Interferon-free treatment for patients with chronic hepatitis C and autoimmune liver disease: higher SVR rates with special precautions for deterioration of autoimmune hepatitis

Background Interferon-free treatment can achieve higher sustained virological response (SVR) rates, even in patients in whom hepatitis C virus (HCV) could not be eradicated in the interferon treatment era. Immune restoration in the liver is occasionally associated with HCV infection. We examined the safety and effects of interferon-free regimens on HCV patients with autoimmune liver diseases. Results All 7 HCV patients with autoimmune hepatitis (AIH) completed treatment and achieved SVR. Three patients took prednisolone (PSL) at baseline, and 3 did not take PSL during interferon-free treatment. In one HCV patient with AIH and cirrhosis, PSL were not administered at baseline, but she needed to take 40 mg/day PSL at week 8 for liver dysfunction. She also complained back pain and was diagnosed with vasospastic angina by coronary angiography at week 11. However, she completed interferon-free treatment. All 5 HCV patients with primary biliary cholangitis (PBC) completed treatment and achieved SVR. Three of these HCV patients with PBC were treated with UDCA during interferon-free treatment. Conclusions Interferon-free regimens could result in higher SVR rates in HCV patients with autoimmune liver diseases. As interferon-free treatment for HCV may have an effect on hepatic immunity and activity of the autoimmune liver diseases, careful attention should be paid to unexpected adverse events in their treatments. Methods Total 12 patients with HCV and autoimmune liver diseases [7 AIH and PBC], who were treated with interferon-free regimens, were retrospectively analyzed.


INTRODUCTION
Hepatitis C virus (HCV) causes chronic and persistent infection and is an important etiologic factor of advanced fibrosis/cirrhosis and hepatocellular carcinoma (HCC) [1]. Eradication of HCV could reduce the risk of the occurrence of HCC and liver-related deaths as well as liver-unrelated deaths, although it is difficult to eliminate HCV [2]. Interferon-free treatment can achieve higher sustained virological response (SVR) rates, even in patients in whom HCV could not be eradicated in the interferon treatment era [3].
Patients with autoimmune liver diseases and hepatitis C virus (HCV) infection are occasionally observed [8,9]. Patients with autoimmune hepatitis (AIH) and HCV infection often have advanced liver diseases at initial clinical and histological assessments [8]. PBC diagnosis in HCV patients is difficult and usually delayed [9]. Those with HCV and PBC do not have better outcomes than those with only HCV [9].
Immune restoration in the liver is occasionally associated with HCV infection [10,11]. Studies using interferon-free regimens demonstrated an immune restoration of immunologic responses after HCV clearance [12][13][14]. Thus, HCV clearance has effects on the human immunologic response. HCV patients with autoimmune liver diseases could not be treated by interferon-including regimens because such regimens were contraindicated in these patients in the interferon era [15]. In the present study, we retrospectively examined the safety and effects of interferon-free regimens on HCV-patients with autoimmune liver diseases.
In a female HCV GT-1-patient with AIH and cirrhosis (no. 9), PSL was not administered at baseline, but she needed to take 40 mg/day PSL at week 8 for liver dysfunction after HCV treatment. She complained of back pain and was diagnosed with vasospastic angina by coronary angiography at 11 weeks but completed her treatment ( Figure 3).
Before treatment, in 7 HCV patients with AIH, 6 and 6 patients had abnormal aspartate aminotransferase (AST) and alanine aminotransferase (ALT) (more than 40 IU/L), respectively. At week 24 post-treatment, in all 7 of these patients, both AST and ALT were normalized.
Before treatment, in 5 HCV patients with PBC, 4 and 4 patients had abnormal AST and ALT (more than 40 IU/L), respectively. At week 24 post-treatment, in all 5 of these patients, both AST and ALT were normalized.
She was diagnosed with vasospastic angina by coronary angiography but completed her treatment ( Figure 3). Finally, SVR24 was achieved (ALT 29 IU/L, T. Bil 0.9 mg/dL, PT 104%, and IgG 1629 mg/dL). At present, she takes UDCA 600 mg/day and PSL 15 mg/day, and she is well.

