The Prevalence of Cervical HPV Infection and Genotype Distribution in 856,535 Chinese Women with Normal and Abnormal Cervical Lesions: A Systemic Review

Abstract

Cervical cancer is the commonest cancer affecting women worldwide. During the last decades, the incidence and mortality rates of cervical cancer have increased in China. This research aims to assess the overall and genotype-specific prevalence of the human papillomavirus (HPV) infection among Chinese women with normal cervix, considering age, and geographic location. We selected studies about HPV prevalence in women from Chinese in Mainland China with normal cervix and abnormal cervical lesions, published between January 1995 and December 2020. The HPV prevalence was analyzed using meta-analysis based on the following: cytological and histological diagnoses, regions, and ages. The overall HPV prevalence in 856,535 women was 14.3%, 95% confidence interval (CI) and it increased from 8.2% to 16.5% in studies published from 2006 to 2020. The prevalence of high-risk (HR) and low-risk (LR) HPV types was 11.3% and 2.7%, respectively. The commonest types of HPV in women from Mainland China were HPV 16 (2.6%), 52 (2.4%), 58 (1.7%), 18 (0.9%), and 33 (0.8%). According to the geographical analysis, the prevalence of different HPV genotypes varied by region, Central China had the highest overall HPV prevalence. HPV16 was the commonest type in all the regions except in South China and East China, where HPV52 was found to be common. Regarding diagnosis, the HPV infection led to cervical cancer diagnosis by cytology and histology with 90.1% and 91.5% rates, respectively. HPV16 and HPV18 were common types associated with cervical cancer diagnosed by cytology and histology. HPV 16, 58, 52, 18, and 33 were the commonest types found in women with normal cervixes from Mainland China. The prevalence of different HPV genotypes varied by age group and region.

BBACKGROUND

Cervical cancer is the fourth most common cancer affecting women in worldwide. An estimated 604,000 new cervical cancer cases and 342,000 deaths were reported globally in 2020.[1] In China, there were up to 110,000 and 60,000 of new cases and deaths from cervical cancer, respectively, in 2020,[2] representing increases of approximately 3.5% and 23.0% relative to 2018.[3] The World Health Organization (WHO) launched the “Global Strategy for Accelerating the Elimination of Cervical Cancer as a Public Health Problem” on November 17, 2020, and 194 countries, which including China, committed to eliminating cervical cancer for the first time.[4,5] Therefore, the Chinese government has taken action to prevent cervical cancer by implementing a National Cervical Cancer Screening Programme in Rural Areas (NACCSPRA) and introducing the human papillomavirus (HPV) vaccine into the Chinese market.

The HPV infection is related to cervical cancer and other cancer types such as anal, vaginal, vulvar, penile, and oropharyngeal. Persistent infections caused by high-risk human papillomavirus (HR-HPV) types are a necessary factor for cervical cancer occurrence, specifically HPV16 and HPV18 − which have demonstrated to cause many cervical cancer cases.[6,7] However, 14 HR-HPV types are recognized as carcinogenic and associated with cervical cancer.[8,9] Further, low-risk human papillomavirus (LR-HPV) types cause benign hyper-proliferative lesions and fail to cause malignant carcinoma in the general population. Because LR-HPV has a lower impact as a carcinogenic agent, lesions are self-limiting and often cleared by the host immune system. Therefore, in some individuals, LR-HPV types produce asymptomatic infections only, and that is why research about LR-HPV types is yet to be prioritized. The distribution of HPV genotypes has regional variation, and the carcinogenicity and consequences of HPV infection are different for each subtype.[10]

Although many articles and systematic reviews have described the prevalence of HPV infection and the distribution of different HPV genotypes in patients with cervical cancer or cervical lesions in China, the information is still limited to specific regions of the country and it is yet to represent the statistics of the general population.[11,12,13,14] Furthermore, most of the information available about cervical cancer in China, lack updated data. The overall HPV prevalence range in Chinese women with normal cervix accounted to be 13.1 − 18.8% in previous meta-analyses done in 2007 to 2013. However, there was yet no analysis that focused on the geographical distribution of HPV subtypes in China. To date, few studies have discussed HPV infection in Chinese women with a normal cervix, especially using a pooled analysis of HPV type-distribution stratified at cervical disease stage by cytology and histology diagnosis.

This study aims to update the previous meta-analysis with data about HPV type-specific prevalence in Chinese women with a normal cervix and abnormal cervical lesions in Mainland China by various regions and ages. In addition, this study intends to evaluate whether the prevalence trends of type-specific HPV have changed during the last 10 years or not. Therefore, we performed a meta-analysis to estimate the geographical prevalence trends of HPV subtypes in the population from Mainland China. Finally, we compared HPV genotype distribution in women affected by different cervical precancerous lesions. We consider it critical to analyze the HPV prevalence and the HPV genotype distribution in women with normal and abnormal cervical lesions to implement future health policies regarding HPV screening and vaccination in China.

