- Human papillomavirus
image_size = 190px
image_caption =EM of "papillomavirus"
virus_group = i
ordo = "Unranked"
familia = "Papillomaviridae"
subdivision_ranks = Genera
subdivision = "Alphapapillomavirus"
Name = Human Papilloma Viruses|
DiseasesDB = 6032
ICD10 = ICD10|B|97|7|b|95
ICD9 = ICD9|078.1 ICD9|079.4
eMedicineSubj = med
eMedicineTopic = 1037
MeshID = D030361
Papillomavirusarticle covers the general biological features of human and animal papillomaviruses.
A human papillomavirus (HPV) is a
papillomavirusthat infects the skin and mucous membranes of humans. Approximately 130 HPV types have been identified. Some HPV types can cause warts (verrucae) or cancer, while others have no symptoms.
About 30-40 HPV types are typically transmitted through sexual contact and infect the anogenital region. Some sexually transmitted HPV types may cause
genital warts, while others do not cause any noticeable signs of infection.
Persistent infection with "high-risk" HPV types — different from the ones that cause warts — may progress to
precancerouslesions and invasive cancer. HPV infection is a cause of nearly all cases of cervical cancer. [cite journal |author=Walboomers JM, Jacobs MV, Manos MM, "et al" |title=Human papillomavirus is a necessary cause of invasive cervical cancer worldwide |journal=J. Pathol. |volume=189 |issue=1 |pages=12–9 |year=1999 |pmid=10451482 |doi=10.1002/(SICI)1096-9896(199909)189:1<12::AID-PATH431>3.0.CO;2-F]
Pap smearis used to detect cellular abnormalities. This allows targeted surgical removal of condylomatous and/or potentially precancerous lesions prior to the development of invasive cervical cancer. Although the widespread use of Pap testing has reduced the incidence and lethality of cervical cancer in developed countries, the disease still kills several hundred thousand women per year worldwide. HPV vaccines Gardasiland Cervarix, which prevent infection with some of the sexually transmitted HPV types that cause the most disease may lead to further decreases in the incidence of HPV-induced cancers. [cite journal |author=Lowy DR, Schiller JT |title=Prophylactic human papillomavirus vaccines |journal=J. Clin. Invest. |volume=116 |issue=5 |pages=1167–73 |year=2006 |pmid=16670757 |doi=10.1172/JCI28607]
Estimates of prevalence vary from 14% to more than 90%. [cite journal |author=Revzina NV, Diclemente RJ |title=Prevalence and incidence of human papillomavirus infection in women in the USA: a systematic review |journal=International journal of STD & AIDS |volume=16 |issue=8 |pages=528–37 |year=2005 |pmid=16105186 |doi=10.1258/0956462054679214"The prevalence of HPV reported in the assessed studies ranged from 14% to more than 90%."] One reason for the difference is that some studies report women who currently have a detectable infection, while other studies report women who have ever had a detectable infection. [cite news
first = Marie
last = McCullough
title = Cancer-virus strains rarer than first estimated
url = http://www.philly.com/mld/inquirer/living/health/16798039.htm
The Philadelphia Inquirer
accessdate = 2007-03-02] [cite news
first = David
last = Brown
title = Study finds more women than expected have HPV
url = http://sfgate.com/cgi-bin/article.cgi?f=/c/a/2007/02/28/MNGOCOCAF61.DTL
San Francisco Chronicle
accessdate = 2007-03-02 (originally published in the
Washington Postas "More American Women Have HPV Than Previously Thought")] Another cause of discrepancy is the difference in strains that were tested for.
HPV is the most common sexually transmitted infection in the United States. According to the National Cervical Cancer Coalition (NCCC), 11% of American women do not have regular cervical cancer screenings. Women who do not have regular cervical cancer screenings substantially increase their risk of developing cancercite web|url=http://www.nccc-online.org/|title=NCCC National Cervical Cancer Coalition|accessdate=2008-07-01] , because precancerous lesions will not be detected and removed. The American Cancer Society estimates that in 2008, about 11,070 women in the United States will be diagnosed with invasive cervical cancer, and about 3,870 US women will die from this disease. [cite web| url=http://www.cancer.org/docroot/CRI/content/CRI_2_4_1X_What_are_the_key_statistics_for_cervical_cancer_8.asp| title = ACS:What Are the Key Statistics About Cervical Cancer?| accessdate=2008-07-01] Most cases of HPV infection which become cancerous are due to a failure to get regular checkups and removal of precancerous lesions. [cite web|url=http://www.imaginis.com/womenshealth/pap_smear.asp| title=Pap Smear| accessdate=2008-10-09] Death from mere HPV infection is unlikely if a woman has regular checkups and participates in necessary follow-up procedures such as removal of lesions.
One study found that, during 2003–2004, at any given time, 26.8% of women aged 14 to 59 were infected with at least one type of HPV. This was higher than previous estimates. 15.2% were infected with one or more of the high-risk types that can cause cancer. However only 3.4% were infected with one or more of the four types prevented by the
Gardasilvaccine, which was lower than previous estimates.cite journal |author=Dunne EF, Unger ER, Sternberg M, "et al" |title=Prevalence of HPV infection among females in the United States |journal=JAMA |volume=297 |issue=8 |pages=813–9 |year=2007 |pmid=17327523 |doi=10.1001/jama.297.8.813] [cite web
url = http://www.newsvine.com/_news/2008/03/11/1358811-study-finds-1-in-4-us-teens-has-a-std
title = Study Finds 1 in 4 US Teens Has a STD
publisher = Newsvine
author = Lindsey Tanner
date = March 11, 2008
accessdate = 2008-03-17 ]
Note that incidence decreases with age. This is most likely due to the fact that HPV infection can clear with time, or at least sink to harmless and undetectable levels while still present in the body.
The concern about life-long recurrences may be based on a misconception rather than a myth. It is true that at present there is no cure for genital human papillomavirus. It will probably remain in the infected person's cells for an indefinite time--most often in a latent state, but occasionally producing symptoms or disease.Fact|date=February 2008
Recent studies from the Albert Einstein College of Medicine and from the University of Washington suggest that HPV may eventually be cleared, or rooted out altogether, in most people with well functioning immune systems. It appears that in some cases the virus does remain in the body indefinitely, producing symptoms if the immune system weakens.Fact|date=February 2008
It was estimated that in the year 2000, there were approximately 6.2 million new HPV infections among Americans aged 15-44; of these, an estimated 74% occurred to people between ages 15-24.cite journal | journal = Perspectives on Sexual and Reproductive Health | volume = 36| number = 1| date = January/February 2004 | title = Sexually Transmitted Diseases Among American Youth: Incidence and Prevalence Estimates, 2000 | author = Hillard Weinstock, Stuart Berman and Willard Cates, Jr. | url = http://www.guttmacher.org/pubs/journals/3600604.html | doi = 10.1363/3600604 | pages = 6] Of the STDs studied, genital HPV was the most commonly acquired.
