Dear Editor:

Chronic infection with hepatitis C virus (HCV) leads to chronic liver disease, cirrhosis, and hepatocellular carcinoma. It was the most common indication for liver transplant (LT) until second-generation direct-acting antivirals became available.¹ Before that, HCV recurrence following LT was universal and associated with poor graft and patient survival.² The spontaneous resolution of chronic HCV infection is rare. Moreover, the spontaneous clearance of HCV after LT is very unusual in the context of immunosuppression, with only 24 cases identified so far.³ It has been hypothesized that some viral and host factors could modify the host’s immunity, leading to viral clearance. We report the case of a LT recipient who presented spontaneous HCV clearance late after LT, after conversion from tacrolimus to everolimus.

A 59-year-old female patient (HLA A*1, A*29, B*44, B*57, DRB1*07, DQB1*0202, DQB1*0303) underwent a first deceased donor LT for decompensated HCV-related liver cirrhosis and hepatocellular carcinoma in November 2004. Her initial immunosuppressive regimen included tacrolimus and steroids. The patient developed histologically confirmed chronic HCV recurrence; a liver biopsy in January 2008 showed recurrent HCV fibrosis, grade 1 and stage F2 (Metavir score). She received a combination of pegylated interferon and ribavirin. After 6 months of antiviral treatment, HCV RNA decreased from 6.4 to 5.1 log IU/mL, genotype 1b. A liver biopsy in October 2011 showed recurrent HCV fibrosis, grade 2 and stage F3 (Metavir score). A second course of pegylated interferon and ribavirin was started; however, the patient did not tolerate interferon, and the treatment was stopped after 6 weeks.

Because of severe chronic renal failure, the patient’s immunosuppressive regimen was modified in March 2012, and tacrolimus was replaced with everolimus. Her HCV RNA was 6.7 log IU/mL before conversion. Virological follow-up showed that HCV RNA became undetectable in October 2013, which was confirmed several times later, until May 2022. The patient finally underwent a first kidney transplant in March 2016; her initial immunosup-pressive regimen included tacrolimus, mycop-henolate mofetil, and steroids. The last liver biopsy in January 2016 showed recurrent HCV fibrosis, grade 1 and stage F2 (Metavir score).

Spontaneous clearance of chronic HCV is a rare phenomenon that is poorly understood. Nevertheless, certain viral and host factors seem to be associated with clearance. Outside LT, various rates of spontaneous virus clearance during chronic HCV infection have been reported. In a study performed in a large Scottish cohort, the clearance rate was 0.36/100 person-years,⁴ whereas another study on an Alaskan population reported a higher rate of 1.15/100 person-years.⁵ Our case is the twenty-fifth case in a LT recipient.

The median time to spontaneous HCV clearance was 11 months in previous cases.³ In our case, clearance occurred very late in comparison (8 years). Suspected factors associated with viral clearance include younger age, low viral load (<1 million IU/mL), coinfection (cytomegalovirus [CMV], hepatitis B virus, HIV), female sex, rejection episodes, HLA (DQB1*03, DQB1*03:01, DQB1*11, and DRB1*11:01), immune reconstitution after highly active antiretroviral therapy, surgery, pregnancy, interleukin 28B gene polymorphism, and withdrawal of immunosuppression.³

In our case, HCV clearance was observed after modification of the patient’s immunosuppressive regimen and conversion from tacrolimus to everolimus. It can be assumed that this consisted of a reduction of immunosuppression. More interestingly, an antiviral effect of mammalian target of rapamycin (mTOR) inhibitors has been more and more supported. The existing literature indicates a potential advantage of an mTOR inhibitor in CMV, polyomavirus, and human herpesvirus 8 infections and a mostly doubtful relation with Epstein-Barr virus and HCV infections.⁶ There is strong evidence that use of an mTOR inhibitor reduces the risk of CMV infection in kidney, heart, and lung transplant recipients, even if CMV risk reduction in LT recipients remains unclear.

Regarding HCV, studies have analyzed the development of fibrosis (ie, time to the diagnosis of fibrosing cholestatic hepatitis or cirrhosis). Several studies have shown milder fibrosis stages or a lower proportion of patients with significant fibrosis (Metavir F2-F4) in patients treated with mTOR inhibitors.⁶ Interestingly, in 2005, Samonakis and colleagues reported 2 patients with diabetes and renal dysfunction who were converted to sirolimus therapy and who showed clearance of HCV infections without antiviral treatment.⁷ In our case, a delayed clearance of HCV after the second course of pegylated interferon and ribavirin is highly improbable since viral load remained unchanged several months after antiviral treatment was stopped.

In conclusion, spontaneous resolution of chronic HCV infection after LT is a very rare phenomenon and could be related to immunomodulatory effects. We agree that a better understanding of this spontaneous viral clearance has low clinical impact in the present era of modern direct-acting antivirals. Nevertheless, we believe that it is of great relevance regarding immunologic physiopathology of chronic viral infections, especially in organ transplant recipients.

References:

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