HPV Infection and Cervical Cancer Introduction Human papillomavirus (HPV) is the most common sexually transmitted infection in the United States; an estimated 14 million persons are newly infected every year Although most infections cause no symptoms and are selflimited, persistent HPV infection can cause cervical cancer in women as well as other anogenital cancers, oropharyngeal
cancer, and genital warts in men and women. Persistent oncogenic HPV infection is the strongest risk factor for development of HPV-associated precancers and cancers. How many types of HPV are there? Which types of HPV are
most likely to cause disease? More than 184 HPV types have been identified, including approximately 40 that infect the genital area. Genital HPV types are categorized according to their epidemiologic association with cervical cancer. Low-risk types (e.g., types 6 and 11) can cause benign or
low-grade cervical cell changes, genital warts, and recurrent respiratory papillomatosis . High-risk types (e.g., types 16 and 18) can cause low-grade cervical cell abnormalities, high-grade cervical cell abnormalities that are precursors to cancer, and cancers. Essentially all cervical cancers are attributable to high-risk HPV types, and approximately 70% of cervical cancer cases worldwide are caused by types 16 and 18.
What are the low risk and high risk types? "Low-risk" types of HPV There are about 12 types of HPV that are called "low risk" because they cannot cause cervical cancer. They can, however, cause genital warts or very minor cell changes on the cervix. These low-risk types of HPV are known by
the numbers 6, 11, 40, 42, 43, 44, 53, 54, 61, 72, 73 and 81. Types 6 and 11 which are linked to about 90 percent of genital wart are the most common. "High-risk" types of HPV There are more than a dozen types of "high-risk" HPV that can cause abnormal cells to form on the cervix. These abnormal cell changes may gradually develop into cervical cancer if not removed. The 13 types of highrisk HPV that are of most concern are known by the numbers 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 and 68. Types 16 and 18 are the most dangerous, since they cause about 70 percent of cervical cancers.
What diseases dose HPV infection cause? Can HPV cause any other kinds of cancer besides cervical cancer?
In addition to cervical cancer, HPV infection also is the cause of some other anogenital cancers such as cancer of the vulva, vagina, penis, and anus, as well as cancer of the oropharynx, esophagus and larynx. HPV-Associated Oropharyngeal Cancers Prevalence increased from 16.3% (1984-89) to 71.7% (2000-
04) Population-level incidence of HPV-positive cancers increased by 225% while HPV-negative cancers declined by 50% If trends continue, the annual number of HPV-positive oropharyngeal cancers is expected to surpass the annual number of cervical cancers by the year 2020 Chaturvedi, 2011, J Clin Oncol- data from SEER
How is HPV infection spread? Can HPV be transmitted by nonsexual transmission routes? Transmission
Genital HPV infection is transmitted primarily by genital contact, usually through sexual intercourse but also through other intimate contact (e.g., oral-genital or genital-genital). Intercourse is not necessary for infection Nonsexual routes of genital HPV transmission are less common and can include intrapartum transmission from
mother to infant In virtually all studies of HPV prevalence and incidence, the most consistent predictors of infection have been measures of sexual activity, most importantly the number of sex partners (lifetime and recent). Transmission is very common between sex partners, and likely more frequent from females to males than from males to females.
What are the signs and symptoms of HPV infection? Most HPV infections are transient and asymptomatic and cause no clinical problems; 70% of persons with new cervical HPV
infection will clear the infection within 1 year, and approximately 90% within 2 years. The median duration of new infections is about 8 months for genital infection among both females and males. The risk for persistence and progression to cancer precursor lesions varies by HPV type as well as host factors (including those with HIV infection). HPV 16 is more likely to persist and progress to cancer than other high-risk HPV types.The usual time between initial HPV infection and development of cervical
cancer is decades but more rapid progression has occurred. Women persistently infected with high risk HPV strains are at risk of the development of high grade cervical intraepithelial neoplasia (CIN) and invasive cervical cancer (CC). Studies have shown that the virus does not "ping-pong" back and forth. This means that a couple cannot re-infect each other within their own relationship. After exposure to HPV and
subsequent clearance of the virus, a person probably has immunity to that type. He or she cannot be re-infected, but could be exposed to a new type of HPV. If a person enters a new relationship, he or she could put a new partner at risk for HPV. A person can be exposed to a new viral type of HPV with a new partner. Can a person be re-
infected with HPV? There appears to be humoral and probably cellular immunity that develops to a specific type of HPV after a person has been infected with it and has cleared it. However, a person can be infected with more than one type of HPV.
