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

OBJECTIVES: Oral lichen planus (OLP) is one of the extrahepatic manifestations of hepatitis C virus (HCV) infection. Presently developed interferon (IFN)-free direct-acting antivirals (DAAs) used to treat HCV infection have low side effect profiles and high efficacy. However, there are no studies examining the relationship between OLP and IFN-free DAAs. The aim of this study was to evaluate the disease course in patients with HCV-associated OLP, who received treatment with IFN-free DAAs.
METHODS: Seven patients with HCV-related OLP (including one with cutaneous LP), who received IFN-free treatment with daclatasvir (DCV)/asunaprevir (ASV) at our hospital in Japan from October, 2014 to February, 2015 were enrolled in the study. The subjects included four males and three females (average age, 73.9 years). We compared the symptoms of OLP in the patients before and at 24 weeks after the end of DAA therapy.
RESULTS: No worsening of symptoms was observed during treatment with the DAAs. The symptoms of OLP had subsided in all seven patients. Lesions of OLP and cutaneous LP disappeared in four, and improved in three of the seven patients after sustained virological response 24. No systemic clinical adverse events were observed in all patients.
CONCLUSIONS: Herein, 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.

INTRODUCTION

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.

METHODS

Patients

Seven patients with clinically and/or histopathologically confirmed HCV-related OLP who received IFN-free treatment with DCV/ASV at the Kurume University Hospital in Japan from October, 2014 to February, 2015 were enrolled in the study (Table 1). The subjects included four males and three females (average age; 73.9), of whom five suffered from CH-C, one from CH-C with post-HCC treatment, and one from HCV-related liver cirrhosis (LC-C), Child-Pugh Class A with post-HCC treatment. One of the subjects (patient number 6) presented with cutaneous LP. Five of the seven patients were treated with the IFN and RBV regimen therapy at the Kurume University Hospital in the past. Hepatologists and an oral surgeon examined all patients. All patients with HCV genotype 1 received both DCV 60 mg once daily and ASV 100 mg twice daily for 24 weeks.

Table 1

The characteristics of seven patients with OLP

No.	1	2	3	4	5	6	7
Sex	F	M	M	F	M	F	M
Age	72	59	76	72	84	77	77
Liver disease	CH-C	CH-C	CH-C	CH-C	CH-C, post HCC	LC-C, post HCC	CH-C
HCV genotype/ level of HCV RNA	Ib/high	Ib/high	Ib/high	Ib/high	Ib/high	Ib/high	Ib/high
IL28B gene (rs8099917) TT/non-TT	Non-TT	Non-TT	Non-TT	Non-TT	TT	Non-TT	Non-TT
History of treatment of IFN	Yes	Yes	No	Yes	No	Yes	Yes
Exacerbation of OLP at past IFN therapy	Yes	Yes	—	Yes	—	Yes	Yes
Systemic disease except the liver disease	No	Hypertension, diabetes mellitus, and ventricular extrasystole	Asthma, reflux esophagitis, and gallbladder polyp	Postoperative coxarthrosis	Hypertension and arrhythmia	Hypothyroidism and osteoporosis	Hypertension and post larynx cancer
Presence or absence of smoking	Never smoker	Ever smoker	Smoking cessation	Never smoker	Never smoker	Never smoker	Smoking cessation
Effect of DAAs therapy	SVR24	SVR24	SVR24	SVR24	SVR24	SVR24	SVR24
Type of OLP before DAA therapy	Erosive	Erosive	Reticular	Reticular	Reticular	Erosive	Erosive and reticular
Sites of OLP before DAA therapy	Bilateral buccal mucosa	Bilateral buccal mucosa, tongue, and lower lip	Bilateral buccal mucosa	Bilateral buccal mucosa	Bilateral buccal mucosa	Bilateral buccal mucosa and bilateral calves skin	Bilateral buccal mucosa and lower lip
Topical steroids to OLP before DAA therapy	Not received	Received	Not received	Not received	Not received	Received	Received
Findings of OLP after SVR24	All disappearance	Lesions at buccal mucosa: disappearance. Lesions at tongue and lower lip: reduction of erosion	All disappearance	Lesion became unclear, but a slight white spot remained	All disappearance	All disappearance	Lesions at buccal mucosa: disappearance. Lesions at lower lip: disappearance of erosion, but a slight white spot remained
Turning point of OLP after SVR24	Disappearance	Improvement	Disappearance	Improvement	Disappearance	Disappearance	Improvement
Topical steroids to OLP after DAA therapy	Not received	Received	Not received	Not received	Not received	Not received	Not received

CH-C, chronic hepatitis C; DAAs, direct-acting antivirals; F, female; IFN, interferon; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; LC-C, liver cirrhosis type C; M, male; non-TT, minor allele; OLP, oral lichen planus; SVR, sustained virological response; TT, major allele.

Outcome for OLP before and after treatment with DAAs

The OLP lesions were clinically examined in all patients before, during, and at 24 weeks after the end of the DCV/ASV combination therapy.

Serological assays

All subjects were tested for red blood cell count, white blood cell count, platelet count, hemoglobin, and the following liver function tests: serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, alpha-fetoprotein, total bilirubin, direct bilirubin, total cholesterol, total protein, and albumin.