METHODS

Literature search strategy

Peer-reviewed research articles reporting HPV prevalence in Mainland China,[15] published from January 1, 1995 (when the HPV detection technology entered the Chinese market) to December 30, 2020, were included in this study only. The included articles were in English (PubMed database) and Chinese language (including CNKI/Wang Fang/other resources). We searched the literature using Mesh and/or index terms combinations: “Human Papilloma Virus (HPV)”, “Cervix neoplasms (epidemiology or virology or prevention and control)”, “epidemiology”, “prevalence”, “DNA probes (HPV)”, “polymerase chain reaction”, “women/female” and “population.” Additional references cited in the retrieved articles were evaluated for inclusion together with the review of abstract books from scientific meetings, the Cochrane library, and the Lancet database.

Inclusion/exclusion criteria

Inclusion criteria for the literature: 1) published SCI/SCIE or Chinese journals articles, 2) cervical HPV infection of women from Mainland China, 3) original research articles, 4) the population including: screening, check-up, community, census and migrant population, 5) sample size larger than 100, 6) use of polymerase chain reaction (PCR) based technology to detect human papillomavirus-deoxyribonucleic acid (HPV DNA); 7) the overall and type-specific HPV elicitation, were data are calculated correctly, 8) the detection of at least two different HPV types. The study had to qualify all inclusion criteria to be included.

Exclusion criteria for literature: 1) duplicate data, 2) reviews, letters, conference reports or degree thesis, 3) patient studies, pregnancy, hospitalized, and any diseases such as the human immunodeficiency virus (HIV) infection, cervical cancer, or other sexually transmitted pathogens, 3) articles about Hong Kong, Macao, and Taiwan; 4) incomplete data, 5) other studies such as questionnaire, investigation about HPV knowledge or mechanism of cervical cancer. The presence of any single exclusion criterion is sufficient to be excluded.

Ethical approval and inform consent

We received ethical approval from the Ethics Committee of the First Affiliated Hospital of Baotou Medical College in Inner Mongolia. In addition, we refused to seek patients' consent and/or form, because this study is a meta-analysis based on published studies.

Quality assessment

We assessed the study quality using the Agency for Healthcare Research and Quality (AHRQ) scale for cross-sectional studies published by the National Institutes of Health, with a total score of 11.[16] Two independent reviewers completed a blinded assessment of the quality of the included studies. If the literature quality score is greater than or equal to 5, then the article meets the inclusion criteria.

Data extraction

Two independent investigators extracted the data with discrepancies resolved by consensus. In situations where different opinions or inconsistencies occurred, they were resolved by a third party. For each eligible study, the following items were retrieved: 1) basic information: first author, journal name, year of publication, study period, study sample type (population-based, screening, check-up, community, and census), study design (derived from cross-sectional studies), sample size, and age. 2) Outcomes: amount, number of HPV-positive, type-specific HPV, and the overall prevalence of HPV infection, stratified by cervical disease grade, ages, and areas.

Study characteristics

We analyzed 29 subtypes and selected 17 commonest types of all HPV genotypes that were discovered. We divided the commonest types into HR-HPV: HPV16, 18, 31, 33, 45, 52, and 58; and LR-HPV: HPV 6, 11, and 42. From the available data, we synthesized the overall HPV and each HPV genotype prevalence as follows: (1) by seven geographical regions (North China, Northeast, East China, Central China, Southwest, Northwest, and South China); (2) nine age-groups (25 years and less, 25 − 30 years, 31 − 35 years, 36 − 40 years, 41 − 45 years, 46 − 50 years, 51 − 55 years, 56 − 60 years, and more than 61 years).

We analyzed the prevalence of each HPV subtype in women with normal and abnormal cervical lesions diagnosed by cytology and histology. The normal and abnormal cervical lesions diagnosed by cytology were classified into four stages: negative for intraepithelial lesion or malignancy (NILM), atypical squamous cells of undetermined significance (ASC-US), low-grade squamous intraepithelial neoplasia (LSIL), high-grade squamous intraepithelial neoplasia, and atypical squamous cells – cannot exclude high-grade squamous intraepithelial lesion and cancer (≥HSIL). The normal and abnormal cervical lesions diagnosed by histology were classified into four stages: NILM, cervical intraepithelial neoplasia grade 1/2 (CIN1/2), cervical intraepithelial neoplasia grade, and cervical cancer (≥CIN3).

Statistical analysis

We conducted the meta-analysis to synthesize HPV prevalence using STATA12.0. Overall and type-specific HPV prevalence was estimated by a weight coefficient. We applied heterogeneity study to determine the difference between the data by a Chi-square test, which was analyzed by I². In all analyses, we selected the random-effects model for the pooled analyses when the results obtained were highly heterogenous. The overall and type-specific HPV pooled prevalence was 95% CI and corresponding P values were recorded. The publication bias was evaluated by Egger's test.

RESULTS

Summary of eligible studies

We retrieved 6573 citations and identified 111 relevant articles for full-text review. Data were obtained from 71 eligible studies that met the eligibility criteria,[17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87] including 45 Chinese studies and 26 English literature [See Figure 1].

Figure 1.

