Introduction
Human papillomavirus (HPV) is one of the most important sexually transmitted viruses [1]. This virus has more than 120 species that cause cervical cancer [2]. Although this cancer has also many environmental and genetic causes, such as smoking, early marriage, high number of births [3], infection with HPV is the most important cause [2]. This cancer is the second most common cancer among women and each year 500,000 new cases of this type of cancer are reported [4]. The prevalence of HPV infection among young and sexually active people is approximately 75% [5, 6]. In Iran, more than 25 thousand women aged 15 and above are at risk of cervical cancer, and cervical cancer is the fourth most common cancer among women after breast cancer, colorectal cancer, and lung cancer [2, 7]. More than 93% of cervical cancer cases are attributed to HPV [8]. Studies have shown that 30-65 people are infected with HPV during sexual intercourse [9, 10]. The global prevalence of HPV infection in women with normal histological findings is estimated at 11.7% [8]. In Iran, the prevalence of this virus is 9.4% among healthy women [5] and about 38.6% in women with cervical infection [11]. HPV infection often resolves within two years without any treatment, which is related to the functioning of the immune system [9, 10]. In addition to the type of HPV transmitted to each person, the persistence and severity of the virus are related to its damage rate. Various studies have shown that the persistence and progress of this virus are related to factors such as lifestyle, immune system resistance, history of physical diseases, history of mental diseases, and health care [9, 10, 12, 13]. In this regard, psychological disorders are among the factors that are related to the persistence and severity of any disease, especially HPV infection [12, 13]. These disorders can affect people’s personal lives and the immune system [14]. They intensify or suppresses the activity of the immune system by stimulating the secretion of the corticotropin-releasing hormone and adrenocorticotropic hormone from the hypothalamus and pituitary gland, and then the secretion of cortisol from the adrenal gland [15]. Stress and anxiety, which are among the most common psychological disorders, produce a physiological and biochemical response that is unique to each individual in terms of duration, intensity, and overall impact. By activating the sympathetic hypothalamus-pituitary-adrenal (HPA) axis, they can increase the heart rate and blood pressure, and by increasing the function of the cardiovascular system and preventing the person from being calm, exert a negative impact on health. Therefore, it can be said that psychological disorders have a direct relationship with the continuation of HPV infection. It can be helpful to investigate this relationship by conducting a comprehensive review of the observational studies that have been conducted so far on the persistence of HPV infection. A scoping review study can give us access to several studies at once and categorized [9, 13, 15, 16].  Since the purpose of a scoping review study is not to critically evaluate and produce a result for a specific question, but rather to provide an overview or draw evidence, a scoping review seems more reasonable [16]. A scoping and systematic review of the relationship between psychological disorders and the persistence of HPV infection has not been done so far. Therefore, due to the information gap in this field, the present study aims to conduct a scoping review to determine the relationship between psychological disorders and the persistence of HPV infection.

Materials and Methods
This is a scoping review study, written according to the JBI methodology [16]. In this regard, the study was conducted at five steps: 1- Defining the research question, 2- Conducting the search for related studies, 3- Selecting included studies, 4- Performing data extraction, and 5- Reporting the results [16]. After defining the research question, MeSH keywords were used for searching related studies in Google scholar, PubMed, Scopus, Springer, Elsevier, Cochrane Library, Science Direct, Web of Science, Magiran and SID databases with no limitation in the publication year. The keywords were: Factors, agents, related factors, psychological factors, anxiety, stress, depression, bipolar disorder, paranoid, delusional disorder, continuity, durability, permanence, persistence, stability, human papillomavirus, and HPV using Boolean operators (OR, AND). The process of selecting included studies was done by two reviewers and there was no disagreement between them. 
The quality of the articles was checked using two checklists including the Appraisal tool for Cross-Sectional Studies (AXIS) and the Critical Appraisal Skills Program (CASP). AXIS is a tool for critical appraisal of cross-sectional studies that can also be used in systematic reviews of health research groups and physicians, guideline development, journal clubs, and other types of review studies. This tool has been developed based on a combination of evidence, epidemiological processes, the experience of researchers, and Delphi method. This tool examines five general sections under the headings of introduction, methods, results, discussion and other information. It has 20 questions in total. Seven questions (1, 4, 10, 11, 12, 16, 18) are related to the quality of reporting, 7 questions (items 2, 3, 5, 8, 17, 19, 20) are related to the quality of study design, and 6 questions (items 6, 7, 9, 13, 14, 15) are related to possible biases in the study. The questions are answered by “yes”, “no”, “don’t know/comment”. In our study, 16 items were used for critical evaluation and bias investigation (Table 1) [17].


