Early emergence of anti‐HCV antibody implicates donor origin in recipients of an HCV‐infected organ

Hepatitis C virus (HCV) seroconversion among HCV‐uninfected transplant recipients from HCV‐infected (NAT+/Antibody+) or HCV‐exposed (NAT?/Antibody+) donors has been reported. However, the origin of anti‐HCV antibody and the implications of seroconversion remain unknown. We longitudinally tested plasma from HCV‐uninfected kidney (n = 31) or heart transplant recipients (n = 9) of an HCV NAT+ organ for anti‐HCV antibody (both IgG and IgM isotypes). Almost half of all participants had detectable anti‐HCV antibody at any point during follow‐up. The majority of antibody‐positive individuals became positive within 1‐3 days of transplantation, and 6 recipients had detectable antibody on the first day posttransplant. Notably, all anti‐HCV antibody was IgG, even in samples collected posttransplant day 1. Late seroconversion was uncommon (≈20%‐25% of antibody+ recipients). Early antibody persisted over 30 days in kidney recipients, whereas early antibody dropped below detection in 50% of heart recipients within 2 weeks after transplant. Anti‐HCV antibody is common in HCV‐uninfected recipients of an HCV NAT+ organ. The IgG isotype of this antibody and the kinetics of its appearance and durability suggest that anti‐HCV antibody is donor derived and is likely produced by a cellular source. Our data suggest that transfer of donor humoral immunity to a recipient may be much more common than previously appreciated.     

Long‐term outcomes and transmission rates in hepatitis C virus‐positive donor to hepatitis C virus‐negative kidney transplant recipients: Analysis of United States national data

The use of kidneys from hepatitis C virus (HCV)‐positive (D+) deceased donors for HCV‐negative recipients (R?) might increase the donor pool. We analyzed the national Organ Procurement and Transplant Network (OPTN) registry from 1994 to 2014 to compare the outcomes of HCV D+/R? (n = 421) to propensity‐matched HCV‐negative donor (D?)/R? kidney transplants, as well as with waitlisted patients who never received a transplant, in a 1:5 ratio (n = 2105, per matched group). Both 5‐year graft survival (44% vs 66%; P < .001) and patient survival (57% vs 79%; P < .001) were inferior for D+/R? group compared to D?/R?. Nevertheless, 5‐year patient survival from the time of wait listing was superior for D+/R? when compared to waitlisted controls (68% vs 43%; P < .001). Of the 126 D+/R? with available post‐transplant HCV testing, HCV seroconversion was confirmed in 62 (49%), likely donor‐derived. Five‐year outcomes were similar between D+/R? that seroconverted vs D+/R? that did not (n = 64). Our analysis shows inferior outcomes for D+/R? patients although detailed data on pretransplant risk factors was not available. Limited data suggest that HCV transmission occurred in half of HCV D+/R? patients, although this might not have been the primary factor contributing to the poor observed outcomes.     

Hepatitis C virus infection in end‐stage renal disease and kidney transplantation

Liver disease secondary to chronic hepatitis C virus (HCV) infection is an important cause of morbidity and mortality in patients with end‐stage renal disease (ESRD) on renal replacement therapy and after kidney transplantation (KT). Hemodialytic treatment (HD) for ESRD constitutes a risk factor for bloodborne infections because of prolonged vascular access and the potential for exposure to infected patients and contaminated equipment. Evaluation of HCV‐positive/ESRD and HCV‐positive/KT patients is warranted to determine the stage of disease and the appropriateness of antiviral therapy, despite such treatment is challenging especially due to tolerability issues. Antiviral treatment with interferon (IFN) is contraindicated after transplantation due to the risk of rejection, and therefore, treatment is recommended before KT. Newer treatment strategies of direct‐acting antiviral agents in combination are revolutionizing HCV therapy, as a result of encouraging outcomes streaming from recent studies which report increased sustained viral response, low or no resistance, and good safety profiles, including preservation of renal function. KT has been demonstrated to yield better outcomes with respect to remaining on HD although survival after KT is penalized by the presence of HCV infection with respect to HCV‐negative transplant recipients. Therefore, an appropriate, comprehensive, easily applicable set of clinical practice management guidelines is necessary in both ESRD and KT patients with HCV infection and HCV‐related liver disease.     

