Impact of hepatitis C virus on oral health: Clinical lesions,immunopathology,and dental management: A narrative review

Abstract

Hepatitis C virus (HCV) infection is a major global public health problem. Although it has traditionally been linked to liver damage, several studies have demonstrated its extrahepatic impact, specifically in the oral cavity. Oral manifestations can be considered early signs of infection or contribute to clinical progression. This narrative review aims to describe the oral alterations associated with HCV, integrating the pathophysiological mechanisms and clinical implications for dental management. The most prevalent manifestations include periodontal disease, oral lichen planus, Sjögren’s syndrome-like sialadenitis, and squamous cell carcinoma of the oral cavity. Recent findings suggest that HCV triggers dysbiosis of the oral microbiome, promotes exacerbated immune responses with overproduction of pro-inflammatory cytokines, and disrupts the homeostatic environment, thereby promoting the progression of inflammatory and neoplastic diseases. In addition, viral RNA has been identified in saliva and gingival crevicular fluid, which could be considered a non-parenteral route of transmission, particularly important in dental interventions. In parallel, direct-acting antiviral therapy, in addition to achieving virus elimination, could also partially correct immunological and microbial disruptions in the cavity, with favorable clinical responses. Understanding these oral alterations can guide dentists in early detection and improve systemic outcomes.

Keywords

hepatitis C oral manifestations periodontal disease oral lichen planus Sjögren’s-like sialadenitis squamous cell carcinoma of the oral cavity oral dysbiosis

Introduction

Hepatitis C Virus (HCV) infection is a major global public health problem. Recent estimates by the World Health Organization indicate that nearly 50 million people worldwide suffer from chronic HCV infection, with approximately 1 million new cases reported each year.¹ Traditionally, HCV has been considered a liver disease; however, its clinical impact extends beyond the liver, encompassing a wide range of extrahepatic manifestations, including numerous alterations in the oral cavity.^2,3

Various studies have shown that approximately 40%–75% of patients with chronic HCV present with extrahepatic manifestations, with oral alterations being one of the first clinical signs of this infection.³ Additionally, antiviral treatment for HCV not only benefits hepatic health but can also induce changes in the oral cavity. The oral cavity is a sensitive and active environment, with its own immune responses and metabolic processes. When an individual is infected with HCV, this balance can be disrupted in several ways, particularly during and after treatment. The most common oral manifestations associated with HCV include periodontal disease, oral lichen planus (OLP), Sjögren’s-like sialadenitis, and oral squamous cell carcinoma.^2–5

This narrative review aims to describe the oral manifestations associated with HCV infection, integrating evidence from the most recent studies and highlighting the importance of an interdisciplinary approach for the diagnosis and comprehensive management of these patients. This review summarizes clinical oral manifestations, explores immunopathological links, and discusses practical dental management and preventive strategies.

Search methodology

The narrative review presented was developed through a strategy aimed at determining the most important scientific evidence on HCV and its direct impact on oral health. To ensure a representative selection of available scientific literature, the bibliographic search was conducted using a systematic and structured approach in the Scopus, PubMed, and Web of Science databases, incorporating publications from 2000 to 2025. This strategy combined free and controlled search terms, such as “hepatitis C virus,” “oral manifestations,” “oral lichen planus,” “oral squamous cell carcinoma,” “periodontal disease,” and “Sjögren’s type sialadenitis.” Original articles, meta-analyses, and systematic reviews in Spanish or English were included, as well as experimental and observational studies that evaluated oral manifestations, immunopathological mechanisms, microbial modifications, or the effects of antiviral therapy.

Peer-reviewed studies incorporating both biological pathways and clinical findings linking HCV infection to oral diseases were prioritized. Additionally, the references of the integrated manuscripts were reviewed to ensure comprehensive coverage and the inclusion of the most relevant and recent scientific literature.

