https://orcid.org/0000-0001-9896-1392
ABSTRACT
The epidemiological and clinical aspects of Human Papillomavirus (HPV) infection in women have been extensively studied. However, there is a lack of information regarding HPV characteristics in males. In this study, we conducted a retrospective and observational study of 3737 consecutive male individuals attending outpatient clinics of Guangdong Women and Children Hospital from 2012 to 2023 in Guangzhou, South China, to determine the age- and genotype-specific prevalence of HPV in men. The results showed the overall prevalence of HPV among men was 42.15% (1575/3737), with variations ranging from 29.55% to 81.31% across distinct diagnostic populations. Low-risk HPV6 (15.47%), HPV11 (8.94%), and high-risk HPV52 (5.51%) were the most common types. The annual HPV prevalence decreased significantly (Z = −3.882, p < .001), ranging from 31.44% to 52.90%. 28.77% (1075/3737) of men manifested infection with a singular HPV type, predominantly identified as a low-risk type. The age-specific distribution of HPV infections revealed distinctive peaks in the < 25 y age group (47.60%, 208/437) and the 40–44 y age group (44.51%, 154/346). Notably, the positive rate of Chlamydia trachomatis was significantly higher among HPV-positive individuals in comparison to HPV-negatives (16.14% vs. 11.25%, p < .05). Our findings reveal a substantial prevalence of HPV infection among outpatient men in Guangzhou, South China. It is recommended to consider the inclusion of HPV vaccination for adolescent males in national immunization schedules, once an adequate supply of vaccines is accessible.
Background
Human Papillomavirus (HPV) is the most widespread sexually transmitted infection worldwide, impacting approximately 80%–90% of individuals throughout their lives.Citation1 With a spectrum comprising over 200 identified types, a subset of at least 12 is designated as oncogenic.Citation2 The causal link between high-risk HPV and cervical cancer (CC) has been firmly established through substantial scientific inquiry.Citation3,Citation4 As a result, several cancer screening methodologies and prophylactic HPV vaccines have been developed and deployed. In the male population, HPV infections frequently manifest as anogenital warts, not only posing a substantial burden on morbidity but also contributing significantly to elevated rates of HPV transmission.Citation5,Citation6 Additionally, penile, anal, and oropharyngeal cancers are attributable to high-risk HPV infections.Citation5 Thus, a comprehensive understanding of HPV’s diverse manifestations is crucial for informing effective public health strategies and interventions.
The incidence, pathogenesis, and distribution patterns of HPV infection in men remains unclear, with a limited number of published reports addressing these critical aspects. A recent comprehensive global review discerned that the overall prevalence of HPV among men is estimated to fall within the range of 15% to 45%, exhibiting variations contingent across geographical region, age group, and the methodologies employed for testing.Citation6 Additionally, factors such as having multiple sexual partners, engaging in oral and anal sex, and having immunodeficiency significantly influence the incidence of HPV infection in men.Citation7,Citation8 In 2009, the U.S. Food and Drug Administration (FDA) sanctioned HPV vaccination for the prevention of genital warts in men, representing a pivotal step in mitigating the impact of HPV-related morbidity.Citation9 Despite the proven effectiveness of HPV vaccination in providing protection to adolescent boys and young men, as of 2022, vaccination strategies for males have been approved in only 45 countries.Citation6,Citation10
Since 2016, the three-dose HPV vaccine series has been available for women in China, authorized by the China Food and Drug Administration.Citation11 Despite its availability, HPV vaccination has not been incorporated into the routine immunization program in mainland China due to high prices and limited vaccine supply.Citation12 Moreover, awareness and knowledge of HPV vaccination among Chinese, particularly university students, remain relatively low.Citation13,Citation14 As a result, the burden of cervical cancer in China remains significant, with HPV infection prevalence is steadily increasing over time.Citation15,Citation16 Since HPV is sexually transmitted, the susceptibility of women is closely linked to the sexual behaviors of their male partners.Citation6 Therefore, implementing preventive HPV vaccination in men not only reduces the incidence of anogenital warts and HPV-related cancers in men but also helps alleviate the burden of HPV infection in young women through herd immunity.Citation17 However, despite the growing demand for HPV vaccination among males, it has not yet been approved for use in mainland China.