The impact of hepatitis C virus donor and recipient status on long-term kidney transplant outcomes: University of Wisconsin experience

Singh N, Neidlinger N, Djamali A, Leverson G, Voss B, Sollinger HW, Pirsch JD. The impact of hepatitis C virus donor and recipient status on long‐term kidney transplant outcomes: University of Wisconsin experience. Abstract: The survival benefit of transplanting hepatitis C (HCV)‐positive donor kidneys into HCV‐positive recipients remains uncertain. The purpose of this study was to assess the effect of HCV‐status of the donor (D) kidney on the long‐term outcomes in kidney transplant recipients (R). We evaluated 2169 consecutive recipients of deceased‐donor kidney transplants performed between 1991 and 2007. The following HCV cohorts were identified: D?/R? (n = 1897), D?/R+ (n = 59), D+/R? (n = 118), and D+/R+ (n = 95). Patients were followed for a mean of 6.02 (standard deviation = 4.26) yr. In a mulitvariable Cox‐proportional hazards model, D+/R+ cohort had significantly lower patient survival (adjusted‐hazard ratio [HR] 2.1, 95% CI [1.4–2.9]) with respect to the reference D?/R? group, whereas mortality was not increased in D?/R+ group. The rate of graft loss was increased in both D+/R+ and D?/R+ but was comparable with each other (adjusted‐HR 1.8, 95% CI [1.4–2.5]) vs. adjusted‐HR 2.0, 95% CI [1.4–2.8], respectively). D?/R+ cohort experienced significantly higher rate of rejection (adjusted‐HR 1.7, 95% CI [1.2–2.5]) and chronic allograft nephropathy (adjusted‐HR 2.1, 95% CI [1.2–3.7]). Neither donor nor recipient HCV‐status impacted the risk of recurrent or de novo GN. Transplanting HCV‐positive kidneys as opposed to HCV‐negative kidneys into HCV‐positive recipients provided similar graft survival but compromised patient survival in the long term.     

Process of selecting and educating HCV‐uninfected kidney waiting‐list candidates for HCV‐infected kidney transplantation

Long waiting times for kidney transplant (KT) and the high risk of mortality on dialysis have prompted investigation into strategies to utilize hepatitis C virus (HCV)‐infected organs to decrease discard rates of potentially viable kidneys. Due the opioid epidemic, the number of HCV‐infected donors has increased significantly. With the development of direct‐acting antiviral therapies for HCV infection, now more than 95% of patients who received treatment are cured. Experimental trials have used direct‐acting antiviral therapy to treat HCV infection in HCV‐uninfected transplant recipients of kidneys from HCV‐viremic donors. To date, HCV has been eradicated in all cases. Though these strategies will potentially increase the donor pool of available kidneys, shorten waitlist times, and ultimately decrease mortality in patients waiting for KT, identifying the ideal candidates and educating them about a protocol to utilize direct‐acting antiviral therapy to cure HCV after it is transmitted is essential. We present our approach to patient selection and education for a clinical trial in transplantation of HCV viremic kidneys into uninfected recipients.     

Hepatitis B and C virus infections transmitted through organ transplantation investigated by CDC,United States, 2014‐2017

We evaluated clinical outcomes among organ recipients with donor‐derived hepatitis B virus (HBV) or hepatitis C virus (HCV) infections investigated by CDC from 2014 to 2017 in the United States. We characterized new HBV infections in organ recipients if donors tested negative for total anti‐HBc, HBsAg and HBV DNA, and new recipient HCV infections if donors tested negative for anti‐HCV and HCV RNA. Donor risk behaviors were abstracted from next‐of‐kin interviews and medical records. During 2014‐2017, seven new recipient HBV infections associated with seven donors were identified; six (86%) recipients survived. At last follow‐up, all survivors had functioning grafts and five (83%) had started antiviral therapy. Twenty new recipient HCV infections associated with nine donors were identified; 19 (95%) recipients survived. At last follow‐up, 18 (95%) survivors had functioning grafts and 14 (74%) had started antiviral treatment. Combining donor next‐of kin interviews and medical records, 11/16 (69%) donors had evidence of injection drug use and all met Public Health Service increased risk donor (IRD) criteria. IRD designation led to early diagnosis of recipient infection, and prompt implementation of therapy, likely reducing the risk of graft failure, liver disease, and death.     

