What is Human Papillomavirus (HPV). How does HPV infection lead to cervical cancer. What are the risk factors for HPV persistence and cervical cancer development. How can we reduce the global burden of cervical cancer. What comprehensive approach is recommended for cervical cancer control.

Understanding Human Papillomavirus (HPV): The Most Common Reproductive Tract Infection

Human Papillomavirus, commonly known as HPV, is a widespread viral infection that primarily affects the reproductive tract. Its prevalence is so high that most sexually active individuals will encounter it at some point in their lives, with some experiencing repeated infections. The virus is particularly common among those who have recently become sexually active.

Transmission of HPV doesn’t necessarily require penetrative sex. Skin-to-skin genital contact is a well-established mode of transmission, making it easier for the virus to spread. While there are numerous types of HPV, not all cause health problems. In fact, most HPV infections clear up on their own within a few months, and about 90% resolve within two years without any intervention.

Types of HPV and Their Effects

HPV types can be broadly categorized into two groups:

• Cancer-causing types (high-risk HPV)
• Non-cancer causing types (low-risk HPV)

High-risk HPV types, when persistent, can lead to various cancers, with cervical cancer being the most common HPV-related disease. Other cancers associated with high-risk HPV include those of the anus, vulva, vagina, penis, and oropharynx.

Low-risk HPV types, particularly types 6 and 11, are responsible for genital warts and respiratory papillomatosis. While these conditions rarely result in death, they can significantly impact quality of life and sexual health.

The Connection Between HPV and Cervical Cancer: A Closer Look

Nearly all cases of cervical cancer can be attributed to HPV infection. But how exactly does this virus lead to such a serious condition? The progression from HPV infection to cervical cancer is a gradual process that typically spans 15 to 20 years in women with normal immune systems. However, for those with weakened immune systems, such as individuals with untreated HIV, this process can accelerate, taking only 5 to 10 years.

The Progression from HPV Infection to Cervical Cancer

1. Initial HPV infection
2. Persistent infection
3. Development of pre-cancerous lesions
4. Progression to invasive cervical cancer

It’s important to note that while most HPV infections clear up on their own and many pre-cancerous lesions resolve spontaneously, there’s always a risk that the infection may become chronic and pre-cancerous lesions may progress to invasive cervical cancer.

Risk Factors for HPV Persistence and Cervical Cancer Development

Several factors contribute to the persistence of HPV infection and the subsequent development of cervical cancer. Understanding these risk factors is crucial for effective prevention and early intervention strategies.

Key Risk Factors

• HPV type: The oncogenicity, or cancer-causing strength, of the HPV type plays a significant role.
• Immune status: Immunocompromised individuals, such as those living with HIV, are more susceptible to persistent HPV infections and rapid progression to pre-cancer and cancer.
• Coinfection with other sexually transmitted infections: Presence of infections like herpes simplex, chlamydia, and gonorrhea can increase the risk.
• Parity and age at first birth: The number of children born and giving birth at a young age are associated factors.
• Tobacco smoking: This habit has been linked to an increased risk of HPV persistence and cervical cancer development.

Are certain HPV types more dangerous than others? Indeed, high-risk HPV types, particularly HPV 16 and 18, are responsible for the majority of cervical cancer cases. These types have a higher oncogenic potential, meaning they’re more likely to cause the cellular changes that lead to cancer.

The Global Burden of Cervical Cancer: A Significant Public Health Concern

Cervical cancer represents a significant global health challenge, particularly in low and middle-income countries. As the fourth most frequent cancer in women worldwide, it has a substantial impact on women’s health and mortality rates.

Key Statistics

• An estimated 570,000 new cases of cervical cancer were reported in 2018, representing 7.5% of all female cancer deaths.
• More than 311,000 deaths from cervical cancer occur annually, with over 85% of these deaths happening in low and middle-income countries.
• Women living with HIV are six times more likely to develop cervical cancer compared to women without HIV.
• Approximately 5% of all cervical cancer cases are attributable to HIV.

Why is the burden of cervical cancer higher in low and middle-income countries? The disparity is largely due to limited access to preventive measures such as HPV vaccination and regular screening. In high-income countries, these preventive strategies allow for early detection and treatment of pre-cancerous lesions. However, in resource-limited settings, cervical cancer is often not identified until it has advanced, and access to treatment for late-stage disease is often limited.

Cervical Cancer Control: A Comprehensive Life-Course Approach

In 2020, the World Health Assembly adopted the Global Strategy towards eliminating cervical cancer as a public health problem. This strategy recommends a comprehensive approach to cervical cancer prevention and control, encompassing interventions across the life course.

The Three Pillars of Cervical Cancer Control

1. Primary Prevention
2. Secondary Prevention
3. Tertiary Prevention

How can we effectively implement these prevention strategies? Let’s break down each pillar:

Primary Prevention

Primary prevention focuses on preventing HPV infection and reducing risk factors. Key interventions include:

• HPV vaccination for girls aged 9-14 years
• Health information and warnings about tobacco use
• Age-appropriate sex education
• Promotion and provision of condoms for those engaged in sexual activity
• Male circumcision

Secondary Prevention

Secondary prevention aims to detect and treat pre-cancerous lesions before they progress to cancer. This involves:

• Screening women 30 years and older with a high-performance test (equivalent to or better than an HPV test)
• Immediate treatment or prompt referral for treatment of detected pre-cancerous lesions

Tertiary Prevention

Tertiary prevention focuses on treating invasive cervical cancer and providing palliative care. This includes:

• Surgery
• Radiotherapy
• Chemotherapy
• Palliative care for advanced cases

The Role of HPV Vaccination in Cervical Cancer Prevention

HPV vaccination plays a crucial role in the primary prevention of cervical cancer. By targeting the most common high-risk HPV types, these vaccines can significantly reduce the incidence of HPV infections and, consequently, the risk of cervical cancer.

Key Facts About HPV Vaccination

• HPV vaccines are most effective when administered before exposure to the virus, ideally before the onset of sexual activity.
• The World Health Organization recommends vaccinating girls aged 9-14 years, as this is the most cost-effective public health measure against cervical cancer.
• Some countries have also included boys in their vaccination programs to prevent other HPV-related cancers and diseases.
• Current HPV vaccines protect against the two most common high-risk types (HPV 16 and 18), which cause approximately 70% of cervical cancers.

How effective are HPV vaccines in preventing cervical cancer? Studies have shown that HPV vaccines are highly effective in preventing infection with the targeted HPV types and the development of cervical precancers. When administered to young adolescents before exposure to HPV, the vaccines can prevent over 90% of HPV-related cancers.

Screening and Early Detection: Crucial Components in Cervical Cancer Control

Regular screening is a vital tool in the early detection and prevention of cervical cancer. By identifying pre-cancerous lesions before they progress to invasive cancer, screening programs can significantly reduce cervical cancer incidence and mortality.

Screening Methods

Several screening methods are available for cervical cancer detection:

• HPV DNA testing: Detects the presence of high-risk HPV types
• Pap smear (cytology): Examines cervical cells for abnormalities
• Visual inspection with acetic acid (VIA): A simple, low-cost method suitable for low-resource settings

What is the recommended screening frequency? The World Health Organization recommends that every woman aged 30-49 years should be screened at least once in their lifetime, and ideally more frequently. However, specific recommendations may vary based on resources and risk factors.

The Importance of Follow-up and Treatment

Screening alone is not sufficient; appropriate follow-up and treatment of detected abnormalities are crucial. This includes:

• Immediate treatment of pre-cancerous lesions when possible (screen-and-treat approach)
• Referral for further diagnostic tests and treatment when necessary
• Ensuring women with positive screening results receive timely and appropriate care

Addressing Disparities in Cervical Cancer Burden: A Global Health Priority

The disproportionate burden of cervical cancer in low and middle-income countries highlights the need for targeted interventions and global cooperation. Addressing these disparities is crucial for achieving global health equity and reducing the overall impact of cervical cancer.

Key Challenges in Low-Resource Settings

• Limited access to HPV vaccination
• Inadequate screening programs
• Lack of awareness about cervical cancer and its prevention
• Insufficient healthcare infrastructure for diagnosis and treatment
• Financial barriers to accessing care

How can we address these disparities? A multi-faceted approach is necessary:

1. Increasing access to HPV vaccination through global initiatives and partnerships
2. Implementing cost-effective screening programs tailored to local contexts
3. Raising awareness about cervical cancer and the importance of prevention
4. Strengthening healthcare systems to improve diagnosis and treatment capabilities
5. Addressing socioeconomic barriers to healthcare access

International collaboration and support are essential in helping low-resource countries implement comprehensive cervical cancer control programs. This includes technology transfer, capacity building, and financial assistance to ensure sustainable and effective interventions.

Human papillomavirus (HPV) and cervical cancer

What is HPV?

Human papillomavirus (HPV) is the most common viral infection of the reproductive tract. Most sexually active women and men will be infected at some point in their lives and some may be repeatedly infected.

The peak time for acquiring infection for both women and men is shortly after becoming sexually active. HPV is sexually transmitted, but penetrative sex is not required for transmission. Skin-to-skin genital contact is a well-recognized mode of transmission.

There are many types of HPV, and many do not cause problems. HPV infections usually clear up without any intervention within a few months after acquisition, and about 90% clear within 2 years. A small proportion of infections with certain types of HPV
can persist and progress to cervical cancer.

Cervical cancer is by far the most common HPV-related disease. Nearly all cases of cervical cancer can be attributable to HPV infection.

The infection with certain HPV types also causes a proportion of  cancers of the anus, vulva, vagina, penis and oropharynx, which are preventable using similar primary prevention strategies as those for cervical cancer.

Non-cancer causing types of HPV (especially types 6 and 11) can cause genital warts and respiratory papillomatosis (a disease in which tumours grow in the air passages leading from the nose and mouth into the lungs). Although these conditions very rarely
result in death, they may cause significant occurrence of disease. Genital warts are very common, highly infectious and affect sexual life.

How HPV infection leads to cervical cancer

Although most HPV infections clear up on their own and most pre-cancerous lesions resolve spontaneously, there is a risk for all women that HPV infection may become chronic and pre-cancerous lesions progress to invasive cervical cancer.

It takes 15 to 20 years for cervical cancer to develop in women with normal immune systems. It can take only 5 to 10 years in women with weakened immune systems, such as those with untreated HIV infection.

Risk factors for HPV persistence and development of cervical cancer

• HPV type – its oncogenicity or cancer-causing strength;
• immune status – people who are immunocompromised, such as those living with HIV, are more likely to have persistent HPV infections and a more rapid progression to pre-cancer and cancer;
• coinfection with other sexually transmitted agents, such as those that cause herpes simplex, chlamydia and gonorrhoea;
• parity (number of babies born) and young age at first birth;
• tobacco smoking 

Global burden of cervical cancer

Worldwide, cervical cancer is the fourth most frequent cancer in women with an estimated 570 000 new cases in 2018 representing 7.5% of all female cancer deaths. Of the estimated more than 311 000 deaths from cervical cancer every year, more than 85%
of these occur in low and middle income countries. Women living with HIV are six times more likely to get cervical cancer compared to women without HIV, and an estimated 5% of all cervical cancer cases are attributable to HIV (2).

In high income countries, programmes are in place which enable girls to be vaccinated against HPV and women to get screened regularly. Screening allows pre-cancerous lesions to be identified at stages when they can easily be treated. 

In low and middle income countries, there is limited access to these preventative measures and cervical cancer is often not identified until it has further advanced and symptoms develop. In addition, access to treatment of such late-stage disease (for
example, cancer surgery, radiotherapy and chemotherapy) may be very limited, resulting in a higher rate of death from cervical cancer in these countries.

The high mortality rate from cervical cancer globally (Age Standardized Rate: 6.9/100,000 in 2018) could be reduced by effective interventions.

Cervical cancer control: A comprehensive approach

The Global strategy towards eliminating cervical cancer as a public health problem adopted by the WHA in 2020, recommends a comprehensive approach to cervical cancer prevention and control. The recommended set of actions includes interventions across
the life course.

The life-course approach to cervical cancer interventions

It should be multidisciplinary, including components from community education, social mobilization, vaccination, screening, treatment and palliative care.

Primary prevention begins with HPV vaccination of girls aged 9-14 years, before they become sexually active. 

Women who are sexually active should be screened for abnormal cervical cells and pre-cancerous lesions, starting from 30 years of age in the general population of women. Screening for sexually active women living with HIV should start at an earlier age,
once they have tested positive for HIV. 

If treatment of pre-cancer is needed to excise abnormal cells or lesions, cryotherapy or thermal ablation both destroy abnormal tissue on the cervix) is recommended and is performed in outpatient clinic.

If signs of cervical cancer are present, treatment options for invasive cancer include surgery, radiotherapy and chemotherapy and patients need to be referred to the right level of services.

HPV vaccination

There are currently 3 vaccines that have been prequalified, all protecting against both HPV 16 and 18, which are known to cause at least 70% of cervical cancers. The third vaccine protects against five additional oncogenic HPV types, which cause a further
20% of cervical cancers. Given that the vaccines which are only protecting against HPV 16 and 18 also have some cross-protection against these other less common HPV types which cause cervical cancer, WHO considers the three vaccines equally protective
against cervical cancer. Two of the vaccines also protect against HPV types 6 and 11, which cause anogenital warts.

Clinical trials and post-marketing surveillance have shown that HPV vaccines are very safe and very effective in preventing infections with HPV infections, high grade precancerous lesions and invasive cancer (3). 

HPV vaccines work best if administered prior to exposure to HPV. Therefore, WHO recommends to vaccinate girls, aged between 9 and 14 years, when most have not started sexual activity. The vaccines cannot treat HPV infection or HPV-associated disease,
such as cancer.

Some countries have started to vaccinate boys as the vaccination prevents genital cancers in males as well as females, and two available vaccines also prevent genital warts in males and females.

WHO recommends vaccination for girls aged between 9 and 14 years, as this is the most cost- effective public health measure against cervical cancer 

HPV vaccination does not replace cervical cancer screening. In countries where HPV vaccine is introduced, screening programmes may still need to be developed or strengthened.

Screening and treatment of pre-cancer lesions

Cervical cancer screening involves testing for pre-cancer and cancer, more and more testing for HPV infection is performed.  Testing is done among women who have no symptoms and may feel perfectly healthy. When screening detects an HPV infection
or pre-cancerous lesions, these can easily be treated, and cancer can be avoided. Screening can also detect cancer at an early stage and treatment has a high potential for cure. 

Because pre-cancerous lesions take many years to develop, screening is recommended for every woman from aged 30 and regularly afterwards (frequency depends on the screening test used). For women living with HIV who are sexually active, screening should
be done earlier, as soon as they know their HIV status. 

Screening has to be linked to treatment and management of positive screening tests. Screening without proper management in place is not ethical.

There are 3 different types of screening tests that are currently recommended by WHO:

• HPV DNA testing for high-risk HPV types
• Visual inspection with Acetic Acid (VIA)
• conventional (Pap) test and liquid-based cytology (LBC) 

For treatment of pre-cancer lesions, WHO recommends the use of cryotherapy or thermal ablation and Loop Electrosurgical Excision Procedure (LEEP) when available. For advanced lesions, women should be referred for further investigations and adequate management.

Management of invasive cervical cancer

When a woman presents symptoms of suspicion for cervical cancer, she must be referred to an appropriate facility for further evaluation, diagnosis and treatment.

Symptoms of early stage cervical cancer may include:

• Irregular blood spotting or light bleeding between periods in women of reproductive age;
• Postmenopausal spotting or bleeding;
• Bleeding after sexual intercourse; and
• Increased vaginal discharge, sometimes foul smelling.

As cervical cancer advances, more severe symptoms may appear including:

• Persistent back, leg and/or pelvic pain;
• Weight loss, fatigue, loss of appetite;
• Foul-smell discharge and vaginal discomfort; and
• Swelling of a leg or both lower extremities.

Other severe symptoms may arise at advanced stages depending on which organs cancer has spread.

Diagnosis of cervical cancer must be made by histopathologic examination. Staging is done based on tumor size and spread of the disease within the pelvis and to distant organs. Treatment depends on the stage of the disease and options include surgery,
radiotherapy and chemotherapy. Palliative care is also an essential element of cancer management to relieve unnecessary pain and suffering due the disease.

WHO response

The World Health Assembly adopted the global strategy to accelerate the elimination of cervical cancer as a public health problem and its associated goals and targets for the period 2020–2030 (WHA 73.2) (4).  The global strategy to
eliminate cervical cancer has set targets to accelerate the elimination: 

• a threshold of 4 per 100,000 women-year for elimination as a public health problem
• 90–70–90 targets that need to be met by 2030 for countries to be on the path towards cervical cancer elimination
• 90% of girls fully vaccinated with the HPV vaccine by age 15.
• 70% of women are screened with a high-performance test by 35, and again by 45 years of age.
• 90% of women identified with cervical disease receive treatment (90% of women with pre-cancer treated; 90% of women with invasive cancer managed).

WHO has developed guidance and tools on how to prevent and control cervical cancer through vaccination, screening and management of invasive cancer and a knowledge repository will make them available through a single point. WHO works with countries and
partners to develop and implement comprehensive programmes in line w the global strategy.

References

(1) Ferlay J, Ervik M, Lam F, Colombet M, Mery L, Piñeros M, Znaor A, Soerjomataram I, Bray F (2018). Global Cancer Observatory: Cancer Today. Lyon, France: International Agency for Research on Cancer. Available from: https://gco.iarc.fr/today

(2) Stelzle D, Tanaka LF, Lee KK, et al. Estimates of the global burden of cervical cancer associated with HIV. Lancet Glob Health 2020; published online Nov 16. DOI:S2214-109X(20)30459-9 
https://www.thelancet.com/journals/langlo/article/PIIS2214-109X(20)30459-9/fulltext 

(3) Lei et al. (2020)  HPV Vaccination and the Risk of Invasive Cervical Cancer.   N Engl J Med 2020;383:1340-8. DOI: 10.1056/NEJMoa1917338

(4) World Health Organization. Global strategy to accelerate the elimination of cervical cancer as a public health problem https://www.who.int/publications/i/item/9789240014107

What Are HPV 16 and 18?

About 40 of the 150 or so types of HPV can infect the genital regions and other mucous membranes (such as the mouth and throat), but only a portion of these can cause cancer.

In most people, HPV infections are transient, since the infected cells are shed from the body naturally. In a minority of people, though, the HPV persists, and if the persistent HPV is type 16 or 18, there is a marked increase in the risk of developing genital, anal, or oral cancer (depending on where the infection is located).

But even in people whose HPV persists, the time from infection with a high-risk HPV type to the development of cancer is generally measured in years.

For women, such slow growth allows precancerous changes in the cervical cells, called dysplasia, to be found on screening Pap tests or, more recently, HPV tests that look for high-risk types of HPV in the cells of the cervix.

No screening tests exist for HPV-related cancers in other areas of the body.

HPV Is Common, Yet Commonly Misunderstood

HPV has been estimated to infect more than 90 percent of the U.S. population, with about 12,000 Americans ages 15 to 24 being infected daily. It’s the most commonly diagnosed sexually transmitted disease (STD) in the United States and abroad.

HPV also causes common skin warts, which are not considered STDs.

In spite of its ubiquity, though, HPV is widely misunderstood.

“The most common misconception that my patients have when they get a positive test for high-risk HPV is that this is an STD similar to chlamydia or herpes,” says Jane Oh, MD, an ob-gyn (obstetrician-gynecologist) in Arlington Heights, Illinois.

