Human papillomavirus infection and screening strategies

Abstract

Human papillomavirus (HPV) infection is a common sexually transmitted disease and a leading cause of cervical, other anogenital, and oropharyngeal cancers. Screening for precancerous lesions is an effective strategy for preventing HPV-related tumors. Although HPV vaccination has significantly reduced the incidence of cervical cancer, achieving universal coverage remains challenging because of cost barriers, particularly in economically disadvantaged regions. This review provides an update of HPV infection characteristics, screening methods, and strategies tailored to low-resource settings. We also discuss the global burden of HPV-related diseases, regional disparities in the implementation of screening, and future research directions. By examining the current challenges and opportunities, this review aims to inform policymakers and healthcare providers in designing effective, affordable, and scalable screening programs.

Key Words: Human papillomavirus; Cervical cancer; Screening strategy; Vaccination

Core Tip: Human papillomavirus (HPV) is the main cause of cervical cancer, and screening for precancerous lesions is an effective measure to prevent tumors caused by HPV. Although HPV vaccination can effectively prevent the occurrence of cervical cancer, universal coverage cannot be achieved due to the cost. For economically disadvantaged areas, affordable and effective HPV cervical cancer screening strategies remain a major public health concern. Therefore, it is necessary to summarize the prevention and control methods and strategies of HPV virus screening to provide references for countries to formulate public policy research.

INTRODUCTION

Cervical cancer remains one of the most prevalent and deadly cancers affecting women globally, particularly in low- and middle-income countries (LMICs), where it imposes a significant public health burden[1,2]. This malignant tumor originates in the cervix and is predominantly driven by persistent infection with high-risk types of human papillomavirus (HPV) such as HPV 16 and HPV 18[3]. Upon infection, viral DNA integrates into the host cell genome, disrupting normal cellular functions and leading to uncontrolled proliferation and malignant transformation[4]. Progression from HPV infection to invasive cervical cancer is typically slow, often spanning years or even decades. During this time, cervical cells undergo a series of pathological changes, evolving from normal epithelium to precancerous lesions [e.g., cervical intraepithelial neoplasia (CIN)] and eventually to invasive cancer[5]. Early stage cervical cancer is often asymptomatic; however, as the disease advances, symptoms such as irregular vaginal bleeding, postcoital bleeding, and abnormal vaginal discharge may emerge, underscoring the critical importance of early detection and intervention[1].

Cervical cancer is largely preventable through effective screening and vaccination programs. Widely used screening techniques, such as Pap smear and HPV DNA testing, have proven effective in detecting precancerous lesions and early stage cancers, enabling timely treatment and significantly reducing mortality rates[6,7]. HPV vaccination has emerged as a powerful tool for primary prevention, significantly reducing the incidence of HPV infection and associated cancers[8,9]. Despite these advances, the implementation of comprehensive screening and vaccination programs remains uneven, particularly in resource-limited settings, where access to healthcare services is often constrained by financial, logistical, and cultural barriers[9,10]. Disparities in screening coverage and vaccine accessibility persist between high- and low-income regions, highlighting the urgent need for tailored strategies to address these inequities[10,11].

In economically disadvantaged regions, the development of affordable and scalable screening strategies remains a critical public health priority in economically disadvantaged regions. Recent advancements in self-sampling technologies and point-of-care diagnostics offer promising solutions for overcoming barriers related to cost, infrastructure, and patient compliance[12,13]. These innovations enhance screening coverage, protect patient privacy and improve adherence to regular screening protocols. The integration of advanced analytical tools such as artificial intelligence and machine learning has the potential to improve the accuracy and efficiency of cervical cancer screening programs[14,15].

This review provides a comprehensive overview of current HPV screening approaches, their applications, and their implications for global cervical cancer prevention. By examining the characteristics of HPV infection, strengths and limitations of existing screening technologies, and challenges faced in resource-constrained settings, we seek to inform policymakers and healthcare providers in designing effective, affordable, and scalable screening programs. Additionally, we explored emerging trends in cervical cancer prevention, including the role of self-sampling, technological innovation, and international collaboration, to address disparities and reduce the global burden of cervical cancer. Through this analysis, we aim to contribute to ongoing efforts to achieve equitable access to cervical cancer prevention and control worldwide.

