Use of a hepatitis C virus (HCV) RNA‐positive donor in a treated HCV RNA‐negative liver transplant recipient

The shortage of livers has led most transplant centers to use extended criteria donors. Hepatitis C virus (HCV) RNA‐positive donor organs are typically not given to patients who have cleared HCV. A 64‐year‐old male with chronic hepatitis C, genotype 1b was listed for LT with hepatocellular carcinoma. While on the waiting list, the patient was treated with sofosbuvir, ledipasvir, and ribavirin and achieved an HCV RNA <15 IU/mL by week 10. At week 18 of a planned 24‐week treatment course, the patient underwent deceased‐donor LT and received an organ from an anti‐HCV‐positive donor. Treatment was stopped at LT. At week 3 post LT, HCV RNA was detectable and revealed a genotype 3 HCV infection, compatible with transplantation of an organ with established infection. With retreatment with sofosbuvir, daclatasvir, and ribavirin for 12 weeks, the patient achieved a sustained virologic response. This report highlights how antiviral therapies can be used to optimize the outcomes of HCV‐infected transplant patients.     

Use of HCV‐infected organs in solid organ transplantation: An ethical challenge but plausible option

Due to the unfortunate epidemic of opioid overdose deaths among people who inject drugs (PWID) in North America, there has been an increase in the availability of hepatitis C (HCV)‐positive organs for transplantation and consequently the potential to decrease waiting times for solid organ transplantation if an HCV‐uninfected recipient is willing to accept an HCV‐positive donor. The confidence in this potential new strategy comes as a result of the advent of safe and highly effective pan‐genotypic direct‐acting antivirals (DAAs). This promising strategy has been the most widely studied in kidney transplantation. Liver transplantation has positive results preliminarily, but has even less available data because viable HCV‐infected donor livers are typically transplanted into HCV‐infected individuals. Further, while HCV‐infected heart and lung transplantation, which face additional post‐transplant issues, have shown encouraging results, these studies are small scale and are limited by short‐term follow‐up. Thus, it would be premature to implement this strategy as standard of care without large scale clinical and real‐world trials and longer‐term follow‐up studies. Further, the ethics of this practice need to be considered. While some transplant professionals argue that more harm will be done by not utilizing HCV‐infected organs, others contend that cautiously conducted multi‐centre studies involving extensive post‐transplant follow‐up are paramount prior to endorsing widespread implementation of this strategy. The ethical permissibility of this practice hinges on whether access to DAA therapy can be secured in advance, and prospective recipients understand and accept all the risks associated with acquiring HCV.     

Transmission of viral hepatitis by kidney transplantation: donor evaluation and transplant policies (Part 1: hepatitis B virus)

Abstract: This two-part article discusses serologic testing of prospective donors for viral hepatitis B and C as part of the comprehensive donor evaluation and reviews of the current policies and practices aimed at preventing donor-to-recipient transmission of hepatitis B and C viruses (HBV, HBC). This second part of the review discusses HCV. Organs procured from HCV-infected donors can transmit the virus to their recipients. Because a number of studies have associated infections with HCV with increased morbidity and mortality among renal transplant recipients, it is important to prevent HCV transmission with renal transplantation. The majority of organ procurement organizations (OPOs) perform routine screening of organ donors for antibodies to HCV (anti-HCV). The prevalence of HCV infection among cadaver organ donors, ascertained based on a positive anti-HCV test by ELISA2, varies worldwide between 1.08% and 11.8%. The use of kidneys from donors negative for anti-HCV by ELISA2 carries negligible or no risk of transmitting HCV infection. The use of organs from anti-HCV-positive donors has been restricted to life-saving transplants (heart, liver or lung) by the majority of OPOs worldwide. However, discarding kidneys from all anti-HCV positive donors would lead to unnecessary waste of organs because not all anti-HCV positive donors are infectious. Recently, the policy of unconditional restriction on the use of kidneys from anti-HCV positive donors has been challenged, and transplantation of organs from anti-HCV-positive donors into anti-HCV-positive recipients has been found to be safe. An even better alternative might be a policy of transplanting kidneys from anti-HCV-positive donors only in HCV RNA-positive recipients. However, until more data become available, these two strategies remain experimental treatments.     