The extensive geographical size and high population density of China have led to a significant lack of research on the estimated burden of HPV in men, creating a considerable obstacle to the development of targeted vaccination programs; therefore, an observational, single-center, retrospective study was conducted on men with HPV infection in Guangzhou, South China. This study aimed to provide updated regional estimates and age-specific HPV prevalence data among men, with the objective of understanding the disease burden and contributing to standardized HPV vaccination practices for men in the future.
Materials and methods
Study design and patients
This retrospective study was conducted in Guangdong Women and Children Hospital in Guangzhou, South China, renowned as the largest tertiary maternity and children’s hospital in southern China, catering to a substantial influx of patients seeking advanced diagnostics, management, and care for male reproductive system diseases. The experienced clinicians conducted comprehensive clinical examinations during each patient visit, with genital specimens procured for pathogen testing when deemed necessary. Pathogen test results were meticulously recorded in a laboratory information management system seamlessly connected to the electronic medical record. From January 2012 to August 2023, a total of 4865 male outpatients underwent genital HPV screening. Finally, 3737 patients were included in this study. Eligibility criteria for study enrollment were as follows:1) male gender; 2) first clinical visit; 3) age ≥18 y; 4) absence of a history of cancer, mental disorders, or systemic diseases; and 5) no prior medication treatment for HPV infection or reproductive tract medication within the preceding week. Ethical clearance for this study was procured from the Ethics Committee of the Guangdong Women and Children Hospital (202301377).
Specimen collection
Genital specimens were collected from the coronal sulcus/glans penis, penile shaft, and scrotum of the patient by a trained clinician using pre-wetted sterile swabs. Subsequently, the specimens were stored at −4°C and sent to the laboratory for processing within 24 hours.
HPV genotyping
HPV genotyping was performed using a 21 HPV GenoArray Diagnostic Kit (Kaipu Biotechnology, China). The kit is based on DNA amplification with the HPV L1 gene and flow-through hybridization technique. It can recognize 15 high-risk HPV types (HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, and 68) and six low-risk HPV types (HPV 6, 11, 42, 43, 44, and CP8304). All protocols were performed according to the supplier’s manual, as previously described.Citation15
Data collection
Data was collected according to the patient’s electronic medical record, which included demographic information, clinical features, and laboratory testing results. The clinical diagnoses were categorized as follows: asymptomatic, anogenital warts, male infertility, inflammation (epididymo orchitis, urethritis, balanoposthitis, prostatitis, etc.), and others (keratosis pilaris, dyspareunia, dysuria, etc.). Furthermore, DNA detection results of sexually transmitted pathogens, including genital herpes simplex virus type 2 (HSV-2), Ureaplasma urealyticum (UU), Chlamydia trachomatis (CT), and Neisseria gonorrhoeae (NG), were also included and analyzed.
Statistical analysis
Categorical variables were described as frequency (percentage) and compared using Chi-square test or Fisher exact test. The 95% confidence intervals (CIs) for prevalence were calculated by the binomial exact test. Quantitative variables were described as median (interquartile range, IQR) and compared using the non-parametric rank sum test by SPSS (version 25.0). The changing trends of HPV prevalence were calculated using the Cochran-Armitage trend test by R Project (version 3.2.5). A p-value of less than .05 was considered statistically significant.
Results
Age distribution
Among the 3737 men enrolled, 1814 (48.54%) were found to be asymptomatic, while 1675 (44.82%) were diagnosed with one or more of the following conditions: anogenital warts, inflammation, and male infertility. The remaining 248 (6.37%) cases exhibited other clinical features. The median age was 31 y (IQR 27–37), and significant variations in age were observed among the different groups (H = 12.563, p < .05). Specifically, the median age of the anogenital warts group was 30 y (27–36), significantly lower than the that of 32 y (28–36) in the male infertility group (p < .05). However, no significant difference in age was observed among the other groups (all p > .05).