Oral manifestations

Periodontal disease

Periodontal disease (PD) is a chronic inflammatory disease of multifactorial etiology that involves the supporting tissues of the tooth, including the gingiva, periodontal ligament, root cementum, and alveolar bone. This condition is characterized by an exacerbated and persistent inflammatory response to subgingival bacterial biofilm, leading to the continuous destruction of periodontal tissues. The presentation of this disease can vary from early stages, such as gingivitis, with inflammation, bleeding on probing, and gingival edema, to advanced stages, such as periodontitis, which involves periodontal pockets, loss of clinical attachment, tooth mobility, and, in severe cases, tooth loss.⁶

Among oral diseases, PD is one of the most prevalent worldwide and is linked to various systemic conditions, including diabetes mellitus, cardiovascular disease, and, more recently, viral infections such as HCV.² In a retrospective study by Nagao et al.,⁷ conducted in a cohort of 351 participants with liver disease associated with HCV and/or hepatitis B, a high prevalence of PD was demonstrated among patients with HCV. Using the saliva occult blood test (Salivaster^®) as an indirect marker of periodontitis, 76 cases, representing 21.6% of patients, had a double positive result, indicative of significant periodontitis. However, when cases with a single positive result were also considered, the percentage of individuals with any degree of PD increased to 73.2%, suggesting that periodontitis is highly prevalent among individuals with hepatitis C. Using data from the National Health and Nutrition Examination Survey (NHANES) 2003–2018, the study by Chen et al.⁸ analyzed a sample of 5755 US adults, showing a positive and significant association between HCV infection and the occurrence of periodontitis (OR: 1.609; 95% CI: 1.51–4.499). When categorizing PD by severity, the association also remained: moderate periodontitis was associated with a significantly increased risk of liver infection (OR: 2.136; 95% CI: 1.194–3.822), while this behavior was even more pronounced in patients with severe periodontitis (OR: 3.583; 95% CI: 1.779–7.217). Complementing this, the descriptive study by Shoukat et al.⁹ in Pakistan, involving 100 HCV-infected individuals and 100 controls, identified a significantly higher prevalence of PD in those infected; it was also shown that rural residence and poor oral hygiene are associated with a higher probability of HCV infection (OR: 3.1 and 2.9, respectively). These findings are consistent with those recently reported by Fang et al.,¹⁰ based on an analysis of data from the 2009 to 2014 NHANES, which showed that hepatitis infection (including HCV) was significantly associated with an increased risk of periodontitis (OR: 1.46; 95% CI: 1.26–1.70), a relationship that remained consistent even after adjustment for sociodemographic and clinical variables.

The association between HCV and PD could be attributed to shared immunological mechanisms. The viral condition promotes a continuous immune system response, in which there is an increase in the production of cytotoxic CD8⁺ T cells, as well as an exacerbated release of proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), interleukin-1 alpha (IL-1α), interleukin-1 beta (IL-1β), interleukin -6 (IL-6), and interleukin-17 (IL-17), which play a fundamental role in the destruction of periodontal tissues. Similarly, subpopulations of Th17 and Th9 lymphocytes are associated with the persistence of gingival inflammation. In the descriptive cross-sectional study by Surlin et al.,¹¹ the impact of chronic liver inflammation due to HCV on the periodontal immune response was determined by quantifying IL-1α and IL-1β in gingival crevicular fluid (GCF) from participants with periodontitis. Three groups were defined: patients with periodontitis without comorbidities, patients with periodontitis and HCV infection, and healthy participants. The parameters of the biomarkers IL-1α and IL-1β were significantly higher in the HCV group, with an increase of 1.8 and 2.1 times, respectively, compared to periodontal subjects without HCV. Additionally, positive associations were demonstrated between cytokine levels and periodontal clinical indicators, as well as with the duration of HCV infection. This evidence suggests that chronic systemic inflammation generated by HCV acts by potentiating the local inflammatory response in periodontal tissues, thereby exacerbating the severity of periodontal disease through processes regulated by shared proinflammatory cytokines.

On the other hand, in the cohort study by Malone et al.,¹² Medicare data were evaluated to analyze whether PD could increase the risk of dementia in participants with HCV. This study of more than 439,000 patients found that subjects with PD had a higher incidence and earlier onset of Alzheimer’s disease and associated dementias. Even after adjusting for sociodemographic factors and comorbidities, the risk was considered to be statistically significant (adjusted HR: 1.35). These findings suggest an interaction between chronic inflammation induced by PD and HCV, which may promote the progression of neurodegeneration. Recent studies have suggested that PD may be associated with an increased risk of cognitive decline and dementia, possibly mediated through chronic systemic inflammation and immune pathways shared with HCV infection.¹²