Hepatitis C genotype change after transplantation utilizing hepatitis C positive donor organs

A shortage in organs for transplantation has led to the increased use of hepatitis C (HCV) infected donor organs for solid organ transplant recipients infected with HCV. However, the donor HCV genotype is not routinely checked or known prior to transplant. Here, we report 4 cases of genotype conversion after transplantation in patients receiving HCV infected donor organs. This change in genotype may potentially impact HCV progression as well as treatment choice for these patients.     

Liver‐specific deceased donor risk indices

In order to assess the quality of the donor liver, procuring surgeons should accurately evaluate not only general donor risk indices, such as donor age, causes of brain death and cold ischemic time, but also consider the specific donor risk indices. In this review, we focus on liver‐specific deceased donor risk indices, including liver steatosis, anti‐hepatitis B core (HBc) positive or hepatitis C virus (HCV) positive donors, hypernatremia and anatomical variations. Liver steatosis is strongly associated with poor graft function after liver transplantation. Liver with more than 40–50% macrosteatosis should not be used. However, at present the quantity of fatty livers lack accepted standards. The computerized image analysis programs should be used to automate the determination of fat content in liver biopsy specimens. Liver grafts from anti‐HBc positive donors can be safely used, preferentially in hepatitis B surface antigen (HBsAg) positive or anti‐HBc/anti‐HBs positive recipients. HCV positive allografts free from fibrosis or severe inflammation are a safe option for HCV positive recipients. The procurement team should consider liver biopsy to evaluate these HCV positive allografts. Donor serum sodium over 150 mm may predict a higher rate of graft primary non‐functions. Recently, however, some investigators reported the sodium level likely has little clinical impact on post‐transplant liver function. The incidence of hepatic artery variations has been reported to be approximately 30%. To avoid injuries, it is very important to know and identify these variations with precision at the time of organ procurement.     

The deceased organ donor with an “open abdomen”: proceed with caution

In solid organ transplantation, the disparity between donor supply and patients awaiting transplant continues to increase. The organ shortage has led to relaxation of historic contraindications to organ donation. A large percentage of deceased organ donors have been subjected to traumatic injuries, which can often result in intervention that leads to abdominal packing and intensive care unit resuscitation. The donor with this “open abdomen” (OA) presents a situation in which the risk of organ utilization is difficult to quantify. There exists a concern for the potential of a higher risk for both bacterial and fungal infections, including multidrug‐resistant (MDR) pathogens because of the prevalence of antibiotic use and critical illness in this population. No recommendations have been established for utilization of organs from these OA donors, because data are limited. Herein, we report a case of a 21‐year‐old donor who had sustained a gunshot wound to his abdomen, resulting in a damage‐control laparotomy and abdominal packing. The donor subsequently suffered brain death, and the family consented to organ donation. A multiorgan procurement was performed with respective transplantation of the procured organs (heart, liver, and both kidneys) into 4 separate recipients. Peritoneal swab cultures performed at the time of organ recovery grew out MDR Pseudomonas aeruginosa on the day after procurement, subsequently followed by positive blood and sputum cultures as well. All 4 transplant recipients subsequently developed infections with MDR P. aeruginosa, which appeared to be donor‐derived with similar resistance patterns. Appropriate antibiotic coverage was initiated in all of the patients. Although 2 of the recipients died, mortality did not appear to be clearly associated with the donor‐derived infections. This case illustrates the potential infectious risk associated with organs from donors with an OA, and suggests that aggressive surveillance for occult infections should be pursued.     