PATHOPHYSIOLOGY OF HPV INFECTION

HPV is a small, double-stranded DNA virus that infects epithelial cells, leading to cellular proliferation and potential malignant transformation[16,17]. HPV is classified into high-, medium-, and low-risk types based on their oncogenic potential. High-risk HPV types, particularly HPV 16 and HPV 18, are responsible for the majority of HPV-related cancers, including cervical, anogenital, and oropharyngeal cancers[18,19]. These high-risk types integrate their viral DNA into the host genome[20,21], disrupting key tumor suppressor genes, such as p53 and Rb, which are critical for regulating cell cycle progression and apoptosis[22-25]. This integration leads to the overexpression of viral oncoproteins E6 and E7[3], which promotes uncontrolled cell proliferation, genomic instability, and malignant transformation[17,26]. In contrast, low-risk HPV types such as HPV 6 and 11 are primarily associated with benign lesions, including genital warts. These types rarely integrate into the host genome, and do not typically cause cancer. However, they can cause significant morbidity owing to the formation of recurrent or persistent lesions[27-31].

The natural history of HPV infection involves several stages[4,32]: (1) Initial infection: HPV infects the basal epithelial cells through microabrasions in the mucosal or cutaneous epithelium; (2) Viral replication: HPV replicates in the differentiated layers of the epithelium, utilizing host cell machinery; (3) Immune evasion: HPV evades immune detection by downregulating interferon responses and other immune mechanisms; and (4) Progression to cancer: In high-risk HPV infections, persistent viral integration and oncoprotein expression lead to cellular transformation and the development of precancerous lesions (e.g., CIN), which can progress to invasive cancer over years or decades.

Understanding the molecular mechanisms of HPV-induced carcinogenesis is critical for the development of targeted prevention and treatment strategies. For example, the role of E6 and E7 oncoproteins in disrupting cellular homeostasis has led to the development of therapeutic vaccines and targeted therapies aimed at inhibiting these proteins[33-35].

HPV GENOTYPING

HPV is primarily transmitted through sexual contact or close physical interactions. To date, > 200 distinct HPV types have been identified[36]. In 2020, it was estimated that there were 604127 new cases of cervical cancer worldwide, resulting in 341831 disease-related deaths. The age-standardized incidence rate of cervical cancer is 13.3 cases per 100,000 women per year, with a corresponding mortality rate of 7.2 deaths per 100000 women per year[37]. Based on their pathogenicity and carcinogenic potential, HPV genotypes are categorized into high- and low-risk groups: (1) High-risk HPV types, including HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68, 69, 73, and 82, are strongly associated with the development of cervical cancer and precancerous lesions[38-41]. HPV 16 and 18 are the most prevalent, accounting for 56.8%-74.8% of cervical cancer cases[42]. Additionally, high-risk HPV types can also cause vaginal, vulvar, and anal cancers[43-46]; and (2) Low-risk HPV types, including HPV 6, 11, 40, 42, 43, 44, 54, 61, and 70, primarily cause benign conditions such as genital warts (condyloma acuminatum)41. These types are generally not associated with malignant transformations such as cervical cancer. HPV 6 and 11 are the predominant types responsible for genital warts[30,31].

HPV genotyping plays a critical role in the prevention and screening of cervical cancer. This facilitates the identification of high-risk populations and provides valuable guidance for clinical diagnosis, treatment, and management strategies. By distinguishing between high- and low-risk HPV types, healthcare providers can tailor interventions to mitigate disease progression and improve patient outcomes.

GLOBAL BURDEN OF HPV INFECTION

HPV infection rates

Recent studies and global statistics have revealed significant variations in HPV infection rates across different regions, reflecting the complex interplay of socioeconomic, geographic, and healthcare factors. According to a meta-analysis of 194 global studies, the overall HPV infection rate among women with normal cervical cytology was approximately 11.7% (95%CI: 11.6%-11.7%)[29,30]. However, regional disparities are striking. The Caribbean exhibits the highest HPV infection rate globally, at 35.4% (95%CI: 29.0%-42.2%), followed closely by East Africa at 33.6% (95%CI: 30.2%-37.1%)[47,48]. Sub-Saharan Africa also reports a high prevalence of 24.0% (95%CI: 23.1%-25.0%), underscoring the disproportionate burden of HPV-related diseases in low-resource settings[49]. Eastern Europe shows a moderate but still elevated rate of 21.4% (95%CI: 20.1%-22.7%)[50]. In contrast, more developed regions such as North America and West Asia exhibit significantly lower HPV infection rates, reflecting better access to preventive healthcare, vaccination programs, and cervical cancer screening initiatives[51,52].

These regional disparities highlight the urgent need for targeted interventions, particularly in resource-limited areas, where HPV infection rates remain alarmingly high.