Genital HPV is the most common sexually transmitted infection. Most sexually active men and women will probably acquire genital HPV infection at some point in their lives.cite journal |author=Baseman JG, Koutsky LA |title=The epidemiology of human papillomavirus infections |journal=J. Clin. Virol. |volume=32 Suppl 1 |issue= |pages=S16–24 |year=2005 |pmid=15753008 |doi=10.1016/j.jcv.2004.12.008 *Note: The authors state on page S17 "Overall, these DNA-based studies, combined with measurements of type-specific antibodies against HPV capsid antigens, have shown that most (>50%) sexually active women have been infected by one or more genital HPV types at some point in time."] The American Social Health Association reported estimates that about 75-80% of sexually active Americans will be infected with HPV at some point in their lifetime. [cite web |url=http://www.ashastd.org/hpv/hpv_learn_men.cfm |title=American Social Health Association - HPV Resource Center |accessdate=2007-08-17] [cite web| url= http://www.ashastd.org/hpv/hpv_learn_patfactsheet.cfm | title=American Social Health Association - National HPV and Cervical Cancer Prevention Resource Center | accessdate=2008-07-01] According to the
Centers for Disease Control(CDC), by the age of 50 more than 80% of American women will have contracted at least one strain of genital HPV.cite web |url=http://www.cdc.gov/std/hpv/STDFact-HPV-vaccine.htm |title=STD Facts - HPV Vaccine |date = 2006-08-01 | accessdate=2007-08-17]
The HPV lifecycle strictly follows the differentiation program of the host
keratinocyte. It is thought that the HPV virioninfects epithelialtissues through micro-abrasions, whereby the virion associates with putative receptors such as alpha integrins and laminins, leading to entry of the virions into basal epithelial cells through clathrin-mediated endocytosis and/or caveolin-mediated endocytosis depending on the type of HPV. At this point, the viral genomeis transported to the nucleus by unknown mechanisms and establishes itself at a copy number between 10-200 viral genomes per cell. A sophisticated transcriptional cascade then occurs as the host keratinocyte begins to divide and become increasingly differentiated in the upper layers of the epithelium. The viral oncogenes, E6 and E7, are thought to modify the cell cycle so as to retain the differentiating host keratinocyte in a state that is amiable to the amplification of viral genome replication and consequent late gene expression. E6 in association with host E6 AP (associated protein), which has ubiquitin ligase activity act to ubiquitinate p53 leading to its proteosomal degradation. E7 (inoncogenic HPV's) acts as the primary transforming protein. E7 competes for pRbbinding, freeing the transcription factor E2Fto transactivate its targets, thus pushing the cell cycle forwards. All HPV can induce transient proliferation, but only 16 and 18 can immortalise cell intes (in vitro). It has also been shown that HPV 16 and 18 cannot immortalise primary rat cells alone, there needs to be activation of the rasoncogene. In the upper layers of the host epithelium, the late genes L1 and L2 are transcribed/translated and serve as structural proteins which encapsidate (Encapsidation is the process of incorporating a nucleic acid sequence (e.g., a vector, or a viral genome) into a viral particle) the amplified viral genomes. Virions can then be sloughed off in the dead squames of the host epithelium and the viral lifecycle continues.Fact|date=February 2008
Once an HPV viron invades a cell, an active infection occurs, and the virus can be transmitted. Several months to years may elapse before squamous intraepithelial lesions (SIL) develop and can be clinically detected. The time from active infection to clinically detectable disease makes it difficult for someone who has become infected to establish which partner was the source of infection.
HPV types and associated diseases anchor|Diseases associated with HPV
Over 100 different HPV types have been identified and are referred to by number.Types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68 are "high-risk" sexually transmitted HPVs and may lead to the development of
cervical intraepithelial neoplasia(CIN), vulvar intraepithelial neoplasia(VIN), penile intraepithelial neoplasia (PIN), and/or anal intraepithelial neoplasia (AIN).
About a dozen HPV types (including types 16, 18, 31 and 45) are called "high-risk" types because they can lead to
cervical cancer, as well as anal cancer, vulvar cancer, and penile cancer. [cite journal |author=Parkin DM |title=The global health burden of infection-associated cancers in the year 2002 |journal=Int. J. Cancer |volume=118 |issue=12 |pages=3030–44 |year=2006 |pmid=16404738 |doi=10.1002/ijc.21731] Several types of HPV, particularly type 16, have been found to be associated with oropharyngeal squamous-cell carcinoma, a form of head and neck cancer.cite journal |author=D'Souza G, Kreimer AR, Viscidi R, "et al" |title=Case-control study of human papillomavirus and oropharyngeal cancer |journal=N. Engl. J. Med. |volume=356 |issue=19 |pages=1944–56 |year=2007 |pmid=17494927 |doi=10.1056/NEJMoa065497 | url = http://content.nejm.org/cgi/content/full/356/19/1944] HPV-induced cancers often have viral sequences integrated into the cellular DNA. Some of the HPV "early" genes, such as E6 and E7, are known to act as oncogenes that promote tumor growth and malignant transformation.
p53protein prevents cell growth in the presence of DNA damage primarily through the BAXdomain, which blocks the anti-apoptotic effects of the mitochondrial BCL-2receptor. In addition, p53also upregulates the p21protein, which blocks the formation of the Cyclin D/Cdk4complex, thereby preventing the phosphorylation of RB and, in turn, halting cell cycle progression by preventing the activation of E2F. In short, p53 is a tumor suppressor gene that arrests the cell cycle when there is DNA damage. The E6 and E7 proteins work by inhibiting tumor suppression genes involved in that pathway: E6 inhibits p53, while E7 inhibits p53, p21, and RB.
