Human Papilloma Virus Infection and Gene Subtypes Analysis in Women Undergoing Physical Examinations: A 2015-2020 Study in Wenzhou,China

Abstract

Background

Persistent infection with high-risk human papillomavirus (HPV) is closely related to cervical cancer. The epidemiologic characteristics of cervical HPV have regional differences. Therefore, it is necessary to develop the most favorable policies according to the actual situation of each region to prevent and reduce the prevalence of cervical cancer. This retrospective cross-sectional study investigated the prevalence, gene subtypes, and temporal trends of HPV in women undergoing physical examination in Wenzhou, to provide a decision-making basis for further prevention and control of HPV.

Methods

A total of 31 131 cervical exfoliated cell specimens obtained from physical examinations in Wenzhou, a coastal city of China, from 2015 to 2020 were collected. The age distribution was analyzed using the chi-squared test, and the time change trend was analyzed using the Mann–Kendall trend test. On this basis, the distribution characteristics of the HPV subtypes were analyzed.

Results

The total prevalence rate was 9.55%, and the prevalence rate in different age groups ranged from 7.77% to 14.16%. The prevalence rate in different years was 8.84%-11.83%. The prevalence rate was bimodal; it was highest in the group 25 years old, followed by the group >61 years old. The top five high-risk gene subtypes were HPV52, HPV58, HPV53, HPV16, and HPV39, whereas the low-risk subtypes were HPV61, HPV81, HPV44, HPV43, and HPV55. Of all the positive samples, 76.03% were infected with a high-risk subtype.

Conclusion

Most female HPV patients in Wenzhou are infected with high-risk gene subtypes. Therefore, physical examination and screening for HPV should be further strengthened, and the corresponding vaccination policy should focus on high-risk gene subtypes.

Plain language summary

Background: Persistent infection with high-risk human papillomavirus (HPV) is closely related to the occurrence of cervical cancer. The epidemic characteristics of cervical HPV have regional differences, Therefore, it is necessary to formulate the most favorable policies according to the actual situation of each region, so as to prevent and reduce the prevalence of cervical cancer. This retrospective cross-sectional study investigated the prevalence, gene subtypes and temporal trends of HPV in women undergoing physical examination in Wenzhou. To provide decision-making basis for further prevention and control of HPV. Methods: A total of 31,131 cervical exfoliated cell specimens obtained from physical examinations in Wenzhou, a coastal city of China from 2015 to 2020, were collected. The age distribution was analyzed by the chi-squared test, and the time change trend was analyzed by the Mann–Kendall trend test. On this basis, the distribution characteristics of HPV subtypes were analyzed. Results: The total prevalence rate was 9.55%, and the prevalence rate in different age groups ranged from 7.77% to 14.16%. The prevalence rate in different years was 8.84%-11.83%. The prevalence rate was bimodal; it was highest in the group less than or equal to 25 years old, followed by the group greater than 61 years old. The top five high-risk gene subtypes were HPV52, HPV58, HPV53, HPV16 and HPV39, while for low-risk were HPV61, HPV81, HPV44, HPV43 and HPV55, respectively. Of all the positive samples, 76.03% were infected with a high-risk subtype.

Keywords

high-risk subtype low-risk subtype vaccines cervical cancer COVID-19 multiple infections

Background

Cervical cancer is the most common type of cancer in women worldwide and is one of the leading causes of cancer-related death in women. In 2020, there were 604 200 new cases of cervical cancer and 310 000 cases of cervical cancer-related death globally,¹ seriously threatening the lives and health of women. Of this, 85% of the cancer burden occurs in developing countries.^2–6 The incidence and mortality rate of cervical cancer in China are at the international medium level.⁷ Cervical cancer is the only malignant tumor with a clear and preventable cause, which is caused by persistent and close infection with the human papilloma virus (HPV).⁸ It is mainly transmitted through sexual activity.^9–11 Early screening can effectively prevent the occurrence and development of precancerous lesions and cancer. In 2020, WHO released the Global Strategy to Accelerate the Elimination of Cervical Cancer, with 194 countries committing to eliminate cervical cancer for the first time.¹² In recent years, the incidence of cervical cancer has been on the rise in China, especially among young people.^13,14 China has the highest number of new cases and deaths from cervical cancer.¹⁵ How to deal with it is a major challenge in the prevention and treatment of cervical cancer. This study investigated the prevalence, genetic subtypes, and time trend of HPV among women who underwent physical examination in Wenzhou City from 2015 to 2020. We analyzed the data using a retrospective cross-sectional epidemiological method to provide a scientific basis for developing prevention strategies.