PRISMA flow diagram for identification of studies for meta-analysis

The prevalence of overall HPV and type-specific HPV

According to the analyzed literature, the overall HPV prevalence, HR-HPV, and LR-HPV types are 14.3, 11.3, and 2.7%, respectively, in 853,945 women with normal cervix from Mainland China. From the prevalence analysis of the 17 commonest HPV subtypes in women with a normal cervix living in Mainland China, we present the prevalent in descending order, such as: HPV 16, 52, 58, 18, 33, 51, 68, 39, 31, 56, 66, 6, 59, 11, 42, 35, and 45. The first most common HPV type was HPV 16 (2.6%), followed by 52 (2.4%), 58 (1.7%), 18 (0.9%), 33 (0.8%), and 51/39/68 (0.7%). The most common LR-HPV subtype was HPV6, with a prevalence of 0.5% (95%CI: 0.4, 0.5), followed by HPV 11, 0.4% (95%CI: 0.3, 0.4) [See Table 1]

Table 1.

Type-specific HPV prevalence and overall HPV prevalence in healthy women from mainland, stratified by geographical region

HPV type	Amount prevalence	North China	Northeast	East China	Central China	Southwest	Northwest	South China
HPV ration	14.3 (13.1, 15.5)	14.5 (11.0,17.9)	12.8 (8.6,17.0)	15.6 (13.4,17.8)	19.8 (15.4,24.2)	13.3 (10.9,15.8)	12.7 (6.3,19.0)	12.1 (10.6,13.6)
HR HPV	11.3 (10.5,12.2)	10.8 (7.1,14.6)	10.3 (7.5,13.1)	11.7 (10.8,12.6)	15.1 (11.6,18.7)	9.2 (6.5,11.9)	9.6 (6.3,13.0)	11.6 (10.0,13.2)
LR HPV	2.7 (2.3,3.2)	2.3 (1.4,3.2)	2.0 (1.1,2.9)	2.9 (1.9,3.9)	4.8 (2.9,6.7)	3.1 (0.9,5.4)	1.7 (1.1,2.3)	2.5 (1.3,3.6)
HPV6/11	0.8 (0.6,0.9)	0.6 (0.3,0.9)	0.7 (0.4,0.9)	0.9 (0.7,1.2)	0.5 (0.1,0.9)	0.5 (0.4,0.6)	0.9 (0.3,1.5)	0.8 (0.5,1.0)
HPV16	2.6 (2.4,2.9)	4.1 (3.1,5.1)	3.0 (1.8,4.3)	2.2 (2.0,2.5)	3.9 (2.5,5.4)	2.7 (1.7,3.6)	5.3 (3.9,6.6)	1.8 (1.6,2.1)
HPV52	2.4 (2.1,2.7)	1.5 (0.8,2.2)	2.0 (1.6,2.4)	2.8 (2.5,3.2)	2.5 (1.4,3.7)	2.1 (1.3,3.0)	1.0 (0.8,1.3)	2.7 (2.3,3.2)
HPV58	1.7 (1.6,1.9)	2.1 (1.5,2.7)	1.6 (1.0,2.2)	1.8 (1.7,2.0)	2.3 (1.8,2.8)	1.6 (1.2,1.9)	2.0 (0.8,3.2)	1.2 (1.1,1.4)
HPV18	0.9 (0.8,1.0)	1.0 (0.7,1.4)	0.9 (0.7,1.1)	0.9 (0.8,1.0)	1.3 (0.7,2.0)	0.7 (0.4,1.0)	1.1 (0.2,2.1)	0.8 (0.6,0.9)
HPV33	0.8 (0.7, 0.8)	1.1 (0.9,1.3)	0.8 (0.5,1.1)	0.9 (0.8,1.0)	1.0 (0.7,1.2)	0.8 (0.5,1.0)	0.5 (0.3,0.7)	0.5 (0.4,0.6)
HPV51	0.7 (0.6, 0.8)	0.7 (0.3,1.0)	0.4 (0.1,0.7)	0.7 (0.5,0.8)	1.3 (0.4,2.3)	0.6 (0.4,0.9)	0.7 (0.1,1.3)	0.7 (0.5,0.8)
HPV39	0.7 (0.6, 0.8)	0.7 (0.3,1.0)	0.9 (0.4,1.3)	0.6 (0.4,0.7)	0.7 (0.4,1.0)	0.8 (0.6,1.0)	1.0 (0.6,1.3)	0.7 (0.5,0.8)
HPV68	0.7 (0.6,0.8)	0.6 (0.4,0.7)	0.6 (0.3,0.8)	0.9 (0.7,1.1)	0.0.8 (0.4,1.2)	0. 6 (0.3,0.8)	0.42 (0.22,0.6)	0.5 (0.4,0.6)
HPV31	0.6 (0.5,0.7)	0.7 (0.5,1.0)	0.6 (0.3,0.9)	0.7 (0.6,0.8)	0.7 (0.4,1.0)	0.5 (0.3,0.7)	0.4 (0.2,0.5)	0.4 (0.3,0.4)
HPV56	0.6 (0.5,0.6)	0.7 (0.5,0.9)	0.3 (0.1,0.5)	0.5 (0.4,0.6)	0.6 (0.2,0.9)	0.8 (0.5,1.1)	1.2 (1.1,1.3)	0.4 (0.3,0.5)
HPV66	0.5 (0.4, 0.6)	0.8 (0.7,1.0)	0.3 (0.1,0.5)	0.5 (0.4,0.6)	1.0 (0.3,1.6)	0.4 (0.3,0.5)	0.5 (0.2,0.9)	0.4 (0.3,0.5)
HPV6	0.43 (0.35,0.50)	0.29 (0.11,0.46)	0.35 (0.20,0.50)	0.45 (0.31,0.60)	0.36 (0.09,0.62)	0.28 (0.12,0.44)	0.61 (0.23,0.99)	0.48 (0.32,0.65)
HPV59	0.36 (0.31,0.40)	0.37 (0.25,0.49)	0.27 (0.10,0.44)	0.38 (0.31,0.45).	0.61 (0.24,0.98)	0.28 (0.14,0.42)	0.65 (0.01,1.28)	0.29 (0.22,0.35)
HPV11	0.34 (0.28, 0.40)	0.34 (0.17,0.52)	0.24 (0.06,0.41)	0.45 (0.30,0.60)	0.51 (0.17,0.84)	0.26 (0.13,0.39)	0.36 (0.15,0.57)	0.25 (0.17,0.34)
HPV42	0.27 (0.22,0.32)	0.22 (0.10,0.34)	0.69 (0.01,1.48)	0.34 (0.25,0.44)	0.21 (0.04,0.39)	0.21 (0.06,0.36)	0.29 (0.24,0.35)	0.24 (0.09,0.39)
HPV35	0.26 (0.22,0.31)	0.22 (0.06,0.38)	0.19 (0.09,0.28)	0.30 (0.21,0.40)	0.36 (0.12,0.60)	0.13 (0.06,0.20)	0.91 (0.31,1.51)	0.23 (0.17,0.29)
HPV45	0.24 (0.20,0.28)	0.18 (0.12,0.24)	0.15 (0.09,0.22)	0.23 (0.16,0.30)	0.27 (0.15,0.39)	0.19 (0.08,0.30)	0.19 (0.14,0.23)	0.32 (0.21,0.43)

