Human papillomavirus infection

Human papillomavirus (HPV) infection is caused by members of a large family of small, double-stranded DNA viruses that infect the skin and mucosal surfaces. It is one of the most common infectious diseases transmitted through sexual contact, and most infections are cleared by the immune system within a few years. A persistent infection with certain high-risk types, however, causes virtually all cases of cervical cancer and contributes to cancers of the anus, vulva, vagina, penis and oropharynx. The gap between how common the infection is and how rarely it becomes cancerous makes HPV a central case study in cancer biology, epidemiology and public health.

The clinical and public-health importance of HPV is large. Its causal role in cervical cancer, established in the 1980s and 1990s, made possible the development of prophylactic vaccines, molecular diagnostic tests and organized screening programs. In 2020 the World Health Organization adopted a global strategy aimed at eliminating cervical cancer as a public health problem, and HPV vaccination and screening sit at the heart of that strategy. The disease is therefore relevant to medicine, health systems, economic policy and questions of ethics and equity in access to care.

This entry covers the classification and virology of HPV, its life cycle and mechanisms of carcinogenesis, transmission and natural history, the spectrum of benign and malignant disease, immune control, diagnosis and screening, prevention through vaccination, treatment of lesions and cancers, the history of discovery, the situation in men and other groups, and the social and policy debates surrounding prevention. It closes with unresolved scientific and public-health questions.

Classification and taxonomy of HPV types

Human papillomavirus belongs to the family Papillomaviridae, whose members have no envelope and carry a circular, double-stranded DNA genome inside an icosahedral capsid. Within this family, HPV types are sorted by sequence comparison of the major capsid gene L1, which places each isolate into a genus, a species and a type. More than 200 HPV types have been isolated from different anatomical sites and fully sequenced, and some recent reviews count more than 220 genotypes, so the total keeps rising as sampling expands. Five genera are recognized: alpha, beta, gamma, mu and nu. The genera are named after letters of the Greek alphabet, and the species within them are numbered. Those species numbers do not correspond to the older type numbers, which is a source of confusion in the literature.

Tissue tropism provides the first major division. Members of the alpha genus include the mucosal high-risk types associated with cervical cancer, a subset of other genital cancers and a subset of oropharyngeal cancers. The beta, gamma, mu and nu genera contain types that infect cutaneous epithelia, and typically result in warts on the hands or feet. The boundary is not absolute. The alpha genus also holds a few skin-associated types, such as HPV2, 3, 7 and 10, which cause common and plantar warts, while the beta genus alone includes roughly fifty characterized types grouped into five species. Some beta types are suspected, together with ultraviolet radiation, of contributing to skin squamous cell carcinoma.

Within the mucosal alpha group, types are further sorted by oncogenic potential. Low-risk types such as HPV6 and HPV11 are the most studied and induce benign genital warts or condylomata acuminata. The high-risk subgroup is defined by epidemiological and biological evidence. The International Agency for Research on Cancer (IARC) places twelve of these types in Group 1, meaning carcinogenic to humans: HPV16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58 and 59. In its 2009 re-evaluation, the IARC working group classified HPV68 as probably carcinogenic (Group 2A), and these thirteen Group 1 and 2A genotypes cluster together in an evolutionary clade within the alpha genus. Risk is not uniform even inside Group 1. HPV16 has by far the highest oncogenic potential, and the IARC notes that carcinogenic types can differ by an order of magnitude in risk for cervical cancer.

The risk categories have been revised repeatedly as evidence has accumulated. The IARC's 1995 evaluation classed only HPV16 and 18 as Group 1, with 31 and 33 in Group 2A, and placed other types in Group 2B. Later working groups added types as data arrived. For example, HPV66 was classified as carcinogenic in 2009, largely based on its detection in cervical intraepithelial neoplasia grade 3, and HPV73 was assigned to Group 2B. Revision is difficult for a structural reason. The IARC states that carcinogenicity is best considered for some agents like HPV as a continuum of probabilities without a clear breaking point, but its categorical scheme forces a boundary. Type-by-type judgments are also hard to make, because confounding and misclassification strain epidemiology, and there has been very little experimental work on the carcinogenicity of HPV types except for HPV16 and HPV18. Because vaccine and screening decisions depend on type-specific information, these uncertainties affect public health policy as well as classification.

Virion structure and genome organization

Papillomavirus particles are compact and lack a lipid envelope. Structural studies describe their shell as a T=7 icosahedral capsid The basic architecture of the papillomavirus virion is a non-enveloped T=7d icosahedral capsid. The shell is built mainly from L1. Each L1 protein first forms a five-membered unit, and the capsid is formed by the association of 72 such capsomeres via interlocking arms and disulfide bridging. Counting individual L1 molecules, this corresponds to about 360 copies per capsid HPV capsids are composed of 360 copies of the major capsid protein, L1. The finished particle measures roughly 45 to 55 nanometres across 72 L1 protein-pentamers form the outer shell of the icosahedral HPV particle (45-55 nm in diameter).

The minor capsid protein L2 sits on the inner face of the L1 shell The L2 protein is located on the inner side of the L1 protein. It is about 470 amino acids long and carries nuclear localization signals at both ends L2 is composed of approximately 470 amino acid residues, with nuclear localization signals at both the N and C termini.. L2 is not sufficient on its own to form particles, but it contributes to assembly. L2 is a minor capsid component and lacks the capacity to form VLPs. However, L2 co-assembles with L1 into VLPs, enhancing their assembly.

The genetic material is a single closed, circular, double-stranded DNA molecule of roughly 8 kilobase pairs The circular, double-stranded viral genome is approximately 8-kb in length.. Inside the particle, host histones condense it into a chromatin-like minichromosome Cellular histones condense the 8 kb genome into a double-stranded, covalently closed circular DNA minichromosome. The genome divides into an early region of about 4.5 kb and a late region of about 2.5 kb, separated by a non-coding control region of roughly 800 to 900 bp that regulates replication and expression the early region (E), about 4.5 kb... late region (L), about 2.5 kb... long regulatory region (LCR)... is about 800-900 bp long and does not encode any protein. The early region encodes non-structural proteins, while the late region encodes the two capsid proteins, L1 and L2 The early region encodes seven non-structural proteins... while the late region encodes two capsid proteins: L1 and L2.. The exact gene count differs between descriptions: the WHO notes 6 early proteins responsible for virus replication and 2 late proteins, whereas other annotations list early genes E1, E2 and E4 through E7 and describe the family's genomes as encoding ten open reading frames Their genome is approximately 8 kb in size and encodes ten open reading frames..

Early genes handle most of the non-structural work. E1 and E2 are central to replicating and transcribing the genome, and the early genes as a group are linked to replication, transcription and cellular transformation encoding E1, E2, E4-E7, a total of 6 non-structural proteins related to viral replication, transcription and transformation. The oncogenic activities of E6 and E7 are discussed in the carcinogenesis section.

L1 has a notable self-assembly property. L1 proteins rapidly assemble into pentamers through hydrophobic interactions. L1 alone can produce capsid-like shells, but packaging the viral DNA requires L2 While L1 alone can form native capsids, DNA encapsidation requires L2 proteins. These empty shells, known as virus-like particles, contain no genetic material. They are the immunogens used in candidate vaccines VLPs are the immunogens in candidate HPV vaccines. Structural modelling suggests that much of the L1 surface is exposed on the outside of the virion, which would make it highly antigenic most of the rebuilt portion of the C-terminal arm is exposed on the surface of the virion. This is the structural basis for the vaccine design discussed later in this entry.