The CASP was used to evaluate the quality of case-control and cohort studies. it examines results, validity and its generalizability. This checklist contains 11 questions for case-control studies and 12 questions for cohort studies, some of which are two-part questions. The questions are answered by “yes”, “no”, “don’t know” (Tables 1, 2, 3) [16-18].




The search yielded 384 articles. Endnote software, version 21 was used to organize them. Three articles were also found by manual search. After removing duplicates, unrelated articles were identified by examining their titles, abstracts, and full texts. Studies with no information about sample size, those whose results were not fully expressed, and conference papers with no available full text, were excluded from the study. In this regard, 18 articles remained of which 7 were removed after checking their abstracts and 4 were removed after reading their full text. Therefore, 8 articles were finally included in the review (Figure 1). The necessary data including the name of the author(s), year of publication, study area, study objective, sample size, instrument, study variable, and results, were extracted from each study and classified (Table 4). 



Results
The participants in the studies were both male and female. Their age range was from 15 to 50 years. The criteria for selecting samples in the studies were reading and writing literacy, willingness to study, HPV infection, and age. In some studies, to control the effect of the confounding factors of lifestyle such as the number of sexual partners, the type of virus, the degree of infection, history of smoking and alcohol consumption, and psychological records were recorded. The total number of participants in the eight included studies [19-26] was 1264. Based on the answer to the main research question, the findings were classified into two categories of immune system movements caused by stress and by depression. Seven studies showed that stress caused by psychological, social and physical issues can cause the change in cervical cells and an increase in the risk of cervical cancer [19-26]. One study showed that depression and related disorders such as sleep disorder can be related to the persistence of HPV infection or deformation of cervical cells and the possibility of cervical cancer such that the people with higher stress and depression, according to the questionnaires or clinical interviews, were found that to be at higher risk of HPV infection persistence and cervical cell deformation [26].

Stress
One of the factors related to the persistence and severity of HPV infection is different types of stress, which has been mentioned in seven articles. The HPV virus, upon entering the human body, will be probably cleared if it encounters a strong immune system [19-25]. If this event not occur, the virus will intensify and continue, depending on the type of virus, the level of body defense, comorbid diseases, age, and lifestyle in the affected person. In 7 studies, the level of stress was measured with a clinical interview or a standard questionnaire [19-25]. In one study, in addition to determining the level of stress, the level of cortisol was measured as a determinant of the stress level [24]. In two studies, the rate of incidence, clearance, response to HPV vaccine, which is a live attenuated virus, were also measured [19, 20]. The determination of antibodies in men, cervical dysplasia, the risk of cervical intraepithelial lesions, cervical neoplasia, and persistence of oncogene infection in women were investigated in these studies [19-25]. The results of some studies showed that the presence of stress in any situation can increase the risk of HPV infection in women [20-24]. The results of a study in men reported a non-significance relationship of perceived stress and the amount of sleep quality with occurrence and clearance of HPV, where occurrence and clearance of the virus were less in men with less stress and more favorable sleep [20].

Depression
Depression is a psychological disorder affecting the response of the immune system [26]. In one study, the relationship of depression and related disorders with the level of immunity against HPV was reported [26]. In this study, 91 women participated. Before the colposcopy, a standard clinical interview based on DSM-III-R was conducted, and then sampling was done and the level of peripheral blood lymphocyte subpopulations (helper T cells, suppressor/cytotoxic T cells, B-lymphocytes and natural killer cells) were measured. Their results showed that depression was significantly associated only with the percentage of cytotoxic T cells [26].