CI: confidence interval; HR-HPV: high-risk human papillomavirus; LR-HPV: low-risk human papillomavirus; East China: including Shan dong, Jiangsu, Anhui, Jiangxi, Zhejiang, Fujian and Shanghai; Central China: including Henan, Hubei and Hunan; North China: including Beijing, Tianjin, Hebei, Shanxi, and Inner Mongolia; Northwest China: including Ningxia, Xinjiang, Qinghai, Shanxi, and Gansu; Southwest China: Including Sichuan, Yunnan, Guizhou, Tibet, and Chongqing; Northeast China: including Liaoning, Jilin, and Heilongjiang; South China: Guangdong, Guangxi, and Hainan

The prevalence of overall HPV and type-specific HPV stratified by regions

The results showed that the prevalence of overall HPV and type-specific HPV varied by geographical region. The prevalence of overall HPV varied from 12.1% in South China to 19.8% in Central China. East China has the second-highest overall HPV prevalence (15.6%) and HR-HPV prevalence (11.7%) after Central China. Similarly, the Southwest showed the second highest prevalence of LR-HPV after Central China. According to the results, South China has the lowest rate of overall HPV prevalence (12.1%). While in Northwest and East China, the prevalence of LR-HPV was 0.9% in both areas. Regarding specific HPV types, HPV16 was the commonest type in all the regions except in South China and East China, where HPV52 was the most common type. The LR-HPV, such as HPV6 and HPV11, were common types in the seven analyzed regions [See Table 1].

Age-specific prevalence

We stratified HPV prevalence by age. The curve of prevalence for overall HPV and HR-HPV healthy women showed two peaks. One was observed at aged ≤25 years, declining to a plateau around middle age. The second peak was observed between 41 and 45 years in overall HPV and HR-HPV with a prevalence of 14.3 and 12.2%, respectively. We observed a decline to a plateau after ≥46 years of age. However, the prevalence of LR-HPV had no significant trends variations with age [See Figure 2].

Figure 2.

Type-specific HPV prevalence and HPV prevalence in healthy women from mainland, stratified by ages

The prevalence of overall HPV and type-specific HPV stratified by cervical disease grade of histology diagnosis