At the level of the oral microbial ecosystem, a pattern of dysbiosis has been demonstrated in patients with HCV, with a predominance of periodontopathogenic bacteria such as Porphyromonas gingivalis, Treponema denticola, Tannerella forsythia, and Prevotella intermedia. Consequently, the presence of these species facilitates the entry and persistence of the virus.¹³ This bacterial overexpression, coupled with an exacerbated immune response, may favorably impact the progression of PD.¹¹

Evidence supports a bidirectional relationship between PD and HCV infection, modulated by immunological, inflammatory, and microbial mechanisms. This mechanism not only exacerbates PD but may also contribute to the systemic viral load or facilitate alternative routes of oral transmission.¹⁰

Oral lichen planus

OLP is a chronic inflammatory mucocutaneous condition that predominantly affects the oral mucosa and has a varied clinical presentation.^2,14 From a clinical standpoint, this disease is usually identified by bilateral and symmetrical lesions that take on different forms, the most common variant being reticular, characterized by whitish streaks (Wickham striae), particularly on the buccal mucosa. Other presentations often include atrophic, papular, erosive, bullous, plaque, and ulcerative forms. Symptoms range from no discomfort to stabbing pain, particularly when eating acidic or spicy foods.¹⁵

Between 10% and 23% of HCV-infected subjects are presumed to have LP.¹⁶ Three consecutively published systematic review and meta- analysis studies evaluated the association between HCV infection and LP, particularly OLP. Overall, the findings support a significant association between the two conditions, although with some variation in the magnitude of risk depending on the population analyzed. The study published by Shengyuan et al.¹⁷ concluded that the relationship is bidirectional: individuals with LP have a significantly higher risk of HCV infection (OR = 5.4), and those with hepatitis C have, in turn, a higher risk of developing LP (OR = 2.5), although with regional variations. Lodi et al.¹⁸ identified a similar risk to that of the previous study; however, in this study, it was found that individuals with chronic infection by this virus showed a marked increase in the occurrence of LP, with an odds ratio of 4.8. The article published by Petti et al.¹⁹ included a case-control study in the Iranian population that did not evidence a statistically significant association; however, by integrating data from 44 international studies through meta-analysis, it was observed that individuals with OLP are approximately 2.8 times more likely to be infected by HCV, suggesting a strong association globally, although subject to geographic variations. Taken together, the accumulating evidence supports the existence of an epidemiologically consistent relationship between the two conditions, which could be due to shared immunological mechanisms or to the chronic immunomodulatory effect of HCV. These findings justify considering serological screening for the virus in subjects with OLP, especially in contexts where its prevalence is high.

The association between HCV infection and OLP could be attributed to complex mechanisms involving both direct effects of the virus and dysregulated immune responses. Although HCV primarily targets hepatocytes, it has been suggested that it can lodge in epithelial tissues (oral keratinocytes), which could trigger a persistent local immune response. In this context, a marked activation of cytotoxic CD8⁺ T cells and Th1 lymphocytes has been observed, as well as an increase in cytokines such as TNF-α, IL-2, and IL-17, favoring a sustained pro-inflammatory environment. Adding to this immune imbalance is the involvement of subpopulations such as Th9, Th17, and altered regulatory T cells, which could contribute to both the perpetuation of inflammation and autoimmune aggression toward epithelial cells.⁷ Furthermore, recent genomic research has identified genetic variants linked to the onset and development of OLP in patients with chronic HCV infection, supporting the immunogenetic basis of this association.²⁰ Significantly, HCV elimination through direct-acting antivirals without interferon has been linked to clinical improvement in OLP manifestations, supporting the hypothesis that viral persistence and altered immune balance contribute to its development.²¹

The relationship between OLP and PD has been the subject of several investigations, with studies suggesting a significant association between the two conditions. The study published by Nunes et al.²² concluded that subjects with OLP present an increase in gingival index (GI), plaque index, and periodontal probing depth (PPD) compared to healthy controls. On the other hand, Sanadi et al.²³ confirmed a similar association, observing that individuals with OLP had an increased risk of bleeding on probing (BOP) and PPD (OR 1.9 and 1.1) compared to the healthy population. Both studies agree that OLP appears to play a role in aggravating periodontal health, especially in terms of inflammation and PPD. These findings suggest that subjects with OLP should receive special and personalized periodontal care, given that lesions in the oral mucosa may hinder oral hygiene and thus predispose individuals to the worsening of PD. Understanding this relationship may be key to improving the clinical management of individuals presenting with both conditions, emphasizing the need for a comprehensive approach in their treatment.

