Impact of hepatitis C virus and direct acting antivirals on kidney recipients: a retrospective study

Hepatitis C virus (HCV) in kidney transplanted patients (KTx‐p) carries a high risk for a worse outcome. This retrospective study evaluates the impact of HCV and of the new direct acting antivirals (DAAs) on patient and graft outcomes in KTx patients. Forty (6.5%) of the 616 KTx‐p, who received a kidney transplantation (KTx) in our Centre had antibodies against HCV: 13 were positive for HCV RNA and received DAAs (Group A); 11 were HCV RNA positive and did not receive any treatment (Group B; n = 11); 16 were negative for HCV RNA (Group C). All Group A patients had HCV RNA negativity after 12 weeks of treatment, and 12 (92.30%) achieved a sustained virological response (SVR). Only two patients, who had proteinuria greater than 500 mg/day showed a worsening of proteinuria after antiviral therapy in Group A. Liver enzyme elevation and death were significantly more frequent in Group B than other groups. Our results support the notion that active HCV infection negatively affects kidney recipients and that DAA have a high safety and efficacy profile after KTx with no significant negative effect on allograft function, particularly in well‐functioning renal grafts.     

Use of direct‐acting agents for hepatitis C virus‐positive kidney transplant candidates and kidney transplant recipients

In some parts of the world, hepatitis C virus (HCV) infection remains a huge problem for kidney transplant candidates and kidney transplant (KT) recipients. Until 2 years ago, anti‐HCV treatment for the general population relied on pegylated alpha‐interferon plus ribavirin, but led to a sustained viral response (SVR) in <50% of cases. This treatment was contraindicated in KT patients because of acute‐rejection issues and was poorly tolerated in patients with end‐stage renal disease (ESRD). Over the last year, direct‐acting antiviral agents (DAAs) have entered the market and are associated in the general population with a SVR of >90%, whatever the patient's HCV genotype. In KT patients, sofosbuvir‐based therapy is associated with a SVR at nearly 100% in patients with a HCV genotype‐1 infection, with almost no side effects and only mild interference with immunosuppressive drugs. Most HCV(+) patients with ESRD are genotype 1: in that setting, a recent study reported that the association of grazoprevir/elbasvir 100/50 mg/day led to a SVR of nearly 95% with very few side effects. Thus, it is concluded that DAAs can be safely used and lead to results in KT candidates and KT patients that are as good as those observed in the nonrenal population.     

Transplantation of kidneys from hepatitis C‐positive donors into hepatitis C virus‐infected recipients followed by early initiation of direct acting antiviral therapy: a single‐center retrospective study

The availability of direct acting antiviral agents (DAA) has transformed the treatment of hepatitis C virus (HCV) infection. The current study is a case series that reports the outcomes from a cohort of twenty‐five HCV‐infected ESRD patients who received a kidney from an anti‐HCV‐positive deceased organ donor followed by treatment with DAAs in the early post‐transplant period. Time to transplantation and the efficacy of DAA therapy as measured by sustained viral response at 12 weeks were assessed. The median waiting time from original date of activation on the United Network Organ Sharing (UNOS) waiting list until transplantation was 427 days; however, the median time from entering the patient into UNet^sm for a HCV‐positive offer until transplantation was only 58 days. The 25 patients were started on antiviral treatment early post‐transplant (median 125 days) and 24 of 25 (96%) achieved a sustained virologic response at 12 weeks. Tacrolimus dose adjustments were required during antiviral treatment in 13 patients to maintain therapeutic levels. Accepting a kidney from an anti‐HCV‐positive deceased donor shortened the waiting time for HCV‐infected kidney transplant candidates. We recommend that kidneys from anti‐HCV‐positive donors should be considered for transplant into HCV‐infected recipients followed by early post‐transplant treatment with DAA agents.     

Direct‐acting antiviral regimens are safe and effective in the treatment of hepatitis C in simultaneous liver–kidney transplant recipients