Women with cervical lesions and cervical cancer showed high significant of HPV prevalence than women with normal cervical histology. The HPV prevalence was 10.5% (8.4% to 12.7%) for the normal group, 73.9% (65.8% to 80.8%) for CIN1, 89.5% (84.3% to 94.4%) for CIN2, and 91.5% (80.3% to 96.8%) for CIN3+. In descending order of HPV prevalence, the ten commonest HR-HPV types were: HPV 16, 52, 58, 18, 39, 33, 68, and 31. The LR-HPV 11 and 6 were the most common types in women with a normal cervical histological diagnosis. In women with CIN1, the most common HR-HPV types were: 16, 52, 33, 58, 18, 68, 31, and 39. The commonest LR-HPV types are 6 and 11. The often-detected types were HPV 16, 58, 52, 33, 31, 18, 35, 51, 68, and 39 in women with CIN2. While, HPV 16 (62.0%) and 18 (15.8%) were the common types in women with ≥CIN3, which led to cervical cancer and increased with the grade of cervical disease diagnosis by histology. HPV58, 52, and 31 prevalence rates failed to show variations when the cervical histological grades were analyzed. Except for HPV16, 18, 58, 52, and 31, the prevalence of all other HPV types ranged from 0.6 to 3.7% in women with ≥CIN3, from 1.2 to 7.7% in CIN2, from 1.5 to 5.4% in women with CIN1, and from 0.2 to 0.7% in women with normal histological results [See Table 2].

Table 2.

Type-specific HPV prevalence and HPV prevalence of tissue-based detection in healthy women from mainland, stratified by cervical disease grade

HPV type	NILM	CIN1	CIN2	≥CIN3
HPV ration	10.5 (8.4,12.7)	73.9 (65.8,80.8)	89.5 (84.3,94.4)	91.5 (80.3,96.8)
HPV6/11	0.4 (0.2,0.6)	3.7 (2.0,5.4)	2.0 (0.8,3.2)	3.5 (1.5,5.4)
HPV16	2.4 (1.8,3.1)	25.0 (16.1,33.9)	49.9 (28.8,70.9)	62.0 (46.5,77.6)
HPV18	0.7 (0.5,1.0)	7.7 (5.5,9.8)	6.9 (2.2,11.5)	15.8 (5.2,20.4)
HPV58	1.4 (0.9,1.8)	13.5 (10.3,16.7)	16.1 (9.74,22.4)	12.3 (8.1,16.5)
HPV52	2.3 (1.1,3.6)	19.3 (12.4,26.1)	13.9 (6.6,21.3)	10.2 (5.0,15.4)
HPV31	0.5 (0.3,0.8)	4.7 (1.8,7.6)	7.7 (2.4,13.0)	6.4 (1.5,11.4)
HPV33	0.6 (0.4,0.8)	17.0 (15.6,18.3)	11.1 (6.9,15.3)	3.7 (2.2,5.3)
HPV68	0.5 (0.3,0.6)	5.4 (4.1,6.6)	3.9 (2.5,5.4)	3.6 (2.0,5.1)
HPV35	0.3 (0.1,0.5)	3.6 (1.2,3.0)	6.6 (3.9,9.4)	2.1 (0.4,3.8)
HPV6	0.1 (0.1,0.2)	2.4 (1.08,3.7)	1.7 (0.1,3.2)	2.1 (0.9,3.4)
HPV59	0.3 (0.2,0.4)	2.8 (1.6,3.9)	1.6 (0.5,2.8)	1.8 (0.7,3.0)
HPV66	0.4 (0.27,0.7)	4.1 (1.5,6.7)	3.4 (1.9,4.9)	1.7 (0.5,2.8)
HPV39	0.7 (0.4,1.0)	4.7 (2.8,6.6)	3.5 (2.1,4.8)	1.3 (0.3,2.3)
HPV51	0.6 (0.3,0.9)	4.3 (3.2,5.4)	4.5 (2.2,6.9)	1.6 (0.4,4.0)
HPV45	0.2 (0.1,0.4)	1.5 (0.8,2.3)	3.1 (1.2,4.9)	0.8 (0.0,1.6)
HPV56	0.5 (03,0.7)	3.1 (2.1,4.0)	3.3 (2.0,4.7)	0.6 (0.1,1.3)
HPV11	0.2 (0.1,0.3)	1.8 (0.7,3.7)	1.2 (0.2,2.2)	0.6 (0.1,1.2)

CIN2=cervical intraepithelial neoplasia grade 2; CIN1=cervical intraepithelial neoplasia grade 1; ≥CIN3=cervical intraepithelial neoplasia grade 3and cancer; NILM: No intraepithelial lesion or malignant cells

The prevalence of overall HPV and type-specific HPV stratified by cervical disease grade of cytology diagnosis

The overall HPV and the type-specific HPV prevalence were stratified by the cervical disease grade of cytology diagnosis. In the ≥HSIL, LSIL, ASCUS, and NILM, the overall HPV prevalence was 90.1, 73.6, 42.2, and 12.5%, respectively. In descending order of HPV prevalence, the five common HPV types in ≥HSIL were: HPV 16, 18, 52, 58, and 59. The frequently detected HPV types were HPV 16, 52, 58, 51, and 33 in LSIL and HPV16, 52, 58, 18, and 66 in women with ASCUS. However, the common types in women with normal cervical cytology were: HPV 52, 16, 58, 18, and 51. The prevalence of HPV16, 18, 58, 31 and 59, increased by cervical lesion degree, however, the prevalence of HPV33, 56, 35, 66, 68, 52, 45, 51, 39, 11, and 6 increased from NILM to LSIL, followed by a decrease in ≥HSIL. In addition, HPV16 was the predominant type in women with ASC-US and other cytological diseases, whose prevalence ranged from 3.3 % to 54.5%. HPV52 was the second most prevalent type in cervix diseases diagnosed by cytology (NILM; 4.1%, ASCUS; 11.4%, LSIL; 14.1%, HSIL; 13.5%). HPV18 was the third common type in ≥HSIL, with a prevalence of 12.3% [See Table 3].