In addition, a pattern of oral dysbiosis has been identified in HCV-infected individuals, with alterations in the microbiota that activate immune pathways associated with defense against bacteria. One study demonstrated that subjects with OLP have higher levels of infection with T. denticola, T. forsythia, P. gingivalis, P. intermedia, and Aggregati-bacter actinomycetemcomitans compared to individuals without OLP.²⁴ Likewise, a preliminary report demonstrated that HCV clearance in individuals with OLP was associated with a decrease in the number of periodontal bacteria (P. gingivalis, T. forsythia, T. denticola), potentially influencing PD progression. These observations not only partially explain the occurrence of OLP but also bear similarity to what occurs in periodontitis, where the same microbial and immune profiles favor the destruction of periodontal tissues.²⁵

The detection of HCV RNA in oral fluids for its possible implication in non-parenteral transmission, especially in clinical-dental contexts, is highly relevant. One study explored the possible source of HCV in the oral cavity by evaluating both GCF and saliva. In this work, viral RNA was detected in 59% of the GCF samples and in 35% of the saliva samples, noting that all positive cases in saliva coincided with detection in GCF. In addition, a relationship was found between the presence of viral RNA in saliva and the existence of blood in the oral cavity, as well as an association between plasma viral load and virus detection in GCF, even in the absence of visible bleeding.²⁵ Another study found that 77% of subjects had higher HCV RNA levels in GCF than in saliva, and although there was no statistically significant correlation between serum viral load and HCV levels in saliva or GCF, individuals with low serum HCV loads were less likely to have detectable HCV in their saliva.²⁶ These results reinforce the hypothesis that GCF could represent a relevant HCV outflow pathway into saliva, especially when there is gingival inflammation or bleeding, common conditions in PD. The higher frequency of detection in GCF suggests that this fluid acts as an interface between systemic infection and the oral environment, being directly influenced by the circulating viral load. Furthermore, the finding of viral RNA in saliva only in the presence of GCF infection suggests a possible common origin, providing a more complete framework for understanding the routes of oral transmission of the virus.^25,26 Together, these studies not only provide evidence for the presence of HCV in the oral cavity but also delineate a possible mechanism of passage from the systemic circulation into the oral cavity, mediated by the periodontal state. Such knowledge highlights the importance of optimal oral health in individuals with hepatitis C and raises questions about the risk of transmission in dental procedures, reinforcing the need for strict biosafety protocols. This interaction between the virus, the immune system, and the microbial environment establishes a pathogenic link between HCV, OLP, and PD.^2,27

Sjögren’s-like sialadenitis

Sjögren’s syndrome (SjS) is an autoimmune condition characterized by chronic inflammation of the exocrine glands, especially the salivary and lacrimal glands, leading to decreased secretory function and resulting in persistent dry mouth (xerostomia) and dry eyes (xerophthalmia), which constitute the cardinal manifestations of the disease.² In the oral setting, patients with this disease often present certain consistent and significant alterations: increased frequency of dental caries, atrophy and burning of the oral mucosa, increased opportunistic conditions (particularly due to Candida albicans), thick saliva with a viscous appearance, and, in certain situations, glandular hypertrophy.²

Chronic HCV infection is not limited to hepatic effects but can trigger broad-spectrum immunologic alterations, including salivary gland manifestations that mimic the features of SS. A systematic review and meta-analysis involving 10 studies demonstrated a statistically significant positive association (OR: 3.31; 95% CI: 1.46–7.48; p < 0.001) between HCV infection and the development of SS.²⁸

In HCV-infected subjects, the presence of lymphocytic infiltrates in major salivary glands, especially the submandibular, with a predominance of CD8⁺ T cells, in contrast to the more typically CD4+ pattern of primary Sjögren’s, has been documented. Although these cases generally do not express classical autoantibodies such as anti-SSA or anti-SSB, they do present other immunological markers such as antinuclear antibodies, anticentromere antibodies, rheumatoid factor, and antibodies against double-stranded DNA, suggesting an autoimmune-based inflammatory process induced by viral infection. These alterations are frequently associated with glandular hypofunction and symptoms of xerostomia, thereby creating an oral environment prone to microbial imbalance.^2,29 In fact, one study concluded that subjects with SS are more susceptible to the development of dental caries than PD.³⁰ However, a systematic review with a more recent meta-analysis showed different results. The meta-analysis of 5 studies (6927 participants) found a positive correlation between periodontitis and SjS (OR: 2.12; 95% CI: 1.43–3.17; p < 0.05). Meanwhile, the meta-analysis of 16 studies (852 participants) showed that the periodontal status (GI and BOP) of SjS subjects was worse compared to the control group, and clinical periodontal parameter scores were higher.³¹