DISCUSSION
In 9 HCV GT-1-patients with autoimmune liver diseases, RVR rates, end of treatment response (EOT) rates and SVR rates were 66.7, 100 and 100%, respectively. In 3HCV GT-2-patients with autoimmune liver diseases, RVR rates, EOT rates and SVR rates were 33.3, 100 and 100%, respectively. The present study found higher SVR rates in HCV patients with autoimmune liver diseases.
Concerning safety, in one patient with AIH, PSL was needed for liver dysfunction during the treatment of SOF/LDV. If liver dysfunction is due to autoimmune liver diseases, it may be important to treat autoimmune liver diseases before or during interferon-free treatment for HCV. Unexpectedly, in this case, vasospastic angina also developed as a complication during the treatment of SOF/LDV. Recently, Nirei et al. [16] reported ventricular tachycardia as a complication of SOF/LDV treatment. We do not know the association between the use of SOF/LDV and vasospastic angina.
Vento et al. [10] reported two patients with HCV who developed fulminant liver failure after stopping chemotherapy, indicating an immune-mediated mechanism for hepatocyte damage in HCV infection. These patients with liver failure seem to have developed immune restoration in the liver after stopping chemotherapy. HCVpositive mothers with increased ALT in the post-partum period, also presented a significant decrease in serum HCV RNA in the post-delivery period, and this event was concomitant with an increase in Th1 cytokine levels [11].
In the present study, one patients with AIH (no. 12) was classified into the AIH type 2, which is positive for anti-liver/kidney microsome type 1 (anti-LKM1) antibody. It has been reported that anti-LKM-1 was occasionally positive in patients with chronic active hepatitis C [17]. Further studies about the effects of DAAs on this type AIH will be needed.
Restoration of immunologic responses after HCV clearance with interferon-free treatment has also been reported [12][13][14]. Hepatitis B reactivation during or after interferon-free treatment for HCV may be associated with the restoration of adaptive and innate immune responses [12-14, 18, 19]. Thus, interferon-free treatment for HCV may have an effect on hepatic immunity and activity of autoimmune liver diseases. Exacerbation of AIH and PBC during the interferon-including regimens for chronic HCV infection has been observed [20][21][22]. Although interferonfree regimens seem safer than interferon-including regimens in patients with autoimmune liver diseases, clinician should pay a special attention to acute exacerbation of liver diseases and unexpected adverse events.

CONCLUSIONS
The interferon-free regimens were relatively safe and effective for HCV-infected patients with autoimmune liver diseases. Some patients with active AIH may require immune therapy before HCV treatment. Close monitoring and careful attention are needed to handle unexpected adverse events.

PATIENTS AND METHODS Patients
A total of 467 HCV-infected patients, some of whom were described previously [23][24][25], started treatment with interferon-free treatment by 2016 at the Department of Gastroenterology, Chiba University Hospital. Among them, 12 patients with autoimmune liver diseases (7 AIH and 5 PBC) were analyzed [25% male, mean age 68±8.4 years, 92% treatment-naive, 75% GT-1b, 33% cirrhosis] ( Table 1). This retrospective study was approved by Ethics Committee of Chiba University School of Medicine (numbers 1462 and 1753). Participants in the study were recruited from Chiba University Hospital. This study was conducted in accordance with the Declaration of Helsinki.

Diagnosis of AIH and PBC
AIH is diagnosed by the international autoimmune hepatitis criteria for the diagnosis of autoimmune hepatitis [26,27]. PBC was diagnosed based on the presence of AMA, elevated cholestatic liver enzyme and/or histologically by CNSDC as described previously [5,7].

Laboratory tests
Laboratory tests were measured by standard laboratory techniques at a central laboratory in Chiba University Hospital. Blood samples were obtained at the baseline, at weeks 4, 8 and 12 of treatment, and then 4, 8, 12 and 24 weeks after the end of treatment [24].

Measurement of HCV RNA
HCV RNA was measured by COBAS TaqMan HCV assay version 2.0 (Roche Diagnostics, Tokyo, Japan), with a lower limit of quantification of 15 IU/mL. We used the definition of rapid virological response (RVR), consisting of HCV RNA <15 IU/mL at week 4 according to the