livers in the recent era. Am J Transplant
et al. MAGELLAN-2: safety and efficacy of glecaprevir/pibren- 2017;17:519-527.
tasvir in liver or renal transplant adults with chronic hepatitis C 33) Kim WR, Lake JR, Smith JM, Skeans MA, Schladt DP,
genotype 1-6 infection. J Hepatology 66:S90-S91. Edwards EB, et al. Liver. Am J Transplant 2016;16 Suppl 2:69-
18) Durand C, Brown R, Wesson N, Bhair F, Naqvi D, Ostrander 98.
M, et al. EXPANDER-1: Exploring renal transplants using hep- 34) Saidi RF, Markmann JF, Jabbour N, Li Y, Shah SA, Cosimi
atitis C infected donors for HCV-negative recipients. Am J AB, et al. The faltering solid organ donor pool in the United
Transplant 2017;17:207. States (2001-2010). World J Surg 2012;36:2909-2913.
19) Pawlotsky JM. Hepatitis C virus resistance to direct-acting anti- 35) Diaz Jaime F, Berenguer M. Pushing the Donor Limits:
viral drugs in interferon-free regimens. Gastroenterology 2016; deceased donor liver transplantation using organs from octoge-
151:70-86. narian donors. Liver Transpl 2017;23:S22-S26.
REVIEW ARTICLE | 839SELZNER AND BERENGUER LIVER TRANSPLANTATION, June 2018
36) Suryaprasad AG, White JZ, Xu F, Eichler BA, Hamilton J, 2010 to 2012. MMWR Morb Mortal Wkly Rep 2014;63:849-
Patel A, et al. Emerging epidemic of hepatitis C virus infections 854.
among young nonurban persons who inject drugs in the United 38) Chhatwal J, Samur S, Bethea ED, Ayer T, Kanwal F, Hur C,
States, 2006-2012. Clin Infect Dis 2014;59:1411-1419. et al. Transplanting HCV-positive livers into HCV-negative
patients with preemptive antiviral treatment: A modeling study.
37) Rudd RA, Paulozzi LJ, Bauer MJ, Burleson RW, Carlson RE,
Hepatology 2017; doi: 10.1002/hep.29723. [Epub ahead of
Dao D, et al. Increases in heroin overdose deaths - 28 States,
print]
840 | REVIEW ARTICLEYou can also read
