Prevalence and genotype distribution of HPV infection among 214,715 women from Southern China, 2012-2018: baseline surveys prior to mass HPV vaccination

Background : The epidemiology on the human papillomavirus (HPV) among females in Southern China is not well-established. Baseline data on the prevalence of HPV infection in China prior to mass prophylactic HPV vaccination would be useful. Thus, this study aimed to determine the type-specific HPV prevalence and distribution among females from Southern China prior to mass HPV vaccination. Methods : A retrospective cross-sectional study employing 214,715 women attending NO.1 People’s Hospital for cervical screening during 2012-2018 was conducted prior to widespread HPV vaccination. HPV genotype was detected using nucleic acid molecular diversion hybridization tests. The overall prevalence, age-specific prevalence, type distributionand annual trend was analyzed. Results : The overall HPV prevalence was 18.71% (95% confidence interval [CI], 18.55%-18.88%) among Southern China females. During 2012–2018, the prevalence of HPV infection showed a downward tendency, from 21.63% (95% CI, 21.07%-22.20%) in 2012 to 18.75% (95% CI, 18.35%-19.16%) in 2018. Age-specific HPV distribution displayed a peak at young women aged less than 21 years (33.11%, 95% CI, 31.13%-35.15%), 20.07% ( 95% CI, 19.70%-20.44% ) among women aged 21-30 years, 17.29% (95% CI, 17.01%-17.57%) among women aged 31-40 years, 17.23% (95% CI, 16.95%-17.51%) among women aged 41-50 years, 21.65% (95% CI, 21.11%-22.20%) among women aged 51-60 years, and 25.95% (95% CI, 24.86%-27.07%) among women aged over 60 years. Of the 21 subtypes identified, the most three prevalent high-risk HPV (HR-HPV) genotypes were HPV52 (5.12%; 95% CI, 21.11%-22.20%), -16 (2.96%; screening and vaccine-based To date, the existing data epidemiological characteristics Southern are still scantly, especially lacking large sample study on the genotype prevalence of HPV. Therefore, this paper was conducted to determine the prevalence and type distribution of HPV among 214,715 females in Southern China, including its trends from 2012 to 2018 and age-specific prevalence. Such data provide a baseline pre-vaccine population-based prevalence of HPV in Southern China, and help guide models evaluating impact and cost-effectiveness by comparison between future vaccinated populations and implementation of the prophylactic HPV vaccine according to the specific types’ distribution in the region.


KEYWORDS
Human papillomavirus, high-risk HPV, low-risk HPV, prevalence, genotype, single HPV infection, multiple HPV infection 4 Background Human papillomavirus (HPV) is the leading cause of cervical cancer and responsible for about 91% of anal cancers, 75% of vaginal cancers and 70% oropharynx cancer [1]. It is estimated that there were over 528,000 new cervical cancer patients and 266,000 death worldwide recorded in 2012, among which 85% occurred in developing countries [2]. In China, 130,000 new cases of cervical cancer are diagnosed annually, especially in young women within the first few years after sexual debuts [3,4].
The morbidity and mortality of cervical cancer incidence in developed countries has fallen over the last two decades because of an enhanced awareness of cervical cancer prevention and effective screening [5]. However, infection rate of HPV has fluctuated and not shown a downward trend, indicating a relatively heavy burden of HPV infection in China [6,7].
HPV genotypes are linked to the degree of cervical lesions [6]. Infections with low-risk HPV (LR-HPV) types, such as HPV6 and − 11, cause benign or low-grade changes in cervix cells, genital warts, and recurrent respiratory papillomatosis. Contrarily, high-risk HPV (HR-HPV) type cause cervical, anal, and other genital cancers, which could be detected in 99% of cervical cancers-the second most common cancer in women worldwide. Especially, HPV16 and − 18 have been found to be the most pathogenic of the HR-HPV types, causing about 70% of cervical cancers worldwide [7][8][9][10]. Of note, most HPV infections are completely asymptomatic, resulting in a delay in diagnosis and follow-up treatment with disastrous consequences [11]. Moreover, HPV-infected individuals without early intervention will develop long-lasting HPV infections that put them at risk for cervical cancer, and increase the risk of sexual transmission to their partners, resulting in approximately estimated $1.7 billion in direct medical costs annually in the United States [12].
The prevalence of HPV varies geographically widely, ranging from 6% in southeastern Asia to 32% in eastern Africa, and from 6.7-44.5% in China [13]. HPV screening and vaccine are considered being the most effective measures for preventing HPV infection. HPV vaccine has been clinically applied for more than 10 years [14], however, officially launched on July 2017 in mainland China and available mainly in the developed regions in China currently, such as Beijing, Shanghai, and Guangzhou.
Besides, the HPV vaccine made in China was approved in 2020. Representative data on type-specific prevalence of HPV infection in China could provide a baseline estimate to measure the burden of HPV 0.07%-0.09%) cases of more than five HPV genotype infections ( Fig. 2 and Table 3). Notably, four of them were found to be infected with nine HPV types (data not shown).
Among the six age groups, there were significant differences in the distribution of single and multiple HPV infections (P < 0.001, Table 2). Young women aged of less than 21 years had the highest prevalence of both single (19.47%) and multiple HPV infection (13.64%), followed by women aged of more than 60 years (17.12% vs. 8.83%) and 51-60 years (15.89% vs. 5.76%) respectively, further confirmed our previous finding of a high susceptibility to HPV infection in the young population.
Prevalence of LR-HPV only, HR-HPV only, and Mixed LR-and HR-HPV infections by number of