HPV, a mucosal and skin epithelial virus, is the primary cause of cervical epithelial hyperplasia and cervical cancer.¹⁶ Previous studies have shown spatial and temporal heterogeneity in the prevalence, age distribution, and subtype distribution of HPV.^17–19 From the perspective of regional prevention and control of cervical cancer, vaccination effectiveness is closely related to the prevalence and distribution of HPV infection.²⁰ However, HPV infection usually does not cause physical discomfort, and the incubation period from precancerous lesions to cervical cancer can be up to 10 years. In general, comprehensive prevention and control measures such as early screening, early diagnosis, early vaccination, and early treatment can effectively reduce the incidence of cervical cancer.^21,22 Physical examination helps to reflect local cervical cancer rates, and screening can detect precancerous lesions earlier in healthy women.¹⁹

The epidemic characteristics of cervical HPV have regional differences. Therefore, it is necessary to develop the most favorable policies according to the actual situation of each region to prevent and reduce the prevalence of cervical cancer. Wenzhou is an economically developed coastal region in eastern China with a population of approximately 9 million. However, data on the prevalence and genetic subtypes of HPV among women examined in Wenzhou and many other areas are still lacking. HPV DNA detection is one of the main methods to screen and diagnose cervical lesions from the angle of etiology, which has the characteristics of high speed and high sensitivity.^23,24 In this study, multiple polymerase chain reaction (PCR) with universal primers and flow cytometry were used to detect HPV DNA in cervical cells of 31 131 women examined at Wenzhou Hospital during 2015-2020. The results revealed the distribution characteristics and genetic subtypes of HPV epidemic and provide epidemiological basis for cervical cancer vaccination. At the same time, it is of great clinical significance to judge the occurrence and development of diseases as an evaluation index for doctors’ diagnosis and treatment.

Materials and Methods

General Information

The data were collected from 31 131 samples of exfoliated cervical cells obtained during physical examinations at a hospital in Wenzhou, Zhejiang Province, China, between January 2015 and December 2020. Duplicate samples from the same woman were excluded. All participants were women who voluntarily visited the hospital for medical examination. Participants ranged in age from 19 to 84 years, with a median age of 44 years and a mean age (±SD) of 44 (±11) years. They were divided into the following nine groups according to their age: ≤25, 26-30, 31-35, 36-40, 41-45, 46-50, 51-55, 56-60, and ≥61 years old.

Patient and Public Participation

This retrospective study was approved by the Ethics Committee of a hospital in Wenzhou, Zhejiang Province (approval number 2021-62). The data were obtained from an anonymized dataset typically used for administrative purposes and did not involve patient interventions. The dataset contains only diagnostic information for outpatients, patient identification number (each patient has a unique number for identification), date of visit, age, and gender. The requirement for informed consent was waived by the Ethics Committee because the data were anonymous. Patients or the public were not involved in the design, implementation, reporting, or dissemination of our studies.

Instrument, Reagents and HPV Genotyping

In this study, HPV DNA in cervical cells was detected by PCR using universal primers and flow cytometry. The Touch thermal cycler with a 96-well module was obtained from Hangzhou Biotechnology Co., Ltd. A Luminex 200 flow cytometry platform was obtained from Luminex. The HPV-DNA typing kit was obtained from Shanghai Tou Jing Life Technology Co., Ltd. The kit can detect 27 HPV subtypes, including 17 high-risk subtypes (HPV16, HPV18, HPV26, HPV31, HPV33, HPV35, HPV39, HPV45, HPV51, HPV52, HPV53, HPV56, HPV58, HPV59, HPV66, HPV68, and HPV82) and 10 low-risk subtypes (HPV6, HPV11, HPV40, HPV42, HPV43, HPV44, HPV55, HPV61, HPV81, and HPV83), as classified by the International Agency for Research on Cancer. HPV genotyping was performed using the HPV typing test kit (PCR + flow fluorescence hybridization). This method was approved by the State Food and Drug Administration (China Food and Drug Administration Certificate (2014):3 400 847). All tests were performed in accordance with the technical operating procedures of the hospital laboratory.