No evidence of occult hepatitis C virus (HCV) infection in serum of HCV antibody‐positive HCV RNA‐negative kidney‐transplant patients

Persistence of hepatitis C virus (HCV) in patients who cleared HCV is still debated. Occult HCV infection is described as the presence of detectable HCV RNA in liver or peripheral blood mononuclear cells (PBMCs) of patients with undetectable plasma HCV‐RNA by conventional PCR assays. We have assessed the persistence of HCV in 26 kidney‐transplant patients, followed up for 10.5 years (range 2–16), after HCV elimination while on hemodialysis. If HCV really did persist, arising out of the loss of immune control caused by institution of the regimen of immunosuppressive drugs after kidney transplantation, HCV reactivation would have taken place. Their immunosuppression relied on calcineurin inhibitors (100%), and/or steroids (62%), and/or antimetabolites (94%). An induction therapy, given to 22 patients, relied on rabbit antithymocyte globulin (59%) or anti‐IL2‐receptor blockers (32%). All patients had undetectable HCV RNA as ascertained by several conventional tests. At the last follow‐up, no residual HCV RNA was detected in the five liver biopsies, the 26 plasma, and in the 37 nonstimulated and 24 stimulated PBMCs tested with an ultrasensitive RT‐PCR assay (detection limit, 2 IU/ml). No biochemical or virologic relapse was seen during follow‐up. The absence of HCV relapse in formerly HCV‐infected immunocompromised patients suggests the complete eradication of HCV after its elimination while on dialysis.     

Outcomes of living donor liver transplantation for hepatitis C virus‐positive recipients in Japan: results of a nationwide survey

A nationwide survey of living donor liver transplantation (LDLT) for hepatitis C virus (HCV)‐positive recipients was performed in Japan. A total of 514 recipients are reported and included in the study. The cumulative patient survival rate at 5 and 10 years was 72% and 63%, respectively. Of the 514 recipients, 142 patients (28%) died until the end of the observation, among which the leading cause was recurrent hepatitis C (42 cases). According to Cox regression multivariate analysis, donor age (>40), non‐right liver graft, acute rejection episode, and absence of a sustained virologic response were independent prognostic factors. Of the 514 recipients, 361 underwent antiviral treatment mainly with pegylated‐interferon and ribavirin (preemptive treatment in 150 patients and treatment for confirmed recurrent hepatitis in 211). The dose reduction rate and discontinuation rate were 40% and 42%, respectively, with a sustained virologic response rate of 43%. In conclusion, patient survival of HCV‐positive recipients after LDLT was good, with a 10‐year survival of 63%. Right liver graft might be preferable for HCV‐positive recipients in an LDLT setting.     

Transplantation of hepatitis C virus (HCV) antibody positive,nucleic acid test negative donor kidneys to HCV negative patients frequently results in seroconversion but not HCV viremia

Anecdotal reports have suggested that transplantation of hepatitis C virus (HCV) antibody positive (Ab+)/nucleic acid test negative (NAT?) donor kidneys into HCV negative recipients is not associated with HCV transmission. We reviewed our center's outcomes of 32 HCV negative patients who received kidney allografts from 25 donors who were HCV Ab+/NAT?. The mean recipient age was 56.9 ± 12.1 years and the mean donor age was 41.5 ± 14 years, with a median Kidney Donor Profile Index (KDPI) of 68%. Twelve donors (48%) met Public Health Service (PHS) increased risk status. All patients received antithymocyte globulin induction followed by tacrolimus, mycophenolate mofetil, and steroid maintenance immunosuppression. With a mean follow‐up posttransplant of 10 ± 2.7 months, 1‐ and 3‐ month serum creatinine levels were 1.7 ± 0.8 and 1.3 ± 0.4, respectively, and patient and graft survival rates were 100% and 97%, respectively. Fourteen patients (44%) seroconverted and became HCV Ab+ posttransplant. However, all 32 patients were HCV RNA negative at 1‐ and 3‐ months posttransplant, and 27 and 8 patients tested at 6‐ and 12‐months posttransplant, respectively, remain HCV RNA negative. In conclusion, transplantation of HCV Ab+/NAT? kidneys to HCV negative recipients frequently causes HCV Ab seroconversion but not HCV viremia.     