Age distribution

The age distribution of HPV infections provides critical insights into the dynamics of HPV transmission and persistence. HPV infection rates peak among young women under the age of 25 years, driven by high-risk sexual behaviors and limited prior exposure to the virus. This age group consistently exhibits the highest prevalence of HPV infection worldwide[53,54]. After middle age, HPV infection rates tend to decline owing to acquired immunity from prior exposure. However, in certain regions, such as Africa, a second peak in HPV infection rates is observed among older women, likely due to persistent infections or reactivation of latent HPV. A similar secondary increase, albeit smaller, has been noted in Asia and the Americas[53,55]. This bimodal distribution underscores the importance of age-specific prevention strategies, including vaccination in adolescents and regular screening in older women.

Common HPV types

The top 10 most common HPV infection types worldwide are: HPV16 (2.8%), HPV52 (1.5%), HPV31 (1.2%), HPV53 (1.2%), HPV18 (1.1%), HPV51 (1.1%), HPV58 (1.0%), HPV39 (0.9%), HPV66 (0.9%), and HPV70 (0.8%)[16,56,57]. A meta-analysis of 115789 HPV-positive women showed that 76% of the women with low-grade cervical lesions and 85% of the women with high-grade cervical lesions were infected with HPV. In cervical lesions and cervical cancer, HPV16/18/31/33/45/52/58 were the most common types[58]. An epidemiological study of HPV infection in 1.7 million women in China revealed that the overall prevalence of HPV among Chinese women was 15.54% (95%CI: 13.83-17.24). The top five common HPV infection types in the general population were HPV16, 52, 58, 18, and 33[59]. In China, HPV16/18 causes approximately 69% of cervical cancer cases, whereas HPV types 31/33/45/52/58 account for approximately 23% of cervical cancer cases. HPV16/52/58/18 were the predominant types at all disease stages. In cervical squamous cell carcinoma, HPV16/18/31/52/58 were the most common types, with infection rates of 76.7%, 7.8%, 3.2%, 2.2%, and 2.2%, respectively[18,60-62].

Global characteristics of HPV infection

Dominant types: HPV16 and 18 are the most common high-risk types globally, accounting for 70%-80% of cervical cancer cases[63,64]. HPV31, 33, 45, 52, and 58 also contribute significantly to cervical cancer. However, the prevalence varies by region. Collectively, these types are considered secondary drivers of HPV-related cancers[58,65].

Region-specific infection characteristics: Sub-Saharan Africa[49,52] has highest rate globally, averaging 24%-35%, with some countries reaching up to 40%. HPV16 and 18 are predominantly seen in cervical cancer cases. HPV35 is more prevalent in this region, potentially due to unique genetic or immunological factors. Other high-risk types, HPV52 and 58, are also frequently detected. The high infection rates are associated with low vaccine coverage. The prevalence of HPV35 may be linked to genetic susceptibility in African populations.

In Asia (including China, India, and Southeast Asia)[52], infection rate averages 15%-20%, with higher rates in rural parts of China and India. HPV16 and 18 are responsible for 69%-70% of cases of cervical cancer. HPV52 and 58 are particularly common in Asian populations, particularly in younger women. HPV33 and 45 are also detected, but at lower frequencies. The high prevalence of HPV52 and 58 may be related to genetic predisposition and sexual behavior patterns in Asian populations. In regions with low vaccine coverage (e.g., India), non-vaccine-covered types remain a significant concern.

In Latin America and the Caribbean[66], infection rate averages 15%-20%, with higher rates in the Caribbean (up to 35%). HPV16 and 18 are dominant in cervical cancer cases. HPV52 and 58 are frequently detected, particularly in younger women. HPV31 and 33 are also prevalent. The high prevalence of HPV52 and 58 is similar to that observed in Asia, possibly because of shared cultural and social behaviors. In the Caribbean, high infection rates are associated with multiple sexual partners and low vaccine coverage.

In North America and Western Europe[67,68], infection rate is the lowest globally, averaging 5%-10%. HPV16 and 18 are still dominant but significantly reduced due to vaccination. HPV31 and 33 are emerging as more common types in vaccinated populations. HPV45 and 52 were detected but contributed less frequently. High vaccination and screening coverage significantly reduced HPV16 and 18 infections. Non-vaccine-covered types (e.g., HPV31 and 33) are now a growing focus of public health efforts.

In Eastern Europe and Central Asia[9,58,69], infection rate averages 21.4%, which is higher than in Western Europe and North America. HPV16 and 18 are predominant in cervical cancer cases. HPV31 and 52 are commonly detected, especially in unvaccinated populations. Limited healthcare resources during economic transition have led to insufficient vaccine coverage. Changes in sexual behavior, such as increased promiscuity and heightened HPV transmission risk.

