Epidemiological Features of Human Papillomavirus ( HPV ) Infection among Women Living in Mainland China

Cancer of the cervix is the third most common cancer in women worldwide, with an estimated 529,000 new cases and 274,000 deaths occurring in 2008 (Ferlay et al., 2010). More than 85% of the cases occur in developing countries such as China. A previous review has demonstrated the unbalanced disease burden of cervical cancer regarding age group, ethnicity and area of residence (rural or urban) in China (Li et al., 2011a). In China, since a national cancer registry is already set up but with geographically limited data generated, the disease burden of cervical cancer is believed to be underestimated. With the causal relation between human papillomavirus (HPV) and cervical cancer being firmly established (Nobbenhuis et al., 1999; Bosch et al., 2002), high-risk human papillomavirus (HR-HPV) prevalence has been shown to correlate well with cervical cancer incidence rates based on the independently obtained HPV prevalence data among women attending routine cervical cancer screening programs (Bruni et al., 2010) and data on the worldwide cervical cancer burden (Arbyn et al., 2011).


Introduction
Cancer of the cervix is the third most common cancer in women worldwide, with an estimated 529,000 new cases and 274,000 deaths occurring in 2008 (Ferlay et al., 2010).More than 85% of the cases occur in developing countries such as China.A previous review has demonstrated the unbalanced disease burden of cervical cancer regarding age group, ethnicity and area of residence (rural or urban) in China (Li et al., 2011a).In China, since a national cancer registry is already set up but with geographically limited data generated, the disease burden of cervical cancer is believed to be underestimated.
With the causal relation between human papillomavirus (HPV) and cervical cancer being firmly established (Nobbenhuis et al., 1999;Bosch et al., 2002), high-risk human papillomavirus (HR-HPV) prevalence has been shown to correlate well with cervical cancer incidence rates based on the independently obtained HPV prevalence data among women attending routine cervical cancer screening programs (Bruni et al., 2010) and data on the worldwide cervical cancer burden (Arbyn et al., 2011).

Epidemiological Features of Human Papillomavirus (HPV) Infection among Women Living in Mainland China
Jing Li 1,2& , Rong Huang 1,2& , Johannes E Schmidt 3 , You-Lin Qiao 2 * Therefore, reviewing data on HR-HPV prevalence will be important in the context of better understanding the cervical cancer burden in the country.In recent years, significant progress has been made in cervical cancer prevention especially with the availability of prophylactic vaccines.HPV vaccination holds a promising future for cervical cancer prevention especially for countries with limited access to screening.
In China, phase III clinical trials of the prophylactic vaccines are ongoing.Before the vaccines were commercially available in China, much needs to be understood about the potential benefit when HPV vaccines are administered in Chinese women.The authors reviewed several multi-centre, hospital-/population-based studies published over a 12-year period (2001)(2002)(2003)(2004)(2005)(2006)(2007)(2008)(2009)(2010)(2011)(2012) including the first population-based HPV study published in China (Zhao et al., 2001) as well as the most recent HPV pooled analysis (Zhao et al., 2012b).The present article aims to report on important additional evidence regarding HPV prevalence and type distribution in women attending cervical cancer screening and in women diagnosed with cervical cancer or precancerous lesions in China, by study population, geographic area and time period.The authors also review evidence regarding the level of awareness about HPV and the acceptability of HPV vaccination among Chinese women, which is thought to be an important element in the prevention of HPV related diseases such as cervical cancer.