Hepatitis C (HCV) remains the single most common etiology of end‐stage liver disease leading to simultaneous liver/kidney transplant (SLKT) and has worse post‐transplant survival compared to non‐HCV patients. We aim to assess the effectiveness and tolerance of the all‐oral direct‐acting antiviral (DAA) agents with or without ribavirin (RBV) in the treatment of HCV recurrence post‐SLKT. Thirty‐four patients were studied retrospectively, composed predominantly of treatment‐naïve (73.5%) non‐Caucasian (61.8%) males (82.4%) infected with genotype 1a (64.7%). 94.1% reached a sustained virologic response (SVR) after 24 weeks (32/34 patients), without difference between 12 and 24 weeks of therapy. 64.7% had no clinical side effects. Three deaths occurred, all unrelated to treatment. One patient had liver rejection; tacrolimus was increased and prednisone was initiated while HCV treatment was continued and the patient ultimately achieved SVR. No liver graft losses. No kidney rejection or losses. We demonstrated that DAA combinations with or without RBV result in a remarkable SVR rate and tolerated in the majority of the studied SLKT patients. It is safe to wait to treat until post–kidney transplant and therefore increase the donor pool for these patients. Our cohort is ethnically diverse, making our results generalizable.     

Cost‐effectiveness of hepatitis C–positive donor kidney transplantation for hepatitis C–negative recipients with concomitant direct‐acting antiviral therapy

Pilot studies suggest that transplanting hepatitis C virus (HCV)–positive donor (D+) kidneys into HCV‐negative renal transplant (RT) recipients (R?), then treating HCV with direct‐acting antivirals (DAA) is clinically feasible. To determine whether this is a cost‐effective approach, a decision tree model was developed to analyze costs and effectiveness over a 5‐year time frame between 2 choices: RT using a D+/R? strategy compared to continuing dialysis and waiting for a HCV‐negative donor (D?/R?). The strategy of accepting a HCV+ organ then treating HCV was slightly more effective and substantially less expensive and resulted in an expected 4.8 years of life (YOL) with a cost of ≈$138 000 compared to an expected 4.7 YOL with a cost of ≈$329 000 for the D?/R? strategy. The D+/R? strategy remained dominant after sensitivity analyses including the difference in RT death probabilities or acute rejection probabilities between using D+ vs D? kidney; time that D?/R? patients waited for RT; dialysis death probabilities while waitlisted for RT in the D?/R? strategy; DAA therapy expected cure rate; costs of transplant, immunosuppressives, DAA therapy, dialysis, or acute rejection. The D+/R? strategy followed by treatment with DAA is less costly and slightly more effective compared to the D?/R? strategy.     

Accepting hepatitis C virus–infected donor hearts for transplantation: Multistep consent,unrealized opportunity,and the Stanford experience

The current mismatch between supply and demand of organs has prompted transplant clinicians to consider innovative solutions to broaden the donor pool. Advancements of direct‐acting antiviral agent (DAA) therapy for hepatitis C virus (HCV) have allowed entertaining the use of viremic donor organs in nonviremic recipients. In this report, we describe the evolution of HCV treatment, ethics and informed consent, cost‐effectiveness of HCV medications in treating acute HCV post‐transplantation, and the Stanford experience with two HCV‐viremic donor heart transplantations. We describe excellent short‐term outcomes post–heart transplantation with HCV NAT‐positive organs. The availability of this therapy may expand the donor pool. While we await larger‐scale clinical data on the effectiveness and safety of DAA therapy in patients after heart transplantation, many transplant centers have already started accepting organs from HCV‐infected donors, balancing the unknown long‐term risks versus the benefits of shorter wait times and expansion of the donor pool. Protocols and multidisciplinary teams are needed to effectively communicate risk to potential recipients, to ensure timely DAA access, and to implement appropriate clinical follow‐up in order to achieve excellent clinical outcomes and to maximize the donor pool by utilizing HCV‐infected organs for heart transplantation.     

History of psychosis and mania,and outcomes after kidney transplantation ‐ a retrospective study

History of psychosis or mania, if uncontrolled, both represent relative contraindications for kidney transplantation. We examined 3680 US veterans who underwent kidney transplantation. The diagnosis of history of psychosis/mania was based on a validated algorithm. Measured confounders were used to create a propensity score‐matched cohort (n = 442). Associations between pretransplantation psychosis/mania and death with functioning graft, all‐cause death, graft loss, and rejection were examined in survival models and logistic regression models. Post‐transplant medication nonadherence was assessed using proportion of days covered (PDC) for tacrolimus and mycophenolic acid in both groups. The mean ± SD age of the cohort at baseline was 61 ± 11 years, 92% were male, and 66% and 27% of patients were white and African‐American, respectively. Compared to patients without history of psychosis/mania, patients with a history of psychosis/mania had similar risk of death with functioning graft [subhazard ratio (SHR) (95% confidence interval (CI)): 0.94(0.42–2.09)], all‐cause death [hazard ratio (95% CI): 1.04 (0.51–2.14)], graft loss [SHR (95% CI): 1.07 (0.45–2.57)], and rejection [odds ratio(95% CI): 1.23(0.60–2.53)]. Moreover, there was no difference in immunosuppressive drug PDC in patients with and without history of psychosis/mania (PDC: 76 ± 21% vs. 78 ± 19%, P = 0.529 for tacrolimus; PDC: 78 ± 17% vs. 79 ± 18%, P = 0.666 for mycophenolic acid). After careful selection, pretransplantation psychosis/mania is not associated with adverse outcomes in kidney transplant recipients.     