Kidney transplantation from an HIV‐positive cadaveric donor

Kidney transplantation is the gold‐standard therapy for select HIV‐positive patients with ESRD. Since the Italian Ministry of Health defined the guidelines for organ donation from HIV‐positive persons in 2018, we report the first case of renal transplantation from an HIV‐positive cadaveric donor in two HIV‐positive recipients in Italy. The donor was a 50‐year‐old male, deceased due to post‐anoxic encephalopathy, with a history of HIV infection in HAART, undetectable viral load, and HCV‐related chronic hepatitis that had been previously treated. The first recipient was a 59‐year‐old female with a prior history of drug addiction, and she suffered from ESRD secondary to HIV nephropathy. The patient followed preoperative HAART with a good viral response and undetectable HIV viral load. She also had a history of HCV‐related chronic hepatitis that had been successfully treated. The right kidney was uneventfully transplanted. The patient developed an asymptomatic reinfection of endogenous BK virus. The second recipient was a 41‐year‐old male with ESRD secondary to polycystic kidney disease. The patient was HIV‐positive in HAART, with a good viro‐immunologic response and an undetectable HIV viral load. He suffered from a severe form of hemophilia A and HCV‐related chronic hepatitis, which had been previously treated with undetectable HCV RNA. The left kidney was uneventfully transplanted. At the end of follow‐up, both patients had a healthy condition with stable renal function, a persistently good viral response and undetectable HIV and HCV viral loads. These encouraging preliminary results seem to confirm the safety and effectiveness of kidney transplantation from select HIV‐positive donors.     

Hepatitis C: Current Controversies and Future Potential in Solid Organ Transplantation

Purpose of Review

To highlight the changing landscape of hepatitis C virus (HCV) infection in the context of organ transplantation. This focuses on areas of controversy and future potential in the era of highly effective direct-acting antiviral (DAA) agents.

Recent Findings

Since the advent of safe and highly effective DAA therapy, HCV infection is now curable in virtually all cases, including organ transplant recipients. Excellent drug tolerability and safety combined with high cure rates across all organ groups means that HCV is no longer a barrier to transplantation or its outcomes. Mounting data demonstrate the safety of using organs from HCV-infected donors with subsequent treatment of HCV in the recipient and a potential to expand the donor pool.

Summary

Historical data demonstrating inferior survival in transplant recipients with HCV is of limited relevance in the DAA era. Virtually all transplant recipients with HCV infection can be cured, while early data also suggest excellent outcomes in recipients of organs from HCV viremic donors. The optimal timing of HCV therapy in relation to transplantation and the optimal use of organs from HCV viremic donors remain areas of controversy and ongoing research efforts.

     

No increased mortality from donor or recipient hepatitis B‐ and/or hepatitis C‐positive serostatus after related‐donor allogeneic hematopoietic cell transplantation

Limited data exist on allogeneic transplant outcomes in recipients receiving hematopoietic cells from donors with prior or current hepatitis B (HBV) or C virus (HCV) infection (seropositive donors), or for recipients with prior or current HBV or HCV infection (seropositive recipients). Transplant outcomes are reported for 416 recipients from 121 centers, who received a human leukocyte antigen‐identical related‐donor allogeneic transplant for hematologic malignancies between 1995 and 2003. Of these, 33 seronegative recipients received grafts from seropositive donors and 128 recipients were seropositive. The remaining 256 patients served as controls. With comparable median follow‐up (cases, 5.9 years; controls, 6.7 years), the incidence of treatment‐related mortality, survival, graft‐versus‐host disease, and hepatic toxicity, appears similar in all cohorts. The frequencies of hepatic toxicities as well as causes of death between cases and controls were similar. Prior exposure to HBV or HCV in either the donor or the recipient should not be considered an absolute contraindication to transplant.     

Non‐response to daclatasvir and asunaprevir therapy in patients co‐infected with hepatitis C virus genotypes 1 and 2

Direct‐acting antiviral agents for hepatitis C virus (HCV) have been developed such as combined daclatasvir (DCV) and asunaprevir (ASV) treatment. This typically enables HCV serotype 1 patients to achieve a high sustained virological response rate, but a small number of such patients fail to respond to therapy. We investigated three HCV patients who showed no response to DCV and ASV therapy. Hepatitis C genotyping was undertaken in the three patients using nested polymerase chain reaction and polymerase chain reaction direct sequencing in the core region of the HCV genome. All three patients possessed HCV serotype 1, and no mutations were identified in either the non‐structural protein 3 or 5A region. The three patients were shown to be co‐infected with HCV genotypes 1 and 2 because genotypes 2a and 2b were also identified. This is the first report into failed response to DCV and ASV therapy in patients co‐infected with HCV genotypes 1 and 2.     