HPV prevalence and type distribution
The prevalence and type distribution of HPV are tabulated in . The overall HPV prevalence was 42.15% (95% CI: 40.58–43.74), with 28.79% (95% CI: 27.36–30.26) identified as having low-risk HPV infection, while 22.91% (95% CI: 21.59–24.28) were infected with high-risk types. Regarding different diagnoses, the overall HPV prevalence was 81.31% (705/867) in anogenital warts, 41.68% (243/583) in inflammation, 30.98% (136/439) in male infertility, 29.55% (536/1814) in asymptomatic cases, and 42.34% (105/248) in other symptoms. The high-risk HPV prevalence among asymptomatic males was 19.90% (361/1814), whereas the rates of infection among patients presenting with anogenital warts, inflammation, infertility, and other symptoms were 30.10% (261/867), 24.01% (140/583), 18.22% (80/439), 28.63% (71/248), respectively. On the other hand, the incidence of low-risk HPV infection in asymptomatic males was 14.28% (259/1814), while the rates of infection among patients with anogenital warts, inflammation, infertility, and other symptoms were 76.01% (659/867), 26.76% (156/583), 17.77% (78/439), 22.58% (56/248), respectively.
Table 1. Distribution of HPV types according to final diagnostic status among men in Guangzhou, South China, 2012–2023.
The two most prevalent types were low-risk types HPV6 (578 cases, 15.47%) and HPV11 (334 cases, 8.94%), followed by high-risk types HPV52 (206, 5.51%), 16 (143, 3.83%), and 51 (128, 3.43%) (). In asymptomatic cases, HPV52 (5.51%), HPV6 (5.46%), and HPV16 (3.20%) emerged as the top three observed types (). In the anogenital warts group, the predominant types were HPV6 (46.88%), HPV11 (28.37%), and HPV52 (6.81%), mirroring a similar rank observed in inflammation (HPV6: 13.04%, HPV11: 8.75%, HPV52: 4.80%) (). Within the male infertility group, the most prevalent types were HPV6 (8.88%), HPV11 (5.69%), and HPV51 (3.64%) (). Comparing with asymptomatic cases, the groups with anogenital warts, inflammation, and male infertility had higher positivity rates of HPV6 and HPV11 (all p < .05) ().
Figure 1. Ranking of the three most common HPV types according to final diagnostic status among men in Guangzhou, South China, 2012–2023. HPV, human papillomavirus.
Trends in HPV prevalence
The HPV prevalence exhibited substantial variability, ranging from 31.44% to 52.90% (χ2 = 57.318, p < .001). An evident downward trajectory was discerned over the study period (Z = −3.882, p < .001) (Supplementary Table). The prevalence of low-risk HPV demonstrated a significant decrease (Z = −5.208, p < .001). Specifically, low-risk types HPV6 and HPV11 exhibited clear downward trends (both p < .001), while HPV 42, 43, and 44 displayed upward trends (all p < .01). Although HPV52 showed an increasing trend (Z = 2.797, p < .01), no discernible upward or downward trend was observed for total high-risk HPV (Z = 0.637, p > .05). Additionally, the annual HPV prevalence of the different diagnostic groups did not show statistically significant trends, except for the male infertility group, which exhibited decreased trend (Z = −3.353, p < .001) ().
Figure 2. The annual prevalence trend of HPV according to final diagnostic status among men in Guangzhou, South China, 2012–2023. HPV, human papillomavirus.
Single and multiple HPV infections
Among the male participants, 28.77% (95% CI: 27.34–30.24) exhibited a single HPV type infection, with a notable predominance of low-risk types (17.85%, 95% CI: 16.92–19.39). Regarding multiple HPV infections (13.38%, 95% CI: 12.33–14.51), 8.30% (95% CI: 7.46–9.23) comprised double infections, 2.76% (95% CI: 2.28–3.34) were triple infections, and 2.33% (95% CI:1.89–2.86) were quadruple infections or more. Comparative analysis with the asymptomatic group revealed that the anogenital warts group exhibited significantly higher rates of both single and multiple HPV infections (both p < .001). In contrast, the inflammation group demonstrated significantly higher rates of single low-risk HPV infection and double infections (both p < .01). However, no statistically significant differences were observed in terms of single and multiple infections between the asymptomatic group and the male infertility group (all p > .05). For a more detailed description, refer to .
