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Prevalence of Human Papillomavirus Infection in Guangdong Province, China: A Population-Based Survey of 78,355 Women

Jing, Lipeng MM*†; Zhong, Xingming MM*†; Zhong, Zeyan MM; Huang, Weihuang MM*; Liu, Yang MM*; Yang, Guang MD; Zhang, Xiaoping MM§; Zou, Jing MM§; Jing, Chunxia MD*; Wei, Xiangcai MD*†

doi: 10.1097/OLQ.0000000000000201
Original Study
Open
SDC

Background The prevalence of human papillomavirus (HPV) infection and the distribution of different HPV genotypes vary greatly within different geographical and ethnic populations, especially in Asia. The HPV infection data based on regional population are extremely important for researchers to develop new efficient HPV screening assays and estimate the effect of vaccines on preventing from cervical cancer.

Methods A total of 78,355 women from Guangdong Province, China, whose ages were from 18 to 75 years were enrolled in this study. All epidemiological data were obtained by face-to-face interview. Cervical exfoliated cells were collected, and HPV-DNA test was conducted with the matrix-assisted laser desorption/ionization time-of flight mass spectrometry.

Results The overall HPV infection prevalence in the study population was 7.3%. The top 6 HPV genotypes were HPV16 (1.5%), HPV52 (1.2%), HPV58 (1.0%), HPV18 (0.7%), HPV45 (0.5%), and HPV6 (0.5%), accounting for 69.7% of all detected HPV infection types. Two peaks of HPV infection were detected in the population of old age group (>50; 9.6%) and young group (<25; 8.2%). Infection with single genotype HPV (6.2% in all; 85.7% in HPV-positive women) was more frequent than infection with multiple HPV (1.0% and 14.3% respectively). Results of multivariate logistic regression revealed that sexual active years, numbers of sexual partner, and numbers of pregnancy were risk factors of HPV infection.

Conclusions This study provides useful epidemiological information on cervical HPV infection prevalence in general female population from Guangdong Province, China. In this population, HPV infection prevalence was 7.3%, and genotypes HPV16, HPV52, and HPV58 showed a relatively high prevalence.

The population-based investigation in Guangdong, China, showed a low prevalence of human papillomavirus (HPV) infection (7.3%) and a relatively high prevalence of HPV16, HPV52, and HPV58 genotypes.

From the *Department of Epidemiology, Medical School, Jinan University, Guangdong Province, China; †Family Planning Research Institute of Guangdong, Guangzhou, Guangdong Province, China; ‡Department of Parasitology, Medical School, Jinan University, Guangdong Province, China; and §Clinical Laboratory Center of the Beijing Genomics Institute (BGI), Shenzhen, Guangdong Province, China

Conflicts of interest and source of funding: The authors declare that we have no conflict of interests. This work was supported, in part, by China Population Welfare Foundation (Grant No. [2011]31), Family Planning Foundation of Guangdong Province (Grant No. 2012004), and Guangdong Province Medical Research Foundation (Grant No. A2014374). Human papillomavirus screening was supported by Clinical Laboratory Center of the Beijing Genomics Institute, Shenzhen, Guangdong Province, China.

Lipeng Jing and Xingming Zhong contributed equally to this work.

Correspondence: Xiangcai Wei, PhD, is to be contacted at Family Planning Research Institute of Guangdong, No. 17, Meidong Rd, Guangzhou, Guangdong Province, China. E-mail: Dxcwei@163.com; Chunxia Jing, PhD, School of Medicine, Jinan University, No 601, Huangpu Road West, School of Medicine, Jinan University, Guangzhou, Guangdong Province, China. E-mail: jcxphd@gmail.com.

Received for publication June 8, 2014, and accepted August 28, 2014.

