Human Papillomavirus (HPV)

Overview

Human papillomavirus (HPV) is the most common sexually transmitted infection worldwide. Nearly 80% of sexually active people will be infected with at least one human papillomavirus type at some point in their lives — yet the vast majority of those people will never know it, because most infections are completely silent and go away on their own.

Scientists have identified over 200 distinct human papillomavirus types. The good news: more than 90% of human papillomavirus infections clear within one to two years because the immune system quietly eliminates the virus without any treatment needed. The infections that linger — particularly with certain "high-risk" types — are what can occasionally lead to cancer over the course of many years.

Human papillomavirus types are broadly divided into two groups:

• High-risk (oncogenic) types — can, if persistent, eventually cause cancers of the cervix, oropharynx, anus, vagina, vulva, and penis. Human papillomavirus 16 and 18 are the most important of these.
• Low-risk (non-oncogenic) types — most commonly human papillomavirus 6 and 11, which cause genital warts and rarely lead to cancer.

The Gardasil-9 vaccine is highly effective at preventing human papillomavirus infection and the cancers it can cause. It works best when given before a person becomes sexually active. Routine vaccination of adolescents is one of the most powerful cancer-prevention tools available today.

Epidemiology

Human papillomavirus is extraordinarily common. The U.S. Centers for Disease Control and Prevention (CDC) estimates that approximately 43 million new human papillomavirus infections occurred in the United States in 2018 alone. Infection rates are highest in people in their late teens and early 20s, reflecting the onset of sexual activity. Both men and women are infected at roughly equal rates, though the disease burden (particularly cancer) falls more heavily on women.

Globally, human papillomavirus causes an estimated 690,000 cancers per year according to the International Agency for Research on Cancer (IARC) and the World Health Organization. Cervical cancer is the fourth most common cancer in women worldwide. The burden is especially severe in low- and middle-income countries, where cervical cancer screening programs are limited or unavailable, allowing treatable precancerous lesions to progress undetected to invasive cancer.

In the United States, widespread Pap smear screening has dramatically reduced cervical cancer deaths over the past 50 years. Since the introduction of human papillomavirus vaccines in 2006, rates of high-grade precancerous cervical lesions and genital warts in young women have fallen sharply in countries with high vaccine uptake.

Biology: Over 200 Types

Human papillomavirus is a small, non-enveloped virus with a circular double-stranded DNA genome. More than 200 distinct types have been identified and classified based on their DNA sequence. Understanding how human papillomavirus types differ helps explain why some cause cancer while others merely cause warts.

High-Risk (Oncogenic) Types

At least 13 human papillomavirus types are classified as high-risk or oncogenic. The two most important are:

• Human papillomavirus 16 and 18 together account for approximately 70% of all cervical cancers, about 85% of anal cancers, around 60% of oropharyngeal cancers, and roughly 65% of vaginal and vulvar cancers.
• Other significant high-risk types include human papillomavirus 31, 33, 45, 52, and 58 — all covered by the Gardasil-9 vaccine.

Low-Risk Types

Human papillomavirus 6 and 11 are responsible for about 90% of genital warts (condylomata acuminata) and for a rare condition called recurrent respiratory papillomatosis (benign growths in the larynx and airways). These types do not cause cancer.

How Human Papillomavirus Causes Cancer

Human papillomavirus infects the basal (deepest) layer of skin and mucosal cells, gaining entry through tiny abrasions during sexual contact. In most cases the immune system clears the infection within months to a couple of years. When a high-risk type persists, its viral proteins — particularly E6 and E7 — interfere with two critical cellular guard proteins:

• E6 targets and inactivates p53, a tumor suppressor that normally triggers cell death when DNA damage is detected.
• E7 inactivates Rb (retinoblastoma protein), the "brake" that controls cell division.

With both brakes disabled, infected cells can accumulate DNA errors and divide uncontrollably over many years — a slow progression from normal cells to precancerous changes to, in some cases, invasive cancer. This process typically takes 10 to 20 years, which is exactly why regular screening is so effective at catching and treating precancerous changes long before cancer develops.

Clinical Manifestations

Most human papillomavirus infections produce no symptoms at all. When human papillomavirus does cause visible disease, the manifestation depends on the type involved.

Genital Warts (Condylomata Acuminata)

Caused by low-risk types human papillomavirus 6 and 11, genital warts appear as flesh-colored, soft, cauliflower-like growths on the genitals, perianal region, or inner thighs. They are not cancerous. Warts can appear weeks to months after infection and range from a single small bump to large clusters. They can be treated but not permanently cured by removal alone — the virus remains in surrounding tissue and warts often recur. Treatment options include:

• Patient-applied: imiquimod cream (stimulates immune response), podophyllotoxin solution
• Provider-applied: trichloroacetic acid (TCA), cryotherapy (liquid nitrogen freezing), surgical excision or electrosurgery

Non-Genital Warts

Common warts (hands, fingers), plantar warts (feet), and flat warts are caused by cutaneous human papillomavirus types that do not infect the genital tract.