While HPV is sexually transmitted, Dr. Oh says almost everyone who has had sex will have HPV at some time or another.

“The only people who won’t have HPV are those who have never had sexual contact with anyone or someone who has had sexual contact with one partner who also has never had sexual contact with anyone else,” adds Oh.

How Will I Know if I Have HPV?

Even though HPV is common, many women will never know they’ve contracted it, since HPV-infected cells are often shed from the cervix with no intervention.

This is particularly true in women under 30 years old.

“Many times, when women acquire HPV at a young age, there is a high clearance rate, and they tend to clear it on their own without any need for procedures like colposcopies, which we used to perform a lot in the early 2000s,” said Salena Zanotti, MD, an ob-gyn at the Cleveland Clinic in Avon, Ohio. “This is because our immune systems are definitely more active the younger we are.”

A colposcopy is a procedure in which a magnifying instrument and bright light are used to examine the cervix.

Because of this, the Centers for Disease Control and Prevention (CDC) and the American College of Obstetricians and Gynecologists recommend that if a woman has a history of normal Pap smears and doesn’t have certain risk factors, such as a compromised immune system, she should have a Pap smear and HPV test together every five years from 30 years old until age 65.

Zanotti says the only time she runs an HPV test on someone in their twenties is if they’ve had a Pap smear come back with abnormal results.

“To help triage that reading, we do the HPV test,” said Zanotti.

While Oh agrees that women in their twenties need not be tested for HPV, she screens her patients at least every three years from age 30 onward.

“In my practice, I have seen women have negative HPV one year and positive the next. A lot can happen in five years, so I don’t space out testing this far,” Oh says.

What if I Test Positive for HPV 16 or 18?

Testing positive for HPV types 16 or 18 doesn’t guarantee you’ll develop cervical cancer, but it does mean that any dysplasia found in a Pap test carries a higher risk of becoming a cancer.

Based on the results of these two tests, your doctor can develop a plan to either treat the dysplasia, do more testing to rule out cancer, or recommend more frequent follow-up visits to look for additional changes.

“Paps of the cervix have been tested for a long time, and we know the changes HPV causes in the cervix,” notes Zanotti.

If you get diagnosed with HPV, and everything else tests okay, then most likely the HPV will clear on its own within one to two years, if you don’t have a suppressed immune system.

What About Screening for Anal HPV?

If you’re concerned about HPV in the anus, Oh adds that HPV doesn’t cause the same changes in the anus as it does in the cervix, so a Pap smear is not going to be an effective test to perform.

Your doctor may refer you to someone who performs anal Pap smears, anoscopies, or high-resolution anoscopies, which use a high-resolution magnifying instrument to identify abnormal cells.

Rise in HPV 16–Related Throat Cancer

For years, heavy tobacco and alcohol use were the primary risk factors for developing cancer of the oropharynx — the back of the throat, including the base of the tongue and the tonsils.

Today, HPV is the primary cause of oropharyngeal cancer around the world.

In the United States, HPV is thought to cause 70 percent of all oropharyngeal cancers, with HPV 16 causing 60 percent of all oropharyngeal cancers, according to the CDC. (1)

Both oral HPV infection and HPV-related oropharyngeal cancer are much more common among men than women.

In addition, oral HPV 16 infection is six times more common in men than women ages 18 to 69, according to a report published in November 17 in Annals of Internal Medicine. (2)

The report additionally found the following:

• The overall prevalence of oral HPV infection was 11.5 percent in men and 3.2 percent in women.
• High-risk oral HPV infection was more prevalent among men than women, 7.3 percent compared with 1.8 percent.
• Among men who reported having two or more same-sex oral sex partners, the prevalence of high-risk HPV infection was 22.2 percent.
• Oral HPV prevalence among men who also had genital HPV infection was fourfold greater (19. 3 percent) than among those without genital HPV (4.4 percent).

The good news is that oropharyngeal cancer caused by HPV has a much higher five-year survival rate after treatment than head and neck cancers not associated with HPV. (3)

RELATED: 5 Things to Know About HPV-Related Throat Cancer

Does the HPV Vaccine Protect Against Types 16 and 18?

The HPV vaccine, Gardasil 9, protects against both types 16 and 18, as well as several other cancer-causing types of the virus and the two main causes of genital warts.

The CDC recommends that all boys and girls get the HPV vaccine at age 11 or 12. However, it can be given through age 26 in women and through age 21 in men.

The CDC additionally recommends the vaccine for any man who has sex with men, and men with compromised or weakened immune systems — including from HIV — through age 26.

Zanotti notes that some parents are hesitant to give their child the HPV vaccine because HPV is associated with sexual activity.

“I tell my patients, ‘If you vaccinated your child against measles, mumps, and rubella, they’re more likely to get HPV than they are to get rubella these days, and HPV is something that causes cancer. It’s pretty clear cut: If you can do something to prevent the cancer, why wouldn’t you?” she says.

Zanotti adds that while more parents are getting their sons vaccinated, it is still not as common as vaccinations in girls. “But if in the next 10 years, boys get the vaccine as often, we will see the amount of HPV going down significantly,” she says.

Still, Oh cautions that the HPV vaccine doesn’t do away with the need for safer sexual practices.

“Everyone needs to know that the HPV vaccine is not a foolproof method of preventing all cervical cancer,” she says. “We still need to protect ourselves: Use condoms, limit partners, support our immune systems, and get those Pap smears to prevent cervical cancer.”

HPV and Cancer

What is HPV?

HPV is short for human papillomavirus. HPVs are a large group of related viruses. Each virus in the group is given a number, which is called an HPV type.

Most HPV types cause warts on the skin, such as on the arms, chest, hands, or feet. Other types are found mainly on the body’s mucous membranes. Mucous membranes are the moist surface layers that line organs and parts of the body that open to the outside, such as the vagina, anus, mouth, and throat. The HPV types found on mucous membranes are sometimes called genital HPV. They generally do not live on the skin.

Genital HPV is not the same as HIV or herpes. HPV is divided into 2 main groups:

Low-risk HPV types

Some types of HPV can cause warts (papillomas) on or around the genitals and anus of both men and women. Women may also have warts on the cervix and in the vagina. Because these HPV types rarely cause cancer, they are called “low-risk” viruses.

High-risk HPV types

Other types of HPV are called “high-risk” because they can cause cancer in both men and women. Doctors worry more about the cell changes and pre-cancers linked to these types, because they’re more likely to grow into cancers over time. Common high-risk HPV types include HPV 16 and 18.

Infection with HPV is very common. In most people, the body is able to clear the infection on its own. But sometimes, the infection doesn’t go away. Chronic, or long-lasting infection, especially when it’s caused by certain high-risk HPV types, can cause cancer over time.

How do people get HPV?

HPV can be passed from one person to another by skin-to-skin contact, such as occurs with sexual activity. The main way HPV is spread is through sexual activity, including vaginal, anal, and oral sex. HPV can be spread even when an infected person has no visible signs or symptoms.

The virus can also be spread by genital contact without sex, although this is not common.

HPV infection is very common. Most men and women who have ever had sex get at least one type of genital HPV at some time in their lives.
Anyone who has had sex can get HPV, even if it was only with only one person, but infections are more likely in people who have had many sex partners.  Even if a person delays sexual activity until marriage, or only has one partner, they are still at risk of HPV infection if their partner has been exposed.

You cannot get HPV from:

• Toilet seats
• Hugging or holding hands
• Swimming pools or hot tubs
• Sharing food or utensils
• Being unclean

You can have HPV:

• Even if it has been years since you were sexually active
• Even if you do not have any signs or symptoms

Cancers linked to HPV infection

To learn more about any of the cancers listed here, visit our website at www.cancer.org or call our toll-free number, 1-800-227-2345.

Cervical cancer

Cervical cancer is the most common cancer linked to HPV in people with a cervix. Nearly all cervical cancers are caused by HPV.

Cervical cancer can be found early and even prevented with routine screening tests. The Pap test looks for changes in cervical cells caused by HPV infection. The HPV test looks for the infection itself.

Cervical cancer is preventable with vaccines and regular screening tests. More than half of the people in the United States who get cervical cancer have never had or rarely had screening tests.

Vulvar cancer

HPV can also cause cancer of the vulva, which is the outer part of the female genital organs. This cancer is much less common than cervical cancer.

There’s no standard screening test for this cancer other than routine physical exams.

Vaginal cancer

Most vaginal cancers contain HPV.

Many vaginal pre-cancers also contain HPV, and these changes may be present for years before turning into cancer. These pre-cancers can sometimes be found with the same Pap test that’s used to test for cervical cancer and pre-cancer. If a pre-cancer is found, it can be treated, stopping cancer before it really starts.

Penile cancer

In men, HPV can cause cancer of the penis. It’s more common in men with HIV and those who have sex with other men.

There’s no standard screening test to find early signs of penile cancer. Because almost all penile cancers start under the foreskin of the penis, they may be noticed early in the course of the disease.

Anal cancer

HPV can cause cancer of the anus in both men and women. It’s more common in people with HIV and in men who have sex with other men.

Screening tests for anal cancer are not routinely recommended for all people. Still, some experts recommend anal cytology testing (also called an anal Pap test because it’s much like the Pap test used for cervical cancer) for people at higher risk of anal cancer. This includes men who have sex with men,
individuals who have had cervical cancer or vulvar cancer, anyone who is HIV-positive,
and anyone who has had an organ transplant.

Mouth and throat cancer

HPV is found in some mouth and throat cancers in men and women. Most cancers found in the back of the throat, including the base of the tongue and tonsils, are HPV-related. These are the most common HPV-related cancers in men.

There’s no standard screening test to find these cancers early. Still, many can be found early during routine exams by a dentist, doctor, dental hygienist, or by self-exam.

Can HPV infection be prevented?

There’s no sure way to prevent infection with all the different types of HPV. But there are things you can do to lower your chances of being infected. There are also vaccines that can be used to protect young people from the HPV types most closely linked to cancer and genital warts.

HPV is passed from one person to another during contact with an infected part of the body. Although HPV can be spread during sexual contact – including vaginal, anal, and oral sex – sex isn’t the only way for the infection to spread. All that’s needed is skin-to-skin contact with an area of the body infected with HPV. There may be other ways to become infected with HPV that aren’t yet clear.

HPV can be present for years without causing any symptoms. It doesn’t always cause warts or any other symptoms. Someone can have the virus and pass it on without knowing it.

Condom use

Condoms (“rubbers”) provide some protection against HPV, but they do not completely prevent infection.

Condoms must be used correctly every time sex occurs. Even then, condoms can’t protect completely because they don’t cover every possible HPV-infected area of the body, such as the skin on the genital or anal area. Still, condoms do provide some protection against HPV, and they also help protect against some other sexually transmitted infections.

A new condom should be used with each sex act. The condom should be put on BEFORE any genital, oral, or anal contact and kept on until sex is finished.

Limiting sex partners

If you are sexually active, limiting the number of sex partners and avoiding sex with people who have had many other sex partners can help lower your risk of exposure to genital HPV. But again, HPV is very common, so having sex with even one other person can put you at risk.

HPV vaccines

HPV vaccines can prevent infection with certain types of HPV, including types that are linked to HPV-related cancers,
as well as types linked to anal and genital warts.

Vaccines are approved for use in males and females. They can only be used to prevent HPV infection – they don’t help treat an existing infection.

• To work best, the HPV vaccines should be given between the ages of 9 and12.
• Teens and young adults ages 13 through 26 years who have not been vaccinated or who have not received all of their shots should get the vaccine as soon as possible. Vaccination of young adults will not prevent as many cancers as vaccination of children and teens.
• The ACS does not recommend HPV vaccination for persons older than 26 years.

Contact your American Cancer Society for more on the HPV vaccines.

Testing for HPV

The HPV tests on the market are only approved to find HPV infection in individuals with a cervix. They can be used alone or as part of a co-test (when an HPV test and a Pap test are done at the same time) to determine your risk of developing cervical cancer. 

• There’s no approved HPV test to find HPV on the penis or vulva, or in the anus, mouth, or throat.
• There’s no test for men or women to check one’s overall “HPV status.”
• For cervical cancer screening, the American Cancer Society recommends that people ages 25 to 65 get a primary HPV test* every 5 years. Because a primary HPV test may not be an option everywhere, a co-test every 5 years or a Pap test every 3 years are still good options. 

(*A primary HPV test is an HPV test that is done by itself for screening. The US Food and Drug Administration has approved certain tests to be primary HPV tests.)

Treatment for HPV or HPV-related diseases

There’s no treatment for the virus itself, but there are treatments for the cell changes that HPV can cause.

Cancer is easiest to treat when it’s found early – while it’s small and before it has spread. Some cancer screening tests can find early cell changes caused by HPV, and these changes can be treated before they even become cancer.

Visible genital warts can be removed with prescribed medicines. They can also be treated by a health care provider.

Things to remember about HPV

• HPV is a very common virus. Most men and women who have ever had sexual contact will get HPV at some time in their lives.
• There is no treatment for HPV, but in most cases it goes away without treatment.
• Having HPV does not mean you will get cancer. Most of the time HPV goes away by itself.
• Certain people are at higher risk for HPV-related health problems. This includes gay and bisexual men and people with weak immune systems (including those who have HIV/AIDS).
• Most HPV infections that lead to cancer can be prevented with vaccines.
• Most cervical cancers can be prevented by regular screening.

Human papillomavirus (HPV) Q&A | UC Davis Comprehensive Cancer Center

Who is most susceptible to HPV-related cancer?

Those most susceptible to HPV-related cancer are:

• People with compromised immune systems such as those with HIV or organ transplant recipients
• Smokers
• People who engage in high-risk sexual behavior or have numerous sexual partners

What types of HPV cause cervical cancer?

The HPV 16 and 18 strains are known to cause cervical cancer.

How long does it take for HPV infection  to progress to cancer?

Progression depends on the type of HPV strain and on the unique characteristics of the individual who is infected. The longer the virus is present, the higher the potential for a cancer to develop. The good news is that more than 90% of HPV 16 and 18 infections go away within 6 to18 months of initial exposure.

How common is HPV and HPV-related cancer?

HPV is the most common sexually transmitted disease. About 20 million Americans are infected. Most sexually active men and women will be exposed to HPV at some point during their lifetime. In the U.S. HPV causes 18,000 cancers in females each year, and 7,000 cancers in men. The virus is especially prevalent in regions with high rates of cervical cancer such as Sub-Saharan Africa, India and Latin America.

How does someone get HPV?

HPV is passed through genital (skin-to-skin) contact, most often during vaginal or anal sex. HPV also can be passed on during oral sex. Most people never even know they have HPV, or that they are passing it to a sexual partner. So it may not be possible to know who gave you HPV or when. HPV is so common that most people get it soon after they start having sex. All women who have had sex are at risk for HPV and cervical cancer.

How does HPV gain entry into the body?

HPV gets into the body through tiny scrapes on the skin. Once it reaches the basal layer of the epithelial cells the virus replicates and causes changes to the normal cervical cell, transforming it into a cancer cell.

Why do some women clear the virus and not others?

Whether a woman clears the virus depends on her immune response and the ability of the virus to evade the immune response and reproduce.

Can I get checked for HPV?

Experts recommend HPV testing for women who are:

• Age 30 or older — as part of regular screening, with a Pap test, or
• Age 21 or older — for follow-up of an abnormal Pap test result.

Why aren’t women under 30 tested for HPV?

HPV is very common in women under age 30 and most of these women will fight off the virus within a few years and never experience health problems as a result of HPV. HPV is less common in women over age 30 and its presence is more likely to signal a health concern. Your doctor can use the results of the HPV test and the Pap test to determine if you need to be more closely followed to look for cervical cancer.

What is the role of HPV for cervical cancer screening?

When a doctor finds the HPV DNA, it may signal cervical cancer and prompt further screening. The DNA test also can determine whether the woman is at high or low risk of invasive cancer.

How many types of HPV vaccine exist, and what do they target?

In the U.S. the HPV vaccine is called Gardasil, which protects against HPV 6, 11, 16 and 18.

How does the HPV vaccine prevent cervical cancer?

The vaccine uses particles from the HPV to cause the immune system to recognize the HPV if and when infected. The vaccine prevents normal cervical cells from becoming cancer cells.

When should I get the vaccine?

The vaccine does not treat HPV infections, so it should be obtained prior to initiation of sexual activity when it is most effective in preventing infection. After a woman engages in sexual activity she is much more likely to be exposed to one or more strains of HPV.

How effective is the vaccine?

In a pivotal randomized trial, Gardasil prevented 98 percent of cervical cancers in women not previously exposed to HPV, and 44% in women with an active HPV 16 or 18 infection.

Are there vaccination risks?

The vaccine can cause pain, redness and itching at the site of the shot. The vaccine may also cause a mild fever, which goes away on its own. Guillain-Barré Syndrome (GBS), which is a rare disorder that causes muscle weakness, has been reported. To date, there is no evidence that Gardasil causes GBS. People have reported blood clots after getting Gardasil.

How many doses do I need and over what time frame?

Three doses are required. The second should be given two months after the first; the third at six months.

Do I really need three doses?

A study published in the Journal of the American Medical Association in 2013 showed that two doses are as effective as three, but the immune response may not last as long with two doses.

Will I need a booster vaccine?

Booster vaccines are not recommended at this time.

How much does the HPV vaccine cost?

With either vaccine, the cost is about $130 per dose.

Is the vaccine covered by insurance companies in the USA?

Gardasil is covered for both girls and boys through the Vaccines for Children Program.

Up to what age is the vaccine given?

In June 2006, the federal Advisory Committee on Immunization Practices recommended HPV vaccine for 11- to 12-year-old girls and young women through age 26 who hadn’t already received the vaccine.

Are they recommended for males?

In October 2009, the federal Advisory Committee on Immunization Practices recommended routine 3-dose vaccination of males aged 11 or 12 years to prevent HPV infection and HPV-related disease.

They recommended that the vaccination could begin as young as age 9 and that boys and young men 13 to 21 years of age who hadn’t already received the vaccine should also be vaccinated.

Information About Human Papillomavirus (HPV)

What Is HPV?

HPV is a sexually transmitted infection. HPV stands for human papillomavirus. It’s very common. Many people don’t have any symptoms, and the infection might go away on its own. But some types of HPV can lead to cervical cancer, head and neck cancer, or cancer of the anus or penis.

HPV isn’t just one virus. There are more than 100 kinds, and some are riskier than others.

Types of HPV

Each human papillomavirus has its own number or type. The term “papilloma” refers to a kind of wart that results from some HPV types.

HPV lives in thin, flat cells called epithelial cells. These are found on the skin’s surface. They’re also found on the surface of the vagina, anus, vulva, cervix and head of the penis. They’re also found inside the mouth and throat.

About 60 of the 100 HPV types cause warts on areas like the hands or feet. The other 40 or so enter the body during sexual contact. They’re drawn to the body’s mucous membranes, such as the moist layers around the anus and genitals.

Not all of the 40 sexually transmitted human papillomaviruses cause serious health problems.

High-risk

High-risk HPV strains include HPV 16 and 18, which cause about 70% of cervical cancers. Other high-risk human papillomaviruses include 31, 33, 45, 52, 58, and a few others.

Low-risk HPV strains, such as HPV 6 and 11, cause about 90% of genital warts, which rarely develop into cancer. These growths can look like bumps. Sometimes, they’re shaped like cauliflower. The warts can show up weeks or months after you’ve had sex with an infected partner.

Low-risk

Low-risk HPV strains, such as HPV 6 and 11, cause about 90% of genital warts, which rarely develop into cancer. These growths can look like bumps. Sometimes, they’re shaped like cauliflower. The warts can show up weeks or months after you’ve had sex with an infected partner.