In Australia[69-72], infection rate is low, averaging 5%-8%. HPV16 and 18 were significantly reduced following widespread vaccination. HPV31 and 33 are currently the most commonly detected high-risk types. National vaccination programs and regular screening systems can effectively control HPV transmissions. The incidence of cervical cancer is nearing its elimination target.

The global burden of HPV infection remains substantial with significant regional and demographic variations. High-prevalence regions, such as sub-Saharan Africa and the Caribbean, face disproportionate challenges, while developed regions benefit from robust healthcare infrastructure and vaccination programs. Understanding age-specific distribution and dominant HPV types is crucial for tailoring prevention and intervention strategies. Continued efforts to expand vaccine coverage, improve screening programs, and address socioeconomic barriers are essential to reduce the global burden of HPV-related diseases and achieve the goal of cervical cancer elimination. Summary of global human papillomavirus infection characteristics as below (Table 1).

Table 1 Summary of global human papillomavirus infection characteristics.

Sub-Saharan Africa	24%-40%	HPV16, 18, 35, 52, 58	High HPV35 prevalence, genetic susceptibility, and limited healthcare resources
Asia	15%-20%	HPV16, 18, 52, 58, 33	High HPV52 and 58 prevalence; genetic and behavioral factors; low vaccine coverage in some areas
Latin America & Caribbean	15%-35%	HPV16, 18, 52, 58, 31	High HPV52 and 58 prevalence; multiple sexual partners; low vaccine coverage in the Caribbean
North America & Western Europe	5%-10%	HPV16, 18, 31, 33	High vaccination coverage and non-vaccine-covered types (e.g., HPV31, 33) are emerging as new concerns
Eastern Europe & Central Asia	21.40%	HPV16, 18, 31, 52	Insufficient healthcare resources and changing sexual behaviors increase transmission risk
Australia	5%-8%	HPV16, 18, 31, 33	High vaccination and screening coverage; incidence of cervical cancer near elimination

HPV: Human papillomavirus.

STANDARD FRAMEWORK FOR CERVICAL CANCER DIAGNOSIS

The diagnosis of cervical cancer is a multistep process, which can be divided into screening, pathologic diagnosis, staging, and treatment. Through early screening and accurate diagnosis, the cure rate can be significantly improved and the mortality rate reduced. Medical resources and technology in different regions may affect specific implementation, but the process described above is a standard framework widely adopted worldwide[73-75]. The standard diagnostic procedure is as follows.

Screening stage

Screening is a critical step in the early detection of cervical cancer and its precursors such as CIN. The primary goal was to identify individuals at a high risk of developing symptoms. According to guidelines from the American Cancer Society, cervical cancer screening is recommended to start at age 25 years. In women aged 25-65 years, HPV DNA testing is preferred every 5 years. If HPV testing is unavailable, a combination of Pap smear and HPV testing can be performed every 5 years. In women aged 21-24 years, a standalone cytological test (Pap smear) is recommended every 3 years. Further evaluation is required if abnormalities are detected (e.g., atypical squamous cells, low-grade squamous intraepithelial lesions, high-grade squamous intraepithelial lesions, or a positive HPV test).

Further examination stage

For women with abnormal screening results, additional testing was performed to confirm the presence of precancerous lesions or cancer. Colposcopy was used to magnify the cervix and identify the abnormal areas. Biopsies of the suspicious areas may be performed during this procedure. Tissue samples were collected from the cervix and examined under a microscope by a pathologist to detect signs of cancer. Common biopsy methods include the following: (1) Puncture biopsy: A small piece of tissue is removed using a sharp hollow instrument; (2) Curettage: A curette is used to collect the cells or tissue from the cervical canal; (3) Loop electrosurgical excision procedure (LEEP): A thin wire loop is used to remove cervical tissue for diagnostic or therapeutic purposes, particularly early lesions; and (4) Cone biopsy: A large, cone-shaped piece of tissue was removed from the cervix and cervical canal to diagnose and treat high-grade lesions.

Pathological diagnosis

Pathological diagnosis is a cornerstone for confirming the presence and nature of cervical cancer. This step involves microscopic examination of biopsy samples to determine the type and extent of the lesion. Pathological diagnosis identifies the presence of cervical cancer and classifies its type (e.g., squamous cell carcinoma or adenocarcinoma). If cervical cancer is confirmed, staging is performed to assess its extent and spread. Staging methods include imaging techniques, such as positron emission tomography–computed tomography, computed tomography, and magnetic resonance imaging.

