Knowledge about Cervical Cancer and Awareness of Human Papillomavirus (HPV) and HPV Vaccine among Female Students from Serbia

Background and objectives: Persistent infection with carcinogenic human papillomavirus (HPV) is the leading cause of cervical cancer. The study explored students’ knowledge about cervical cancer and awareness of human papillomavirus and the HPV vaccine. Materials and Methods: A questionnaire-based survey was carried out among 1616 first-year female college students at the University of Niš. It examined socio-demographic characteristics, measured the score of knowledge about cervical cancer, assessed awareness regarding HPV and the HPV vaccine and inquired about the source of information about cervical cancer and HPV. Results: The average cervical cancer knowledge score was 16.35 ± 7.92 (min 0, max 30), with medical professional education, parents’ education level, place of residence and relationship status having significant effects on the score. The awareness about HPV and the HPV vaccine was low, with only 14.2% of students having heard about both HPV and its vaccine. The most commonly reported sources of information were the media, while the most competent one was organized health education. Conclusions: Health promotion campaigns and educational programs are necessary in order to reduce cervical cancer burden and should be directed particularly towards those who have demonstrated low cervical cancer knowledge and low awareness regarding HPV and its vaccine.


Introduction
Malignant disease rates have reached enormous proportions globally and are appropriately considered a modern age plague. Cervical cancer (CC) is the most common gynecological malignancy and has the fourth highest incidence and mortality rate among women worldwide, with about 570,000 cases and 311,000 deaths in 2018 [1]. This dreadful statistic is mostly the result of inefficiently organized health systems in developing and especially in underdeveloped countries. Accordingly, particularly affected by CC are sub-Saharan African and Southeast Asian countries, in which this disease represents the leading cause of cancer death ahead of breast and lung cancer [1].
As registered vaccines do not provide protection against all oncogenic HPV types and no vaccine is 100% effective, it is necessary to adhere to national recommendations for cervical cancer screening regardless of vaccine status [18].
In addition to chronic HPV infection, other risk factors play an important role in the development of CC as well. Among them, the most notorious are smoking, immunodeficiency, long term use of oral contraceptives, promiscuous behavior and having more than two pregnancies. A family history of CC and other descriptive characteristics, obesity and poor diet are also associated with CC [19][20][21][22].
Although in Serbia there is an organized CC screening program and the HPV vaccine is recommended and available for purchase, CC still remains one of the most prevalent malignancies. According to data from the last available national registry in 2015, it was the fourth most common cancer among women in Central Serbia [23]. In 2018, it was assessed that it causes about 1300 new cases and 550 deaths annually. In addition, Serbia has the highest age-standardized CC mortality rates when compared with other Southeast European countries [2].
The objective of the study was to evaluate knowledge about CC, as well as awareness of HPV and HPV vaccination among first-year female college students from Niš, Serbia. In addition, the sources of students' information about the subjects were also analyzed. The idea was to identify potential target groups for the implementation of customized health promotion programs.

Study Design
The study was designed as a cross-sectional survey conducted between December 2018 and March 2019. Participants were female, first-year college students at the University of Niš during a mandatory medical check-up. All subjects were informed that participation in the study was voluntary and that by completing the questionnaire the consent for publication was given. It was made clear that the data collected would remain anonymous. The approval for the study was obtained from the Ethics Committee of the Faculty of Medicine, Niš (number of decision: 01-10204-11/2012).
A total of 2008 questionnaires were distributed and 1616 fully completed, valid questionnaires were included in the study.

Questionnaire
Data were collected using a semi-structured questionnaire specially created for this investigation. It was a self-administered questionnaire with three distinct sections (Supplement File 1).

1.
Section 1: The first section explored respondents' socio-demographic characteristics, including age, type of faculty, mother's and father's education level, place of residence, type of secondary school completed and financial and relationship status. In addition, participants were asked if they ever had sexual intercourse and, if yes, how many sexual partners they had had.

2.
Section 2: The second section consisted of 22 items divided into three subsections (CC knowledge, HPV awareness, HPV vaccination awareness). CC knowledge was evaluated by a composite score estimated using a total of 18 items regarding risk and protective factors, preventive measures and the outcome of CC. Participants had three possible response options regarding proposed factors (protective factor, risk factor and do not know) and correct answers were coded with either one or two points, deepening factor significance. As for the rest of the questions, the given options were "true", "false" and "do not know" and correct answers were given two points. The total number of points represented the participant's CC knowledge score (CC-KS), with higher scores meaning better knowledge. The maximum number of points was 30. All questions were based on data from the relevant literature and information provided by the American Cancer Society [14][15][16]. Awareness about HPV was determined based on whether or not participants had heard about HPV infection. The remaining three items were related to HPV vaccination. Subjects were asked to indicate if they have heard about the HPV vaccine. If the answer was positive, they then answered when the best time to get the HPV vaccine is and if the HPV vaccine is available in Serbia.