HPV prevalence and type distribution in different populations
HPV prevalence and type distribution in women attending screening: An overall average HR-HPV prevalence of 17.7% was reported recently based on a pooled analysis of 17 population-based screening studies conducted between 1999 and 2008 in mainland China using Hybrid Capture 2 (HC2, Qiagen) (Zhao et al., 2012b).Table 1 listed the HPV prevalence among women participating in population-based cervical screening studies by using HC2 or polymerase chain reaction (PCR) as the detecting method, including the pooled analysis.
Figure 1 shows the HPV prevalence of women attending population-based screening, by age group.Studies using GP5+/6+ mediated PCR lab assays to detect 14 HR-HPV and 30 low risk HPV (LR-HPV) suggest that among women aged 15-59 years, the prevalence of any HPV-type showed a first peak at age 15-24 years from 13.3% to 15.0%, to then decline to less than 10.0% at age 25-29 years, to then increase again to form a second peak in women at age 35-54 years from 17.0% to 24.4% ( Li et al., 2006;Dai et al., 2006;Wu et al., 2007).A similar age pattern was observed for HR-HPV prevalence in studies using HC2.The HR-HPV prevalence presented two peaks, one at age 15-24 years (16.2% to 19.3%) and the other in women aged 35-49 years (15.2% to 28.2%), respectively ( Shen et al., 2003;Zhao et al., 2006;Li et al., 2007;Li et al., 2010;Zou et al., 2011;Hu et al., 2011).Conversely, for LR-HPV prevalence, no significant age-specific trend was observed (Zhao et al., 2009b).
The "two peak" pattern pertained to both rural and urban women.The crude HR-HPV prevalence was seen to peak among urban women aged 15-24 years (18.7%) and among women older than 40 years of age (16.0%).Among rural women, it peaked at age 15-24 years (16.2%) and 35-39 years (18.6%)(Zhao et al., 2012b).This pattern differs from that observed in women from Western countries, among whom, HPV prevalence peaked only at their mid-twenties, then steadily decline as age increases ( Moscicki et al., 2006;Stanley, 2010;Grant et al., 2011;Wheeler et al., 2012).
The first peak in China may due to the fact that younger women are more sexually active and more likely to have multiple partners, especially in urban areas (Zhao et al., 2012c).Reasons for the second peak in Chinese women are not well understood; viral persistent infection may be one of the explanations (Castle et al., 2005) or reactivation of a latent HPV infection (Li et al., 2005).
Women with human immunodeficiency virus (HIV) infection are more likely to be HPV positive due to their immunosuppression ( Palefsky and Holly, 2003;Strickler et al., 2005).In mainland China, approximately 15,000 women were reported to have an HIV infection or Acquired Immune Deficiency Syndrome (AIDS) (Wang and Ni, 2008), accounting for 1/3 of 47,982 HIV/AIDS cases reported in 2007 in China.Zhang et al reported an HPV prevalence of 49.4% (41/83) among women with HIV/AIDS in Yunnan province, China, which is significantly higher than that of the general population (Zhang et al., 2012).
It is well known that the prime mode of transmision of HPV is sexual activity.Gupta et al reported that male partners of women with invasive cervical cancer (ICC) were more likely to be HPV positive ( Nicolau et al., 2005;Gupta et al., 2006).High HPV positivity in females increases the risk of developing condylomata acuminata (CA), as well as penile and anal cancers for the male partners (Castellsagué et al., 2004).Few studies have evaluated the concordance of HPV infection among couples in China.One population-based HPV prevalence study was conducted among 400 Uyghur couples in Xinjiang province, reporting an overall HPV prevalence of 14.3% and 8.0% in women and their husbands, respectively (Ablimit et al., 2011).
HPV prevalence and type distribution in women with abnormal histology: Worldwide, oncogenic HPV types 16 and 18 are attributible for approximately 70% of ICC cases (Munoz et al., 2003).In China, variations in HPV prevalence of ICC cases between studies are observed due to differences in study methodology and laboratory testing protocols ( Peng et al., 1991;Lo et al., 2002;Smith et al., 2007).A nation-wide, multi-center hospitalbased study using the highly sensitive SPF 10 LiPA25 for HPV DNA detection indicated that HPV prevalence was 97.6% in squamous cell carcinoma (SCC) and 85.3% in adenocarcinoma (ADC).HPV16 (76.7%) and HPV18 (8.0%) were the most common types in SCC, followed by HPV31, HPV52 and HPV58 (Chen et al., 2009).
Recently, a pooled analysis including 30,371 women from 17 cross-sectional, population-based studies in various parts of China showed that HR-HPV prevalence was 11.2% in women with normal histology, 79.7% in cervical intraepithelial neoplasia grade 1 (CIN1), 95.0% in cervical intraepithelial neoplasia grade 2 (CIN2), 97.4% in cervical intraepithelial neoplasia grade 3 (CIN3), and 98.0% in SCC and ADC (Zhao et al., 2010).Figure 2 demonstrates that HPV prevalence is positively related to the severity of cervical abnormalities.It is lower in women with normal cervical histology (13.1%) than in women with CIN1 (75.0%), or in women with CIN2 and/ or CIN3 (93.4%-99.3%),or in women with SCC or ADC (85.3%-100%).It also shows that HPV DNA is more likely to be present in SCC than in ADC ( Bao et al., 2007;Chen et al., 2009;Zhao et al., 2009a)..

