Four-week direct-acting antiviral prophylaxis for kidney transplantation from hepatitis C-viremic donors to hepatitis C-negative recipients: An open-label non-randomized study

BACKGROUND

Kidneys from HCV-viremic deceased donors are increasingly available, yet 500–1000 are discarded annually due to limited HCV-viremic candidates(1). An innovative strategy of HCV positive-donor-to-negative-recipient (HCV D+/R−) kidney transplantation (KT) with direct-acting antivirals (DAAs) has shown early success, but the optimal timing and duration of DAAs remains unclear.

Our first trial of DAA prophylaxis (first dose pre-transplant followed by a post-transplant course), found 12-weeks prevented chronic HCV without complications in 10 recipients(2). Here we explored 4-week prophylaxis with the pan-genotypic combination glecaprevir 300mg/pibrentasvir 120mg (G/P) (REHANNA: Renal transplants in hepatitis C negative recipients with RNA positive donors; NCT03627299).

METHODS AND FINDINGS

In this single-center, open-label, non-randomized study approved by the Johns Hopkins Institutional Review Board, eligible candidates were HCV antibody and RNA negative, on the deceased-donor KT waitlist, without HIV, active hepatitis B, or liver disease. Eligible donors were 13–55 years old with a positive HCV nucleic acid test, creatinine <3.5mg/dL, and no chronic changes on renal biopsy.

Participants received one G/P dose prior to organ perfusion, then once-daily for 4 weeks. HCV RNA was measured post-operative day 1, 4, prophylaxis weeks 1, 2, 4, and post-prophylaxis follow-up weeks (FW) 1, 4, 8, 12 (Cobas^® 6800, Roche; lower limit of quantification (LLOQ) <15 international units (IU)/milliliter (mL)). Donor HCV genotype was determined with Sanger sequencing (3500 Series Genetic Analyzer, Applied Biosystems).

The primary efficacy endpoint was the proportion of recipients with HCV RNA <LLOQ at FW12. Regarding power, with 10 patients, if true efficacy was 79%, we would observe one failure >90% of the time. The primary safety endpoint was the proportion of recipients with treatment-related adverse events (AEs) ≥ grade 3 (National Cancer Institute’s Common Terminology Criteria for AEs v4).

From 10/2018–8/2019, 10 HCV D+/R− KTs were performed (Table 1). Median donor HCV RNA was 377,500 IU/mL (range 19 – 12,900,000 IU/mL); genotypes were 1a (n=6), 1b (n=1), 3 (n=2) and not determined (n=1) from insufficient RNA (Figure 1).

Table 1.

Recipient and Donor Characteristics

Characteristics
Recipients	N=10
Age at transplant, years, Med (range)	67 (40–75)
Female sex, No.	3
Race, No.
Caucasian	7
African American	2
Asian	1
Primary cause of renal failure, No.
Hypertension	4
Polycystic kidney disease	2
Glomerulonephritis	2
Nephrolithiasis	1
Reflux nephropathy	1
Blood Type, No.
O	4
A or AB	5
B	1
Hepatitis B core IgG positive	1
Time from waitlist to trial consent, days, Med (range)	81 (0–615)
Time from trial consent to transplant, days, Med (range)	24 (0–160)
Donors	N=10
Age at transplant, years, Med (range)	38.5 (20–45)
Female sex, No.	4
Race, No.
Caucasian	10
Cause of death, No.
Overdose	8
Trauma	1
Cerebrovascular accident	1
Body mass index, kg/m2, Med (range)	25.5 (20–35)
Hypertension, No.	2
Kidney donor profile indexa, Med (range)	60 (29–76)
Terminal creatinine, g/dL, Med (range)	0.77 (0.5–1.93)

^aKidney Donor Profile Index, scale 0–100%, higher values indicate greater predicted graft failure risk.

Figure 1. HCV RNA in HCV-viremic donors and HCV-negative recipients who received prophylaxis.

