Kidney transplant recipients with hepatitis C virus experienced 100% sustained virologic response at 12 weeks when treated with sofosbuvir–ledipasvir

Hepatitis C virus (HCV) infection affects 5%-15% of kidney transplant (KT) recipients and is associated with worse graft and patient survival. Until now, there has been no safe and effective way to treat HCV after KT because interferon-α, an integral part of all prior HCV regimens, caused an increased risk of organ rejection. Recently, because of the high rates of efficacy, lack of significant drug–drug interactions with immunosuppressive agents, and successful use in the liver transplant population, there has been tremendous interest in the use of sofosbuvir–ledipasvir in KT recipients. Results of a highly anticipated trial in HCV-infected KT recipients were recently published.1 Adult patients (n = 114) who received a KT more than 6 months prior to the baseline study visit were recruited from five European centers. The majority (75%) had genotype 1b, 16.5% had genotype 1a, and 8.5% had genotype 4 infection. Median age was 53 years (range 25-75), 94% were white, 58% were male, 15% had compensated cirrhosis, and 69% were treatment-naive. Baseline nonstructural protein 5A resistance-associated substitutions (15% cutoff) were present in 19%. Patients with human immunodeficiency virus or hepatitis B coinfection were excluded, and all patients had estimated glomerular filtration rate ≥40 mL/minute. Patients were randomized 1:1 to receive 12 weeks or 24 weeks of sofosbuvir–ledipasvir 400 mg/90 mg. All achieved sustained virologic response at 12 weeks after completion of therapy. The regimen was well tolerated. Adverse events experienced by ≥10% were similar to the general population taking sofosbuvir–ledipasvir: headache, weakness, and fatigue. Although 18% required adjustment in their immunosuppressant medications, there were no documented episodes of acute rejection. Two patients had grade 3 creatinine increases during treatment; one recovered by sustained virologic response at 12 weeks, while the other continued to progress to estimated glomerular filtration rate <15 mL/minute by the end of the follow-up period.

While this is the only prospective trial to evaluate a direct-acting antiviral (DAA) treatment of HCV in KT recipients, real-world experience with sofosbuvir-based regimens has also shown 92%-100% sustained virologic response at 12 weeks in retrospective series (Table 1). Taken together, these studies usher in a new era of HCV management in the KT recipient. Before this, HCV treatment after KT was relatively contraindicated due to the reliance on interferon-α, which led to increased risk of acute rejection. Additionally, interferon-α and ribavirin use in the posttransplant setting led to many side effects and limited efficacy. Ribavirin monotherapy is ineffective. Because of the inability to safely and effectively treat HCV after KT, the 2008 Kidney Disease Improving Global Outcomes guidelines recommended treating dialysis patients who were on the transplant waiting list in order to eradicate HCV prior to KT. However, despite these recommendations, because interferon-α and ribavirin are so poorly tolerated by dialysis patients, <5% of HCV-infected dialysis patients on the waitlist ever received treatment.2 Thus, the vast majority of KT recipients with HCV infection currently remain untreated.

HCV infection in a KT recipient is associated with higher rates of posttransplant rejection, opportunistic infections, new-onset diabetes mellitus, extrahepatic neoplasia, shorter graft survival, and increased mortality. However, the above risks were all determined prior to the DAA era. Colombo and colleagues have shown that eradication of HCV infection can be achieved in KT recipients with HCV infection without compromising graft function or leading to acute rejection.1 The study has some limitations; the lack of kidney biopsy data limits understanding of the two episodes of acute kidney injury. The study excluded patients with estimated glomerular filtration rate <40 mL/minute, so the optimal treatment of patients with advanced allograft dysfunction remains uncertain. Future studies will need to address the management of patients with genotypes 2, 3, 5, and 6 and determine the optimal timing of treatment after KT. Fundamentally, the most important question that remains is whether or not long-term outcomes in KT recipients with HCV who undergo DAA treatment posttransplant are improved. It will be important to know whether or not the known risks associated with HCV infection in the KT recipient are mitigated with early eradication of HCV and if graft and patient survival matches that of non-HCV-infected transplant recipients. This study gives us reason to be optimistic that we will have the answers to these important questions in the coming years.

Patients with HCV who undergo KT have improved survival compared to those who remain on the waitlist.3 In many parts of the United States, patients willing to accept a transplant from an HCV-infected donor can expect to shorten their wait time by a number of years. With the opioid epidemic ravaging the country, the number of HCV-infected donors is rising substantially and the age of these donors is decreasing. Despite this, many transplant centers across the nation do not accept kidneys from HCV-infected donors, and as a result, nearly 500 kidneys/year are discarded.4 In order to optimize organ use and shorten wait times, HCV-infected dialysis patients who are waiting for a deceased donor should be offered the opportunity to accept a transplant from an HCV-infected donor and be treated with DAAs posttransplant. The public draft of the updated Kidney Disease Improving Global Outcomes guidelines (expected publication late 2017), supports this approach to management.

Colombo et al. demonstrated that sofosbuvir–ledipasvir is safe and extremely effective at eradicating HCV in KT recipients with genotype 1 and 4 infection.1 The results of this trial will certainly impact the care of KT recipients with HCV infection and hopefully clear the way for increased use of HCV-positive kidneys for transplantation into HCV-infected dialysis patients.

Author names in bold designate shared co-first authorship.