Prevalence, trends, and geographic distribution of human papillomavirus infection in Chinese women: a summative analysis of 2,728,321 cases

Abstract

Background

Cervical cancer (CC), primarily caused by human papillomavirus (HPV) infection, remains a significant global health concern. We aimed to comprehensively investigate the epidemiological status of HPV in China.

Methods

Data from 2,728,321 women undergoing routine cervical examinations at 2127 medical institutions nationwide from January 2017 to June 2023 were analyzed. HPV genotype testing was conducted using HPV DNA typing kits.

Results

The overall HPV prevalence was 17.70%, with 13.12% classified as high-risk HPV (HR-HPV) and 4.58% as low-risk HPV (LR-HPV). Notably, HPV52 emerged as the most common carcinogenic type, followed by HPV58 and HPV16. Age-specific prevalence revealed a bimodal distribution, with peaks observed in women under 21 and over 61 years of age. Geographically, the south (19.48%) exhibited the highest infection rate, while the northwest (12.36%) had the lowest. Furthermore, HPV infection rates were higher during winter and spring. Although HPV infection rates have remained stable overall over the past 7 years, the infection rate in 2023 (14.76%) has declined relative to 2017 (16.17%) (P < 0.05).

Conclusions

This study provides comprehensive insight into HPV epidemiology in China and guidance for future vaccine development and cervical cancer prevention strategies.

Background

The global cancer burden has emerged as a major challenge in the public health and economy of society in the 21st century, resulting in approximately 16.8% of the global population deaths [1]. Globally, in 2020, there were an estimated 604,127 cervical cancer (CC) cases and 341,831 deaths, with a corresponding age-standardized incidence of 13.3 per 100,000 women-years and a mortality rate of 7.2 per 100,000 women-years. It is estimated that more than half of CC cases and deaths occur in Asia, with 40% of deaths occurring in China (17%) and India (23%) [2]. Human papillomavirus (HPV) is a necessary, but not sufficient, cause of CC [3, 4]. The World Health Organization (WHO) guideline for screening and treatment of cervical pre-cancer lesions for cervical cancer prevention (2021) [5] and the “Cervical Cancer Screening Work Plan,” formulated by the National Health Commission of China in 2022, established the use of high-risk HPV testing for initial screening of CC. HPV DNA testing specifically refers to the detection of a group of highly carcinogenic HPV genotypes, including 14 high-risk HPV types (HPV16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68).

HPV, a DNA virus, can infect human skin and mucous membranes, leading to the proliferation of squamous epithelial cells [6]. At present, more than 200 types of human papillomavirus have been isolated and identified, which can be divided into low-risk human papillomavirus (LR-HPV) and high-risk human papillomavirus (HR-HPV) types according to pathogenicity or carcinogenic risk. LR-HPV generally lacks carcinogenicity, and includes types such as 6, 11, and 42, while HR-HPV, including types 16, 18, 31, 52, 56, and 58, is closely associated with high-grade cervical lesions, persistent HPV infection, and progression to invasive CC [7,8,9].

A meta-analysis of 194 global studies found a crude HPV infection rate of 7.2% (95% CI: 7.1–7.2%). After adjusting for factors, such as regional distribution, mean age of women, study year, and study methods, the estimated HPV infection rate among women with normal cervical cytology worldwide is approximately 11.7%. The highest prevalence of cervical HPV among women is in sub-Saharan Africa (24%), followed by Latin America and the Caribbean (16%), eastern Europe (14%), and South-East Asia (14%) [10].