Hepatitis C virus, an important risk factor for tuberculosis in immunocompromised: experience with kidney transplantation

Little is known about the role of hepatitis C virus (HCV) infection in the development of tuberculosis (TB) in patients with immunosuppression. We performed a retrospective case–control study (1:4) to investigate by univariate and multivariate logistic regression analysis the importance of HCV infection in the development of TB in a cohort of kidney transplant recipients (KTR). TB was diagnosed in 16 out of 2012 (0.8%) KTR between 1976 and 2004. The percentage of HCV-positive patients was significantly higher in cases than in controls (56.3% vs. 18.8%; P  = 0.02). By multivariate analysis, the only two independent risk factors associated with the development of TB were the presence of HCV infection ( P  = 0.003; OR = 6.5; 95% CI 1.9–23) and serum creatinine over 1.5 mg/dl ( P  = 0.03; OR = 4.8; 95% CI 1.1–21). HCV infection and chronic graft dysfunction are important risks factors for TB in KTR.     

Fibrosing cholestatic hepatitis after kidney transplantation from HCV‐viremic donors to HCV‐negative recipients: A unique complication in the DAA era

Fibrosing cholestatic hepatitis (FCH) posttransplantation can lead to graft failure and death. In the era of direct acting antiviral therapy (DAA), several studies have demonstrated the efficacy and safety of transplanting hepatitis C virus (HCV)–positive allografts into HCV‐negative recipients. In this case series, we present two cases of HCV‐negative recipients who underwent kidney transplantation from viremic donors and developed FCH. Both patients presented after transplant with abnormal liver function tests and HCV viral loads of greater than 100 000 000 IU/mL. FCH was diagnosed by histology and/or clinical data. Both patients were started on DAA therapy within 24 hours of admission with improvement in LFTs. One patient has undetectable HCV 12 weeks after completing treatment and the other patient has undetectable HCV after completing DAA treatment. The introduction of DAAs has changed the landscape of solid organ transplantation with the potential to expand the donor pool and increase access to organs. While HCV viremic organs have tremendous potential to increase access to a scarce resource, FCH is a potentially fatal complication and therefore clinicians must maintain a high index of suspicion for this unique complication.     

Efficacy and Safety of Sofosbuvir‐Based Antiviral Therapy to Treat Hepatitis C Virus Infection After Kidney Transplantation

There is no approved therapy for hepatitis C virus (HCV) infection after kidney transplantation, and no data regarding the use of new‐generation direct antiviral agents (DAAs) have been published so far. The aims of this pilot study were to assess the efficacy and safety of an interferon‐free sofosbuvir‐based regimen to treat chronic HCV infection in kidney transplant recipients. Twenty‐five kidney transplant recipients with chronic HCV infection were given, for 12 (n = 19) or 24 weeks (n = 6), sofosbuvir plus ribavirin (n = 3); sofosbuvir plus daclatasvir (n = 4); sofosbuvir plus simeprevir, with (n = 1) or without ribavirin (n = 6); sofosbuvir plus ledipasvir, with (n = 1) or without ribavirin (n = 9); and sofosbuvir plus pegylated‐interferon plus ribavirin (n = 1). A rapid virological response, defined by undetectable viremia at week 4 after starting DAA therapy, was observed in 22 of the 25 patients (88%). At the end of therapy, HCV RNA was undetectable in all patients. At 4 and 12 weeks after completing DAA therapy, all had a sustained virological response. The tolerance to anti‐HCV therapy was excellent and no adverse event was observed. A significant decrease in calcineurin inhibitor levels was observed after HCV clearance. New‐generation oral DAAs are efficient and safe to treat HCV infection after kidney transplantation.     