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Cervical cancer is the second most common cancer and contributes to 9.8% of all cancers in female population around the world.1 There are approximately 75,500 new cases (14% of all cervical cancer worldwide) and 34,000 deaths (12%) per year in China.1 It has been established that human papillomavirus (HPV) is a causal and necessary factor for cervical cancer.2 Human papillomavirus prevalence was 1.4% to 25.6%, and the distribution of HPV types varied between world regions.3 Furthermore, HPV is responsible for 5.2% of all cancers (i.e., anal, vaginal, penile, vulvar, and oropharyngeal tumors), which indicates the importance of HPV epidemiological data.

More than 150 HPV types have been identified, and 30 are high risk (HR) types,4 in which 15 are highly associated with the development of cervical cancer.5 Human papillomavirus–based screening was strongly advised for hygienic resource limited country, with more sensitive and cost-effectiveness compared with cytology-based screening.6 Human papillomavirus infection was common among female population; however, women with HPV infection who have no cytological leisions might have different progressive potential. Furthermore, previous studies demonstrated that HPV16 and HPV18, HPV58, HPV33, HPV52, HPV45, HPV31, and HPV35 are the prevalent types in Asia, which account for approximately 90% of cervical cancer cases in Asia.7 Thus, detection targeted for these HPV types may improve cost-effectiveness.

Regional population-based data on the prevalence and HPV type are perquisite of developing new HPV-screening tests and estimating the impact of vaccines on cervical cancer. However, these data are limited in Guangdong province, which located at southern of China with a total area greater than 179,000 km2 and a population approximately 105.9 million in 2012. The Pearl River Delta Region is located in mid-southern coastal part of Guangdong, notably, and this area accounts for 10% of China’s gross domestic product and more than 80% of Guangdong’s gross domestic product, which shows high-economy activity.8 This population-based survey aims to obtain epidemiological data on HPV prevalence in women across a broader age range and the distribution of HPV types in the PDR, a relatively developed region in China.

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MATERIALS AND METHODS

Study Population and Procedures

This study was conducted from May 2011 to November 2012 in Guangdong province, China. Nine cities (Dongguan, Guangzhou, Huizhou, Jiangmen, Qingyuan, Shenzhen, Zhaoqing, Zhongshan, and Zhuhai; Fig. 1) in the Pearl River Delta Region were selected from 21 cities of Guangdong Province by a convenience sampling technique. A multistage stratified cluster sampling method was used to recruit participants. The stratification factors included geographical locations. In each city, 3 counties and 1 central city zone were randomly selected, and the sample size was calculated based on expected HPV prevalence derived from previous studies.9 The formula was

, where n is the estimated sample size; π, expected prevalence of HPV, 5% was used; δ = 0.15π; α = 0.05; and uα = 1.96. Furthermore, with an expanded sample size of 110%, the estimated sample size for each city was approximately 8029. The sampling strategy and method are shown in Figure 2.

Figure 1

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Figure 2

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Figure 3

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Figure 4

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Table 1

Table 1

Table 2

Table 2

Eligible women were sexually active, with an intact uterus, not pregnant, and physically and mentally competent; had no history of miscarriage, cervical cancer, medical treatment, or surgery; and lived in Guangdong for more than half a year. Almost all women in the study had never been screened for cervical cancer in the past 3 years. All participants were informed by notices on community billboards and doctors’ household visits. Eligible participants interested in free screening test can come directly to the nearest Family Planning Service Stations or medical institutions in each city, where each participant was explained about the study and written consent for their participation was obtained. Then the information and exfoliated cervical cells were collected by doctors. The study protocol was approved by the research ethics committee of the Family Planning Research Institute of Guangdong province.

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Data and Sample Collection

First, trained nurses conducted investigations via face-to-face interview to collect the information on sociodemographic status, sexual behavior, and reproductive history. Then, exfoliated cervical cell samples were collected with cyto-brush. The cyto-brush was inserted into the endocervial canal and rotated 3 full turns in clockwise direction. The sampler was conserved in denaturation buffer (Qiagen, Valencia, CA) and stored at 4°C according to the uniform protocol. No cervical samples were collected among women without history of vaginal sexual intercourse. Instructions were written on how to conduct the fieldwork, face-to-face interviewing, and collecting and storing the cervical samples. The local doctors and stuff were trained before investigation. Cervical samples were transported to Beijing Genomics Institute (Shenzhen, China) for HPV testing.