An infection with one or more high-risk HPV types is believed to be a prerequisite for the development of cervical cancer (the vast majority of HPV infections are not high risk); according to the
American Cancer Society, women with no history of the virus do not develop this type of cancer. However, most HPV infections are cleared rapidly by the immune system and do not progress to cervical cancer. Because the process of transforming normal cervical cells into cancerous ones is slow, cancer occurs in people who have been infected with HPV for a long time, usually over a decade or more. [Greenblatt R.J. 2005. [http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T5D-4H6P7Y9-1&_user=10&_handle=V-WA-A-W-W-MsSAYZA-UUA-U-AABAVZDCWU-AAWEUVYBWU-BEAYVEYEY-W-U&_fmt=summary&_coverDate=09%2F15%2F2005&_rdoc=1&_orig=browse&_srch=%23toc%235000%232005%23999729981%23607092!&_cdi=5000&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=42b5289fd6b206fd7ae9269741210c39 Human papillomaviruses: Diseases, diagnosis, and a possible vaccine] . "Clinical Microbiology Newsletter", 27(18), 139-145. Abstract available.] cite journal |author=Sinal SH, Woods CR |title=Human papillomavirus infections of the genital and respiratory tracts in young children |journal=Seminars in pediatric infectious diseases |volume=16 |issue=4 |pages=306–16 |year=2005 |pmid=16210110 |doi=10.1053/j.spid.2005.06.010]
Sexually transmitted HPVs also cause a major fraction of
anal cancers and approximately 25% of cancers of the mouth and upper throat (known as the oropharynx) (see figure). The latter commonly present in the tonsil area and HPV is linked to the increase in oral cancers in non-smokers. [cite journal |author=Gillison ML, Koch WM, Capone RB, "et al" |title=Evidence for a causal association between human papillomavirus and a subset of head and neck cancers |journal=J. Natl. Cancer Inst. |volume=92 |issue=9 |pages=709–20 |year=2000 |pmid=10793107|doi=10.1093/jnci/92.9.709] [cite journal |author=Gillison ML |title=Human papillomavirus and prognosis of oropharyngeal squamous cell carcinoma: implications for clinical research in head and neck cancers |journal=J. Clin. Oncol. |volume=24 |issue=36 |pages=5623–5 |year=2006 |pmid=17179099 |doi=10.1200/JCO.2006.07.1829] Engaging in anal sexor oral sexwith an HPV-infected partner may increase the risk of developing these types of cancers.
Studies show a link between HPV infection and penile and anal cancer, and the risk for anal cancer is 17 to 31 times higher among gay and bisexual men than among heterosexual men.cite web |url=http://www.cdc.gov/std/hpv/STDFact-HPV-and-men.htm |title=STD Facts - HPV and Men |accessdate=2007-08-17] [cite journal |author=Frisch M, Smith E, Grulich A, Johansen C |title=Cancer in a population-based cohort of men and women in registered homosexual partnerships |journal=Am. J. Epidemiol. |volume=157 |issue=11 |pages=966–72 |year=2003 |pmid=12777359| url = http://126.96.36.199/cgi/content/full/157/11/966 | quote=However, the risk for invasive anal squamous carcinoma, which is believed to be caused by certain types of sexually transmitted human papillomaviruses, notably type 16, was significantly 31-fold elevated at a crude incidence of 25.6 per 100,000 person-years. |doi=10.1093/aje/kwg067]
Some HPV infections can cause warts (verrucae), which are noncancerous skin growths. Infection with these types of HPV causes a rapid growth of cells on the outer layer of the skin. [Mayo Clinic.com, Common warts, http://www.mayoclinic.com/print/common-warts/DS00370/DSECTION=all&METHOD=print] Types of warts include:
* Common warts: Some "cutaneous" HPV types, such as HPV-1 and HPV-2,Fact|date=March 2008 cause "common" skin
warts. Common warts are often found on the hands and feet, but can also occur in other areas, such as the elbows or knees. Common warts have a characteristic cauliflower-like surface and are typically slightly raised above the surrounding skin. Cutaneous HPV types do not usually cause genital warts and are not associated with the development of cancer.
Plantar warts are found on the soles of the feet. Plantar warts grow inward, generally causing pain when walking.
* Subungual or periungual warts form under the
fingernail(subungual), around the fingernail or on the cuticle(periungual). They may be more difficult to treat than warts in other locations. [cite journal |author=Lountzis NI, Rahman O |title=Images in clinical medicine. Digital verrucae |journal=N. Engl. J. Med. |volume=359 |issue=2 |pages=177 |year=2008 |pmid=18614785 |doi=10.1056/NEJMicm071912 |url=http://content.nejm.org/cgi/pmidlookup?view=short&pmid=18614785&promo=ONFLNS19]
Flat warts: Flat warts are most commonly found on the arms, face or forehead. Like common warts, flat warts occur most frequently in children and teens. In people with normal immune function, flat warts are not associated with the development of cancer. [MedlinePlus, Warts, http://www.nlm.nih.gov/medlineplus/warts.html#cat42 (general reference with links). Also, see ] Genital warts are quite contagious, while common, flat, and plantar warts are much less likely to spread from person to person.
Genital or anal warts (condylomata acuminata or venereal warts) are the most easily recognized sign of genital HPV infection. Although a wide variety of HPV types can cause genital warts, types 6 and 11 account for about 90% of all cases. [cite journal |author=Greer CE, Wheeler CM, Ladner MB, "et al" |title=Human papillomavirus (HPV) type distribution and serological response to HPV type 6 virus-like particles in patients with genital warts |journal=J. Clin. Microbiol. |volume=33 |issue=8 |pages=2058–63 |year=1995 |pmid=7559948 |doi=] [cite web | author = Gearheart PA, Randall TC, Buckley RM Jr | year = 2004 | url = http://www.emedicine.com/med/topic1037.htm | title = Human Papillomavirus | publisher = eMedicine]
Most people who acquire genital wart-associated HPV types clear the infection rapidly without ever developing warts or any other symptoms. People may transmit the virus to others even if they don't display overt symptoms of infection. However, in the vast majority of cases, this is not a cause for concern if proper tests are routinely administered.
HPV types that tend to cause genital warts are not the same ones that cause cervical cancer. However, since an individual can be infected with multiple types of HPV, the presence of warts does not rule out the possibility of high risk types of the virus also being present.
