Among cancer patients undergoing chemotherapy, liver dysfunction resulting from HBV reactivation has been observed in 14–72% of patients who did not receive prophylactic antiviral therapy, leading to liver failure in 13% of patients and death in 6% of patients. [12, 13]. On the other hand, in a prospective observational study, HCV reactivation occurred in 23% of the patients with cancer receiving chemotherapy, but none of the patients exhibited liver failure or death. [14].

HCV reactivation was reported to be caused by several anticancer drugs and immunosuppressive agents, such as rituximab, bortezomib, doxorubicin, cisplatin, docetaxel, vincristine, bendamustine, fludarabine, gemcitabine, vinorelbine, cytarabine, alemtuzumab, mitomycin, crizotinib, cyclophosphamide, methotrexate, thalidomide, fingolimod, and corticosteroids [14,15,16,17,18,19]. More recently, HCV reactivation after COVID-19 vaccination was reported [20]. Rituximab, among these agents, is reported to be a high-risk drug related to HCV reactivation [15]. In addition, steroids are likewise considered a risk factor of HCV reactivation. In most HCV reactivation cases with steroids, they were used with anticancer drugs and there are only two reports so far demonstrating HCV reactivation case caused by steroid monotherapy (Table 2) [21, 22]. In the previous reports, the peak ALT level was approximately 200–350 U/L during HCV reactivation, but in this case, the elevation was as high as 1000 U/L. In a report by Torres et al. summarizing 23 patients with cancer receiving chemotherapy and exhibiting HCV reactivation, no patients suffered from liver failure, and unlike HBV reactivation, the degree of hepatitis was often mild [14]. In addition, the total steroid dose in this case was lower, and the duration of administration was also shorter than that previously reported [21, 22].

In this case, serum level of HCV RNA was not measured prior to PSL administration and a liver biopsy was not performed; therefore, other possible causes of acute hepatitis, such as autoimmune hepatitis and drug-induced liver injury, cannot be completely ruled out. Most drug-induced liver injury occurs within 6 months of initiation of drug administration [23]. Given that amlodipine was initiated 3 years prior to the onset of hepatitis and the liver injury persisted after the discontinuation of amlodipine, the possibility of drug-induced liver injury due to amlodipine is extremely low. This is also supported by the fact that there was no relapse of hepatitis when amlodipine was restarted after SOF/LDV treatment for HCV. In addition, the patient has no history of taking drugs other than amlodipine, including herbal medicine and supplements. Furthermore, in this case, serologically, it was unlikely that there was any other possible cause of liver damage other than HCV, and based on the clinical course, we considered the development of a hepatitis flare as HCV reactivation. The fact that ALT remained within the normal range after achieving SVR24 may also suggest that the cause of ALT flare was HCV reactivation. The incubation period of HCV until the onset of hepatitis is 7 weeks (range 3–30 weeks) [24]. The patient has not had any blood transfusions, sexual activity, or tattoos that could cause re-infection during the period prior to the onset of hepatitis (3–30 weeks); therefore, the possibility of HCV re-infection is considered extremely low. In this case, it took approximately 2 months from the time of referral to our hospital to the start of DAA treatment. This is because SOF/LDV treatment is very expensive and it took time to receive medical subsidy for hepatitis C virus treatment in Japan.

Multiple pathogenic mechanisms have been proposed concerning the correlation between steroids and HCV reactivation. These mechanisms include an intensified infectivity of HCV resulting from an increased expression of viral receptors on the outer membrane of hepatic cells, which are recognized as pivotal players for the entry of HCV into hepatocytes [25]. In addition, steroids might induce cytokines that enhance HCV replication both in vitro and in vivo [26].

The risk of HCV reactivation with hepatitis flare is significantly associated with HCV genotype 2 [14, 27,28,29]. The hypervariable region 1 of the HCV envelope glycoprotein E2, which contains epitopes of neutralizing antibodies for HCV, has been known to be more variable during the course of infection in HCV genotype 2 than that in genotype 1 [27, 30]. This implies the existence of more potent antibody-mediated immune pressure on the genotype 2 virus and may help elucidate the difference in HCV dynamics observed among genotypes. The genotype of this case was type 2, similar to the two previously reported cases. In the present case, we could not obtain a serum sample before the reactivation and could not analyze the changes in nucleotides/amino acids of HCV during the reactivation. The validity of viral factors for HCV reactivation and detailed mechanisms should be elucidated in a future study.

Several studies have shown that hepatic dysfunction caused by HCV reactivation may lead to frequent alterations and interruptions in treatment for the primary disease, thereby exacerbating the overall prognosis [15, 31]. Furthermore, the long-term impact of chronic HCV infection can be severe, since the utilization of cytotoxic and immunosuppressive treatment may accelerate progression to cirrhosis [32].

In summary, we treated a rare case of HCV reactivation with severe hepatitis flare after a steroid monotherapy for sudden deafness. At present, no reliable methods exist to predict an individual’s risk of HCV reactivation, and unlike for HBV reactivation, no drugs are currently approved to prevent HCV reactivation. It should be noted that HCV reactivation can occur even if the total steroid dose is low, as in this case, or even if the dose is administered for a short period of time. The recent HCV elimination rate with DAAs therapy is extremely high and can be achieved in a short period of time even if the patients are elderly, have comorbidities, or have cirrhosis [3,4,5]. Then, it may be desirable to perform HCV elimination before the treatment using anticancer drugs or immunosuppressive agents for the primary disease, if possible.