Recurrent Respiratory Papillomatosis (RRP)

A rare but serious condition in which human papillomavirus 6 or 11 causes benign papillomas (growths) in the larynx, vocal cords, and airways. It occurs in two forms: juvenile-onset (transmitted from mother to baby during delivery) and adult-onset. Management requires repeated surgical removal of papillomas to maintain an open airway; adjunct therapies such as cidofovir or bevacizumab are used in severe cases.

Precancerous Cervical Changes

High-risk human papillomavirus types can cause abnormal cervical cells detected on Pap smear or biopsy. These are graded by severity (CIN 1, 2, 3 — see Screening section). High-grade changes (HSIL/CIN2-3) are treated to prevent progression to cancer.

Cervical Cancer

Almost all cervical cancers (99%+) are caused by human papillomavirus, with human papillomavirus 16 and 18 responsible for the majority. Cervical cancer develops over a long period — typically 10 to 20 years from initial human papillomavirus infection to invasive cancer — which is why routine screening is so effective.

Other Human Papillomavirus-Related Cancers

• Oropharyngeal cancer (base of tongue, tonsils) — human papillomavirus 16 is now the leading cause of oropharyngeal squamous cell carcinoma in the United States, surpassing tobacco-related cases in frequency
• Anal cancer — human papillomavirus 16 is the dominant type; rates are rising, especially in human immunodeficiency virus-positive men who have sex with men (MSM)
• Vaginal and vulvar cancers — majority caused by high-risk human papillomavirus types
• Penile cancer — a minority are human papillomavirus-related; human papillomavirus 16 is the most common type involved

Cervical Cancer Screening

Cervical cancer screening is one of modern medicine's great success stories. Because cancer develops slowly over many years from detectable precancerous changes, regular screening catches the process early — when it is easily treatable. All women with a cervix should follow screening guidelines regardless of human papillomavirus vaccination status.

Screening Tests

• Pap smear (cervical cytology): A sample of cervical cells is examined under a microscope for abnormalities. Sensitive to moderate and severe changes but misses some early abnormalities on its own.
• Human papillomavirus test: Detects the DNA of high-risk human papillomavirus types in cervical cells. More sensitive than cytology alone for identifying women at risk. Can be done from the same sample as the Pap smear.
• Co-test (Pap + human papillomavirus): The combination provides the highest sensitivity and is the preferred option for women ages 30–65.

Current Guidelines (USPSTF / ASCCP 2018–2019)

• Ages 21–29: Pap smear alone every 3 years (human papillomavirus testing not recommended in this age group because transient human papillomavirus infections are very common and self-resolve)
• Ages 30–65: Co-test (Pap + human papillomavirus) every 5 years (preferred), OR Pap smear alone every 3 years, OR human papillomavirus test alone every 5 years
• Over 65: Screening can stop after adequate recent normal results and no history of high-grade precancers
• Hysterectomy with cervix removal: Routine screening not needed if no history of high-grade precancer or cervical cancer

Understanding Abnormal Results

Abnormal Pap or positive human papillomavirus results lead to further evaluation, most often with colposcopy — a magnified examination of the cervix — and biopsy if needed. Biopsies are graded using the CIN system:

• CIN 1 (mild dysplasia): often clears on its own; usually managed with observation
• CIN 2 (moderate dysplasia): often treated, especially in women over 25; some regress spontaneously
• CIN 3 / CIS (severe dysplasia / carcinoma in situ): always treated to prevent cancer

The most common treatment for CIN 2–3 is LEEP (loop electrosurgical excision procedure), which removes the abnormal tissue with a thin wire loop. It is highly effective and usually done as an outpatient procedure.

Gardasil-9 Vaccine

Vaccination is the most powerful tool available for human papillomavirus prevention. The Gardasil-9 (9vHPV) vaccine protects against nine human papillomavirus types: the two that cause most genital warts (6 and 11) and seven high-risk types that cause most human papillomavirus-related cancers (16, 18, 31, 33, 45, 52, and 58). Together, these nine types account for approximately 90% of all human papillomavirus-related cancers and nearly all genital warts.

Who Should Get Vaccinated

• Routine vaccination: All preteens at age 11–12 (can be given as early as age 9)
• Catch-up vaccination: Recommended for everyone through age 26 who was not previously vaccinated
• Ages 27–45: Shared clinical decision-making with your doctor (U.S. Food and Drug Administration-approved in 2018, but benefit is lower because most adults have already been exposed to some human papillomavirus types)

Dosing Schedule

• 2-dose series (0 and 6–12 months apart): for those who start the series before age 15 and are not immunocompromised
• 3-dose series (0, 1–2 months, 6 months): for those who start at age 15 or older, or who are immunocompromised

How Effective Is It?