HPV types 6 and 11 can cause a rare condition known as recurrent respiratory papillomatosis, in which warts form on the larynx or other areas of the respiratory tract. [cite journal |author=Wu R, Sun S, Steinberg BM |title=Requirement of STAT3 activation for differentiation of mucosal stratified squamous epithelium |journal=Mol. Med. |volume=9 |issue=3-4 |pages=77–84 |year=2003 |pmid=12865943|doi=10.2119/2003-00001.Wu]
These warts can recur frequently, may require repetitive surgery, may interfere with breathing, and in extremely rare cases can progress to cancer. [cite journal |author=Moore CE, Wiatrak BJ, McClatchey KD, "et al" |title=High-risk human papillomavirus types and squamous cell carcinoma in patients with respiratory papillomas |journal=Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery |volume=120 |issue=5 |pages=698–705 |year=1999 |pmid=10229596 |doi=10.1053/hn.1999.v120.a91773]
HPV in immunocompromised patients
In very rare cases, HPV may cause
epidermodysplasia verruciformisin immunocompromised individuals. The virus, unchecked by the immune system, causes the overproduction of keratin by skin cells, resulting in lesions resembling warts or cutaneous horns. [Moore, M. [http://www.telegraph.co.uk/news/main.jhtml?xml=/news/2007/11/12/wtree112.xml "Tree man 'who grew roots' may be cured"] (November 21, 2007). "The Telegraph".]
Cervical cancer prevention
Avoiding sexual contact with an infected person is the only 100% effective prevention method; however, many people are unaware that they are infected with HPV. Condoms offer some protection, but exposed skin can transmit the virus. Two vaccines are currently available (see "HPV vaccines" below) to women between the ages of 9 and 26.
Pap smear screening
koilocytes: enlarged (x2 or x3) nuclei and hyperchromasia.]
Certain types of sexually transmitted HPVs can cause
cervical cancer. Persistent infection with one or more of about a dozen of these "high-risk" HPV types is an important factor in nearly all cases of cervical cancer. The development of HPV-induced cervical cancer is a slow process that generally takes many years. During this development phase, pre-cancerous cells can be detected by regular cervical cytology Papanicolaou screening, colloquially known as "Pap" smear testing. The Pap test is an effective strategy for reducing the risk of invasive cervical cancer. The Pap test involves taking cells from the cervix and putting them on a small glass slide and examining them under a microscope to look for abnormal cells. This method is 70% to 80% effective in detecting HPV-caused cellular abnormalities.Fact|date=February 2008 A more sensitive method is a “Thin Prep,” in which the cells from the cervix are placed in a liquid solution. This test is 85% to 95% effective in detecting HPV-caused cellular abnormalities.Fact|date=February 2008 The latter method is mainly used on women over 30. It is a combination Pap-HPV DNA test. If this test comes back negative women can usually wait 3 years before having the test done again. Detailed inspection of the cervix by colposcopymay be indicated if "abnormal cells" are detected by routine Pap smear. A frequently occurring example of an "abnormal cell" found in association with HPV is the koilocyte. (See figure.)The American College of Obstetricians and Gynecologistsstates that the newer liquid based cytology methods (Thinprep and Surepath) may miss 15-35% of CIN3's and cancer.
Center for Disease Control(CDC) recommends that women get a Pap test no later than 3 years after their first sexual encounter and no later than 21 years of age. Women should have a Pap test every year until age 30. After age 30, women should discuss risk factors with their health care provider to determine whether a Pap test should be done yearly. If risk factors are low and previous Pap tests have been negative, most women only need to have tests every 2-3 years until 65 years of age (Centers for Disease Control 2005).All women are encouraged to get a yearly pap smearsolely to detect cellular abnormalities caused by HPV.cite web |url=http://www.cdc.gov/std/hpv/STDFact-HPV-vaccine.htm |title=STD Facts - HPV Vaccine |date = 2006-08-01 | accessdate=2007-08-17]
Since the Pap test was developed there has been a 70% decrease in cervical cancer deaths over the last 50 years.Fact|date=February 2008 Pap smear testing has proven to be one of the most successful screening tests in the history of medicine.Fact|date=February 2008
A study published in April 2007 suggests that the act of performing a Pap smear produces an inflammatory
cytokineresponse, which may initiate immunologic clearance of HPV, therefore reducing the risk of cervical cancer. Women who had even a single Pap smear in their history had a lower incidence of cancer. "A statistically significant decline in the HPV positivity rate correlated with the lifetime number of Pap smears received." [cite news| url = http://www.oncolink.com/resources/article.cfm?c=3&s=8&ss=23&Year=2007&Month=5&id=14201 | title = Pap smears cause cytokine response that may help clear HPV | work = OncoLink | quote = J Inflamm 2007;4.]
It has been suggested that anal Pap smear screening for anal cancer might be of benefit for some sub-populations of men or women who engage in anal sex. [cite journal |author=Chin-Hong PV, Vittinghoff E, Cranston RD, "et al" |title=Age-related prevalence of anal cancer precursors in homosexual men: the EXPLORE study |journal=J. Natl. Cancer Inst. |volume=97 |issue=12 |pages=896–905 |year=2005 |pmid=15956651 |doi=10.1093/jnci/dji163]
The HPV test detects many common "low" and "high-risk" HPV genotypes. This test is an important screening option, since a doctor may recommend more frequent Pap testing if the HPV test is positive for "high-risk" HPV. In March 2003, the US FDA approved a "hybrid-capture" test, marketed by
Digene, as a primary screening tool for detecting HPV. This test was also approved for use as an adjunct to Pap testing, and may be performed during a routine Pap smear.
When patients are screened with both HPV testing and Pap testing the sensitivity reaches 100%. HPV testing can diagnose CIN 2-3 among women older than 30 years.cite journal |author=Mayrand MH, Duarte-Franco E, Rodrigues I, "et al" |title=Human papillomavirus DNA versus Papanicolaou screening tests for cervical cancer |journal=N. Engl. J. Med. |volume=357 |issue=16 |pages=1579–88 |year=2007 |pmid=17942871 |doi=10.1056/NEJMoa071430 |url=http://content.nejm.org/cgi/pmidlookup?view=short&pmid=17942871&promo=ONFLNS19] The sensitivity of HPV testing alone was 94.6% and specificity was 94.1%. For patients at similar risk to those in this study (0.4% had CIN 2-3), this leads to a
positive predictive valueof 6.0% and negative predictive valueof 100.0% ( [http://medinformatics.uthscsa.edu/calculator/calc.shtml?calc_dx_SnSp.shtml?prevalence=0.4&sensitivity=94.6&specificity=94.1 click here] to adjust these results for patients at higher or lower risk of CIN 2-3).