Treatment stage

Based on pathological diagnosis, heterogeneity of the cervical cancer microenvironment, and staging results, an individualized treatment plan can be developed. Personalized treatment strategies are formulated based on factors such as stage and type of cervical cancer, patient age, and overall health status. Common treatment modalities include surgery, radiotherapy, chemotherapy, and patient-derived xenograft model[76]. Regular follow-up is essential after treatment to monitor disease progression and evaluate the effectiveness of the intervention.

VACCINATION: A CORNERSTONE IN HPV PREVENTION

Vaccination is the most effective strategy for preventing HPV infection and associated diseases. Currently, three primary HPV vaccines have been approved worldwide; all designed to provide preventive protection against high-risk HPV infections.

Bivalent vaccine (Cervarix): Targets HPV16 and HPV18, which account for approximately 70% of cervical cancer cases. Quadrivalent vaccine (Gardasil): Targets HPV16, HPV18, HPV6, and HPV11 and offers protection against cervical cancer and reduces the incidence of genital warts. Nine-valent vaccine (Gardasil 9): Targets HPV6, 11, 16, 18, 31, 33, 45, 52, and 58, extending coverage to approximately 90% of cervical cancer cases.

These vaccines demonstrate exceptional efficacy in protecting against their targeted HPV types, with protection rates reaching 100% in certain populations. For instance, a subgroup analysis of East Asian women aged 16-26 years in the PPE population revealed that the nine-valent HPV vaccine provided 100% protection against CIN1+ lesions associated with HPV31/33/45/52/58 (95%CI: 33.5%-100%)[77]. Clinical trials have shown that the quadrivalent HPV vaccine is equally effective, offering 100% protection against CIN2+ lesions in women aged 15-26 years who are not infected with the vaccine-targeted HPV types[78,79]. Even individuals that are already infected with HPV can benefit from vaccination. A retrospective analysis of three global multicenter phase 3 clinical trials demonstrated that the nine-valent HPV vaccine significantly reduced the disease burden associated with non-infected HPV types[79,80].

Despite these advancements, current HPV vaccines do not provide complete protection against all HPV types that cause cervical cancer. Other HPV strains can also lead to cervical cancer, beyond the nine high-risk types covered by existing vaccines. Therefore, the development of vaccines that target a broader range of HPV types is imperative. Although the development and deployment of HPV vaccines have achieved remarkable success, becoming a cornerstone in the prevention of cervical cancer and other HPV-related diseases, global vaccination rates remain uneven. Substantial disparities in vaccination rates persist among countries. High-income countries tend to achieve higher coverage rates, whereas LMICs often face challenges such as resource shortages and cultural barriers that continue to pose significant challenges[9].

Expanding HPV vaccine coverage will require robust policy support and technological innovation. Key priorities include promoting male vaccination, advancing the development of novel vaccines (such as therapeutic and polyvalent vaccines), and enhancing public education. With ongoing advancements in vaccine technology and strengthened global collaboration, HPV vaccines hold the potential to further reduce the burden of HPV-related diseases and contribute to the ambitious goal of eliminating cervical cancer worldwide[81].

SCREENING APPROACHES AND COST

Pap smear method

In the 1940s, Greek physician Papanicolaou and Traut[82] pioneered the Pap smear method, a groundbreaking technique that enables doctors to detect early cellular changes in the cervix through microscopic examination of cervical smears. The widespread implementation of this method has played a pivotal role in reducing global cervical cancer mortality rates by 50%-70%[83]. The primary advantage of the Pap smear is its low cost, which has made it accessible and effective for lowering cervical cancer mortality over the past few decades. However, this method is not without its limitations. Key disadvantages include the need for professional expertise and specialized equipment, low sensitivity and specificity, high risk of false positives and false negatives, and significant subjectivity in result interpretation. These drawbacks can lead to misdiagnosis or missed diagnosis, underscoring the importance of skilled technicians and careful evaluation[84-87]. The cost of a Pap smear typically ranges from $30 to $300 (without insurance) depending on the healthcare setting and region. Although it remains a valuable tool in cervical cancer screening, its limitations highlight the need for complementary or alternative methods, particularly in resource-limited settings[88,89].

Acetic acid/iodine staining visual inspection

In the 1990s, visual inspection with acetic acid/iodine staining (VIA/VILI) became widely adopted in developing countries for cervical cancer screening. This technique involves application of a chemical solution to the cervix and direct observation of the epithelial reaction with the naked eye. Its key advantages include independence from specialized equipment, ease of operation, and low cost, making it particularly suitable for resource-limited settings. However, it has notable drawbacks, such as a high false-positive rate and significant susceptibility to operator subjectivity[90-92]. It costs $10–$50 (without insurance)[88].