In clinical trials, Gardasil-9 was over 90–95% effective at preventing infection with the human papillomavirus types it covers when given to people before exposure. In per-protocol analyses (people who received all doses and had no prior human papillomavirus exposure), the vaccine showed near-100% efficacy against CIN 2/3 (precancerous cervical lesions) and genital warts caused by vaccine types.

Safety

Gardasil-9 has an excellent safety record. Post-marketing surveillance has now covered more than 270 million doses delivered worldwide. The most common side effects are mild: pain, redness, or swelling at the injection site. Syncope (fainting) can occur shortly after any injection — clinics ask patients to sit for 15 minutes afterward as a precaution. Large-scale studies have found no increased risk of serious adverse events compared to control groups.

Why Vaccinating Boys and Men Matters

Human papillomavirus vaccination is gender-neutral — males benefit directly (prevention of genital warts, anal and oropharyngeal cancers, and penile cancer) and indirectly (reducing transmission to partners). Vaccinating both sexes maximizes herd immunity and has the greatest population-level impact on reducing human papillomavirus-related cancers.

Oropharyngeal and Anal Human Papillomavirus

While cervical cancer is the best-known human papillomavirus-related malignancy, two other cancer sites deserve attention because their rates are rising — often in people who are unaware of their risk.

Oropharyngeal Cancer

Human papillomavirus 16 is now the most common cause of oropharyngeal squamous cell carcinoma (OPSCC) in the United States — cancers of the base of the tongue, tonsils, and soft palate. This represents a dramatic epidemiological shift: while tobacco-related head and neck cancers have been declining, human papillomavirus-related OPSCC rates have risen sharply over the past 30 years, particularly in middle-aged men. Human papillomavirus-positive oropharyngeal cancers tend to respond better to treatment and have a better prognosis than tobacco-related head and neck cancers, though they are still serious diagnoses requiring intensive therapy.

There is currently no approved screening program for oropharyngeal human papillomavirus (unlike cervical cancer). Early symptoms — persistent sore throat, difficulty swallowing, a lump in the neck, or ear pain — should prompt medical evaluation.

Anal Cancer

Anal cancer rates have been rising steadily, with the sharpest increases in human immunodeficiency virus-positive men who have sex with men (MSM), among whom anal human papillomavirus infection is highly prevalent. Human papillomavirus 16 accounts for the majority of anal cancers. An anal Pap smear (anal cytology) and human papillomavirus testing are increasingly used in high-risk populations (MSM and people living with human immunodeficiency virus, HIV) to detect precancerous anal changes, though no universally accepted screening guideline has been established. Referral for high-resolution anoscopy is used when abnormalities are detected.

Natural History and Clearance

Perhaps the most reassuring fact about human papillomavirus is how effectively the immune system deals with it. Approximately 90% of human papillomavirus infections clear within 1–2 years through the normal workings of the immune system. Many people will never know they were infected. The body generates robust T-cell and antibody responses against the virus, and for most people this is more than sufficient to eliminate it completely.

It is persistent infection — when a high-risk human papillomavirus type is still detectable after two or more years — that carries cancer risk. Even then, progression to invasive cancer is not inevitable and typically takes another decade or more. This slow timeline is precisely why cervical screening programs are so effective: there is a long window during which precancerous changes can be detected and treated before cancer ever develops.

Risk Factors for Persistence

• Older age at infection — immune responses tend to be less vigorous
• Immunosuppression — human immunodeficiency virus infection, organ transplantation, or immunosuppressive medications significantly impair human papillomavirus clearance and increase cancer risk
• Smoking — cigarette smoke compounds cervical cancer risk by both impairing local immune defenses and acting as a direct carcinogen on cervical tissue
• Hormonal factors — long-term oral contraceptive use has been associated with a modest increase in cervical cancer risk (the mechanism is not fully understood)
• Co-infections — other sexually transmitted infections may alter the local immune environment

Diagnosis and Testing

Human papillomavirus diagnosis works quite differently from most other infections because the virus cannot be cultured in a standard laboratory and there is no useful blood test to detect it.

• For women (cervical human papillomavirus): The approved human papillomavirus test detects high-risk HPV DNA from cervical cells, collected during a pelvic exam — the same swab used for a Pap smear. It identifies whether high-risk human papillomavirus is present but does not identify which specific type (except that some tests separately report human papillomavirus 16 and 18).
• For men: There is no U.S. Food and Drug Administration-approved human papillomavirus test for men in clinical practice. In research settings, penile, scrotal, and anal swabs can detect HPV DNA, but these are not routinely used.
• Genital warts: Diagnosed by visual examination by a clinician. No test is typically needed for classic-appearing warts.
• Uncertain lesions: Biopsy (tissue sample examined by a pathologist) is used to confirm the diagnosis and rule out cancer in ambiguous cases.
• No blood test: Antibody tests for human papillomavirus exist in research settings but are not clinically useful because prior infection does not reliably confer immunity, and a positive antibody test cannot distinguish between past cleared infection and active infection.

