Objectives: Kidneys from hepatitis C virus-positive donors were often discarded due to the lack of an effective treatment for hepatitis C virus. However, the advent of direct-acting antivirals has facilitated great progress for treatment of hepatitis C virus, providing additional opportunities for patients waiting for kidney transplant. We explored the feasibility and safety of kidney transplant from hepatitis C virus-positive donors to hepatitis C virus-negative recipients in combination with direct-acting antiviral therapy.
Materials and Methods: This was a single-center retrospective study of 7 recipients of hepatitis C virus-positive kidneys from June 2018 to June 2021. All recipients were treated with sofosbuvir/velpatasvir for 12 weeks after kidney transplant. The primary recipients’ outcome was achievement of sustained viral eradication at 12 weeks after treatment, and follow-up secondary outcomes were kidney function recovery, liver function, and adverse drug reactions. We reviewed previous studies, from 2017 to 2022, to analyze achievement of sustained viral eradication at 12 weeks after treatment, recipient and graft survival, and adverse event of kidney transplant from a hepatitis C virus-positive donor to a hepatitis C virus-negative recipient.
Results: Median follow-up time was 71 weeks (range, 56-183 weeks). All recipients achieved sustained viral eradication at 12 weeks after treatment, and their kidney function recovered without severe liver damage or adverse drug reactions. Previous studies suggested that transplant of hepatitis C virus-positive donor kidneys is safe and feasible when combined with direct-acting antiviral therapy. However, details regarding optimal duration of treatment and direct-acting antiviral regimen remain undetermined, so prospective randomized studies are warranted.
Conclusions: Our study further confirms that kidney transplant from hepatitis C virus-positive donors to hepatitis C virus-negative recipients is safe and feasible with direct-acting antiviral treatment. Grafts from hepatitis C virus-infected donors may be effective to resolve the problem of kidney shortage.

Key words : Direct-acting antiviral drugs, Graft shortage, Graft survival, Kidney transplantation, Patient survival

Introduction

Kidney transplant is the most effective treatment for patients with end-stage renal disease.^1,2 The latest data show that, since 2015, the total number of kidney transplant patients in the United States has been increasing, and there were 24 273 transplants in 2020,³ which leads to problems such as a shortage of kidney grafts and longer wait times for kidney transplants. Recent data show that, globally, an estimated 58 million people are chronically infected with hepatitis C virus (HCV), and approximately 290 000 people died from HCV in 2019.⁴ About 10 million people were infected with HCV in China.⁵ If HCV-infected patients could be used as extended criteria kidney donors, these problems should be effectively resolved. However, since the 1990s, numerous studies have shown that organ transplant can lead to the transmission of HCV, and liver disease caused by HCV infection is an important cause of death in kidney transplant recipients.^6-12

Before 2013, the treatment of HCV infection was based on interferon-α and ribavirin. However, ribavirin is nephrotoxic, so it cannot be used in patients with glomerular filtration rate less than 50 mL/min.¹³ In addition, in kidney transplant patients, interferon-α partly depends on the patient’s own immune system and interferon treatment may lead to acute rejection and is not suitable for HCV-infected patients after kidney transplant. Therefore, kidneys from HCV-positive donors were often discarded.^14,15 However, since 2013, direct-acting antivirals (DAA) that directly act on the replication mechanism of the virus have been developed and gradually optimized, which has facilitated significant progress in the treatment of kidney disease complicated with HCV infection. In the THINKER-1 clinical trial (Transplanting Hepatitis C Kidneys into Negative Kidney Recipients),^16,17 20 HCV-negative recipients received HCV-positive kidneys. Within 5 days after kidney transplant, HCV RNA was detected in all recipients (100%), so a 12-week regimen of elbasvir/grazoprevir was initiated for these patients. Eventually, all treated recipients achieved sustained viral eradication at 12 weeks after treatment (SVR12). Since then, there has been growing interest in kidney transplants from HCV-positive donors to HCV-negative recipients (HCV D+/R−). In this study, we also reviewed previous studies and retrospectively analyzed the safety and feasibility of HCV D+/R− kidney transplant when combine with DAA therapy.

Materials and Methods

Study population
From June 2018 to June 2021, there were 340 people who underwent kidney transplant at the Renmin Hospital of Wuhan University. Among them, recipients aged 18 to 60 years who had received HCV-positive donor kidneys were included in our study, and we excluded patients who met the exclusion criteria (exclusion criteria are shown in Figure 1). We defined HCV-positive status as positive for HCV core antigen (HCV-Ag) or detection of HCV RNA above the minimum detection limit.¹⁴ Fourteen recipients (4.11%) received HCV-positive donor kidneys. Seven of these 14 patients were excluded, 5 of whom showed HCV-positive test results and 2 others lacked follow-up data. A total of 7 HCV-negative recipients who received HCV-positive kidneys were eventually included in our study (Figure 1). All patients provided written informed consent for kidney transplant. This study was approved by the Ethics Committee of the Renmin Hospital of Wuhan University (No. WDRY2021-KS059).