The risk for re-infection with that specific type of HPV appears is rare. Re-detection of the same HPV type is relatively common, occurring in at least 1020% of women observed to have cleared the virus. Furthermore, convincing data from multiple studies of immune compromised, sexually abstinent, older, less sexually active populations and adolescents with longterm intensive follow-up support the phenomena of immunologically controlled re-detection or reactivation of a previously acquired type-specific
HPV infection. An important consideration, however, is that reactivation of previously acquired, latent HPV infection, rather than re-infection, may explain the apparent lack of protection against re-infection from natural antibodies in the older age group. These results suggest that, in the presence of naturally acquired antibodies, reactivation or intermittent viral shedding of a previously acquired infection is a more probable source of new HPV detection than new acquisition.
No HPV test can determine which HPV infection will clear and which will progress. Having HPV does not mean that a person or his/her partner is having sex outside the relationship. Having HPV does not make it harder for a woman to get pregnant or carry a pregnancy to term. However, some of the precancers or cancers that HPV can cause, and the treatments needed to treat them, might lower a womans
ability to get pregnant or have an uncomplicated delivery. Treatments are available for the conditions caused by HPV, but not for the virus itself. HPV is found in virgins Study examined the frequency of vaginal HPV and the association with non-coital sexual behavior in
longitudinally followed cohort of adolescent women without prior vaginal intercourse HPV was detected in 46% of women prior to first vaginal sex 70% of these women reported non-coital behaviors that may in part explain genital transmission Shew, J Infect Dis. 2012
Wart The average incubation period of visible warts is 3 weeks to one year. Latency periods of years have been reported before the emergence of warts or cervical abnormalities. This can be quite confusing and stressful for partners in long term relationships. An example of this is the person whose immune system, on its own, keeps HPV under control or latent for so many years and then a long-delayed symptom may appear
which seems to come from nowhere. Women with genital warts do not need Pap tests more often than other women. Condoms might lower the chances of transmitting genital warts if used consistently and correctly; however, HPV can infect areas that are not covered by a condom and might not fully protect against HPV.
Time of HPV acquisition cannot be definitively determined. Genital warts can develop months or years after getting HPV. HPV types that cause genital warts can be passed on to another person even in the absence of visible signs of warts. Sex partners tend to share HPV, even though signs of HPV (e.g., warts) might occur in only one partner or in neither partner. Although genital warts can be treated, such treatment does not cure the virus itself. For this reason, it is common for genital warts to recur after treatment, especially in the first 3 months
Because genital warts can be sexually transmitted, patients with genital warts benefit from testing for other STDs. Sexual activity should be avoided with new partners until the warts are gone or removed. HPV might remain present and can still be
transmitted to partners even after the warts are gone. Virus can remain in surrounding tissue after warts have been destroyed. What is primary goal for treatment of visible warts?
Wart Treatment Primary goal for treatment of visible warts is the removal of symptomatic warts Therapy may reduce but probably does not eradicate infectivity
Difficult to determine if treatment reduces transmission No laboratory marker of infectivity Variable results utilizing viral DNA What are HPV Treatment Options? Chemical agents
Cryotherapy Electrosurgery Surgical excision Laser surgery Imiquimod (Aldara) Natural therapies Updates on Pap Smear Guidelines 2015
What are risk factors for Cervical Cancer? HPV infection (16/18) Early onset of sexual activity (<16) High number of sexual partners (>4) Hx of genital warts
HIV seropositive Immunosuppresive therapy Active/passive Cigarette Smoking Chronic inflammation associated with other STDs Long term use of oral contraceptives High number of live births LACK OF SCREENING IS THE MOST IMPORTANT FACTOR
How does cervical cancer occur? HPV Most young women have an effective immune response that clears the infection in an avg of 8 months. CIN 1 is a manifestation of acute HPV and has a high rate
of regression to normal cells. CIN 2 is a mix of low-grade and high-grade lesions (70% regression in 3 years in some papers) CIN 3 and AIS are cancer precursors HSIL is associated with a persistent and transforming infection and cancer risk. HPV and the Development of Cancer What is the role of Colposcopy?
