The success of direct-acting antivirals (DAA) against hepatitis C virus (HCV) was a major breakthrough in medicine. Many studies showed that DAA are safe and effective for chronic HCV infection treatment after kidney transplantation.1 In 2018 KDIGO updated the Guidelines on chronic HCV in chronic kidney disease (CKD) including the recommendation that all infected kidney transplant recipients (KTR) should be evaluated for treatment.2

About KTR treated in our kidney transplantation unit3 we would like to report two fatal cases.

The first was a 71-year-old male with IgA nephropathy with prior HCV infection (genotype 1b), who underwent kidney transplantation in 1991. In 2016 hepatic fibrosis (fibroscan F3) was documented and HCV treatment with ledipasvir/sofosbuvir was prescribed reaching sustained viral response (SVR) at 12 weeks. One year after therapy, elevation of alpha-fetoprotein (AFP) from 2.9 to 10.9ng/ml (reference value <8.8ng/ml) was noticed, despite undetectable HCV viral load. Hepatic ultrasound found no abnormalities but computed tomography showed extensive hepatic nodular involvement and partial portal vein thrombosis, suggestive of hepatocellular carcinoma (HCC). The patient died four months after HCC diagnosis, before treatment with sorafenib was started.

The second patient was a 72-year-old female with CKD due to chronic pyelonephritis who underwent renal transplantation in 2003. She had prior chronic HCV infection (genotype 1a) and had documented hepatic cirrhosis (fibroscan F4). Treatment with sofosbuvir/ledipasvir/ribavirin was given 13 years after transplantation, reaching SVR at 24 weeks. Eleven months later, AFP increased (7.2–2864ng/ml). Despite normal hepatic ultrasound, magnetic resonance imaging showed a nodular lesion compatible with HCC. The lesion was successfully embolized. Ten months later, bone metastasis was evident as she suffered a fracture on her left hip. Bone biopsy confirmed metastatic HCC. Although HCV viral load remained undetectable, the patient died 14 months after the diagnosis.

Even after HCV eradication by DAA, the risk of progression to HCC remains a threat. As illustrated in these two cases, the suspicion was raised by an increasingly AFP despite an unsuspected ultrasound.

In patients with chronic HCV infection and cirrhosis, the risk of developing HCC remains uncertain. However this risk is significantly reduced compared to untreated patients or in the ones who did not achieve SVR.4 The European Association for the Study of the Liver recommends that patients with advanced fibrosis or cirrhosis with SVR should undergo surveillance for HCC every 6 months by means of ultrasound.5 However, in these two KTR cases, ultrasound was ineffective for detection of HCC, which occurred less than one year after apparently successful DAA therapy.

The purpose of reporting these two cases is fourfold: (1) to alert for the need to fully evaluate patients who display an increase of AFP levels; (2) ultrasound may not be a sensitive method to HCC diagnosis; (3) to raise the possibility that immunosuppression may eventually increase the oncogenic potential of previous HCV infection; (4) as HCV infection lasted for many years and HCC developed shortly after DAA a causal relation cannot be discarded.