1. Introduction

Hepatitis C virus (HCV) infection affects approximately 71 million people worldwide and is a leading cause of chronic liver disease and liver cancer deaths [1, 2]. In Japan, liver cancer accounts for about 30,000 deaths per year, 80% of which are caused by hepatitis B virus (HBV) and HCV [3]. HCV-infected patients in Japan are generally older than in other countries and are characterized by a high proportion of patients with complications such as cirrhosis and liver cancer [4, 5]. Since 2014, the treatment of chronic hepatitis C has been revolutionized by the advent of oral direct-acting antiviral agents (DAAs) [6]. Because DAA treatment has enabled the elimination of HCV, in May 2016, the World Health Organization (WHO) aimed to eliminate viral hepatitis as a major public health threat by 2030 [7, 8].

HCV infection is known to cause manifestations other than liver disease [9]. Oral lichen planus (OLP), which is recognized as an oral potentially malignant disorder (OPMD), is one of these extrahepatic manifestations [10, 11]. In addition to glucocorticoids and immunosuppressive drugs (cyclosporine), the efficacy of tacrolimus, clobetasol [12], pimecrolimus [13], and glycyrrhizin [14] has been reported for the treatment of OLP. We have reported that OLP can be cured when HCV is eliminated by antiviral treatments, such as with interferon (IFN) [15] and DAA [16–19]. Achieving a sustained virological response (SVR) has been shown to reduce not only liver cancer deaths and liver disease-related deaths but also extrahepatic mortality [20, 21].

Periodontal disease is associated with systemic health [22] and with liver disease, particularly nonalcoholic steatohepatitis (NASH) [23]. As a new biomarker involved in periodontal inflammation, galectin-3 has recently been shown to have the potential to discriminate between periodontitis and periodontal health [24]. We reported previously that there is an association between the severity of periodontal disease and the progression of viral liver disease [25] and that the so-called red-complex bacterial species (Porphyromonas gingivalis, Tannerella forsythia, and Treponema denticola) which are associated with severe periodontal disease are also associated with liver cirrhosis [26]. However, the changes in periodontal pathogens with and without HCV elimination have not been reported. Here, we report, as a preliminary study, the changes in periodontal species after HCV elimination by antiviral therapy in four OLP patients. The aim of this study was to investigate the effect of periodontal bacteria and OLP lesions before and after HCV elimination.

2. Subjects and Methods

3. Results

4. Discussion

DAA treatment of hepatitis C is a remarkable development. The elimination of HCV by DAA treatment has long-term benefits [31] and leads to improved outcomes at all stages of liver disease [32]. HCV elimination with DAA treatment shows the following benefits: reduction of liver fibrosis and portal hypertension [33], reduced incidence of HCC [34], reduced liver-related mortality [35], reduced incidence of diabetes [36], reduced incidence of cardiovascular disease [37], reduced risk of developing mixed cryoglobulinemia, glomerulonephritis, and lichen planus [38], improved patient quality of life [39], and reduced all-cause mortality [35].

In this study, we investigated the effects of DAA on periodontal disease and OLP. Not only did OLP lesions disappear or improve when HCV was eliminated but also the number of periodontal bacteria and the content of red-complex periodontal bacteria decreased. This is the first report of a decrease in the number of periodontal disease bacteria following HCV elimination. The conventional IFN treatment of OLP patients with HCV infection has the disadvantage that OLP often worsens during treatment and the treatment cannot be completed [40–42]. However, DAA therapy has fewer side effects than IFN therapy and results in an SVR rate of over 90% [43–45]. We reported previously that DAA treatment of HCV-infected OLP does not worsen OLP lesions during treatment and that OLP improves or is cured after HCV elimination [16, 17, 19]. Su et al. reported that elimination of HCV also reduced the incidence of oral cancer; in a nationwide population study, HCV-infected individuals had a significantly increased risk of both OLP and oral cancer compared to noninfected individuals and antiviral therapy with pegylated IFN (PegIFN) and RBV significantly reduced the risk of HCV-related oral cancer [46]. We reported previously a high prevalence of HCV infection in oral cancer [47] and multiple primary squamous cell carcinoma of the head and neck [48, 49]. HCV-positive OLP lesions are considered to be at high risk of malignant transformation [50]. A genome-wide association analysis (GWAS) analysis of Japanese HCV-infected patients showed that HLA-DR/DQ genes were significantly associated with the development of HCV-related OLP [51], which supported previous reports [52]. Furthermore, we identified rs884000 of neuropilin-2 (NRP2) and rs538399 of insulin-like growth binding protein factor 4 (IGFBP4) as novel associations, indicating that these two SNPs may be involved in the malignant transformation of HCV-infected OLP [51]. Further studies are needed to clarify the link between HCV and oral carcinogenesis, but there is no doubt that HCV elimination is beneficial.