Geographic differences in HPV infection rates are associated with levels of economic development. Sometimes the incidence of CC is lower in more developed areas, but this does not mean that these areas have lower HPV infection rates, but rather may be due to more effective screening and treatment programs in economically developed areas. In China, the adjusted overall HPV infection rate among the general population ranges from 13.1 to 18.8%. Most of the existing studies in China are focused on specific regions, while nationwide infection studies are mostly derived from systematic reviews and meta-analyses, which may result in heterogeneity due to differences between individual studies. Regarding HPV prevention, existing evidence suggests that HPV vaccination is feasible [11, 12]. Vaccination programs can safely prevent 70% to 90% of HPV infection-related cancers, reducing the risk of CC and other anogenital cancers in women, providing long-term protection for vaccinated individuals [13, 14]. However, in China, the HPV vaccination rate among adolescents is less than 3%, and the vaccination rate among the entire population is less than 6% [15]. Additionally, China’s complex and diverse geographical environment has led to regional differences in HPV genotype predominance. This phenomenon underscores the importance of targeted HPV vaccine development and promotion in preventing CC in China. Understanding the specific HPV infection situation in each region, including genotype distribution and the prevalence of single and multiple infections, can help determine targeted vaccine types and vaccination strategies. Strengthening research on HPV infection in China is important for safeguarding women’s health and reducing the occurrence of CC. Therefore, we collected HPV testing data from different provinces in China to determine the HPV burden among women, guiding HPV vaccination strategies and CC prevention plans.

Methods

Study population

The study population comprised the examination results of women who underwent routine cervical examinations at 2127 hospitals, community health clinics, and other medical institutions nationwide from January 2017 to June 2023. Initially, 2,923,683 cases were collected. Inclusion criteria were as follows: (1) subjects were between 18 and 80 years of age, (2) location information involved the province, (3) there were clear positive or negative test results of any type, and (4) gender was limited to females. Exclusion criteria included pregnancy, total hysterectomy, systemic infection or autoimmune disease, uterine surgery within 3 days, or other cancers. Exclusion also included the removal of duplicate cases according to the uniqueness of the test kit strip number. Ethical approval was obtained from the Ethics Committee of the First Affiliated Hospital of Shantou University Medical College (Approval B-2024-113).

We further analyzed the basic characteristics of the study population and showed the distribution of the main characteristics through graphs. The study subjects ranged in age from 18 to 80 years (Additional file 1: Fig. S1A). Women were mainly concentrated between the ages of 25 and 50, with the largest number in the 31 to 35 age group, numbering more than 120,000 and accounting for a significant proportion of the total population. This may be related to the higher motivation of women in this age group to undergo cervical screening. From 2016 to 2023, the number of subjects fluctuated, peaking in 2021 at more than 680,000 screenings, with slightly lower numbers in 2020 and 2022 (Additional file 1: Fig. S1B). The Monthly distribution is shown in Additional file 1: Fig. S1C. The number of screenings gradually increased from January, peaked in May–June, and then decreased in November–December. As for regional distribution across the country, the geographical distribution of subjects showed some imbalance (Additional file 1: Fig. S1D). Population screening numbers were higher in eastern and central regions (such as Henan and Jiangsu provinces), and lower in western and remote regions. This may be related to regional economic development level, distribution of medical resources, and differences in health screening coverage.

HPV genotyping

HPV deoxyribonucleic acid (DNA) typing was performed using HPV genotype testing kits (Kai Pu Biotechnology, China), which are based on HPV L1 consensus polymerase chain reaction primers and flow hybridization technology for DNA amplification. A total of 38 different HPV types were detected in this study, including 14 high-risk types [5] (types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68), and 23 low-risk types (types 6, 11, 26, 34, 40, 42, 43, 44, 53, 54, 55, 57, 61, 67, 69, 70, 71, 72, 73, 81, 82, 83, 84), which were suggested by the WHO and the National Health Commission of China. The number of cases tested for different HPV types varied due to differences in regional testing practices. Not all cases were uniformly tested for all 37 HPV types. In some regions, the number of cases for each type varied due to local clinical and epidemiological conditions, and the number of cases tested for different types is shown in Table 1.