Reduced salivary flow not only compromises antimicrobial defense functions but also favors the growth of pathogenic species associated with caries and periodontitis. A systematic review of clinical studies found that in 14 of 15 studies, there was an alteration in the oral microbiome and differences in microbial diversity in patients with SjS. Higher oral microbial counts of Prevotella, Veillonella, and Firmicutes were reported in patients with SjS, while a higher prevalence of caries-associated bacteria such as Streptococcus, Lactobacillus, and Veillonella was found in patients with SjS.³² The study by Singh et al.³³ described that, from dental biofilm samples, through identification and quantification by the “checkerboard” DNA-DNA hybridization method, it was shown that Veillonella parvula, Fusobacterium nucleatum ss. Vincenti, and Propionibacterium acnes were elevated in SjS compared to the control group. In subgingival samples, the levels of V. parvula were significantly higher in subjects with SjS compared to the healthy population, whereby SS was characterized by high levels of the purple complexes and low levels of the orange and red complexes as opposed to the normal composition under periodontitis conditions.³³

This is in addition to the sustained activation of proinflammatory cytokines such as IL-17, IL-33, and IL-23, which are involved in both glandular fibrosis and periodontal tissue destruction. Indeed, the relationship between HCV and periodontitis is reinforced by the detection of viral particles and specific antibodies in the GCF, suggesting a viral migration pathway that may be facilitated by the inflamed gingival environment. In this context, HCV infection not only acts as a trigger of glandular alterations similar to SjS but may also play an indirect role as a modulator of the periodontal microenvironment, promoting disease progression through convergent immune and micro-biological mechanisms.⁴

Oral squamous cell carcinoma

In the oral cavity, squamous cell carcinoma (OSCC) is the most common malignant neoplasm, accounting for 90% of all oral cancers.² From a clinical standpoint, this neoplasm presents as a persistent ulcer, an indurated mass, leukoplakia that becomes indurated, or more frequently as erythroplakia, the latter manifestation being associated with the highest malignant potential.² The areas most commonly affected include the lateral edge of the tongue, the buccal mucosa, the floor of the mouth, and the soft palate.^2,3

HCV infection has been associated not only with liver disease and extrahepatic immunologic manifestations, but also with an increased likelihood of developing epithelial neoplasms, such as OSCC. The persistence of HCV in oral tissues, together with its potential to promote chronic inflammation and immune dysregulation, may contribute to the malignant transformation of epithelial cells. In this context, elevated levels of pro-inflammatory cytokines such as IL-6, TNF-α, and TGF-β, in addition to sustained T-cell activation, factors that may favor a tumorigenic microenvironment, have been observed. This chronic inflammatory condition might be exacerbated in the presence of periodontitis, an inflammatory disease affecting dental supporting tissues that shares similar immunopathological mechanisms.^2–4 The meta-analysis published by Li et al.³⁴ demonstrated that PD was positively associated with the prevalence of OSCC (OR: 3.28; 95% CI: 1.87–5.74), especially for severe PD (OR: 4.23; 95% CI: 2.92–6.13). However, this study did not find evidence of an increased risk of OSCC among individuals with PD according to the pooled results (RR: 1.50; 95% CI: 0.93–2.42). Individuals with OSCC tended to present greater alveolar bone loss, clinical attachment loss, and BOP compared to controls.³⁴ In addition, the most commonly detected periodontal pathogens in subjects with OSCC include Fuso-bacterium, Prevotella, Peptostreptococcus, Alloprevotella, Capnocytophaga, and Catonella.^35,36 An interesting aspect about the microbial dysbiosis that occurs under these circumstances is the role of P. gingivalis in OSCC, since it has been shown that this periodontopathogen has been suggested to participate in three stages of tumorigenesis: epithelial-mesenchymal transition, neoplastic proliferation, and tumor invasion.³⁷