The genome also contributes to the particle's physical integrity. Its presence increases the stability of the capsid, increasing its resistance to environmental stresses such as proteolysis. Genome packaging occurs late in the viral life cycle. L2 helps encapsidate the genome in the nucleus of terminally differentiated epithelial cells, and neither L1 nor L2 is detectably expressed in infected basal cells L2 also facilitates encapsidation of the ∼8 kbp circular and nucleosome-bound viral genome during assembly of the non-enveloped T=7d virions in the nucleus of terminally differentiated epithelial cells. The timing of this process is covered in the life cycle section.

Life cycle and productive infection

Papillomaviruses need a breach in the surface barrier to start an infection. Virions reach the basal layer through micro-wounds, and the stem-like basal cells that renew the epithelium are thought to be the main targets (The virion enters basal keratinocytes, probably targeting stem cells through microwounds or the hair follicles). In animal models, skin abrasion combined with exposure to naked viral DNA, without any capsid, can reproduce the natural course of infection (skin abrasion and exposure to the naked viral genome are able to recapitulate the complete natural history of the infection in different animal models).

After entry, the genome undergoes a brief round of replication that raises its copy number to roughly 50–100 per cell (Upon entry, HPV undergoes a transient round of replication referred to as "establishment replication", which results in a copy number of 50–100 viral genomes per cell.). It is then kept as an extrachromosomal episome and copied alongside host DNA as basal cells divide (Viral episomes are subsequently maintained in the undifferentiated basal cells by replicating along with the host cell chromosomes.). The E2 protein tethers the genome to host chromosomes, with Brd4 acting as the best-studied anchor, which allows the genome to be partitioned into daughter cells (circular viral genomes are replicated in concert with replication of cellular DNA and equally partitioned into daughter cells through tethering of virus genomes to host cell chromosomes via E2 bound to the viral LCR and chromatin-binding proteins. Brd4, via E2, is the most studied anchor for HPV genomes to cellular chromosomes). When a basal cell divides, one daughter is displaced upward and carries its genomes into the differentiating layers (as they divide, individual infected daughter cells are pushed upwards and begin the differentiation process).

The productive phase is switched on by differentiation. Differentiation normally removes cells from the cell cycle, so the virus relies on E6 and E7 to push differentiating cells back into division, largely by degrading p53 and deregulating pRb (epithelial differentiation normally results in an exit from the cell cycle. To provide an environment conducive to productive replication, HPV has evolved mechanisms to push differentiating cells back into the cell cycle, largely through E6 and E7′s ability to deregulate cell cycle control). The DNA damage response is also needed for amplification (The ATM DNA damage is necessary for HPV genome amplification.). In these suprabasal cells, the genome is amplified to thousands of copies per cell, and late gene expression and virion assembly begin (Only upon epithelial differentiation is the productive phase of the viral life cycle activated, resulting in the amplification of viral genomes to thousands of viral copies per cell in the suprabasal layers, as well as activation of late gene expression and virion assembly and release). The capsid proteins L1 and L2 are made in the upper layers, enter the nucleus and assemble around newly synthesized genomes (viral gene expression shifts towards the L2 and L1 capsid proteins, which are targeted to the nucleus and autoassemble into virions, encapsidating the viral genome).

Release is also unusual. Many viruses escape by destroying the host cell, but HPV does not (viral release proceeds without cell lysis.). Instead, virions leave with the cells that are shed from the surface during normal desquamation (virions are essentially released through the normal process of desquamation). The whole sequence from entry to release takes about three weeks, roughly the time the basal keratinocytes need to differentiate and be shed (the time from infection to release of virus is approximately 3 weeks). Because viral gene expression is kept low in basal cells, and infected keratinocytes release little inflammatory cytokine, the infection produces few danger signals (It avoids high expression levels of the viral proteins in basal keratinocytes and thereby avoids activation of host immune pathways.; Infected keratinocytes release little inflammatory cytokine, which limits the activation of resident Langerhans cells and dendritic cells). Together, the absence of cell death and inflammation leaves few visible signs, which helps explain why infections often go unnoticed.

Mechanisms of HPV-induced carcinogenesis

In most cancers linked to high-risk HPV, the viral genome is found inserted into host chromosomes rather than existing only as a free episome. Integration appears to be essentially random with respect to the host insertion site, but it frequently breaks the viral E2 open reading frame, and the loss of E2 removes its normal restraint on the viral oncogenes. The result is derepression and sustained overexpression of E6 and E7, which are retained in the integrated genome. Not all cases follow this pattern. In one study, about half of HPV-positive cervical and pharyngeal cancers showed a subtype with episomal expression of E2, E4 and E5 and no integration into the host genome, which suggests that integration-dependent E6/E7 expression is not the only route to malignancy.

E6 and E7 act on two central regulators of the cell cycle. The high-risk E6 protein recruits the cellular E3 ubiquitin ligase E6AP, which tags the p53 tumor suppressor for proteasomal destruction. Because p53 normally halts the cycle or triggers apoptosis in response to damage, its loss removes a major safeguard. E6 also stimulates telomerase, which helps cells maintain their chromosome ends during repeated division. E7 binds the retinoblastoma protein (pRB), disrupting its complex with E2F transcription factors. Released E2F then activates genes needed for the G1-to-S transition, such as those encoding cyclins A and E. E7 also interferes with the cyclin-dependent kinase inhibitors p21 and p27. Low-risk E7 proteins bind pRB but do not degrade it, and low-risk E6 proteins do not target p53, which is one reason the two risk groups differ in oncogenic behavior. The older textbook model, in which E7-mediated pRB inactivation is the initiating event, has been questioned in recent work on how high-risk E7 triggers cellular stress.

Together, the loss of p53 and pRB function permits cells with DNA damage to keep dividing. Acute loss of pRB family members through E7 has been shown experimentally to induce centrosome amplification and aneuploidy, and this kind of mutation accumulation and genomic instability is what allows a low-grade lesion to acquire the additional changes needed for invasion. Because these steps are rare and sequential, progression from infection to invasive carcinoma typically spans years to decades. Most lesions do not progress. In one review of cervical data, 60.0–79.4% of HPV-associated low-grade lesions regressed to normal cytology, while 3.6–17.0% progressed to high-grade disease.

Host and environmental cofactors determine how often persistent infection advances. Tobacco smoking is the best-established example. Epidemiological studies show that women who smoke are more susceptible to cervical cancer than non-smokers when they carry high-risk HPV. Experimental work suggests several routes: smoke-derived compounds such as benzo[a]pyrene have been reported to raise viral genome copy numbers and viral titers in cell models, and exposure of cervical cancer cell lines to cigarette smoke components increased E6 and E7 levels in a dose-dependent manner. Smoking has also been proposed to weaken local immunity, for example by reducing Langerhans cells in the cervix, though mechanistic evidence remains incomplete. Systemic immunosuppression also raises risk: an umbrella review found that HIV infection and immunosuppressive medications were associated with worse HPV and cervical disease outcomes, and local factors such as an altered vaginal microbiota showed a similar association. Other co-factors reported in the literature include multiparity and early age at first full-term pregnancy, although the strength of evidence varies among them.

Transmission and natural history of infection

Genital HPV spreads mainly when the skin or mucosa of one person touches that of another, and it does not depend on bodily fluids such as semen or saliva. HPV is not transmitted through bodily fluids such as semen or saliva, but through skin-to-skin contact. Sexual activity, including vaginal, anal and oral sex, is the most common setting for this contact. Penetration is not required, because the virus can enter through any mucous membrane, such as mouths, lips, anus and parts of the genitals. Condoms lower the risk but do not remove it, since they cover only part of the skin that the virus can reach. Casual sharing of objects is considered unlikely to spread the virus. HPV is not transmitted through casual contact such as sharing towels or bathroom surfaces.