With directed bx remains the standard for disease detection Technique of choice for treatment decisions Endocervical sampling Screening Today
When to start? When to stop? How often? HR HPV testing Continue in patients after hysterectomy? No change in women vaccinated against HPV Possible harms of screening Anxiety over a positive test
Stigma of an STI Pain/bleeding from procedures Number of colposcopies is a marker for harms Principles in Interpreting Guidelines Current strategies cannot eliminate the risk of developing cancer. No screening test has 100% sensitivity. Attempts to eliminate often result in unanticipated harm
from excessive evaluation and treatment. Start screening at age 21 0.1% of cervical cancer cases 1-2 cases/1 million females age 15-19 US and UK studies demonstrated that earlier screening did NOT decrease cervical cancer rates in this population. Testing can be performed using either conventional or liquidbased cytologic tests (i.e., Pap tests)
Liquid-based cytology is an acceptable alternative to conventional Pap tests, as it has similar test-performance characteristics. In the presence of cervical friability, liquid-based cytology should be used; conventional pap testing might need to be deferred in the presence of heavy bleeding until cervicitis is treated.
Cervical cancer screening should begin at age 21 Women <21 should not be screened regardless of age of sexual contact. Prevalence of oncogenic HPV types are high among adolescents aged <21 years, and oncogenic HPV and squamous intraepithelial lesions caused by HPV in
adolescent girls are more likely to regress than those in older women. Screening 21 - 29 Every 3 years Co-testing with HPV should NOT be performed (HPV frequent in this population and >90% will spontaneously clear within 2 yrs)
Rational for Avoiding HPV tests among women ages 21-29 Prevalence of carcinogenic HPV approaches 20% in teens and early 20s Most carcinogenic HPV infections resolve without intervention Identifying carcinogenic HPV that will resolve leads to
repeated call-back, anxiety and interventions without benefits. Screening 30 - 65 Every 5 yrs Co-testing of HPV 16/18 Rational for cotesting, ages 30-64 Increased detection of prevalent CIN3
Decreased CIN3 in subsequent screening rounds Achieves risk of CIN3 equal to cytology alone 1-3 year intervals Enhances detection of adenocarsinoma/AIS Minimizes the increased number of colposcopies thus it reduces harm What are Risk Factors for
Continued Annual Screening? Hx of CIN2/3/cervical cancer within the past 20 yrs HIV infection or immunosuppression (transplant recipients) When to stop screening?
Age 65 and not at high risk for cervical cancer (USPSTF, ACOG, ASCCP) Adequate negative screening as: three consecutive negative cytology results or 2 negative cytology results with (-) co-testing within the prior 10 yrs with one within 5 yrs No prior hx of cervical cancer, CIN2/3. If any present, continue screening for 20 yrs
When to stop? After hysterectomy (with cervix removal) if no CIN 2/3 or cervical cancer If CIN 2+, and cervix removed, continue screening of vaginal cuff for 20 yrs, even if > 65 If hysterectomy and cervix not removed, continue screening as recommended for age
Screening a vaccinated cohort Recommended screening practices should not change on the basis of HPV vaccination. Vaccination against HPV16/18 Reduces CIN3 by 17-33% Reduces colposcopy by 10% Reduces treatment by 25%
HIV patient In adolescents with HIV infection, providers should screen 1 year after onset of sexual activity, regardless of age or mode of HIV infection (e.g., perinatally acquired or sexually acquired); such screening is warranted because of the reported high rate of progression of abnormal cytology in adolescents with HIV infection.