Severe periodontitis may lead to a constant release of inflammatory mediators and proteolytic enzymes and may favor the migration of activated immune cells into the oral epithelium, conditions that could potentially amplify the carcinogenic effects associated with HCV. In addition, the presence of viral RNA and anti-HCV antibodies has been documented in GCF, suggesting that inflamed tissues in periodontitis might facilitate colonization or persistence of the virus in the oral cavity. This interplay between periodontal inflammation, viral infection, and cellular transformation suggests a potential indirect relationship through which periodontitis could act as a cofactor in HCV-associated oral carcinogenesis, but also raises the need to consider periodontal health as an integral part of oncologic surveillance of HCV-infected individuals.^13,25,26

HCV infection is associated with multiple oral manifestations, ranging from alterations in the salivary glands to visible changes in the oral mucosa. These manifestations may be interrelated with periodontitis due to factors such as immune dysfunction, xerostomia, and side effects of antiviral treatments. In addition, the chronic inflammation linked to both conditions may increase the likelihood of damage to periodontal tissues and may contribute to the progression of PD. It is critical that subjects with viral hepatitis receive adequate follow-up of their oral and periodontal health, and that dental health professionals are aware of the systemic implications of hepatitis on oral health.

Oral pathophysiology associated with HCV and effects of antiviral therapy

Immune and metabolic changes in saliva and oral environment

HCV infection alters salivary composition in ways that compromise the oral cavity’s natural defense mechanisms. Studies have found that often patients produce saliva with lower levels of sodium and mucin-5B. Since mucins are essential for lubrication and antimicrobial protection, and ions like sodium help maintain pH and enzyme activity, these changes can have detrimental effects. They may lead to discomfort, altered taste, and even shifts in the oral microbiome, which normally helps maintain balance in the oral cavity.² After antiviral treatment, some patients may experience partial recovery of salivary function. However, the degree of improvement often depends on how long the infection has been active and how much damage has already occurred in the salivary glands.

HCV also triggers immune activity in the oral cavity. One major sign of this is the presence of cytotoxic CD8-positive T cells in the salivary glands. This suggests that the immune system is responding to a localized process, not solely to hepatic involvement.³ This ongoing immune response is connected to oral conditions like OLP and Sjögren-like syndromes, which are more commonly found in people with chronic HCV infection.

In HCV-related OLP, the immune system tends to produce a strong Th1-type response. Cytokines like TNF-alpha, interferon gamma, and interleukin-2 are released, mostly by activated CD4-positive helper T cells and CD8-positive cytotoxic T cells.³⁸ These immune cells sustain inflammation over time. Other T-cell types, such as Th9, Th17, and regulatory T cells, also play roles in promoting inflammation and contributing to tissue damage.³⁹ Saliva from patients with OLP has shown higher levels of IL-17, IL-23, IL-33, TGF-beta, and IL-25.^40,41 These molecules are associated with chronic inflammation and tissue fibrosis. Even when the virus is successfully treated with direct-acting antivirals, these cytokines can remain elevated, which may explain why some oral symptoms persist longer than others.⁴¹

Some studies suggest that HCV is capable of replicating directly in the tissues of the oral cavity. Viral RNA has been detected in oral lesions using molecular tools such as in situ hybridization and PCR. Additionally, T cells that specifically target HCV have been found more often in oral tissues than in the blood. These cells even have different T-cell receptor structures than those in circulation, which supports the idea that the immune response in the oral cavity is compartmentalized and uniquely targeted.³ This localized viral activity may partly explain the persistence of oral symptoms even after the virus is no longer detectable in the blood.

In some cases, HCV seems to trigger an autoimmune-like response in the salivary glands. This can resemble SjS and is marked by symptoms such as dry mouth and inflammation. These effects appear to be driven by B-cell overactivity. In particular, CD5-positive B cells expand and start producing a wide range of antibodies.⁵

Several different mechanisms may be involved here. The virus may directly infect cells in the salivary glands. It may also mimic the body’s own proteins, confusing the immune system into attacking healthy tissue. Another possibility is that immune complexes containing viral material form and build up in the glands. All of these can lead to long-term damage and reduced saliva production. In summary, salivary changes reduce protective functions and alter the microbiome, while immune activation leads to chronic inflammation. Even after the virus is treated, some changes may persist if the immune system remains overactive or if tissue damage has already occurred^5,41,42 (Figure 1).

Figure 1.

Overview of immune and metabolic alterations in the oral cavity during and after hepatitis C virus (HCV) infection.