Table 2. Single and multiple infection status among men in Guangzhou, South China, 2012–2023.
Age-specific HPV prevalence
The age-specific prevalence of HPV among men between 2012 and 2023 is depicted in . The prevalence of HPV exhibited a gradual decline from the highest point (47.60%, 208/437) in the <25 y age group to the lowest point (38.35%, 390/1017) in the 30–34 y age group. Subsequently, there was a rapid increase to the second-highest point (44.51%, 154/346) in the 40–44 y age group. A similar pattern was observed for low-risk HPV, with an initial decrease, followed by an increase, and then another decrease. Conversely, high-risk HPV demonstrated an initial decrease followed by an increase. Furthermore, a significant increase in low-risk HPV was observed with age, specifically from the 25–29 y age group to the 40–44 y age group (Z = 2.063, p < .04), while high-risk HPV displayed a significant decrease with age, specifically from the <25 y age group to the 40–44 y age group (Z = −2.841, p < .001). Notably, the prevalence of HPV in the anogenital warts group ranged from 78.11% to 90.00%.
Figure 3. Age-specific HPV prevalence among men according to final diagnostic status among men in Guangzhou, South China, 2012–2023. Shaded areas represent 95% CIs. HPV, human papillomavirus.
Co-infection of HPV with HSV-2, UU, CT, and NG
A total of 56.06% (2095/3737) of men underwent at least one nucleic acid detection for HSV-2, UU, CT, and NG. Among 918 HPV-positive patients, 51.20% (95% CI: 47.97–54.42) simultaneously tested positive for one or more pathogens, including HSV-2, UU, CT, and NG. In 1177 HPV-negative patients, 49.87% (95% CI: 47.02–52.72) tested positive for HSV-2, UU, CT, or NG. There was no statistically significant difference between these two groups (p > .05). For specific diagnostic groups, the positive rates of HSV-2, UU, and NG did not exhibit significant differences between HPV-positive and HPV-negative individuals (all p < .05). However, the positive rate of CT was significantly higher in those positive for HPV compared to those negative for HPV (16.14%, 95% CI: 13.20–19.59 vs. 11.25%, 95% CI: 9.13–13.78, p < .05). This difference was particularly pronounced in the male infertility group, where the positive rate for CT in the HPV-positive group was 11.48%, as opposed to 3.45% in the HPV-negative group (p < .05). For further details, please refer to .
Table 3. Co-infection of HPV with HSV-2, UU, CT, and NG among men in Guangzhou, South China, 2012–2023.
Discussion
This retrospective study presents the inaugural estimate of genital HPV infection prevalence among outpatient men in Guangzhou, China, revealing an overall prevalence of 42.15% with variations ranging from 29.55% to 81.31% across distinct diagnostic populations. Comparisons with other regions in China indicate similarities with the 42.0% prevalence reported among men in Shandong,Citation18 but lower rates compared to Qingyuan (54.3%)Citation19 and Shanghai (58.4%),Citation20 and higher rates compared to Anyang (17.5%)Citation21 and Liuzhou (9.4%).Citation22 Additionally, a previous systematic review encompassing 65 HPV prevalence studies from 35 countries estimated the global overall HPV prevalence among men to be 31%, with study-specific prevalence varying widely from 1% to 84% among low-risk men and from 2% to 93% among high-risk men.Citation23 The apparent differences in HPV prevalence may be attributed to various factors. These factors include regional variations in HPV types, potential selection bias in the tested population (e.g., sexually active men, men who have sex with men), variations in the anatomical site of sampling, and differences in the sensitivity of type-specific detection methods.