Table 3.

Type-specific HPV prevalence and overall prevalence of HPV cell -based detection in healthy women from mainland, stratified by cervical disease grade

HPV type	NILM	ASCUS	LSIL	≥HSIL
HPV ration	12.5 (8.9,16.1)	42.2 (21.5,63.0)	73.6 (59.9,87.2)	90.1 (83.6,96.7)
HR-HPV	11.9 (9.8,14.1)	28.3 (7.9,48.8)	64.7 (41.8,87.7)	69.4 (24.2,90.7)
LR-HPV	2.6 (0.8,4.4)	1.4 (0.0,2.8)	8.3 (1.7,15.1)	7.2 (0.8,13.6)
HPV6/11	2.1 (1.2,3.0)	4.5 (3.2,5.8)	5.4 (2.5,8.2)	3.4 (1.4,5.3)
HPV16	3.3 (2.0,4.6)	12.2 (5.9,18.5)	14.5 (9.5,19.5)	54.5 (19.2,60.1)
HPV52	4.1 (2.6,5.5)	11.4 (5.5,17.3)	14.1 (7.2,21.0)	13.5 (5.9,15.5)
HPV18	1.2 (0.7,1.8)	4.6 (1.5,7.7)	6.4 (4.7,8.1)	12.3 (3.2,18.9)
HPV58	2.1 (1.3,2.8)	7.1 (2.7,11.4)	10.8 (5.1,16.4)	9.3 (2.8,13.8)
HPV59	0.5 (0.2,0.7)	1.2 (0.3,2.2)	2.3 (1.4,3.3)	6.9 (2.5,11.3)
HPV33	0.8 (0.5,1.1)	2.5 (1.7,3.2)	8.0 (3.9,12.0)	6.2 (4.6, 9.4)
HPV51	1.1 (0.7,1.6)	3.9 (1.3,6.6)	9.0 (6.5,11.5)	6.0 (0.7,7.2)
HPV31	0.7 (0.4,1.0)	3.3 (1.6,5.0)	3.5 (2.0,5.0)	4.6 (1.5, 4.7)
HPV56	0.6 (0.4,0.9)	1.9 (1.1,2.8)	6.8 (3.0,10.6)	3.9 (1.3,6.6)
HPV45	0.7 (0.3,1.1)	1.9 (0.3,3.6)	3.7 (0.8,6.6)	3.5 (1.9,5.1)
HPV42	0.4 (0.1,0.6)	0.7 (0.1,1.4)	-	3.0 (0.1,15.8)
HPV39	1.0 (0.6,1.5)	3.5 (1.1,5.9)	6.2 (4.2,8.2)	2.7 (1.2,4.1)
HPV66	1.1 (0.6,1.6)	4.0 (2.3,5.6)	7.6 (5.8,9.3)	2.4 (0.6,4.2)
HPV11	0.6 (0.2,0.9)	1.2 (0.5,1.9)	2.2 (1.2,3.2)	2.1 (0.7,4.9)
HPV35	0.5 (0.2,0.7)	1.3 (0.4,2.2)	2.7 (0.4,5.1)	1.6 (0.3,2.8)
HPV6	0.3 (0.1,0.5)	3.2 (2.1,4.3)	4.4 (3.0,5.8)	1.6 (0.4,2.8)
HPV68	0.9 (0.6,1.3)	2.2 (1.5,2.9)	4.2 (1.8,6.6)	1.2 (0.2,2.3)

NILM: No intraepithelial lesion or malignant cells; ASCUS: Atypical squamous cells of undermined significance; LSIL: Low-grade squamous intraepithelial lesion;≥HSIL: High-grade squamous intraepithelial lesion and cancer. HR-HPV:high-risk human papillomavirus,LR-HPV:-risk human papillomavirus

DISCUSSION

HPV is one of the sexually transmitted infections worldwide, especially the persistent HR-HPV infection that causes cervical cancer. This study provides up-to-date evidence to propel potential HPV vaccination and cancer screening programs for women in Mainland China. First, compared with previously published systematic reviews, we have added new data about the prevalence and distribution of HPV genotypes among women with a normal cervix over nearly 10 years. Second, our results show the prevalence and distribution of HPV subtypes using the gold-standard method for cervical cancer screening in China, histology diagnosis. The distribution of HPV subtypes reported in cytology is different from those in histology assessment. Third, we further analyzed the prevalence and distribution of HPV subtypes in different geographical regions of China and other factors influencing HPV prevalence, such as age trends, in this study, which have been rarely analyzed in previous studies.