Discussion
The purpose of this scoping review study was to investigate the relationship between psychological disorders and the persistence of HPV infection. The review of various studies in this field indicated a complex and two-way interactions between psychological disorders, the central nervous system, endocrine glands, and the immune system. Stress and depression lead to a physiological or biological reaction to allow organisms to face and deal with the stimulus that can be an opportunity or a threat [27]. When environmental events or demands exceed a person’s ability to cope or are contrary to a person’s desires, they lead to psychological stress [28]. Living with dangerous diseases is an example of these uncontrollable events that may be a stressful experience for a person. Stresses have a wide spectrum in terms of intensity (severe and sudden or mild and daily) and duration (short or long), and can have multiple effects on body functions [29]. Savard et al. in 1999 [26] conducted a study on people with HPV and reported that the level of depression had a significant relationship with the percentage of cytotoxic T cells. In Rires’ study in 2022 [20], the amount of antibodies after receiving the vaccine in men with favorable psychological level such as low stress and regular sleep, was more than in normal men after receiving the vaccine. However, this level of antibody did not last long in months 6 and 12, which could be due to the existence of reminder doses and forcing the body to secrete antibodies after receiving reminder doses. In the study by Kolar et al. in 2013 [19], perceived stress and sleep quality had no significant relationship with the incidence and clearance of HPV in men. This can explain the lower risk of HPV for men. It has been pointed out in many studies that HPV infection is more prevalent and dangerous in women; therefore, its influence from psychological disorders is more in women than in men [2-9]. Fang et al. in 2008 [21] and Wilkerson et al. in 2009 [22] during studies to determine the level of stress and the risk of cervical intraepithelial lesions, found a direct relationship between stress and the consequences of HPV infection. In another study, Kuebler et al. in 2021 [24] found that chronic stress and high daily cortisol levels were associated with the presence of HPV infection and thus may play a role in HPV-related cervical carcinogenesis. Some studies, even after controlling the effects of confounding factors such as age, lifestyle factors including smoking, and history of mental and physical illnesses, reported the significant associations [20-24, 26]. Several studies in the field of psychoneuroimmunology have shown that stress and depression through the HPA axis and the sympathetic-adrenal- medullary axis can lead to a disturbance in the function of the immune system. Lymphatic tissues are covered by sympathetic and adrenergic nerve fibers [28-30]. The interaction between the hormone and its cell surface receptor is directly related to the immune response regulation. Stress hormones, which are responsible for stimulating the HPA axis and sympathetic (adrenergic) activity, have receptors on almost all immune cells, including, macrophages, B and T lymphocytes, monocytes, P glucocorticoids, neuropeptides, growth hormones, catecholamines, serotonin and prolactin. It also has receptors for corticotropin-releasing hormone. The interaction of stress hormones, depression and its receptors on the surface of immune cells can affect the initial reaction of cells that lead to changes in cell function. The immune response is also indirectly regulated by stress hormones and affects the production of cytokines IL-6, IL-2, IL-1, and TNF-α [31-33]. In a study on 109 depressed people and 109 healthy people, Maes et al. found that the number of leukocytes increased significantly in depressed people [34]. Kronferol et al. also reported increased neutrophil and lymphopenia in depressed people [35].
One of the limitations of our study is that although we included all the studies that met the inclusion criteria, some of the studies may have been missed. Heterogeneity between studies in terms of the used instruments was another limitation which did not allow for their meta-analysis. Other limitations were the unavailability of the full text of some articles and excluding non-English or non-Persian articles.

Conclusion
Based on the findings of this review study, it can be concluded that some psychological disorders such as stress and its types, depression, their associated disorders can be related to the continuation or aggravation of the HPV infection or its complications. The studies in this field are not sufficient, but these factors can be used as a guide to identify related reasons for the persistence of HPV infection and, by planning to manage or weaken them, to increase the chances of curing the patients. The results of this study can help in the design of clinical trials for improving the physical and mental health of patients with HPV infection.

Ethical Considerations
Compliance with ethical guidelines
All ethical principles were considered in this study. The study was approved by the ethics committee of Mazandaran University of Medical Sciences (Code: IR.MAZUMS.REC.1402.142).

Funding
This study was funded by Mazandaran University of Medical Sciences.

Authors' contributions
Initial draft preparation and data collection: Mobina Moghassemi and Zeinab Hamzehgardeshi; Searching and examining eligibility: Kosar Miraei and Mobina Moghassemi; Writing original draft: Zeinab Hamzehgardeshi, Mobina Moghassemi, Shayesteh Jahanfar ,Soghra Khani, Forouzan Elyasi, and Nasser Behnampour; Editing: All authors.

Conflict of interest
The authors declare no conflict of interest.

Acknowledgments
The authors would like to thank  Mazandaran University of Medical Sciences for the financial support.


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