Steroid‐free living donor liver transplantation for HCV – a multicenter prospective cohort study in Japan

This prospective, non‐randomized, multicenter cohort study analyzed the safety and efficacy of a steroid‐free immunosuppressive (IS) protocol for hepatitis C virus (HCV)‐positive living donor liver transplant (LDLT) recipients in Japan. Of 68 patients enrolled from 13 transplant centers, 56 fulfilled the inclusion/exclusion criteria; 27 were assigned the steroid‐free IS protocol (Fr group) and 29 the traditional steroid‐containing IS protocol (St group). Serum HCV RNA levels increased over time and were higher in the St group until postoperative day 90 (POD 14, p = 0.013). Preemptive anti‐HCV therapy was started in a higher percentage of recipients (59.3%) in the Fr group than in the St group (31.0%, p = 0.031), mainly due to early HCV recurrence. The incidence of HCV recurrence at one yr was lower in the Fr group (22.2%) than in the St group (41.4%; p = 0.066). The incidence of acute cellular rejection was similar between groups. New onset diabetes after transplant, cytomegalovirus infection, and renal dysfunction were significantly less frequent in the Fr group than in the St group (p = 0.022, p < 0.0001, p = 0.012, respectively). The steroid‐free IS protocol safely reduced postoperative morbidity and effectively suppressed both the HCV viral load in the early post‐transplant period and HCV recurrence in HCV‐positive LDLT recipients.     

直接抗病毒药物抗丙型肝炎病毒治疗改善肝纤维化程度的疗效

目的探讨应用直接抗病毒药物（DAAs）成功清除丙型肝炎病毒（HCV）后慢性丙型肝炎（CHC）患者肝纤维化程度的改善。 方法共纳入111例经DAAs治疗后获得持续病毒学应答（SVR）的CHC患者,比较患者治疗前后白细胞（WBC）、红细胞（RBC）、血小板（PLT）、丙氨酸氨基转移酶（ALT）、天门冬氨酸氨基转移酶（AST）、总胆红素（TBil）、血尿素氮（BUN）、血肌酐（Cr）、肝硬度（LSM）、AST和血小板比率指数（APRI）和Fib-4评分（Fib-4 score）的变化;将患者按应用DAAs治疗前的诊断进行分组,其中慢性肝炎组77例,代偿期肝硬化组13例,失代偿期肝硬化组21例,比较各组患者DAAs治疗前后LSM、APRI和Fib-4评分的变化;采用Logistic二元回归分析性别、基因型、体重指数（BMI）、WBC、PLT、ALT、AST、TBil、APRI和Fib-4评分的基线值对LSM变化值的影响。 结果入组111例患者,WBC、PLT升高,ALT、AST和TBil降低,与治疗前差异均有统计学意义（Z =－3.842、P < 0.001,Z =－3.854、P < 0.001,Z =－8.919、P < 0.001,Z =－8.882、P < 0.001,Z =－4.487、P < 0.001）,而入组111例患者血肌酐（Cr）和血尿素氮（BUN）与治疗前差异均无统计学意义（Z =－0.287、P = 0.774,Z =－0.424、P = 0.671）。111例患者的3种无创肝纤维化指标,即LSM、APRI和Fib-4下降,与治疗前差异均有统计学意义（Z =－6.955、P < 0.001;Z =－8.836、P < 0.001;Z =－6.838、P < 0.001）,其中代偿期肝硬化组、失代偿期肝硬化组患者LSM、APRI和Fib-4下降幅度均较慢性肝炎组显著（LSM：χ² = 13.52、P < 0.001,χ² = 34.00、P < 0.001;APRI：χ² = 10.84、P < 0.001,χ² = 28.38、P < 0.001;Fib-4：χ² = 16.83、P < 0.001,χ² = 29.36、P < 0.001）。代偿期肝硬化组与失代偿期肝硬化组患者LSM、APRI和Fib-4下降幅度差异均无统计学意义（LSM：χ² = 1.08、P = 0.58,Fib-4：χ² = 0.84、P = 0.66,APRI：χ² = 0.09、P = 0.96）。较高ALT基线值[P = 0.045,OR（95%CI）= 0.918（0.844～0.998）]、AST [P = 0.013,OR（95%CI）= 0.862（0.767～0.969）]和APRI基线值[P = 0.032,OR（95%CI）= 0.001（0.000～0.555）]或较低WBC基线值[P = 0.019,OR（95%CI）= 2.508（1.161～5.421）]患者获得SVR后LSM得到显著改善。 结论成功清除CHC患者的HCV可使其肝纤维化显著改善,且肝硬化患者肝纤维化程度改善更为显著。对CHC患者应尽早启动抗病毒治疗,尽早实现SVR可阻滞CHC患者肝脏炎症及肝纤维化进展,从而减少肝硬化失代偿并发症的发生。     