Table 1 Prevalence of HPV types in China

Cervical cast-off cells were collected by healthcare providers following a standardized procedure. A vaginal dilator was used to expose the cervix, mucus was wiped off with a cotton swab at the cervical opening, inserts the cervical brush into the cervical opening, turns the cervical brush 3 to 5 times clockwise, then the cervical brush was slowly removed and put into a sample tube containing cell preservation solution. The excess brush handle was broken off at the tube opening, leaving the brush head in the sample tube, which was covered with a lid to complete the sampling. The tube was labeled with a number and date. After sample collection, DNA was extracted immediately or stored at 4 °C for 48 h. For sample storage and transportation, if the sample could not be sent for testing immediately, it was stored at 4 °C, and testing was conducted within 2 weeks. Specimens were transported using low-temperature storage. The DNA extraction process followed the manufacturer’s guidelines provided by the HPV genotype testing kit (Kai Pu Biotechnology, China). For patient preparation instructions, patients were instructed to:

• 1. Avoid using vaginal medications or douching within 3 days prior to testing.

• 2. Avoid sexual intercourse within 48 h before sampling.

• 3. Ensure that sampling is conducted outside of the menstrual period.

• 4. Do not apply acetic acid or iodine solution to the vaginal area before sampling.

Quality control

(1) The blank control should display “Undet” for Ct values in all fluorescence detection channels. (2) The positive control should have a Ct value ≤ 36 in the corresponding fluorescence detection channel. If the above two conditions were met, the experiment was considered valid. Regarding result interpretation: (1) If the Ct value of globin in the Cy5 fluorescence detection channel was ≤ 40 and the Ct values in all other fluorescence detection channels were “Undet” the result was considered negative. (2) If the Ct value of the sample in fluorescence detection channels other than globin was 40 < Ct < 45, retesting was recommended. If the retest Ct value was < 40, the result was considered positive; otherwise, it was negative. If all fluorescence detection channels for the sample displayed “Undet” the result was invalid, and resampling was required.

Statistical analysis

This study utilized both Excel and R 4.3.1 statistical software for establishing a database, performing initial analyses, and creating charts. Continuous variables are presented as mean ± standard deviation, while categorical data are expressed as rates or proportions (%), and analyzed using rates and confidence intervals (CIs) of at least 95%. Comparison of categorical data was conducted using the chi-square test (${\chi }^{2}$). A P < 0.05 was considered to indicate statistical significance. Geographic regions in China were classified into seven cultural–geographic regions based on natural factors and economic comprehensive elements. Mapping software, including Arc GIS Pro 3.0.1 and GraphPad Prism 9.5, was employed for spatial analysis and visualization. Statistical analyses included data filtering, processing, and interpretation using R 4.3.1. HPV infection rates were analyzed across different demographic subgroups, detailing overall prevalence and subgroup-specific trends. To evaluate infection patterns across different age groups, we stratified the enrolled women, 18 to 80 years of age, into the following age brackets: < 21 years, 22–25 years, 26–30 years, 31–35 years, 36–40 years, 41–45 years, 46–50 years, 51–55 years, 56–60 years, and 61–80 years. Data sources included women from 31 provinces and municipalities in China, ensuring robust representation across various regional and demographic characteristics.

Results

Demographics and HPV prevalence

A total of 2,728,321 females, with a median age of 48 years (IQR 40–54), were included in the final analysis. The overall HPV prevalence was 17.70%; 13.12% of patients were identified with high-risk HPV infection, while 4.58% were recognized with low-risk types. The infection rates of the different HPV types are shown in Table 1. Among the HR-HPV cases, HPV52 (36,727/835,507, 4.40%) was the most common type, followed by HPV58 (22,181/835,507, 2.65%), HPV16 (58,757/2,728,321, 2.15%), HPV51 (13,281/835,507, 1.59%), and HPV39 (12,945/835,507, 1.55%). Among the LR-HPV cases, HPV53 (15,677/835,507, 1.88%) was the most common type, followed by HPV61 (1,947/111,524, 1.75%).