HPV prevalence and type distribution among women from population-based screening studies and hospital-based studies in different geographic areas
HPV prevalence and type distrubution in urban and rural Chinese women: When women from populationbased screening studies and hospital-based studies in mainland China were classified as living in either rural or urban areas, HPV prevalence showed a similar pattern but different rates (Table 2).In rural women, the HPV prevalence was somewhat higher than that in urban women.A pooled-analysis of 17 population-based reported a crude HR-HPV prevalence of 18.0% and 15.2% in rural and urban women, respectively (Zhao et al., 2012b).Six studies conducted in rural areas reported a HPV prevalence of 14.8% to 29.6% depending on the targeted age group and the HPV DNA detection method used ( Zhao et al., 2001;Shen et al., 2003;Dai et al., 2006;Wu et al., 2006;Li et al., 2007;Zou et al., 2011).However, in five studies conducted in urban areas, HPV prevalence varied from 6.7% in Beijing to 22.5% in Fuzhou, Fujian province (Li et al., 2006;Wu et al., 2007;Zhao et al., 2009b;Li et al., 2010;Wu et al., 2010).
The most commonly used method for detection of HPV DNA was different between urban (GP5+/6+ mediated PCR) and rural (HC2) area.The sensitivity of HC2 assay was higher than that of the PCR detection (Kulmala et al., 2004;Schiffman et al., 2005).Moreover, the procedure of the HC2 assay is standardized and can be easily controlled, whereas PCR contains several steps and is difficult to standardized (Kulmala et al., 2004).Another potential bias was that most sites for rural studies were located in high risk area in China, such as Yangcheng, Xiangyuan, so the figures for rural could be probably overestimated.
Although differences in HPV prevalence were observed between rural and urban areas, the predominant HPV types do not significantly differ.Among all, HPV16, 52 and 58 were the most commonly detected HPV types in the population-based study when GP5+/6+ -based PCR assay was used for HPV typing (Dai et al., 2006;Li et al., 2006;Wu et al., 2007).
HPV prevalence and type distribution in women from population-based screening studies and hospitalbased studies in seven geographic areas: Evidence on HPV type distribution varies greatly across geographic regions of China.Traditionally, China is regarded as consisting of seven distinct geographic regions: Northeast, North, Northwest, Central, Southwest, South, and East China.This section reports on HPV prevalence and type distribution in women from population-based screening studies and hospital-based studies in each of the seven regions (Table 3).Northeast China: A population-based screening study in Shenyang reported an overall HPV prevalence of 16.8% among women aged 15~59 years old (Li et al., 2006).In Shenyang, a hospital-based study among 4,780 women with cervical disease and 165 women with normal cytology reported that the HPV prevalence was 21.8% in women with no obvious disease, 35.7% in cervicitis, 54.6% in ASCUS, 64.1% in CIN and 83.4% in cervical cancer.In this study, using HPV GenoArray test kit (HybriBio, Hong Kong) for HPV DNA detection, HPV16 (19.6%) was the most prevalent genotype, followed by HPV58 (8.4%), HPV52 (6.4%), HPV33 (4.6%) and HPV53 (3.2%) (Sun et al., 2010).North China: A population-based screening study using HC2 assay among women aged 25-54 years in Beijing found that the HR-HPV prevalence was 9.9% overall, 39.9% in women with CIN1, and 88.6% in women with ≥ CIN2.PCR with the PGMY09/11 primer was used for HPV typing.The most commonly detected HPV types were HPV16 (26.5%),HPV58 (8.8%), HPV33 (7.8%) and HPV56 (5.3%) in women with cervical lesions (Li et al., 2010).
China Nationwide: A hospital-based, multi-center large scale type distribution study in histologically confirmed cervical lesions using highly sensitive, state-of-the-art PCR methods (SPF10 LiPA 25 version 1 assay) in 7 geographical areas of China showed that HPV was highly prevalent among women with high-grade precancerous lesions and cervical cancer regardless of where they live (Figure 3).Same as worldwide, HPV16 (76.7%) and HPV18 (7.8%) were the most common types in all regions.The importance of other HPV types varied by region.HPV58 and HPV52 were more prevalent in the South and Southwest compared to other regions among women with precancerous lesions and cervical cancer (Chen et al., 2009).
In a recent meta-analysis, after adjusting for histological diagnosis of the tumor, source of specimen and type of PCR primers used, the HPV prevalence in ICC showed an increasing trend over different time periods in China.The adjusted HPV prevalence was 64.3% before the year 2000, then increased to 85.0% from 2000 to 2003, to further increase to 86.7% from 2004 to 2006 (Bao et al., 2007).