HCV infection is known to stimulate the immune system, causing cytokine production and chronic inflammation [53]. HCV is involved in vascular inflammation through the activation of tumor necrosis factor alpha (TNFα), causing the activation and adhesion of inflammatory cells in the blood vessels [54]. HCV core proteins cause immune activation, inflammation, and tumorigenesis through the signal transducer and activator of the transcription 3 (STAT 3) pathway [55]. On the other hand, lipopolysaccharide (LPS), a component of the cell wall of periodontopathogenic bacteria, invades gingival tissues, activates neutrophils and macrophages, and produces various proinflammatory factors such as interleukin- (IL-) 1β, IL-6, TNFα, and matrix metalloproteinases (MMPs) [56]. Gingipain, a cysteine protease produced by P. gingivalis, a major periodontopathogenic bacterium, activates MMP precursors [57], and P. gingivalis fimbriae act on macrophages and gingival fibroblasts to induce the production of inflammatory cytokines [58]. Azatyan et al. reported that oral fluid cytokine levels were significantly higher in patients with HCV, HBV, and HIV than in controls [59].

HCV infection is associated with a higher incidence of dental caries and periodontal disease than in healthy individuals, a trend that is likely to become more pronounced as liver fibrosis progresses. Coates et al. pointed out a trend of poor periodontal disease in hepatitis C patients, although this was not statistically significant [60]. We reported previously that the following five factors were associated with periodontal disease in 351 patients with liver disease attributable to HBV or HCV: Plt count <80,000, daily tooth brushing, current IFN treatment, age >65 years, and obesity [25]. The adjusted odds ratios for these factors were 5.80, 3.46, 2.87, 2.50, and 2.33, respectively, and were statistically significant. The periodontal pathogens’ composition is generally influenced by aging [61]. Toljić et al. reported that HIV infection significantly increases the bacterial load in the oral cavity and alters the pattern of microflora composition during the aging process [61]. We also reported that the prevalence of fimA genotype II was higher in cirrhotic patients with advanced fibrosis than in chronic hepatitis [25] and that the red complex was associated with cirrhotic patients [26].

The reasons for the decreased risk of the red complex after HCV elimination in this study may be the reduction of inflammatory cytokines in the oral cavity, improvement of insulin resistance, improvement of OLP lesions, and involvement of the gut microbiota. Recently, it has been reported that disruption of the gut microbiota (so-called dysbiosis) is associated with liver diseases, such as nonalcoholic fatty liver (NAFL) and NASH [62], liver cirrhosis [63], primary biliary cholangitis [64], and HCV-related liver disease [65–67]. It has been reported that gut microbiota dysbiosis in HCV-infected patients already appears at the stage of PNALT (persistently normal serum alanine aminotransferase) and is associated with the severity of the clinical stages (i.e., PNALT, chronic hepatitis, liver cirrhosis, and HCC) [65]. In a study investigating the effects of antiviral drugs on the gut microbiota of HCV patients, Ponziani et al. reported significant improvement in gut microbiota dysbiosis after successful DAA treatment of HCV-infected patients [68]. In our preliminarily study, all four patients had a reduction in periodontal bacteria after SVR. Whether HCV elimination affects both gut bacteria and oral periodontal bacteria is a question that needs further investigation.

Among the subjects of this study, case No. 4 (77 years old, male), a cirrhotic patient with HCV infection who had been treated for HCC (see Table 1), was recommended by an oral surgeon to a hepatologist for DAA treatment. He had never received any explanation from his family doctor about antiviral treatment with DAA therapy. So, the oral surgeon explained to him that DAA treatment is the standard treatment for hepatitis C in Japan and that HCV elimination reduces the recurrence of HCC and may also cure OLP and then referred him to a hepatologist. The patient was treated with DAA which resulted in SVR and disappearance of the OLP lesions. It has been four and a half years since SVR, and the patient’s HCC has not recurred.

In recent years, the number of HCV-infected people has been decreasing due to the development of DAA treatment, but the existence of HCV-infected individuals who have not yet been diagnosed and HCV patients who have not received appropriate treatment remains a challenge. It is estimated that about 3 million individuals in Japan are infected with HBV and HCV and about 800,000 are unaware of their infection [5]. Of the HCV-infected individuals in Japan, it is estimated that about 470,000 visit medical institutions, about 300,000 are unaware that they are infected, and about 250,000–750,000 are aware that they are infected with HCV but do not receive treatment [69]. We reported that it is possible for dentists to pick out HCV-infected patients from among those who visit dental clinics for the treatment of dental and oral diseases [17, 18, 70, 71]. The detection of potential HCV-infected patients by dentists as gatekeepers can contribute to the reduction of liver carcinogenesis [72].

The present study has some limitations. First, the sample was very small. Second, the study was not conducted in a control group setting. Future studies need to be large case-control studies to clarify the effects of periodontal bacteria.

5. Conclusions

In this pilot study, HCV elimination was found to not only improve OLP but also reduce the number of periodontal bacteria. It is important to emphasize that further studies are needed due to the small number of cases. HCV elimination will bring a new perspective on the importance of oral management since HCV infection may be a risk for worsening periodontal disease.

Conflicts of Interest

The authors declare no conflicts of interest.

Authors’ Contributions

YN designed the study, collected data from participants, and wrote the manuscript. MT interpreted data and added intellectual revision. Both the authors have read and approved the final version.