Effect of antivirals on oral microbiota after HCV eradication by direct-acting antivirals

Recent research has highlighted significant changes in the oral microbiota following the elimination of HCV through direct-acting antiviral agents (DAAs). These changes not only affect bacterial diversity but also influence the progression of oral conditions linked to chronic HCV infection.

In a study by Nagao et al.,¹³ patients suffering from both OLP and HCV infection experienced a marked reduction in periodontal pathogens, notably P. gingivalis, T. forsythia, and Fusobacterium nucleatum, after completing DAA treatment. The decrease in these red-complex bacteria was accompanied by clinical improvement or resolution of OLP lesions, suggesting that viral eradication plays a key role in modulating the oral inflammatory environment.¹² Similarly, Su et al.⁴³ reported that clearing HCV not only lessened inflammatory oral conditions but also reduced the risk of oral cancer, emphasizing the broader systemic benefits of antiviral therapy.

Furthermore, findings by Gamal-AbdelNaser et al.⁴⁴ showed that prior to antiviral therapy, individuals with chronic HCV infection harbored a highly diverse and pathogen-rich oral microbiome. Post-treatment, their microbiota shifted toward a more balanced state, partially resembling the profiles found in healthy individuals, indicating progressive microbial normalization following viral clearance.

Together, these studies suggest that successful HCV treatment can restore microbial and immune balance in the oral cavity, reduce oral disease burden, and potentially lower oncogenic risk, highlighting the importance of integrating oral health monitoring into hepatitis C management (Table 1).

Table 1.

How hepatitis and its treatment affect the oral cavity—before and after antiviral therapy.

Area of oral health	During hepatitis or antiviral treatment	After successful treatment (Post-DAA)
Salivary flow	↓ (Ribavirin-induced xerostomia)	↑ (Recovery to baseline)
Saliva composition	Altered mucins, ion imbalance	Normalization anticipated
Immune response	T-cell infiltrates, cytokine ↑	Reduced mucosal inflammation
Microbiome	Dysbiosis, ↑ periodontal pathogens	↓ Pathogens, restored microbial balance
Mucosal lesions	Worsened (OLP, candidiasis risk)	Improvement or resolution
Periodontitis	↑ Prevalence/severity (immune + bacterial factors)	↓ Inflammation, clinical improvement

Note. The arrows indicate only the direction of change (increase or decrease) of the described parameter and do not represent the magnitude of the effect.

Dental management

Dental management of patients with active HCV or a history of HCV should be conducted under strict biosafety protocols. Detection of HCV RNA in oral fluids, such as GCF and saliva, even in the absence of bleeding, confirms the potential risk of non-parenteral transmission, particularly during procedures involving gingival bleeding or invasive interventions.

In patients with HCV, it is essential to obtain a detailed medical history, including information on whether direct-acting antiviral therapy has been administered. Standard universal precautions should be implemented, with particular emphasis on surface disinfection, the use of protective barriers, and appropriate management of contaminated instruments. Invasive procedures should be avoided in patients with active hepatitis until clinical stabilization occurs. Likewise, efforts should be made to minimize procedures that generate aerosols, ensuring that the operating area has adequate ventilation. Stabilization of the periodontal status is essential before performing invasive procedures, as inflammation and gingival bleeding may promote viral release. Prior to surgical procedures, liver function must be assessed due to certain alterations in hemostasis, drug metabolism, and healing in cases of chronic liver dysfunction. Consultation with the treating physician is also essential to assess parameters such as INR, prothrombin time, and platelet function.

In the multidisciplinary care network for patients with HCV, the integration of a dentist is essential, not only to improve the quality of oral health but also to contribute to the early diagnosis of a systemic condition that might otherwise go unnoticed in its early stages.

Future prospects

Recent scientific evidence on oral manifestations linked to HCV opens up new opportunities for biomedical research, clinical practice, and public health policies. First, longitudinal, multicenter studies are needed to evaluate the progression of oral diseases in patients with HCV, as well as the impact of antiviral therapy on the composition of the oral microbiome, the local immune response, and periodontal clinical biomarkers. This line of research will clarify whether viral eradication allows for complete reversal of oral immunopathological changes or whether chronic sequelae persist, particularly in patients with long-standing infections. Additionally, the exploration of diagnostic and prognostic salivary biomarkers is a promising field. The development of specific cytokine, viral RNA, or dysbiotic profiles could optimize the early detection of oral manifestations of HCV, particularly in clinical settings with limited access to serological testing. In this same context, saliva could be a non-invasive diagnostic tool, serving as a useful resource for epidemiological surveillance and evaluation of therapeutic success.