HPV genotypes
As shown in Table 3

Discussion
Cervical cancer burden occurs more often in Southern China where had been classified as "less developed region", hence special attention should be paid to the primary prevention in the region.
Here we measured the prevalence of 21 distinct HPV types prior to widespread HPV vaccination among 214,715 women. The large sample sizes enable precise estimates of both increases and decreases in HPV type specific prevalence, which could be used as a baseline for comparison to future samplings of the population. The overall prevalence of HPV DNA in this representative sample of women was 18.71%, with the highest prevalence (33.11%) among women aged less than 21 years, corresponding with the data reported by Curacao (19.7%) [15]. Global HPV prevalence estimates are well-known to vary by the region, study design, target population and calendar time [16]. HPV positive rates range from 6. . It is possible that most women from the physical examination center enrolled in our study were more likely to detect HPV types not related to cervical infection. Apart from HPV16, -18-a common genotype of cervical cancer-was relatively low compared to the data performed by Chen [5]. Our data also indicated that HPV52, -16, and − 58 were consistently the top three HR-HPV genotypes from 2012 to 2018, suggesting the HPV vaccine covering these HR-HPV types is routinely recommended, especially for those females at a young age exposed to HPV.
A two-variable analysis of HR-HPV infection-related variables showed a statistically significant association for age, number of sexual partners, hormonal contraception use and smoking [28]. The trend here in HR-HPV infection exhibiting elevated rates in younger groups and low rates in middle age groups reflected the natural history of HPV infection. Evaluations in the United States also showed that young women had the highest HPV prevalence [3], as well as the findings of the highest HPV prevalence (33.11%) among women aged less than 21 years in our study. Young women often have a high infection rate, mainly because they are more sexually active before their immune systems become less sensitive [17]. Besides, the prevalence of HPV slightly declined in middle age, yet significantly increased among the oldest people, which are consistent with those in most developed countries and the data on Bruni and colleagues [29]. The mechanism of this increase in infection rates is unclear at present. Other than persistent infections seeming to be more prominent among female with such ages [19], this increase could be also explained by re-marriage, reactivation of latent HPV in menopausal women and the cohort variation [16].
Multiple HPV genotype infections were detected in approximately 22% of all positive cases in our study, consistent with that of Shanxi (24.30%) and international populations [29], yet lower than that of Shanghai (36.60%) [5]. In an unweighted analysis of these women, we found that most were multiple infections occurred either in young women aged less than 21 or those older than 51, and HR-HPV genotypes accounted for over 80% of multiple infections. Young women were known to have a high risk of HPV infection, however it is temporary and supposed to disappear within a year or two, The overall strengths of this study included the large sample size, PCR testing rather than serologic tests which allowed accurate determination of simultaneous co-infection, and the study was a decade long to measure a yearly trend of HPV infection. However, several limitations exist in our study. First, HPV DNA testing can't totally reflect the cumulative incidence of HPV and previous infection, which only represent current infection; second, our study included numerous specimens from women, not men, without pathological data, for example, cervical cytology and histology results, which was unable to explain the relationship between HPV infection and pathology, and unable to reflect the infection of HPV in general population in the region; and third, the detailed information about the patients, such as education level, economic status and background related to HPV infection, were not documented in this study, hindering a more comprehensive evaluation of the effects of these different backgrounds on the prevalence of HPV infection.
In conclusion, we report the overall rate of HPV was 18.71%, which showed a downward trend from  HPV, human papillomavirus; HR-HPV, high-risk HPV; LR-HPV, low-risk HPV; CI, confidence interval.