Specimen Collection and Treatment

Specimens were collected as follows. First, the vagina was opened and the cervix was exposed using a vaginal dilator. Second, the cervix and its secretions were wiped with a cotton swab. Third, the cervical brush was rotated four to five times in a clockwise direction. Finally, the cervical brush head was placed into an eluent tube containing cell preservation solution, and the tube was closed and marked, keeping the tube upright. Samples were stored at 4°C and tested within 3 days using a kit following the manufacturer’s instructions.

Statistical Methods

All HPV data from 2015 to 2020 were entered into an Excel spreadsheet and then analyzed using SPSS, and the overall and type-specific prevalences of HPV were calculated. All genotypes from single and multiple infections were computed individually. These data were also stratified by age (≤25 years, 26-30 years, 31-35 years, 36-40 years, 41-45 years, 46-50 years, 51-55 years, 56-60 years, and ≥61 years). Count data are expressed as frequency or percentage. The chi-square test was used to compare the positive rate of each group, and the Bonferroni method was used to adjust the P-value for paired comparisons between the two groups. The time trend of the positive rate over the years was analyzed using the Mann–Kendall trend test. Statistical tests were two-tailed. Statistical analysis was performed using R. If P ≤ .05, the differences were considered statistically significant.

Results

HPV Infection Status

Among the 31 131 patients, 2973 were infected, with a total prevalence rate of 9.55% (Table 1). As shown in Table 1, 86.77% of the subjects were aged 26-55. The prevalence of HPV infection was bimodal; it was highest in the ≤25 years age group (14.16%), followed by the ≥61 years age group (13.23%). The HPV-positive rate in women aged 26-30, 31-36, 36-40, and 41-45 years was relatively low, with an average of 8.60%. Prevalence was different among age groups (χ2 = 124, P < .001). There was no significant difference in prevalence between the different age groups after Bonferroni correction.

Table 1.

Prevalence of HPV in Different Age Groups.

Age Group (Years)	Number of Positive Samples	Number of Negative Samples	Number of Samples	Positive Rate (%)
≤25	65	394	459	14.16
26-30	244	2845	3089	7.90
31-35	451	4906	5357	8.42
36-40	441	5232	5673	7.77
41-45	455	4644	5099	8.92
46-50	433	3903	4336	9.99
51-55	402	3000	3406	11.82
56-60	236	1621	1857	12.71
≥61	246	1613	1859	13.23
Total	2975	28 158	31 131	9.55

During 2015-2020, the annual positive rate fluctuated in the range of 8.69%-11.83%, with an average of 9.70% (Table 2). The difference in the HPV-positive rate in different years was statistically significant (χ2 = 33, P < .001). After Bonferroni correction, there was no significant difference in the prevalence rate. According to the Mann–Kendall trend test, there was no statistical significance in the time trend of the HPV positive rate during the study period (Z = .73, P = .46).

Table 2.

Prevalence of HPV in Different Years.

Year	Number of Positive Samples	Number of Negative Samples	Number of Samples	Positive Rate (%)
2015	462	4417	4879	9.47
2016	384	2863	3247	11.83
2017	375	3703	4078	9.20
2018	588	6182	6770	8.69
2019	654	5731	6385	10.24
2020	510	5262	5772	8.84
Total	2973	28 158	31 131	9.55

Distribution of HPV Subtypes

Among the 2973 HPV-positive samples, 3587 strains with 27 subtypes were detected (Table 3), of which 17 were high-risk and 10 were low-risk, accounting for 71.79% and 28.21% of the total subtypes detected, respectively. The top five high-risk subtypes were HPV52, HPV58, HPV53, HPV16, and HPV39, accounting for 14.44%, 8.75%, 8.34%, 6.86%, and 5.07%, respectively. The top five low-risk subtypes were HPV61, HPV81, HPV44, HPV43, and HPV55, accounting for 6.58%, 5.30%, 4.15%, 3.18%, and 3.15%, respectively.

Table 3.

Distribution of HPV Subtypes.

