2. Human Papillomavirus (HPV)
Genital Warts
F.Iraji MD
There are more than 100 types of HPV. About types can infect the genital area-vulva, vagina, cervix, rectum, anus, penis and scrotum. Some types cause genital warts, some cause changes in cells (cervix). Most types seem to have no harmful effect at all.
Some studies estimate that the majority of the sexually active population is exposed to at least one or more types of HPV-although most do not develop symptoms. Because HPV is so common and prevalent, a person does not need to have a lot of sex partners to come into contact with this virus.

3. A human papillomavirus (HPV) is a virus that infects the epidermis and mucous membranes.
Over 130 HPV Types
Lifecycle somewhat unknown.
Several months to years may elapse before the abnormal growth of cells

5. Human Papillomavirus (commonly called Genital Warts)
Human Papillomavirus (HPV) is a virus that can cause various disease states including “genital” or “venereal” warts
Papillomaviruses are a complex group of DNA tumor viruses. They can cause benign growths (papillomas), cancers, or more commonly, transient infections
HPV infection is causally associated with cervical cancer ; other genital cancers including anal, penile, vulvar, and vaginal cancers may have HPV as co-factor
In most cases, genital HPV infection is transient, asymptomatic, and resolves without treatment or without a person ever being aware they had the infection.
They can’t be routinely grown in the lab
HPV and genital warts are usually spread by direct, skin-to-skin contact during sex. Warts might appear within several weeks or they might take months to appear, or they might never appear. Very little is known about the transmission of subclinical HPV infection. The majority of visible warts are caused by one of two types of HPV…Types 6 or 11. These two types cause 90% of the visible warts seen in the US. The new HPV vaccine protects against both of these types.

8. Human Papillomavirus Cervical Cancer
Next few slides are a quick reminder that HPV is the major cause of cervical cancer.
As I just mentioned if left untreated cervical cancer will lead to death but even if it is caught in time it is associated with significant morbidity.
The treatment whether surgical or chemoradiotherapy will majority of the time result in loss of fertility.
Cervical Cancer

9. HPV Prevalence Most common STD
Yearly incidence of 6.2 million
20 million currently infected
80 million infected at least once between the ages of 15-49
An estimated 9.2 million sexually active adolescents and young adults years of age are infected with genital HPV
An estimated 5%-30% of people infected with genital HPV are infected with multiple types of the virus
316,000 initial visits to physicians’ offices (2004)-genital wart diagnosis
HPV is one of the most common causes of STDs in the world. According to the Centers for Disease Control and Prevention, there are approximately 6.2 million new cases of HPV infections reported each year. At least 20 million Americans are already infected.
An estimated 1million people have genital warts at any one time in the US. That’s about 1% of the sexually active population, making genital warts one of our most common STDs.
It is estimated that 20 million persons are currently infected and approximately 80 million persons between the ages of have been infected with some type of HPV at one point in their life.
At present in the US, most young women become infected with HPV within a few years after becoming sexually active. Multiple, concurrent and sequential infections with different types of HPV are common. The majority of these infections are subclinical, unrecognized, transient and benign.

10. GENITAL HPV INFECTION 1%. 1. 4 MILLION. VISIBLE WARTS 4%. 5 MILLION
GENITAL HPV INFECTION 1% MILLION VISIBLE WARTS 4% MILLION Subclinical (Colposcopy) 10% MILLION Subclinical (DNA testing) 60% MILLION Prior infection (+ antibodies) 25% MILLION No prior/current infection

11. Epidemiology of HPV and Cervical Cancer
Over 99% of cervical cancers have HPV DNA detected within the tumor
70% of cervical cancer is caused by one of two types of HPV, 16 or 18
The quadrivalent HPV vaccine protects against Types 6, 11, 16 and 18

