Characteristic of persistent human papillomavirus infection in women worldwide: a meta–analysis

Introduction

Cervical cancer (CC) is a common malignant tumor, and ranks the fourth in the incidence of female malignant tumors in the world (Sung et al., 2021). The etiology of CC is clear, preventable and controllable, effective screening can control the incidence of CC (Van Dyne et al., 2018). Persistent high risk-human papillomavirus (HR-HPV) infection is the main cause of the development of CC (Sinno et al., 2014).

HR-HPV infection is common, especially in sexually active young women, but most infections are transient, spontaneous, and have no clinical symptom. However, 10% of women have persistent HR-HPV infection and are at risk of CC and its precursors (Huh et al., 2015). Persistent HPV infection can increase the risk of high-grade squamous intraepithelial lesions (HSIL) by 250 times (Dalstein et al., 2003). Therefore, adequate attention should be given to persistent HPV infection. To date, the studies mostly focus on the factors that contribute to persistent HPV infection (Rositch et al., 2013; Yang & degree, 2021). However, there is no consensus on which genotypes of persistent HPV infection are most likely to occur. Age is considered a major factor in relation to HPV infection, but the relationship between the age and persistent HPV infection is still controversial.

Studying specific genotypes of persistent HPV infection in clinical practice is crucial for reducing HSIL and guiding CC prevention and treatment. Therefore, we analyzed the prevalence of persistent HPV infection in female worldwide to optimize prevention strategies for CC and provide references for the development of HPV vaccines.

Materials and Methods

The present meta-analysis was performed following the guidelines in the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement (Moher et al., 2009). The PRISMA 2009 flow diagram is attached in Fig. 1. Our protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO) under the code of CRD42022339057.

Results

Overall prevalence of persistent HPV infection

The total number of positive results was 26,170, and 8,706 of them were persistent HPV infection. The overall pooled persistent HPV infection prevalence was 29.37% (95% CI = [24.05∼35.31]), and the forest plot was shown in Fig. 2.

Table 2:

Results of meta-analysis on persistent HPV infection prevalence.

HPV subtypes	Persistent infection prevalence % (95% CI)
	Global	Asia		Europe
HPV16	35.01[29.86∼41.06]	31.65[26.36∼38.01]	40.21[30.15∼50.26]
HPV52	28.19[23.15∼34.34]	29.99[23.50∼38.28]	24.06[16.55∼32.37]
HPV58	27.06[20.31∼33.81]	32.92[25.91∼39.92]	22.52[18.46∼27.46]
HPV18	25.99[19.92∼32.50]	27.59[21.22∼33.97]	29.53[19.81∼41.53]
HPV33	24.37[17.86∼31.53]	22.99[17.14∼30.10]	33.30[18.87∼47.73]
HPV31	23.35[16.58∼30.89]	19.28[13.18∼26.23]	38.03[24.82∼53.29]
HPV59	21.87[13.42∼31.71]	24.46[14.00∼36.74]	20.25[10.37∼39.56]
HPV39	19.54[13.89∼25.90]	18.38[12.30∼26.55]	22.55[7.70∼42.35]
HPV68	16.61[11.52∼22.29]	19.21[13.62∼25.41]	13.05[5.43∼23.33]
HPV45	15.05[9.80∼20.93]	14.81[8.57∼22.40]	26.27[16.11∼42.85]

DOI: 10.7717/peerj.16247/table-2

Subgroup analysis

The heterogeneity test showed that there was significant heterogeneity among the studies (I² = 98.2%, P < 0.01), so the random effect model was used in the meta-analysis. Subgroup analysis was conducted according to the area, year of publication, sample number, quality score, follow-up time and the source of sample to explore the heterogeneity. As a rule, at least three studies should be available per subgroup. The results showed that the follow-up time might be the sources of heterogeneity (P < 0.05). The prevalence of persistent HPV infection decreased gradually with longer follow-up time, as shown in Fig. 3.

