Can HCV Viremic Organs Be Used in Liver Transplantation to HCV Negative Recipients?
Department of Medicine, Greater Baltimore Medical Center, MD, USA
Division of Gastroenterology and Hepatology, Transplant Hepatology, Johns Hopkins University School of Medicine Baltimore, MD, USA
Division of Liver Diseases Icahn School of Medicine at Mount Sinai, New York, NY, USA
Academic Editor: Chung-Feng Huang
Special Issue: Unmet Need in the Management of Chronic Hepatitis C
Received: February 02, 2020 | Accepted: April 21, 2020 | Published: April 24, 2020
OBM Hepatology and Gastroenterology 2020, Volume 4, Issue 2, doi:10.21926/obm.hg.2002046
Recommended citation: Muhammad H, Hammami MB, Ting PS, Simsek C, Saberi B, Gurakar A. Can HCV Viremic Organs Be Used in Liver Transplantation to HCV Negative Recipients? OBM Hepatology and Gastroenterology 2020;4(2):8; doi:10.21926/obm.hg.2002046.
© 2020 by the authors. This is an open access article distributed under the conditions of the Creative Commons by Attribution License, which permits unrestricted use, distribution, and reproduction in any medium or format, provided the original work is correctly cited.
Hepatitis C virus (HCV) infection is a major cause of liver cirrhosis and hepatocellular carcinoma and can eventually lead to the need of liver transplantation (LT) , which is considered the only curative and lifesaving option. The median wait time in the United States for an LT is 11.3 months; consequently, mortality while on the waitlist is remarkably high . Due to recent surge in opioid use which correlates with intravenous drug abuse, there has been a rise in HCV seropositive donors. Sustained virologic response (SVR) is achieved when HCV ribonucleic acid (RNA) is no longer detectable 12 weeks after completion of treatment and highly correlates with decreased liver-related morbidity and mortality [3,4]. Historically, HCV recurrence following liver transplant is almost universal, resulting in cirrhosis, graft loss, and re-transplantation. A subset of patient may develop fibrosing cholestatic hepatitis that may progress to rapid graft failure with high mortality . Newer drugs that act on the steps involved in viral replication have led to the availability of several oral HCV treatment regimens [6,7]
In the interferon (IFN) era, viral eradication led to improved clinical and histological outcomes (reduction in portal pressure, regression of fibrosis, and resolution of clinical decompensations in cirrhotic patients [8,9] .However, IFN based therapies correlated with decreased rate of SVR and an increased rate of treatment termination due to adverse events . Fortunately, the introduction of direct‐acting antivirals (DAAs) has completely changed treatment of HCV infection. Randomized control trials and real‐life cohort studies based on HCV‐mono-infected LT recipients have shown positive results in terms of efficacy and safety .
Table 1 Terminology used for Hepatitis C virus (HCV) infection status .
2. HCV Positive Liver Donors
The U.S. opioid epidemic continues to increase, and deaths from opioid misuse increased threefold between 1999 and 2014. Out of 47,055 deaths caused by excess drug use in 2014 in the United States, 28,647 (60.9%) attributed to opioid use. As per the CDC, between 2014 and 2015, the number of natural/semisynthetic opioid deaths increased in males and the age range of deaths in males and females was reported between 25 and 44 years. In 2015, death rates with newer opioids were highest in males aged between 25 and 44 years (8.9 / 100,000), rising 102.3% from 2014 to 2015 . In all common use of opioids has led to a tremendous rise in drug overdose deaths .
Goldberg et al reviewed data from the Organ Procurement and Transplantation Network (OPTN) of all deceased donors who donated minimum of 1 organ between January 1, 2003, and December 31, 2014. When comparing the causes of death in these donors, they found out those who lost their life due to drug misuse were majority Caucasian (86.3% vs. 56.3–72.3% compared to other five categories).They were also younger (median age: 31; p < 0.001) when compared to donors who expired from cardiovascular causes (median: 47) and stroke (median: 52). These characteristics correlates with the general pattern of population who were not deceased due to drug misuse. The impact of the drug overdose epidemic on organ donation was most evident in the field of liver transplantation. From 2003 to 2014, the absolute number of deceased-donor LT increased by 1000; nearly 40% of the rise was contributed to by patients who died of drug misuse (103 in 2003 vs. 490 in 2014).  Thus, there was a rise in the number of donor organs which were younger, however majority of them were not transplanted due to concern of disease transmission including HCV, HIV and HBV. The predicted prevalence of HCV among donors is 8.5% with a potential of 4% of donors who are NAT positive at the time of transplantation  Study done by Durand et al reported that prevalence of HCV infection increased from 7.8% in 2000 to 30.0% in 2017 in donor organs who died of drug overdose .Bari et al published a prospective study where HCV positive/NAT negative livers were transplanted to HCV negative recipients (n= 25) resulting in 16%(n=4) HCV transmission to recipients at 11 months follow up. Upon further evaluation it was reported that all donors to these recipients died of opioid overdose .
