Three recent studies focused on the efficacy and safety of direct-acting antivirals (DAAs) in hepatitis C virus (HCV)-negative recipients of kidneys and livers from deceased HCV-viremic donors.
The first, the Multi-center Study to Transplant Hepatitis-C Infected Kidneys (MYTHIC) trial, was a prospective, open-label interventional study conducted at seven U.S. transplant centers. Researchers assessed 30 patients who underwent kidney transplantation from an HCV-viremic deceased donor (median kidney donor profile index, 53%) from May through October 2019. Transplantation was followed by eight weeks of once-daily coformulated glecaprevir and pibrentasvir, which was initiated within two to five days after transplant. Key outcomes were sustained virologic response (undetectable HCV RNA 12 weeks after completing antiviral treatment), adverse events, and allograft function. AbbVie, the manufacturer of glecaprevir/pibrentasvir, funded the study and provided the medication. Results were published online on Aug. 25 by the Journal of the American Society of Nephrology.
Overall, the median time between patient consent and transplantation of a kidney from an HCV-viremic donor was 6.3 weeks. All 30 recipients achieved a sustained virologic response. One recipient died of complications of sepsis four months after achieving a sustained virologic response. However, no severe adverse events in any patient were deemed likely to be related to HCV infection or treatment with glecaprevir/pibrentasvir. Three recipients developed acute cellular rejection, which was borderline in one case. Three recipients developed polyomavirus (BK) viremia near or greater than 10,000 copies/mL that resolved after reduction of immunosuppression. All recipients had good allograft function, with a median creatinine level of 1.2 mg/dL and a median estimated glomerular filtration rate (eGFR) of 57 mL/min/1.73 m2 at six months. The study was limited by its exclusion criteria (e.g., patients with evidence of chronic liver disease) and upper age limit of 65 years, the authors noted. “The MYTHIC study should encourage more transplant centers to develop formal programs with rigorous patient education and informed consent to support the increased utilization of HCV-infected donors,” they wrote.
The second study, the Renal Transplants in Hepatitis C Negative Recipients With RNA Positive Donors (REHANNA) trial, also looked at kidneys from deceased donors with HCV. Researchers at a single center again tested glecaprevir/pibrentasvir in HCV-negative kidney recipients, but as a four-week prophylactic regimen. Participants received one dose before organ perfusion, then one dose daily for four weeks. The primary efficacy end point was the proportion of recipients with an HCV RNA level below the lower limit of quantification (<15 IU/mL) at week 12 of follow-up. The primary safety end point was the proportion of recipients with grade 3 or higher treatment-related adverse events. Results were published online on Sept. 8 as a brief research report by Annals of Internal Medicine.
From October 2018 to August 2019, 10 HCV-negative participants received kidney transplants from HCV-positive donors. During a median post-transplant follow-up of 12 months, no recipients died. After day seven of follow-up, HCV RNA was undetectable in all recipients. No recipient had grade 3 or higher treatment-related adverse events or aminotransferase or bilirubin levels 2.5 times the upper limit of normal or more at any time point. At week 12 of follow-up, the median eGFR was 54.5 mL/min/1.73 m2 (range, 30 to 79 mL/min/1.73 m2). One graft failed at day 261 as the result of venous thrombosis unrelated to HCV or the study drug. No rejection episodes occurred. The trial's generalizability is limited due to its small sample size, the authors noted. “However, our study provides important proof of concept that HCV [donor positive, recipient negative] kidney transplantation with 4-week DAA prophylaxis may prevent recipient HCV infection and shorten wait times,” they concluded.
Finally, the Prevention of De Novo HCV with Antiviral HCV Therapy Post-Liver and Post-Kidney Transplant Recipients (PRO-ACT) study focused on both kidney and liver transplantation from HCV-viremic donors to HCV-uninfected recipients who received a different pre-emptive antiviral strategy. Six U.S. transplant programs prospectively treated organ recipients with sofosbuvir-velpatasvir for 12 weeks, starting once viremia was confirmed post-transplant and once the patient was judged to be clinically stable (including having an eGFR >30 mL/min/1.73 m2). The primary end points were sustained virologic response at 12 weeks post-transplant and safety, as assessed by the proportion of treatment-related adverse and serious adverse events. The study was supported by the drug manufacturer, Gilead Sciences, and results were published online on Sept. 14 by Hepatology.
Of 24 patients who received a transplant (liver, n=13 [including two with prior treated HCV infection]; kidney, n=11), 23 became viremic post-transplant. The median time from transplant to start of antiviral therapy was 7.0 in liver recipients and 16.5 days in kidney recipients. By week four of treatment, 10 of 13 (77%) liver transplant recipients but only two of 10 (20%) kidney transplant recipients had undetectable HCV RNA (P=0.01). At the end of treatment, all liver transplant recipients had undetectable HCV RNA, while three (30%) of the kidney recipients still had detectable, but not quantifiable, viremia. All participants achieved a sustained virologic response at 12 weeks. Serious adverse events considered possibly related to treatment were antibody-mediated rejection, biliary sclerosis, cardiomyopathy, and graft-versus-host-disease, with the latter associated with multiorgan failure, premature treatment discontinuation, and death. Limitations of the study included its modest sample size and variability in the start time of antiviral therapy, the authors noted. “The kinetics of viral infection differs in kidney versus liver recipients, with a delayed but higher HCV RNA peak in kidney recipients and a lower proportion achieving unquantifiable HCV RNA within 4 weeks of treatment,” they wrote. “This finding is relevant to strategies that are considering a shorter treatment duration for non-liver recipients.”
Of note, this month's Annals of Internal Medicine In the Clinic also focused on HCV, offering clinical information on transmission and prevention, screening, diagnosis and evaluation, treatment, and practice improvement and quality measures.