Knowledge of HPV-related Disease, Attitudes and Acceptability of HPV Vaccination
With prophylactic HPV vaccines being licensed in many developed and developing countries, the era of comprehensive cervical cancer prevention is coming.In China, phase Ⅲ clinical trials are ongoing to evaluate the efficacy of the vaccines in Chinese women.Lack of knowledge about and negative attitude towards HPV and HPV vaccination were reported to be a major potential obstacle to be expected during the time of introduction of HPV vaccination (Hu et al., 2011).In general, awareness of HPV was low (15.5%)among Chinese women, but when women were defined as living in rural or urban areas, urban women were twice as likely to have heard of HPV (21.6%) compared to those living in rural areas (9.3%) (Li et al., 2009).In Beijing, a typical metropolitan city in China, 38.2% of women aged older than 40 years reported to be aware of the relationship between HPV and cervical cancer (Fu et al., 2010).By contrast, in the rural areas, where cervical cancer remains a critical public health problem, HPV awareness was extremely low.In Xiangyuan, a county with a high disease burden due to cervical cancer, only 5.9% of women reported that they had ever heard of HPV (Song, 2007).In the southern Xinjiang autonomous region, none of the women reported that they had heard about HPV (Ablimit et al., 2009).
In a recent multicenter survey, researchers interviewed 11,852 women from the general population aged 15-59 years from seven urban and 14 rural areas of China, as well as 763 government officials and 760 healthcare providers.HPV awareness among urban and rural healthcare providers was 96% and 80%, respectively, and was therefore higher than that among government officials (44%), urban women (34%) and rural women (16%).Less people reported to have heard of HPV vaccination in government officials (33%) and the general population (23%).Approximately 80% of government officials and medical personnel were willing to vaccinate themselves and their daughters (Zhao et al., 2012d).
Apart from safety, efficacy and cost of the vaccines, HPV awareness and knowledge are directly related to the acceptance of HPV vaccination (Hu, 2011).In order to ensure a high level of acceptance of vaccination in order to prevent cervical cancer especially in the rural areas, education and HPV awareness campaigns represent an urgent concern.For both rural and urban women, recommendations from doctors or nurses in favor of getting vaccinated and educational lectures carried out in hospitals played an important role in helping women decide to get vaccinated (Song, 2007;Li et al., 2009).Therefore, educating doctors and nurses on HPV and HPV vaccination is a critical initial step of such a campaign.

Conclusions
In conclusion, invasive cervical cancer and precancerous lesions are important public health concerns DOI:http://dx.doi.org/10.7314/APJCP.2013.14.7.4015 Epidemiological Features of HPV Infection among Women Living in Mainland China in China.In cervical cancer, HPV 16 and 18 consistently represent the most commonly detected types across China.HPV 58 and 52 are found to be more prevalent in women with cervical cancer and precancerous lesion from Southern and coastal regions of mainland China.Cervical cancer is a malignancy that can be prevented by vaccination especially in countries and regions where cervical cancer screening is not universally available or accepted, as is the case in China.Factors essential to the successful implementation of HPV vaccination in China include a widespread public health campaign about HPV and HPV vaccination, government endorsement of vaccination programs with commitment of resources, affordable vaccines, and the establishment of a health care infrastructure to ensure efficient vaccine delivery especially in the rural areas of China.