Sensitivity analysis

According to the leave-one-out sensitivity analysis, the pooled prevalence of persistent HPV infection was relatively stable, as shown in Fig. 4.

Publication bias

We assessed the publication bias by funnel plot, Egger’s, and Begg’s test. The funnel plot was symmetric, as shown in Fig. 5. No publication bias was found according to the results of both Egger’s (P = 0.085) and Begg’s test (P = 0.399). The p-value in the Egger’s test seemed borderline probably because of the small number of studies. The results of Begg’s and Egger’s tests was consistent, indicating that there was no publication bias in this study.

Discussion

This systematic review and meta-analysis presented the most recent information about the distribution and prevalence of persistent HPV infection in women globally (Ingabire et al., 2018; Liu et al., 2020), which would provide evidence for the screening, diagnosis, treatment of CC and the development of HPV vaccines.

Persistent infection with HR-HPV is the primary cause of cervical precancerous lesions or CC (Rodriguez et al., 2008; Trottier & Franco, 2006). More than 200 genotypes of HPV have been recognized, of which more than 40 can infect the genital tract (Barros et al., 2020). HPV infection is common, especially in young women, and the majority (∼90%) of newly acquired HPV infection frequently showed a transient course, a phenomenon routinely described as “viral clearance” (Schiffman et al., 2007). Studies have shown that persistent HPV infection varied significantly across different regions (Liu et al., 2019; Ramanakumar et al., 2016). The prevalence of persistent HR-HPV infection was 36.1% in the United States (Bennett et al., 2015) and 26.9%∼38.8% in Europe (Nielsen et al., 2010; Plummer et al., 2007; Schmeink et al., 2013). The study showed that the persistent HPV infection prevalence was 28.38%, which was linked with 27.86% in Shandong, China (Hu, Ren & Zhang, 2021) and 31.40% in Denmark (Stensen et al., 2016), which was lower than a global meta-analysis in 2013 (43%) (Rositch et al., 2013), and it was higher than Korea (12.40%) (Ingabire et al., 2018), the difference might due to the target population’s risks of persistent HPV infection, along with the gap between baseline and the intervals of follow-up. At present, the international definition of persistence HPV infection is not unified, and the duration of persistent infection was controversial. Subgroup analysis showed that the follow-up time was the source of heterogeneity. The previous studies have shown that lower prevalence of persistent HPV infection detected in studies with intervals of 12 months or more compared to studies with intervals of 6 months or less (Rositch et al., 2013).

The distribution of HPV varied greatly in different geographic regions among different ethnic groups (Xu et al., 2021). The study revealed that the most common genotype of persistent HPV infection was HPV 16, which was followed by HPV 58, 52, 18, 33, 31, 59, 39, 68, 45, these results were different from the previous studies (Liang, Chen & Zhang, 2017). Liu et al. (2020) found that HPV58 and53 were the most persistent genotypes, followed by HPV52, 16 and 39. The ranking of persistent HPV infection was HPV16, 18, 33, 31, 52, 39, 56, 45, 58, 35, 68, 51, 66 in 2013 (Rositch et al., 2013). In Asian populations, HPV52 and HPV58 were more common, especially in China (Bee et al., 2021; Yi et al., 2022). In China, HPV52 (21.7%) was the most common genotype, followed by HPV58 (18.2%) (Zhao et al., 2019), while the prevalence of HPV52 and HPV58 was lower in Sweden (Lagheden et al., 2018). The prevalence of HPV45 in European countries was relatively high, especially 7% in Sweden (Lagheden et al., 2018). A global study showed the prevalence of HPV45 was 11.6% (Pirog et al., 2014). However, the prevalence of HPV45 was low in Asia, only 0.5% in Guangdong, China (Jing et al., 2014) and 2.2% in India (Munjal et al., 2014). Most of the study population were from Asia, which might contribute to the lower persistent infection prevalence of HPV45, but higher persistent infection prevalence of HPV52 and 58 in current study. Epidemiological evidence has confirmed that HPV carcinogens are mainly HPV16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58 and 59. HPV68 is a possible carcinogen because it can transform infected cells into malignant tumor cells (Manini & Montomoli, 2018). These genotypes are called high-risk (World Health Organization, 2017; De Martel et al., 2017). Although HPV vaccines have been proved to prevent most genotypes of HPV infection (De Oliveira, Fregnani & Villa, 2019), currently available 9-valent HPV vaccine do not fully cover all genotypes of HPV related diseases (De Martel et al., 2017). Molina-Pineda et al. (2020) found the prevalence of HPV59 reached 11.5% in CC patients, and it was also found in the top five genotypes of HPV infection detected in different regions of the world, such as Ghana (Krings et al., 2019b), China (Ye et al., 2015) and Switzerland (Dobec et al., 2009). 31% cervical intraepithelial neoplasia I (C1N I) and 26% cervical intraepithelial neoplasia II (CIN II) or above were ascribed to HPV51, HPV53, HPV56, HPV68, and among the 14 HPV genotypes did not covered by the 9-valent vaccine, HPV68 had a higher infection prevalence (9.3%) (Ma et al., 2022). A higher prevalence of HPV68 was also found in non-vaccine in 2021 (Schlecht et al., 2021). Due to the high prevalence of persistent infection and carcinogenesis of HPV 59, 39 and 68 in the biological importance of invasive CC, it was recommended to include them in the next generation of preventive HPV vaccines. Also, to prevent CC, it was necessary to reinforce the follow-up and detect cervical lesions at an early stage, as well as to extend the duration of clinical intervention.