The CDC states on its "STD Facts-HPV Vaccine" page that "An HPV test or a Pap test can tell that a woman may have HPV, but these tests cannot tell the specific HPV type(s) that a woman has."
In Australia, a self-sampling HPV DNA test - that women can do at home using an ordinary tampon - is being marketed by Tam Pap. It has been approved by the
Therapeutic Goods Administrationfor distribution in Australia.Fact|date=May 2008
The recent outcomes in the identification of molecular pathways involved in cervical cancer provide helpful information about novel biomarkers that allow monitoring these essential molecular events in histological or cytological specimens. These biomarkers are likely to improve the detection of lesions that have a high risk of progression in both primary screening and triage settings.E6 and E7 mRNA detection (
HPV OncoTect) or p16 cell-cycle protein levels are examples of these new molecular markers. According to published results these markers, which are highly sensitive and specific, allow to identify cells going through malignant transformation. [Wentzensen, N. and M. von Knebel Doeberitz, Biomarkers in cervical cancer screening. Dis Markers, 2007. 23(4): p. 315-30.]
HPV testing in males
Although it is possible to test for HPV DNA in men, [cite journal |author=Dunne EF, Nielson CM, Stone KM, Markowitz LE, Giuliano AR |title=Prevalence of HPV infection among men: A systematic review of the literature |journal=J. Infect. Dis. |volume=194 |issue=8 |pages=1044–57 |year=2006 |pmid=16991079 |doi=10.1086/507432] there are no FDA-approved tests for general screening in the United States or tests approved by the Canadian government [cite web |url=http://www.phac-aspc.gc.ca/std-mts/hpv-vph/hpv-vph-man-eng.php |title=Human Papillomavirus (HPV) and Men: Questions and Answers |accessdate=2008-09-10 |year=2007 |quote=Currently, in Canada there is an HPV DNA test approved for women but not for men.] , since the testing is inconclusive and considered medically unnecessary. [cite web |url=http://www.thehpvtest.com/HPV-for-men-FAQ.html#testmen |title=What Men Need to Know About HPV |accessdate=2007-04-04 |year=2006 |quote=There is currently no FDA-approved test to detect HPV in men. That is because an effective, reliable way to collect a sample of male genital skin cells, which would allow detection of HPV, has yet to be developed.]
Genital warts are the only visible sign of low-risk HPV in men, and can be identified with a visual check of the genital area. These visible growths, however, are the result of non-carcinogenic HPV types. 5% acetic acid (vinegar) is used to identify both warts and squamous intraepithelial neoplasia (SIL) lesions with limited successcite web |url=http://www.cdc.gov/std/hpv/STDFact-HPV-and-men.htm |title=STD Facts - HPV and Men |accessdate=2008-03-28] by causing abnormal tissue to appear white, but most doctors have found this technique helpful only in moist areas, such as the female genital tract.
On June 8, 2006, the US
Food and Drug Administrationapproved Gardasil, a prophylactic HPV vaccinewhich is marketed by Merck. The vaccine trial, [cite journal |author=Harper DM, Franco EL, Wheeler CM, "et al" |title=Sustained efficacy up to 4.5 years of a bivalent L1 virus-like particle vaccine against human papillomavirus types 16 and 18: follow-up from a randomised control trial |journal=Lancet |volume=367 |issue=9518 |pages=1247–55 |year=2006 |pmid=16631880 |doi=10.1016/S0140-6736(06)68439-0] conducted in adult women with a mean age of 23, showed protection against initial infection with HPV types 16 and 18, which together cause 70% of cervical cancers, and can cause other cancers, such as anal cancer. The vaccine also protects against HPV types 6 and 11, which cause 90 percent of genital warts. GlaxoSmithKlineis seeking approval for a prophylactic vaccine known as Cervarixtargeting HPV types 16 and 18. It is delivered in three shots over six months. It is intended for females from 10 years of age onwards. [cite web |url=http://emc.medicines.org.uk/emc/assets/c/html/displaydoc.asp?documentid=20207|title=Cervarix PACKAGE LEAFLET: INFORMATION FOR THE USER |accessdate= 2008-06-21]
Gardasil vaccine is delivered in a series of three shots over six months at a cost of approximately $360 (US dollars). The CDC recommends that girls and women between the ages of 11 and 26 be vaccinated, though girls as young as 9 may benefit. [cite web |url=http://www.cdc.gov/std/hpv/STDFact-HPV-vaccine-hcp.htm |title=HPV and HPV Vaccine - HCP |date = 2006-08-01 | accessdate=2007-08-17] Females not yet sexually active can be expected to receive the full benefit of vaccination. Women over 26 can be vaccinated at the discretion of a doctor, but the vaccination has not yet been approved by the FDA for this age range, and may not be covered by insurance. Studies have not yet conclusively shown benefits for patients over 26, possibly due to the high prevalence of infection and the fact that the vaccine has no effect upon current infections.
HPV vaccine is made up of proteins from the outer coat of the virus (HPV). There is no infectious material in this vaccine. There is also no
thimerosal, a mercury based preservative, in the HPV vaccine. This vaccine has been tested in over 11,000 females (ages 9-26 years) around the world. These studies have shown no serious side effects. The most common side effect is soreness at the injection site. CDC, working with the FDA, will continue to monitor the safety of the vaccine after it is in general use. [cite web| title = Centers for Disease Control, HPV Vaccine - Questions & Answers For The PublicAbout the Safety and Effectiveness of the Human Papillomavirus (HPV) Vaccine | accessdate = 2007-06-28 | url = http://www.cdc.gov/vaccines/vpd-vac/hpv/hpv-vacsafe-effic.htm]
The vaccine does not appear to protect against HPV types that females are infected with at the time of vaccination. However, females already infected with one or more vaccine HPV types before vaccination would be protected against disease caused by the other vaccine HPV types covered by the vaccine. Therefore, although overall vaccine effectiveness would be lower when administered to females who have been sexually active, and would decrease with age and likelihood of HPV exposure with increasing number of sex partners, the majority of females in this age group will derive at least partial benefit from vaccination. The vaccine will not have any therapeutic effect on existing HPV infection or cervical lesions.