HPV Symptoms

Often, HPV infections cause no symptoms, and the body clears the infection on its own in a few years. Many people never know they were infected with HPV.

But sometimes an infection with high-risk types of HPV will last longer. This can cause changes in the cells of the cervix that could lead to cancer, including vulvar cancer. The same thing could cause abnormal changes in cells of the penis and anus, but this is rare.

The symptoms of a low-risk HPV infection are warts. The kind of warts you get will depend on which kind of HPV you have.

• Genital warts. These are either flat spots or raised bumps. In women, they usually grow on the vulva, but can also show up on the anus, cervix, or vagina. Men get them on the penis, scrotum, or anus.
• Common warts. These rough bumps typically show up on the hands and fingers.
• Plantar warts. Plantar warts are hard, grainy, painful bumps that affect the bottom of your feet.
• Flat warts. These are slightly raised spots with a flat top. You can get them anywhere, but they’re common on the face and legs.

HPV Causes and Risk Factors

The human papillomavirus infects you by entering your body through a cut, scrape, or tear in your skin. You get it from skin-to-skin contact, or vaginal, anal, or oral sex. You can pass HPV to your baby if you have genital warts when you’re pregnant. In rare cases, this can cause a noncancerous growth in your baby’s voice box (larynx).

The warts are contagious. You can get them by touching someone else’s wart, or by touching a surface that came into contact with one.

Certain things make your chances of getting HPV go up. They include:

• Damaged skin. Places on your skin that have been cut a lot or have holes are more likely to get common warts.
• Direct contact. If you touch someone’s warts or come into contact with surfaces warts have touched, you can get HPV.
• Number of sexual partners. The more sexual partners you have, the higher your risk of getting HPV. If you have sex with someone who has many partners, that increases your risk, too.
• Age. Children are more likely to get common warts. Genital warts are more common in adolescents and young adults.
• Weak immune system. If you have a condition such as HIV or AIDS, or are on treatment that weakens your immune system, you’re more likely to get HPV.

HPV Diagnosis

Your doctor may be able to tell you have HPV just by examining your warts. But there are also several tests they can use if you don’t have symptoms you can see.

• Vinegar solution test. This test uses a vinegar (acetic acid) solution. Your doctor applies it to your genital area. If you have lesions in the area, they’ll turn white.
• Pap test. Your doctor uses a swab to collect samples from your cervix or vagina. They send the samples to a lab to see if you have abnormal cells. Abnormal cells can lead to cancer.
• DNA test. If you’re a woman over 30, your doctor may recommend this test along with a Pap test. They look at the DNA of the cells of your cervix to see if you have the type of HPV that can lead to cancer.

HPV Treatments

Warts may go away without treatment, especially in kids. But there are also medications that treat them, including:

• Salicylic acid. You put treatments with this ingredient directly on the wart. They destroy the wart one layer at a time. You shouldn’t use it on your face.
• Imiquimod. This is a prescription cream that helps your immune system get rid of HPV. It can cause some redness and swelling around the area you apply it.
• Podofilox. You apply this gel directly to genital warts to destroy their tissue. You may get some burning and itching from it.

Trichloroacetic acid. This burns off warts on your palms, soles of your feet, and genitals. It may irritate your skin.

Usually your doctor will recommend medication first. If that doesn’t work, they can remove them with:

• Cryotherapy (freezing with liquid nitrogen)
• Electrocautery (burning with an electric current)
• Surgery
• Laser surgery (using intense light to destroy warts and abnormal cells)

For HPV on your cervix, your doctor may use a procedure called colposcopy to find and remove cells that look abnormal. They’ll use an instrument called a colposcope to magnify your cervix and take samples of (biopsy) these areas.

To remove any precancerous cells on your cervix, your doctor may use:

• Loop electrosurgical excision procedure (LEEP). This uses a thin wire loop with an electric current to remove a layer of cervical tissue.
• Cold knife conization (cone biopsy). A doctor removes a cone-shaped piece of tissue from your cervix and sends it to a lab to look for abnormal cells.
• Cryosurgery. Your doctor uses extreme cold to destroy abnormal tissue.
• Surgery
• Laser surgery

There aren’t any FDA-approved tests to screen for HPV-caused cell changes in the anus, penis, or head and neck. But Pap tests for the anus may help your doctor see early cell changes or precancerous cells. Your doctor may suggest you get one if you are in a high-risk category for HPV.

HPV Complications

When HPV doesn’t go away, it can lead to other problems. Some HPV infections cause lesions, or abnormal areas on your tongue, tonsils, soft palate, or in your nose or larynx.

HPV can also cause cancer. Certain strains of HPV can lead to cancer of the:

• Genitals
• Anus
• Mouth and upper respiratory tract

HPV Prevention

You can get HPV through sex (vaginal, anal, or oral). It spreads through skin-to-skin contact.

HPV can infect skin not normally covered by a condom, so using one won’t fully protect you.

You can’t get HPV from a toilet seat, swimming pools, or from an infected person’s blood.

The only way to avoid all risk of any type of HPV infection is to never be sexually active — no vaginal, anal, or oral sex.

To lower your risk, you can also limit the number of sex partners you have. And you can choose partners who’ve had few or no sex partners before you.

Three vaccines — Cervarix, Gardasil, and Gardasil-9 — protect against HPV. They’re available to boys and girls as young as 9 and adults up to age 26.

The vaccines focus on some of the higher-risk types of HPV. All three guard against HPV 16 and 18. Gardasil and Gardasil-9 are also effective against HPV 6 and 11, which cause most genital warts. Gardasil-9 also covers against the high-risk strains 31, 33, 45, 52, and 58.

While you can’t completely avoid the low-risk HPV infections that cause common or plantar warts, you can reduce your chances if you:

• Don’t pick at warts you already have.
• Don’t bite your nails.
• Wear shoes or sandals in locker rooms or public pools.

Redetection of Cervical Human Papillomavirus Type 16 (HPV16) in Women With a History of HPV16 | The Journal of Infectious Diseases

Abstract

Background. The purpose of this study was to examine the rate of and risks for cervical human papillomavirus type 16 (HPV16) redetection in women with documented or suspected HPV16 infection.

Methods. A convenience sample of women aged 13–21 years were seen at 4-month intervals for HPV DNA testing and cytology. Serum samples were obtained at baseline and annually.

Results. A total of 1543 women entered the study. Of the 295 women with detection of HPV16 DNA and subsequent clearance, 18.1% had HPV16 redetected by 8.5 years (88% cleared this second detection by 3 years). Of the 247 women who had antibodies to HPV16 and were HPV16 DNA negative at baseline, 15.3% had HPV16 redetected by year 5. Risks for redetection included douching, current use of medroxyprogesterone, reporting >1 sex partner or having a new sex partner, and having a sexually transmitted infection. Development of cervical intraepithelial neoplasia 2/3 was rare in women with redetection, except for those with prevalent HPV16 infection.

Conclusions. Reappearance of HPV16 DNA was observed in 18% of women. Most are associated with sexual exposure and appear benign. Interpretation of the studies is more complex in women with prevalent infections as it appears that this small subset reflects women with persistence already present at entry.

Human papillomavirus (HPV), the cause of cervical cancer, is an extremely common infection of the cervix with a lifetime risk of approximately 80% [1]. The majority of HPV infections in women “clear” over time with few progressing to cancer. One of the remaining controversial questions is whether women truly “clear” an HPV infection, or if HPV goes into a latent state where redetection of infection reflects reactivation rather than a new exposure [2]. The prevalence of HPV DNA in the genital tract peaks by 20–25 years of age followed by a decline to a plateau by 30–35 years of age. Data from Central and South America, but not North America, show a second, albeit lower, peak of HPV DNA prevalence around 50–55 years of age [3]. This second peak has been considered a possible reactivation of a prior HPV infection associated with a loss of immune memory response with age. However, this age period also reflects a common time when divorce occurs with the increased possibility of reexposure via a new sexual partner. Trottier et al [4] found that in adult women, redetection after known clearance of HPV type 16 (HPV16) was strongly associated with the report of new sexual partners. Certainly, the frequency of redetection after a documented clearance will likely vary with age of cohort, interval time between testing, length of follow-up, and definition of clearance [4–6]. In a group of women reporting recent sexual activity, redetection of the same HPV type occurred in 19.5% of women within 1 year. However, this study used only 1 intervening negative HPV test to define clearance, which may have resulted in misclassification and risks for reinfection not being determined [7]. Studies using HPV serology as a marker of previous infection also demonstrate that 8%–13% of women have HPV16 DNA identified on follow-up. Estimates of infection based on serology are problematic, as many women never seroconvert [4, 6, 8].

The purpose of this analysis was to examine the rate of and risks for cervical HPV16 redetection in a cohort of women with evidence of HPV16 infection and clearance. Two groups were examined: (1) women with observed cervical HPV16 DNA detection and clearance and (2) women with serological evidence of previous HPV infection and clearance, defined as positive HPV serology and negative HPV16 DNA at entry. Risks for HPV16 DNA detection included sexually transmitted infections (STIs) and self-reported sexual behaviors. Rates of and risks for the clearance of the redetected HPV16 infections were also examined.

MATERIALS AND METHODS

Subject Population

Since its inception in 1990, 1559 women have been recruited into the University of California HPV natural history study. Recruitment of these women has been previously published [9–12]. Although follow-up of the cohort is ongoing, we report here on data collected through September 2007.

This study was approved by the University of California, San Francisco and San Francisco State University institutional review boards. Women were interviewed on sexual and substance use behaviors and examined at 4-month intervals [10, 11, 13]. Examinations included cervical samples for HPV DNA testing using cervical vaginal lavages with normal saline, cytology, and wet mounts for diagnosis of Trichomonas vaginalis, yeast, and bacterial vaginosis [9, 11–13]. Samples for Chlamydia trachomatis and Neisseria gonorrhoeae were obtained at annual visits or if symptomatic. Lesions suggested of HSV were tested at commercial laboratories.

HPV Testing

HPV DNA typing for cervical samples used the polymerase chain reaction (PCR)–based PGMY09/11 primer system as previously described using denatured biotin-labeled PCR product hybridized to an array of immobilized oligonucleotides [11, 12, 14]. Ongoing quality assurance (QA) shows a reproducibility of HPV16 DNA detection of 91%. Samples negative for HPV16 DNA sandwiched between first and second detection were reamplified and retested. At baseline and at annual visits, all women were asked but not required to have their blood drawn. For those with serum samples available at baseline, HPV16 serology testing was performed using an HPV16 L1 antibody binding assay, using glutathione S-transferase fusion proteins on a Luminex platform [15–19]. Testing was performed in the laboratories of 2 of the authors (M.P., D.A.G.).

Statistical Approach

We followed 2 analytic approaches in examining cervical HPV redetection. The first included all women (group 1) with either incident or prevalent (defined as by HPV16 DNA status at enrollment) HPV16 infection detected by HPV DNA testing, who also had at least 2 follow-up visits after HPV16 was detected. In these women, we first estimated the distribution of time to clearance as defined by 2 consecutive negative tests for HPV16 DNA, taking the initial positive visit as the time origin. Estimates were based on the Kaplan-Meier method. Among women observed to clear according to the above definition, we also estimated the distribution of time to next incident HPV16 DNA detection, taking the time of the first of the 2 consecutive negative tests as the time origin.

In our second analysis, we estimated the distribution of time to first detection of HPV16 DNA in women (group 2) observed to be HPV16 DNA negative at both baseline and the next consecutive visit but who were also seropositive for HPV16 antibodies—a surrogate marker for a previous HPV16 DNA infection. The baseline visit was the assumed time origin for this analysis. Because the sensitivity of HPV16 serology to detect all HPV16 infections is known to be low, we also estimated the analogous distribution in the HPV16 seronegative group [6]. Kaplan–Meier estimates were also used to summarize the cumulative probability of redetection and clearance of the redetection.

Two-sample t tests and χ² tests were used to evaluate differences in sociodemographic characteristics between women with prevalent and incident infections (group 1), between women with and without serology test results, and between seropositive and seronegative women (group 2). Crude redetection rates were estimated using person-time methods and expressed as the number of HPV16 redetection events per 1000 woman-years of observation. Confidence intervals (CIs) for crude redetection rates were calculated using the Poisson distribution. Cox proportional hazards regression models were used to examine associations between both fixed and time-varying predictors and HPV16 redetection and subsequent clearance. Candidate predictors for regression models with marginal associations significant at the 10% level or less were retained for further analyses. Variables of interest are listed in the corresponding tables. All models were adjusted for age, condom use, and, for group 1, HPV16 prevalence. Because of the low observed redetection rate, too few cases of clearance after detection were observed to allow for regression modeling. Only marginal associations are reported for this outcome. All analyses were repeated using 3 consecutive negative tests as a definition for clearance. Results were similar (data not shown).

RESULTS

A total of 1543 women completed a baseline visit. Supplementary Figure 1 demonstrates the number of women eligible for each of the analysis. None of the women received the HPV vaccine. Demographics of the cohort are described in Table 1 by statistical approach (group 1 and 2). Group 1 included 460 women: 250 with prevalent and 210 with incident HPV16 infections. Compared to women with incident infections, women with prevalent infections were less likely at baseline to smoke marijuana (11.7% vs 20%; P = .01), were slightly older (mean, 19.4 vs 18.9 years; P = .01), and had less follow-up (mean days in study, 1867 [SD, 1521] vs 2219 [SD, 1407]; P < .001). No other behavioral differences were found.

Table 1.

Demographics of Groups 1^a and 2^b

Table 1.

Demographics of Groups 1^a and 2^b

In the second analysis (group 2), 1293 women were cervical HPV16 DNA negative at baseline and the following consecutive visit. Of these women, 406 women refused a blood draw. However, women with serology available were more likely to have longer follow-up (1951.96 days [SD, 1284.8 days]) vs those who refused blood draws (mean days in study, 1096.71 [SD, 1034.0]; P < .001). No other behavioral differences were found. None of the women received the HPV vaccine.

Of the 887 women with serology, 247 (27.8%) were seropositive. Baseline demographics of the women are given in Table 1. Overall, characteristics of group 1 women and the seropositive women in group 2 were similar.

Rate of Cervical HPV16 Redetection in Group 1

Of the 460 women with a documented cervical HPV16 DNA infection, 52.9% (95% CI, 47.7%–58.2%) cleared within 1 year and 83.2% (95% CI, 78.3%–87.5%) cleared within 3 years. Of the 295 women who cleared and had follow-up, none had HPV16 DNA redetected within 1 year, 9.1% (95% CI, 6.0%–13.4%) within 3 years, and 18.1% (95% CI, 12.5%–25.7%) within 8.5 years. No differences were found for clearance or redetection between prevalent and incident cases (Figure 1A and 1B). The redetection of HPV16 DNA was 21.96 per 1000 women-years (Table 2).

Table 2.

Redetection Rate of Human Papillomavirus Type 16 DNA per 1000 Women-years

Table 2.

Redetection Rate of Human Papillomavirus Type 16 DNA per 1000 Women-years

Figure 1.

Among women with human papillomavirus type 16 (HPV16) DNA detection (group 1), either prevalent or incident, time to clearance (A), time to second detection of HPV16 DNA among women who cleared the virus (B), time to clearance of the second HPV16 DNA detection (C), and time to a third detection among women who cleared their second HPV16 DNA detection (D) are shown. Women with prevalent infections are noted by a solid line and incident infections by a dashed line. P values are based on log-rank test. Abbreviation: HPV16, human papillomavirus type 16.

Figure 1.

Among women with human papillomavirus type 16 (HPV16) DNA detection (group 1), either prevalent or incident, time to clearance (A), time to second detection of HPV16 DNA among women who cleared the virus (B), time to clearance of the second HPV16 DNA detection (C), and time to a third detection among women who cleared their second HPV16 DNA detection (D) are shown. Women with prevalent infections are noted by a solid line and incident infections by a dashed line. P values are based on log-rank test. Abbreviation: HPV16, human papillomavirus type 16.

Of the 33 women with redetection, 75.6% (95% CI, 58.0%–89.9%) of women cleared their second detection within 1 year and 87.8% (95% CI, 76.0%–96.9%) cleared within 3 years. No differences were found between incident and prevalent cases. (Figure 1C). However, if we defined clearance as no further detection of HPV16 DNA during follow-up, prevalent cases were less likely to clear than incident cases. The mean observation time for both groups was 9.2 years. Figure 1D shows that none of the incident cases that cleared their second detection had a reappearance, whereas 7.7% (95% CI, 1.1%–43.4%) of prevalent cases had a third detection by 3 years and 50.4% (95% CI, 22.8%–85.1%) by 12 years (P = .04).

Development of Cervical Intraepithelial Neoplasia 2/3

None of the 16 women with incident infection who experienced redetection (depicted in Figure 1C) developed HPV16-associated cervical intraepithelial neoplasia (CIN) 2/3. However, 1 woman developed HPV51-associated CIN 2/3 three years after her HPV16 clearance. Of the 17 women with prevalent infection who had redetection, 2 were immediately lost to follow-up at the time of their second HPV16 DNA detection, 8 cleared with no further detection, and 7 continued to be persistently or intermittently positive. Two of these women developed HPV16-associated CIN 2/3, 1 within 4 years after the second detection; the other women had been negative for HPV16 for 8 years and then developed CIN 2/3 within 2 years of the third detection—10 years after the second detection. Four women had normal cytology as of 5–12 years of follow-up. One case continued to be HPV16 persistent at the time she was lost to follow-up and had developed abnormal cytology, but because she was pregnant, no biopsy was obtained.

Rate of HPV16 DNA Detection Among Group 2 Women

Of the 247 women who were HPV seropositive at baseline but cervical HPV16 DNA negative, 3.3% (95% CI, 1.6%–6.8%) had cervical HPV16 detected by 1 year, 5.8% (95% CI, 3.0%–9.3%) by year 2, 7.5% (95% CI, 6.6%–12.2%) by year 3, and 15.3% (95% CI, 10.7%–21.6%) by year 5 (Figure 2A). In comparison, time to HPV16 detection was faster among the 640 women who were initially HPV16 DNA negative and HPV seronegative—2.4% (95% CI, 1.4%–4.0%) had an incident HPV16 by year 1, 8.5% (95% CI, 6.4%–11.3%) by year 2, 14.7% (95% CI, 11.9%–18.1%) by year 3, and 22.3% (95% CI, 18.7%–26.4%) by year 5 (Figure 2A; P = .03). Detection of cervical HPV16 DNA among the seropositive group was 17.76 per 1000 women-years compared to 31.44 per 1000 women-years among the HPV seronegative group (Table 2).

Figure 2.

Among women who were human papillomavirus type 16 (HPV16) DNA negative at baseline but have evidence of a prior HPV16 infection by serology (seropositive), time to detection of HPV16 DNA (A) and time to clearance of these HPV16 infections (B) are shown. Among the women who cleared these incident HPV16 infections, time to another HPV16 infection (C) and time to clearance of these infections (D) are shown. For comparison, time to clearance and acquisition are shown in each panel for women who were HPV16 negative and HPV16 seronegative at baseline. Women HPV16 seropositive at baseline are noted by a solid line and seronegative by a dashed line. P values are based on log-rank test. Abbreviation: HPV, human papillomavirus type 16.

Figure 2.