Donor‐transmitted malaria after heart transplant managed successfully with artesunate

Donor‐transmitted malaria is a rare complication in solid organ transplantation, which causes high mortality. Data concerning the use of artesunate in solid organ transplant recipients are lacking. We report a heart transplant patient who developed donor‐derived severe Plasmodium falciparum malaria, successfully treated with artesunate. Transmission of malaria to 2 of the other transplant recipients from the same donor was also documented.     

Outcomes of transplantation using organs from a donor infected with Klebsiella pneumoniae carbapenemase (KPC)‐producing K. pneumoniae

Transmission of pathogens from donor to recipient is a potential complication of organ transplantation. Herein, we describe the clinical course and outcomes of 4 transplant recipients who received tissues from a donor with multi‐organ infection with Klebsiella pneumoniae carbapenemase (KPC)‐producing K. pneumoniae. Recipient 1 underwent simultaneous liver and kidney transplantation for alpha‐1 antitrypsin deficiency and alcohol‐related cirrhosis, and acute tubular necrosis, respectively. Soon after transplantation, he developed an infected hematoma and peritonitis due to KPC‐producing K. pneumoniae despite receiving tigecycline prophylaxis. He was treated with a prolonged course of tigecycline, amikacin, and meropenem, in conjunction with surgical evacuation and percutaneous drainage of the infected fluid collections. Recipient 2 underwent living‐donor liver transplantation for cholangiocarcinoma and primary sclerosing cholangitis using vein graft from the donor infected with KPC‐producing K. pneumoniae. Culture of the preservation fluid containing the vein graft was positive for KPC‐producing K. pneumoniae. The patient received preemptive amikacin and tigecycline, and he did not develop any infection (as evidenced by negative surveillance blood cultures). The isolates from the donor and Recipients 1 and 2 were indistinguishable by pulsed‐field gel electrophoresis. Recipients 3 and 4 underwent kidney and heart transplantation, respectively; both patients received perioperative tigecycline prophylaxis and did not develop infections due to KPC‐producing K. pneumoniae. All transplant recipients had good short‐term outcomes. These cases highlight the importance of inter‐institutional communication and collaboration to ensure the successful management of recipients of organs from donors infected with multidrug‐resistant organisms.     

Utilization of increased risk for transmission of infectious disease donor organs in solid organ transplantation: Retrospective analysis of disease transmission and safety

The inadequate supply of transplantable organs necessitates new approaches to organ availability. Serologies and nucleic acid testing (NAT) for hepatitis C virus (HCV), hepatitis B virus (HBV), and human immunodeficiency virus (HIV) are used in microbiologic screening of potential organ donors. Organs from donors considered at “high risk” (Centers for Disease Control and Prevention, CDC 1994) or “increased risk” (U.S. Public Health Service, PHS 2013) for transmission of viral infection to recipients may provide an expanded source of organs for transplantation. We review a single‐center experience with 257 adult organ recipients of organs from donors meeting either CDC 1994 or PHS 2013 risk criteria between 2011 and 2016. Tracking these transplants required modification of the Transplant Center electronic database to identify all recipients of increased‐risk donor (IRD) organs, documentation of informed consent, and microbiologic testing data. No transmissions of HIV, HBV, or HCV were identified by NAT or clinically. Nine patients developed positive serologic assays for one of the tested viruses; all recipients were retested and remain negative by NAT. Notably, post‐transplant HBV core serologies reverted to negative on re‐testing; these positive serologies are likely false positives caused by receipt of blood products. Use of IRD organs can be performed safely with appropriate informed consent and rigorous pre‐ and post‐transplant microbiological testing.     