Transmission can occur even when neither partner has visible lesions. Infected cells can pass into a quiet phase, and symptoms may appear months or years after exposure. Latent virus without outward signs can still be passed to a sexual partner. It is possible for infected cells to undergo a latency (quiet) period, with the first occurrence or a recurrence of symptoms happening months or years later. Latent HPV, even with no outward symptoms, is still transmissible to a sexual partner.

Infection is widespread among sexually active adults, and most infections are temporary. The vast majority of HPVs cause only benign or even asymptomatic infections in immunocompetent hosts and, according to longitudinal studies, more than 90 % of these infections are expected to be cleared within two years. Clearance is not fully explained. A prospective cohort of young women in France, followed every two months, showed that the factors driving infection clearance are poorly known and could involve the adaptive and the innate immune response, but also random events occurring during cell division. Duration also differs by viral type. In one summary of duration data, types 16 and 18 are among those with the longest average durations.

Vertical transmission from mother to child is possible but uncommon. The virus can reach the infant during labor, delivery or breastfeeding. Most infants exposed in this way do not develop disease. The most notable outcome is juvenile-onset recurrent respiratory papillomatosis (RRP), which is linked to HPV types 6 and 11. Several factors are associated with a higher risk of this condition. The three main risk factors for JORRP are as follows: firstborn child, vaginal delivery, mother younger than 20 years. Maternal genital infection is also relevant, since between 30% and 60% of mothers of children affected with JORRP have genital HPV, compared with 5% of mothers of unaffected children. Caesarean delivery does not provide complete protection. Vaginal delivery is a risk factor, but cesarean delivery is not completely protective. Adult-onset RRP follows a different pattern. Its route is not established, but sexual transmission is considered likely. The mode of transmission of HPV in AORRP is not known. Sexual transmission is likely.

Persistence is the main determinant of whether infection leads to disease. Most infections clear, but those that remain for longer than one to two years carry the greatest risk of precancerous lesions and cancer. Persistence is itself uncommon: based on organised screening data, it is estimated that on average 3.2 to 4.7 % of the women aged 30 living in France at the end of 2023 were infected with HPV16 or HPV18. Several host and behavioural factors have been associated with persistence, including high parity, a large number of sexual partners, host genetic susceptibility, smoking, or co-infection with other sexually transmitted pathogens such as herpes simplex virus type 2 (HSV-2) and Chlamydia trachomatis. However, the causality in these associations is often unclear and our mechanistic understanding remains limited. Persistence therefore marks a higher risk of progression rather than a diagnosis of cancer.

Benign disease: warts and papillomas

Genital warts (condylomata acuminata) are the visible form of infection with low-risk types, most often HPV 6 and 11. Those two types account for roughly 90% of cases, and they do not cause anogenital cancer. The lesions are soft, fleshy, skin-coloured growths that appear singly or in clusters on the external genitalia, perianal skin and anal canal. Many are asymptomatic, while others cause burning, itching or discomfort. They are the most frequent symptomatic form of genital HPV infection, and the incubation period is commonly one to eight months. Transmission occurs mainly through penetrative intercourse, although direct contact with anogenital skin can also spread the virus. Lesions in the mouth, larynx and oropharynx are also reported in association with these types.

Genital warts are notable for their tendency to return after treatment. The reasons are not fully understood: recurrence may reflect reinfection or reactivation of virus that persists in the body. One study detected HPV 6 and 11 DNA in plucked pubic and perianal hairs, suggesting a possible endogenous reservoir. Most lesions regress without treatment within about 18 months, but a minority persist, and long-standing lesions can occasionally progress to Buschke–Löwenstein tumour, a slow-growing, locally destructive lesion that does not metastasize.

Common warts on the hands and plantar warts on the soles of the feet are caused by cutaneous HPV types, which infect keratinised skin rather than the mucosal linings of the genital, anal and oral tracts. This places them in a separate group from the mucosal types associated with cancer, and they are generally regarded as benign.

Recurrent respiratory papillomatosis (RRP) is a rare, chronic disease in which benign, finger-like lesions grow on the mucosa of the airway, most often the larynx. It is driven mainly by types 6 and 11. It is the most common benign laryngeal tumour in children, and the lesions can cause hoarseness, airway obstruction and, in some cases, spread into the lower respiratory tract. Surgical debulking remains the standard of care, and because the papillomas tend to regrow, patients may need repeated procedures; in juvenile-onset disease, the average has been reported at about 4.4 operations per year. Type 11 is generally associated with a more aggressive course, with earlier onset, more frequent surgery and lower remission rates than type 6. Adjuvant agents such as cidofovir, bevacizumab and interferon are used when surgery alone fails, but none is curative, and no systemic therapy is approved for the disease. Malignant transformation is rare.

Focal epithelial hyperplasia (Heck disease) is a separate, uncommon benign condition in which multiple soft, mucosa-coloured papules appear on the lips, buccal mucosa and tongue. It is linked mainly to types 13 and 32, is most frequently seen in children and adolescents, and often occurs in people of indigenous heritage, although it has been reported worldwide. Most lesions regress spontaneously, have no known tendency to become malignant, and are treated only for cosmetic or functional reasons. Conjunctival papillomas have been associated with types 6, 11 and 16, and a 2005 case report described HPV 13 in multiple conjunctival papillomas in a healthy patient, the first such description outside the oral mucosa.

Precancer and HPV-associated cancers

Cervical precancer is graded under the cervical intraepithelial neoplasia (CIN) scheme, a three-tier system that was divided into grades 1, 2 and 3 in 1968 by Richart. Grade 1 lesions are characterized by a proliferation of immature basal/parabasal squamous cells that stays within the lower third of the epithelium. Higher grades show undifferentiated cells across a greater proportion of the thickness of the epithelium. Grading is subjective: considerable inter-observer variation in the judgment of dysplastic status and CIN grade has been shown by many studies. For this reason, the CAP-ASCCP terminology consensus recommended a two-tier approach in which lesions are divided as low- or high-grade squamous intraepithelial lesions. A 2025 British and European consensus statement goes further and treats CIN 1 as a state of continuous viral replication rather than a true invasive precursor.

Only a minority of high-grade lesions become invasive. CIN 2 has an uncertain course, since some lesions advance, some regress and some persist. Estimates for CIN 3 vary. Some reference texts give up to 40% of CIN 3 lesions progress to invasive carcinoma if left untreated, while a series of clinical studies found that less than half of CIN3s will progress to cancer. This gap matters for management, because treating every CIN 3 and most CIN 2 lesions may lead to overtreatment of many lesions that would not progress.

Cervical cancer accounts for most of the HPV burden. In global estimates for 2012, it made up 84% of all HPV‐attributable cancers. Registry-based studies classify squamous cell carcinomas and adenocarcinomas, along with several rarer histologies, as potentially HPV-associated, which is why the category covers more than one tumour type. Cervical cancer is the reference point against which the other sites are measured.

The other sites form a second group of HPV-associated cancers, which includes anal, vulvar, vaginal, penile and oropharyngeal tumours. In the worldwide estimates of de Martel and colleagues, the attributable fraction was about 88% for anal cancer and 78% for vaginal cancer, but only about 31% for oropharyngeal cancer and 25% for vulvar cancer. Oropharyngeal cancer is the site where the change is most visible. HPV-positive oropharyngeal squamous cell carcinoma has one of the most rapidly increasing incidences of any cancer in high-income countries. In the United States, the number of HPV-linked oropharyngeal cases has surpassed that of cervical cancer. Attributable fractions are higher in more developed countries than in less developed countries, and the number of cancer cases attributable to HPV among males was about 4-fold greater than that among females. In contrast, data from Brazil's largest public cancer centre detected HPV in only 6.1% of OPCs.