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HPV DNA Detection

Total DNA from cervical cells was extracted using the commercial magnetic beads kit (Chemagen; PekinElmer, Waltham, MA), according to the manufacturer’s instructions. Then 16 HPV genotypes were detected, including HPV16, HPV18, HPV31, HPV33, HPV35, HPV39, HPV45, HPV51, HPV52, HPV56, HPV58, HPV59, HPV66, and HPV68 (HR HPV), and HPV6 and HPV11 (both LR HPV) with MassARRAY (Sequenom, Sandiego, CA) technique based on the matrix-assisted laser desorption/ionization time-of flight mass spectrometry.10 All these procedures were performed in the clinical standard laboratory of Beijing Genomics Institute.

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Statistical Analysis

The χ2 test was used to assess categorical variables. The unconditional logistic regression was used to calculate odds ratio (ORs) with 95% confidence intervals (CIs) to estimate independent risk factors for HPV infection. Factors significantly associated with HPV infection (P < 0.05) in the bivariate analysis were included in crude and age-adjusted logistic regression models to identify risk factors (including age, educational level, smoking status, occupation, marital status, sexual active years, number of sexual partners, and number of pregnancy) associated with HPV infection. Then, multivariate logistic regression model was conducted among all variables that remained significant after adjusting for age. Ordinal variables were treated as continuous to assess the statistical significance of trends for ORs (P for trend). Data analysis was performed by SPSS13.0 (SPSS, Chicago). All statistical tests were 2 sided; P values less than 0.05 were considered statistically significant.

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RESULTS

We enrolled 78,531 women in the study between 2011 and 2012, and excluded 176 of them who failed to provide sufficient specimens for analyses. The ages of 78,355 women included in the final analyses ranged from 18 to 75 years old (median age, 37.0 years). Nearly all of the population belonged to the Han ethnic group. Only 0.2% of the study subjects were unmarried, including 99 widowed or divorced, and the rest was single (Table 1).

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HPV Prevalence

Overall, the prevalence of HPV infection was 7.3% among the women surveyed. Women positive for a single HPV genotype accounted for 6.2% of all women surveyed and 85.7% of all HPV-positive women. Multiple HPV infections were much less frequent than single HPV infections (1.0%, 14.3%). Furthermore,single HPV infection was more common in women older than 50 years (8.5%), whereas multiple HPV infections was more prevalent in women younger than 25 years (1.7%), compares with other age groups (Supplementary Table 1, http://links.lww.com/OLQ/A90). High-risk HPV (14 types) infections accounted for 89.1% among HPV-positive women. Women with 2 to 3 lifetime sexual partners had higher chance of HPV infection than did those who had fewer or more (11.7% vs. 7.1, or 7.3%; P < 0.05; Supplementary Table 1, http://links.lww.com/OLQ/A90).

The prevalence of HPV infection was significantly different in different age groups (χ2 = 58.20, P for trend < 0.01), ranging between 6.5% among women aged 30 to 34 years and 9.6% among those older than 50 years (Fig. 3). Two peaks of HPV infection were detected, one for >50-year and another for <25-year age group, with the prevalence of 9.6% and 8.2%, respectively. Interestingly, the incidence for the 25- to 34-year group was the lowest (6.5%). The prevalence of HPV infection did not progressively increase with age for women aged 35 to 45 years, but climbed up rapidly among the old population (>50 years old). These data clearly demonstrate a correlation between ages and HR HPV genotypes. However, the low-risk (LR) HPV types were much less common in our study subjects. They were more frequent in women younger than 25 years and then decreased to a stable level among other age groups (Fig. 3).

