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Hepatitis C virus (HCV) infects >170 million people worldwide and causes chronic liver disease, liver cirrhosis, and hepatocellular carcinoma (HCC).1 HCV infection is one of the most common infections affecting ~1.5–2 million people in Japan, where >30,000 deaths from HCC occur each year.2 According to the World Health Organization survey involving 182 countries in 2008, the number of deaths from liver cancer in Japan ranked second in the world, after only China.3, 4 Moreover, HCV induces extrahepatic manifestations including glomerular disease, hematologic diseases such as cryoglobulinemia and lymphoma, autoimmune disorders such as thyroiditis, and dermatologic conditions such as lichen planus (LP) and porphyria cutanea tarda.5, 6 Until recently, the pegylated interferon (IFN) and ribavirin (RBV) regimen was the standard therapy for HCV chronic hepatitis. However, this combination therapy could achieve sustained virological response (SVR) rates of only 40–50% in patients with genotype 1, and is associated with significant gastrointestinal, hematological, and psychiatric side effects.7, 8 The currently developed IFN-free, direct-acting antivirals (DAAs) used to treat HCV infection have low side effect profiles and high efficacy.9, 10, 11 In July 2014, Japan approved the use of a combination therapy with daclatasvir (DCV; NS5A inhibitor) and asunaprevir (ASV; NS3 protease inhibitor), making it the first approved, all-oral, IFN-/RBV-free DAAs therapy. One year later, Japan’s Ministry of Health, Labour and Welfare approved Harvoni, a combination of sofosbuvir (nucleotide polymerase inhibitor) and ledipasvir (NS5A inhibitor, as the first once-daily single tablet regimen for the treatment of genotype 1 chronic hepatitis C (CH-C)). LP is a chronic, mucocutaneous disease that can affect the oral mucosa, skin, genital mucosa, scalp, and nails. LP is considered as one of the extrahepatic manifestations of HCV infection.12, 13 Oral LP (OLP) can develop, become exacerbated, and persist in patients receiving IFN treatment for hepatitis C.14, 15, 16, 17 In previous studies, we examined hepatitis C patients for oral lesions before, during, and after IFN treatment; OLP was seen in 11.7–16.7%.14, 17 Furthermore, in another study, we reported the case of a 65-year-old, Japanese, CH-C patient presenting with exacerbation of preexisting erosive OLP, and the appearance of cutaneous LP, and larynx leukoplakia following IFN and RBV therapy.15 The larynx leukoplakia had developed into malignancy, subsequently. Safety and efficacy of IFN-free DAAs in patients with OLP have not been proved yet. In this study, we examined the disease course in patients with HCV-associated OLP, who received treatment with IFN-free DAAs using the DCV/ASV combination therapy. Three patients received topical steroid therapy for the erosion of OLP before DAAs treatment, and only one received steroid therapy after treatment. The elimination of HCV reduces not only the development of HCC, but also the onset of conditions such as malignant lymphoma, Type 2 diabetes, and chronic kidney disease.21, 22, 23 Furthermore, the elimination of a virus has been shown to reduce bone fracture, osteoporosis, and the development of hemorrhagic stroke.24, 25 In a previous study, we have reported that the disappearance of HCV RNA and improvements in liver function over a period of >3 years appears to resolve OLP lesions.26 Thus, the elimination of HCV inhibits the onset of various extrahepatic manifestations. In 2014, a 24-week treatment with DCV/ASV provided a highly effective option for patients who had no effective treatment options available (ineligible for, or intolerant to IFN-based therapy) and for those who did not achieve SVR following prior treatment.9 SVR24 was achieved by 87.4% of the IFN-ineligible/-intolerant patients and 80.5% of the nonresponders (null and partial patients); rates were similar in cirrhosis (90.9%) and noncirrhosis (84.0%) patients, and in patients with IL28B (rs12979869) CC (84.5%) or non-CC (84.8%) genotypes. In the present study, all subjects (IL28B (rs8099917) non-TT; six patients, TT; one patient) achieved SVR12 and SVR24. This result was comparable with the phase 3 study of DCV/ASV therapy in Japan.9 Recently, Garcovich et al.27 reported that it is possible, but not proven that more effective and rapid antiviral responses observed with IFN-free antiviral regimens will improve outcomes in clinical settings, especially when HCV infection is burdened by extrahepatic manifestations. Makara et al.28 reported a successful case of HCV-associated mixed cryoglobulinemia effectively treated with an IFN-free combination of newly approved DAAs and RBV. However, there are no reports about IFN-free DAA treatment for HCV-associated OLP. The safety and efficacy of IFN-free DAA therapy in patients with OLP has not been proven yet. In the present study, we have reported the outcomes of HCV-associated OLP in patients who received successful treatment with IFN-free DAAs, using the DCV/ASV combination therapy. We consider that OLP lesions may completely disappear by long follow-up in patients after the extermination of HCV. In this study, the lesions of OLP in three of the seven patients did not completely disappear after IFN-free DAAs therapy. Presence of smoking and diabetes were considered as one of the reason why OLP lesions did not disappear. Tobacco use was reported to be a risk factor that develops cancer in OLP.29 Klosek et al.30 reported smoking in OLP patients correlated with both microvessel density and c-Met-positive staining. The authors showed the c-Met expression with smoking habit was statistically significant within the OLP group (P<10−6). c-MET is the receptor for hepatocyte growth factor, tyrosine kinase with downstream targets involved in a variety of cellular signaling pathways including proliferation, motility, migration, and invasion.31 c-Met receptor is expressed selectively in several normal human epithelial tissues as well as in carcinoma. Diabetes has been also supposed to have a role in the OLP pathogenesis.32 Baykal et al.33 revealed the prevalence of metabolic syndrome in LP patients. Among the metabolic syndrome criteria, mean fasting blood glucose and diastolic blood pressure were also significantly higher in LP patients than in controls (P=0.012 and P=0.021, respectively). We previously reported an association OLP and insulin resistance induced by HCV infection.34, 35 Conventionally, there were problems such as inability to complete IFN therapy due to worsening of OLP lesions following IFN therapy. IFN therapy has led to the development of oral mucosal lesions, resulting in oral candidiasis and inhibited salivary secretion.36 Treatment of HCV infection using IFN-free therapeutic methods may help improve the associated extrahepatic manifestations seen in the patients. Awareness of extrahepatic manifestations is necessary not only for the hepatologist, but also for the non-hepatologist. Guidelines on DAA therapy for the treatment of HCV-associated extrahepatic manifestations in Japan are expected to come into effect immediately. Our study showed that patients with HCV-associated OLP were treated safely and effectively with IFN-free DAA therapy. We intend to conduct further studies involving larger samples in future.  Guarantor of the article: Yumiko Nagao, DDS, MD, PhD. Specific author contributions: Data collection, design of the work, and drafting the work: Yumiko Nagao; analysis and interpretation of data: Kanae Kimura and Yuji Kawahigashi; design of the work and interpretation of data: Michio Sata; approved the final version of the submitted work: all the authors. Financial support: This study was supported in part by a Grant-in-Aid for Scientific Research (C) (No.25463274) from the Ministry of Education, Culture, Sports, Science and Technology of Japan. Professor Nagao, Dr Kimura, and Dr Kawahigashi belong to a department funded by Nishinihon hospital. Potential competing interests: The authors declare no conflict of interest. We thank Keisuke Amano (Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan) for providing the data.

Successful Treatment of Hepatitis C Virus-associated Oral Lichen Planus by Interferon-free Therapy with Direct-acting Antivirals