Type-specific HPV prevalence and HPV prevalence

We found that the overall prevalence of HPV was 14.3% in women with normal cervix in Mainland China, similar to other findings in the Chinese population (13.1 − 18.8%), and higher compared to the values presented in the International Agency for Research on Cancer (IARC) previous survey − which showed a prevalence of 11.7% of women worldwide with cervical HPV.[10,15,88] The HPV subtype confirmation tests have different sensitivities that might explain the disparity of HPV prevalence in China. However, the HPV prevalence included single and multiple infections, though, it may lead to a higher prevalence in some areas. But compared with previous published meta-analyses in China, due to cervical cancer screening programs and the administration of the HPV vaccine, the HPV prevalence has decreased.[15] In our study, the prevalence of HR-HPV and LR-HPV types was 11.3% and 2.7%, respectively. According to previously mentioned information, it is necessary to promote cervical cancer vaccination and cervical cancer screening programs for women with normal cervix. Consistent with previous epidemiological studies,[89,90] our analysis suggested that HPV16 is the main HR-HPV type, followed by 52, 58, and 18 in women with normal cervix in Mainland China − which differs from the IARC survey findings.[91] The prevalence of all dominant HPV types (HPV16, 18, 52, and 58) was higher than other subtypes reported in a study that analyzed HPV prevalence in five continents.[10] The HPV16 (2.6%) was not only the most prevalent type, but it also showed the highest relative contribution to cervical cancer compared with other types. The second prevalent HPV type in Mainland China was HPV52 accounts for 2.4% prevalence, but other HR-HPV types' prevalence ranges from 0.2 to 1.7%. Our findings show the most common LR-HPV type is HPV6 with a prevalence of 0.4%, followed by HPV11, which shows a prevalence of 0.3%.

Type-specific HPV prevalence and overall HPV prevalence, stratified by regions

Worldwide, the incidence of each common HPV type in Chinese female populations varies by region.[92] Our results confirmed that the variation also occurs across different Chinese territories. Central China accounted for the highest overall HPV prevalence-HR-HPV and LR-HPV 9.8, 15.1, and 4.8%, respectively, in healthy women from the Chinese mainland − which is consistent with a higher cervical cancer mortality in that region. This result is consistent with the findings of Ma XM et al.[14] Compared with other regions, East China and South China have less variability in HPV prevalence, though the data available in these regions are larger than that in other areas. East China has the second-highest overall HPV prevalence and LR-HPV prevalence, which accounted for 15.6 and 2.9%, respectively. However, women from South China have the lowest HPV prevalence, which demonstrates the vaccination access women from this region (South China) receive from neighboring cities such as Hong Kong and Macau − where the HPV vaccine has been used for over a decade. That might be one of the reasons why the HPV52 prevalence was higher than HPV16 in East China and South China.[19] This evidence suggests that geographical differences in HPV prevalence may be related to accessibility to vaccines, but further investigations are required to confirm this statement. Consistent with previous epidemiological studies,[78,88] our study shows that HPV16, 52, 58, and 18 were the most common types in all regions, which might be related to HPV variants, habits, and hygienic conditions.

Age-specific prevalence

In this study, we confirm that the overall HPV prevalence and HR-HPV prevalence have two peaks, aged ≤25 years and aged 41~ years in healthy Chinese women. However, the results are not consistent with previous articles reporting that the overall HPV prevalence and HR-HPV prevalence formed a “U-shaped curve” at aged 30~ years and aged 41~years in Chinese and Asian women.[92,93] It may be that the age-specific phenomenon observed at aged ≤25 years in healthy Chinese women of Mainland China is compatible with underlying causes. First, the finding showed that the average age of the first sexual intercourse of girls was 17-year-old, so it may be the first-time transient HPV infection and insufficient adaptive immune responses up to peak at the age of 18 − 24 years. Second, Chinese women may have changed their attitudes toward sexual intercourse. The three reasons to explain the second peak at aged 41~ years: studies showed that the women and/or their husbands have extramarital relationships with more than two sexual partners at middle age[94,95]; the time at which women got cervical cancer screening, so, it could be the reflection of population-specific period and/or cohort effects; and women aged 41~ years have HPV persistent and co-infection. The prevalence of LR-HPV had no significant trends or variations with age because it is rarely detected by HPV testing.

The prevalence of overall HPV and type-specific HPV stratified by cervical disease grade of histology diagnosis

Women with abnormal cervical lesions and cervical cancer had high HPV prevalence than women with normal cervical histology 10.5% for the NILM, 73.9% for CIN1, 89.5% for CIN2, and 91.5% for ≥CIN3, which was higher than the findings reported in a similar systematic review where 87%, and 67.1% in ≥HSIL and LSIL, respectively, were observed.[9,15] It may be related to HPV detection methods, especially the sensitivity of different PCR protocols used in the included studies. Though the type-specific HPV prevalence was varied in different cervical lesion grades, the main common LR-HPV types were HPV 16, 52, 58, and 18. However, these results are consistent with reports from 2019 that demonstrated that HPV 18, 16, 58, and 33 were the most prevalent HPV types in different cervical lesion grades.[91] The change might be related to an increase in cervical cancer screening programs, prevention, and pathogenicity.[96] The present study shows overall HPV, HPV16, and HPV18 prevalence increases with the grade of cervical lesion, which is different from the other HPV subtypes that failed to show the same trend. HPV16 (from 2.4 to 62.0%) and HPV18 (from 0.7 to 15.8%) were the commonest types in cervical histological grades, consistent with previously reported findings. The HPV18 was the second most prevalent type in women with ≥CIN3, compared to the worldwide data report of 2017.[96] According to Huang, S., et al.,[97] HPV 58 and 52 were the third and fourth most prevalent among women with ≥CIN3 in China. Therefore, the prevalence of HPV6 in cervical cancer was higher than other cervical lesion degrees, which may suggest an alternative to promoting HPV vaccination.