12. HPV
Small virus – 130 types
Low-risk e.g. 6, 11
High-risk e.g. 16, 18
Associated with various disease from skin warts to cervical cancer
Transmission via skin-to-skin/sexual
Most common STD
There are over 100 different types of HPV; around 20 or so infect the LGT. These can be divided into LR types which cause genital warts, the most common of which are HPV6 and 11 and HR types which are assoc with cx neoplasia the most common being HPV16 and 18.
GW - considerable psychosocial and psychosexual morbidity and costs~ £30m/yr.
Highest prevalence rates following initiation of sexual activity >25%. Lifetime risk 80%. Overall prevalence 10-15%
80% clear infection in 18 months. Median duration of HPV infection 12 months, possibly slightly longer duration of infection for HR types eg HPV16

13. HPV Genotyping System Genital HPV types are generally characterized
Pathogenesis
HPV Genotyping System
Genital HPV types are generally characterized
in terms of oncogenic potential.
Low-risk types (nononcogenic types)
Most genital warts caused by HPV types 6 and 11
Recurrent respiratory papillomatosis associated with HPV types 6 and 11
High-risk types (oncogenic types)
HPV types 16 and 18 found in 70% of cervical cancers
Most women with high-risk HPV infection have normal Pap test results and never develop cellular changes or cervical cancer.

14. Pathogenesis
Pathology
HPV infects the basal cell layer of stratified squamous epithelium and stimulates cellular proliferation.
Affected cells display a broad spectrum of changes, ranging from benign hyperplasia, to dysplasia, to invasive carcinoma.

15. Pathogenesis
Natural History of HPV
Most genital HPV infections are transient, asymptomatic (subclinical), and have no clinical consequences in immunocompetent individuals.
Time to development of clinical manifestations is variable.
Median duration of new cervical infections is 8 months, but varies.
90% of infections clear within 2 years
Gradual development of an effective immune response is the likely mechanism for HPV DNA clearance.

16. Natural History of HPV-continued
Pathogenesis
Natural History of HPV-continued
Persistent HPV infection
Not cleared by the immune system
Characterized by persistently detectable type-specific HPV DNA
Persistent oncogenic HPV infection is most important risk factor for precancerous cervical cellular changes and cervical cancer.

17. How does HPV cause cancer?
HPV infection
Persistent HR HPV infection
Normal epithelium
CIN
Invasive
carcinoma
years
This is a v simplified diagram of HPV carcinogenesis where most (over 80%), HPV infections are cleared without causing a clinical problem. In the minority HPV persists and over a period of years may progress to pre-invasive lesions, in the case of the cervix to cervical intraepithelial neoplasia, and eventually some of these lesions progress to invasive cancer. This is not inevitable however and lesions may regress dependent on age, immune status and severity of the abnormality.
5% high risk progress to cervical cancer in unscreened women
1-2% progress in screened women
HPV clearance No lesion > 80%
HPV clearance & regression dependent on age, degree of CIN lesion & immune status

18. Strength of Association
Relative
Risk Carcinogenic Agent
> 500 High Risk HPV and cervical cancer Philippines, Costa Rica, Bangkok
Hepatitis B virus and liver cancer Taiwan, Greece
20 Hepatitis C virus and liver cancer Italy, Spain
10 Cigarette smoking and lung cancer
This shows you the strength of the association between HR HPV and cacx. Here you can see a relative risk of > 500 for…
There is data to show that these countries mentioned have higher risk.
This is an extremely high risk as far as ca risk factors go! Cf to a RR of 10 for cigarette smoking and lung ca and yet everyone knows that smoking causes ca.

19. HR HPV
In fact HR HPV is the most carcinogenic environmental agent known to mankind.

20. 2 opportunities to prevent cervical cancer
Normal cervix
HPV infection
Precursor disease – Cervical Intraepithelial Neoplasia (CIN)
Cervical cancer
Cervical screening & treatment
Prophylactic HPV vaccination
We have 2 opportunities to prevent cervical cancer – two points on the pathway to the development of cervical cancer. I will talk mainly about the vaccine and briefly mention the affect on cervical screening. I am not going to talk about the treatment of the cervical cancer only that there is research currently ongoing to develop a therapeutic vaccine. 20

21. Questions?

22. Epidemiology of HPV and Cervical Cancer
Over 99% of cervical cancers have HPV DNA detected within the tumor
70% of cervical cancer is caused by one of two types of HPV, 16 or 18
The quadrivalent HPV vaccine protects against Types 6, 11, 16 and 18

23. Risk Factors for Acquiring a Genital HPV Infection
Young age (less than 25 years)
Multiple sex partners
Early age at first intercourse (16 years or younger)
Male partner has (or has had) multiple sex partners
Estimates for prevalence of genital warts caused by low-risk types of HPV are relatively imprecise. However, estimates indicate that as many as 100 per 100,000 people develop genital warts. About 1.4 million people (about 1% of sexually active people) currently have genital warts.