The biggest gain in reducing cervical cancer incidence and mortality would be achieved by increasing screening rates among women rarely or never screened. >30 Cytology Negative, (+) HPV Repeat cytology in 1 year is acceptable If repeat is (+) HPV, or ASCUS or worse, then
colposcopy. If repeat cytology (-) and HPV (-), then repeat 3 yrs Risk of CIN 2+ is small with single HPV (+) and negative cytology. Reflex testing of 16/18 if HPV (+) is acceptable When we use HPV test? HPV test
The HPV test can be used at the same time as the Pap test (known as co-testing) for women aged 30 years. The HPV test also can be used after an inconclusive Pap test among women aged 25 years; testing for this purpose is known as reflex HPV testing. HPV 16/18 testing HPV 16/18 testing is one follow-up option for women
who have discordant results (normal Pap test accompanied by a positive HPV test). If the HPV 16/18 test is positive, women should immediately receive colposcopy. If negative, these women should repeat the HPV co-test in 1 year. HPV testing (including oncogenic HPV and HPV 16/18 tests) should not be performed in the
following situations Testing women aged <30 years as part of routine cervical cancer screening Not a screening test for STDs Do not use as a test to determine whether to give HPV vaccine Providing care to persons with genital warts or their partners Conducting screening for cervical cancer as a stand-alone test (i.e., without a concurrent Pap test)
HPV tests are available to detect oncogenic types of HPV infection and are used in the context of cervical cancer screening and management or follow-up of abnormal cervical cytology or histology. These tests should not be used for male partners of women with HPV or women aged <25 years, for diagnosis
of genital warts, or as a general STD test. What is the best way to protect against HPV infection? HPV Vaccines Currently, three HPV vaccines are available that can prevent the most
common types of HPV infection, including bivalent Cervarix, targeting HPV types 16 and 18, quadrivalent Gardasil, targeting HPV 16, 18, 6 and 11 and 9-valent (Gardasil-9), targeting HPV 31, 33, 45, 52 and 58 in addition to HPV 16, 18, 6 and 11. All 3 HPV vaccines protect against HPV types 16 and 18, which cause 70% of cervical cancers. HPV type 16 also causes the majority of other cancers attributable to HPV. Quadrivalent Gardasil also protects against HPV types 6 and 11, which cause >90% of genital warts and recurrent respiratory papillomatosis. Gardasil-9 protects against infection with the HPV types
covered by Gardasil (HPV 16, 18, 6 and 11) and also protects against five other HPV types (HPV 31, 33, 45, 52 and 58). HPV Vaccine technology Empty Shell formed by recombinant biotechnology to mimic the viral 3D shape. Does not contain infectious
DNA Vaccine Real Virus Does not contain mercury
(thimerosal) GARDASIL is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA. *VLP = Virus-like particle. 1. Villa LL, Costa RL, Petta CA, et al. Lancet Oncol. 2005;6:271278. Image courtesy of Dr. Ian 66 Frazer
HPV Prophylactic Vaccines Recombinant L1 capsid proteins that form virus like particles (VLP) Non-infectious and nononcogenic Produce higher levels of
neutralizing antibody than natural infection HPV VLP Quadrivalent HPV vaccine (Gardasil, produced by Merck and Co, Inc., Whitehouse Station, New Jersey) is licensed for use in females and males aged 9 through 26 years.
(ACIP recommendation) Bivalent HPV vaccine (Cervarix, produced by GlaxoSmithKline, Rixensart, Belgium) is licensed for use in aged 9 through 26 years. (ACIP recommendation) Both are composed of type-specific HPV L1 protein, the major capsid protein of HPV. What is the recommended schedule
for administering HPV vaccine? Vaccination Schedule and Use In October 2016, CDC recommended that healthy adolescents who initiated HPV vaccination before age 15 years should receive two doses of any HPV vaccine. The second dose of HPV vaccine should be given 6-12 months after the first dose (0, 6-12 month schedule). Cases that start the HPV vaccine
series at ages 15-26 years, need three doses of HPV vaccine to protect against cancer-causing HPV infections. Three dose series are still recommended for cases with immunocompromising conditions aged 9- 26 years The recommendations for adult immunization schedule are as follows: Adult females and males through age 26 years who have not
received any HPV vaccine should receive a 3-dose series of HPV vaccine at 0, 12 and 6 months. Adult females and males through age 26 years who initiated the HPV vaccination series before age 15 years and received 2 doses at least 5 months apart are considered adequately vaccinated and do not need an additional dose of HPV vaccine. Adult females and males through age 26 years who initiated the HPV vaccination series before age 15 years and received only 1
dose or 2 doses less than 5 months apart, are not considered adequately vaccinated and should receive 1 additional dose of HPV vaccine. Adult females and males through age 26 years with immunocompromising conditions such as HIV infection, malignant neoplasm, transplantation, autoimmune disease and immunosuppressive therapy should receive a 3-dose series of HPV vaccine at 0, 12, and 6 months. Because
HPV vaccines are subunit vaccines, they can be administered to immunosuppressed subjects. However, the immune response and vaccine efficacy might be less than immunocompetent persons. Women who are breastfeeding may receive HPV vaccine. Although routine vaccination is recommended at age 9 years, older adolescents and young adults through the
recommended ages can benefit from vaccination . HPV vaccines are most effective when administered before exposure to HPV. Adolescents and young adults who are not yet sexually active can be expected to receive the full benefit of vaccination. Although sexually active persons in this age group might have been infected with one or more vaccine HPV types, studies suggest that only a small percentage have been infected with both HPV16 and 18 or all four
vaccine types . Although vaccine effectiveness would be lower when administered to those who are sexually active, and would decrease with older age and likelihood of previous HPV exposure, the majority of persons in the recommended age groups will derive at least partial benefit from vaccination.