Posttransplant treatment
All recipients received antithymocyte globulin or basiliximab/methylprednisolone immunosuppres-sion induction after surgery and were started on a triple immunosuppressive regimen consisting of tacrolimus/cyclosporine, mycophenolate mofetil, and prednisone. Dosages of each medication were performed according to drug instructions and clinical guidelines. We chose a pan-genotypic DAA regimen, and all recipients started antiviral treatment 1 week after transplant. The sofosbuvir/velpatasvir regimen (fixed-dose combination of sofosbuvir 400 mg and velpatasvir 100 mg) was given orally once each day, 1 tablet at a time.

Outcomes
We recorded baseline clinical data, including pretransplant and posttransplant kidney and liver functions (including serum creatinine [SCr], urea, alanine aminotransferase [ALT], and aspartate aminotransferase [AST]), hepatitis virus-related testing, and blood testing.

The primary outcome was achievement of SVR12. The levels of HCV antibody (anti-HCV), HCV-Ag, and HCV RNA were recorded at 4 weeks, 8 weeks, and 12 weeks after transplant; 12 weeks after DAA treatment; and at the end of the follow-up period.

Secondary outcomes were kidney function recovery, liver function, and adverse drug reactions (including clinical symptoms such as headache, fatigue, nausea, and vomiting) in recipients during follow-up. Kidney and liver functions were assessed by SCr, ALT, and AST at 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 8 weeks, and 12 weeks after transplant and at each visit during follow-up.

Statistical analyses
Statistical analyses were performed with the SPSS (version 25.0, IBM) and Prism (version 8.0, GraphPad) software packages. Results are expressed as mean values ± SD for normally distributed variables or as median values (with IQR) for nonnormally distributed variables, depending on data type, and count data are expressed as number of patients (with percent).

Results

Patient characteristics
The 7 recipients (5 male, 2 female) had an average age of 42.43 ± 13.16 years (range, 19-57 years). They were negative for HCV and hepatitis B virus, and their liver function was normal before the kidney transplant. The primary diseases related to renal failure included chronic glomerulonephritis (42.8%), immunoglobulin A nephropathy (28.6%), lupus nephritis (14.3%), and diabetic nephropathy (14.3%). Six recipients had received hemodialysis prior to kidney transplant, and their median duration of dialysis was 22 months (IQR 3.3, 76.0). Seven recipients received kidneys from 6 donors after circulatory death. Six donors were male, with an average age of 47.67 ± 10.17 years (range, 31-55 years). The pretransplant liver and kidney functions of the donors are shown in Table 1.

Hepatitis C virus infection
The 7 recipients had a median of 71 weeks (range, 56-183 weeks) of posttransplant follow-up. Anti-HCV positive was detected in 3 recipients (42.86%) at 4 weeks, 4 recipients (57.14%) at 12 weeks, and 6 recipients (85.71%) at the end of the follow-up period, after DAA treatment. The presence of HCV RNA was undetected (ie, below limits of quantification) in all recipients until the end of follow-up, and there were no DAA-related adverse drug reactions during the follow-up period.

Posttransplant kidney function
The renal function of all recipients is shown in Figure 2. Renal function recovered well in all but 1 recipient. At 12 weeks after kidney transplant, the mean SCr of the 7 recipients was 153.14 ± 46.10 μmol/L. One recipient developed delayed graft function (DGF, defined as at least 1 hemodialysis treatment within week 1 after surgery or SCr greater than 400 μmol/L on the postoperative day 7 without dialysis),^18,19 and SCr was 824 μmol/L on day 7 after transplant. Then, his kidney function gradually recovered, and SCr decreased to 139 μmol/L at 9 months after kidney transplant.

Posttransplant liver function
During the follow-up period, none of the recipients had any acute hepatitis clinical symptoms such as jaundice, fatigue, anorexia, nausea, and vomiting. At 12 weeks after kidney transplant, the 7 recipients showed the median ALT was 16 U/L (IQR 9, 22) and median AST was 17 U/L (IQR 13, 25). Two recipients had a transient elevation of ALT at 2 weeks and 8 weeks after transplant (peak 95 U/L, at week 2 after surgery), and ALT returned to the reference range 1 week later, with the AST levels within the reference range. Liver function results of all recipients within 12 weeks after kidney transplant are shown in Figure 3.