Short‐term outcomes of deceased donor renal transplants of HCV uninfected recipients from HCV seropositive nonviremic donors and viremic donors in the era of direct‐acting antivirals

The United States opioid use epidemic over the past decade has coincided with an increase in hepatitis C virus  (HCV) positive donors. Using propensity score matching, and the Organ Procurement Transplant Network data files from January 2015 to June 2019, we analyzed the short‐term outcomes of adult deceased donor kidney transplants of HCV uninfected recipients with two distinct groups of HCV positive donors (HCV seropositive, nonviremic n = 352 and viremic n = 196) compared to those performed using HCV uninfected donors (n = 36 934). Compared to the reference group, the transplants performed using HCV seropositive, nonviremic and viremic donors experienced a lower proportion of delayed graft function (35.2 vs 18.9%; P < .001 [HCV seropositive, nonviremic donors] and 36.2 vs 16.8% ;  P < .001[HCV viremic donors]). The recipients of HCV viremic donors had better allograft function at 6 months posttransplant (eGFR [54.1 vs 68.3 mL/min/1.73 m2; P = .004]. Furthermore, there was no statistical difference in the overall graft failure risk at 12 months posttransplant by propensity score matched multivariable Cox proportional analysis (HR =  0.60, 95% CI  0.23 to  1.29 [HCV seropositive, nonviremic donors] and HR =  0.85, 95% CI 0.25 to  2.96 [HCV viremic donors]). Further studies are required to determine the long‐term outcomes of these transplants and address unanswered questions regarding the use of HCV viremic donors.     

Post‐transplant lymphoproliferative disorder following kidney transplantation: a population‐based cohort study

Post‐transplant lymphoproliferative disorder (PTLD) incidence is difficult to determine, mainly because both early and other lesions may go unrecognized and unregistered. Few studies have included systematic pathology review to maximize case identification and decide more accurately PTLD frequency after long‐term post‐transplantation follow‐up. A retrospective population‐based cohort study including all kidney transplant recipients at two Danish centres (1990–2011; population covered 3.1 million; 2175 transplantations in 1906 patients). Pathology reports were reviewed for all patient biopsies to identify possible PTLDs. Candidate PTLDs underwent histopathological review and classification. Seventy PTLD cases were identified in 2175 transplantations (3.2%). The incidence rate (IR) after first transplantation was 5.4 cases per 1000 patient‐years (95% CI: 4.0–7.3). Most PTLDs were monomorphic (58.5%), or early lesions (21.5%). Excluding early lesions and patients <18 years, IR was 3.7 (95% CI: 2.9–5.5). Ten patients with PTLD were retransplanted, 2 developing further PTLDs. Post‐transplant patient survival was inferior in patients with PTLD, while death‐censored graft survival was not. Using registry data together with extensive pathological review and long follow‐up, a rather high incidence of PTLD was found.     

The impact of direct‐acting antiviral agents on liver and kidney transplant costs and outcomes