24. Friction and abrasion are key factors.
HPV Transmission
Direct skin-to-skin contact
Usually, but not always sexual contact
Infected birth canal
Fomites (very rare)
Friction and abrasion are key factors.
Difficult to determine how and where infection occurred due to poor standardized tests and variable latency periods.
As is the case with warts on other parts of the body, direct skin-to-skin contact spreads HPV most easily because HPV lives primarily in the skin and mucosal cells and is not transmitted via blood or body fluids.
Genital papillomavirus is transmitted through:
1) sexual contact (genital tract HPV)
2) during passage through an infected birth canal (Discuss in more depth tomorrow)
3) fomites (rare) Fomites are inanimate objects that may harbor the infectious organism and transmit it when the fomite is introduced to a non-infected person. Some experts believe that in rare cases HPV may be transmitted through shared bath towels, for example, towels that are used by a person with genital papillomavirus and then soon after are rubbed into the genital area of a non-infected person, causing the transmission of HPV(abrasion is important for transmission). In the end, science simply does not have the tools to pin down explanations for these rare instances of alleged nonsexual transmission. Dr. Kay Stone of the CDC stated that, “ this (HPV) is such a common virus that if you really could get it from inanimate objects such as underwear, sweaty bicycle seats at your health club, or the water in a swimming pool; we would expect to see HPV infections in more people who have never been sexually active.” The virus infects the epidermis, but the exact mechanism by which this occurs is unknown. As stated above, friction plays a key role in this process and HPV is most efficiently transmitted into mucous membranes and abraded skin.
The types of HPV that cause genital warts do not usually seem to cause warts on other body parts such as the hands or feet.

25. How is HPV spread?
Any kind of sexual activity involving skin to skin genital contact with an infected person — intercourse isn't necessary.
People with HPV may not show any signs or symptoms, so they can pass the virus on without knowing it. 25

26. What about oral sex?
It can occur in the mouth, throat or respiratory tract
It is relatively uncommon
It appears to be an inefficient mode for transmission
It does not appear to “take hold” as easily in the mouth, throat and/or respiratory tract of adults

27. HPV Incubation Average incubation is 3 weeks to 1 year
Possibly years before appearance of warts or cervical abnormalities
Some will be transient and may never be detected
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.

28. Common Symptoms of Genital Warts in Males & Females
The symptoms may include single or multiple fleshy growths around the penis, scrotum, groin, vulva, vagina, anus, and/or urethra
They may also include: itching, bleeding, or burning, and pain
The symptoms may recur from time to time
Condyloma Acuminata-bumps or warty growths on the external genitals or the anus cause by certain types of HPV. Usually benign.
They tend to be flesh-colored or whitish in appearance. They do not usually cause itching or burning.
Genital warts often occur in clusters and can be very tiny or can spread into large masses in the genital or anal area.

29. Genital Warts-Duration and Transmission
Clinical Manifestations
Genital Warts-Duration and Transmission
May regress spontaneously, or persist with or without proliferation.
Frequency of spontaneous regression is unclear, but estimated at 10–30% within three months.
Persistence of infection occurs, but frequency and duration are unknown.
Recurrences after treatment are common.

30. Genital Warts and High-Risk HPV
Clinical Manifestations
Genital Warts and High-Risk HPV
High-risk HPV types occasionally can be found in visible warts and have been associated with squamous intrepithelial lesions (squamous cell carcinoma in situ, Bowenoid papulosis, Erythroplasia of Queyrat, or Bowen’ s disease of the genitalia).
The lesions can resemble genital warts.
Unusual appearing genital warts should be biopsied.