Attributable fractions are estimates rather than direct counts. They are derived from published studies reporting the prevalence of transforming HPV infection in cancer tissue. The cervix is treated as fully attributable, while for other sites the methods include HPV DNA and p16^INK4a overexpression for vulva, vagina and anal cancer. Results are sensitive to the chosen markers: the exclusive use of HPV DNA results in higher attribution to HPV, and adding other biomarkers reduced the oropharyngeal figure to 67.2%. Registry data from Germany show the same sex-based contrast, with cervical tumours making up 70.9% of female cancers, while oropharyngeal cancer accounted for 46.9% of male cancers.

Immune response and viral evasion

Weak innate alarm signals

HPV is a poor trigger for innate immune alarms. Infected epithelial cells do not die in the way that releases obvious danger signals, and the virus does not spread into the bloodstream, so the cell death and systemic viremia that usually summon inflammation are largely absent. Once an infection is established, the viral oncoproteins also dismantle the sensing machinery itself. Through its ability to degrade p53, the E6 oncoprotein also restrains IRF-3 and STAT1, so that output of type I interferon falls. The E7 protein dampens IRF1 and IRF3, which weakens antiviral gene transcription and leaves dendritic cells maturing poorly. Detection of cytosolic DNA is further curtailed, because E7 blocks the cGAS–STING axis and reduces interferon-β production.

Silencing also takes place at the level of gene regulation. Immune-regulatory genes such as TLR9, cGAS and STING can be quieted by DNA methylation and histone modification driven by E6 and E7 interactions with host chromatin modifiers, which reduces innate detection. These changes are part of the broader epigenetic reprogramming seen in HPV-driven lesions.

Blocking antigen presentation and cytokine recruitment

Infected cells are also harder to recognise by cytotoxic T cells. The virus interferes with the presentation of viral peptides on MHC class I molecules. Interference with antigen presentation to antigen-specific cytotoxic T lymphocytes allows HPV to avoid the killing of infected cells. The E5 protein contributes by reducing MHC-I expression while keeping HLA-C and HLA-E, a configuration that helps infected cells avoid natural killer cells. E6 and E7 impair the maturation of dendritic cells and their antigen-presenting function.

Reduced secretion of signalling molecules compounds the problem. Impaired production of interferons and pro-inflammatory cytokines lowers the attraction of immune cells to the lesion, and the tissue becomes less responsive to incoming immune signals.

Adaptive control and its limits

The adaptive response is central to containment. Episomal HPV DNA remains transcriptionally silent in immunocompetent hosts, a state maintained by CD4-dependent T-cell surveillance and intact interferon signalling. Clearance is associated with T-cell and antibody responses directed at viral proteins, and their strength differs among individuals, which contributes to variation in how long infections last. Persistence is the critical step: in a Tanzanian cohort of 4,080 women, the estimated probability of type-specific persistence at 18 months after enrollment was 34.2%, showing that a substantial share of infections do not resolve quickly.

Immunosuppression and the loss of control

When host immunity is impaired, these controls fail. HIV-associated depletion of immune cells and impaired interferon responses remove this restraint and allow the viral genome to reactivate. Under chronic inflammation and oxidative stress, reactivated episomes are more likely to insert into host DNA, which accelerates progression toward high-grade lesions and invasive cancer. Clinical data show that CD4 levels correlate significantly with the occurrence of high-risk HPV infection.

The cancer risk is substantial. In a meta-analysis summarised by a later review, the standardised incidence ratio for cervical cancer was 5.82 among HIV-positive women, compared with 2.13 among transplant recipients. The pattern differs by site: anal cancer ratios were 28.75 in HIV-positive individuals and 4.85 in transplant recipients, while vulvar and vaginal cancer ratios were 6.45 and 22.7 respectively. Immunosuppression is widely recognised as a major risk factor for HPV infection and persistence, including in transplant patients on long-term drug therapy. Chronic immunosuppression thus acts as a shared risk factor for virus-associated cancers.

Diagnosis and clinical assessment

Diagnosis of HPV-related disease uses two families of test that answer different questions. Cytology, the Pap test, examines cells collected from the cervix for morphological abnormality, and it is classed as a screening tool rather than a definitive diagnostic one. Because cytology reads the effects of infection on cells, it does not show whether the virus itself is present. Cytology is often the first detector of cervical precancer in screening programmes, which is why abnormal results lead to further testing.

Molecular tests detect the virus directly by identifying HPV DNA or, in some assays, RNA. In the ESTAMPA analysis from Latin America, cytology was found to have limited sensitivity for CIN3 and higher (48.5%), whereas HPV testing reached 98.1% for the same endpoint. We demonstrated that cytology had a limited sensitivity for detecting CIN3+ (48.5% and 43.4 for CIN2+) and was highly variable among study centres, while the HPV test was consistently very sensitive in all study centres. Combining the two tests adds little in that analysis, and co-testing was judged not cost-effective since many cytology tests would be run with no added benefit. A smaller comparison from a resource-limited setting, using histopathology as the reference standard, reported 90% sensitivity for HPV DNA testing against 75% for cytology, and found that co-testing gave the highest sensitivity but the lowest specificity. These findings are one reason screening has moved toward primary HPV testing, although the evidence on co-testing is still debated.

Genotyping separates the high-risk types into groups. Testing for HPV16 and HPV18 separately from other high-risk types gives a more detailed risk estimate. In a Chinese cohort of women with normal cytology, the three-year cumulative risk of CIN2+ was 20.9% among HPV 16/18-positive women, 6.6% among women with other high-risk types, and 0.1% among HPV-negative women. A population-based Italian study found that HPV16 infection was associated with high-grade cytology and CIN3+ detection, whereas HPV18 seems to behave much more similarly to the other HPV types and does not provide additional stratification. Genotype-based triage has therefore been adopted in some programmes but not uniformly, and the role of HPV18 in particular remains under study.

Colposcopy is the next step after an abnormal screening result. The examiner views the lower genital tract under magnification and illumination after applying dilute acetic acid, typically at 3–5%. Colposcopy allows localization of the lesion(s), evaluation of the lesion(s) severity, and facilitates directed biopsy for diagnosis. Acetic acid causes abnormal epithelium to turn white, a change known as acetowhitening, but normal regions can also whiten, so the method yields false positives. Accuracy depends heavily on examiner experience. In one review, sensitivity for high-grade lesions was ranging from 55.9% to 60%, and the first colposcopy-directed biopsy detected only about half of CIN2+ cases. For this reason, guidelines favour taking several biopsies from suspicious areas. In a cohort from one centre, colposcopy-directed biopsy identified 50.8% of high-grade CIN, whereas four-quadrant biopsy identified 86.4%.

Histopathological grading of the biopsy specimen sets the final severity. Under WHO terminology, tissue is classed as normal, CIN1, CIN2 or CIN3, and in the Bethesda-based cytology system the corresponding lesions are LSIL and HSIL. The distinction between grades determines whether a patient is monitored or treated. Pathologists do not always agree: in one study, the first and second readings of cytology showed only moderate agreement for LSIL. Histological review remains the reference standard against which cytology, HPV testing and colposcopy are judged.