Among women who were human papillomavirus type 16 (HPV16) DNA negative at baseline but have evidence of a prior HPV16 infection by serology (seropositive), time to detection of HPV16 DNA (A) and time to clearance of these HPV16 infections (B) are shown. Among the women who cleared these incident HPV16 infections, time to another HPV16 infection (C) and time to clearance of these infections (D) are shown. For comparison, time to clearance and acquisition are shown in each panel for women who were HPV16 negative and HPV16 seronegative at baseline. Women HPV16 seropositive at baseline are noted by a solid line and seronegative by a dashed line. P values are based on log-rank test. Abbreviation: HPV, human papillomavirus type 16.

Among the 34 cervical HPV16 DNA detections in the seropositive group 2 women, time to clearance was similar to the 117 seronegative group 2 women, with 52.1% (95% CI, 43.7%–61.1%) clearing by year 1 and 86.0% (95% CI, 77.9%–92.3%) by year 3 (Figure 2B; P = .36). Of the 27 seropositive and 78 seronegative women who showed clearance, 0% had HPV16 redetected once more by year 1 and 9.4% (95% CI, 4.7%–17.9%) by year 3 with no difference noted by serostatus (Figure 2C; P = .41). Of the 13 women who had a second HPV16 DNA redetection, 76.6% (95% CI, 47.8%–96.1%) cleared within 1 year, and 100% cleared within 3.5 years (Figure 2D). The small sample size in this last group of women prohibits any statistical comparison.

CIN 2/3 Development Among Seropositive Women

Among the 34 seropositive women who acquired HPV16 (Figure 2A), none developed HPV16-associated CIN 2/3. In comparison, among the 117 HPV16 infections in the seronegative women, 4 developed HPV16-associated CIN 2/3.

Risks for Redetection of Cervical HPV16

Table 3 describes the unadjusted and adjusted hazard ratio (HR) estimates for factors associated with risk of redetection of cervical HPV16 among women who had documented HPV16 DNA infection and clearance (group 1). Adjusted analysis found younger age of first intercourse (P = .07), history of douching since the last visit (P = .05), current use of medroxyprogesterone (P = .02), having >1 sex partner (P = .04), having a new sex partner (P = .02), and having a documented STI (P = .03) associated with HPV16 redetection.

Table 3.

Factors Associated With Redetection of Human Papillomavirus Type 16 (HPV16) DNA Among Women Who Had Evidence of HPV16 DNA Infection and Clearance (Group 1; n = 460)

Table 3.

Factors Associated With Redetection of Human Papillomavirus Type 16 (HPV16) DNA Among Women Who Had Evidence of HPV16 DNA Infection and Clearance (Group 1; n = 460)

Table 4 provides results for factors associated with cervical HPV16 DNA detection in women HPV16 negative at baseline but who were HPV seropositive (group 2). Adjusting for age and condom use, currently smoking cigarettes (P = .02) and current use of medroxyprogesterone (P = .002) remained significant with a trend for having >1 sexual partner in the past 8 months (P = .069). Condom use and having >1 sex partner were highly correlated (data not shown). When we adjusted for age only, having >1 sex partner remained significant (HR = 2.13 [95% CI, 1.03–4.42]; P = .04].

Table 4.

Risk Factors for Acquisition of Human Papillomavirus Type 16 (HPV16) by HPV 16 Serostatus Among Women Who Were HPV 16 DNA Negative at Baseline (Group 2)

Table 4.

Risk Factors for Acquisition of Human Papillomavirus Type 16 (HPV16) by HPV 16 Serostatus Among Women Who Were HPV 16 DNA Negative at Baseline (Group 2)

We also examined factors associated with acquisition of HPV16 among seronegative women for comparison. Factors associated with acquisition were similar to those found among women with documented HPV16 DNA infection and clearance (group 1) and are shown in Table 4. The risk of acquiring HPV16 was enhanced if other HPV types were also found at the visit with HPV16 detection. This was true for both groups. For group 1, the HR was 2.19 (95% CI, 1.08–4.45) and for group 2, 4.08 (95% CI, 2.95–5.63) if multiple types were present. HPV detection at the preceding visit did not increase the risk. Last, we examined factors associated with clearance of the second HPV16 detection in groups 1 and 2, which are summarized in Table 5. Factors that were associated with clearance with both groups included condom use and any sexual contact.

Table 5.

Factors Associated With Clearance of Second Detection of Human Papillomavirus Type 16 DNA

Table 5.

Factors Associated With Clearance of Second Detection of Human Papillomavirus Type 16 DNA

DISCUSSION

Among women with evidence of prior HPV16 infection and clearance defined via HPV DNA tests, only 4% were observed to have a second detection within 2 years. Subsequently, this rate remained relatively stable over time, with approximately one-fifth of women experiencing redetection within 8.5 years of follow-up. When we examined redetection rates in women with serologic evidence of prior infection, very similar rates were found. In contrast, in women with no evidence of prior HPV infection either by DNA tests or serology, rates of HPV16 detection were much higher, specifically within the first 2 years, suggesting that women with a previous infection had some type of immune protection [4, 6, 8]. On the other hand, the difference between the seropositive and seronegative groups gradually narrowed over time. This observation may be due to the fact that the cohort was aging and becoming more monogamous, so potential exposures in both groups were lessening, or that the seronegative group was becoming seropositive over time due to HPV16 exposures. Repeat serology was not performed. It is also possible that antibody response is a measure of a previous established infection but irrelevant to redetection. The rapid clearance of the observed redetections suggests that a cell-mediated immune response is most likely accountable for clearance in these second infections [9]. One of the striking findings was the difference in clearance for the second detection between the women with prevalent and incident HPV16 infections. Among women with incident infections, almost all cleared and more importantly, none developed HPV16-associated CIN 2/3. In contrast, those women who entered the study with a prevalent infection were more likely to persist or have recurrent detection than women with an incident infection, and 2 developed HPV16-associated CIN 2/3. This observation suggests that some of the women with prevalent infections are a different group and reflect persistent infections and had either missed detections or had intermittent shedding. Rodriguez et al [20] also found that prevalent infections were much more likely to result in CIN 3 than incident infections.

Similar to incident HPV16 infection in HPV16-naive women and our previous studies of HPV acquisition [13], sexual risk behavior was the predominant risk for HPV16 redetection in women with evidence of prior infection. The association with >1 male partner and new sexual partners with redetection demonstrates that most of the redetections were a consequence of a new exposure, similar to the conclusions reached by Trottier and colleagues [4]. A recent study by Theiler et al [21] showed that redetection of the same type in healthy women who reported abstinence was extremely rare with a detection rate of <0.1 per 100 women-years. Notably, having an STI also increased the risk of HPV16 redetection. STIs are certainly markers of partner risk behavior; however, STIs also create inflammation and decrease epithelial barriers, potentially exposing basal epithelial cells to infection with HPV [14]. The association with medroxyprogesterone is interesting as its use has been associated with the development of cervical cancer [22]. Potential mechanisms may include progesterone’s ability to enhance E6 and E7 transcription and induce cellular proliferation [23]. Behaviors associated with birth control choice not measured in this study may have also influenced our finding.

The differences observed in risk for redetection between the seropositive group from group 2 and group 1 (ie, those with documented HPV16 DNA acquisition and clearance) is also worth noting. It has been demonstrated that not all women who acquire HPV16 infection seroconvert, and those with transient infections are least likely to seroconvert or develop memory immune responses [6, 24–27]. It is plausible to surmise that seroconversion is more likely to occur in women with HPV persistence. One might hypothesize that redetection of HPV DNA in women who seroconvert is more likely to reflect HPV reactivation. The lack of association with new sex partners in the seropositive group may support this premise. On the other hand, the lack of association may have been due to the smaller sample size in this group, which is of older age and in which having a new sexual partner was less frequent than reporting >1 partner. The observed association with smoking is also interesting, as nicotine and its byproducts are known to suppress immune responses in the cervix and smoking is associated with high-risk sexual behavior [25, 28]. This suppression could result in lack of protection from reexposure or allow reactivation. It remains important to underscore that in either situation, the redetected infections were likely to clear rapidly and CIN 2/3 was uncommon. The association between lack of sexual contact and condom use and clearance of the redetected infections underscores the importance of partners in reinfection.

The rate of redetection in our study is difficult to compare to other studies, as length of follow-up and type of cohort influence this rate. In a longitudinal cohort study, Trottier et al [4] found a lower redetection rate for HPV16 of 1.05 per 1000 women-months. Because rates expressed as a function of person-time are dependent on length of follow-up, this difference may not be too surprising. Our total women-months of observation was almost 5 times longer than that reported in the study by Trottier et al [4]. In addition, their cohort was older at entry and may have had overall less exposure to new partners. Rodriguez et al [5] also found a lower recurrence rate than ours of only 3.7% over 7 years for any HPV type (HPV16 was not singled out). This difference is likely due to the nature of their cohort, which was population-based in Guanacaste, Costa Rica. Risk behaviors such as alcohol and marijuana use and multiple sexual partners were likely not as common in their cohort, and the population was also older.

Lack of association with new sex partners in the seropositive group likely underscores the limitations of serology. Wentzensen et al [6] used 2 different serologic methods to define seropositivity in a selected population from the Guanacaste study referred to earlier—one was a standard viruslike particle ELISA and the other a competitive Luminex immunoassay. The authors conclude that the competitive Luminex immunoassay measures a subset of the overall polyclonal responses and is more type specific. The differences in serologic tests likely contribute to the conflicting data regarding antibodies and protection and rate of recurrence [4, 26, 27, 29, 30]. We also did not do DNA sequencing of HPV16. However, redetection of the same HPV16 variant does not preclude reinfection. Also, false-negative and -positive DNA test results may have influenced our estimates.

In conclusion, redetection of HPV16 in most healthy young women is likely due to new sexual exposures. To our knowledge, this is the first study to demonstrate the rapid clearance of these redetections and the absence of CIN 2/3 development, supporting the premise that most women who clear HPV infections develop memory immune responses. Interpretation is more complex in women with prevalent infections, as this group appears to include a subset of women with failed immune responses resulting in HPV persistence. The recurrent detection of HPV in these cases may reflect reactivation with subsequent risk for the development of CIN 2/3.

Notes

Acknowledgments. The authors acknowledge the contributions of the following staff for data collection and management: Susanna Miller-Benningfield, Janet Jonte, Lynn Hanson, Julie Jay, Cheryl Godwin de Medina, Lisa Clayton, Robert Wilson, and Jenny Broering. The authors also acknowledge Anthony Kung for manuscript preparation.

Author contributions. A.-B. M. had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Financial support This work was supported by the National Institutes of Health (grant number R37 CA051323). These studies were carried out in part in the Pediatric Clinical Research Center, Moffitt Hospital, University of California San Francisco with funds provided by the National Center for Research Resources, U.S. Public Health Service [grant number 5 M01 RR-01271]. Roche Molecular Diagnostics (Pleasanton, CA) provided supplies for HPV DNA detection.

Disclaimer. The sponsors had no role in design and conduct of the study, nor collection, management, analysis, or interpretation of the data, nor preparation or review of the manuscript.

Potential conflicts of interest. All authors: No reported conflicts.

All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

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© The Author 2013. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: [email protected].

Incidence and Duration of Cervical Human Papillomavirus 6, 11, 16, and 18 Infections in Young Women: An Evaluation from Multiple Analytic Perspectives

Abstract

Objective: To estimate the incidence and duration of cervical human papillomavirus (HPV)-6, HPV-11, HPV-16, and HPV-18 infections in a population of young American women.

Methods: The study population consisted of U.S. women who at baseline were 16 to 23 years of age, reported zero to five lifetime sexual partners, never having been pregnant, and never having had a prior abnormal Papanicolaou test and were enrolled in the placebo arm of a randomized multicenter clinical trial of a HPV-16 L1 virus-like particle vaccine. Women underwent type-specific endocervical/ectocervical swab HPV DNA testing at ∼6-month intervals for up to 48 months of follow-up. To contribute person-time in the analyses of type-specific HPV incidence, a woman must have had at least three satisfactory swab specimens available and been negative for the relevant HPV type (HPV-6, HPV-11, HPV-16, or HPV-18) on her first two trial swabs. The duration of incident HPV infections was estimated using Kaplan-Meier survival analysis methods.

Results: Person-years of exposure ranged by type-specific analysis from 2,645 to 3,188, with an incidence rate per 100 person-years of 3.6 for HPV-6, 0.4 for HPV-11, 5.4 for HPV-16, and 2.1 for HPV-18. With censoring at the time of treatment for cervical intraepithelial neoplasia, where done, the mean duration of incident infections was 9.3, 8.4, 18.2, and 16.4 months, respectively, for HPV-6 (n = 103), HPV-11 (n = 13), HPV-16 (n = 142), and HPV-18 (n = 62). When the duration of HPV infections was truncated at the time of cervical intraepithelial neoplasia detection (any grade), where applicable, mean duration figures were 8.4, 8.1, 14.0, and 15.1 months for HPV-6, HPV-11, HPV-16, and HPV-18 infections, respectively.

Conclusions: Previous studies of the mean duration of cervical HPV infection have been based on prevalent infections and/or featured relatively short duration of follow-up. This study tested women for HPV infection over a period of up to 48 months and observed a mean duration of incident HPV-16/HPV-18 infections approximately twice that of HPV-6/HPV-11. (Cancer Epidemiol Biomarkers Prev 2007;16(4):709–15)

• human papillomavirus
• incidence
• duration
• clearance
• cervix

Introduction

Human papillomavirus (HPV) infection is the most commonly occurring sexually transmitted infection in the United States (1). HPV infections can lead to cancers and precancers of the cervix (2), anus, penis, vagina and vulva (3, 4), anogenital warts (5, 6), and recurrent respiratory papillomatosis (7, 8), with growing evidence for a role in the pathogenesis of cancers of the head and neck (9). A diagnosis of HPV can lead to distress (10), shame, and anger and negatively affect sexual activity and enjoyment (11).

A vaccine targeting HPV-6, HPV-11, HPV-16, and HPV-18 (12) has recently been approved by the U.S. Food and Drug Administration, with a second vaccine targeting HPV-16 and HPV-18 also in development (13). HPV-16 and HPV-18 have been observed in ∼70% of U.S. cervical cancer cases (14), with HPV-6 and HPV-11 detected in >90% of anogenital warts (5, 6) and in 10% of low-grade cervical intraepithelial neoplasia (CIN; refs. 15-18). Data on the natural history of HPV infection are critical for policy evaluations of these and other emerging technologies (19-21).

The present study describes the type-specific incidence, mean and median duration, and clearance rates of cervical HPV-6, HPV-11, HPV-16, and HPV-18 infections among U.S. young women enrolled in the placebo arm of a 4-year randomized double-blind clinical trial of a HPV-16 vaccine (22, 23). Several previous studies have examined the duration or clearance over time of cervical HPV infections from other perspectives, with analysis of prevalent rather than incident HPV infections (or mixture of prevalent and incident infections; refs. 24-28), aggregation of data across multiple HPV types (29-31), and/or type-specific data for HPV-16 only (32). Some analyses have featured follow-up of <2 years, which has generally been adequate for assessing clearance and mean duration of prevalent HPV infections (24, 27, 31), but resulted in a greater degree of right censoring and potential underestimation in studies of incident infections (33). Two prior studies with >2 years of postinfection follow-up have estimated the median duration of incident type-specific HPV infections; however, mean infection duration was not described (34, 35). Data on the type-specific incidence of HPV infection in the United States are sparse, with data from the two prior studies conducted among women recruited in Arizona and Washington state yielding somewhat disparate results (24, 36). Additional data on the incidence and mean duration of type-specific HPV infections from various perspectives can be of value to clinicians and patients as well as those conducting policy evaluations.

Materials and Methods

Study Participants and Procedures

Data were analyzed from women enrolled in the placebo arm of a randomized double-blind clinical trial of a HPV-16 L1 virus-like particle vaccine (Merck Research Laboratories, West Point, PA). The study population and trial design have been described in detail elsewhere (22, 23, 37). Briefly, the trial population consisted of 2,391 U.S. women who at enrollment were 16 to 23 years of age, nonpregnant, without a prior abnormal Papanicolaou test, and with no more than five lifetime male sexual partners. Virgins were enrolled if they were seeking contraception. Women in the placebo arm received i.m. injections of 225 μg of aluminum adjuvant in a total carrier volume of 0.5 mL visually indistinguishable from vaccine.

Women underwent type-specific endocervical/ectocervical swab HPV PCR testing for HPV-6, HPV-11, HPV-16, and HPV-18 at ∼6-month intervals through 48 months of follow-up. At these visits, cervical samples were also collected for thin-layer (ThinPrep, Cytyc) Papanicolaou testing.

An algorithm was used to guide further evaluation for cytologic findings. A single Papanicolaou test result of high-grade squamous intraepithelial lesion, or repeated Papanicolaou tests showing low-grade squamous intraepithelial lesions or atypical squamous cells of undetermined significance, prompted colposcopy. Investigators were allowed to manage single atypical squamous cells of undetermined significance and low-grade squamous intraepithelial lesion results based on local standards of care, with some women referred for colposcopy. All women attending the month 48 trial visit were referred for colposcopy, with biopsy done if a CIN lesion was suspected. If more than one biopsy was obtained during colposcopy, then each tissue sample was processed separately. Cervical biopsy specimens were processed and assigned histologic diagnoses for purposes of medical management by central laboratory pathologists and were typed by PCR for HPV-6, HPV-11, HPV-16, and HPV-18 (37). Women diagnosed with CIN grades 2 to 3 or adenocarcinoma in situ underwent loop electrosurgical excision procedure. Women with repeated biopsy diagnoses of CIN 1 were referred for therapy at the discretion of the physician.

HPV Testing Methods

The HPV testing methods used have been described in detail elsewhere (22, 23). Briefly, cervical swabs were prepared for PCR using a QIAamp DNA Blood kit (Qiagen, Inc., Valencia, CA). DNA was analyzed by qualitative PCR using HPV-6, HPV-11, HPV-16, and HPV-18 type-specific and gene-specific primers based on the L1, E6, and E7 genes for these types (37). β-Globin PCR assay was done to verify that purified samples contained a sufficient quality and quantity of DNA for PCR amplification. PCR products were dot blotted, hybridized to the corresponding ³²P-labeled β-globin or HPV-6/HPV-11/HPV-16/HPV-18 gene-specific oligonucleotide, and visualized by autoradiography. Appropriate negative and positive controls were run with each assay, and any specimen testing positive for at least two of the three genes was considered positive. Specimens testing positive for only one gene were considered positive if, on retesting, they were positive for two or three genes or the same single gene. Laboratory validation studies rigorously evaluated assay sensitivity against known copy number type- and gene-specific plasmids. The assay was shown to have a >95% probability of detecting at least 13 copies per sample, with 95% upper confidence bounds for sample false negativity and false positivity of 0.7% and 0.8%, respectively. All PCR assays were done at Merck Research Laboratories.

Measures

The type-specific incidence of HPV-6, HPV-11, HPV-16, and HPV-18 infections per 100 person-years was estimated. To contribute person-time to the analyses, a woman was required to have had at least three satisfactory cervical swab specimens available and to have been negative for the relevant HPV type (HPV-6, HPV-11, HPV-16, or HPV-18) on her first two trial swabs and any cervical biopsy specimens obtained on or before the date of her second swab. The selection of eligible enrollees for analyses of the incidence of each HPV type is illustrated in Fig. 1

.

Figure 1.

Sample selection criteria for analyses of HPV-6, HPV-11, HPV-16, and HPV-18 incidence. The final samples eligible for each type-specific analysis are represented within the bottom box, labeled by HPV type, reflecting placebo arm women negative on PCR testing for the relevant HPV type on the first two trial endocervical/ectocervical swabs and any intervening cervical biopsies.