In the therapeutic field, it would be interesting to implement updated guidelines for dental care for patients with active HCV infection or a history of HCV, taking into account factors such as liver stability, immune homeostasis, and potential interactions with medications commonly used in dentistry. Likewise, the management of these conditions should take a comprehensive approach, integrating the dentist as an active member of the multidisciplinary team, not only for the therapeutic care of oral manifestations, but also as a potential agent for the early detection of hepatitis in patients with nonspecific oral signs.

In the area of prevention, it is suggested that educational campaigns be strengthened, targeting both health professionals and the general population to increase the identification of oral manifestations of HCV and their potential impact. These campaigns are particularly relevant in vulnerable communities, where oral and systemic manifestations often coexist and are aggravated by socioeconomic factors and the availability of health services.

Finally, an emerging and interdisciplinary perspective is based on research into the common inflammatory axis between chronic HCV infection, periodontal disease, and neurodegenerative conditions such as Alzheimer’s disease. Understanding these interactions allows us to generate new approaches for the primary prevention of systemic diseases based on the control of oral inflammation, positioning oral health as a fundamental pillar in the preventive medicine of the future.

Conclusion

HCV infection can lead to a variety of oral manifestations, ranging from inflammatory conditions such as oral lichen planus and periodontal disease to Sjögren’s-like glandular conditions and potentially malignant neoplasms such as squamous cell carcinoma of the oral cavity. These diseases not only represent the complex association between the virus, the immune system, and the oral microbiome but also highlight clinical opportunities for early diagnosis and interdisciplinary management. In this context, dentists play an indispensable role both in identifying early signs of HCV infection and in using biosafety measures for the adequate and safe care of this group of patients. Early diagnosis and management of oral manifestations associated with HCV can contribute to improved quality of life, better systemic prognosis, and the prevention of future complications.

Footnotes

Abbreviations

HCV Hepatitis C Virus

LP Lichen planus

OLP Oral lichen planus

PD Periodontal disease

NHANES National Health and Nutrition Examination Survey

TNF-α Tumor necrosis factor-alpha

IL-1α Interleukin-1 alpha

IL-1β Interleukin- 1 beta

IL-6 Interleukin- 6

IL-17 Interleukin-17

GCF Gingival crevicular fluid

GI Gingival index

PPD Periodontal probing depth

BOP Bleeding on probing

SjS Sjögren’s syndrome

OSCC Oral squamous cell carcinoma

DAAs Direct-acting antiviral agents

Author contributions

Conceptualization, M.A.A.-S, V.H.-D, L.S.E.-V, M.M.-N, G.E.G.-A, A.A.-M, A.-H, and S.M.L.-M.; validation, M.A.A.-S, V.H.-D, L.S.E.-V, M.M.-N, G.E.G.-A, A.A.-M, A.-H, and S.M.L.-M.; formal analysis, M.A.A.-S, V.H.-D, L.S.E.-V, M.M.-N, G.E.G.-A, A.A.-M, A.-H, and S.M.L.-M.; investigation, M.A.A.-S, V.H.-D, L.S.E.-V, M.M.-N, G.E.G.-A, A.A.-M, A.-H, and S.M.L.-M.; writing—original draft preparation, M.A.A.-S, V.H.-D, L.S.E.-V, M.M.-N, G.E.G.-A, A.A.-M, A.-H, and S.M.L.-M.; writing—review and editing, M.A.A.-S, V.H.-D, L.S.E.-V, M.M.-N, G.E.G.-A, A.A.-M, A.-H, and S.M.L.-M.; visualization, M.A.A.-S, V.H.-D, L.S.E.-V, M.M.-N, G.E.G.-A, A.A.-M, A.-H, and S.M.L.-M.; supervision, M.A.A.-S, A.-H, and S.M.L.-M.; project administration, M.A.A.-S, A.-H, and S.M.L.-M.; All authors have read and agreed to the published version of the manuscript.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Mario Alberto Alarcón-Sánchez

Melissa Martínez-Nieto

Gustavo Eder González-Alvarez

Artak Heboyan

Sarah Monserrat Lomelí-Martínez

Availability of data and materials

The data supporting this study’s findings are available from the corresponding author upon reasonable request.*

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