Screening strategies and their evolution

Cervical screening was built around cytology, the microscopic examination of cells collected from the cervix. Cytology proved useful, but its sensitivity is limited. In a Cochrane review, pooled sensitivity for cytology was about 70% for CIN2+ lesions, while HPV testing reached 96% sensitivity in the studies assessed, with HPV testing having lower pooled specificity than cytology at any threshold. A 2025 synthesis of eight randomized trials covering 414,846 participants found that HPV DNA-based screening detected CIN2+ lesions at a rate 61% higher than cytology. National data from China pointed the same way: HPV testing detected more CIN2+ (5.5 vs. 4.4 per 1000) and had a higher PPV (13.8% vs 10.9%). WHO guidelines recommend replacing cytology with primary HPV testing, and the 2021 WHO guideline designates HPV DNA as the recommended primary screening test for the general female population. In the United States, guidance from the American Cancer Society has likewise endorsed HPV testing as the preferred primary method beginning at age 25, with cytology used mainly when primary HPV testing is unavailable.

Self-collected samples and access

Self-collection of vaginal samples was developed to reach women who do not attend clinic-based screening. WHO describes self-sampling as a safe and easy approach that can reach women who would otherwise not be screened. Accuracy is a concern, however. In a pooled analysis, the sensitivity of hrHPV assays for CIN2+ and CIN3+ was lower for self-sampling than for health professional sampling. For this reason the Enduring Consensus guidelines state that clinician-collected specimens are preferred, while self-collected vaginal specimens are acceptable. The WHO mRNA guidance also specifies provider-collected samples. Programs that have switched to self-sampling report gains in participation: in one population-based study, the switch to self-sampling, together with a catch-up vaccination program, more than doubled the population coverage of HPV tests among women below 30. That study also notes that roughly half of samples continue to be taken by health personnel even after self-sampling became available to all women.

Intervals, age ranges and the mRNA option

Intervals and protocols differ across guidelines. HPV testing permits longer intervals than cytology, which reduces program costs and the frequency of recall for negative results. WHO's 2021 mRNA guidance offers an alternative approach that includes 5-year screening intervals, but the same document notes that choosing this option implies having the capacity to provide follow-up screening at 5-year intervals. The guidance also states that no recommendation was made for using HPV mRNA in women living with HIV, which leaves that group under the DNA-based approach. Age thresholds and triage rules are likewise revised as new evidence appears.

Anal cancer screening in high-risk groups

Anal cancer screening is more recent and less uniform. The ANCHOR trial found that routine screening for and removal of precancerous anal lesions could significantly reduce the risk of anal cancer, and the U.S. guidelines for people with HIV now recommend that adults aged 35 years and older who are cisgender men who have ever had sex with men, transgender women, or transgender men who have sex with men receive annual anal cancer screening. Cost-effectiveness is a live question: in one modelling study, screening initiation at age 35 years or older using cytology dominated initiation at ages 40 and 45 years or older, with ICERs from $87,731 to $350,100 per QALY depending on the interval. Evidence for younger men is thinner. One clinic-based study of men aged 18 to 34 found that cytology for anal cancer screening had high unsatisfactory rates and poor correlation with histology, and its authors supported symptom-driven testing rather than routine screening in this age group. Outside people with HIV, screening for anal dysplasia in high-risk adolescents and young adults is not standardized or universally recommended.

Oropharyngeal cancer

No validated population screening program exists for HPV-associated oropharyngeal cancer. Research into salivary and serological markers, and into the feasibility of targeted screening among high-risk groups, continues, and implementation differs widely between health systems.

Prophylactic vaccines

Prophylactic HPV vaccines are built from L1 virus-like particles (VLPs). When L1 is produced alone in expression systems, it self-assembles into hollow capsid-like shells that resemble the virion but contain no viral DNA and cannot establish infection. Immunization with these particles provokes neutralizing antibodies directed at the capsid, which block the virus before it reaches basal epithelial cells. Because the antibodies recognize the L1 proteins of specific types, protection is type-specific and extends only to the types included in a given formulation.

Licensed products have been developed in three generations. The bivalent vaccine targets types 16 and 18, the two types most often found in cervical cancer. The quadrivalent vaccine adds types 6 and 11, which cause most genital warts. The nine-valent vaccine (9vHPV) includes all four of these types and adds five further oncogenic types: 31, 33, 45, 52 and 58. Together these seven oncogenic types account for roughly 90% of cervical cancers, so the nine-valent formulation has become the most widely used option in high-income settings where it is available.

The pivotal efficacy trials of the nine-valent vaccine enrolled women aged 16 to 26 and compared it with the quadrivalent product. The prevention of high-grade cervical disease (CIN2 or worse) caused by the five added types reached about 96%, and efficacy against six-month persistent infection was similar. In the subgroup of women who had no evidence of HPV infection at enrollment, efficacy against disease caused by vaccine types was 100%, with a lower confidence bound of about 70%. This pattern reflects the trial design: the vaccine prevents new infections, so its benefit is greatest in people who have not yet been exposed to the targeted types, and it has limited effect on infections already established.

Dose number has been the subject of an extensive evidence base. The original schedule required three injections over six months. Trials in Kenya (KEN SHE) and Costa Rica (ESCUDDO, which randomized 20,330 girls aged 12 to 16 and followed them for five years) found that one dose protected against persistent cervicovaginal HPV infection with efficacy of at least 97%, a level comparable to two doses. An earlier Costa Rican study (CVT) reported that single-dose efficacy against high-risk types remained similar to two- or three-dose efficacy at about 11 years of follow-up. Immunogenicity data are more nuanced: antibody levels against HPV 16 and 18 are lower after one dose than after two or three, but they have remained stable for more than a decade in the available follow-up, and the durability of single-dose protection remains an active question.

On the basis of this evidence, the World Health Organization's Strategic Advisory Group of Experts on Immunization recommended in April 2022 that a single dose be accepted as an alternative schedule, and the WHO position paper of December 2022 extended this option to girls and boys aged 9 to 20. Because national vaccine licences had been granted for two- or three-dose regimens, single-dose use was classed as off-label in many countries, and several high-income countries, including the United Kingdom, Ireland, Australia, Spain and Canada, nonetheless adopted it by early 2025. The change has altered program design: a single dose lowers per-person cost, reduces the number of clinic visits needed for completion, and eases supply constraints, which in turn bears on coverage in low- and middle-income countries.

Global vaccination policy and coverage

WHO has recommended that HPV vaccination be included in national immunization programmes, and the number of countries doing so has grown steadily. By the end of 2025, the vaccine was on the national schedule for girls in 162 of WHO's 194 member states, and 15 countries introduced it during that year, including China, Pakistan and Ghana. WHO also reported that more than 85% of girls vaccinated in 2025 received a single-dose schedule, and that 93 countries had adopted a one-dose schedule by the end of that year. Single-dose schedules have reduced the number of doses needed per girl, which has eased supply constraints, although the programme design is discussed in a separate section.

In August 2020 the World Health Assembly adopted the Global Strategy to Accelerate the Elimination of Cervical Cancer, which sets 90–70–90 targets for 2030. The first target is that 90% of girls are fully vaccinated against HPV by age 15. The other two are that 70% of women are screened with a high-performance test at ages 35 and 45, and that 90% of women with cervical disease receive appropriate treatment. WHO defines elimination as a rate of fewer than 4 new cases per 100,000 women per year, and as of the latest available reporting, no country had reached that level.

Coverage has risen but remains far below the 90% target. WHO's 2025 estimate put first-dose coverage among girls at 33%, compared with about 27% in 2023 and 21% in 2024, according to earlier WHO-based figures. Independent analyses use different denominators and methods and produce higher figures. One study estimated first-dose coverage among girls aged 9–14 at 56.9% in 2024, and a 2025 systematic review found that the 132 countries reporting data in 2023 averaged 61.6% for the first dose. Upper-middle-income countries had the highest coverage, while only 15 of the reporting countries had reached 90% for the first dose. These differences in estimates reflect the reporting base and should be read with that in mind.