Type-specific HPV prevalence and overall prevalence HPV, stratified by cervical lesion degrees cytology diagnosis

Our study shows an overall HPV prevalence of 90.1, 73.6, 42.2, and 12.5% in the ≥HSIL, LSIL, ASCUS, and NILM, respectively, which is higher compared with a previous systematic review that showed 87% and 67.1% in ≥HSIL and LSIL.[15] The previously mentioned values were lower than the HPV prevalence worldwide.[98] The type-specific HPV prevalence varied in different cervical disease grades detected by cytology, where the commonest HPV types were HPV16, 52, 18, and 58. These results demonstrated that the main HPV types are different to those described in worldwide reports about the Chinese population,[98] which may be due to the overtime change of HPV types, especially in cancer screening in China and the lack of cervical cytology diagnosis. HPV genotypes vary in different cervical stages by cervical cytology diagnosis. The prevalence of HPV16, 18, 58, and 31 was increased by ASCUS and more advanced disease grades. The increase demonstrated strong carcinogenicity in ≥HSIL and other types that may accelerate the carcinogenic process. HPV16 was the most predominant type in cervical disease, except for normal cytological diagnosis, which ranged from 3.3 to 54.5%, which was different from histological due to the lack of cytology diagnosis in cervical cancer screening. HPV18 was the second most common type in ≥HSIL, which has been proven to be the main HPV type reported in many articles that have studied the Chinese population.[15] This is a target to be achieved in cervical cancer prevention by 2013–2020 through the Global Action Plan for “call to action ending cervical cancer. “

Study strengths and limitations

This study has some limitations. First, the included studies lack information about the occupations and ethnic groups of the analyzed healthy populations, which may be unequal in every province; thus, we ignored some critical points in our analysis leading to weak homogeneity that might affect the prevalence of HPV. Second, the prevalence of specific types of HPV included in multiple and single infections was counted in this analysis to contribute to a higher positive − which could have potentially increased the attributable fraction of HPV and specific types of HPV in intraepithelial cervical cancer cases, especially in HPV16 or other HR-HPV types. Third, the type-specific HPV prevalence in the analyzed studies had variation in histopathology and cytology diagnoses. But due to limited resources, we are unable to identify the real association between HPV and the range of cervical diseases detected by cytology or histology.

Disclosure

This meta-analysis demonstrated that HPV16, 52, 58, 18, and 33 are the most common HPV types in women from Mainland China. The HPV infection is widely prevalent in the Chinese mainland population, such as those in Central China. The overall HPV and HR-HPV prevalence in healthy women showed a peak at two different ages, under 25 years and between 41 and 45 years of age. Regarding histology and cytology analysis, women with cervical lesions and cervical cancer showed a significantly higher HPV prevalence than women with normal results. In conclusion, this study helps to update the available data about HPV in Mainland China and further provides important information that might be useful for implementing and guiding new policies in China and/or other developing environments worldwide.

Abbreviations

SPSS = Statistical Package for Social Science, ASMR = age-standardized mortality rate, HPV = Human papillomavirus, ≥HSIL = High-grade squamous intraepithelial lesion or worse, LSIL = Low-grade squamous intraepithelial lesion, ASCUS = Atypical squamous cell of undetermined significance, CIN1 = Cervical intraepithelial neoplasia grade 1, CIN2 = Cervical intraepithelial neoplasia grade 2, ≥CIN3 = Cervical intraepithelial neoplasia grade 3 or worse, PCR = Polymerase chain reaction.

Availability of data and materials

Data within this manuscript were presented in part as Excel. The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Authors' contributions

Yan Qin Yu, Shi Lan Fu, JinQi Hao,Maria J. G. Mendez, Bangura Mohamed S, Fang Hui Zhao, and You Lin Qiao participated to design the study, performed data analysis, visualization, validation the whole work, and prepared the manuscript. Yan Qin Yu and Shi Lan Fu took part in data collection, supervision and software, and other resources. All authors read and approved the final manuscript.

Ethics approval and consent to participate

Ethics approval and patient consent were not required because this study is a meta-analysis based on published studies.

Consent for publication

All authors have given their consent to publishing this work.

Financial support and sponsorship

The study was funded by Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences (No. 2021-I2M-1-004) and Foundation of Baotou Medical College (No. BYJJ-YF 201723).

Conflicts of interest

There are no conflicts of interest.