31. Genital Warts in a Male
Source: CDC/ NCHSTP/ Division of STD Prevention,
STD Clinical Slides
Source: Cincinnati STD/HIV Prevention Training Center

32. HPV Penile Warts
Source: Cincinnati STD/HIV Prevention Training Center

33. In males, condylomata occur earliest near the frenulum (part of the foreskin that unites with the under side of the glans penis) and are most frequent on the coronal sulcus (the ridge below the hood of the glans penis), the shaft, and the preputial borders (the edges of the foreskin.)

34. Pearly Penile Papules
Pearly penile papules are frequently found on the glans penis of males. They are normal and should not be confused with warts.
Pearly penile papules are not STDs, but some people worry about STDs when they see them. Pearly penile papules are upgrowing, smooth, small, dome- or finger-shaped, skin-colored papules that are located on the sulcus or the corona of the glans penis (Brown, 2001). While the lesions are often mistaken for sexually transmitted diseases such as genital warts (which is a source of anxiety and fear for those who have not yet received the diagnosis of pearly penile papules), they are not contagious. The lesions, which are usually found around the corona in one or more rows, are actually just natural anatomical variants (Brown, 2001). It is not known what causes pearly penile papules to develop.
In the US: “the incidence of pearly penile papules reportedly ranges from 8-48%.”
Pearly penile papules usually begin to appear between the ages of 20 and 40 years (Dean, 2000). These lesions are somewhat rare and are not sexually transmitted. The pearly penile papules will not hurt an afflicted man’s partner (Brown, 2001).
Pearly penile papules are benign and natural.

35. Vestibular papillomatosis

36. Intra-meatal Wart of the Penis (and Gonorrhea)
Source: Florida STD/HIV Prevention Training Center

37. Circumcision and HPV Risk for penile cancer
May influence the risk of HPV acquisition, transmission and cervical cancer
Penile cancer is almost nonexistent in the circumcised male and the small ~1% risk of penile cancer in men is almost entirely in the uncircumcised male.
The theory is that the mucosal lining of the prepuce may be more vulnerable to HPV.
During intercourse, the foreskin is pulled back, exposing the mucosal surface of the prepuce to potentially infected vaginal secretions and HPV might be afforded access through minute ulcers or small epithelial abrasions.
However, routine circumcision is not recommended as a way to prevent HPV transmission.
However, for the first time, strong epidemiological evidence suggests that male circumcision may influence the risks of HPV transmission, acquisition and cervical cancer in women.
Because males do not have overt symptoms for the types of HPV linked to cervical cancer, it is difficult to effectively diagnose and treat men with subclinical or invisible infection.

38. Female Genital Warts
Source: CDC/NCHSTP/Division of STD, STD Clinical Slides

39. Perianal Warts Clinical Manifestations
Source: Seattle STD/HIV Prevention Training Center at the University of Washington/ UW HSCER Slide Bank

40. Vulvar Warts Clinical Manifestations
Source: Reprinted with permission of Gordon D. Davis, MD.

41. Although almost all genital warts are not cancerous, large and confluent lesions should be carefully examined and multiple biopsies obtained to rule out underlying malignancies. It may be important to biopsy the darker warts to rule out the possibility of underlying skin cancer.
Some studies show that women with genital warts are at an increased risk for cancer of the cervix. Women with genital warts should have a yearly pap smear to catch any abnormalities in early stages.

42. Here we see a classic presentation of warts on the perianal skin.

43. HPV Warts on the Thigh
Source: Cincinnati STD/HIV Prevention Training Center

44. Perianal Warts
Source: Cincinnati STD/HIV Prevention Training Center

45. Complications of Genital Warts (if untreated)
It may destroy body tissue around the genitals and anus
For pregnant women
Delivery complications or need for C-section
Juvenile Onset Recurrent Respiratory Papillomatosis (JO-RRP)
Juvenile Onset Recurrent Respiratory Papillomatosis (JO-RRP) will be discussed tomorrow

46. Testing & Treatment for Genital Warts
Can be detected in a clinical exam;
Can be treated by removing the warts;
The virus cannot be removed, so the warts may grow back.
Your health care provider can usually tell if you have genital warts because he/she can see them. Sometimes they may be so small that your health care provider might put a vinegar type solution on the wart and use a magnifying glass or microscope to see the wart.
A Pap smear is the best way to detect cervical changes due to HPV.
A biopsy is only necessary if the wart is unusual looking or discolored.
There are currently no blood tests available.