Comparison to women, men typically exhibit a lower prevalence of specific HPV types at a similar age.Citation5 However, contrary to this general trend, our study identified an HPV prevalence of 42.15% among men, surpassing the prevalence of 21.66% among females with outpatient visits in the same period and city, as evidenced in our prior study.Citation15 Other investigations by Shi et al.Citation24 He et al.Citation21 and Wei et al.Citation22 similarly reported higher HPV prevalence among men compared to women. These discrepancies could potentially be attributed to variations in HPV type distribution between male genitalia and the female cervix, as well as differences in population characteristics such as age distribution, geographic location, or socioeconomic status. In addition, HPV testing in men usually only occurs when typical HPV infection symptoms are present, resulting in a higher HPV positivity rate among men compared to the systematic and widespread cervical HPV screening in women. HPV infection can easily be transmitted between sexual partners, and male HPV infection significantly contributes to infection rates and subsequent diseases in women.Citation25 Therefore, the high rate of HPV infection in males, as revealed in this study, may play a significant role in driving the increased HPV infection rate among women in this particular region.Citation15
According to our study findings, the positivity rate for low-risk HPV among men (28.79%) is higher than that for high-risk HPV (22.91%). This supports the idea that penile tissue may be less susceptible to the oncogenic potential of HPV.Citation5 Specifically, HPV6 and HPV11 have the highest infection rates, with high-risk HPV52 ranking third. These three types of HPV together are the most common types of genital HPV infection in men, which is consistent with previous research.Citation22,Citation26–28 However, notable differences were observed when compared to other studies conducted in various locations, such as Anyang (HPV16, 3, and 18),Citation21 Taizhou (HPV16, 52, and 6),Citation29 Liuzhou (HPV58, 52, and 39) in China,Citation22 Italy (HPV16, CP6108, and 53),Citation30 Brazil (HPV89, 62, and 61),Citation31 America (HPV64, 82, and 89),Citation32 and a global systematic review of genital HPV prevalence among males (HPV16, 6, and 51).Citation6 The variability in the ranking of HPV types across different regions may be attributed to geographical preferences for utilizing HPV assays with varying sensitivities in detecting specific types, as highlighted in a previous study.Citation33 While known differences in primer efficiency were considered for amplifying certain types (e.g., GP5+/6+ and HPV53),Citation34 these distinctions alone do not comprehensively elucidate the observed variations.
As previously described, oncogenic HPV52 has emerged as the most prevalent type among women in Guangzhou, a trend that is still evolving.Citation15 However, in contrast to this pattern, HPV52 only ranks third among all enrolled males in our study. One plausible explanation is that a substantial proportion of the exfoliated cells were collected from skin tissue. These cells may have contained cutaneous HPV types, which are typically low risk for mucosal lesions.Citation21 Additionally, another contributing factor to this finding could be that 34.95% of the enrolled population presented with evident clinical symptoms of anogenital warts and inflammation, conditions often caused by low-risk HPV types. Despite this, HPV52 continues to be the most prevalent type among asymptomatic males with a clear upward trend observed (Supplementary Table), aligning with a well-documented high incidence of HPV52 in Asia.Citation15,Citation35,Citation36 The heightened detection rate of HPV52 in both men and women implies a substantial prevalence of HPV52 infection not only in asymptomatic individuals but also in cervical precancerous lesions, alongside HPV16 and HPV18 types.Citation15 Consequently, the recommendation for the use of the HPV nine-valent vaccine (HPV16, 18, 31, 33, 45, 52, 58, 6, and 11) is emphasized, as it offers protection against the frequent type of HPV52 compared to the quadrivalent HPV vaccine (HPV16, 18, 6, and 11).
The observed peak in HPV prevalence among men aged <25 y indicates a rapid increase in infections shortly after the initiation of sexual activity. There is a gradual decline in HPV prevalence after the age of 25, followed by a progressive increase starting from the age group of 30–34 y, culminating in a distinct second peak observed among men aged 40–44 y. However, these estimates diverge from data reported in studies on the natural history of HPV infection in men, which consistently demonstrate stable rates of detection of new genital HPV infections across various age groups.Citation6,Citation37 Notably, the age-specific profile of HPV infection in men mirrors a ‘two-peak’ pattern observed in women in the same region.Citation15 This parallel pattern in men and women underscores the need for a nuanced understanding of HPV transmission dynamics that considers both gender-specific and regional factors.