3.
Section 3: The last part of the questionnaire inquired about the source of respondents' knowledge about the subject. Thirteen multiple choice answers, from three categories of source (personal contact, organized health education (OHE) and media) were offered. The opportunity to declare not having any knowledge was also given.

Statistical Analysis
Data are presented as the mean and standard deviation (SD) or as frequencies and proportions. Comparison of the mean values between two groups was done using t-tests or Mann-Whitney tests depending on data distribution, while the mean values between the three groups were compared using either ANOVA or Kruskal-Wallis tests. The chi-squared test was used for the comparison of categorical variables. The p-value was set at p < 0.05 (two-tailed). All statistical analyses were performed using R software, version 3.0.3 [24].

Results
Overall, 1616 participants completed the whole questionnaire, meaning that the response rate was 80.5%. The average age of the study population was 19.13 ± 0.73 years (min 17, max 29), with the majority of the subjects coming from urban areas (75.7%). Their other socio-demographic characteristics are presented in Table 1. a Missing data due to death of a parent; b Other response options were not chosen by our participants; c Of those that had had sexual intercourse; 5+-five and more.

Knowledge about CC
As described in the methodology, the knowledge about CC was evaluated using a composite score. It was established that the average score in our students was 16.35 ± 7.92 (min 0, max 30). Statistical analysis showed that medical students had significantly a higher knowledge score compared to other, non-medical students (p < 0.001). Pre-college education also significantly influenced participants' scores (p < 0.001), with the highest score noted in students that previously attended medical high school, followed by those that attended grammar schools (Table 2). Furthermore, a significant difference in the score was established between participants from urban and rural areas (p = 0.01), with the former being better informed about CC. Mother's and father's level of education also influenced the CC knowledge of our subjects (p < 0.001 and p = 0.006, respectively). The knowledge was significantly higher in students whose mothers had middle (p = 0.002) and high (p < 0.001) education compared to those with low education. Likewise, having a father with high education meant having higher score ( Table 2). The financial status of participants was significantly associated with knowledge score (p = 0.008). Thus, participants with high and middle incomes demonstrated higher scores ( Table 2). Students in a relationship showed better knowledge than single students (p = 0.019). Hohd On the other hand, no significant difference was proven between women that had sexual experience and those who did not ( Table 2). It is correct. Those who were in relationship were more aware both of HPV infection and CC.

HPV and HPV Vaccine Awareness
The total number of participants that had heard of HPV infection was 788 (48.8%), with a significantly higher percentage of medical students being aware of this infection (p < 0.001). Furthermore, knowledge of this infection differed significantly depending on the type of secondary education (p < 0.001). Thus, students that had finished medical high school had significantly higher knowledge compared to those from grammar school (p < 0.001) and non-medical high schools (p < 0.001). Finally, students that were in a relationship (p = 0.005) and that were sexually active (p = 0.001) knew about HPV infection significantly more often (Table 3). * Chi-squared test; ** vs. medical high school, p < 0.05; *** vs. high educated mother, p < 0.05; a only those that had also heard about HPV were taken into account; b only those that had heard about HPV and the HPV vaccine were taken into account; c missing data due to death of a parent; d of those that had had sexual intercourse; 1 -not significant; 5+-five and more; Human papillomavirus-HPV.
When it comes to HPV vaccine, the overall awareness was quite low (21.3%), whereas an even lower percentage of students had heard of both HPV and its vaccine (14.2%). A statically significant difference was noted relative to mother's education and relationship and sexual status. Students raised by highly educated mothers had heard of the HPV vaccine more often (compared to students whose mothers had low education, p = 0.028), just as the students that were in relationships (vs. single, p = 0.041) and that had had sexual intercourse (compared to those who had not had sexual intercourse, p = 0.001) ( Table 3).
The other two questions about HPV vaccination were correctly answered by only a small number of subjects. Of those who declared that they were aware of HPV and the vaccine, only 37 knew when the best time to get the HPV vaccine is and 48 knew that it is available in Serbia. No difference between distinct demographic groups was established (Table 3).

