This chapter should be cited as follows:
Gallio N, Borella F, et al, Glob. libr. women's med.,
ISSN: 1756-2228; DOI 10.3843/GLOWM.419943

The Continuous Textbook of Women’s Medicine Series – Gynecology Module

Volume 12

Infections in gynecology

Volume Editors: Professor Francesco De Seta, Department of Medical, Surgical and Health Sciences, Institute for Maternal and Child Health, University of Trieste, IRCCS Burlo Garofolo, Trieste, Italy
Dr Pedro Vieira Baptista, Lower Genital Tract Unit, Centro Hospitalar de São João and Department of Gynecology-Obstetrics and Pediatrics, Faculdade de Medicina da Universidade do Porto, Portugal

Chapter

Human Papillomavirus (HPV) Infection

First published: December 2024

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INTRODUCTION

Human papillomavirus (HPV) infection has been identified as the major cause of infection-related cancer, in both women and men, as it is responsible of 4.5% of all new cancer cases worldwide.¹ Cervical cancer is the most common HPV driven tumor, with 604,127 new cases and 341,831 deaths reported in 2020,² and the fourth leading cause of female cancer. Virtually, all cases of cervical cancer are caused by HPV; a fraction of other anogenital (vulvar, vaginal, penile and anal) and head and neck cancers (particularly oropharyngeal, base of the tongue and tonsil) are related to high-risk HPV infection.

Since the discovery of the causative role of HPV by zur Hausen,³ many efforts have been made to reduce the incidence of cervical cancer, including by the introduction of HPV screening and HPV vaccines. The majority of HPV driven cancers can be avoided, by both primary and secondary prevention. Nevertheless, a long road still lies ahead worldwide, especially in developing countries, until the World Health Organization (WHO) call for elimination of cervical cancer is fulfilled.⁴

CLASSIFICATION OF PAPILLOMAVIRUSES

Human papillomaviruses are double-stranded circular DNA viruses constituting the Papilloma genus of the Papillomaviridae family.⁵

The genomic organization is typical of all papillomaviruses and contains approximately 8000 base pairs, with 8 or 9 open reading frames (ORFs).⁶ It is organized into three main regions:

• Early (E), containing early genes E1, E2, E3, E5, E6 and E7
• Late (L), coding L1 (major) and L2 (minor) capsid proteins
• Long control region (LCR), a non-coding region essential for regulatory elements participating in viral transcription and replication

The L1 ORF is the most conserved gene and is used for the identification of new genotypes: if L1 differs more than 10% from the closest known papillomavirus type, then a new genotype is recognized. Lesser differences (between 2 and 10%) identify a “subtype”, while <2% are considered “variants”. HPV types should be referred to as genotype rather than serotypes, as they are classified according to genomic differences instead of their antigenicity. A HPV phylogenetic tree has been developed, grouping different HPVs into genera, based on the nucleotide sequence of the L1 major capsid protein.⁷ The alpha genus is the largest one and comprises HPV genotypes that infect the human genital tract mucosa, causing both benign disease (i.e. warts) and cancer.

More than 200 genotypes have been identified up to date, but a minority are responsible for most of the disease burden. According to their oncogenic potential, alpha mucosal HPVs are divided into low risk (LR), causing genital warts, condylomas or benign cervical lesions, and high risk (HR), which are etiological agents of cervical cancer, as well as of several other genital tumors and oral cancers. The International Agency for Research on Cancer (IARC) classified 13 HPV genotypes as carcinogenic to humans (group 1 and 2A): HPV type 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68.⁸ HPV 16 and 18 have a predominant role in the etiology of cervical cancer, together accounting for >70% of the cases of squamous cell carcinoma of the cervix.⁹ LR genotypes, such as 6 and 11, are responsible for a high burden of benign genital lesions (condyloma, skin warts), and also of the rare but often dramatic cases of recurrent respiratory papillomatosis (RRP). LR types (i.e. HPV 6 and 11) have no carcinogenic potential and are considered group 3 by IARC (not classifiable as to their carcinogenicity to humans).⁸

HPV-MEDIATED ONCOGENESIS

HPV is the most common sexually transmitted viral infection worldwide, and during their lifetime 85 and 95% of women and men, respectively, will become infected.¹⁰