Since the current vaccine will not protect women against all the HPV types that cause cervical cancer, women should continue to seek Pap smear testing, even after receiving the vaccine. Cervical cancer screening recommendations have not changed for females who receive HPV vaccine.cite journal| url = http://www.cdc.gov/mmwr/PDF/rr/rr5602.pdf | journal = CDC, Morbidity and Mortality Weekly Report Recommendations | date = March 23, 2007 | volume = 56 / RR-2 | title = Quadrivalent Human Papillomavirus Vaccine, Recommendations of the Advisory Committee on Immunization Practices | pages = 17, Cervical Cancer Screening Among VaccinatedFemales]
Both men and women are carriers of HPV. [cite web | url = http://www.webmd.com/sexual-conditions/hpv-genital-warts/hpv-virus-information-about-human-papillomavirus | title = HPV Virus: Information About Human Papillomavirus | publisher = WebMD ] Possible benefits or efficacy of vaccinating men are being studied.
In addition to preventive vaccines, laboratory research and several human clinical trials are focused on the development of therapeutic HPV vaccines. In general, these vaccines focus on the main HPV
oncogenesE6 and E7. Since expression of E6 and E7 is required for promoting the growth of cervical cancer cells (and cells within warts), it is hoped that immune responses against the two oncogenes might eradicate established tumors. [ [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=15297964&query_hl=4&itool=pubmed_docsum Vaccination to prevent and treat cervical cancer] Hum Pathol. 2004 Aug;35(8):971]
Centers for Disease Control and Preventionsays that "While the effect of condoms in preventing HPV infection is unknown, condom use has been associated with a lower rate of cervical cancer, an HPV-associated disease." [cite web |url=http://www.cdc.gov/std/HPV/STDFact-HPV.htm |title=STD Facts - Human papillomavirus (HPV) |accessdate=2007-08-17 |format= |work=]
According to Marcus Steiner and Willard Cates in the "New England Journal of Medicine", "the protection that condoms offer cannot be precisely quantified."cite journal |author=Markus J. Steiner and Willard Cates, Jr. |title=Condoms and Sexually-Transmitted Infections |journal=N. Engl. J. Med. |volume=354 |issue=25 |pages=2642–3|year=2006 |doi=10.1056/NEJMp068111 |pmid=16790696 [http://content.nejm.org/cgi/content/full/354/25/2642] ] However, in a study reported in the same issue,cite journal |author=Winer RL, Hughes JP, Feng Q, "et al" |title=Condom use and the risk of genital human papillomavirus infection in young women |journal=N. Engl. J. Med. |volume=354 |issue=25 |pages=2645–54 |year=2006 |pmid=16790697 |doi=10.1056/NEJMoa053284 [Free online] ] of 82 female university students followed for eight months, the incidence of genital HPV infection was 37.8 per 100 patient-years among women whose partners used condoms for all instances of intercourse, compared with 89.3 per 100 patient-years in women whose partners used condoms less than 5% of the time. The researchers concluded that "Among newly sexually active women, consistent condom use by their partners appears to reduce the risk of cervical and vulvovaginal HPV infection."
Other studies have suggested that regular condom use can effectively limit the ongoing persistence and spread of HPV to additional genital sites in individuals who are already infected. [cite journal |author=Moscicki AB |title=Impact of HPV infection in adolescent populations |journal=The Journal of adolescent health : official publication of the Society for Adolescent Medicine |volume=37 |issue=6 Suppl |pages=S3–9 |year=2005 |pmid=16310138] [cite journal |author=Bleeker MC, Berkhof J, Hogewoning CJ, "et al" |title=HPV type concordance in sexual couples determines the effect of condoms on regression of flat penile lesions |journal=Br. J. Cancer |volume=92 |issue=8 |pages=1388–92 |year=2005 |pmid=15812547 |doi=10.1038/sj.bjc.6602524]
Thus, condom use may reduce the risk that infected individuals will progress to cervical cancer or develop additional genital warts.
Planned Parenthoodrecommends condom use to reduce the risk of contracting HPV. [cite web |url=http://www.plannedparenthood.org/sexual-health/std/hpv.htm |title=Planned Parenthood - HPV |accessdate=2007-08-17]
Ongoing research has suggested that several inexpensive chemicals might serve to block HPV transmission if applied to the genitals prior to sexual contact. [cite journal |author=Howett MK, Kuhl JP |title=Microbicides for prevention of transmission of sexually transmitted diseases |journal=Curr. Pharm. Des. |volume=11 |issue=29 |pages=3731–46 |year=2005 |pmid=16305508 |doi=10.2174/138161205774580633] These candidate agents, known as topical microbicides, are currently undergoing clinical efficacy testing. A recent study indicates that some sexual lubricant brands that use a gelling agent called
carrageenancan inhibit papillomavirus infection " in vitro". [cite journal |author=Buck CB, Thompson CD, Roberts JN, Müller M, Lowy DR, Schiller JT |title=Carrageenan is a potent inhibitor of papillomavirus infection |journal=PLoS Pathog. |volume=2 |issue=7 |pages=e69 |year=2006 |pmid=16839203 |doi=10.1371/journal.ppat.0020069] See Carrageenan#Sexual lubricant and microbicidefor details.