Single and multiple HPV infections

Among the 835,507 women tested for multiple HPV types, 172,502 (20.6%) cases were infected, of which 69.28% (119,487/172,505) were single infections, and 30.73% (53,015/172,502) were multiple infections. Among the multiple infections, double infections accounted for 20.23% (34,900/172,502), triple infections for 6.70% (11,560/172,505), quadruple infections for 2.31% (3,989/172,502), and five or more infections for 1.49% (2,566/172,502) (Table 2). Additionally, according to the chord diagram results (Fig. 1A), the two most common combinations of different HPV types in multiple infections were HPV52 with HPV58 (2825 times), HPV52 with HPV16 (2570 times), and HPV52 with HPV53 (2284 times).

Table 2 Prevalence of single and multiple HPV infections

Fig. 1

Chord diagram of HPV type correlations, the fan width represents the number of people infected, and the chord width between the two fans represents the number of people infected with both types (A); The left Y-axis and bar chart represent the number of positive and negative number of population, and the right Y-axis and line chart represent the prevalence (B). Line chart of the infection rate over years, HR-HPV, high-risk human papillomavirus, LR-HPV, low-risk human papillomavirus (C). Seasonal line chart of prevalence, spring: Mar, Apr, May; summer: Jun, Jul, Aug; autumn: Sep, Oct, Nov; winter: Dec, Jan, Feb (D)

Age-specific HPV prevalence

Figure 1B illustrates the age-related changes in HPV infection rates. Women under 21 years old had the highest infection rates, which then declined rapidly. In the 61–80 age group, the infection rates for all HPV types increased and reached a second peak, indicating a high infection rate among both young and elderly individuals in China. The HR-HPV infection rate was lowest between ages 36 and 40, while the LR-HPV infection rate reached its lowest point between ages 56 and 60. Additional file 1: Fig. S2 provides more details on the age-specific distribution of HR-HPV and LR-HPV types. The bar chart shows the distribution of individuals testing positive for high-risk HPV (HR-HPV) across different age groups. The number of HR-HPV-positive individuals peaks in the 51–55 and 56–60 age groups (Additional file 1: Fig. S2A). The heatmap shows that for HR-HPV, types such as HPV52, HPV16, and HPV58 were more common in most age groups, with infection rates prevalent in young women aged 18–21 and older women aged 61–80 (Additional file 1: Fig. S2B). Similarly, for LR-HPV, the infection rates of HPV81, HPV53, HPV42, and other types were higher, especially in young women in the 18–21 age group (Additional file 1: Fig. S2C).

Year and seasonal trends

Overall, over the past 7 years, the HPV infection rate in China has remained relatively stable. From January 2017 to June 2023, apart from a slight increase in 2020, the overall rate was lower compared to 2017 (Fig. 1C and D). The trends for HR-HPV and LR-HPV types were both similar to the overall infection rate. Additionally, HPV infection rates were high in the winter and spring seasons, with a decline observed during the summer and autumn seasons (P < 0.05). The highest infection rate occurred in January (17.40%), while the lowest appeared in September (13.54%).

Geographical distribution

To investigate the geographical distribution of HPV, we divided China into seven major regions based on geographic information to describe the current prevalence of HPV: northern, eastern, central, southern, southwestern, northeastern, and northwestern. The division of each region is shown in Fig. 2A.