Treatment of Human Papillomavirus-related Conditions

There is currently no antiviral medication that eliminates human papillomavirus itself from the body. Treatment focuses on managing the conditions that human papillomavirus causes — warts, precancerous changes, and cancers.

Genital Warts

• Patient-applied treatments: Imiquimod cream 3.75% or 5% (stimulates local immune response; applied 3 times weekly for several weeks), podophyllotoxin 0.5% solution or gel (applied twice daily for 3 days, then 4 days off, repeated for up to 4 cycles)
• Provider-applied treatments: Trichloroacetic acid (TCA) — applied directly to warts in the clinic; cryotherapy (liquid nitrogen freezing); surgical excision or electrosurgery for large/refractory warts
• Important caveat: All treatments remove visible warts but do not eradicate the virus from surrounding skin. Recurrence rates are 20–30% within 3 months regardless of treatment method. Partners should be examined.

Precancerous Cervical Lesions (HSIL / CIN 2–3)

• LEEP (loop electrosurgical excision procedure): The most common treatment; removes the transformation zone (where most abnormal cells develop) using a thin electrified wire loop under local anesthesia; highly effective (cure rate ~90–95%)
• Cold knife conization: Surgical removal of a cone-shaped piece of cervix; used for larger lesions or when margins need to be assessed histologically
• Cryotherapy: Freezing of the cervical transformation zone; used for lower-grade lesions (CIN 2) when the entire lesion is visible
• After treatment: close follow-up with co-testing at 6 months, then annually for several years, is essential because treated women remain at elevated risk compared to the general population

Cervical Cancer

Invasive cervical cancer is treated with standard oncologic approaches: surgery (hysterectomy ± lymph node dissection for early-stage disease), radiation therapy (often with concurrent chemotherapy — cisplatin-based chemoradiation for locally advanced disease), and immunotherapy (pembrolizumab has been U.S. Food and Drug Administration-approved for recurrent/metastatic cervical cancer with PD-L1 expression).

RRP (Recurrent Respiratory Papillomatosis)

Repeated surgical removal (microlaryngoscopy with microdebrider or laser) is the primary approach. Adjunct therapies including intralesional cidofovir injections and anti-VEGF therapy (bevacizumab) are used in severe cases to slow regrowth. There is no cure; management is lifelong for severe cases.

Key Research Papers

1. Garland SM et al. (2007) — Quadrivalent HPV vaccine efficacy in women (FUTURE I trial). N Engl J Med 356:1928–43. — PubMed PMID: 17494926
2. FUTURE II Study Group (2007) — Quadrivalent HPV vaccine to prevent high-grade cervical lesions. N Engl J Med 356:1915–27. — PubMed PMID: 17494925
3. Search PubMed
4. Search PubMed
5. Search PubMed
6. Search PubMed
7. PubMed: HPV cervical cancer screening and ASCCP guidelines
8. PubMed: HPV oropharyngeal cancer incidence and epidemiology
9. PubMed: HPV anal cancer HIV MSM screening
10. PubMed: HPV immune clearance and persistence natural history
11. PubMed: Gardasil-9 (9vHPV) vaccine efficacy and safety
12. PubMed: HPV E6 E7 p53 Rb carcinogenesis mechanism

Back to Table of Contents

PubMed Research

1. Human papillomavirus epidemiology and prevalence in the United States
2. Human papillomavirus vaccine adolescent immunogenicity
3. Human papillomavirus cervical cancer LEEP treatment outcomes
4. Human papillomavirus genital warts treatment and recurrence
5. Human papillomavirus oropharyngeal squamous cell carcinoma prognosis
6. Human papillomavirus cervical intraepithelial neoplasia CIN regression
7. Human papillomavirus smoking risk factor cervical cancer
8. Human papillomavirus immunosuppression human immunodeficiency virus cancer risk
9. Recurrent respiratory papillomatosis human papillomavirus treatment
10. Human papillomavirus anal cytology and high-resolution anoscopy
11. Human papillomavirus vaccination herd immunity population effect
12. Human papillomavirus in low- and middle-income countries cervical cancer burden

Connections

• Infectious Disease
• Chlamydia
• Gonorrhea
• Syphilis
• Herpes Simplex
• Human Immunodeficiency Virus / Acquired Immunodeficiency Syndrome
• Cervical Cancer
• Infertility
• All Conditions
• Lab Tests

Back to Table of Contents

Featured Videos