Clinical trials are needed to determine whether carrageenan-based sexual lubricant gels are effective for blocking the sexual transmission of HPVs "
Fruits and vegetables
There is weak evidence to suggest a significant deficiency of
retinolcan increase chances of cervical dysplasia, independently of HPVinfection.A small (n~=500) case-control study of a narrow ethnic group (native Americans in New Mexico) assessed serum micro-nutrients as risk factors for cervical dysplasia. Subjects in the lowest serum retinolquartile were at increased risk of CIN I compared with women in the highest quartile.cite journal |author=Yeo AS, Schiff MA, Montoya G, Masuk M, van Asselt-King L, Becker TM |title=Serum micronutrients and cervical dysplasia in Southwestern American Indian women |journal=Nutrition and cancer |volume=38 |issue=2 |pages=141–50 |year=2000 |pmid=11525590|doi=10.1207/S15327914NC382_1]
However, the study population had low overall serum retinol, suggesting deficiency. A study of serum retinol in a well-nourished population reveals that the bottom 20% had serum retinol close to that of the highest levels in this New Mexico sub-population. [cite journal |author=Michaëlsson K, Lithell H, Vessby B, Melhus H.|title=Serum Retinol Levels and the Risk of Fracture|journal=NEJM|volume=348|issue=4|pages=287–294|year=2003|pmid=12540641|doi=10.1056/NEJMoa021171]
Risk of type-specific, persistent HPV infection was lower among women reporting intake values of
vitamin Cin the upper quartile compared with those reporting intake in the lowest quartile. [cite journal |author=Giuliano AR, Siegel EM, Roe DJ, "et al" |title=Dietary intake and risk of persistent human papillomavirus (HPV) infection: the Ludwig-McGill HPV Natural History Study |journal=J. Infect. Dis. |volume=188 |issue=10 |pages=1508–16 |year=2003 |pmid=14624376 |doi=10.1086/379197]
HPV clearance time was significantly shorter among women with the highest compared with the lowest serum levels of
tocopherols, but significant trends in these associations were limited to infections lasting =120 days. Clearance of persistent HPV infection (lasting >120 days) was not significantly associated with circulating levels of tocopherols. Results from this investigation support an association of micronutrients with the rapid clearance of incident oncogenic HPV infection of the uterine cervix.cite journal |author=Goodman MT, Shvetsov YB, McDuffie K, "et al" |title=Hawaii cohort study of serum micronutrient concentrations and clearance of incident oncogenic human papillomavirus infection of the cervix |journal=Cancer Res. |volume=67 |issue=12 |pages=5987–96 |year=2007 |pmid=17553901 |doi=10.1158/0008-5472.CAN-07-0313 |url=http://cancerres.aacrjournals.org/cgi/content/full/67/12/5987]
A statistically significantly lower level of
alpha-tocopherolwas observed in the blood serum of HPV-positive patients with cervical intraepithelial neoplasia. The risk of dysplasia was four times higher for an alpha-tocopherol level < 7.95 mumol/l. [cite journal |author=Kwaśniewska A, Tukendorf A, Semczuk M |title=Content of alpha-tocopherol in blood serum of human Papillomavirus-infected women with cervical dysplasias |journal=Nutrition and cancer |volume=28 |issue=3 |pages=248–51 |year=1997 |pmid=9343832 |doi=]
Higher folate status was inversely associated with becoming HPV test-positive. Women with higher folate status were significantly less likely to be repeatedly HPV test-positive and more likely to become test-negative. Studies have shown that lower levels of antioxidants coexisting with low levels of folic acid increases the risk of CIN development. Improving folate status in subjects at risk of getting infected or already infected with high-risk HPV may have a beneficial impact in the prevention of cervical cancer. [cite journal |author=Piyathilake CJ, Henao OL, Macaluso M, "et al" |title=Folate is associated with the natural history of high-risk human papillomaviruses |journal=Cancer Res. |volume=64 |issue=23 |pages=8788–93 |year=2004 |pmid=15574793 |doi=10.1158/0008-5472.CAN-04-2402 |url=http://cancerres.aacrjournals.org/cgi/content/full/64/23/8788] [cite journal |author=Kwaśniewska A, Tukendorf A, Goździcka-Józefiak A, Semczuk-Sikora A, Korobowicz E |title=Content of folic acid and free homocysteine in blood serum of human papillomavirus-infected women with cervical dysplasia |journal=Eur. J. Gynaecol. Oncol. |volume=23 |issue=4 |pages=311–6 |year=2002 |pmid=12214730 |doi=]
Higher circulating levels of
carotenoidswere associated with a significant decrease in the clearance time of type-specific HPV infection, particularly during the early stages of infection (=120 days). Clearance of persistent HPV infection (lasting >120 days) was not significantly associated with circulating levels of carotenoids.
The likelihood of clearing an oncogenic HPV infection is significantly higher with increasing levels of
lycopenes. [cite journal |author=Sedjo RL, Papenfuss MR, Craft NE, Giuliano AR |title=Effect of plasma micronutrients on clearance of oncogenic human papillomavirus (HPV) infection (United States) |journal=Cancer Causes Control |volume=14 |issue=4 |pages=319–26 |year=2003 |pmid=12846362|doi=10.1023/A:1023981505268] A 56% reduction in HPV persistence risk was observed in women with the highest plasma [lycopene] concentrations compared with women with the lowest plasma lycopene concentrations. These data suggests that vegetable consumption and circulating lycopene may be protective against HPV persistence.cite journal |author=Sedjo RL, Roe DJ, Abrahamsen M, "et al" |title=Vitamin A, carotenoids, and risk of persistent oncogenic human papillomavirus infection |journal=Cancer Epidemiol. Biomarkers Prev. |volume=11 |issue=9 |pages=876–84 |year=2002 |pmid=12223432 |doi=] cite journal |author=Giuliano AR, Siegel EM, Roe DJ, "et al" |title=Dietary intake and risk of persistent human papillomavirus (HPV) infection: the Ludwig-McGill HPV Natural History Study |journal=J. Infect. Dis. |volume=188 |issue=10 |pages=1508–16 |year=2003 |pmid=14624376 |doi=10.1086/379197] [cite journal |author=Giuliano AR, Papenfuss M, Nour M, Canfield LM, Schneider A, Hatch K |title=Antioxidant nutrients: associations with persistent human papillomavirus infection |journal=Cancer Epidemiol. Biomarkers Prev. |volume=6 |issue=11 |pages=917–23 |year=1997 |pmid=9367065 |doi=]
Women who had either CIN or cervical cancer had markedly lower levels of
CoQ10in their blood and in their cervical cells than the women who were healthy.Fact|date=August 2007
In a 1999 study,
Docosahexaenoic acidinhibited growth of HPV16 immortalized cells. [cite journal |author=Chen D, Auborn K |title=Fish oil constituent docosahexa-enoic acid selectively inhibits growth of human papillomavirus immortalized keratinocytes |journal=Carcinogenesis |volume=20 |issue=2 |pages=249–54 |year=1999 |pmid=10069461|doi=10.1093/carcin/20.2.249]
"There is currently no cure or treatment for HPV infection."cite web |url=http://www.cancer.org/docroot/CRI/content/CRI_2_4_2X_What_are_the_risk_factors_for_cervical_cancer_8.asp |title=What Are the Risk Factors for Cervical Cancer? |author=American Cancer Society |accessdate=2008-02-21]
"Therapies for conditions caused by HPV are addressed in main articles covering the various HPV-related diseases."