For the purposes of this analysis, incident HPV-6, HPV-11, HPV-16, and HPV-18 infections were defined by a positive test for the relevant HPV type on at least one cervical swab or biopsy specimen. Because HPV testing occurred at discrete intervals (typically every 6 months), it is likely that a positive HPV test result observed on a particular date was preceded by an unobserved period of HPV positivity of indeterminate length. For the calculation of person-time at risk, it was therefore assumed that the HPV infection occurred at the midpoint between the initial positive test date and the previous negative test. Time elapsed following the point of incident HPV infection was not included in estimates of person-time at risk. For individuals testing negative for a specific HPV type throughout the trial, person-time was estimated through the time point of the last HPV test, rather than the trial conclusion date, as this was the last opportunity to observe a HPV infection.

The monthly duration of each incident HPV infection was examined from three perspectives (Fig. 2

). First, the time elapsed from incident infection until the clearance of a given HPV type, as measured by negative cervical swab specimen(s), was estimated. This “clinical practice” perspective describes most completely the course of each infection under the clinical management practices within the trial, without statistical adjustment for the treatment of disease. These data can provide insight into the actual duration of HPV infections in a screened population. Second, the time elapsed from the incident infection, until either the detection of a CIN grade 1 to 3 lesion testing positive for the relevant HPV type or infection clearance, was examined. This “health state” perspective is consistent with how the duration of HPV infection is often conceptualized in cost-effectiveness models and other policy evaluations of technologies to prevent and diagnose HPV disease (19, 20), where women may transition from a health state characterized by infection in the absence of clinically detectable CIN to clinically detectable CIN grades 1, 2, and 3. Third, the time elapsed from incident infection until infection clearance was analyzed, with censoring of infection duration at the time of treatment, if done. Given that treatment may eliminate infection (38), by censoring on-going infections at the time of therapy, this “natural history” perspective can yield estimates more consistent with the duration of infection in the absence of treatment. This perspective can be useful for understanding the complete course of HPV infections as would be observed among unscreened populations.

Figure 2.

Health state, clinical practice, and natural history perspectives for analyzing duration of type-specific HPV infections. This example illustrates how the duration of a hypothetical HPV-6 infection would be categorized based on the health state, clinical practice, and natural history analytic perspectives. From all three perspectives, infection duration begins at the midpoint between the prior negative and the first positive HPV test result; in this example, at month 9. For the health state perspective (A), HPV infection duration continues until either clearance or detection of CIN; in this case, until CIN 1 is detected at month 18. For the natural history perspective (B), infection duration either ends with clearance or is censored at the time of disease treatment; in this case, with censoring at treatment in month 24. For the clinical practice perspective (C), the duration of infection ends at the midpoint between the last positive and the first negative HPV test irrespective of treatment; in this case, at month 33.

Women were required to have two consecutive negative endocervical/ectocervical swabs for a given HPV type before the start of an incident infection. For consistency, if two consecutive negative swabs for that type were subsequently observed, the infection was assumed to have cleared.

Several women were found to have a positive HPV swab sample(s) for a given type followed by only a single negative swab, as of their last available sample. Among women with incident HPV-6 infections, 19 (18.4%) fell into this category compared with 2 (15.4%) with HPV-11, 16 (11.3%) with HPV-16, and 9 (14.5%) with HPV-18. Because these women lacked two consecutive negative swabs, some previous analyses have evaluated them as censored at the date of the negative swab (28). However, this approach would be expected to considerably overestimate the actual duration of infection for these women because, in actuality, many would likely have cleared their infection around the time of their last positive swab and differ with respect to their subsequent course from women who were otherwise censored with a positive swab at their last trial visit. For instance, among 63 women with an incident HPV-6 infection followed by a negative swab sample, and at least one additional swab in the trial, only 2 (3.2%) had a nonnegative HPV-6 result on the second swab or a concurrent biopsy specimen. Similarly, for incident HPV-11 infections, the proportion was 0/6 (0.0%), for HPV-16 it was 8/76 (10.5%), and for HPV-18 it was 3/31 (9.7%). This would suggest that nearly all of the women with only a single negative HPV test at the conclusion of their trial follow-up would have previously cleared their HPV infections, and we therefore evaluated these women as having cleared their infections following their final positive test. Women observed to have had positive swab or biopsy specimens followed by a single negative swab followed by a swab or biopsy specimen positive for the same HPV type were analyzed as having persistent infections. Women with a positive test on the date of their final trial swab sample were evaluated as censored.

Consistent with previous studies (25, 32), in the primary analysis, it was assumed that women acquired type-specific HPV infections at the midpoint in time between their most recent prior negative HPV test and their initial positive test and cleared infections at the midpoint in time between their final positive and their first subsequent negative swab tests. For women with only a single positive HPV test, this yielded a length of infection of ∼6 months. In sensitivity analyses, we explored the effect on results of selecting lower and upper bounds reflecting 50% longer and 50% shorter intervals for the estimated time from first positive HPV test back to incident infection and from last positive HPV test to infection clearance (e.g., among women with only a single positive HPV test, the lower and upper bounds would simulate approximately 3- and 9-month infections, respectively).

Statistical Analysis

HPV type-specific incidence rates per 100 person-years were estimated along with 95% confidence intervals (95% CI). The mean and median duration of HPV infections and the proportion of women clearing infections at 12, 24, and 36 months of follow-up were estimated using Kaplan-Meier methods (39). SEs for the Kaplan-Meier survivorship function S(t) are typically estimated using Greenwood’s formula:where n_j is the number surviving to the start of interval j and d_j is the number of deaths during interval j (40). However, when the survivorship function nears 0, SEs calculated using Greenwood’s formula will lead to confidence intervals that overlap zero. Therefore, in these instances, confidence intervals in the present analysis were estimated using a log(-log) transformation of the survivorship function as described by Collett (41):These SEs were then back transformed to obtain confidence intervals using the formula: , where z_α/2 is the upper α/2 point of the standard normal distribution.

Results

Among all 1,203 women enrolled in the placebo arm of the trial who underwent HPV testing at baseline, the prevalence of individual HPV types on endocervical/ectocervical swab PCR testing was as follows: HPV-6, 3.2%; HPV-11, 0.5%; HPV-16, 6.8%; and HPV-18, 2.6%. The combined baseline prevalence of HPV-6, HPV-11, HPV-16, or HPV-18 infections was 12.1%.

Baseline characteristics were generally similar across samples eligible for each type-specific analysis of HPV incidence, with sample sizes ranging from 895 to 995 women. The size of each sample was directly correlated with the baseline prevalence of the relevant HPV type. Approximately 41% of eligible women were between the ages of 16 and 19 years and the remainder between the ages of 20 and 23 years. By self-reported race, 74% were White, 16% were Black or Hispanic, and 10% were of other racial designation. Nearly 15% reported a history of pregnancy and 24% as being current smokers. Five percent reported being virgins, with 24%, 38%, and 33% reporting one, two to three, and four to five lifetime sexual partners, respectively.

Table 1
reports incidence rates of HPV-6, HPV-11, HPV-16, and HPV-18 infections, per 100 person-years, among eligible women. Excluding the time covering the first two trial cervical swabs, women had an average of 3.0 to 3.2 person-years at risk for each HPV type. Of the four types examined, HPV-16 infection was the most commonly occurring (5.4 per 100 person-years) followed by HPV-6 infection (3.6 per 100 person-years). Women with incident HPV-6 (n = 103), HPV-11 (n = 13), HPV-16 (n = 142), and HPV-18 (n = 62) infections contributed a total of 675 unique sampling dates with a positive HPV test for the relevant HPV type. Of the 320 incident infections analyzed, 266 had at least one subsequent cervical swab result, with 59% of the latter group having multiple HPV tests positive for a given type versus 41% for a single positive test.

Table 1.

Incidence of HPV-6, HPV-11, HPV-16, and HPV-18 infections

The duration and clearance of HPV infections, inclusive of the detection of CIN and treatment, are reported in Table 2

. HPV-16 infection was observed to have the longest duration (17.1 months), with the duration of HPV-6 and HPV-11 infections roughly one half that of HPV-16 and HPV-18. Adjusting the time point for the incidence and clearance of HPV infections from the midpoint to one fourth and three fourths of the interval between discordant tests resulted in lower and upper bound estimates for the duration of infection of approximately ±3 months the mean duration estimated in the primary analyses. The mean duration of infection exceeded the median by 25% to 37% depending on HPV type. Whereas an estimated 70% of women were cleared of their incident HPV-6/HPV-11 infections within 12 months, only 40% of women cleared their HPV-16/HPV-18 infections over this period. By 36 months, nearly all women had cleared their incident HPV-6/HPV-11 infections, with 7.5% still infected with HPV-16 or HPV-18.

Table 2.

The monthly duration and clearance of HPV-6, HPV-11, HPV-16, and HPV-18 infections inclusive of the detection of CIN and treatment

Given that a small proportion of infections were estimated to persist beyond the conclusion of the observed follow-up (3.8% of all infections), the mean duration of infection is underestimated for all types, except HPV-11, where ascertainment was complete. However, even for HPV-18, which exhibited the highest degree of persistence (9.0%) of the four types at 36 months, a sensitivity analysis suggests that the degree of underestimation may well be minimal. In the data, 62.5% of HPV18 infections persisting beyond 12 months cleared between months 12 and 24 and 60% of infections persisting beyond 24 months cleared between months 24 and 36. Assuming a similar 60% annual clearance rate for the 9.0% of infections persisting beyond 36 months, the estimated mean duration of HPV-18 infections (16.6 months) would increase by ∼1 month if the full duration of infections persisting beyond 36 months is to be added. For HPV-6 and HPV-16 infections, the increment would be considerably smaller.

Table 3
displays the duration and persistence of HPV infections up to the time of detection of CIN grades 1 to 3 or clearance. The following numbers of women with incident HPV infections were observed to develop CIN positive for the same HPV type during the course of follow-up: HPV-6, n = 15; HPV-11, n = 0; HPV-16, n = 37; and HPV-18, n = 9. The mean durations of infections excluding persistence following the detection of CIN are generally shorter than estimates from Table 2, which include infection progression to CIN. For instance, for HPV-16, the duration was roughly 20% shorter (13.9 versus 17.1 months). Virtually all women with incident HPV infections were observed to either develop CIN or clear the infection within 36 months (within 24 months for HPV-6/HPV-11).

Table 3.

The monthly duration and persistence of HPV-6, HPV-11, HPV-16, and HPV-18 infections up to the time of diagnosis of CIN or clearance

Although women routinely underwent colposcopy at their month 48 trial visits, CIN diagnoses observed at earlier trial time points were based solely on biopsies done as follow-up for an abnormal Papanicolaou smear. Consequently, among women diagnosed with CIN, it is likely that the actual period from incident infection to initial CIN development is shorter than that based on the actual date of detection. Although it is not possible to determine the exact time of development of clinically detectable CIN, a sensitivity analysis was conducted in which the time from incident HPV infection to CIN development was reduced by half for women with HPV-16, representing the infection group with the largest proportion of women developing CIN. This resulted in a minor decrease in the estimated mean duration of HPV-16 infection across all infected women (12.5 versus 13.9 months).

Few women who were HPV-6, HPV-11, HPV-16, or HPV-18 positive at the time of the month 48 trial visit, and underwent routine colposcopy at month 48, had clinically detectable CIN. For instance, among women with HPV-16 infection on endocervical/ectocervical swab (n = 45), four (8.9%) were found to have CIN on colposcopically directed biopsy. Similarly, among women with HPV-6 (n = 16), HPV-11 (n = 5), and HPV-18 (n = 21) infections at month 48, two (10.0%), zero (0.0%), and three (14.3%), respectively, were found to harbor CIN.

An additional sensitivity analysis was conducted to examine the effect of not distinguishing between HPV infection and CIN 1 and truncating infection duration only with the detection of CIN 2 or CIN 3. Treated CIN 1 lesions (n = 4) were censored at the time of treatment. Mean (95% CI) infection durations by type were 9.1 (8.2-10.0) months for HPV-6, 8.1 (5.5-10.7) months for HPV-11, 16.1 months (14.1-18.1) for HPV-16, and 15.8 months (12.7-18.9) for HPV-18. The mean duration of HPV infections where CIN 1 was diagnosed (16.9 months) was longer than for HPV infections without histologic diagnosis of CIN (12.9 months; P = 0.0008).

Table 4
reports the duration and clearance of HPV infections, with censoring of infections at the time of treatment, where done. During the period of their on-going infections, 2 women with HPV-6 underwent treatment for a CIN lesion compared with 1 with HPV-11, 14 with HPV-16, and 3 with HPV-18 infections. The mean duration of HPV infection from this perspective was 1% to 6% longer, depending on the HPV type, than when infection duration was not censored at the time of treatment (Table 2).

Table 4.

The monthly duration and clearance of HPV-6, HPV-11, HPV-16, and HPV-18 infections with censoring at the time of treatment

Among the 17 women with HPV-16/HPV-18 infections undergoing treatment, 4 (23.5%) failed to clear their respective HPV infections by the time of their next cervical swab sample, collected an average of 3.3 months following the date of treatment. All of the women with persistent infection after therapy had a pretherapy cervical biopsy specimen testing positive for HPV-16 or HPV-18 infection, an average of 1.2 months before undergoing treatment.

Discussion

This study has reported the type-specific incidence and duration of cervical HPV-6, HPV-11, HPV-16, and HPV-18 infections among young women. Unique features of the analysis have included the examination of the duration and clearance of HPV infection over time from multiple perspectives (clinical practice, health state, and natural history) and longer follow-up than prior studies estimating the mean duration of incident HPV infection (27, 33), allowing for more complete ascertainment. Excluding studies in recognized high-risk (e.g., women infected with HIV) or specialized (e.g., women first initiating sexual activity) populations, relatively few prior analyses have described the type-specific incidence of HPV infection in the U.S. population. In a smaller study, with ∼200 total person-years at risk, Giuliano et al. (24) reported incidence rates (converted to per 100 person-years) for HPV-6 (1.0), HPV-11 (1.4), HPV-16 (7.1), and HPV-18 (1.0) among women ages 18 to 35 years attending a Planned Parenthood clinic for routine gynecologic care in southern Arizona. A second study, among female students ages 18 to 20 years attending the University of Washington (n = 553), with >800 person-years at risk, reported incidence rates (converted to per 100 person-years) for HPV-6 (3.9), HPV-11 (0.5), HPV-16 (5.5), and HPV-18 (2.1) virtually identical to those estimated in the present study (36). One additional U.S. study has reported the cumulative incidence of type-specific HPV infections over time (34).

With women enrolled from 16 academic centers from across the United States, the study population in the present analysis is more geographically diverse than that of prior analyses of HPV incidence. However, similar to earlier studies, it does not reflect a nationally representative sample of the population. The 2002 National Survey of Family Growth reported the following distribution of lifetime male sexual partners among U.S. females ages 15 to 24 years: 0 (23.4%), 1 to 2 (36.9%), 3 to 6 (25.7%), and 7+ (14.1%; ref. 42). For comparison, across all females ages 16 to 23 years enrolled in the placebo arm of the present study, the distribution of lifetime sexual partners was as follows: 0 (4.5%), 1 to 2 (43.2%), 3 to 5 (52.3%), and 6+ (0.0%). Thus, the present study includes fewer women with the lowest and highest numbers of lifetime sexual partners compared with the general U.S. population. Nonetheless, the baseline prevalence of HPV-6, HPV-11, HPV-16, and HPV-18 infections was observed to be relatively similar to that obtained from a nationally representative sample of 18- to 25-year-old U.S. women (43).

Although populations may differ across studies, the high incidence of HPV infection among young women is a common theme with, for instance, a cumulative 2-year incidence of HPV due to any type among university aged women of 39% to 43% and for HPV-16 of 7% to 10% reported in prior analyses (34, 36). U.S. data comparing the type-specific incidence and duration of HPV infection among women at different ages are generally unavailable and constitute an area for future research.

Several studies have reported the type-specific median duration of incident HPV infections from a perspective most similar to the natural history perspective in Table 4. Using cervicovaginal lavage specimens and a 6-month testing interval, Ho et al. (34) estimated median durations of incident HPV-6 (6 months) and HPV-18 (12 months) infections that were similar to those reported in this study, with a comparatively shorter duration for HPV-16 (11 months). In contrast, based on testing of cervical smear samples taken at 6-month intervals, Woodman et al. (35) reported a relatively longer median duration of incident HPV-6/HPV-11 (9.4 months) infections and a relatively shorter duration for HPV-16 (10.3 months) and HPV-18 infections (7.8 months). Results obtained by Richardson et al. (33) and Xi et al. (32) were generally more consistent with the present analysis. The former study collected samples using an Accelon cervical biosampler with a 6-month testing interval, whereas the latter used cervical and vulvovaginal swabs and a 4-month testing interval. Subjects in each of the preceding studies were U.S. female university students, with the exception of the analysis by Woodman et al., which was conducted among women ages 15 to 19 years attending a center for sexual and reproductive health in the United Kingdom.

The mean durations of incident type-specific HPV infections have not generally been reported in prior analyses, with the lone exception being abbreviated estimates from a study with <2 years of follow-up after infection (33). In the natural history perspective of the present study, a substantial proportion of HPV-16 and HPV-18 infections were observed to persist beyond 2 years, with more than half of these estimated to resolve between years 2 and 3. A consistent finding across all analyses was that the mean duration of incident HPV infection exceeded the median duration, with the differential varying from 15% to 40% depending on the HPV type and perspective adopted.

Prior studies of the course of incident type-specific HPV infections (32-35) have not examined infection duration from a health state perspective. This has represented a gap in the literature, as data from this perspective are particularly needed for cost-effectiveness models and other policy evaluations of technologies to prevent and diagnose HPV disease, which typically consider HPV infection without progression to clinically detectable CIN as a separate health state from that of clinically detectable CIN grades 1, 2, and 3 due to HPV (19, 20). In this study, the mean duration of HPV-16 infection was observed to be >30% higher when evaluated from the natural history perspective than when infection alone was evaluated as a separate health state from CIN due to HPV-16. Differences in duration were of a lesser magnitude for other HPV types evaluated. As some natural history models used in policy analyses have modeled persistent HPV infection in the absence of CIN as a separate health state from transient infection (44), it is also interesting to note that persistent HPV infections without detected CIN were generally not found to exist beyond 18 months for HPV-6 and HPV-11 infections or beyond 36 months for HPV-16 and HPV-18 infections.

Our study has several potential limitations. First, similar to prior studies of HPV infection duration, it is possible that a proportion of infections of shortest duration would be missed by the analysis testing interval, which would tend toward overestimating infection duration (34). A trade-off may exist, however, in that increasing numbers of false-positive test results in studies with relatively more frequent testing would tend toward underestimation of mean duration.

Second, consistent with previous natural history studies of the duration of incident type-specific HPV infections (32, 33, 35), women with high-grade or otherwise persistent CIN were referred for treatment. Although these women were evaluated as censored at the time of treatment in the natural history analysis, it is possible that the subsequent course of their HPV infections differed from those of women with HPV infections of similar duration not undergoing treatment. Informative censoring of this type could potentially lead to an underestimate or overestimate of infection duration in the natural history analysis of this and other prior studies.

Third, because of the additional censoring at the time of treatment, the natural history analysis estimate of mean infection duration for HPV-16 (14.7% persisting at the conclusion of follow-up) is likely to be underestimated by at least a few months. The degree of censoring is likely to be much less of a concern for the other analyses as described in Results.