Duration of Protection of Vaccine Data from follow-up through 8 to 10 years showed no evidence of waning protection. (ongoing research) There is no known serologic correlative of immunity or minimum titer determined to be protective. The high efficacy found in the clinical trials to date has precluded identification of a minimum protective antibody titer. Modeling studies have shown consistently that the routine vaccination of
12-year-old girls with either HPV2 or HPV4 is a cost-effective use of public health resources, as long as vaccine duration of protection is sufficient (e.g., 30 years). What is the duration of Protection of Vaccine? Efficacy against vaccine type persistent infection or disease was 95.8%
(95% CI = 83.899.5) and efficacy against vaccine type-related CIN or external genital lesions was 100%. Both Gardasil and Cervarix are effective against their respective HPV types. In addition to protection against the HPV types included in these vaccines, the vaccines provide cross-protection against additional HPV types that can cause cancer. Cervarix also has more cross-protection against oncogenic HPV types in addition to types 16 and 18 than Gardasil. Cervarix uses a novel aluminum salt (AS04) adjuvant, which is responsible for
eliciting a strong immunologic response. So after vaccination with Cervarix, higher anti-HPV 16 and 18 antibodies and neutralization titers are seen in comparison to Gardasil although whether that correlates with clinical endpoints is unknown. Avidity of antibodies is similar between the two vaccines. There was no efficacy against progression to disease or impact on clearance of infection of that type. How long is the duration of protection
Is booster dose needed? How long is the duration of protection Is booster dose needed? US CDC 2012 Feb: Gardasil vaccine information statement Protection from HPV vaccine is expected to be long-
lasting Additional (booster) doses are not recommended. http://www.cdc.gov/vaccines/pubs/vis/downloads/vis-hpv-gardasil.pdf 79 HPV Vaccine Safety Most common adverse events reported-considered mild
For serious adverse events, no unusual pattern or clustering that suggest events caused by HPV vaccine What are the adverse effects for HPV vaccines? Adverse Reactions Following Vaccination
The HPV vaccine is very safe, and it is effective at preventing HPV. Vaccines, like any medicine, can have side effects. Many people who get the HPV vaccine have no side effects at all. Some people report having very mild side effects, like a sore arm from the shot. The most common side effects are usually mild. Common Side Effects of HPV Vaccine: Pain, redness, or swelling in the arm where the shot was given Fever Headache or feeling tired Nausea Muscle or joint pain
Brief fainting spells and related symptoms (such as jerking movements) can happen after any medical procedure, including vaccination. Sitting or lying down for about 15 minutes after a vaccination can help prevent fainting and injuries caused by falls. Guillain-Barre Syndrome, seizures, stroke, venous thromboembolism and appendicitis were not more common after HPV vaccination than other adolescent vaccinations. A variety of systemic adverse reactions were reported by vaccine recipients including fever, nausea, dizziness, myalgia and malaise. However, these symptoms occurred with equal frequency among both vaccine and placebo recipients.