Fig. 2

Division of geographical regions in China (A). Total infection rate of each province in China, with the box plot showing the infection rate by region (B). High-risk HPV infection rate of each province in China, with the box plot showing the infection rate by region (C). Low-risk HPV infection rate of each province in China, with the box plot showing the infection rate by region (D)

Taking the average infection rates of each geographic region, the results indicated that southern and northeastern China had the highest infection rate (19.48%), while northwestern China had the lowest (12.36%) (Fig. 2B–D). According to the statistical results of the geographical situation, Hainan Province had the highest overall infection rate at 25.11%, followed by Heilongjiang Province at 24.28%. The province with the lowest overall infection rate was the Xinjiang Uygur Autonomous Region, at only 8.02%. Among the provinces, Hainan also had the highest HR-HPV infection rate at 23.42%, followed by Heilongjiang at 18.12% and Inner Mongolia Autonomous Region at 17.83%. The Xinjiang Uygur Autonomous Region also had the lowest HR-HPV infection rate at 8.02%, whereas Tianjin Municipality had the highest LR-HPV infection rate at 11.79%, followed by Heilongjiang at 10.78%. The more detailed comprehensive infection rate of each province is shown in Additional file 1: Table S1.

Discussion

This study investigated the epidemiological status of HPV in China, based on data from 2,728,321 participants, to yield representative epidemiological results. Globally, the prevalence of HPV varies significantly, and our data indicate an overall HPV infection rate of 17.70% in China, with 13.12% classified as HR-HPV and 4.58% as LR-HPV. This further validates the findings of previous systematic reviews and multicenter studies that HPV prevalence in the general population is between 13.1% and 18.8% [16]. For the period of January 2017 to June 2023, the annual infection rate showed a declining trend from 2017 to 2019, with a noticeable increase in 2020, followed by a significant decrease (P < 0.05) in 2021 compared to 2020, after which the trend showed an upward trajectory until 2023. Despite 80% of women experiencing HPV infection at some point in their lives [17], the majority of HPV infections are transient and asymptomatic until progressing to CC, underscoring the importance of early detection for prevention.

Regarding predominant types, HPV 16 and HPV 18 pose the highest risk for high-grade lesions and invasive cancer and are the most common high-risk types of HPV worldwide [18,19,20,21], our study identifies HPV52 as the most common carcinogenic type in China, followed by HPV58 and HPV16. This contrasts with existing studies showing that HPV16 is the most common HPV type among the global population, suggesting that HPV52 may have surpassed HPV16 as the most prevalent HR-HPV type in China. Additionally, HPV18, the second most common carcinogenic type globally [8], ranks 11th in our study, consistent with reports of low prevalence in Chinese studies [22, 23]. However, this differs from meta-analyses indicating HPV18 as the second most commonly observed HPV type among cytologically normal women in East Asia and Southeast Asia. Furthermore, the prevalence trend of HPV58 has shifted, ranking as the second most common type in our study, with a prevalence rate of 2.65%, compared to 1.94–2.10% reported in 2019 studies [12]. These observations will contribute to guiding future HPV vaccine development strategies for cervical cancer prevention.

Consistent with previous studies, our research also reveals a “bimodal” distribution of age-specific HPV prevalence in China. The first peak occurs in young women under 21 years old, with the highest prevalence reaching 27.12%. However, our study shows HPV prevalence gradually decreases after the age of 21, reaching its lowest point in the 36–40 age group, followed by an upward trend, culminating in a second peak in the > 61 age group. Globally, the second peak occurs in individuals 44 years old and above in the Americas, 45 and above in Europe and Africa, and nearly 50 in China [24]. This seems to differ from our study, but similar trends have been consistently observed in several large-scale studies conducted in China, suggesting that this phenomenon may be the epidemiological trend of HPV in China. For instance, a study conducted in Guangzhou involving 198,111 women from 2015 to 2021 reported that HPV prevalence was highest in women under 21 years old and increased again after 46 years old, peaking in the 55–60 year group. This age-specific distribution was observed across different diagnostic groups, including women with normal cervices and inflammation [25]. Similarly, a study in Shanghai analyzed 3788 women between 16 and 90 years old and found that the prevalence of HPV was highest in those over 60 years old, with a significant increase in older age groups [26]. Furthermore, a study in Wuhan based on 105,679 women also reported a “two-peak” pattern, with peaks in the under 21 age group (37.4%) and the 61–65 age group (41.72%) [27]. These consistent research results indicate that there is indeed a bimodal distribution of HPV infection among Chinese women, and the phenomena observed in the research and our study may be explained by biological and behavioral factors. Young women have relatively frequent sexual activity and change sexual partners more frequently, so they are more likely to be infected with HPV. Research showed that HPV infection rates can reach up to 82% in some populations of young women [28]. However, young women have strong immunity [29]. Most women have cleared HPV through their immune system after being infected with HPV. Only a few women will show persistent infection of HPV. Additionally, the low vaccination rates among young Chinese women increase their risk of HPV infection [30]. Therefore, young women have a high rate of HPV infection, but the incidence rate of cervical cancer is not high. On the other hand, the frequency of sexual behavior of older women has declined, but when they get older, the function of the immune system has gradually declined, and the ability to clear the virus is insufficient, which makes it easier for the elderly women to continue to be infected with HPV, and also brings about a higher incidence rate of cervical cancer [31]. Moreover, samples from different studies may have different characteristics and representativeness.