The gap between countries is wide. In 2025, about 35% of eligible children lived in countries that had not yet introduced HPV vaccination. A 2025 review found that 14 of 26 low-income countries and 20 of 54 lower-middle-income countries still did not include the vaccine in their national programmes. For several years, rising global demand produced a supply shortage that hindered introduction in some countries and distributed available doses unevenly. Financial constraints in low- and lower-middle-income countries have also slowed adoption, and the pace of implementation depends on financing mechanisms, donor partnerships and the capacity of national health systems.

WHO and modelling studies present the 90–70–90 targets as a means of averting a large share of future disease. WHO estimates that meeting these targets in 78 low- and middle-income countries would avert about 74 million new cervical cancer cases and 62 million deaths in the coming decades. Achieving the goals in each country by 2030 would require sustained investment in vaccination, screening and treatment at once, since the three pillars depend on one another.

Treatment of precancerous lesions and cervical cancer

No antiviral drug can clear HPV from the body, so treatment of precancer is aimed at the lesion rather than the virus. Ablative treatment removes the dysplastic lesion but not necessarily all the infected tissue. Effective treatment thus results both from removal of the entire lesion and viral clearance as well. Lesion removal is therefore the immediate goal, and viral clearance follows only partly from it.

Treatment of cervical intraepithelial neoplasia (CIN) falls into two groups of outpatient surgical procedures: ablative methods, which destroy abnormal epithelium in place, and excisional methods, which remove it as a specimen. Cryotherapy, electrocoagulation, cold coagulation and laser ablation are different methods of ablative treatment of CIN. Cryotherapy is the cheapest option to set up: it relies on transportable tanks of highly compressed refrigerant gas rather than a supply of electricity. Because of this, one guide argues that cryotherapy is the most practical choice in low-resource settings, provided the lesion lies entirely on the ectocervix. LEEP is the treatment of choice if the lesion involves the endocervical canal. Thermal ablation is a further ablative option, and a randomized non-inferiority trial compared it with two forms of cryotherapy in women with biopsy-confirmed CIN2 or higher. It compares CO2 gas-based cryotherapy, non-gas cryotherapy, and thermal ablation.

Excisional procedures remove a cone-shaped piece of the cervix. These can be performed using a scalpel, electrosurgery (loop electrosurgical excision procedure, LEEP), or laser. The cone includes the transformation zone where cervical precancers and cancers are most likely to start. Electrosurgical loops have displaced lasers in most settings, because laser is expensive, technically difficult, and can cause harm to medical personnel. Cone biopsy can also serve as treatment, since it can sometimes completely remove precancers and some very early cancers. Across comparative studies, there were no substantive differences in outcomes regarding persistence and resolution for cone biopsy, cryotherapy, laser ablation, or LEEP. The main difference lies in morbidity. In one analysis, significant hemorrhage occurred most frequently in subjects who received cone biopsy, and ablative techniques such as cryotherapy or CO2 laser have less impact on future fertility than surgical conization.

Invasive cervical cancer is managed according to stage. For early invasive cancer, surgery is the treatment of choice. In more advanced cases, radiation combined with chemotherapy is the current standard of care. For stage IA1 disease, accepted surgical options include simple hysterectomy, radical hysterectomy and conization. For locally advanced disease, the standard is platinum-based chemotherapy combined with radiotherapy plus intracavitary brachytherapy, which has been shown to result in improved overall survival compared to radiotherapy alone. In the RTOG 9001 trial, patients with stages IB2 to IVA were randomized to radiation alone or concurrent with cisplatin/5FU. Survival was better in the chemoradiation arm. Five-year survival with exclusive chemoradiotherapy is between 60 and 75%, according to stage of disease. Surgery can also be combined with chemoradiation: radical surgery has been proposed as an alternative to vaginal brachytherapy after chemoradiation to improve local disease control and reduce radiation dose and toxicity. The choice of surgical approach remains debated, since the LACC trial found that minimally invasive surgery had a higher recurrence rate and lower disease-free and overall survival than open surgery.

Follow-up after treatment is a central clinical concern, because HPV infection persistence, particularly of high-risk genotypes, during the follow-up period is strictly related to residual or relapsed disease. Persistent positivity is detected in up to one-third of women after CIN2+ treatment. Guidelines differ on timing. According to the World Health Organization, HPV DNA testing is recommended at 12 months after treatment, with an additional retest at 24 months before resuming routine screening intervals. The 2019 ASCCP guideline instead prefers HPV-based testing at 6 months regardless of the margin status of the excisional specimen. In one study of women who were HPV negative at six months, none were found to have residual or recurrent CIN2+ during the surveillance period. Risk also depends on the original lesion: post-treatment risk was dependent on the severity of the treated histology (CIN2 = 10% versus CIN3/AIS = 16%). Surveillance is long-term; ASCCP recommends continued surveillance with HPV testing or cotesting at 3-year intervals for at least 25 years after treatment.

Therapeutic vaccines and immunotherapy research

Therapeutic vaccines differ from prophylactic ones. Prophylactic vaccines, based on L1 virus-like particles, aim to prevent infection, while therapeutic designs try to treat people who already have HPV-associated lesions or cancer. Most candidates target the viral oncoproteins E6 and E7, which are expressed in transformed cells. Because these antigens are foreign, they can prompt a cytotoxic T-cell response against infected or malignant cells, and E7 and E6 are attractive therapeutic targets because they are absent from healthy tissue, which limits off-target damage in principle.

The most advanced therapeutic vaccine is VGX-3100, a DNA vaccine delivered with electroporation. In a randomized phase II trial in women with CIN2/3 associated with HPV-16 or HPV-18, lesion regression occurred in 49.5% of 107 VGX-3100 recipients in the per-protocol analysis, compared with 30.6% of 36 placebo recipients. The subsequent phase III REVEAL 1 trial reported a primary endpoint of histopathological regression combined with viral clearance in 23.7% (31/131) of the treatment group versus 11.3% (7/62) of the placebo group. Results were not uniform across analyses: in a biomarker-based subpopulation of women with high-grade lesions, VGX-3100 was no better than placebo, although it significantly improved regression and viral clearance in the original all-participants population. Efficacy claims for this class therefore remain tied to the trial population and endpoint definitions.

Checkpoint inhibitors have been the most clinically established immunotherapy in HPV-related cancers, mainly cervical cancer. On June 12, 2018, the US Food and Drug Administration approved pembrolizumab for recurrent or metastatic cervical cancer that progressed during or after chemotherapy. The approval rested on a non-randomized cohort in which the objective response rate in 77 patients was 14.3%, and no responses were observed in patients whose tumors lacked PD-L1 expression. Later, pembrolizumab was approved with chemoradiotherapy for patients with stage III-IVA cervical cancer, based on the randomized phase III KEYNOTE-A18 trial. Cemiplimab showed a survival benefit over chemotherapy in the phase III EMPOWER-Cervical 1 trial, with a 31% reduction in the risk of death in the squamous cell carcinoma subgroup, and the European Commission approved it for recurrent or metastatic disease after platinum-based chemotherapy.