The most common transmission route is by sexual contact and the transformation zone of the uterine cervix is the preferred site for infection. In most cases, the HPV infections remain asymptomatic and are progressively cleared by the immune system within 12–18 months.¹¹ A minority of HPV infection persists over time and may give rise to squamous intraepithelial lesions and, after years, to invasive cervical carcinoma. The impairment of the immune system, such as in people living with human immunodeficiency virus (HIV), facilitates infection persistence. Other factors associated with persistence and progression include smoking, multiple sexual partners, and oral contraceptives.¹² The oncogenic mechanism has been widely studied in the cervical setting: basal cells of the metaplastic transformation zone are the main targets and HPV enters into the epithelium via microabrasions or microwounds.¹³ In some cases, viral DNA integrates into the host cells’ genome, a phenomenon more frequent for HR types. HPV infection goes through three phases of gene expression: (1) latent, (2) productive and (3) transforming phase. The latent phase is not associated with viral production and it is thought that the majority of infections are cleared at this stage. Then, it may enter a phase of DNA transcription (productive phase) with expression of E1 and E2, controlling the promoter regions of E6 and E7, which are the two main regions responsible for cell immortalization and replication.¹² E6 contributes to the degradation of tumor suppressor protein p53 and other genomic events, such as activation of human telomerase and inhibition of apoptotic response via degradation of Bak.¹² E7 stimulates the cell cycle progression via degradation of tumor suppressor gene pRb and activation of cyclin complexes.¹² Finally, the transforming phase may begin, with a shift in the viral gene expression profile. This phase corresponds histologically to high grade intraepithelial lesion (HSIL), and the viral E6 and E7 production is strongly elicited, with elimination of the negative E2 feedback. The disruption leads to the abolition of apoptosis, genomic instability and accumulation of multiple mutations, thus leading to progression to invasion.

HPV-RELATED BENIGN DISEASE

Anogenital warts are benign lesions that still represent a huge burden of disease. Incidence rates are reported to range between 160 and 289 per 100,000 individuals per year.¹⁴ Transmission is almost always mediated through sexual contact and other risk factors such as immunodepression and smoking increase the risk of persistence and recurrence.

More than 90% of warts are caused by the non-oncogenic HPV genotypes 6 and 11, but coinfection with other LR and/or HR genotypes is common. The diagnosis is usually established upon examination, but a biopsy may be warranted if uncertain or suspicious findings are present, to rule out preinvasive or invasive disease.

HPV 6 and 11 (and less, frequently, other genotypes) can lead to the development of RRP. It is estimated to affect 4.5 children per 100,000 and 1.8 per 100,000 adults.¹⁵ It is believed that the infection is acquired during the passage through the birth canal of an HPV infected mother. This condition involves the growth of warts on the larynx or other respiratory passages, posing a risk of airway blockage. RRP appears in two main forms: (1) juvenile onset RRP, resulting from the transmission of HPV from mother to child during childbirth, typically manifesting in childhood; and (2) adult onset RRP, likely acquired through sexual activity, with onset usually occurring in young adulthood, typically in the third decade of life. RRP can lead to significant health issues, often requiring multiple surgical intervention, and in rare cases, it can be fatal (owing to airway blockage or progress to malignancy).

HPV-RELATED MALIGNANCIES

Over the years, HPV infection has also been found to be an important carcinogenic agent in other genital sites, for both men (penis) and women (vulva and vagina). In particular, HPV is the cause of 39%¹⁶ and 66% of the vulvar and vaginal cancers, respectively.¹⁷ Another emerging HPV-related cancer is anal cancer the incidence of which is increasing in many countries, and is caused by HPV genotypes 16 and 18 in more than 90% of the cases.¹⁸

As the first HPV viral carcinogenic model, cervical cancer has been widely studied and virtually all cases are driven by persistent HPV infection.¹⁹ However, many other factors are involved in HPV clearance and persistence, thus making the HPV infection a necessary but not a sufficient cause of cervical cancer.²⁰ The interval between HPV infection and the development of invasive cervical cancer is long, 15 to 20 years, and it may be accelerated by further risk factors such as the immune status, use of hormonal contraceptives, smoking, or HIV infection.