Fourth, estimates from the clinical practice perspective are reflective of infection duration under the screening and follow-up practices occurring in the trial. Results may vary somewhat in other settings to the extent that women are managed more or less aggressively. However, with most infections not resulting in clinically treated CIN, the degree of variation may be relatively modest, as the mean infection duration estimated from the clinical practice perspective only differed by 1% to 6%, depending on the HPV type, from that in which no treatment was assumed.

Finally, some prior analyses of HPV natural history have censored women before the point of CIN treatment, such as at the time of initial colposcopy/cervical biopsy (32, 33). We instead elected to censor women at the time of treatment in the natural history analyses, as a randomized clinical trial of women undergoing no biopsy, central biopsy, and peripheral biopsy at baseline found no difference across groups in change in lesion size at 6-week follow-up, with colposcopic and histologic confirmation of CIN grade 1 to 3 persistence (45). This allowed for more complete ascertainment of infection natural history, particularly in instances where treatment was not subsequently done.

This analysis has estimated the type-specific incidence and duration of cervical HPV-6, HPV-11, HPV-16, and HPV-18 infections. The development of type-specific HPV vaccines and HPV DNA tests has amplified the need for descriptive data on HPV infection for policymakers, physicians, and patients. Through assessment of the duration of HPV infection from clinical practice, health state, and natural history perspectives, the results of this analysis can be useful for a variety of purposes.

Acknowledgments

We thank Christine K. Gause, Ph.D. (Merck Research Laboratories) for statistical consultation in the preparation of this manuscript.

Footnotes

• Grant support: Merck Research Laboratories.

• The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

• • Accepted February 7, 2007.
  • Received October 5, 2006.
  • Revision received February 2, 2007.

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    Chenoy R, Billingham L, Irani S, et al. The effect of directed biopsy on the atypical cervical transformation zone: assessed by digital imaging colposcopy. Br J Obstet Gynaecol 1996;103:457–62.

90,000 HPV tests price – get tested for human papillomavirus in St. Petersburg

Human papillomavirus (HPV) – one of the most common sexually transmitted infections and skin-to-skin contact. There is no exact statistics on how many people in the world are infected with HPV, because in most of the infected, the virus does not manifest itself in any way. Biologists believe that about 80% of the world’s population is HPV carriers.

The danger of the virus is that some of its types can lead to cancer.98% of cervical cancers (according to US scientists – 100%) are associated with HPV. The virus provokes cancer of the vagina, vulva, anal canal, male genital organs, throat, mouth. Moreover, a deadly disease can develop years, decades after infection, if conditions are favorable for this.

In total, the HPV group includes more than 170 viruses and strains, of which about 40 are sexually transmitted, and 13 are capable of causing cancer.

Infection with certain types of HPV – in the presence of high immunity – passes imperceptibly, without a trace for the body.Other strains cause skin cells to rapidly divide, resulting in warts, papillomas, condylomas (“venereal warts”). The third types, integrating into human DNA, act as oncogenes and promote malignant cell transformation and tumor growth.

This is important! HPV is not a sufficient factor for the development of cancer. But he is one of the most important oncoferts, a “provocateur” of cell malignancy.

In order for the degeneration of healthy tissue into cancerous tissue to begin, a combination of several conditions is necessary, including malfunctioning of the immune system.It is immunity that is the main protector, including from an increase in the HPV viral load.

It is very important to periodically get tested for HPV to prevent the danger caused by the virus. So, you can cure a precancerous condition of the cervix. Other HPV-related cancers respond better to treatment if it starts early in the disease and is monitored by periodic viral load lower / higher viral load tests.

HPV: methods of infection, symptoms, oncogenic types of virus

The main methods of infection:

• vaginal, oral, anal sex with a person infected with HPV;

• in case of skin-to-skin contact with a person infected with papillomavirus, or contact with surfaces that an infected person touched – household infection is possible if there are cuts, abrasions, or other injuries on the skin;

• during childbirth – from mother to child.

Recent studies by American and European scientists have shown that there is a high probability of contracting HPV in medical institutions – through blood transfusions, using medical equipment, inhaling viral particles, for example, during laser ablation or electrocoagulation of genital warts.

The difficulty of dealing with asexual infections is that the virus is extremely resistant to most disinfectants. HPV is the first virus that turned out to be insensitive to inactivation (processing) with glutaraldehyde (a means for sterilizing surgical instruments that require absolute cleanliness).Doctors and technologists were faced with the problem of disinfecting devices that cannot be autoclaved or exposed to aggressive chemical compounds.

Symptoms and types of human papillomavirus

The symptoms of infection differ depending on the type of HPV. Some types, for example – HPV5, persist in the human body without clinical symptoms and can only be detected by special studies. HPV strains 1, 2, 4, 7, 22, 63 cause the formation of warts on the hands, feet, and soles.

Types 6, 11, 42, 44 can cause the development of genital warts, laryngeal papillomatosis; 6, 16, 18, 31 and others – anal dysplasia; 60 – viral cysts.

Strains 26, 53, 66 can lead to cancer of the genital organs. Strains with high cancer risk – 33, 35, 39, 51, 52, 56, 58, 59. Types 16, 18, 31, 45 have the highest risk of cell transformation into malignant ones. .

Tests for HPV in women and men

When assigned

HPV tests need to be passed by each adult on their own, without an appointment, i.e.Because the probability that you are infected is 8 out of 10.

A referral for analysis is usually issued by a dermatologist, urologist, gynecologist in the presence of characteristic external signs or diseases that can be caused by a virus.

HPV tests are taken when planning pregnancy, when identifying the causes and treatment of infertility, pathologies of pregnancy and gestation. In this case, both partners are tested.

Risk factors and the reason for passing the test in women are also:

• early sexual activity;

• relationships with different, sometimes several sexual partners at once;

• general chronic, gynecological diseases, pathologies;

• weak immunity.

Risk factors and reason for passing the test in men are also:

• multiple sex contacts;

• having sex with women infected with HPV;

• poor hygiene;

• narrowing of the foreskin;

• weak immunity.

HPV diagnostic methods

Colposcopic examination

Colposcopy – examination with a colposcope of the vaginal part of the cervix, the entrance and the walls of the vagina. It is a simple, inexpensive, but highly informative method for diagnosing cervical diseases.

An extended colposcopy with the use of several tests – with 3% acetic acid, Lugol’s iodine solution is of clinical importance.Tests reveal various types of epithelium, allow to assess the size and quality of pathological formations (if any), vascular pattern, quality of the cervical glands.

During colposcopy, targeted biopsy is performed from the most atypically altered areas.

Cytological examination

The task of cytological examination of cervical smears (Papanicolaou test, pap test) is to identify cells specific for HPV infection – coilocytes and dyskeratocytes.

Confirmation of papillomavirus infection is the detection of coylocytes, transepithelial lymphocytic infiltration, basal cell hyperplasia in a biopsy specimen (biomaterial taken for research).

Pap test is required for:

• women after 30 years;

• women who have been previously diagnosed with HPV;

• women who, during colposcopy, found zones with altered epithelium.

According to the results of the pap test, the class of danger to the health of a woman is determined: 1–2 class – without suspicion of cancer, 3 class – suspicion of oncology, 4–5 class – the presence of cancer cells in small or large numbers.

The disadvantages of cytological research include the complexity of execution, high qualification requirements for a cytologist. Therefore, it is necessary to undergo research in diagnostic centers and laboratories, whose staff constantly confirms their professionalism.

Histological examination

The histological method for detecting HPV could be considered the gold standard for diagnosing the virus, but its high cost, the impossibility of frequent testing and not always accurate targeted sampling of a biopsy from the cervix interfere with it. To carry out histological diagnostics, specialists of very high qualifications are also required.

Therefore, the histological examination of the biopsy specimen often serves as an adjunct to the pap analysis.It allows you to assess the state of cells, the degree of damage, to determine what the neoplasm is – a tumor or warts.

PCR diagnostics of papillomavirus

Polymerase chain reaction (PCR) refers to high-resolution technologies for the detection of nucleic acids. Modern PCR test systems are highly sensitive, they are used not only to detect HPV, but also the viral load on the body (a quantitative indicator of infection) of the main clinically significant genotypes (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59), which are responsible for almost 94% of cases of severe cervical dysplasia and cervical cancer.PCR test systems are also used to detect HPV 6 and 11 strains.

Such capabilities of the test system allow predicting the course of HPV infection and assessing the effectiveness of therapy. It was found that human papillomavirus infection has a dose-dependent effect: the higher the concentration of the virus DNA in the test material, the higher the risk of developing neoplasia and cancer.

The test results indicate the concentration of HPV:

• Lg <3 - the papillomavirus was detected in a clinically insignificant amount;

• Lg 3-5 – papillomavirus detected in clinically significant quantities;

• Lg> 5 – papillomavirus was detected in high concentration, the viral load on the body is high.

Types of test material, sampling rules:

• for dad test – cervical smear;

• for a cytological study – a biopsy taken aimingly from atypically altered areas of the mucous membrane.

• for PCR test – scraping of cells of the mucous membranes of the genital tract.

A smear in women is taken from the cervical canal, in men – from the urethra.For a smear, use a soft brush or cotton swab. They are carefully inserted into the canal, then carefully removed by rotating. On the surface of the brush / tampon, epithelial cells remain on the surface, which are necessary for research.

How to prepare for an HPV test

Biomaterial sampling is not carried out during menstruation, 5 days before its start and within 5 days after the end. You cannot undergo a study if there are inflammatory processes.

2 days before the sampling of the biomaterial, women and men need to refrain from sexual intercourse.Women should not use vaginal creams, medications, suppositories, douching, tampons within 48 hours; instead of a bath, you need to take a shower. A smear is taken before any gynecological manipulations or 2 days after them.

If the biomaterial is taken from the urethra, then at least 90 minutes should pass from the last urination to the sampling of the biomaterial.

When taking a biopsy for histological examination, the same rules are followed as when preparing for taking a smear.After a biopsy for 2-3 weeks, you must not:

have sex,

• experience significant physical activity,

• overheat (bath, sauna, hot weather),

• swim in an open pond or pool,

• take medications that thin the blood;

• use vaginal products.

If bleeding occurs, use only pads (not tampons!)

The accuracy of the result can be influenced by antibiotics, probiotics, local antiseptics that you took / used even 2 months ago. Before collecting the material, you need to tell the doctor about all the medicines you have used or are using.

Cost of research for the presence of human papillomavirus infection in JSC “ SZDTSM”

The cost of a study for HPV infection depends on the type of study, coverage of virus strains, type determination / without determination, calculation of viral load.

Prices for the types of research in the medical departments of SZDTSM JSC represent various combinations in terms of coverage, details, and predictive value.

The doctor – gynecologist, dermatologist, venereologist will tell you which method of research to choose. If you take tests on your own initiative, choose a study for the presence of oncogenic HPV strains.

Where to get tested for HPV

You can take HPV tests in the medical departments of SZDTSM JSC located in St. Petersburg, Leningrad Region, Veliky Novgorod, Staraya Russa and other cities.

To find the nearest point to you, use the interactive map or the list of medical institutions of SZDTSM JSC.

In all our branches – terminals and centers – you will be greeted by attentive, experienced and highly qualified specialists. Medical institutions of SZDTSM JSC are equipped with modern equipment, laboratory materials, disposable instruments and consumables.

We guarantee you the accuracy of research, a caring attitude, complete confidentiality of your personal data and survey results.

Be healthy! And for this, on time and regularly undergo important examinations at SZDTSM JSC.

We will help you maintain and restore your health!

90,000 HPV – what do we know about it?

What is HPV?

Human papillomaviruses are a group of human papillomaviruses, consisting of 27 types of virus and more than 170 strains. At least 14 types of HPV are considered oncogenic, and in 70% of cases, cervical cancer is caused by types 16 and 18.Most cases of cervical cancer are caused by this virus.

HPV is the most commonly sexually transmitted disease. 80% of people in the world will be infected with the virus during their entire life, 660 million people are already carriers of it.

How is it transmitted?

HPV is transmitted in several ways:

• Sexual transmission (including oral sex) is the main route of transmission of the virus;
• Through mucous membranes and microcracks in the skin;
• In everyday life (common objects, handshake, touch).

The virus can live for some time in public places: baths, saunas, gyms, etc. It is also considered to be quite resistant to antiseptics.

How to identify it in the body?

Pass the HPV screening. You can do an analysis for several specific strains of the virus or take a comprehensive test. HPV is diagnosed by PCR.

And what are the consequences of HPV infection?

The virus can lead to the formation of papillomas and warts (especially types 6 and 11), and HPV of high oncogenic risk – to cervical cancer.There are also studies supporting the link between HPV and cancer of the anus, vulva, vagina, penis, and oropharynx. But many strains of HPV are not dangerous to health: often this infection disappears from the body by itself in a few years and does not make itself felt in any way.

Do all HPVs lead to cancer?

No, only oncogenic types. This is especially true for 16 and 18 types of the virus, but in total there are at least 14 types of HPV of high oncogenic risk.

Can HPV be cured?

No, to date there is not a single drug with proven effectiveness that can cure HPV infection.You can only treat manifestations of the virus, for example, papilloma, as well as regularly and timely examined to prevent the development of precancerous changes in the cervix.

Note that in many medical institutions, doctors prescribe antiviral drugs supposedly for HPV, but at the moment there is not a single drug that can really cure this infection.

But I was prescribed medication and the virus disappeared.

In many cases, their own immunity copes even with dangerous types of HPV (16 and 18), and they are no longer detected.However, a gynecologist’s supervision is necessary for several years. The “disappearance” of the virus in the analyzes can create a false sense of security, while hidden processes can continue. And remember, there is no proven cure for HPV yet.

If I have high-risk HPV, will I definitely have cancer?

No. A combination of factors contributes to the development of the oncological process, and the virus is only one of them, therefore, it will not necessarily lead to cancer in all carriers of HPV.For cervical cancer, the main risk factors are chronic inflammation in the genital tract and smoking. But regular observation by a gynecologist and a healthy lifestyle will avoid the development of oncology. Early changes caused by HPV respond well to correction.

Do condoms protect against HPV?

Condoms must be used during sexual intercourse, but they do not give a 100% guarantee that you will not get infected: after all, the virus can also be transmitted through oral sex and through the skin.

Is there a vaccine for the virus?

Yes, and very effective. HPV is usually vaccinated with Gardasil or Cervarix. Vaccination gives about a 90% guarantee that HPV will no longer be dangerous for you. Vaccination against the virus is done in 3 stages in several months. Before vaccination, we recommend passing an extended screening for HPV and visiting a gynecologist: if the analysis shows the presence of an infection, then you need to discuss with the doctor the need for vaccination and further actions.

I passed the HPV test.The analysis came back negative. So I don’t have HPV?

No, unfortunately, this is not always the case. In many cases, the virus does not appear immediately. The duration of the incubation period for HPV is not yet precisely known. It should also be borne in mind that HPV has a lot of strains, and extended screening is usually prescribed only in case of deviations from the norm in a cytological study, these factors also complicate the diagnosis.

Is it true that women are more likely to contract HPV?

Both men and women are equally likely to contract HPV.But since cervical cancer in most cases is the result of infection with oncogenic strains of this virus, women are primarily prescribed for HPV screening.

Men are not afraid of HPV?

Of 42.5% of cases of HPV infection of high oncogenic risk, 25.1% are in men. In addition, a number of studies have shown a link between infection with certain HPV strains and the development of cancer of the penis and anus. Therefore, men also need to be checked and not forget about prevention.

Is HPV transmitted from child to mother during childbirth?

This happens infrequently and is associated only with HPV types 6 and 11 – those that lead to the formation of genital papillomas and genital warts. In order not to risk it, we recommend that you resolve the issue with these formations even before pregnancy. To do this, you need to contact a gynecologist.

My partner was diagnosed with HPV. Does this mean that he / she is cheating on me?

Don’t jump to conclusions. Remember that the virus can be latent for a long time and appear much later than the moment of infection.

To summarize: what needs to be done to prevent HPV?

• Get vaccinated against the virus,
• Use condoms during intercourse,
• Take care of your health: do not miss a scheduled appointment with a gynecologist, take the necessary tests as prescribed by a doctor, do not smoke and be less nervous.

Our gynecologist, reproductologist M.I. Bobrova helped in compiling the material.

90,000 EXPRESSION OF ONCIPOL E6 OF THE HUMAN PAPILLOMA VIRUS IN THE EPITHELIUM OF THE UTERINE APPEARANCES IN OVARIAN CANCER AND GENETIC PREPOSITION TO IT

INTRODUCTION

…In the last decade, the solution to the issues of etiology, early diagnosis and prevention of ovarian cancer (OC) is associated primarily with medico-genetic studies aimed at studying the genetic predisposition to the development of a malignant process in the ovaries [4]. According to modern concepts, the hereditary risk factor for the development of ovarian cancer, 5–10% of cases of which are caused by mutations in genes BRCA1 and BRCA2 , is one of the most significant [1, 17].In addition, the presence in the pedigree of the proband of 2 first-degree relatives with OC also increases the risk of ovarian neoplasms in members of this family [19]. It should be noted that in the United States and some European countries, the presence of mutations in genes BRCA1 / 2 and a family history of breast cancer (BC) and ovary cancer are the basis for prophylactic salpingo-oophorectomy [12].

At the same time, the etiopathogenesis of OC is still insufficiently studied: the question of the significance and correlation of hereditary, as well as external environmental factors in the development of this neoplasm remains open.A study carried out on cultures of cells of the surface epithelium of the ovary of women with a genetic predisposition to OC showed the presence of tissue-specific genetic instability

of these cells and their high sensitivity to alkylating agents, in particular mitomycin C [20]. According to the authors, these features determine the increased susceptibility of the surface epithelium of the ovary to the action of external factors, including those of a viral nature.

Currently, the etiological relationship of HPV with the development of cervical cancer (CC) and other anogenital tumors has been established.The transforming effect of oncogenic HPV types (16, 18, 31,

33, 35, 39, 45, etc.) is provided by the functioning of oncogenes E6 and E7 [18]. The products of these genes disrupt the functions of cellular proteins, which are key regulators of the cell cycle. Thus, the E6 oncoprotein binds the p53 protein, which leads to the degradation of the latter by ubiquitin-dependent proteolysis, which results in a violation of the mechanisms that control proliferation, apoptosis, and DNA repair.In addition, the interaction of the E6 protein with telomerase also contributes to an increase in the proliferative activity of cells. The mechanism of action of the E7 oncoprotein is associated with functional inactivation of the tumor suppressor pRb, resulting in the release of the transcription factor E2F, which activates genes whose protein products stimulate the entry of the cell into the S-phase of the cell cycle [18]. Data on the presence of viral sequences in OC cells are not numerous, and the question of the role of HPV in the development of OC remains controversial.Many scientists do not exclude the role of human papillomavirus infection in the pathogenesis of this neoplasm [2, 3, 10, 24]. Studies of HPV

HPV infection of epithelial cells of the upper genital tract in women with a genetic predisposition to OC have not been conducted.

The aim of the work was to study the expression of the HPV 16 and 18 HPV oncoprotein E6, as well as the p53 protein in samples of the fallopian tubes and ovaries of women with a genetic predisposition to the development of OC and patients with OC.