Infection with cutaneous HPVs is ubiquitous. [cite journal |author=Antonsson A, Forslund O, Ekberg H, Sterner G, Hansson BG |title=The ubiquity and impressive genomic diversity of human skin papillomaviruses suggest a commensalic nature of these viruses |journal=J. Virol. |volume=74 |issue=24 |pages=11636–41 |year=2000 |pmid=11090162|doi=10.1128/JVI.74.24.11636-11641.2000] Some HPV types, such as HPV-5, may establish infections that persist for the lifetime of the individual without ever manifesting any clinical symptoms. Like
remorasuckerfish that hitchhike harmlessly on sharks, these HPV types can be thought of as human commensals. Other cutaneous HPVs, such as HPV types 1 or 2, may cause common warts in some infected individuals. Skin warts are most common in childhood and typically appear and regress spontaneously over the course of weeks to months. About 10% of adults also suffer from recurring skin warts. All HPVs are believed to be capable of establishing long-term "latent" infections in small numbers of stem cells present in the skin. Although these latent infections may never be fully eradicated, immunological control is thought to block the appearance of symptoms such as warts. Immunological control is likely HPV type-specific, meaning that an individual may become immunologically resistant to one HPV type while remaining susceptible to other types.
A large increase in the incidence of genital HPV infection occurs at the age when individuals begin to engage in sexual activity. The great majority of genital HPV infections never cause any overt symptoms and are cleared by the immune system in a matter of months. As with cutaneous HPVs, immunity is believed to be HPV type-specific. Some infected individuals may fail to bring genital HPV infection under immunological control. Lingering infection with high-risk HPV types, such as HPVs 16, 18, 31 and 45, can lead to the development of cervical cancer or other types of cancer. [cite journal |author=Schiffman M, Castle PE |title=The promise of global cervical-cancer prevention |journal=N. Engl. J. Med. |volume=353 |issue=20 |pages=2101–4 |year=2005 |pmid=16291978 |doi=10.1056/NEJMp058171] In addition to persistent infection with high-risk HPV types, epidemiological and molecular data suggest that co-factors such as the cigarette smoke carcinogen benzo ["a"] pyrene (BaP) enhance development of certain HPV-induced cancers. [cite journal |author=Alam S, Conway MJ, Chen HS, Meyers C |title=Cigarette Smoke Carcinogen Benzo [a] pyrene Enhances Human Papillomavirus Synthesis|journal=J Virol |year=2007 |pmid=17989183 |volume=82 |pages=1053 |doi=10.1128/JVI.01813-07]
High-risk HPV types 16 and 18 are together responsible for over 65% of cervical cancer cases. [cite journal |author=Cohen J |title=Public health. High hopes and dilemmas for a cervical cancer vaccine |journal=Science |volume=308 |issue=5722 |pages=618–21 |year=2005 |pmid=15860602 |doi=10.1126/science.308.5722.618] Type 16 causes 41 to 54% of cervical cancers, [cite journal |author=Noel J, Lespagnard L, Fayt I, Verhest A, Dargent J |title=Evidence of human papilloma virus infection but lack of Epstein-Barr virus in lymphoepithelioma-like carcinoma of uterine cervix: report of two cases and review of the literature |journal=Hum. Pathol. |volume=32 |issue=1 |pages=135–8 |year=2001 |pmid=11172309|doi=10.1053/hupa.2001.20901] and accounts for an even greater majority of HPV-induced vaginal/vulvar cancers, [cite journal |author=Edwards QT, Saunders-Goldson S, Morgan PD, Maradiegue A, Macri C |title=Vulvar intraepithelial neoplasia: varied signs, varied symptoms: what you need to know |journal=Advance for nurse practitioners |volume=13 |issue=3 |pages=49–52 |year=2005 |pmid=15777042] penile cancers, anal cancers and head and neck cancers. [cite journal |author=Bolt J, Vo QN, Kim WJ, McWhorter AJ, Thomson J, Hagensee ME, Friedlander P, Brown KD, Gilbert J |title=The ATM/p53 pathway is commonly targeted for inactivation in squamous cell carcinoma of the head and neck (SCCHN) by multiple molecular mechanisms |journal=Oral Oncol. |volume=41 |issue=10 |pages=1013–20 |year=2005 |pmid=16139561 |doi=10.1016/j.oraloncology.2005.06.003]
Although genital HPV types are sometimes transmitted from mother to child during birth, the appearance of genital HPV-related diseases in newborns is rare. Perinatal transmission of HPV types 6 and 11 can result in the development of juvenile-onset recurrent
respiratory papillomatosis(JORRP). JORRP is very rare, with rates of about 2 cases per 100,000 children in the United States. Although JORRP rates are substantially higher if a woman presents with genital warts at the time of giving birth, the risk of JORRP in such cases is still less than 1%.
History of discovering link between virus and cancer
The fact that prostitutes have much higher rates of cervical cancer than
nuns was a key early observation leading researchers to speculate about a causal link between sexually transmitted HPVs and cervical cancer. [cite journal |author=zur Hausen H, de Villiers EM |title=Human papillomaviruses |journal=Annu. Rev. Microbiol. |volume=48 |issue= |pages=427–47 |year=1994 |pmid=7826013 |doi=10.1146/annurev.micro.48.1.427]
Harald zur Hausenof the German Cancer Research Centre, Heidelberg, Germany, was awarded 2008 Nobel Prize in Physiology or Medicinefor his discovery of human papilloma viruses causing cervical cancer. [http://nobelprize.org/nobel_prizes/medicine/laureates/2008/]
Loop electrical excision procedure
* [http://www.cdc.gov/STD/HPV/default.htm HPV Fact sheets] from the
Centers for Disease Control and Prevention
* [http://www.ashastd.org/hpv/hpv_learn_myths.cfm Myths and misconceptions about HPV] —
American Social Health Association
* [http://www.oralcancerfoundation.org/hpv/index.htm HPV's links to oral cancers] peer reviewed information from The Oral Cancer Foundation
* [http://www.hpvsafety.com/hpv_virus_and_pregnancy.html HPV and pregnancy] Answers for those pregnant with HPV
* [http://www.pbs.org/now/shows/308/index.html NOW on PBS: "Vaccine Debate"] — The political controversy over requiring HPV vaccinations for girls.
* [http://thedaily.washington.edu/article/2007/8/8/hpvIsAtYourFingertips HPV found under the fingernails of young men] The Daily, University of Washington
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