Adoptive T-cell therapy is at an earlier stage. Tumor-infiltrating lymphocytes have produced responses in HPV-associated cervical cancer, with objective tumor responses in 3 of 9 patients with cervical cancer in one trial. Engineered T-cell receptor (TCR) approaches target specific HPV epitopes; for example, a phase I study of an HPV-16 E7-specific product (KITE-439) enrolled eight HLA-A02:01-positive patients, and no dose-limiting toxicities occurred during the trial. Such therapies are restricted by HLA type, since the E7 (11–19) epitope is recognized in the context of HLA-A02:01, and earlier trials reported severe toxicity linked to the lymphodepleting chemotherapy and high-dose aldesleukin used in the regimen.

Across these approaches, the main challenges are tumor immune evasion, which can suppress the T-cell response that vaccines and cellular therapies try to induce, and the design of antigen delivery, including the choice of vector, adjuvant and HLA-compatible epitopes. Clinical trials of therapeutic vaccines are continuing, and all of these strategies are developed mainly for patients who already have disease rather than for prevention.

History of discovery and research

The study of papillomaviruses began with animal disease rather than human cancer. Wild cottontail rabbits with horn-like skin growths were known to hunters for years, and in the early 1930s Richard Shope traced these growths to a transmissible agent. His work is generally regarded as the first description of a papillomavirus, and it later helped other researchers connect these viruses to warts and, eventually, to cervical cancer. The rabbit virus also became one of the first DNA viruses associated with malignant progression in a mammal.

The idea that a human papillomavirus causes cervical cancer ran against the prevailing view. Through the 1970s, the suspected culprit was herpes simplex virus type 2, and many researchers doubted that viruses could cause common cancers at all. Harald zur Hausen tested cervical tumour samples for herpesvirus and did not find it. He also noticed that women with genital warts, which were known to be caused by HPV, often went on to develop cervical cancer, and he redirected his work accordingly. He published his hypothesis in 1976, though some sources date it to 1975. A competing herpesvirus explanation was actively contested for years afterward.

Proving the hypothesis required molecular tools that were not yet available. Zur Hausen's group at the University of Freiburg first isolated and cloned HPV-6 from a genital wart in 1979, but HPV-6 was not found in cancer cells. A related type, HPV-11, then served as a DNA probe and matched material in only one of 24 cervical cancer biopsies. The decisive step came when a student in the laboratory found a new viral DNA fragment in a cancer biopsy. The resulting clone, HPV-16, was found in more than half of the cervical cancer samples examined. HPV-18 was identified in 1984, and together these two types account for roughly 70 percent of cervical cancers. Zur Hausen's reasoning was that viral DNA should be integrated into tumour genomes and therefore detectable by targeted searches, but the search was difficult because only parts of the viral genome were incorporated into the host DNA.

Zur Hausen received the 2008 Nobel Prize in Physiology or Medicine, with the other half of the prize shared by Françoise Barré-Sinoussi and Luc Montagnier for their work on HIV. The Nobel committee noted that his findings clarified the natural history of HPV infection, explained mechanisms of HPV-induced carcinogenesis, and made prophylactic vaccines possible. Although the discovery was made in the 1980s, pharmaceutical companies approached by zur Hausen at that time did not consider a cervical cancer vaccine commercially attractive, and the first HPV vaccine was not approved until 2006. Zur Hausen died in May 2023 at the age of 87.

Cross-references: viruses, DNA, cancer, vaccines, Nobel Prize in Physiology or Medicine

HPV in men and other populations

Men are an important link in HPV transmission, yet their epidemiology has been studied far less than that of women. Compared with cervical HPV infection, relatively little is known about the epidemiology of HPV infection in men. Pooled data nonetheless show that infection is widespread. A 2018 analysis of 16 studies estimated that about half of men carry some genital HPV type, and roughly one in three carry a high-risk type. A study published in 2018 examined risk factors for HPV in men, including having sex with men, and estimated a global pooled prevalence of any type of genital HPV in men of 49%. Reported figures vary because the result depends on the anatomical site sampled, the detection method and the population studied. HPV prevalence varied on the basis of sampling, testing methods, and the anatomical site or specimen sampled. In one US national survey, infection rates did not decline steadily with age; they formed two peaks, one in men in their late twenties to early thirties and another in men in their late fifties. The distribution of genital HPV infection in U.S. men appeared to be widespread among all age groups and followed a bimodal pattern, with a peak among men aged 28 to 32 years (50.8%) and a second higher peak among men aged 58 to 59 years (59.6%).

In men, the most frequent symptomatic presentation is genital warts. Genital warts are the most common clinical presentation caused by HPV infection in men. Most of these lesions trace back to low-risk types: although genital warts are primarily benign lesions of which 90% are associated with LR-HPV types 6 and 11, they can limit patients psychosocially and are highly infectious. In a 1999–2004 US survey, 4.0% of sexually active males aged 18–59 years reported having ever been diagnosed with genital warts. The lesions are not fatal, but they cause psychosocial distress such as shame and embarrassment.

HPV is also linked to penile cancer. The virus has been detected in one-third to one-half of penile cancers. HPV 16 is the most prevalent serotype, accounting for 46% to 62.5% of HPV-associated penile cancers. The disease burden differs sharply by region: penile cancer is less than 1% of cancers in men in the United States, however, is much more common in some parts of Asia, Africa, and South America, where it accounts for up to 10% of cancers in men. Uncircumcised men show higher HPV prevalence than circumcised men. Most studies report estimates greater than 20% in men, with higher prevalence in uncircumcised versus circumcised men.

The largest concentration of HPV-related disease in men is anal cancer. A meta-analysis finding over 80% of anal cancers to be linked to HPV infection, most strongly with HPV-16, and the highest rates occur in HIV-infected men and women, particularly MSM. The gradient is steep: an incidence of 131/100,000 among HIV-infected MSM in the U.S. has been reported, compared with 34 cases per 100,000 men at age 60 or above among HIV-negative MSM. Anal infection is also common across ages. Anal HPV infection and anal intraepithelial neoplasia are very common throughout a wide range of ages in both HIV-negative and HIV-positive men who have sex with men. In a Toronto cohort, the prevalence of any HR-HPV infection was 65.3% and 50.7% in the HIV-positive and HIV-negative MSM, respectively. Disparities also appear within HIV-positive groups: in a multicenter US cohort, the weighted hazard ratio for anal cancer in Black MSM (adjusting for demographics, HIV disease factors, and co-infection/behavioral factors) was 2.37 compared with non-Black MSM.

Case counts can look different from rates because group sizes differ. A 2023 US modeling study found that 54% of all anal cancer incidence occurred in HIV-negative MSW, 19% occurred in HIV-negative MSM, and 27% occurred in men living with HIV, and its authors cautioned that population sizes in these groups differ significantly. Screening for anal disease in men lags behind cervical screening. Given the increased prevalence of disease among MSM living with HIV, the extant literature only includes limited discussion of screening practices for additional at-risk groups. Cytology of anal samples is one option under study: cytology may be a useful tool for the detection of anal precancerous lesions.

Vaccination has extended to boys and men. In 2011, the Advisory Committee on Immunization Practices recommended routine use of the HPV4 vaccine in boys 11 to 12 years old, as well as catch-up vaccination in adolescent boys, and the guidance also covered previously unvaccinated males aged 22 to 26 years who are immunocompromised, who test positive for HIV infection, or who have sex with men. Vaccination has been linked to reduced disease in men: recent interim data have shown that the quadrivalent HPV vaccine is highly effective in reducing external genital lesions in young men. Protection is greatest before exposure. The study of nearly 1,200 men confirmed that HPV vaccination is most effective when given at a young age, before people are exposed to the virus. Coverage remains uneven. At least 85 countries now offer HPV vaccines to both boys and girls. The World Health Organization (WHO) estimates that none of the boys in the Eastern Mediterranean and Southeast Asia have completed the three-dose HPV vaccine regimen, while only 1% of boys have in the African and Pacific regions.