Successful treatment of donor‐derived hepatitis C viral infection in three transplant recipients from a donor at increased risk for bloodborne pathogens

We report here the successful treatment of hepatitis C virus (HCV) transmitted from a nucleic acid testing (NAT)‐negative donor to three HCV‐negative recipients—two renal transplants and one liver. Both renal recipients underwent standard deceased‐donor renal transplantation with immediate graft function. The liver recipient underwent standard orthotopic liver transplantation and recovered uneventfully. The donor was a 39‐year‐old woman with a terminal serum creatinine of 0.7 mg/dL. She was high risk for bloodborne pathogens, based upon a history of sexual contact with an HCV‐infected male partner. Recipient 1 was a 45‐year‐old man with a history of end‐stage renal disease from systemic lupus erythematosus. Recipient 2 was a 62‐year‐old woman with a history of end‐stage renal disease caused by hypertension and insulin‐dependent diabetes. Recipient 3 was a 42‐year‐old man with acute liver failure from acetaminophen ingestion. All recipients became HCV polymerase chain reaction positive on post‐transplant follow‐up. Both kidney recipients were treated with ledipasvir/sofosbuvir combination therapy for 12 weeks without side effects or rejection episodes. Recipient 3 was treated with ledipasvir/sofosbuvir in combination with ribavirin for 12 weeks without side effects. All patients achieved a sustained viral response at 12 weeks and are considered cured of HCV. The kidney recipients maintained good allograft function with a serum creatinine of 1.4 mg/dL and 1.0 mg/dL, respectively. Both renal recipients maintained normal liver function post treatment and did not develop any evidence of fibrosis. The liver recipient's liver function tests returned to normal without further incident. This case report provides evidence for the successful treatment of donor‐derived HCV in transplant recipients.     

Chronic viral hepatitis in kidney transplantation

Chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection in potential kidney transplant candidates-once considered absolute contraindications to kidney transplantation-no longer creates overt barriers to transplantation. Advances in the medical management of HBV and HCV infection have created opportunities for a substantial number of patients to be effectively treated with antiviral therapy before transplantation. For HBV infection, a number of new drugs enable clearance of the virus with minimal adverse effects and drug resistance. Pretransplantation antiviral therapy is advisable for patients with HCV infection, but adverse effects are common and viral eradication remains challenging. Regardless of viral clearance, pretransplant patients without bridging fibrosis (as confirmed by liver biopsy) or clinical stigmata of cirrhosis should be considered for kidney transplantation as survival is superior when compared to treatment with dialysis, and progression of liver disease is unlikely. For patients with advanced liver disease, simultaneous liver-kidney transplantation is an important consideration. These treatment advances further increase the burden of organ donor shortage; however, organs from deceased donors with chronic HBV or HCV infection could be efficiently allocated to certain individuals with a viral infection of the same type to increase the pool of available transplant organs.     

Aggressive Epstein‐Barr virus‐negative B‐cell post‐transplant lymphoproliferative disorder in a hepatitis C‐negative liver transplant recipient who received a hepatitis C‐positive graft: Implications for D+/R− hepatitis C virus seroconversion

Post‐transplant lymphoproliferative disorder (PTLD) is an uncommon, but well‐described complication after liver transplantation. Most recently, Hepatitis C virus (HCV) has been implicated in the development of PTLD. A HCV‐negative 62‐year‐old man with autoimmune hepatitis received a HCV nucleic acid amplification test‐positive liver graft from a 73‐year‐old brain‐dead donor (D+/R?). After his recovery from the operation, the patient was treated for HCV and achieved an undetectable viral load. He was readmitted 6 months after transplant with a spontaneous perisplenic hematoma, weight loss, failure to thrive, low‐grade fevers, and abnormal liver function tests. He had a rapid clinical deterioration and expired shortly after admission. His liver biopsy demonstrated EBV‐negative monomorphic B‐cell PTLD. Our case is the first to report an aggressive early‐onset EBV‐negative monomorphic B‐cell PTLD in a HCV D+/R? liver transplant. This case illustrates the paucity of knowledge on HCV seroconversion and its involvement in EBV‐negative monomorphic B‐cell PTLD development.     

