When treating hepatitis E virus (HEV), the addition of sofosbuvir to a ribavirin-based regimen in solid organ transplant recipients does not result in sustained virologic response, according to a study published in Open Forum Infectious Diseases.
In the Netherlands, HEV genotype 3 is a common cause of acute viral hepatitis. Patients who are immunocompetent are commonly able to clear HEV infection spontaneously; however, immunocompromised patients develop chronic infection in about 60% of cases, defined as HEV RNA detectable in plasma for more than 3 months, which can lead to liver fibrosis and cirrhosis. The first step treatment for chronic HEV infection is reduction of immunosuppression followed by ribavirin monotherapy, which can lead to a sustained virologic response in 78% of patients, and 85% after retreatment.
The United States Food and Drug Administration has approved the use of sofosbuvir in combination with other antiviral agents for chronic hepatitis C virus infection, and previous studies have shown that sofosbuvir can inhibit HEV g3 replication in vitro and has an additive effect when combined with ribavirin. Combining sofosbuvir with ribavirin treatment has also shown mixed results in previous immunosuppressed patients with HEV. Therefore, this study describes 3 solid organ transplant recipients treated with sofosbuvir and ribavirin after failing ribavirin monotherapy.
Patient 1 was a 24-year-old man with end-stage heart failure caused by a cardiomyopathy, who required a heart transplantation in 2012. In 2015, he was diagnosed with a HEV genotype 3c infection with elevated alanine aminotransferase (ALT) levels, and he was started on a regimen of 600 mg ribavirin daily. This regimen was subsequently intensified twice: first to 400 mg twice daily and then to 600 mg twice daily. Sofosbuvir (400 mg daily) was started 2 years later, and combined treatment continued for 24 weeks. Of note, as a result of concern for allograft rejection, this patient did not receive treatment to improve immunosuppression.
Patient 2 was a 64-year-old woman who had severe emphysema and required a bilateral lung transplantation in 2000. In 2017, she had elevated ALT levels and was diagnosed with a HEV infection; therefore, treatment with ribavirin 600 mg once daily was initiated. Three months later, treatment was increased to 600 mg twice daily, and 7 months after this, sofosbuvir (400 mg daily) was started and ribavirin was decreased to original dose; combination treatment continued for 12 weeks. This patient received treatment for the reduction of immunosuppression, but signs of rejection resulted in modest success.
Patient 3 was a 52-year-old woman who had restrictive lung disease and required bilateral lung transplantation in 2011. In 2017, elevated ALT levels were observed and HEV RNA was detected in plasma. She was diagnosed with chronic HEV g3 infection, and ribavirin treatment at 400 mg twice daily was initiated. However, because of high ribavirin levels, treatment was adjusted 5 months later to 200 mg twice daily. After 7 months of ribavirin, sofosbuvir was added, and combination therapy was continued for 8 weeks.
In all patients, HEV RNA remained detectable in feces, even after the addition of sofosbuvir treatment to ribavirin. This resulted in the cessation of treatment. Of note, after 4 months of cessation of combination antiviral treatment, HEV RNA spontaneously cleared in plasma and feces of patient 2. Conversely, 3 months after stopping treatment, HEV RNA was detected in the plasma of patient 3 and ALT levels increased, ultimately leading to patient 3 developing decompensated liver cirrhosis.
The 3 cases presented suggest that sofosbuvir treatment may be dependent on the combined effect with ribavirin, and because these patients experienced failure with ribavirin monotherapy, that may have compromised the effectiveness of combination therapy. Therefore, ribavirin remains the first-line therapy and sofosbuvir would only be indicated in those who fail ribavirin monotherapy.
Overall, the study authors concluded that, “[S]ofosbuvir showed variable antiviral activity against HEV but did not result in [sustained virological response] in our patients. Alternative treatment options are urgently needed for [solid organ transplant] recipients with chronic HEV infection failing ribavirin treatment and being at risk for progression of liver fibrosis leading to cirrhosis and, in some cases, decompensation and death.”
van Wezel EM, de Bruijne J, Damman K, et al. Sofosbuvir add-on to ribavirin treatment for chronic hepatitis E virus infection in solid organ transplant recipients does not result in sustained virological response. Open Forum Infect Dis. 2019;6:ofz346.