The occurrence of genital warts, primarily attributed to HPV6 or HPV11 infections, is typically found in 70–100% of exophytic genital wart tissue.Citation5 In alignment with this, our study demonstrates that HPV6 and HPV11 are collectively responsible for 73.47% (637/867) of genital warts. Contrary to conventional beliefs that peak genital wart incidence is concentrated in the 20–24 y age group,Citation5 our findings reveal the highest incidence rate of genital warts is observed in the 40–44 y age group. This unexpected age-specific prevalence highlights the importance of continuously reassessing and updating our understanding of HPV-related conditions. Additionally, HPV vaccination efforts should target not only adolescents but also older age groups, as they remain at risk of acquiring HPV infections.
The potential impact of HPV infection on male fertility is a complex and evolving area of research.Citation38 While the study did not find a significant difference in the overall HPV infection rate between the infertility group and the asymptomatic group, the infertility group did exhibit a higher positive rate of HPV6 and HPV11. Previous research has suggested a connection between HPV infection and alterations in sperm parameters, including changes in volume and pH value.Citation38,Citation39 However, the direct impact of HPV on male fertility remains unclear. Further investigations are necessary to delve into the nuanced relationship between HPV infection, especially specific HPV types, and male reproductive health, including potential effects on sperm parameters and fertility.
In this study, CT was more frequently detected in individuals testing positive for HPV compared to those testing negative (16.14% vs. 11.25%, p < .05). This suggests a strong correlation between HPV and CT infections. These findings are consistent with previous European studies that have reported a higher prevalence of HPV among individuals with CT infections.Citation40,Citation41 CT infection triggers inflammatory responses, resulting in exudate discharge and clinical symptoms. The presence of inflammatory cells further enhances viral adhesion. Additionally, intracellular CT infection may upregulate HPV oncogenes, which can contribute to tumorigenesis and immunosuppression.Citation42,Citation43
While our study has provided valuable insights, it is crucial to acknowledge certain limitations that warrant consideration. First, the single-center study may restrict the generalizability of our findings to a broader population. To enhance the external validity of our results, future research could encompass diverse settings and populations. Second, our study included a mix of outpatients, both symptomatic and asymptomatic, as well as individuals with various sexually transmitted diseases. This heterogeneity might not fully represent the overall prevalence of HPV among healthy males. To obtain a more accurate estimate of HPV prevalence, conducting studies specifically targeting the general male population is crucial. Third, due to limitations in medical record information, we are unable to comprehensively analyze factors beyond age, such as multiple sexual partners, smoking, income levels, etc. Understanding these potential risk factors is crucial for preventing and managing HPV infection and its associated diseases. Additionally, our study did not differentiate between transient and persistent HPV infections in men. Distinguishing between these types of infections is critical for a comprehensive understanding of the natural history of HPV in men. Future research endeavors should incorporate this differentiation to provide nuanced insights into the duration and dynamics of HPV infections, contributing to a more thorough comprehension of the epidemiology of HPV in the male population.
Conclusions
In summary, this study reveals a high genital HPV prevalence of 42.15% among outpatient men in Guangzhou, China, highlighting the significant burden of HPV-related morbidity in this population. HPV6, 11, and 52 were the most prevalent types, with distinct age-specific distribution patterns. The observed peaks in HPV prevalence among >25 y age group and 40–44 y age group emphasize the importance of targeted vaccination strategies beyond adolescence. Additionally, men with HPV were found to be more prone to CT infections. Overall, integrating HPV vaccination for males into national immunization programs could mitigate the burden of HPV infection and associated diseases.
Author contributions
XY and PL designed the study. PL, XY, HZ, LL, and MC conducted the laboratory tests. PL, AY and XY analyzed the data. The first draft of the manuscript was produced by PL. XY edited and reviewed the manuscript. All the authors approved the final version of the manuscript.
Ethics approval
This study was approved by the ethics committee of the Guangdong Women and Children Hospital (No. 202301377).
Supplementary Table.docx
Download MS Word (22.3 KB)Acknowledgments
The authors extend their sincere appreciation to all clinicians for their valuable contributions to the clinical diagnosis process and all participants involved in the specimen collection in this study.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Data availability statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Supplementary material
Supplemental data for this article can be accessed on the publisher’s website at https://doi.org/10.1080/21645515.2024.2337161.
Additional information
Funding
References
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