HPV Subtype	Number of Strains	Proportion (%)
High-risk
HPV52	518	14.44
HPV58	314	8.75
HPV53	299	8.34
HPV16	246	6.86
HPV39	182	5.07
HPV51	151	4.21
HPV18	144	4.01
HPV56	138	3.85
HPV59	122	3.40
HPV33	97	2.70
HPV66	95	2.65
HPV68	69	1.92
HPV31	65	1.81
HPV35	50	1.39
HPV82	43	1.20
HPV45	40	1.12
HPV26	2	.06
Low-risk
HPV61	236	6.58
HPV81	190	5.30
HPV44	149	4.15
HPV43	114	3.18
HPV55	113	3.15
HPV6	86	2.40
HPV42	63	1.76
HPV11	36	1.00
HPV83	14	.39
HPV40	11	.31

HPV is a mucosal and skin epithelial virus that is a major factor in cervical epithelial hyperplasia and cervical cancer. The main factors of cervical epithelial hyperplasia and cervical cancer include more than 100 subtypes, among which more than 30 subtypes can infect human reproductive tract mucosa, and the pathogenic ability of different subtypes is quite different. Based on whether the hyperplastic lesions caused by them are carcinogenic, they are divided into two categories: high-risk type and low-risk type,²⁵ among which the high-risk type is related to cervical cancer.

Multiple HPV Infections

Of the 2973 HPV-positive samples, single infections were the most common (2478 cases, 83.35%), followed by double infection (401 cases, 13.49%), triple infection (73 cases, 2.46%), quadruple infection (17 cases, .57%), and quintuple infection (4 cases, .13%) (Table 4). Of the positive samples, high-risk subtypes were detected in 76.03% of the cases. In single, double, and triple infection samples, the detection rates of high-risk subtypes were 71.12%, 89.78%, and 94.52%, respectively.

Table 4.

Multiple Infections of HPV.

Category	Number of Samples	Proportion of Positive Samples (%)	Number of High-Risk Subtypes Detected	Proportion of High-Risk Subtypes Detected (%)	Major High-Risk Subtypes
Single infection	2478	83.35	1812	71.12	HPV52, HPV58, HPV53, HPV16, HPV39
Double infection	401	13.49	360	89.78	HPV52, HPV58, HPV53, HPV16, HPV39
Triple infection	73	2.46	69	94.52	HPV53, HPV52, HPV58, HPV56, and HPV39

Discussion

Cervical cancer is one of the major causes of cancer death in women worldwide²⁶ and one of the major public health problems worldwide. Seriously threatening the lives and health of women. In this study, 31 131 cervical exfoliated cell samples were collected from female physical examinations in Wenzhou, China, from 2015 to 2020. Mann-Kendall trend test was used to analyze the time change trend of the prevalence rate and the distribution characteristics of HPV genotypes. In contrast to previous studies, physical examination is usually carried out without any symptoms, to reflect the incidence of cervical cancer more objectively in the region and help to develop cervical cancer screening and prevention strategies in line with local conditions. Simultaneously, screening can detect cervical precancerous lesions earlier in healthy women and get active treatment in early detection, to achieve the purpose of early detection, early diagnosis, and early treatment. The results of this study can provide a basis for further improvement of HPV diagnosis and vaccine application in the region. In addition, it is of great clinical significance to judge the occurrence and development of diseases as an evaluation index of doctors’ diagnosis and treatment.

The study found that the total infection rate of HPV was 9.55%, and mainly high-risk subtypes were detected. Among high-risk HPV subtypes, HPV52 was the most common (14.44%), followed by HPV58 (8.75%), HPV53 (8.34%), HPV16 (6.86%), and HPV39 (5.07%). In HPV-positive cases, monotypic infection was significantly more common than polytypic infection. In contrast, polygenic infection rates were significantly higher in those aged ≤25 years and those aged ≥61 years. The HPV infection rate was bimodal in the different age groups. The first infection peak occurred in the age group ≤25, the infection rate of 14.16 %; The second infection peak occurred in the ≥61 age group, with an infection rate of 13.23%. The infection rate of these two groups was significantly higher than the total infection rate of 9.55%. It was highest among young people and second highest among older people. This might be due to different sexual activity, cervical local immune susceptibility, or immune self-clearance status. The higher positive rate in women under 25 years of age is related to the lack of self-protection awareness and also to imperfect acquired immunity, frequent sexual life, and more induced abortion.²⁷ For young women, health literacy education, especially sex education, should be strengthened. The prevalence of HPV infection in middle-aged and elderly women is on the rise, which may be due to changes in menopausal hormones and sex, the decline of immune function in the elderly, and the weakening of the ability to inhibit or eliminate HPV infection.²⁸ Another reason may be the latent and reactivated high-risk infection, which leads to the second peak of prevalence in middle-aged and elderly women.²⁹ For postmenopausal middle-aged and elderly women, it is also necessary to strengthen screening for early cervical cancer.^30–32