Reinfection of HCV post LT is common, however, the natural pattern of hepatitis C on the liver allograft varies. Natural history of recurrent Hepatitis C is accelerated, with 20% to 40% progressing to cirrhosis within 5 years  HCV reinfection strongly correlated with morbidity and mortality in the interferon era.  Peg interferon and Ribavirin used for post-transplant HCV recurrence were linked with major adverse effects in addition to low SVR rates.  However, with introduction of DAA treatment, the recipients may now be treated with less adverse outcomes. SVR with the current DAA is 95-98% . The use of DAA led to threefold increase in LT from HCV positive to HCV negative recipients between 2015 and 2016 . Therefore, HCV positive livers which have been discarded in high volumes until now, may be used with high success rate, with the DAA agents.
3. Liver Transplantation from HCV Viremic Donor
The number of patients needing LT is rising steadily, whereas the donor pool is stationary. Due to opioid surge, majority of the patients infected with HCV are younger and candidates for liver donation. Therefore, keeping in view the critical shortage there has been an inclination to use less favorable grafts such as HCV positive grafts. As per United Network for Organ Sharing (UNOS) database the organ donor group between 2015 and 2016 was comprised of 93.8% antibody negative and NAT negative (Ab− NAT−), 0.15% antibody negative and NAT positive, 1.8% antibody positive and NAT negative (Ab+ NAT−), 4.2% antibody and NAT positive (Ab+ NAT+) . Therefore, if we include more donors with Ab+, NAT + in the donor pool it will reduce wait time mortality.
Large study done by Northup et al on 934 HCV positive donors suggested that HCV positive liver donors do not increase the mortality risk in HCV positive recipients when compared to HCV negative liver donors . With the introduction of DAAs, there has been improvement in liver transplant outcomes due to increased sustained virologic response (SVR) and less adverse effects.
Ting et al published a retrospective study consisting of 26 hepatitis C seronegative recipients who received hepatitis C seropositive donor livers followed by preemptive antiviral therapy with DAA treatment, defined as initiation of DAA (median 5.3 weeks after LT), after the first positive HCV NAT in LT recipient. All 12 recipients who completed their DAA courses and reached sufficient follow-up for SVR achieved SVR. Out of the 12 recipients who achieved SVR, 1 received Ledipasvir/Sofosbuvir for 12 weeks, 1 received Sofosbuvir/Velpatasvir for 8 days followed by Ledipasvir/Sofosbuvir for 23 weeks and 10 recipients were treated with Glecaprevir/Pibrentasvir for 12 weeks.  Wijarnpreecha et al presented a preliminary data of 22 HCV-seronegative LT recipients who received grafts from HCV-seropositive donors (12 NAT positive, 9 NAT negative). DAA was initiated at a median of 28 days (range 6-67) post LT, resulting in undetectable HCV-RNA in all patients by week 8. However, in this ongoing study recipients of NAT positive livers developed acute membranous nephropathy (n=1), biopsy proven acute cellular rejection (n=4) and intraoperative death (n=1). 
Chhatwal et al published a paper which was a virtual trial formulated using Markov-based mathematical model, using data from the United Network for Organ Sharing (UNOS). It showed that transplanting liver irrespective of their HCV status when compared to only transplanting HCV negative liver resulted in increase in life span, when MELD >20 and highest when MELD 28. 
Bethea et al used the same Markov-based mathematical model and reported that it is cost effective if recipients with MELD ≥ 22 receive any livers rather than waiting for only HCV negative livers  Regional variations on the MELD score for accepting HCV positive grafts for transplantation in HCV negative liver recipients have been reported. 
Recent publication from Cotter, et al have suggested the usage of Hepatitis C viremic organs among patients with and without Hepatitis C, after reviewing Scientific Registry of Transplant Recipients database. They reported 87 HCV RNA positive donor being used among Hepatitis C negative recipients, with 2-year graft survival being similar in all groups. 
In order to prevent complications in the graft, i.e. fibrosing cholestatic hepatitis, initiation of DAA should be considered as soon as possible in post LT phase. In the United States, approval of DAA by insurance companies may be time consuming, but treatment is usually started within 4 weeks of transplant.
Though there has been a shift towards transplanting HCV viremic organs, there is still a need for long term data before a final consensus is reached. As per literature it seems that for now HCV NAT positive LT should be considered in a subset of patients such as those with acute liver failure in whom the timing of LT is sensitive, patients with hepatocellular carcinoma where there is a chance of dropout and patients with low MELD but with serious complications from portal hypertension, where their native MELD does not reflect the degree of their illness. Whether preemptive treatment with DAA after LT is sufficient or DAA treatment at the time of transplant would lead to better outcomes, remains to be determined.
Haris Muhammad: Literature search, writing of the manuscript, final editing.
Muhammad Baraa Hammami: Editing, Literature search.
Peng-Sheng Ting: Critical review.
Cem Simsek: Critical Review, editing.
Behnam Saberi: Critical Review.
Ahmet Gurakar: Supervision, final editing.
The authors authors have declared that no competing interests exist.
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