Evaluation of liver diseases

Anti-HCV was measured using a chemiluminescent enzyme immunoassay kit (Lumipulse II HCV, Fujirebio; Tokyo, Japan). HCV RNA levels were analyzed in serum by quantitative polymerase chain reaction assay (COBAS AMPLICOR HCV MONITOR v 2.0 Test, COBAS AmpliPrep/COBAS Taq-Man HCV Test, Roche Molecular Systems; Branchburg, NJ, USA).[18, 19] HCV genotype was determined by polymerase chain reaction assay using a mixture of primers for the subtype, as reported previously.[20] Ultrasonographic examination was performed on all patients to investigate the shape of the liver and to identify lesions within the liver. Computed tomography was also performed on some patients. We used other possible predictors of progression of LC, including serum albumin, total bilirubin, prothrombin time, and platelet. Liver biopsy was performed in some patients.

Ethical considerations

This investigation was undertaken with the understanding and consent of each participating subject, and was conducted in full accordance with the ethical principles of the World Medical Association Declaration of Helsinki. The study protocol was approved by the Ethics Committee of Saga Medical School (reference number: 27–36) in accordance with the Declaration of Helsinki. Written informed consent for participation in the study was obtained from each patient.

Statistical analysis

All data were expressed as mean±s.e. Differences between baseline and SVR24 were analyzed using Wilcoxon signed-rank test. Differences were significant at P<0.05 (two-tailed). All statistical analyses were conducted using JMP Version 11.1.1 software (SAS Institute, Cary, NC, USA). The level of statistical significance was defined as P<0.05.

RESULTS

Treatment outcomes for liver disease

All subjects presented with undetectable HCV RNA levels at 8 weeks after DAAs treatment. Furthermore, all subjects achieved SVR 12 weeks (SVR12) and 24 weeks (SVR24) after the end of treatment. A comparison of the biochemical data at baseline and SVR24 is shown in Table 2. Serum aspartate aminotransferase and alanine aminotransferase levels, and alpha-fetoprotein were decreased, whereas albumin levels were increased. No systemic clinical adverse events were observed in the patients.

Table 2

Comparison of the biochemical data in baseline and SVR24

		Baseline	SVR24	P value
BMI	Mean±s.d.	19.1±8.3	23.1±4.1	0.0469
AST (U/I)	Mean±s.d.	57.1±29.1	28.9±9.4	0.0313
ALT (U/I)	Mean±s.d.	52.9±31.1	18.4±4.7	NS
ALP (U/l)	Mean±s.d.	357.1±140.9	303.9±110.0	NS
γGTP (U/l)	Mean±s.d.	36.6±20.7	25.4±13.1	NS
T.pro (g/dl)	Mean±s.d.	7.40±0.4	7.67±0.4	NS
Alb (g/dl)	Mean±s.d.	3.83±0.6	4.19±0.3	NS
BUN (mg/dl)	Mean±s.d.	15.1±2.5	17.0±3.1	0.0469
AFP (ng/dl)	Mean±s.d.	40.5±65.0	5.9±4.2	NS
PIVKAII (mAU/ml)	Mean±s.d.	18.8±5.8	25.2±6.0	0.0313
RBC (× 104/μl)	Mean±s.d.	431±36.9	438.6±25.4	NS
Hb (g/dl)	Mean±s.d.	14.0±1.5	13.9±1.1	NS
WBC (μl)	Mean±s.d.	46.0±12.7	52.0±20.8	NS
Plt (× 104/μl)	Mean±s.d.	13.6±4.2	13.8±4.6	NS

AFP, alpha-fetoprotein; Alb, albumin; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; BUN, blood urea nitrogen; γGTP, γ-glutamyl transpeptidase; Hb, hemoglobin; NS, not significant; PIVKAII, protein induced by vitamin K absence or antagonists II; Plt, platelet; RBC, red blood cell; T.pro, total protein; WBC, white blood cell.

Outcomes for OLP

No deterioration of symptoms was observed in the patients during DAAs treatment. The symptoms of OLP/cutaneous LP had subsided in all patients; the lesions had disappeared in four, and improved in three of the seven patients after SVR24 (Table 1; Figures 1 and 2). Disappearance of OLP lesions on the buccal mucosa, bilaterally, and decrease in erosive lesions on the tongue and lower lip were observed in a 59-year-old Japanese male patient (Table 1). Similar findings were observed in another 77-year-old male patient. In one of the patients, a 72-year-old Japanese female, the OLP lesions appeared to fade away until a slight white spot remained. We conducted an extended follow-up for OLP. Although OLP lesions did not completely disappear about three patients, the symptom and the discomfort of two patients (number 4 after SVR40 and number 7 after SVR52 in Table 1) disappeared, and the lesion of one patient (number 2 in Table 1) reduced after SVR52.

Figure 1

Clinical photographs showing disappearance of OLP lesions from the buccal mucosa of the patient. (a) OLP lesions affecting the buccal mucosa on both sides of the mouth. (b) Disappearance of OLP 13 months later, following the treatment with DAAs. DAAs, direct-acting antivirals; OLP, oral lichen planus.

Figure 2

Clinical photograph showing the disappearance of OLP lesions from the buccal mucosa of another patient. (a) OLP lesions affecting the buccal mucosa on both sides of the mouth. (b) Disappearance of OLP 13 months later, following the treatment with DAAs. DAAs, direct-acting antivirals; OLP, oral lichen planus.

Three patients received topical steroid therapy for the erosion of OLP before DAAs treatment, and only one received steroid therapy after treatment.

DISCUSSION

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.

Study Highlights