This study shows that the HPV positive rate in physical examination women in Wenzhou is at a low level compared with the other areas in China (Table 5). The reason may be that both the sample size and period are different. For example, The prevalence of HPV in gynecological outpatients and women undergoing medical examinations in 2018-2020 was higher than that in 2015-2017.³³ Developing countries on a global scale, the distribution of HPV gene subtypes can also vary across geographic regions and among different populations. In the Central Anatolian region of Turkey, the prevalence of HPV among women aged 30-65 years was 3.16%, with HPV16 being the most commonly tested type (14.8%).³⁴ In Lampang, Thailand, the prevalence of HPV among women aged 30-65 years was 5.40%, and the most common gene subtype was HPV52 (17.6%).³⁵ In Benin, West Africa, data showed a very high HPV prevalence of 33.2% among women, with HPV59 and HPV35 being the most common types tested.³⁶ The above-cited references are only a few regional survey reports, but the results show the differences in the epidemiological characteristics of HPV infection among different regions. It is mainly manifested in the following aspects: the positive rate of the screening population is different; and the most mainstream infection types were different. The age group at the highest risk is also different. The prevalence of HPV in Wenzhou, China, is in the lower middle level; however, because most of the infected samples detected high-risk gene subtypes, the situation is not optimistic. The results of this study can provide a data basis for the monitoring and prevention of HPV infection and a decision-making basis for the prevention of cervical cancer in the study area.

Table 5.

HPV-Positive Rate in Women Tested in Other Regions of China.

Region	Time	Number of Samples (Case)	Positive Rate (%)	Reference
Shanghai	2017.8-2019.10	14 394	16.45	11
Shandong	2018.1-2018.12	1678	18.95	12
Anhui	2018.4-2018.12	17 160	17.42	13
Fuzhou	2014.2-2017.12	18 542	15.7	9
Dalian	2017.6-2018.8	1132	18.73	14
Hefei	2016.1-2017.12	2558	15.52	15
Zhengzhou	2018	14 426	12.4	16
Chongqing	2019.4-2019.12	2062	14.21	17
Huizhou	2016.8-2017.6	702	14.4	18
Wenzhou	2015.1-2020.12	31 131	9.55	This study

The presence of HPV infection and the HPV subtype(s) are important factors for assessing a woman’s risk of cervical cancer. Studies have shown that there are differences in HPV subtype between different regions and different ethnic groups. In western developed countries such as Britain and the United States, the most common high-risk subtype is HPV16, followed by HPV18, HPV45, HPV33, and HPV31.³⁷ In Greece the most commonly detected gene subtype was HPV16 (5.3%), followed by HPV53 (4.9%).³⁸ The geographical environment of China is quite different from that of the West, and the distribution of HPV subtypes is different from that of the West. However, China has a vast territory, and the economic development level and medical service capacity of different regions are different, so there are certain differences in female HPV infection rates. Previous studies on women in Mainland China showed that HPV infection of subtypes HPV16, HPV52, HPV58, HPV53, and HPV18 was the main mode of infection in China, with infection rates as high as 19.0%.^39–41 Therefore, further longitudinal studies on cervical cancer prevalence and incidence, as well as age stratification and classification strategies in initial HPV screening, are necessary. Based on regional HPV epidemiology, vaccines that are more suitable for inhibiting high-risk HPV subtypes can be developed to make cervical cancer vaccine coverage more accurate and effective.