Vulvar cancer is a rarer female cancer, accounting for 4% of all genital tract cancer, the most frequent being the squamous subtype (VSCC). HPV infection drives oncogenic alterations in one of the two main malignant pathways, and it is preceded by a preinvasive lesion (vulvar HSIL). An HPV-independent pattern is also recognized, associated with chronic inflammatory dermatoses and having differentiated vulvar intraepithelial neoplasia (dVIN) as the precursor lesion.²¹ A recent meta-analysis calculated overall HPV DNA prevalence of 76.1% in vulvar preinvasive lesions (comprising both HPV-related and HPV-independent ones), and of 83.2% in HPV-related intraepithelial lesions, VHSIL, with HPV 16 the dominant genotype (pooled prevalence of 80.8%) followed by HPV33 (6.3%) and HPV6 ²² (2.9%). In invasive VSCC a pooled HPV prevalence of 39.1% was calculated, with HPV16, 33 and 18 being the most prevalent genotypes.²²

Vaginal squamous cancer (VaSCC) makes up to 2% of gynecological cancers and is preceded by preinvasive vaginal HSIL, but the exact prevalence and progression rates are still unknown due to its rarity.²³ HPV has an etiologic role in vaginal HSIL and VaSCC development, with an HPV pooled prevalence of 85% and 67%, respectively.¹⁷ The majority of HPV positive VaSCC also shows p16 overexpression, thus indicating an active role of the virus in the malignant transformation process.

Another emerging issue of HPV related malignancies is anal cancer, with an increasing incidence expected in the coming years and high burden for some groups, including people living with HIV, men who have sex with men (MSM) and women with vulvar cancer.²⁴ It is also preceded by a preinvasive squamous intraepithelial lesion (anal HSIL). HPV DNA is detected in more than 95% of anal HSIL, and in more than 88% of the invasive anal cancers.²⁵

The causative role of HPV goes beyond the genital tract, and plays a role in the pathogenesis of head and neck cancers,²⁶ particularly the oropharyngeal squamous cell carcinomas (OPSCC) of the base of the tongue, soft palate, uvula, and tonsils. OPSCC is one of the most rapidly increasing cancers,²⁷ especially in high-income countries where it surpassed the incidence rate of cervical cancer. This rise is expected to continue to rise until the protective effect of HPV vaccination kicks in. HPV positive OPSCCs account for more than half of the cancers of this anatomic region,²⁸ with HPV16 playing a role in 85% of the cases.²⁹ The oncogenic mechanism is similar to that of other HPV-associated malignancies, and HPV positive OPSCC have a substantially better prognosis compared to those HPV negative.³⁰

HPV VACCINATION

The HPV vaccines have proven to be an extremely effective tool for primary prevention of HPV infection; more recently, it has been shown that they also reduce the risk of recurrence in women with HPV-related intraepithelial neoplasias and invasive cancers.^31,32 Several extensive randomized clinical trials demonstrated the vaccination efficacy in the prevention of cervical, vulvar and vaginal diseases.

There are six prophylactic vaccines licensed, all containing viral like particles (VLPs), from the L1 structural protein, and therefore they are not infectious. The nonavalent vaccine contains VLPs against HPV 6, 11, 16, 18 , 31, 33, 45, 52 and 58, the quadrivalent vaccines against HPV 6, 11, 16, 18, and the bivalents against HPV 16 and 18.

The vaccination should ideally be administered to boys and girls before the onset of sexual activity, since HPV vaccination is a prophylactic intervention, and not therapeutic once the infection is established. Thus, the ideal range are boys and girls aged 9 years or older, with a 2-dose schedule, as recommended by WHO, with a minimum interval between the first and second dose of 6 months. Alternatively, in order to overcome the global shortage and for a better worldwide coverage, the WHO recommends a single-dose schedule in girls and boys aged 9–20 years (off-label option). The available evidence suggests that a single-dose option offers comparable efficacy and duration of protection to the 2-dose schedule, and may offer substantial benefits in terms of risk protection, overcoming the concern that immunization may wane with time.³³

HPV vaccines are highly immunogenic and induce a humoral response lasting many years, probably life-long.

The nonavalent HPV vaccine (9-HPV) has the potential to cover over 90% of the genotypes responsible for vulvar HSIL, including HPV 16, 33, and 18. Available data from vaccinated cohorts demonstrate total efficacy in preventing these lesions.³⁴ Additionally, 9-HPV appears to provide benefits in reducing the risk of recurrence post-excisional treatment, although these benefits are lower compared to the efficacy observed in HPV-naive patients.³⁵

A recent Danish study has highlighted lower rates of vaginal HSIL in vaccinated individuals aged 17 to 26 compared to those who were not vaccinated (hazard ratio [HR] 0.3, 95% confidence interval 0.13–0.68).²⁷ The cumulative incidence of vaginal intraepithelial neoplasia (VaIN) is low, given the young age of the patients, and further follow-up studies in the coming decades are needed to demonstrate its effectiveness, especially in postmenopausal women.³⁶

PRACTICE RECOMMENDATIONS

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