47. Cervical Cellular Abnormalities
Clinical Manifestations
Cervical Cellular Abnormalities
Usually subclinical
Lesions associated with these abnormalities can be detected by Pap test or colposcopy, with or without biopsy.
Can be caused by HPV
Low-grade lesions often regress spontaneously without treatment.

48. Classification of Cervical Cellular Abnormalities
Clinical Manifestations
Classification of Cervical Cellular Abnormalities
2001 Bethesda System
Atypical Squamous Cells (ASC-US and ASC-H) are cells that do not appear to be completely normal
Atypical Squamous Cells of Undetermined Significance (ASC–US)
Changes are often caused by HPV infection.
Changes are usually mild.
Atypical Squamous Cells cannot exclude a High-Grade Squamous Intraepithelial Lesion (ASC–H).
Changes are more likely to be associated with precancerous abnormalities than ASC-US.

49. Classification of Cervical Cellular Abnormalities-continued
Clinical Manifestations
Classification of Cervical Cellular Abnormalities-continued
Low-grade squamous intraepithelial lesion (LSIL)
Usually transient, caused by HPV infection
High-grade squamous intraepithelial lesion (HSIL)
Generally changes due to persistent infection with a high-risk HPV type
Lesions associated with HSIL have a higher risk for progression to cervical cancer.

50. HPV Diagnostic Techniques
History
Visual exam
Pap smears
DNA testing
Although there is no one standard test for HPV, a number of methods are used to diagnose HPV infection. These include sexual history, visual exam, and Pap smears. The health care professional should take a careful history from the patient to include the following:
sexual history, including: number of sex partners; sexual practices; and age of first intercourse
history of STDs in patient and sex partners
if female, history of previous Pap smears and results
A 1992 survey by the CDC found that only 49% of primary care physicians asked new patients about STDs, 31% asked about condom use, and 22% asked about sexual partners. By comparison, 94% asked the same patients about cigarette smoking.
In addition a complete physical exam should be conducted on the patient, as well as the sex partners, to rule out other STD’s.
The VISUAL EXAM is of value in identifying warts visible to the naked eye, and are diagnosed based on their appearance. When warts are located in the urethra or rectum, a special instrument called an endoscope is used to visualize them. When flat warts ( condyloma planum) are suspected, application of 3 to 5% acetic acid enhances visualization by producing acetowhite areas. Examination of these areas with a colposcope ( an instrument inserted into the vagina to magnify the tissue of the vagina and cervix) or hand lens will improve diagnostic accuracy and recognition of flat warts.
Vaginal warts are not seen as commonly as cervical or vulvar warts.
Flat warts (condylomata planum) are often identified noting certain changes in form and structure such as: color, margin contour, vascular pattern, and iodine staining. These are quite useful in distinguishing cervical HPV infection from dysplasia or other abnormalities.
The PAPANICOLAOU SMEAR is often the tool which first identifies signs of HPV infection. Although the Pap is not a specific test for HPV, the Pap test can detect abnormal cells associated with HPV before they become cancerous. Identification can lead to early treatment and can preserve life and fertility.
DNA TESTING is too expensive to be used as a screening tool. However, it has been used successfully to identify types of HPV in certain lesions and cancers, and has been valuable in choosing treatment type.

51. Diagnosis of Genital Warts
Diagnosis is usually made by visual inspection with bright light.
Consider biopsy when
Diagnosis is uncertain;
Patient is immunocompromised;
Warts are pigmented, indurated, or fixed;
Lesions do not respond or worsen with standard treatment; or
There is persistent ulceration or bleeding.

52. Diagnosis of Genital Warts-continued
Use of type-specific HPV DNA tests for routine diagnosis and management of genital warts is not recommended.
Application of acetic acid to evaluate external genitalia is not routinely recommended due to its low specificity.
Acetowhitening will occur at sites of prior trauma or inflammation.
External genital warts are not an indication for cervical colposcopy or increased frequency of Pap test screening (assuming patient is receiving screening at intervals recommended by her healthcare provider).