Liquid-based cytology assay

Liquid-based cytology assay (TCT) is an advanced version of the traditional Pap smear technique. Emerging in the late 20^th century as one of a new generation of cytological methods, it was first approved for the United States market in 1996[87]. In this procedure, doctors use a specialized brush to collect the shed cervical cells, which are then rinsed into a small bottle containing a cell preservation solution. The samples undergo centrifugation, slide preparation, and staining, allowing high-quality images to be observed under a microscope. Compared with traditional Pap smears, TCT offers higher sensitivity, reduces the risk of sample contamination, and significantly lowers the false-negative rate. These advantages have led to their rapid adoption in the developed regions worldwide. However, this method is expensive and requires specialized laboratories[93,94]. It costs $100–$400 (without insurance)[95,96].

HPV nucleic acid testing

In the 1970s, German scientist zur Hausen[97] made a groundbreaking discovery by identifying the association between cervical cancer and HPV infection. This pivotal finding laid the foundation for further research on the role of HPV in cervical carcinogenesis. By the late 1990s, with advances in the understanding of the relationship between HPV and cervical cancer, HPV testing began to be incorporated into cervical cancer screening programs. In 1999, the United States FDA approved the HC2 test, which became the gold standard for HPV testing. This marked a significant shift in cervical cancer screening, transitioning from reliance on cytology alone to an integrated approach that combines cytology with nucleic acid testing[22,98]. In the early 21^st century, HPV testing emerged as the preferred method for cervical cancer screening owing to its high sensitivity and strong negative predictive value[99]. This method involves sequencing to detect the type of HPV infection, thereby enabling the identification of high-risk HPV types associated with cervical cancer[100]. The key advantages of HPV testing include its ability to extend the screening interval (e.g., every 5 years), reducing the frequency of testing, and conserving healthcare resources[101]. However, this method is not without its limitations. It is expensive and there is a potential risk of overdiagnosis in low-risk populations, which could lead to unnecessary follow-up procedures[102]. It costs $50-$200 (without insurance)[103-108].

Combined screening

Combined screening, which integrates cytology and HPV testing, is the primary method used in regions with sufficient healthcare resources[85]. This approach leverages the strengths of both tests, thereby significantly improving accuracy and efficiency. For instance, one study demonstrated that combining cervical TCT with HPV-DNA testing achieved a sensitivity of 99.8%, which was markedly higher than HPV-DNA testing alone (72.0%) or TCT testing alone (75.4%)[100]. Owing to the high accuracy of combined testing, the screening interval can be appropriately extended. The American Cancer Society 2020 guidelines recommend primary HPV screening or combined cytology and HPV testing every 5 years[75,109,110]. Extending the screening interval reduces the frequency of testing, lowers costs, and conserves medical resources[95,96,111-117]. Although combined testing is expensive and requires more resources and technical support, its high sensitivity and extended screening intervals help reduce missed diagnoses, ultimately lowering follow-up treatment costs and health risks for patients[118]. It costs $150-$600 (without insurance).

HPV self-sampling

HPV self-sampling allows women to collect samples at home for HPV testing, eliminating the need to visit a hospital for sample collection by a physician. This method is particularly beneficial for women in remote areas, regions with limited transportation, and areas with constrained medical resources, as it can significantly enhance the coverage of cervical cancer screening. For women who may feel shy or embarrassed about undergoing cervical sampling at a healthcare facility, self-sampling offers a private and convenient alternative that can be completed within the comfort of their home environment[41]. This approach not only protects privacy but also improves patient compliance by reducing discomfort and stigma. Additionally, self-sampling is simple and cost-effective, reducing both the time and financial burden associated with hospital visits, thereby encouraging more women to participate in regular cervical cancer screening[29]. Self-sampling also aligns with global health goals, contributing to the World Health Organization target of achieving 70% cervical cancer screening coverage by 2030. However, there are some limitations to consider[101]. The quality of self-collected samples may not always be as consistent or reliable as those collected by trained healthcare professionals, which could impact the test accuracy[119]. To mitigate this issue, robust detection technologies and clear instructions for proper sample collection are essential. It costs $50-$200, depending on the testing method and geographic location[95].

Cone biopsy

Cone biopsy involves removal of cervical tissue for pathological diagnosis[120]. Its primary advantage is that it can simultaneously serve both diagnostic and therapeutic purposes, particularly in high-grade lesions[121]. However, the procedure is invasive, costly, and may lead to complications such as bleeding or infection[122]. It costs $500-$2000 (without insurance)[95].