Posttransplant infection
One recipient (the same patient who developed DGF) presented with clinical symptoms such as fever and anuria in week 2 after kidney transplant, and the condition improved after anti-infective treatment. The blood culture results suggested Candida albicans infection. Cytomegalovirus DNA was detected at 3060 copies/mL (low detection limit of 500 copies/mL) at week 8 after kidney transplant in 1 recipient, which improved after antiviral treatment. Also, BK virus DNA (low detection limit of 5000 copies/mL) and Epstein-Barr virus DNA (low detection limit of 400 copies/mL) were not detected. For the other 6 recipients, BK virus DNA, EB virus DNA, and cytomegalovirus DNA were not detected.

Posttransplant blood test
During the follow-up period, the white blood cell (WBC) counts of recipients gradually decreased and eventually stabilized. Five of the 7 patients (71.43%) experienced leukopenia during the follow-up period (detected at least once), the lowest WBC count was 2.65 × 10⁹ cells/L, which appeared 4 months after transplant (leukopenia defined as WBC count <4.0 × 10⁹ cells/L). Hemoglobin and platelet levels of all recipients tended to be stable. Recipient blood cell results within 12 weeks after kidney transplant are shown in Figure 4.

Systemic review on hepatitis C-positive donors
To further evaluate the safety and feasibility of HCV D+/R− kidney transplant, we performed a systematic review of studies published from 2017 to 2022, as identified in the databases of PubMed, Embase, and the Cochrane Library. We collected a total of 14 clinical series, and these are listed in Table 2 in chronological order of the year of publication (comprises 8 pros-pective studies and 6 retrospective studies).^16,17,20-31

Discussion

In our center, 4.11% of recipients received kidneys from HCV-positive donors, indicating that HCV-positive donors account for a certain percentage that reduced the wait times for kidney transplant candidates. Were these events to have occurred before the advent of DAA, these kidneys would have been discarded.

In this single-center study, we had a median follow-up time of 71 weeks, and the longest follow-up was 3.5 years. No HCV RNA was detected in any recipient up to 12 weeks after treatment, all recipients achieved SVR12, and none developed chronic viral hepatitis C during the follow-up period. All recipients tested negative for anti-HCV before transplant, and 6 recipients were positive for anti-HCV during the follow-up period, which indicates that recipients had been infected with HCV but the virus had been eliminated.³² None of the 7 recipients had any DAA-related adverse drug reaction, which is consistent with the results of many studies mentioned in Table 2.

Direct-acting antiviral regimen
In our study, all recipients were treated with sofosbuvir/velpatasvir. In the study by Terrault and colleagues,²⁹ 10 recipients of HCV-positive kidneys were given the sofosbuvir/velpatasvir regimen, and all of them achieved SVR12. This result was consistent with our study. In the research published by Goldberg, Reese, Durand, and colleagues,^16,17,20 they used elbasvir/grazoprevir. In addition, most of the other studies used glecaprevir/pibrentasvir. The elbasvir/grazoprevir regimen is recommended for recipients of HCV genotypes 1, 1b, and 4, according to clinical guidelines (evidence grading A). Because glecaprevir/pibrentasvir is not eliminated through the kidneys, it is suitable for patients at any stage of kidney disease.³³ However, drug-drug interactions must be considered when using DAA, especially in posttransplant patients.

The elbasvir/grazoprevir regimen is known to affect the concentration of some drugs such as cyclosporin, statins, enalapril, rifampin, digoxin, some angiotensin-receptor blockers, and phenytoin.³⁴ Therefore, combined use of elbasvir/grazoprevir with such drugs is generally not recommended. Elbasvir/grazoprevir treatment increases levels of tacrolimus; thus, levels need to be closely monitored so that the drug dosage can be modified, if needed. Glecaprevir/pibrentasvir also interacts with calcineurin inhibitors, so the levels of calcineurin inhibitors need to be monitored and adjusted as needed during treatment and after the end of treatment.

Sofosbuvir, a polymerase inhibitor, is the basis of several DAA regimens. Sofosbuvir is mainly eliminated by the kidneys (80%) and was previously not recommended for patients with glomerular filtration rate <30 mL/min/1.73 m². However, recent studies have shown that sofosbuvir is well-tolerated and safe for patients with end-stage renal disease and for patients on hemodialysis.³³ Sofosbuvir/velpatasvir is pan-genotypic DAA treatment, so it is not necessary to test the patient’s HCV genotype before treatment. Sofosbuvir/velpatasvir treatment for HCV was approved by the National Medical Products Administration in China in 201835 and was added to China’s National Reimbursement Drug List in 2020.³⁶ Studies have concluded that sofosbuvir/velpatasvir treatment has no significant drug interactions with cyclosporine or tacrolimus.³⁴ The European Association for the Study of the Liver recommends that the treatment of hepatitis C with sofosbuvir/velpatasvir does not require adjustment of the dose of immunosuppressive agents and so has become the preferred choice after transplant.³³