Source of Information
The media was listed as the dominant source of information about the investigated topics by 1011 of the examined students. The other two categories, organized health education (OHE) and personal contact, were reported as sources by 866 and 538 students, respectively. Two hundred and fifty-five subjects declared having no knowledge about the investigated topics.
The knowledge score was significantly higher in subjects that received information from any of the three source categories compared to subjects who denied receiving information from those particular categories (Table 4). A similar relationship is noted between information sources and HPV awareness. Among the students who knew about HPV, significantly more reported acquiring information through each of the source categories (vs. not acquiring information through those sources). Finally, OHE was the only information source category associated with a significantly higher number of subjects that had heard about the HPV vaccine (p < 0.001), that knew when it should be administered (p = 0.039) and that it is available in Serbia (p = 0.029). Table 4. Source of information and its association with cervical cancer knowledge score, HPV and HPV vaccine awareness. The complete statistical analysis regarding the sources of information among our participants and their relationship with CC-KS, HPV and the HPV vaccine awareness is shown in Table 4.

Discussion
"An ounce of prevention is worth a pound of cure," an old quote popularized by Benjamin Franklin (1735), makes a lot of sense in medicine [25]. Prevention is especially important in oncology, since cancer is one of the biggest public health issues in the modern world. Paradoxically, despite being highly suitable for thriving preventive programs, CC still represents the most common gynecological cancer worldwide [1]. Therefore, public education is needed for a better understanding of CC, its risk factors and for better disease prevention. Such education programs are only efficient when planned with carefully selected target groups. Aiming to define possible groups for these education programs in Serbia, in this article, we analyzed the knowledge and awareness of first-year female students about CC and HPV.
Our students demonstrated decent knowledge about CC, with the mean score being more than half of the total possible score. However, in a study done in Serbia's capital, Belgrade, a considerable portion of women had insufficient knowledge about CC, especially those who did not participate in mass screening [26]. This discrepancy can be explained by differences in the study population, since our research included only college students, the future intellectual elite of the state. Furthermore, a good share of our participants had affiliation with the medical profession, which greatly contributed to a higher CC knowledge level. In that manner, we proved that subjects involved in medical studies or those that attended medical high school had the highest knowledge about CC. Other authors also confirmed that medical students are highly educated on this matter [27,28], which is understandable and very commendable, as they represent the leaders of further education of the general public about CC. In accordance with the previous interpretation, the results of another Serbian study showed that both students of a secondary medical school and midwives who had finished at that same school had significantly better knowledge than patients [29]. Apart from education, we also identified good financial status, living in urban areas and having parents with higher education as factors that contribute to better knowledge about CC. This means that higher socio-economic status is associated with a better health standard and can explain the fact that the highest prevalence of CC is seen in underdeveloped countries [1]. However, data from relevant studies are inconsistent regarding this matter, occasionally showing low knowledge about CC even in people from developed countries. For example, in other Balkan countries, the situation regarding CC and HPV knowledge is generally quite poor. In Romania, even though the majority of interviewed women had heard of HPV, the level of knowledge was low, especially about risk factors for infection [30]. Likewise, Greek adolescents were also insufficiently informed about risk factors and protection methods against CC [31]. A similar situation is also recorded in Hungary and Slovenia [32,33]. The inconsistency of the results from different studies was also noted regarding the association between relationship status and knowledge about CC. While in our study, students in relationship had a higher CC-KS, there are other studies in which being single was associated with knowledge about CC screening [34].
Despite relatively good knowledge about CC in the investigated population, HPV awareness was quite low. We established that a bit less than 50% of the investigated students had heard of HPV infection. Research performed in Slovenia [33] that included women of a wide range of ages and research that included adolescents from Greece [31] also noted low awareness of HPV. On the other hand, studies in the UK [35] and in neighboring Romania [30] showed that between two thirds and three quarters of questioned women had heard about HPV. Such a result was also recorded in our study among subjects that finished medical high school and those attending a medical faculty. Furthermore, these participants had significantly more chance of knowing about HPV, just as other studies established [36]. In addition, in our study, females in relationships and the ones that had sexual experience were more likely to have heard about HPV. This is encouraging since it implies that the subjects who enter into a relationship at least have basic awareness about HPV. Research completed in Germany also found that women that had had sexual intercourse at least once had more often heard of HPV [37].