Liver,simultaneous liver-kidney,and kidney transplantation from hepatitis C-positive donors in hepatitis C-negative recipients: A single-center study

Transplantation of organs from hepatitis C virus (HCV)-antibody (Ab) and -nucleic acid test (NAT) positive donors into HCV-negative recipients has been proposed to expand the donor pool and shorten waiting times. Data on early single-center outcomes are lacking. Nineteen liver (LT, including seven simultaneous liver-kidney [SLKT]) and 17 kidney transplant (KT) recipients received organs from HCV (+) donors; of these, 13 were HCV NAT (+) in each group. All patients who received organs from HCV NAT (+) donors developed HCV viremia post-transplant except for 2 KT recipients. Patients were treated with a variety of direct-acting antiviral regimens, with high rates of sustained virologic response among those with at least 12 weeks of follow-up past the end of treatment: 12/13 (92%) and 8/8 (100%) among LT/SLKT, and KT recipients. Median time to treatment start was 42 days (interquartile range [IQR] 35-118 days) and 40 days (IQR 26-73) post-LT/SLKT and KT, respectively. One death occurred in a SLKT recipient unrelated to HCV or its treatment. There was no significant increase in rejection, proteinuria, or changes in immunosuppression in any group. Organs from HCV-viremic donors can be utilized for HCV-uninfected recipients with good short-term outcomes.     

Hepatitis C virus infection in renal transplant patients: a comparative study with immunocompetent patients

The behavior of hepatitis C in states of immunodeficiency is poorly understood and it is still unclear whether the characteristics of hepatitis C virus (HCV) infection in renal transplant patients differ from those observed in immunocompetent subjects. The aim of this study was to compare the biochemical and histologic characteristics of chronic HCV infection between renal transplant and immunocompetent patients. Forty-one HCV-RNA-positive renal transplant patients and 41 immunocompetent controls matched for gender, age at infection and time of infection were included in the study. The groups were compared regarding laboratory and histologic variables. Renal transplant patients showed lower alanine aminotransferase (ALT) levels (p = 0.005) and higher levels of gamma-glutamyltransferase (p = 0.003), alkaline phosphatase (p < 0.001), and direct bilirubin (p < 0.001) when compared with controls. Histologic analysis revealed less intense portal (p < 0.001) and periportal (p = 0.046) inflammatory infiltrate in renal transplant patients but a larger proportion of cases with confluent necrosis (p = 0.043). No difference in the presence of septal fibrosis, hepatic steatosis, bile duct injury and siderosis was observed. However, there was a difference in the presence of lymphoid aggregates, which were less frequent in the renal transplant group (p < 0.001). In conclusion, the characteristics of hepatitis C in renal transplant patients differ from that observed in immunocompetent patients. In renal transplant patients, HCV infection is biochemically characterized by lower ALT levels and higher frequency of cholestasis. Regarding histology, despite lower frequency of lymphoid aggregates and less intense portal/periportal inflammatory infiltrate, a greater lobular damage was observed. The impact of these differences on the progression of fibrosis remains to be established.     

Center‐level trends in utilization of HCV‐exposed donors for HCV‐uninfected kidney and liver transplant recipients in the United States

Several single‐center reports of using HCV‐viremic organs for HCV‐uninfected (HCV‐) recipients were recently published. We sought to characterize national utilization of HCV‐exposed donors for HCV‐ recipients (HCV D+/R?) in kidney transplantation (KT) and liver transplantation (LT). Using SRTR data (April 1, 2015‐December 2, 2018) and Gini coefficients, we studied center‐level clustering of 1193 HCV D+/R? KTs and LTs. HCV‐viremic (NAT+) D+/R? KTs increased from 1/month in 2015 to 22/month in 2018 (LTs: 0/month to 12/month). HCV‐aviremic (Ab+/NAT‐) D+/R? KTs increased from < 1/month in 2015 to 26/month in 2018 (LTs: <1/month to 8/month). HCV‐ recipients of viremic and aviremic kidneys spent a median (interquartile range [IQR]) of 0.7 (0.2‐1.6) and 1.6 (0.4‐3.5) years on the waitlist versus 1.8 (0.5‐4.0) among HCV D?/R?. HCV‐ recipients of viremic and aviremic livers had median (IQR) MELD scores of 24 (21‐30) and 25 (21‐32) at transplantation versus 29 (23‐36) among HCV D?/R?. 12 KT and 14 LT centers performed 81% and 76% of all viremic HCV D+/R? transplants; 11 KT and 13 LT centers performed 76% and 69% of all aviremic HCV D+/R? transplants. There have been marked increases in HCV D+/R? transplantation, although few centers are driving this practice; centers should continue to weigh the risks and benefits of HCV D+/R? transplantation.