LEEP

LEEP utilizes a thin wire loop to remove cervical tissue. Its main advantage is its dual functionality, as it can be used for both diagnosing and treating early-stage lesions[123]. The disadvantages include relatively high costs and potential for minor complications[122]. It costs $300-$1000 (without insurance)[95]. The costs associated with each screening method are summarized in the table below (Table 2).

Table 2 The costs associated with each screening method.

Pap smear	$30-$300
VIA/VILI	$10-$50
TCT	$100-$400
HPV DNA testing	$50-$200
Combined screening	$150-$600
Self-sampling	$50-$200
LEEP	$300-$1000
Cone biopsy	$500-$2000
Pap Smear	$30-$300
VIA/VILI	$10-$50
TCT	$100-$400

HPV: Human papillomavirus; TCT: Liquid-based cytology assay; LEEP: Loop electrosurgical excision procedure; VIA/VILI: Acetic acid/iodine staining.

SELECTION OF DIFFERENT SCREENING STRATEGIES

High-income countries

High-income countries, with their robust healthcare infrastructure and financial resources, predominantly adopt advanced screening tools such as HPV DNA testing or combined screening (cytology and HPV testing)[101]. These methods are favored because of their high sensitivity, specificity, and ability to extend the screening interval, thereby reducing the frequency of testing while maintaining effectiveness[96]. The United States introduced HPV testing in 2012, and HPV DNA testing is now the primary recommended method for cervical cancer screening[124]. Women are advised to undergo HPV testing every 5 years starting at age 30 years. If HPV testing is unavailable, combined screening (cytology + HPV testing) is an alternative option[74]. The United Kingdom adopted HPV testing as the preferred screening method in 2019. Women are recommended to undergo HPV testing every 5 years starting at age 25 years[125]. Australia introduced HPV testing as the preferred screening method in 2017[81]. Women are advised to undergo HPV testing every 5 years starting at age 25 years. These countries leverage their economic and medical resources to implement large-scale HPV DNA testing programs, ensuring high screening coverage and early detection of cervical cancer. The extended screening intervals (e.g., every 5 years) also reduce healthcare costs and improve efficiency without compromising accuracy[95].

Middle-income countries

Middle-income countries often face economic constraints, leading them to rely on low-cost traditional screening methods such as cytology or VIA/VILI. However, in certain regions, there is a gradual shift toward introducing HPV testing where feasible[126]. In China[127], currently, there is no nationwide systematic screening program. However, some regions have implemented localized screening initiatives. For example, in Changsha city, HPV testing is used as the primary screening method, supplemented by cytological examination55. In Brazil[128,129], women aged 30-64 years are recommended to undergo cytological examinations every 3 years. HPV testing is offered as an additional measure for high-risk groups. Self-sampling has also been piloted in select areas[130]. Middle-income countries generally favor traditional screening tools (e.g., cytology or VIA/VILI) due to their affordability and simplicity. Where economic conditions permit, HPV testing is gradually being introduced to improve screening accuracy and coverage. Significant regional disparities exist, with some areas advancing screening technologies through pilot projects or targeted initiatives. These efforts aim to bridge gaps in healthcare access and enhance early detection of cervical cancer.

Low-income countries

Low-income countries face significant economic and resource constraints, leading them to rely primarily on low-cost screening tools such as visual inspection with VIA/VILI. While HPV testing is considered the ideal method for cervical cancer screening, its practical application remains limited in these regions due to financial, technological, and infrastructural barriers[67,131-136]. In Kenya, HPV testing is recommended as the preferred screening method. However, due to economic and resource limitations, acetic acid staining for gross visual observation (VIA) remains the primary screening approach[137]. In Uganda, HPV testing is recommended, but VIA/VILI is still widely used in practice due to its affordability and simplicity[138]. In low-income countries, VIA/VILI is favored because it is inexpensive, easy to perform, and does not require advanced equipment or laboratory facilities. However, this method has significant drawbacks, including low sensitivity and a high risk of false-positive and false-negative results, which can compromise the effectiveness of screening programs. The implementation of HPV testing is hindered by challenges such as the lack of necessary equipment, trained personnel, and sustainable funding. Despite these limitations, international organizations are playing a crucial role in promoting and supporting the adoption of HPV testing in these regions.

Key influencing factors in cervical cancer screening

Economic resources: High-income countries can afford large-scale implementation of advanced screening methods like HPV DNA testing, ensuring high coverage and accuracy[95]. In contrast, LMICs face significant financial constraints, limiting their ability to adopt costly technologies and restricting them to simpler, less effective methods such as VIA/VILI[139].