HCV plasma RNA log₁₀ in donors at organ recovery shown to the left of the dashed line and recipient HCV plasma RNA to the right on post-operative day (POD) 1 and 4, on prophylaxis weeks (PW) 1, 2, 4 and after prophylaxis on follow-up week (FW) 12. The lower limit of quantification (LLOQ) of the HCV RNA assay is 1.18 log₁₀ IU/mL. HCV RNA values <LLOQ target not detected are shown on the zero line and values <LLOQ target detected not quantifiable are halfway between zero and 1.18 log10 IU/mL, the LLOQ. Donor and recipient pairs share the same symbol. Color corresponds to HCV genotype (GT). Five recipients (1,4,5,7,10) had no virus detected at all post-transplant timepoints. Two recipients (2,3) had HCV RNA <LLOQ, target detected on POD 1 and 4 and no HCV detected at all later timepoints. Three recipients (6,8,9) had low-level viremia (range 34–161 IU/mL) in the first week post-transplant. Overall, the proportion of recipients with HCV RNA <LLOQ at FW12 after prophylaxis was 100% (95% confidence interval 69–100%).

Median post-transplant follow-up was 12 months (range 7.4–12 months) with no recipient deaths. HCV RNA was undetectable in all recipients after day 7 (Figure 1). There were no treatment-related AEs ≥ grade 3 and no transaminase or bilirubin ≥ 2.5 upper limit of normal at any timepoint. At FW12, median eGFR was 54.5 mL/min/1.73 m² (range 30–79). One graft failed (day 261) from venous thrombosis unrelated to HCV or G/P. There were no rejection episodes.

DISCUSSION

In all 10 HCV D+/R− KT recipients, 4-week G/P prophylaxis prevented HCV without treatment-related AEs or significant liver enzyme abnormalities.

EXPANDER, the first prophylaxis trial in 10 HCV D+/R− KT, showed 12 weeks of grazoprevir/elbasvir prophylaxis was effective(2); this approach was confirmed in another study of 8 HCV D+/R− KTs(3). In DONATE-HCV, 4 weeks of sofosbuvir/velpatasvir (SOF/VEL) post-exposure prophylaxis was successful in 44 HCV D+/R− thoracic transplants(4). In contrast to our approach, DAAs were started ≈6 hours post-transplant; most (42/44) recipients had viremia (median HCV RNA 1800 IU/mL) and rejection was more frequent than in HCV- donor recipients, suggesting there may be benefit to starting DAAs pre-transplant. Recently, the DaPPER trial studied ultrashort SOF/VEL prophylaxis: one dose pre-KT and 1–3 doses post-KT(5). Unfortunately, this failed with transmissions in 3/10 receiving 2-day prophylaxis and 3/40 receiving 4-day prophylaxis. Among 6 transmissions, 3 had DAA resistance and only 3 were cured with first-line DAAs. Based on this trial, 2–4 day prophylaxis cannot be recommended.

Transmit-and-treat is an alternative to prophylaxis, whereby recipient HCV viremia is confirmed post-KT, followed by a full course of DAAs. THINKER was the first transmit-and-treat trial including 10 HCV D+/R− KT recipients. DAAs were started day 3 post-KT with 100% cure(6). Transmit-and-treat is appealing since DAAs can be provided by insurance after recipient HCV infection is confirmed. However, in real-world series DAAs were started >60 days post-KT and complications including transaminitis, donor-specific antibodies, rejection, BK and CMV viremia, and fibrosing cholestatic hepatitis were reported(7–9). Prophylaxis might avoid this and offers shorter, less expensive therapy.

Due to small sample size our trial has limitations to generalizability and may not have identified rare risks such as emergence of resistance. However, it provides important proof-of-concept that HCV D+/R− kidney transplantation with 4-week DAA prophylaxis can prevent recipient HCV infection and shorten wait-times.