The time to start direct-acting antiviral treatment
At present, the time to start DAA after transplant remains controversial. In our study, recipients started sofosbuvir/velpatasvir at 1 week after transplant. In studies from Kapila and colleagues and Molnar and colleagues, the median time to start DAA was extended to more than 2 months after transplant, and almost all recipients achieved SVR12.^21,22,31 In the THINKER-1 trial,^16,17 recipients started the DAA regimen after detection of HCV RNA, and 100% of the recipients achieved SVR12. In the EXPANDER trial (Exploring Renal Transplants Using Hepatitis C Infected Donors for HCV-Negative Recipients),²⁰ 10 recipients received DAA prophylactically at the preoperative stage, with 5 of them were positive for HCV RNA within 1 week after transplant, and all patients achieved SVR12. These results suggest that prophylactic use of DAA can reduce the rate of HCV transmission. However, in a prospective study, Gupta and colleagues²³ treated 50 recipients within 6 hours before surgery and on the first day of transplant (total 2 doses) and within 6 hours before surgery and daily for the first 3 days after surgery (total of 4 doses). Six of the 50 recipients were positive for HCV RNA (12%), and 4 achieved SVR12. Gupta and colleagues suggested that prophylactic regimens can reduce the rate of HCV transmission. In summary, prophylactic use of DAA can reduce HCV transmission, but the precise timing of the regimen remains uncertain and will require extensive prospective studies to determine.

Duration of direct-acting antiviral treatment
In our study, recipients received sofosbuvir/velpatasvir for 12 weeks, according to clinical guidelines.³⁷ The latest guidelines from the European Association for the Study of the Liver suggest that glecaprevir/pibrentasvir treatment duration should also be for 12 weeks (the same as for sofosbuvir/velpatasvir). Recently, however, studies have begun to investigate whether the shorter periods of DAA treatment can be effective. In the study by Durand and colleagues,²⁸ 10 recipients were given glecaprevir/pibrentasvir before organ perfusion and maintained for 4 weeks. All recipients acquired SVR12, and 1 recipient developed DGF (10%). In the MYTHIC trial (Multicenter Study To Transplant Hepatitis C-Infected Kidneys),²⁶ 30 HCV-positive donor kidneys were transplanted into HCV-negative recipients, and 8-week glecaprevir/pibrentasvir treatment was started 2 to 5 days after transplant. All of the 30 recipients achieved SVR12, but DGF occurred in 7 patients (23.3%) and acute rejection in 3 patients (10%). Therefore, whether the duration of DAA treatment can be shortened from 12 weeks to 8 weeks or less remains to be proved by further experiments.

Adverse events related to direct-acting antivirals
In our study, 1 recipient developed DGF, and we believe this was not caused by HCV but rather may be related to factors such as the patients’ autoim-munity status. Otherwise, the kidney function recovered well for the remaining 6 recipients. There were 2 recipients with transient elevation of ALT, but this elevation was absent on reexamination after 1 week. Also, AST levels were within the reference range. These details indicate that the elevation of ALT in patients was not associated with the HCV virus. Cytomegalovirus DNA was detected in 1 recipient at week 8 after kidney transplant, but this condition improved after antiviral treatment. We believe that this event was not related to HCV infection.

The WBC status of recipients fluctuated greatly after transplant, which may be related to factors such as recipient infection. In a study by Gupta and colleagues,²³ 5 of 6 HCV-infected recipients (83%) had significant posttransplant leukopenia. In our study, 5 of the 7 patients (71.43%) experienced leukopenia during the follow-up period. This proportion of leukopenia is higher than that reported in previous studies.^38-40 Leukopenia after kidney transplant can be caused by a single drug or a single factor, but this adverse effect can also be the result of the interaction of multiple drugs and multiple factors. Thus, it is possible that the high incidence of leukopenia is related to the transplant of HCV-positive donor kidneys, but there is no strong evidence, as yet.

In summary, our study complements previous studies and further confirms that HCV D+/R− kidney transplant is safe and effective when combined with DAA treatment. If HCV D+/R− kidney transplant were to be established as an expanded criteria option, then this should create a meaningful expansion of the donor pool and effectively solve the problem of kidney shortage. Prophylactic use of DAA is effective to reduce HCV transmission. Shortening the duration of DAA treatment would contribute to a reduction of the (1) financial expense and (2) adverse effects of a DAA regimen. However, the details of an optimum treatment regimen remain unclear; therefore, a large-sample, prospective study is needed. The results of our study suggest that a 12-week regimen of sofosbuvir/velpatasvir therapy is presently the best postoperative treatment option against post-transplant HCV infection for recipients of HCV D+/R− kidney transplants.

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