A significant part of our study was also an investigation of HPV vaccination awareness. This topic was especially important, as CC prevalence in Serbia is very high [22,23]. Unfortunately, the obtained results are disappointing. Although 10 years have passed since the first shot was administered in Serbia, only one fifth of the students knew about the existence of the HPV vaccine and only 14.2% knew about both HPV and its vaccine. Even worse are the findings that, among those who were aware of the vaccine's existence, only a few knew when it should be administered and that it is available in Serbia. These findings suggest that awareness about the prevention of CC, as an important public health issue, is still at a very low level, which can and should be raised by educating the populace. Another important element in the promotion of CC prevention is introducing the HPV vaccine into the National Immunization Program (NIP). Unfortunately, the HPV vaccine, although recommended, is not yet integrated in the Serbian NIP. On the other hand, this was done years ago in most EU countries, so their good perception about CC prevention is not surprising. In Italy, one of the world's most developed countries, a remarkably high percentage of adolescents that know about HPV vaccine is observed [38]. Likewise, Serbia's neighbors, Romania [30] and Hungary [32], as well as nearby Greece [31], also register good awareness of the HPV vaccine, despite the previously mentioned low knowledge. All these countries are in the EU and have included the vaccine in their NIPs, indicating its importance. On the other hand, data from Ukraine, an underdeveloped country that had not introduced the HPV vaccine in its NIP yet, show relatively low awareness of the vaccine among second-year medical students, but still a bit better than among our participants [39]. There were a small number of female adolescents that received the HPV vaccine, after a gynecologist's recommendation. We do not have the data about vaccinated persons yet and we do not know the exact number of vaccinated persons.
Finally, we investigated the source of participants' awareness and knowledge. The most frequently chosen source was the media with, 1011 students answering that this source contributed to their knowledge on the subject. Likewise, in another Serbian study, participating females identified the media as the main source of information about CC risk factors [40]. This is a substantial change from previously reported results that the media is a "poor source of comprehensive information on cervical cancer" [41]. Two separate pieces of research from Hungary and Slovenia also found that the media, namely the internet and magazines, to be dominant sources of information about this topic [32,33,42]. This confirms that the media has a great impact on public opinion and thus can be a powerful tool for increasing the awareness of CC. This source was also the most commonly selected among students that had heard about HPV, just as it was in an American study that also included young women [43]. Like so, those who selected the media as source of information had a significantly greater chance of knowing about HPV. In addition, a statistically significant difference in the CC-KS was established between participants who had been informed through the media and those who had not. Unfortunately, the knowledge score was more than one point lower than the score of participants who chose OHE or personal contact as a source. Such a result indicates that, although information from the media is important, it often does not have enough credibility and can even, if not critically assessed, produce counter effects and mislead the audience. Therefore, the accuracy of the information is crucial. Furthermore, the finding that there is no significant difference in HPV vaccination awareness between those who did and did not select the media as a source indicates that future media campaigns should be especially focused on this topic. Messages about HPV infection and HPV vaccination and its importance for the prevention of CC conveyed through media-to parents, providers, policymakers and the general public-may contribute to a rise in vaccination coverage. Regarding the competence of the source, according to the results of this study, OHE is the most efficient one, with the CC-KS being the highest in the participants who picked it. Besides, OHE significantly affected the awareness of HPV and was the only source that was associated with a significant likelihood of participants having knowledge about the HPV vaccine. While this is an expected result, it is more than welcome since it shows that OHE represents a trustworthy source, which should have a dominant role in educational programs. Other surveys also showed that physicians are the most desirable source of information, which is highly positive and means patients also recognize OHE as a qualified and authoritative source [44,45]. The third possible way of gaining information about CC was interpersonal communication with friends or family, which in our survey produced paradoxical results. Students that acquired knowledge through this source had a significantly higher CC-KS. On the other hand, a significantly smaller number of subjects that knew about HPV marked friends or family as an information source, while having knowledge about the vaccine was not associated with this source. Accordingly, although obtaining information from family or friends is easy, convenient and often the most common source of the subjects' knowledge [45] our data suggest that it should not have the main role in education.

Conclusions
The present study revealed sufficient knowledge about CC in the examined population, but awareness about HPV infection was rather low. The situation about HPV vaccine awareness was even more disappointing, since only 14.2% had heard of both HPV and the HPV vaccine. Moreover, only a negligible number of students had knowledge about the best time to get the HPV vaccine and that the vaccine is available in Serbia. Since the highest score of knowledge about CC was determined in the group of students who denoted organized health education as a source of information, this established scenario should serve as a guide for the development of high-quality education programs directed particularly towards raising awareness about CC prevention and the importance of HPV vaccination. It can be recommended that a special focus should be on students whose commitments in education are not related to health sciences. Furthermore, in accordance with the result that the media was the most common source of information, these campaigns should be conducted using exactly this information source. However, steps must be taken in order to increase its reliability, thus making the media a powerful instrument through which correct information could be spread to general public. In addition to such well-targeted health promotion campaigns, an official national strategy is also necessary with the goal to introduce the HPV vaccine in the NIP, with monitoring and real support from authorities. Only by achieving these goals can the CC burden be reduced.