Among the 5681 HPV-positive women, 16 HPV types were identified. The top 6 types were HPV16 (1.5%), HPV52 (1.2%), HPV58 (1.0%), HPV18 (0.7%), HPV45 (0.5%), and HPV6 (0.5%), which accounted for 69.7% of all HPV types detected (Supplementary Table 1, http://links.lww.com/OLQ/A90; Fig. 4). There was a significant difference between HPV types (including HPV11, HPV16, HPV31, HPV33, HPV58, and HPV59) and age groups (P < 0.05). The combined prevalence of HPV 52 and HPV58 accounted for 29.3% of total HPV-positive women, which was nearly the same with HPV16 and HPV18 (29.2%). Interestingly, the prevalence of HPV16 and HPV18 did not increase significantly with age among women older than 25 years, whereas HPV52 and HPV58 increased significantly with age and peaked at age group of women older than 50 years (Fig. 5). The prevalence of a single HPV type infection was more common than multiple infections, except for HPV45, HPV6, HPV39, and HPV35, which were more often seen together with other types (Fig. 4).

The relationship between HPV positivity and age and major characteristics of the study women are presented with age-adjusted ORs and 95% CIs in Table 1. Based on univariate logistic regression, women with 2 to 3 sexual partners (2–3 partners vs. 1; OR, 1.77; 95% CI, 1.43–2.18) were at a higher risk for HPV infection. Compared with women with more than 4 pregnancies, women with 1 or 2 pregnancies were less likely to be infected with HPV (ORs, 0.83 [95% CI, 0.75–0.91] and 0.86 [95% CI, 0.78–0.95], respectively), whereas women who never got pregnant were more likely to be infected with HPV (OR, 1.47; 95% CI, 1.16–1.86). Single women showed an OR of 2.99 (95% CI, 1.24–7.23), whereas no increase in HPV positivity was found among divorced or widowed women compared with currently married women.

Multiple logistic regression analysis was used to show the effect of age group and significant risk factors for HPV positivity in age-adjusted analyses in Table 2. Among all women, sexual active years, number of sexual partners, number of pregnancy, and occupation retained a significant association in the multivariate analyses.

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DISCUSSION

Human papillomavirus prevalence varies significantly in different countries, with 15.6% in Europe, 17% in India, 26% in Nigeria, and 13% to 18% in Latin America.3 It is of great importance to obtain a picture of the status quo in the population. Although some studies have reported HPV infection rate in Shenzhen (13.5%) and Chaozhou (7.9%),11,12 which are conducted within our studied area; to our best knowledge, there are limited large-scale population-based epidemiological data on the prevalence of HPV infection and HPV genotype distribution in whole Guangdong province, Southern China. This population-based study demonstrated that HPV prevalence in the general population in Guangdong province is 7.3%, which was lower than most other regions of China (i.e., Shenyang [11.7%], Shanxi [12.2%], Zhejiang [10.2%], Taiwan [32.4%], and Yunnan [8.3%]), except for Beijing (6.7%),9,13–16 and also lower than other countries in Asian (9.1% in Thailand; 11.4% in Indonesia).17,18 This relatively lower prevalence of HPV infection in Guangdong may be because of the relatively high-level economical income, better sexual health knowledge, and habits of participants in this region. Also, because 99.8% women in our study were married, the stable marital status and sexual partner may explain the lower prevalence of HPV infection in our studied population.19,20

The incidence for each common HPV type in general female population worldwide varies by region.21 The top 6 HPV types in our study were HPV16, HPV52, HPV58, HPV18, HPV6, and HPV45. The most prevalent 4 HPV types in Guangdong were also the top 4 in whole China, although the infection rate of individual HPV type was lower.22 Consistent with the previous studies in China and other populations, HPV16 was the most common type in Guangdong,9,12,13,15 but in contrast to surveys in Taiwan and Zhejiang of Southeast China, Japan, and Indonesia.18,21 The preponderance of HPV52 and HPV58 present in Asian populations was also found in our study population (29.3% of all women, equally to HPV16 and HPV18).3,7,12,13,21 Thus, future HPV prophylactic vaccines including HPV52 and HPV58 may offer higher protection for women in China. Two LR HPV6 and HPV11 types associated with approximately 90% of genital warts and low-grade cervical lesions23 showed relatively a higher prevalence in age group of women younger than 25 years (1.0% and 0.8%, respectively) in our study. This information would be very helpful for future vaccine development to protect young women in this region against genital diseases. Previous studies showed that complex geographical and biological interplay between different HPV types and host immunogenetic factors (e.g., HLA polymorphisms) may contribute to the difference in the prevalence of HPV types.24 Noteworthily, HPV16 was less likely to be influenced by immune status than other HPV types.25 It is thus likely that some disease conditions including chronic cervical inflammation, malnutrition, and parasitic infection might influence the detection sensitivity of HPV types other than HPV16.