To compare HPV infection rates before and after the COVID-19 pandemic, data from 2019 and 2020 were further analyzed. As can be seen from Table 2, the HPV infection rate decreased from 10.24% to 8.84% in 2019, Prevalence in the first 4 years ranged from 8.69% to 11.83%. Thus, the decrease could be due to normal fluctuations, or it could be that control measures during the COVID-19 pandemic may have reduced HPV transmission. During the COVID-19 pandemic, strict outbreak control measures and social distancing measures, which limited all types of contact among people, not only stopped the spread of COVID-19, but also reduced the spread of HPV. While these measures negatively affected the mental health of the general public and routine cancer screening and treatment, they also controlled the spread of HPV, other seasonal respiratory viral infections,and sexually transmitted infections.^42,43 During the COVID-19 pandemic, not only seasonal respiratory virus infection rates dropped dramatically, but also the incidence of several sexually transmitted diseases, including syphilis, chlamydia, and gonorrhea^.44,45

HPV vaccination is an important part of the primary prevention measures for cervical cancer.^39,40 This study shows that, In Wenzhou area, the detection rates of high-risk HPV gene subtypes were 71.12%, 89.78% and 94.52% in single infection samples, double infection samples and triple infection samples, respectively. At present, there are bivalent HPV vaccine (Cervarix, HPV16/18) and quadrivalent HPV vaccine (Gardasil, HPV6/11/16/18) on the market in China. Overall, we found that HPV52, HPV58, HPV53, HPV16 and HPV39 were the main high-risk subtypes of HPV in Wenzhou, which was similar to most regions in China (Table 6). Since bivalent and tetravalent cervical cancer vaccines cannot fully cover the main high-risk subtypes in Wenzhou, nine-valent HPV vaccine (Gardasil 9, HPV6/11/16/18/31/33/45/52/58) is recommended.^46,47 In addition, there are still many shortcomings in this paper. On the one hand, although the time span of data collected in this paper is relatively long, the sample size is still relatively small. On the other hand, the results of cervical fluid based cytology were not compared with the results of colposcopic biopsy, making the relationship between HPV infection and cervical lesions impossible to analyze in depth. In the future, the relationship between HPV infection types and cervical lesions, as well as the pathogenic mechanism of HPV, will be the focus of our research.

Table 6.

Common HPV High-Risk Subtypes of Physical Examination Women.

Region	High-Risk Subtype	Reference
Shanghai	HPV52, HPV53, HPV58, HPV68	11
Shandong	HPV16, HPV58, HPV52, HPV51	12
Anhui	HPV52, HPV16, HPV53, HPV48	13
Fuzhou	HPV52, HPV58, HPV53, HPV16	9
Dalian	HPV52, HPV53, HPV58, HPV16	14
Hefei	HPV52, HPV16, HPV58, HPV53	15
Zhengzhou	HPV52, HPV16, HPV58, HPV51	16
Chongqing	HPV52, HPV58, HPV51, HPV16	17
Huizhou	HPV52, HPV16, HPV58	18
Wenzhou	HPV52, HPV58, HPV53, HPV16	This study

Conclusions

In the present study, we analyzed the epidemiologic characteristics of cervical HPV in Wenzhou, with a focus on the distribution characteristics of HPV subtypes. It was found that the high-risk subtypes were HPV52, HPV58, HPV53, HPV16, and HPV39, and 76.03% of the infected persons were infected with high-risk subtypes. Our study highlights that countermeasures are needed to strengthen the prevention and control of HPV. The results of this study provide a basis for further improving HPV diagnosis and vaccine application locally and provide guidance for the subsequent prevention and control of cervical cancer. We also hope to provide a useful reference for the prevention and control of HPV in other areas.

Footnotes

Author’s Note

All authors agree to publish the final manuscript.

Author Contributions

HX conceptualized and designed this study. HH and MZ developed methodologies for data collection and analysis. YG and YZ participated in data collection and analysis. YG and HX participated in writing and editing. All authors were subsequently involved in critically revising the manuscript. All authors have approved the final version of the manuscript to be published and agreed to be accountable for all aspects of the work.

Declaration of Conflicting Interests

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

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by Soft Science Project of Ministry of Science and Technology (2011GXQ4D050), Natural Science Foundation of Zhejiang Province (LY12H12002).

Ethical Statement

ORCID iDs

Yang Gao

Hongli Xie

Data Availability Statement

All data generated or analyzed during this study are included in this published article.*

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