Social, ethical and policy debates

The most visible controversy has concerned vaccine safety, and Japan offers the clearest case. Media attention to reported adverse events, which were later found to be unrelated to vaccination, led the government to suspend its proactive recommendation in June 2013 (In June 2013, proactive recommendations for the HPV vaccine in Japan were suspended following reports of adverse events since found to be unrelated to vaccination, but which were extensively covered in the media.). The national committee that examined the events concluded in 2014 that vaccination had not caused them, but the suspension stayed in place for roughly eight more years. Uptake fell sharply during this period. Coverage that had approached 70% among girls born in the late 1990s dropped below 1% for those born after 2002 (this HPV vaccination crisis caused a sharp drop in coverage from a peak of approximately 70% among girls born between 1995 and 1999 to less than 1% among girls born after 2002). Japanese researchers, whose earlier work linked the period to higher infection rates and more cytological abnormalities, pressed for the recommendation to be restored (the suspension of the proactive recommendation for human papillomavirus (HPV) vaccination in Japan led to an increase in infection rates and incidence of cytological abnormalities). The government reversed course in November 2021, and a catch-up scheme was then created for women who had missed the vaccination window (the government decided to offer catch-up vaccinations to affected cohorts until March 2025).

Public debate has also been shaped by the way the topic is communicated. A content analysis of social-media posts after the Japanese decision found that the most frequently discussed theme was concerned with the safety and side effects of HPV vaccines; it was mostly mentioned from a negative perspective. The same study noted that approximately half of the health professionals, researchers and politicians (groups considered to be influential in promoting HPV vaccine uptake) tweeted neutrally about HPV vaccines. Clinician behaviour matters as well. In a survey cited by the same analysis, only 35% of physicians and 11% of nurses reported recommending vaccination to eligible adolescent girls (In a previous study of Japanese physicians and nurses, only 35% of physicians and 11% of nurses recommended HPV vaccination for eligible adolescent girls). These findings have made strategic communication with parents, clinicians and the media a research topic in its own right, alongside questions about informed consent and ethical duties to explain risks accurately.

Access is also unequal. While most new cases and deaths from cervical cancer occur in LMICs, the worldwide HPV vaccine completion rate for girls aged 9–14 years (the primary target population for HPV vaccination) was only 17% in 2022. The gap therefore falls most heavily on countries with the greatest cervical cancer burden, where health system capacity and financing are most constrained. Inequities also exist within countries, between urban and rural areas and across income groups, and these disparities reflect broader social determinants of health rather than vaccine characteristics alone.

Program design involves trade-offs that are as economic as they are clinical. The option of a single dose gained formal endorsement in December 2022, leaving countries free to choose between one and two doses for non-immunocompromised girls aged 9–14 (enabling countries to decide between a single-dose or two-dose schedule for non-immunocompromised girls aged 9–14 years). Proponents argue that fewer doses cut purchasing and delivery expenses and make campaigns easier to run (With greatly reduced costs for vaccine supply and delivery and simplified implementation potentially allowing more countries to introduce HPV vaccination or increase uptake). Adoption has been rapid, and by June 2024, following further recommendations from WHO Regional Technical Advisory Groups on Immunization (Pan American Health Organization and WHO African Region), more than 50 countries had adopted the single-dose schedule. Regulatory questions have accompanied this shift, since licences in many countries covered only two or three doses (existing vaccine licences from national regulatory bodies exclusively covered two-dose or three-dose HPVV). Other design questions, including whether to vaccinate boys, the appropriate age of vaccination and how to reach older adolescents, are weighed in similar terms of cost, coverage and equity, and the answers differ by country.

Some objections are rooted in the sexual nature of the infection. Because HPV is transmitted through sexual contact, parents and communities have sometimes questioned whether vaccinating adolescents implies sexual activity, and consent rules differ across jurisdictions, which affects whether vaccination is delivered through schools or through parental permission. Stigma attached to a sexually transmitted infection can also discourage people from seeking screening or treatment, so the social dimension of HPV is examined alongside clinical outcomes in public health research.

Unresolved questions and future directions

Why most HPV infections clear while a minority persist is still only partly explained. Clearance is associated with adaptive immune responses, but the strength of those responses differs between individuals, and HIV infection lowers the neutralizing antibody response to vaccination (immune factors such as T-cell activity are discussed in other sections). Researchers also lack a validated threshold: There is no immune metric, such as antibody concentration, that correlates with the protection afforded by HPV VLP vaccines. Without such a marker, antibody levels cannot serve as a simple proxy for protection in individual patients or in trials of new products.

The durability of vaccine protection is another open question. The duration of protection against HPV-16/18 from prophylactic vaccination remains unknown. Follow-up data are reassuring so far. In one study of the AS04-adjuvanted bivalent vaccine, seropositivity rates for anti-HPV-16 remained high (≥96.3%) in all age groups 10 years after first vaccination. A randomized trial found that two doses provided robust protection against persistent HPV-16 and HPV-18 infection for up to 13 years. Its authors concluded that a booster dose administered at 60 months would not provide additional benefit. The need for boosters in other schedules, and in people vaccinated later in life, is less settled. Because the risk of HPV exposure persists throughout a person's sexual life, the timing of vaccination and any later doses remain relevant questions.

Single-dose schedules raise a related issue. In a U.S. trial, children vaccinated once maintained high antibody levels for up to two years before a delayed booster, but longer-term data are needed to evaluate the effectiveness of a single dose beyond 2 years. The effect of vaccination on long-term cancer incidence can only be measured over decades, since cervical cancer develops slowly after infection, so the full cancer-prevention benefit of the vaccinated cohorts born after programs began will not be known for many years.

Screening for men and for other high-risk groups has an even weaker evidence base. For anal cancer, the International Anal Neoplasia Society has recommended swab-based screening as a first step, because the gold-standard examination, high-resolution anoscopy, is costly, difficult to perform, and burdensome for participants, and its capacity in many places is limited. The U.S. Centers for Disease Control and Prevention has stated that it has found insufficient data about the natural history of anal HPV infection to provide a recommendation for routine screening. For the oropharynx, oropharyngeal cancer precursors have yet to be identified, and current biomarkers have low sensitivity or very low prevalence, so large numbers would need to be screened to detect a single case. This matters because HPV-associated oropharyngeal cancer is growing: it accounts for 71% of all OPSCCs in the US and 51% in the UK.

Global elimination targets raise further questions about implementation. The WHO strategy aims for 90% of girls fully vaccinated with the HPV vaccine by the age of 15; 70% of women screened using a high performance test by the age of 35, and again by the age of 45; and 90% of women with cervical disease receiving treatment by 2030. Progress is uneven. In a baseline assessment of six African countries, vaccination against HPV has reached between 74% and 98% of girls in the age bracket in most of them, yet HPV testing, recommended by WHO, is being introduced slowly. A cancer registry analysis found that progress in reducing the cervical cancer burden has been markedly imbalanced across countries and world regions, and the IARC researchers warned that unless countries scale up screening programmes and improve coverage of HPV vaccination and access to affordable treatment, the WHO 2030 elimination targets will be missed.

Whether these targets are met therefore depends less on biology than on financing, health system capacity and the performance of newer tools. Lower-cost regimens may help: one analysis notes that the shift to one-dose vaccine schedules has increased vaccine supply and opened options such as catch-up vaccination and concomitant vaccination and screening. Whether that shift translates into durable protection, and whether new diagnostics can be deployed at scale in low- and middle-income settings, remain to be determined.

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