Prevalence of human papillomavirus genotypes and precancerous cervical lesions in a screening population in the Republic of Korea, 2014–2016

The prevalence of cervical cancer remains high in Korea, despite a decreasing trend [1]. Korean screening guidelines for the prevention of cervical cancer call for a conventional Pap smear or liquid-based cytology every 3 years for asymptomatic women; an additional optional human papillomavirus (HPV) test is also recommended [2]. Because primary HPV screening can lower cancer risk compared to conventional cytology-only screening, it has been considered a viable alternative [3]. HPV is the most important factor that induces transformation of cervical epithelial cells into precancerous lesions or cancer [4]. HPV infection status is thus a crucial element in cervical cancer screening. Consequently, the HPV test has emerged as an important screening tool [5, 6].

Many countries have carried out large-scale vaccination projects that have been highly efficient and lifesaving against cervical cancer [5, 7]. Gardasil^® is a commonly used quadrivalent vaccine against HPV types 6, 11, 16, and 18; HPV types 6 and 11 are low-risk (LR) genotypes that induce genital warts or condylomas [8]. Gardasil 9, approved by the United States Food and Drug Administration (US FDA) in 2014, provides protection against HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58 [9]. The preventive efficacy of the HPV vaccine against infection has been proven in several studies [8, 10, 11]. However, all high-risk (HR) HPV types that could cause cervical cancer are not fully covered by Gardasil 9, and prevalent HPV types vary among countries [12]. In addition, various HPV types have different HPV-attributable cancer burdens [13].

Although many studies have reported the prevalence of HPV genotypes based on the presence of precancerous lesions and invasive cancer [14, 15, 16], a reliable, large-population study has not been reported previously. For these reasons, it is very important to investigate HPV prevalence and type distribution according to cytology and age in Korea. We reviewed data from women who visited a large private Korean healthcare company, and, based on these cross-sectional data, evaluated the prevalence of HPV genotypes according to cervical cytology and age.

Among the 18,170 women who enrolled our study, 3,037 (16.7%) were positive for HPV and 2,268 (12.5%) were positive for HR HPV. A notable finding of this study was that HPV 53 was the most common type in Korea and HPV 58, 52, and 16 were also common. Among LR HPV types, HPV 54 and 70 were common. Obviously, HPV positivity was higher in women whose cervical cytology was most advanced (HSIL/ASC-H), higher in LSIL than ASCUS, and higher in ASCUS than in those with normal cytology. Overall and in the normal cytology groups, the most common HPV genotype was HPV 53, whereas HPV 58 was more common in women with ASCUS or LSIL cytology. In addition, HPV 16, widely known to be associated with invasive cervical cancer, was the most common type in HSIL/ASC-H cases [19]. When we classified cervical cytology into normal and ASCUS/LSIL, there was not a significant difference in the prevalence of the 19 HR HPVs among women <59 years old.

In a retrospective worldwide study of HPV-type distribution in invasive cervical cancer, 8,977 of 10,575 patients were positive for HPV. HPV 16 and 18 were the most common types, and those 2 types accounted for 71% of all HPV types detected in invasive cervical cancer [20]. HPV 58 was more frequently detected in Asian cervical cancer cases than in Europe or Africa. Forty-seven years of research on type-specific HPV prevalence among women with invasive cervical cancer in Korea found that HPV 16 (63.1%) was the most prevalent type in invasive cervical cancer, followed by HPV 18 (8.5%), HPV 33 (4.5%), and HPV 58 (3.9%) [21]. Although we did not investigate the prevalence of HPV types in invasive cervical cancer, HPV 16 (24.62%) was the most common type in patients with HSIL/ASC-H, which was the most severe classification in our study. Our findings were consistent with previous research, showing that HPV 16 is most common type in patients with precancerous neoplasia lesions both in Korea [22] and worldwide [14, 23, 24].

Another Korean study assessed data collected via health check-up from 2008 to 2010 at a single center. Of 7,014 women, 19.7% had HPV, which was higher than our results of 16.7%; however, their reported prevalence of HR HPV (8.4%) was lower than the current study (12.5%) [16]. In that study, the most frequently detected HPV genotypes among all women were HPV 58 (23.9%), HPV 16 (21.8%), HPV 52 (16.6%), and HPV 18 (11.7%), which is discordant with our results. The prevalence of HPV types in their report was 14.51% for HPV 53, 11.83% for HPV 58, 11.69% for HPV 52, and 8.77% for HPV 16, which was somewhat different from our results. However, since their study population had geographical limitations as a single institutional survey of individuals living in an urban setting, the distribution of HPV types in their results are unlikely to reflect national averages. According to recent reports in Korea, HPV prevalence is reported from as low as 16.7% to as high as 40.7% [16, 25], depending upon the HPV detection method and target population. In particular, the study reporting HPV positivity of 40.7% had the highest prevalence because they targeted commercial sex workers [25]. Although our study population was from a single institution, there were broadly distributed branches nationwide, and so they more accurately represent Korean women in general.

We found that HPV 53 was the most prevalent type in Korea, which was inconsistent with previous Korean studies, [16, 22, 25, 26, 27, 28] with one exception; So et al. [22] reported that the most common HPV type in Korea was HPV 53. Because we analyzed patients who visited 7 centers of Korea Medical Institute (KMI) nationwide in Korea, our results could more closely mirror the general population. In addition, our data were more recent, from January 2014 to December 2016, and the only large-population study in Korea to date, and so the results could be interpreted as indicating that the incidence of HPV 53 has increased over time. Unfortunately, although HPV 53 was the most frequent HPV type in our data, it is not an HPV genotype that Gardasil 9 targets. Nonetheless, HPV 53-related cervical cancer is very rare, not only in Korea, but also internationally [20, 27, 29].

This study has several limitations. First, we enrolled women who underwent health examinations at KMI, which was a private corporation. These results may not reflect the general population of Korea, since women who participated in our study were volunteers who were screened at KMI. Due to the small number of volunteers aged >50, the results may not be accurate for this age group. Furthermore, numerous women avoid HPV tests or Pap smears because of a fear of pelvic examinations [30]. Second, we could not access information on whether participants were vaccinated. However, it was important to analyze the present prevalence of HPV, so we focused on the standard HPV prevalence data for Korea. Lastly, HPV DNA testing was carried out using 2 different systems, the HPV Liquid Bead Microarray and Anyplex™ II HPV 28. Although both detection systems have been validated, [31, 32] using 2 systems might be less accurate than using just one HPV genotyping method.

In conclusion, we described the prevalence and distribution of HPV genotypes by age and cytology for 18,170 women who voluntarily visited a healthcare institute. Knowledge of epidemiologic HPV genotypes will be helpful for creating effective HPV screening strategies and developing targeted, protective HPV vaccines. Furthermore, our study of HPV genotypes in Korea provides important baseline data for evaluating the effectiveness of the newly implemented National Immunization Program (NIP) HPV vaccine program. Further studies of changes in the prevalence and distribution of HPV genotypes after implementation of the NIP are needed.