This study found that multiple HPV infections were more likely to occur persistent infection than single infection, which was linked with the previous studies (Van der Weele et al. 2016; Yang & degree, 2021), the reasons were related to the synergistic effects between different genotypes of HPV infection in multiple infections. The limited number of studies included created wide confidence intervals. It is hoped that more samples will be included for evaluation in the future.

To date, the relationship between age and the persistent HPV infection is still controversial. Some studies have reported that lower age was related with increased risk of persistence infection (Rijkaart et al., 2006; Rosa et al., 2008). Additionally, other studies found no association between persistent HPV infection and age (Munoz et al., 2009; Trottier et al., 2008). The patients under the age of 30 and those over 50 should receive special attention during follow-up since they were more likely to have persistent HPV infection. These women under 30 were highly affected by persistent infection, which might be due to their active sexual activity. Indeed, the immature cervix did not produce enough cervical mucus which can increase the risk of HPV infection (Tounkara et al., 2021). One possible explanation for the high persistent infection prevalence in women over 50 years old was that women’s immune function gradually weakens with time, which might lead to HPV escape from the host immune system (Gonzá lez et al., 2010). This was in line with some studies that women over the age of 50 have a high prevalence of persistent infection (Zhang et al., 2015).

There were some limitations in the study. First, there was substantial heterogeneity of the included studies. Despite the fact that heterogeneity is often unavoidable when conducting meta-analyses of observational studies, it does not necessarily mean that the results were invalid (Noubiap et al., 2019). Second, the distribution of genotypes in other regions could not be studied, because of the limited data on the prevalence of persistent infection of specific subtypes in continents, other than Asia and Europe. Third, due to the limited studies on specific single / multiple persistent infections, the specific genotypes of multiple infections that were prone to occur persistent HPV infection have not been studied yet. Additionally, the relationship between the genotypes of persistent infection and the grade of cervical lesions will be the focus of our next study.

It was widely accepted that persistent HR-HPV infection was a major factor in the progression of CC, making it necessary to have extensive screening programs, particularly for women under 30 and over 50 years old, women with high-risk HPV infection (HPV59, 39, 68) and multiple infections. Despite its limitations, the study has important implications for clinical screening of CC and the development of HPV vaccine.

Conclusion

The study would provide a basis for the development of CC screening strategies and HPV vaccines. In addition to HPV vaccination, we should emphasize the follow-up management for women under 30 and over 50 years old, women with high-risk HPV infection (HPV59, 39, 68) and multiple infections.

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