In our study, the highest HPV infection rates were observed in southern and northeastern China. Specifically, Hainan province exhibits the highest overall infection rate and HR-HPV infection rate, while Heilongjiang province has relatively high overall infection rates. Tianjin municipality has the highest LR-HPV infection rate. These findings align partially with previous studies, but differences exist. For example, a systematic review and data review in China’s seven geographical regions reported the highest HPV infection rate in the Northeast (19.85% (95% CI: 3.46 ~ 36.23%)), followed by northern China (18.43% (95% CI: 13.39 ~ 23.46%)) [16]. Regarding seasonal trends, our results indicate that HPV infection rates are higher in winter and spring compared to summer and autumn. Chi-square test results demonstrated a statistically significant difference among the four seasons (P < 0.05), suggesting that seasonal variation is unlikely to be attributed to random sampling bias. On the contrary, it may be influenced by environmental and behavioral factors [32]. Some pathogens may be sensitive to light and temperature, and due to factors such as prolonged sunlight and high temperatures, their survival time in summer and autumn may be shortened. In addition, colder weather in winter and spring may reduce outdoor activities and increase indoor interaction, which may create more favorable conditions for the spread of infectious diseases.

The observed differences in HPV infection rates across different regions and seasons deserve careful consideration and further analysis. Compared to existing research, these variations may stem from differences in study design, population characteristics, statistical methodologies employed, and underlying biological mechanisms. For instance, regional disparities could be influenced by varying socioeconomic factors, healthcare access, and cultural practices affecting sexual behaviors and HPV transmission dynamics. The seasonal fluctuations in infection rates may be due to the survival time of the virus and changes in human outdoor activities or climate conditions. Understanding these factors is crucial for developing effective public health interventions and HPV vaccination strategies aimed at reducing regional and seasonal disparities in HPV burden.

While this study provides insights into the current prevalence of HPV in China, it does have limitations. Firstly, the sample primarily comprises women undergoing cervical examinations, potentially introducing selection bias. However, the substantial sample size supports the study’s representativeness. Secondly, although this cross-sectional study provides evidence for HPV infection and related disease prevention nationwide, future longitudinal research is necessary to confirm the specific outcomes of HPV infection. Thirdly, while seasonal trends in HPV infection rates were observed, this study did not include statistical testing or adjust for potential confounding factors, such as health-seeking behaviors or environmental influences. These limitations highlight the need for further investigation to confirm and explain the seasonal patterns. Lastly, the study only focuses on HPV infection rates and type distributions in China without considering other influential factors, such as immune status or lifestyle behaviors, which require additional further research.

Conclusions

Based on our study, we found distinct age and geography-specific distributions of HPV infection in China, with higher rates among young women and in the southern regions. Additionally, there is a prevalent occurrence of multiple HPV infections. These findings underscore the importance of developing targeted HPV vaccination strategies and enhancing preventive and control measures for high-risk populations.