Severe adverse effects such as persistent headache,gastroenteritis, hypertension and bronchospasm were reported in no more than 0.5% of cases. No increased risk of autoimmune, venous thromboembolic or neurologic disease has been shown among HPV vaccine recipients in long-term observation studies . HPV vaccine In the United States, the vaccines are not licensed or recommended for use in men or women aged >26 years. HPV vaccines are not recommended for use in pregnant women. HPV vaccines can be
administered regardless of history of anogenital warts, abnormal Pap/HPV tests, or anogenital precancer. Women who have received HPV vaccine should continue routine cervical cancer screening if they are aged 21 years. Recent results of Phase III vaccination trials have documented that vaccine efficacy among adult women (shown to age 45/55) is excellent, provided they are HPV negative at the time of vaccination. Therefore, the European Medicines Agency (EMA) extended the indication of HPV vaccine to women aged 9+ with no
upper limit. What can you do to protect yourself from HPV and its effects? Management of Sex Partners The benefit of disclosing a positive oncogenic HPV test to current
and future sex partners is unclear. The following counseling messages can be communicated to sex partners: Sex partners do not need to be tested for HPV. Sex partners tend to share HPV, even though signs of HPV such as an abnormal Pap-test result might occur in only one partner. Sex partners of persons with HPV infection also likely have HPV. When used correctly and consistently, condoms might lower the risk for HPV infection and might decrease the time to clear in
women with HPV infection. However, HPV can infect areas not covered by the condom and might not fully protect against HPV. Prevention of Sexual Transmission Abstaining from sexual activity (i.e., refraining from any genital contact with another person) is the surest way to prevent genital HPV infection. Persons also can lower their chances of becoming infected
with HPV by being in a monogamous relationship with one partner, limiting their number of sex partners, and choosing a partner who has had no or few previous sex partners. However, even persons with only one lifetime sex partner can be infected with HPV. Consistent and correct condom use can reduce the risk for
HPV and HPV-associated diseases (e.g., genital warts and cervical cancer). Neither routine surveillance for HPV infection nor partner notification is useful for HPV prevention. Genital HPV infection is so prevalent that most partners of HPV-infected persons have already acquired HPV themselves. Does HPV interfere with a
woman's ability to get pregnant? HPV and Childbirth The risk of HPV transmission to the baby during childbirth is very low. Even if babies do get the HPV virus, their bodies usually clear the virus on their own. Most of the time, a baby born to a woman with genital warts does not have HPV-related complications. In very rare cases, a
baby born to a woman who has genital warts will develop recurrent respiratory papillomatosis. In pregnancy the route of HPV transmission (i.e., transplacental, perinatal, or postnatal) is not completely understood. Whether cesarean section prevents respiratory papillomatosis in infants and children is unclear; therefore, cesarean delivery should not be performed solely to prevent transmission of HPV infection to the newborn. Cesarean delivery might be indicated for women with genital warts if the pelvic outlet is obstructed or if vaginal delivery would result in excessive
bleeding. HPV Prevention Abstinence Monogamy Condoms Removal of warts Vaccine 50% to 70% of sex partners of people with
genital warts already have or do develop warts. Iran HPV Types The most frequent HPV type was HPV 16 (79.2%), which was followed by HPV types 18, 6, and 33 at the frequencies of 6.5%, 5.1%, and 2.7%, respectively. The least HPV types were found to be 31, 45, 53, 58, and 66. In conclusion, this study shows that the current HPV vaccines could have great impact to reduce the burden of cervical cancer in Iran.J Med Virol.2017 Aug 8
Among mono-infected patients, the most frequent genotype was HPV-6 (30%) which was followed by HPV-53 (15%), HPV-16 (12.5%), HPV-66 (7.5%), HPV-18 (7.5%), HPV-11 (7.5%), HPV-58 (5%), HPV-39 (2.5%), HPV-45 (2.5%), HPV-51 (2.5%), HPV-52 (2.5%), HPV-68 (2.5%), and HPV-82 (2.5%). In multiple-infected patients, the most frequent genotype was HPV6 (40%) followed by HPV-53 (32.5%), HPV-66 (30%), HPV-16 (27.5%), HPV-52 (22.5%), HPV39 (20%), HPV-18 (20%), HPV-51 (15%), HPV-11 (10%), HPV-56 (7.5%), HPV-33 (7.5%), HPV-31 (7.5%), HPV-54 (5%), HPV-58 (5%), HPV-82 (5%), HPV-35 (2.5%), HPV-44 (2.5%), HPV-45 (2.5%), HPV-68 (2.5%) and HPV-69/71 (2.5%).Iran J Public Health. 2014 Aug; HPV16 was the most prevalent HPV type for all five histological types, followed by HPV18,
6/11, 31 and 33 types. Also HPV45, 58, 59, 68 and 73 types were detected in a minority of subjects. Asian Pac J Cancer Prev. 2014;15(17):7029-35
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