Medical infrastructure: The availability of equipment, laboratory facilities, and trained healthcare professionals plays a crucial role in determining the feasibility of specific screening methods. Regions with well-established medical infrastructure are better positioned to implement advanced techniques like TCT or HPV testing, while resource-limited areas often rely on basic visual inspection methods.

Policy support: Government funding and international collaborations are essential for scaling up cervical cancer screening programs. Financial backing from global health organizations can help bridge gaps in resource-limited settings, enabling the adoption of more accurate and cost-effective screening technologies[140].

FUTURE TRENDS

Technological innovation

Innovations such as self-sampling techniques and portable HPV testing devices are emerging as game-changers for improving screening coverage in resource-limited areas. These methods address barriers like accessibility, affordability, and privacy concerns, making it easier for women to participate in screening programs.

International collaboration

Partnerships between governments, nonprofit organizations, and international organizations are critical for expanding access to advanced screening technologies. By pooling resources and expertise, these collaborations can help overcome economic and infrastructural challenges in low- and middle-income regions[140]. Addressing disparities in cervical cancer screening requires a multifaceted approach that considers economic resources, medical infrastructure, and policy support. Leveraging technological advancements and fostering international cooperation will be key to reducing the global burden of cervical cancer, particularly in underserved populations.

SUGGESTIONS FOR SELECTING APPROPRIATE SCREENING METHODS

The choice of an effective screening strategy should consider the following factors: (1) Medical resources: Availability of professional equipment, trained personnel, and laboratory facilities. High-income regions can support advanced methods like HPV DNA testing, while low-resource areas may prioritize simpler, cost-effective techniques like VIA/VILI; (2) Economic conditions: Affordability of screening programs is critical. Low-cost methods are essential in economically disadvantaged regions, while wealthier nations can invest in more expensive but accurate technologies; (3) Demographic characteristics: considerations such as the age distribution, health status, and cultural preferences of the target population play a vital role. For instance, self-sampling may be more acceptable in populations where privacy concerns or stigma around cervical cancer screening exist; and (4) Policy support: Governmental and international financial backing is crucial for implementing large-scale screening programs. Partnerships with global health organizations can help bridge gaps in resource-limited areas.

By optimizing cervical cancer screening strategies based on available resources, economic conditions, and demographic needs, it is possible to significantly enhance early detection rates and reduce the global burden of cervical cancer. Tailored approaches that integrate innovative technologies, such as self-sampling and portable HPV tests, hold great promise for improving outcomes, particularly in underserved regions.

CONCLUSION

Cervical cancer, a paradigmatic manifestation of HPV-associated diseases, remains a critical global health challenge marked by pronounced regional disparities and inequities in technological access. Through comprehensive evaluation of HPV epidemiology, advancements in screening modalities, and vaccine implementation landscapes, this study highlights the geographically heterogeneous distribution of high-risk HPV genotypes-exemplified by the predominance of HPV35 in African populations and HPV52/58 in Asian cohorts-as well as age-stratified infection dynamics, characterized by peak prevalence in young women (< 25 years) and emergent reinfection risks among older age groups. Current screening paradigms demonstrate pronounced resource dependency: high-income nations utilize HPV DNA testing and co-testing (cytology + HPV detection) to achieve precision prevention, whereas low- and middle-income regions, constrained by economic and infrastructural limitations, predominantly rely on visual inspection with VIA/VILI or conventional cytology, resulting in stark disparities in screening efficacy and population coverage.

Although existing prophylactic vaccines (bivalent, quadrivalent, and nonavalent) prevent approximately 90% of cervical cancers, their global uptake remains inequitable, with coverage rates in resource-limited settings lagging significantly behind high-income regions. Persistent challenges-including incomplete protection against all oncogenic subtypes, cultural barriers to vaccination programs, and cost-prohibitive pricing-underscore the urgent need for next-generation broad-spectrum vaccines and optimized immunization strategies tailored to diverse sociocultural contexts.

To overcome these barriers, multi-faceted approaches are imperative: Technological innovations such as point-of-care HPV diagnostics, artificial intelligence-driven cytological analysis, and refined self-sampling methodologies must be prioritized to enhance accessibility; international collaborations should focus on resource redistribution and technology transfer to under-resourced regions; and region-specific screening protocols must be developed, integrating local epidemiological profiles, economic capacities, and cultural preferences. Only through synergistic efforts to expand vaccine access, democratize screening technologies, and foster global partnerships can the WHO’s 2030 cervical cancer elimination targets be realized, thereby mitigating the profound burden of HPV-driven morbidity and mortality worldwide.