OBJECT AND RESEARCH METHODS

The study was performed on the operating material of the fallopian tubes and ovaries of 20 women who underwent preventive salpingo-oophorectomy due to a high risk of developing ovarian cancer, and 55 patients with serous ovarian cancer.Surgical specimens from women at high risk of developing ovarian cancer were obtained from the Medical University of Oregon (USA). According to the US Preventive Services Task Force Recommendation, the patient was classified as a high-risk group based on one of the following criteria [19]: a) the presence of mutations in genes BRCA1 / 2 ; b) the presence in the family of the proband of 1 or more relatives of the 1st degree of relationship (mother, daughter, sister) with a diagnosis of OC at the age of up to 50 years; c) the presence in the proband’s family of 1 relative of the 1st degree of kinship with a diagnosis of OC, as well as 1 or more relatives of the 2nd degree of kinship (grandmother, granddaughter, cousin, aunt, niece) with a diagnosis of breast cancer or OC; d) BC in the proband and the presence in the pedigree of 1 or more relatives of the I and II degrees of relationship with the diagnosis of BC or OC.Patients with OC were treated at the Department of Oncogynecology of the National Cancer Institute of the Ministry of Health of Ukraine (Head of the Department – Doctor of Medical Sciences, Prof. L.I. Vorobieva). The average age of patients at high risk of developing OC and patients with OC at the time of surgery was 45.0 ± 2.7 (26–74) and 50.7 ± 1.9 (16–79) years, respectively –

, respectively. All patients gave informed consent to be included in the study.

Surgical material was fixed in a 10% solution of buffered neutral formalin.The diagnosis was verified using histological preparations stained with hematoxylin and eosin. Both ovaries were examined morphologically. Immunohistochemical detection of HPV 16 and

18 types E6, as well as p53 protein, was carried out on paraffin sections using mAb to HPV16 E6 + HPV18 E6 at a dilution of 1: 100 (clone C1P5, “AbCam”) and p53 (clone DO7, “DaKoCytomation” ). The immunohistochemical reaction was carried out using a standard one-step protocol with antigen unmasking by high-temperature treatment (power – 700 w) in citrate buffer (pH 6.0).Visualization was performed using the EnVision system and diaminbenzidine dye (DakoCytomation). Nuclei were counterstained with Mayer’s hematoxylin. The result of the immunohistochemical reaction was assessed by a semi-quantitative method by calculating the percentage of positively stained cells – the index of the label (MI,%). Expression of

E6 was considered negative in the absence of staining; focal – in the presence of 10-30% of stained cells located in separate areas of the epithelium; diffuse – in the presence of more than 30% of stained cells located throughout the epithelium.Expression of p53 was considered low when the MI was below the median, and high – when the MI was above the median. As a positive control (HPV 16+ DNA), histological sections of cervical intraepithelial neoplasia grade III were used.

The significance of differences between groups was assessed using the nonparametric two-sided Fisher test in Statistica 7.0 software.

RESULTS AND DISCUSSION

Analysis of anamnestic and genealogical data of 20 patients with a genetic predisposition to OC confirmed the burden of their pedigree for breast cancer and / or OC.Genetic testing revealed the presence of mutations in genes BRCA1 and BRCA2 in 5 of them (Fig. 1).

Fig. 1. Pedigree of the proband M ., 40 years old, from the sub-ethnic group of Ashkenazi Jews. The proband and the proband’s cousin have a mutation in the gene BRCA1 (187delAG). Relatives of the proband І and ІІ degrees of kinship (mother, cousin, grandmother) suffered from breast cancer and OC. The mother of the proband died of multiple primary breast cancer and ovarian cancer at the age of 40.Note: the proband is marked with an arrow. Arabic numerals indicate the age of the onset of the disease, Roman – generations,? – age unknown

When analyzing the morphological features of prophylactically removed ovaries in women with a high risk of ovarian cancer, the presence of multiple follicular, serous, inclusion cysts, corpus luteum cysts, glandular structures with serous epithelium, hyperplasia of the theca tissue, superficial papillosis and fibromatosis was revealed. A characteristic feature of follicular and inclusion ovarian cysts in women with a mutation in genes BRCA1 / 2 was the presence of papillary growths on their walls, the epithelial cover of which was characterized by signs of hyperplasia.Polycystic ovary disease was diagnosed in 5 patients. Histological examination of the fallopian tubes in high-risk women revealed sclerosis of the villi with foci of perplasia of the epithelium of individual villi, and paratubar cysts were also noted.

The results of the morphological study of the operating material of OC patients showed that all neoplasms were serous carcinomas of varying degrees of differentiation: 4 – high (G1), 26 – moderate (G2) and 25 – poorly differentiated (G3).

In women with a genetic predisposition to OC, the HPV 16/18 E6 protein was found in 12 (60%) cases, including in 4 women with breast cancer in history and in 2 Ashkenazi Jewish women with a mutation in the BRCA1 gene. At the same time, both nuclear and cytoplasmic localization of the protein were noted. In 4 women, E6 expression was detected only in the epithelium of the fallopian tubes, in 8 – in the epithelium of the fallopian tubes and ovaries. When studying the nature of E6 expression, diffuse staining was found in the epithelium of the fallopian tubes (Fig.2), focal – in hyperplastic and unchanged superficial ovarian epithelium, granulosa cells of follicles (Fig. 3), epithelium of follicular cysts (Fig. 4) and glandular structures of the ovaries with serous epithelium (Fig. 5).

Fig. 2. Fragment of the fallopian tube. Diffuse expression of HPV 16/18 oncoprotein E6 in the villi of the fallopian tube and capillary endothelium. Arrows indicate “light” cells, which are, according to the literature, indicators of HPC-associated changes in epithelial cells.Uv. x 400

Fig. 3. Expression of HPV 16/18 oncoprotein E6 in granulosa cells of the primary ovarian follicle. Uv. x 100

Fig. 4. Expression of the oncoprotein E6 HPV16 / 18 in the epithelium of the follicular cyst. Uv. x 400

Fig. 5. Expression of the HPV 16/18 oncoprotein E6 in the glandular structures of the ovary with serous epithelium. Uv. x 400

It should be noted that in the epithelium of the fallopian tubes expressing the E6 protein, light cells with pyknotic nuclei, similar to coylocytes, which are noted in the epithelium of the cervix during HPV infection, were detected.These cells were localized both in the basal layer of the epithelium and in the thickness of the epithelial layer (see Fig. 2). According to the literature, the effect of HPV on the cell is manifested by a cytopathic effect, as a result of which coilocytes (with enlarged nuclei, uneven folded membrane and hyperchromatosis) are found, the presence of which serves as an indicator of early HPV-associated morphological changes in epithelial cells [14]. Based on the latter and the expression of the E6 protein we detected in the epithelium of the fallopian tubes, it can be concluded that the presence of coylocyte-like cells is an objective indicator of HPV infection.

Positive expression of E6 was also noted in the endothelial cells of the vessels of the fallopian tubes (see Fig. 2) and ovaries of women at high risk of ovarian cancer, which clearly indicates the tropism of HPV to the vascular endothelium and a possible hematogenous pathway of virus dissemination.

The results of an immunohistochemical study of the tumor suppressor p53 in women at high risk of developing ovarian cancer showed the absence of expression of this protein in the tissue of the fallopian tubes and ovaries, in whose cells the HPV oncoprotein E6 was found.At the same time, in 2 HPV E6-negative observations in patients with mutations in genes BRCA1 and BRCA2 , p53 protein expression was observed in the epithelium of ovarian cystic formations (MI p53 – 30.2 and 62.1%) and in the epithelium of villi fallopian tubes (MI p53 – 4.8 and 9.8%).

In the group of patients with serous OC, the E6 protein was expressed in 9 out of 55 (16.3%) cases, which is significantly lower than in cases of high risk of OC (p = 0.01). The frequency of HPV 16/18 infection we revealed, determined by the expression of the viral oncoprotein E6, is consistent with the data of some European authors who found the presence of these types of HPV in tumor cells in 4.2–37.5% of OC cases [2, 3, 10].In 7 cases of serous OC, staining was diffuse, in 2 – focal. In all cases, both nuclear and cytoplasmic localization of the protein were also noted. It should be noted that E6 was expressed only in moderately (66.7%) and poorly differentiated (33.3%) serous ovarian carcinomas.

An immunohistochemical study of p53 expression yielded a positive result in 86.8% of OC cases. It should be noted that significant variability in the number of cells expressing p53 (4.0–73.0%) was found in ovarian neoplasms, the median of p53 expression was 30.0%.Low expression (MI ≤ 30.0%) p53 was found in 37.7%, and high expression (MI> 30.0%) – in 49.1% of cases of serous OC (Fig. 6), while the average expression level in patients OC – ​​31.2 ± 2.9%.

Fig. 6. Distribution of patients with OC (%) by expression of protein p53

The dependence of the expression of the tumor suppressor p53 on the presence and features of expression of the oncoprotein E6 in the cells of serous OC draws attention. Thus, in serous carcinomas, in whose cells the HPV E6 oncoprotein was found, the level of p53 expression (MI 19.6 ± 4.08%) was significantly lower,

, than in tumors with no viral oncoprotein (MI – 33.4 ± 3.2 %) (p = 0.04) (table).

Table Expression of the tumor suppressor p53 depending on the characteristics of expression of the HPV oncoprotein E6 in serous ovarian cancer cells

Moreover, in neoplasms with focal localization of the HPV E6 oncoprotein, p53 protein expression was high and amounted to 53.0 and 39.0%.In contrast, ovarian tumors with diffuse localization of the E6 oncoprotein (Fig. 7) showed negative and low expression of p53 (MI 0.0–26.0%) (Fig. 8).

Fig. 7. Diffuse expression of HPV 16/18 oncoprotein E6 in serous OC cells. Uv. x 400

Fig. 8. Low expression of p53 in serous OC with diffuse localization of oncoprotein E6 HPV 16/18. Uv. x 400

Thus, the analysis of the expression of the E6 oncoprotein made it possible to establish a high frequency of HPV 16/18 infection in the unchanged epithelium of the uterine appendages in patients with a genetic predisposition to OC and a significantly lower level of tumor cell infection in patients with serous OC.High HPV infection of the ovarian epithelium in high-risk cases is most likely due to the instability of the genome of these

–

cells, which determines their sensitivity to the action of external factors. The latter is confirmed by the features of some hereditary syndromes of chromosomal instability, in particular Fanconi anemia, in which in more than 80% of cases the development of carcinomas of the anogenital tract is associated with infection with oncogenic HPV types [16]. This suggests that HPV infection of the superficial ovarian epithelium of women with a genetically determined risk of ovarian cancer may be an additional exogenous inducer of the transformation of ovarian epithelial cells.It is possible that the detection of the E6 protein in the granulosa cells of the follicles reflects their possible participation in the maintenance of the productive life cycle of HPV, since, according to [21], in the culture of the human ovarian epithelium, cells produce a number of protein products (AP-1, Sp-1, Oct -1, NF-1), characteristic of epithelial-specific transcription of early HPV genes. In addition, the granulosa cells of the follicles can be a reservoir of viral particles, which, when the wall of the ovulating follicle ruptures, reach the surface epithelium of the ovaries and thus cause local infection.It is possible that local inflammatory processes in the surface epithelium of the ovaries, initiated by ovulation, along with HPV infection, can provoke the appearance of cystic formations and increase the risk of epithelial malignancy [9].

It has now been established that such an exogenous factor as HPV is a promoter of malignant transformation of proliferating epithelium, since the protein products of its oncogenes E6 and E7 disrupt the functions of key regulators of the cell cycle p53 and pRb [18].In addition, as a result of numerous experimental studies of HPV-associated neoplasms, the resistance of the mutant form of the p53 protein to the degrading effect of the HPV oncoprotein E6 by ubiquitin-dependent proteolysis was established [22, 23].

The absence of p53 protein expression in serous OC cells that express HPV oncoprotein E6, revealed in our study, apparently indicates its inhibitory effect on the suppressor protein. These results are consistent with the few data of other researchers who showed the inactivation of the p53 protein due to its interaction with the HPV type 16 oncoprotein E6 in ovarian and breast neoplasms [15, 11].It should be noted that the mAb (clone DO7) used in our work visualizes the protein product of both the “wild” and mutant gene TP53 . Therefore, the absence of the p53 protein in serous OC cells with diffuse localization of the HPV oncoprotein E6 is most likely associated with the interaction of E6 with

“wild” form of p53. At the same time, a low or high level of expression of the p53 tumor suppressor in neoplasies with diffuse and focal localization of the E6 oncoprotein indicates the presence of a population of cells with a mutated form of p53, which, as mentioned above, is resistant to the action of viral oncoproteins.The variability of the phenotypic characteristics of serous ovarian carcinomas, established in our study, both in the expression of the tumor suppressor p53 and in the frequency of detection of the HPV E6 oncoprotein, the peculiarities of its localization in tumor tissue, suggests that serous OC is an etiologically heterogeneous neoplasm in terms of the participation of genetic and environmental factors. in its development.

Summarizing the above, it is necessary to

once again emphasize the relevance of studies aimed at studying the role of HPV in the development of OC, in particular the importance of viral oncoproteins in the regulation of the proliferation of ovarian epithelium, reflecting the biological properties of the tumor.In addition, the features of the functioning of viral oncogenes in ovarian tumor cells may differ in tissue-specificity, which also requires further, more in-depth studies.

In conclusion, it should be noted that the establishment of a causal relationship between viral infection and the development of OC will contribute to both the determination of the etiopathogenetic significance of highly oncogenic HPV types and the development of measures for the prevention of these neoplasms.

CONCLUSIONS

1. The results of the presented study indicate a high susceptibility of epithelial cells of the upper genital tract to HPV infection in women with a genetically determined risk of developing ovarian cancer.

2. The heterogeneity of serous OC was established in terms of the number of cells expressing p53, depending on the presence of expression of the HPV oncoprotein E6 and its prevalence in the tumor tissue.

3. The revealed expression of the oncoprotein E6 HPV 16/18 in the unchanged epithelium of patients with a high risk of OC and tumor cells of patients with OC, apparently, reflects the importance of highly oncogenic HPV types in the pathogenesis of this neoplasm.

The work was supported by the target complex interdisciplinary research program of the National Academy of Sciences of Ukraine “Fundamentals of Molecular and Cellular Biotechnologies”, within the framework of which the research work “Investigation of genetic prerequisites and the influence of environmental factors on the realization of hereditary predisposition to the development of malignant tumors” (state registration number 0110U005761).

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Human papillomavirus: truth and myths

March marks the Day of Fight Against Human Papillomavirus, a dangerous and widespread disease throughout the world.

HPV is indeed an extremely dangerous disease: more than ten types of this virus lead to the development of cancerous tumors. There are many myths around human papillomavirus infection. To debunk them, the correspondent of “KN” met with the deputy chief physician of the Krasnodar Regional Clinical Dermatovenerologic Dispensary, a doctor of the highest category, Candidate of Medical Sciences Alexey Shevchenko .

• HPV is sexually transmitted

TRUTH.According to the World Health Organization, human papillomavirus infection is transmitted primarily through sexual contact. The likelihood of contracting HPV through personal care products is almost zero.

• HPV is present at some stage in a significant part of women during life

TRUTH. HPV is common. Doctors divide it into two groups: viruses of low cancer risk (6, 11 and others) and viruses of high cancer risk (types 16, 18, 31, 33, 35, 58 and others).In the first case, warts and condylomas occur. They require treatment, examination for concomitant urogenital and other infections, but sometimes the body can cope with them on its own within 6-24 months. Re-infection is possible because HPV is not immune. Therefore, it is necessary to be observed by a dermatovenerologist or gynecologist for up to two years.

High-risk viruses cause precancerous and cancerous changes in the cervix and sometimes other organs. In 75 percent of cases, cancer is associated with the presence of a virus of the 16th and 18th types.They have the highest degree of oncogenicity: 3-4 years pass from HPV infection to cancer. Therefore, it is important for women to undergo gynecological screening every year.

• Condoms and other barrier contraceptives protect against HPV transmission

MYTH. Using condoms reduces the risk of contracting HPV, but does not completely protect against infection. It is advisable to combine the use of barrier protection and special disinfectant solutions: miramistin, gibitan.

• A pregnant woman with HPV can transmit the infection to her newborn

MYTH. Science knows very rare cases of genital warts of the vocal cords of a newborn. Women with HPV and even those with condylomas are allowed to have a natural birth in the absence of special obstetric indications.

• The presence of HPV in the body is determined by a blood test for antibodies

MYTH.Human papillomavirus infection can be detected by a blood test. However, the study of this biomaterial is diagnostically less significant: the presence of HPV in the body does not necessarily mean the development of an infection. Only its detection in the epithelium means that the virus has actually reached a significant concentration and infected the body.

That is, it is not a blood test that is informative, but a smear analysis by the PCR method. To begin with, they do a simple PCR test of epithelial tissues for the presence of a virus in the body.If it is positive, then a more detailed analysis with genotyping is carried out to establish what type of virus is in the body.

• HPV can cause precancerous changes and cervical cancer

TRUTH. High-risk HPV can cause serious health problems. It is found in 95–97 percent of patients with cervical cancer. In only 3-5 percent of cases, this disease is not associated with HPV. The low-risk virus provokes the appearance of genital warts and warts of the vaginal mucosa, cervix and external genital skin.These growths are not precancerous, but still require treatment.

• HPV testing is done for all women

MYTH. The recommended age to start annual HPV testing is 30 years. Up to this age, testing is carried out only for individual indications when pathology is detected in a cytological smear.

• When HPV is detected, it is important to determine the amount of the virus

MYTH.Quantitative tests have no clinical use. It is important to understand whether HPV is present in the body and what type it is. Good quality PCR typing tests are ideal for this.

• There is an effective and proven HPV treatment

TRUTH. At the moment, there are several methods of treating HPV, but the complete disappearance of the virus from the body, as a rule, does not occur.

• HPV can disappear on its own and without special treatment.

TRUTH. This phenomenon is called “self-elimination”. It most often occurs with women under 30. After 30 years, the likelihood of self-healing is significantly reduced: 10-15 percent of women remain carriers of high-risk HPV.

• Vaccines are available to prevent HPV infection

TRUTH. To date, three vaccines are licensed in the world: tetravalent Gardasil (against types 6, 11, 16 and 18), nine-valent Gardasil-9 (6,11,16,18 + 5 highly oncogenic types) and Cervarix (bivalent against types 16 and 18) …

• If HPV is already present in the body, the vaccine can activate the infection, a complete examination is required before vaccination

MYTH. The vaccine is prepared in a laboratory and is virus-free. Therefore, it is impossible to become infected with HPV during vaccination. Vaccination is recommended for all women and men under 26 years of age, almost without exception (a very large group with the maximum risks of HPV infection).

• The vaccine is not without side effects, sometimes it leads to infertility in young women

MYTH.In world practice, there was no data on the effect of the vaccine on fertility. Moreover, the vaccine is practically free of side effects. For the entire period of use (since 2001), the only side effects were local reactions in the injection area and extremely rare dizziness.

symptoms, treatment and prevention of the disease – ISIDA Clinic Kiev, Ukraine

HPV – Human Papillomavirus (HPV) is a family of viruses that includes about 100 species.

Diseases of the external genital organs today are the most common, aggressive pathology. For example, HPV infection is asymptomatic for a long time and can have serious consequences. Certain strains of the virus can lead to cancer of the rectum, vagina, and cervix. Therefore, it is important to diagnose it on time and start appropriate treatment.

What is HPV?

Human papillomavirus is a common infection of the genital tract.This pathogen is found in almost every sixth inhabitant of the planet. When infected, the pathogen enters the epithelial cells, disrupting the division process, which activates the development of various diseases. Mostly, the virus infects the organs of the genitourinary system, the anorectal region. Diseases that occur during HPV infection:

1. Formation of genital warts.
2. Development of papillomatosis of the respiratory tract.
3. Damage to the genital organs with the development of a tumor process.