Direct‐acting antiviral medications (DAAs) have revolutionized care for hepatitis C positive (HCV+) liver (LT) and kidney (KT) transplant recipients. Scientific Registry of Transplant Recipients registry data were integrated with national pharmaceutical claims (2007‐2016) to identify HCV treatments before January 2014 (pre‐DAA) and after (post‐DAA), stratified by donor (D) and recipient (R) serostatus and payer. Pre‐DAA, 18% of HCV+ LT recipients were treated within 3 years and without differences by donor serostatus or payer. Post‐DAA, only 6% of D‐/R+ recipients, 19.8% of D+/R+ recipients with public insurance, and 11.3% with private insurance were treated within 3 years (P < .0001). LT recipients treated for HCV pre‐DAA experienced higher rates of graft loss (adjusted hazard ratio [aHR] _1.341.85_2.10, P < .0001) and death (aHR _1.471.68_1.91, P < .0001). Post‐DAA, HCV treatment was not associated with death (aHR _0.340.67_1.32, P = .25) or graft failure (aHR _0.320.64_1.26, P = .20) in D+R+ LT recipients. Treatment increased in D+R+ KT recipients (5.5% pre‐DAA vs 12.9% post‐DAA), but did not differ by payer status. DAAs reduced the risk of death after D+/R+ KT by 57% (_0.190.43_0.95, P = .04) and graft loss by 46% (_0.270.54_1.07, P = .08). HCV treatment with DAAs appears to improve HCV+ LT and KT outcomes; however, access to these medications appears limited in both LT and KT recipients.     

Direct‐acting antivirals are effective and safe in HCV/HIV‐coinfected liver transplant recipients who experience recurrence of hepatitis C: A prospective nationwide cohort study

Direct‐acting antivirals have proved to be highly efficacious and safe in monoinfected liver transplant (LT) recipients who experience recurrence of hepatitis C virus (HCV) infection. However, there is a lack of data on effectiveness and tolerability of these regimens in HCV/HIV‐coinfected patients who experience recurrence of HCV infection after LT. In this prospective, multicenter cohort study, the outcomes of 47 HCV/HIV‐coinfected LT patients who received DAA therapy (with or without ribavirin [RBV]) were compared with those of a matched cohort of 148 HCV‐monoinfected LT recipients who received similar treatment. Baseline characteristics were similar in both groups. HCV/HIV‐coinfected patients had a median (IQR) CD4 T‐cell count of 366 (256‐467) cells/µL. HIV‐RNA was <50 copies/mL in 96% of patients. The DAA regimens administered were SOF + LDV ± RBV (34%), SOF + SMV ± RBV (31%), SOF + DCV ± RBV (27%), SMV + DCV ± RBV (5%), and 3D (3%), with no differences between the groups. Treatment was well tolerated in both groups. Rates of SVR (negative serum HCV‐RNA at 12 weeks after the end of treatment) were high and similar for coinfected and monoinfected patients (95% and 94%, respectively; P = .239). Albeit not significant, a trend toward lower SVR rates among patients with advanced fibrosis (P = .093) and genotype 4 (P = .088) was observed. In conclusion, interferon‐free regimens with DAAs for post‐LT recurrence of HCV infection in HIV‐infected individuals were highly effective and well tolerated, with results comparable to those of HCV‐monoinfected patients.     

DAA‐based antiviral treatment of patients with chronic hepatitis C in the pre‐ and postkidney transplantation setting

DAA‐based regimens for chronic hepatitis C infection encourage treatment of “difficult‐to‐treat” cohorts. This study investigated efficacy and safety of DAA‐based regimens in HCV patients on dialysis or postkidney or liver/kidney transplantation. Twenty‐five patients treated with DAA combinations were evaluated: 10 were on dialysis (eight: hemodialysis, two: peritoneal dialysis), eight were kidney transplant recipients, and seven were liver/kidney transplant recipients. Except for one patient treated with daclatasvir ([DCV]/60 mg/QD)/simeprevir ([SMV]/150 mg/QD), the others received sofosbuvir‐based regimens ([SOF];400 mg/QD) combined with SMV:eight, DCV:13 or either ledipasvir ([LDV]90 mg/QD), ribavirin ([RBV];weight based) or pegylated interferon/RBV. HCV‐RNA was determined by Abbott RealTime (LLOQ]:12 IU/ml) or Roche AmpliPrep/COBAS TaqMan assay (LLOQ:15 IU/ml); treatment response evaluated every 4 weeks, at the end of treatment, and 4 and 12 weeks thereafter. Twenty‐four (96%) patients achieved SVR 12/24 (ITT‐analysis). Mean treatment duration was 15.1 ± 5.1 weeks (±SD), and two patients terminated prematurely – both reached SVR12. Six patients were hospitalized due to complications of underlying disease. One patient achieved SVR24 but was re‐infected (week 27). Kidney function remained stable; serum creatinine increased in only one patient – SOF was reduced to 400 mg/48 h. Treatment with DAA combinations in renally impaired HCV patients is highly effective and well tolerated. These findings call for further controlled trials and data from real‐life cohorts.