Bimodal age distribution of HPV positivity was observed in our study. The higher probability of exposure to new HPV infections, and immature adaptive immune system may contribute to the first peak of HPV infection in women younger than 25 years. The actual first peak of HPV infection might be before 25 years old, as women usually infected with HPV after sexual initiation26 and relatively small proportions (3.2% of all participants) of participants younger than 25 years in the current study may underestimate it. The second peak was observed in perimenopausal women. This may be partly because of physiologic and immunologic dysregulation, caused by hormone fluctuations, which then contributes to HPV persistence or reactivation of latent HPV. Compared with young women, the old women with HPV positivity are more likely to have persistent HPV infection,27 women older than 50 years showed the highest HPV prevalence (9.6%) in the studied population. A relatively higher prevalence of multiple HPV infection was observed in women younger than 25 years in our study (Supplementary Table 1, http://links.lww.com/OLQ/A90), which may be partly explained by a relative lack of viral clearance or more than 1 sexual partner, both of which contributed to the coinfection. Also, our results revealed that LR HPV prevalence was relatively high in women younger than 25 years, which may be because of the higher probability of exposure to new HPV infections and insufficient adaptive immune responses. Our results indicated that women younger than 25 years and women older than 50 years need close monitoring and clinical management.

Pivotal determinants for HPV infection among female population have been demonstrated in previous studies, including early sexual initiation, sexual partner infected with HPV, and more than 1 sexual partner. However, few independent risk indicators about HR sexual behavior were found in our study because women in this region refused to answer questions of sexual behavior; thus, only a few questions were included in the analysis. Inconsistent with previous study,28 women who had been pregnant 2 to 3 times are less likely to be infected with HPV in our study, which might be due to traditional Confucian culture lifestyles and stable marriage. In traditional Confucian culture, the more children women have, the more stable their marriage will be. Surprisingly, though, women with more than 3 sexual partners did not have increased risk of HPV infection in our study. This contrasting finding may be a result of a small number of participants in this category.

Human papillomavirus screening has been supported in hygienic resource-limited country. This MassARRAY (Sequenom) technique based on the matrix-assisted laser desorption/ionization time-of flight mass spectrometry was rapid, high-throughput, and affordable, and its accuracy has been found to be equivalent to the method of HC2, which may be one of the promising methods for HPV screening in China.29

There are some limitations in our study. The main limitation was that few married women younger than 25 years participated in the study because vaginal examination was acceptable only to married women. Furthermore, in most areas, women were unaware that HPV is asymptomatic and mainly transmitted through sexual intercourse, thus reducing the self-selection bias. Besides, the accuracy of the information about their sexual and reproductive history might also impact result analyses.

In conclusion, our study reveal that the most common HPV types in the general female population of Guangdong are HPV16, HPV52, and HPV58. Our results will offer guidance to future development of custom-formulated, more effective prophylactic vaccines for this region.

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CONCLUSIONS

This study provides baseline epidemiological data on cervical HPV prevalence as well as risk factors in the female population of Guangdong Province, Southern China. The results show low-prevalence HPV types and high-prevalence HPV16, HPV52, and HPV58, which indicate that future HPV prophylactic vaccines including HPV52 and HPV58 may offer higher protection for women in China.

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