Almost 70% of the population are carriers of the pathogen without clinical manifestations of disease. Re-infection is also possible during life. Because not all those who have had papillomavirus infections develop resistance to the virus.

HPV types

More than 100 types of HPV are currently known. Some of them are relatively safe for human health, while others can activate the development of the oncological process.Most often, clinical signs of the disease do not appear in the early stages. Usually, the first symptoms occur after the action of provoking factors.

According to oncological activity, such viruses are classified into:

1. Strains with high oncogenic risk (18, 16, 31, 33, etc.)
2. Strains with low oncogenic risk (6, 11, 32, 40 -44, 72)

Low-oncogenic strains of viruses lead to the appearance of warts and papillomas of the skin on the surface of the body.

Highly oncogenic strains cause the formation of genital warts in the anogenital zone, on the surface of the cervix in women and the penis in men.

Prolonged exposure to 16.18, 31.33 types of the virus can lead to cervical dysplasia and a more formidable disease – cervical cancer.

However, even in the presence of high oncogenic risk in the body of HPV, oncological pathology does not always develop. Timely appeal to experienced doctors for diagnostics, correctly selected treatment, will allow you never to face dangerous clinical manifestations of the human papillomavirus.

How you can get infected

Women and men are infected with this pathogen equally often.

The main route of transmission is considered to be sexual. Usually HPV is infected after the first sexual contact, but other transmission routes are also distinguished:

1. Vertical. That is, during the passage through the birth canal of a woman infected with HPV, the newborn can become infected.
2. Autoinoculation. Self-infection (transfer from one part of the body to another) is possible during epilation or shaving.
3. Contact and household. The human papillomavirus remains viable in the environment for some time. Therefore, they can become infected after visiting public places (bathhouse, gym, swimming pool).
4. Contact. Possible infection through the wound surface on the skin or mucous membranes (abrasions, wounds, bruises).
5. Genital. The most common route of infection.

Anyone can get a viral infection. In order to diagnose it in a timely manner, you need to undergo preventive examinations with a doctor to determine the first symptoms of pathology.

Main manifestations of infection

The presence of papillomavirus infection may not have clinical manifestations for a long time. The incubation period of the disease can last for several years, during which the patient can become infected with various types of the virus. Only after exposure to provoking factors (immunodeficiency, hypothermia, stressful situations), signs of HPV infection can be observed. In most cases, self-healing from this infection occurs within 1-2 years, but in some patients the pathology becomes chronic.

The disease can manifest itself with the following formations:

1. Genital warts (genital warts). Outwardly, these are papillary growths that resemble cauliflower or a comb in shape. They are flesh-colored or pink, and can be single or multiple. They can form everywhere, but are most often found on the skin and genital mucosa. Formations are characterized by low oncogenic potential. They rarely turn into malignant neoplasms, usually do not cause discomfort to the patient.
2. Flat warts. They have a characteristic structure – they do not protrude above the surface of the mucous membrane of the affected organ. Such formations have a high oncological potential, therefore, they require a more thorough diagnosis. Usually located on the mucous membrane of the walls of the vagina, urethra, cervix. To diagnose the nature of condyloma, a biopsy is required.
3. Dysplasia. It is characterized by a violation of the differentiated structure of the tissue. Often there is the presence of atypical cells that can cause the development of oncological pathology.

Requires close monitoring and, if necessary, surgical correction.

Each form of pathology must be carefully monitored by a doctor. To reduce the risk of developing an oncological process, it is recommended to remove such growths on the skin and mucous membranes.

HPV diagnostics

It is necessary to diagnose the presence of HPV in stages, for this a number of physical, laboratory and instrumental studies are used.

1. Doctor’s examination.It can help identify the presence of warts. When genital warts are found, the cervix must be examined. Ureteroscopy is also possible.
2. Colposcopy. Specific tests are performed with acetic acid and Lugol’s solution. With their help, you can determine the presence of atypical cells, signs of HPV infection and cervical cancer.
3. Cytological examination. Pap smears are performed on the cervical mucosa. This is a screening test for the presence of precancerous and cancer cells in the wall of the vagina or cervix.

Histological examination of tissues can also be carried out, detecting sexually transmitted diseases with which HPV infection is often associated. The PCR method has a high diagnostic value. It can be used to identify the HPV strain.

Treatment of HPV (Human Papilloma Virus)

It is impossible to completely eliminate the virus from the patient’s body. The doctor can only deal with the consequences of the life of the infectious agent.As a general therapy, symptomatic agents, antivirals and drugs that stimulate immune processes can be used.

To combat various types of genital warts, the following can be used:

1. Cryodestruction, electrocoagulation, cauterization with a laser or chemical substances. Such methods are effective for getting rid of genital warts.
2. Electrosurgical methods of treatment are used to remove the affected area on the surface of the cervix (dysplasia, condyloma).

Prevention of HPV

In order to prevent the development of the disease, various methods are used. The most effective ones are:

1. Monogamous relationships. You only have sex with a person for whom you are the only sexual partner. This method will allow you to protect yourself from all sexually transmitted infections, including HPV.
2. Use of barrier contraception. It is easy, affordable, but not always 100% safe for infection.The patient can become infected with the virus, even if the damaged skin is in contact with the area.
3. Periodic preventive examinations. Girls need to be examined regularly by a gynecologist. Thus, you can detect the first signs of the disease and begin treatment in a timely manner.
4. Vaccination. It is an effective and convenient preventive method. Vaccinations can be given to both men and women. The following vaccines are available:

Cervarix (bivalent against type 16 and 18)

Gardasil (tetravalent type 16, 18, 6, 11).

The most effective vaccination prior to sexual activity (use allowed from 9 years). Or persons who are sexually active in the absence of contraindications.

If you suspect an infection or the first manifestations of the disease, it is important to consult a doctor for a high-quality diagnosis and timely treatment.

HPV (human papillomavirus) – symptoms, treatment

HUMAN PAPILLOMA VIRUS

Papillomas and condylomas are benign neoplasms on the mucous membranes of the genitals, the skin of the perineum and around the anus, as well as in the respiratory tract.

The reason for the formation of papillomas is human papillomaviruses ( HPV ) . To date, more than 120 types of HPV are known.

Human papillomavirus infection is one of the most common viral diseases.

Certain types of HPV do not harm the human body, but some are capable of causing a variety of malignant tumors that arise from epithelial cells and, above all, in the genital area:

· Malignant tumor that develops on the mucous membrane of the cervix (cervical oncology) in women.

Precancerous and pathological changes in the cervix (the so-called changes in the cells of the cervix, which carry the risk of developing and transforming into a malignant tumor).

· Malignant tumor of the female external genital organs (cancer of the vulva and vagina).

· Condylomas (warts) in the genital area in the female and male population.

Currently, there is an increase in cancer incidence.Despite the availability of diagnostic tests, cervical cancer ranks second in the world among malignant tumors of the reproductive organs in women and is second only to breast cancer.

How is the human papillomavirus transmitted and spread?

1. In case of non-observance of the rules of personal hygiene. When several people use the same things.For example, a towel and clothes (underwear).
2. When visiting public places. These can be baths, saunas, swimming pools, sports clubs.
3. Upon contact with a carrier of the virus. Certain strains of the virus can be infected even by shaking hands. What to say about close ties. If a family has an HPV carrier, then the likelihood that the rest of the family is infected is very high.
4. Vertical transmission path. The frequency of transmission of HPV from mother to fetus varies very significantly – from 4 to 87%. The most likely ascending HPV is an infection of the amniotic fluid and placenta.
5. Self-infection. Transfer of the virus from one area of ​​the body to another during hair removal or shaving.

People between the ages of 16 and 20 are most at risk for HPV infection.In the chronic course of the disease, it contributes to the development of a precancerous condition, and subsequently (after 20-30 years) go into cancer.

Risk factors for HPV infection:

early onset of sexual activity,

the presence of a large number and frequent change of sexual partners,

high prevalence of sexually transmitted infections,

young age,

smoking, alcohol,

pregnancy,

endometriosis,

endogenous factors (vitamin deficiency, changes in the immune status).

Symptoms of the disease.

Genital warts are one of the most striking manifestations of HPV. These are pink mastoid formations, more often they are lighter than the mucous membrane, but sometimes they have a brighter color.

Human papillomavirus symptoms in men may differ from those found in women.This is due to the difference in the structure of their reproductive organs.

HPV in women, affects the mucous membrane of the cervix, sometimes polyps can form in the uterine cavity.

In men, it more often affects the skin of the perianal region and rectal mucosa. It is in these areas that the development of genital warts is observed, and they often lead to squamous cell carcinoma of the rectum.

Diagnostic methods:

patient examination,

colposcopy,

cervical smear cytology,

tissue histology,

PCR.

Treatment of human papillomavirus.

There are 2 main directions:

· Elimination of the virus from the human body. For this, various antiviral, immunomodulatory agents are used.

· Correction of cosmetic defects.For this, various methods of removing papillomas are used: liquid nitrogen, coagulator, laser, etc.

Prevention.

Non-specific prevention is the observance of personal hygiene, rules of conduct in public places, an increase in general immunity and the need to avoid promiscuous sexual intercourse.

Specific prophylaxis, this is vaccines!

There are two types of vaccines produced in the world .One vaccine is quadrivalent, that is, it protects against infection with four types of HPV – 6, 11, 16 and 18. And the second vaccine is bivalent, and protects only against two types of HPV – 16 and 18. The quadrivalent vaccine against human papillomavirus is called Gardasil , and is produced by the Dutch pharmaceutical company “MSD – Merck Sharp and Domu BV”, and bivalent, produced in Belgium by the company “GlaxoSmithKline Biologicals” and has the name Cervarix .

Today, vaccines against human papillomavirus can be used for both boys and girls.

Thanks to the effects of vaccination, it is possible to prevent the development of cancer in 90 – 95% of cases.

Human papillomavirus Digene test (HPV Digene test, “hybrid capture” method; Digene HPV Test, Hybrid Capture Technology) – determination of DNA types of high oncogenic risk (16/18/31/33/35/39/45 / 51/52/56/58/59/68 types)

Screening test used to diagnose precancerous conditions and cervical cancer.

There are more than 100 genotypes of human papillomavirus. Infection with this virus is quite common. The infection is usually transmitted sexually, in rare cases, vertical transmission of the virus from mother to child during childbirth is possible.

Infection with the papilloma virus may not have clinical manifestations; natural cleansing of the virus from the body is often observed, especially at a young age. But the persistence of the virus in the epithelium of the cervix for a long time can cause its pathological changes.

Cervical cancer is one of the few types of malignant neoplasms for which the main cause of the disease has been established. Numerous studies have shown that human papillomavirus DNA is found in almost all cases of precancerous conditions and in cervical cancer. Papilloma virus infection precedes subsequent squamous (squamous) intraepithelial dysplasia of the cervix. The third stage of intraepithelial neoplasm of the cervix occurs only in the presence of persistent infection with high oncogenic risk papillomavirus genotypes.It has been proven that long-term persistence (5-10 years) of papillomavirus genotypes of high oncogenic risk in women over 30 is associated with a significant increase in the risk of developing malignant changes in the cervix. Infection with papillomavirus of genotypes of low oncogenic risk can clinically manifest itself in the form of genital warts.

Digene HPV test is a molecular technology from Digene, protected by international patent law, aimed at detecting specific DNA fragments of the human papillomavirus (“hybrid capture” method).

Digene HPV test makes it possible to differentiate between 2 groups of virus genotypes – high and low cancer risk. Test No. 394 reveals the presence of HPV DNA of the high-risk genotype group (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68). Test No. 395 reveals the presence of HPV DNA from the low-risk genotype group (6/11/42/43/44).

Digene HPV test is widely used due to its reliability and ease of use. The sensitivity of the test in combination with a cytological study (PAP-test, test No. 517 in the INVITRO laboratory) in detecting precancerous changes in the cervix and cervical cancer is much higher than performing a cytological study alone.It is considered advisable to perform the Digene HPV test if the PAP test results are uncertain. Currently, the combination of the Digene HPV test and the cytological PAP test is becoming the “gold standard” in this area of ​​diagnosis and is proposed for screening women over 30 years of age. The method is standardized. It is the only FDA-approved high risk HPV test. The test was approved by the Federal Service for Supervision of Healthcare and Social Development of the Russian Federation.

Digene-test reveals a clinically significant level of infection with human papillomavirus, leading to the development of cervical neoplasia (in contrast to conventional PCR methods aimed at maximizing the sensitivity of detecting viral DNA, which does not always have direct clinical correlations). A positive Digene HPV test in women younger than 30 is an indication for retesting after 9 months, since HPV infection can be transient in younger women.

A positive Digene HPV test in women over 30 years of age may indicate persistence of the virus. With an appropriate cytological test result, this means that a woman has a high risk of developing cervical cancer and she needs special prevention or treatment. Modern methods of treatment allow, in case of early detection, to dramatically reduce the incidence of cervical cancer and especially its incurable cases. Testing for the presence of the virus after treatment has been carried out to ensure that it is effective.

Human papillomavirus: questions and answers

What is human papillomavirus infection?

Human papillomavirus infection is a group of viral infectious diseases characterized by the development of papillomatous (warty) formations on the skin and mucous membranes, chronic recurrent course, widespread, high contagiousness, i.e. the ability to be easily transmitted from person to person.

The manifestations of human papillomavirus infection (PVI, HPV) have been known to physicians for a long time.They are described by the doctors of Ancient Greece under the name “condylomas”. Hippocrates also called them “genital warts.”

Human papillomavirus (HPV) is a fairly common virus that can cause serious illness up to the onset of cancer.

According to epidemiological estimates, 10-13% of the population, or approximately 630 million people, are infected worldwide. When conducting mass screening studies, HPV is found in 40-50% of sexually active men and women, but in most of them, especially at a young age, it can disappear without any treatment.

How can you get infected with the human papillomavirus?

HPV infects everyone – men and women – and is transmitted through sexual intercourse, as well as through any direct contact with the skin of an infected person, but very rarely metastasizes to individual organs and tissues of a person.

It is no coincidence that the human papillomavirus is the most sexually transmitted infection. According to some researchers, the probability of HPV infection during sexual intercourse is up to 60-70%, the frequency of infection with the virus is directly proportional to the number of sexual partners: with one partner, HPV is detected in 17-20% of women, in the presence of 5 or more partners – in 70- 80%.

Clinical forms of human papillomavirus infection are found in 40-60% of men who are sexual partners of infected women. Their lesions are caused by the same types of HPV as in women, and in about 2/3 of cases there are characteristic rashes on the skin and mucous membranes of the genital organs.

Despite the fact that the human papillomavirus is found in the amniotic fluid, the risk of infection of the fetus from the mother is assessed as low and amounts to up to 3%.

What diseases can the presence of human papilloma virus cause?

More than 300 different types of human papillomavirus are known to date.Among them, there are types of HPV of high, medium and low oncogenic risk. In this case, a person can be infected with one or several types of the virus at the same time.

Different types of HPV cause or are involved in development:

• cervical, vulval, vaginal dysplasia of the cervix;

• pre-invasive and invasive cervical, vaginal and perianal cancer;

• genital warts, urinary tract;

• genital warts.

According to epidemiological studies, the incidence of genital PVI varies significantly across ethnic and geographic regions. The prevalence of the papilloma virus is due to numerous factors, and is also largely determined by socio-economic, behavioral and medical and hygienic conditions. For example, the lowest incidence of HPV infection (5%) is observed in Spain. This country belongs to countries with a “low” risk of cervical cancer.Countries – Argentina, Mexico, Brazil, Morocco are traditionally considered “high” risk of HPV infection. On the other hand, in the United States and Canada, despite the high socioeconomic level, the HPV detection rate ranges from 22 to 26%.

Despite the obvious medical and social significance of the problem, systemic studies to assess the prevalence of PVI in the Russian Federation have practically not been carried out. Currently, separate, uncoordinated studies are being carried out, according to which it is impossible to objectively assess the state of the problem as a whole and to carry out even an approximate forecast of the epidemiological situation of the prevalence of HPV in the population.

How does human papillomavirus infection develop and manifest itself?

Human papillomavirus lives in the skin and mucous membranes of the genital organs. As shown by medical and laboratory studies, the amount of the virus depends on the state of immunity of the skin and mucous membranes – the higher the activity of the immune system, the less virus is contained in them. In order for the virus to manifest itself with any symptoms, a certain amount of it must accumulate. And this is possible only if immunity is reduced: after infections, during (after) taking antibiotics, during pregnancy, during severe stress, etc.Having accumulated sufficiently on the skin or mucous membrane, the papilloma virus changes the function of epithelial cells. As a result, they begin to divide uncontrollably, which leads to the overgrowth of the skin area and the appearance of all sorts of formations – papillomas and genital warts.

Depending on the manifestations of PVI on the genitals, clinical, subclinical and latent forms are distinguished.

The clinical form of infection is mainly genital warts in the form of pointed (exophytic) formations.In rare cases, condylomas of the external genital organs grow rapidly, turning into a semi-malignant giant formation – the Buschke-Levenshtein tumor, with exo- and endophytic growth and the ability to penetrate into neighboring tissues.

The subclinical form of PVI manifests itself in the form of flat warts. They are more often localized on the cervix, less often in the vagina, and in most cases are not noticeable on examination.

The latent form of PVI is not accompanied by morphological changes in the infected tissue, and the DNA of the virus is often determined where there are no noticeable clinical signs of infection.

How to diagnose the presence of human papillomavirus?

Evidence for the presence of papilloma virus is:

• manifestations of HPV infection;

• results of a cytological study (study of the nature of cells under a microscope), indicating cervical dysplasia;

• detection of HPV by PCR;

• detection of antibodies to HPV in the blood (used only for scientific purposes).

In laboratory practice, two methods are used to diagnose HPV: PCR and hybridization analysis (Daijin test). In the Independent Laboratory INVITRO, both methods are used to diagnose the human papillomavirus.

The most common, affordable and fairly sensitive method is PCR. It allows diagnosing subclinical and latent forms of infection and detecting from 10 to 100 copies of the HPV genome and identifying at least 43 different types.

Despite the high sensitivity of PCR, it is not always possible to detect the virus in asymptomatic HPV infection. This is due to the peculiarities of this infection:

• HPV infection can be in a latent (dormant) state indefinitely. In this case, the virus is located deep in the skin and mucous membranes, but does not stand out on the surface. In this state, it is difficult to detect it by PCR.

• HPV infection in most cases affects large areas of the skin.In the absence of symptoms, it is not entirely clear which area of ​​the skin will be more reliable.

Daijin – test – allows you to detect not only 13 types of high-risk virus and 5 types of low-risk HPV cancer, but also to determine the clinically significant concentration of the virus in the tissue. This helps to develop further tactics of the doctor in the management of the patient. The sensitivity of the test in combination with cytological research in the detection of dysplasias and cervical cancer is much higher than conducting a cytological analysis alone.

Pap smear staining (PAP test) is often used for cytology, which can also be performed at the Independent Laboratory INVITRO.

Currently, the combination of the Daijin test and the PAP test is the “gold standard” in the diagnosis of cervical pathology and is proposed for screening examination of women over 30 years of age. A positive test in women younger than 30 years is an indication for retesting after 9 months, since the infection can be transient in young people.

A positive Daijin test in women over 30 years old may indicate the persistence of the virus. With a corresponding result of cytological examination, this means that there is a high risk of developing cervical cancer and this requires special prevention and treatment.