Long‐term remission in an adult heart transplant recipient with advanced Burkitt’s lymphoma post‐transplant lymphoproliferative disorder after anthracycline‐free chemotherapy: A case report and literature review

Incidence of Burkitt's lymphoma post‐transplant lymphoproliferative disorder (BL‐PTLD) in solid organ transplant (SOT) recipients in 1.4%‐1.6% with unknown cure rate. We report a case of Epstein‐Barr virus (EBV) positive, late‐onset BL‐PTLD in a 24‐year‐old EBV donor positive/recipient negative female. This is the first reported case of advanced BL‐PTLD post‐heart transplant in an adult. This is also the first reported case of treatment of advanced BL‐PTLD in a heart transplant recipient with a combined chemotherapy regimen without anthracyclines to avoid cardiotoxicity. The patient received 6 cycles of R‐COEP (rituximab with cyclophosphamide, vincristine, etoposide, prednisone) over 6 months and subsequently 3 cycles of high‐dose methotrexate (MTX) over 3 months for CNS prophylaxis. She remains without evidence of disease at 19 months post‐treatment. This case demonstrates that an anthracycline‐free regimen can be the therapy option for patients with BL‐PTLD after heart transplantation.     

Clustering of end‐organ disease and earlier mortality in adults with sickle cell disease: A retrospective‐prospective cohort study

Chronic end‐organ complications result in morbidity and mortality in adults with sickle cell disease (SCD). In a retrospective‐prospective cohort of 150 adults with SCD who received standard care screening for pulmonary function abnormalities, cardiac disease, and renal assessment from January 2003 to 2016, we tested the hypothesis that clustering of end‐organ disease is common and multiple organ impairment predicts mortality. Any end‐organ disease occurred in 59.3% of individuals, and 24.0% developed multiple organ (>1) end‐organ disease. The number of end‐organs affected was associated with mortality (P ≤ .001); 8.2% (5 of 61) of individuals with no affected end‐organ, 9.4% (5 of 53) of those with 1 affected organ, 20.7% (6 of 29) of those with 2 affected end‐organs, and 85.7% (6 of 7) with 3 affected end‐organs died over a median follow up period of 8.7 (interquartile range 3.5‐11.4) years. Of the 22 individuals who died, 77.3% had evidence of any SCD‐related end‐organ impairment, and this was the primary or secondary cause of death in 45.0%. SCD‐related chronic impairment in multiple organs, and its association with mortality, highlights the need to understand the common mechanisms underlying chronic end‐organ damage in SCD, and the urgent need to develop interventions to prevent irreversible end‐organ complications in SCD.     

The use of virologically compromised organs in liver transplantation

The present organ donor crisis has led to accepted use of organs from donors infected with hepatitis C virus (HCV) and hepatitis B virus (HBV). Although capable of transmitting disease, these grafts offer opportunities to expand the donor pool for certain populations. Anti-HBc positive grafts can be used if care is taken to provide prophylaxis. Good quality grafts from HCV+ donors may be used in recipients who are themselves HCV+ with good outcomes.     

Pan‐genotypic treatment regimens for hepatitis C virus: Advantages and disadvantages in high‐ and low‐income regions

During the last 5 years, the availability of direct‐acting antiviral (DAA) agents has revolutionized the treatment of hepatitis C virus (HCV). Compared with interferon/ribavirin—the previous standard of care—DAA combination regimens offer improved sustained virological response (SVR) rates, shorter treatment durations of 8‐24 weeks, convenient once‐daily single‐tablet formulations and more favourable tolerability profiles. HCV treatment is complex, and the choice of therapy must consider a complex range of factors, including baseline viral load, fibrosis stage, the HCV genotype and subgenotype, and the presence of resistance‐associated substitutions at baseline. Globally, HCV genotype 1 predominates, and there are extensive data and various treatment options available for this genotype. Genotypes 2–6 are prevalent and may even predominate in different geographical regions, reflecting diverse factors including human migration patterns and unsafe use of injection drugs and blood products. Such factors are themselves influenced by socio‐economic factors, and poor regions often have the greatest unmet need for effective HCV therapies. The latest pan‐genotypic DAA combination regimens provide the potential to eradicate HCV around the globe, regardless of genotype, hence minimizing the need for virological testing services, which often are unavailable in poorer regions. Economics inevitably remain a barrier to access, and extensive cooperation will be required between clinical organisations and pharmaceutical manufacturers to agree appropriate pricing policies, especially in poorer economic regions. This review considers key data and treatment guidelines for DAA therapies, including pan‐genotypic combination regimens, in the context of regional differences in HCV genotype and socio‐economic factors.