53. Differential Diagnosis of Genital Warts
Other infections
Condylomata lata
Tend to be smoother, moist, more rounded, and darkfield-positive for Treponema pallidum
Molluscum contagiosum
Papules with central dimple, caused by a pox virus; rarely involves mucosal surfaces
Acquired dermatologic conditions
Seborrheic keratosis
Lichen planus
Fibroepithelial polyp, adenoma
Melanocytic nevus
Neoplastic lesions

54. Differential Diagnosis of Genital Warts-continued
Normal anatomic variants
“Pink pearly penile papules”
Vestibular papillae (micropapillomatosis labialis)
Skin tags (acrochordons)
External genital squamous intraepithelial lesions (SIL)
Squamous cell carcinoma in situ
Bowenoid papulosis
Erythroplasia of Queyrat
Bowen’s disease of the genitalia

55. Diagnosis of Cervical Cellular Abnormalities
Cytology (Pap test)
Useful screening test to detect cervical cell changes
Provides indirect evidence of HPV because it detects squamous epithelial cell changes that are almost always due to HPV

56. Diagnosis of Cervical Cellular Abnormalities-continued
HPV DNA tests
FDA-approved:
To triage women with ASC-US Pap test results, and
As an adjunct to Pap test screening for cervical cancer in women 30 years or older.
HPV DNA tests should not be used
In men,
In adolescents <21 years,
To screen partners of women with Pap test abnormalities,
To determine who will receive HPV vaccine, or
STD screening for HPV.

57. Diagnosis of Cervical Cellular Abnormalities-continued
Colposcopy
Indication guided by physical exam or Pap test findings with or without HPV DNA test findings
Cervical biopsy
May be indicated if there is/are
Visible exophytic lesions on cervix
Pap test with HSIL, ASC-H, or other findings

58. General Treatment of Genital Warts
Management
General Treatment of Genital Warts
Primary goal is removal of warts.
If left untreated, genital warts may regress spontaneously or persist with or without proliferation.
In most patients, treatment can induce wart-free periods.
Currently available therapies may reduce, but probably do not eliminate infectivity.
Effect of current treatment on future transmission is unclear.

59. General Treatment of Genital Warts-continued
Management
General Treatment of Genital Warts-continued
No evidence that presence of genital warts or their treatment is associated with development of cervical cancer.
Some patients may choose to forgo treatment and await spontaneous resolution.
Consider screening persons with newly diagnosed genital warts for other STDs (e.g., chlamydia, gonorrhea, HIV, syphilis).

60. Management
Treatment Regimens
Patient-applied and provider-administered therapies are available.
Providers should be knowledgeable about and have available, at least one patient-applied and one provider-administered treatment.
Choice of treatment should be guided by
Patient preference,
Available resources,
Experience of the healthcare provider,
Location of lesion(s), and
Pregnancy status.

61. Treatment Regimens-continued
Management
Treatment Regimens-continued
Factors influencing treatment selection include
Wart size,
Number of warts,
Anatomic site of wart,
Wart morphology,
Patient preference,
Cost of treatment,
Convenience, and
Adverse effects.

62. Papillomavirus 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
The goal of any treatment should be to remove visible warts to get rid of annoying symptoms. No one treatment is best for all cases.
Treatment of the warts may possibly help reduce the risk of transmission to a partner who may never have been exposed to HPV.
When choosing a treatment, the health care provider should consider: size, location, number of warts, changes in warts, patient preference, cost of treatment, convenience, adverse effects, and their own past experience with the treatments.

63. HPV Treatment Options Chemical agents Cryotherapy Electrosurgery
Surgical excision
Laser surgery
Imiquimod (Aldara)
Defer treatment
Natural therapies
SUMMARY OF TREATMENT OPTIONS
Clearly, the immune system plays a significant role in the outcome of a clash between the human and HPV.
New research is appearing to indicate that persons with healthy immune systems, once they mount an immune response, run little chance of ever having a recurrence – they stand a good chance of clearing even the genetic materials of the virus, as well.
A variety of methods are used to treat HPV with varying success. The goal of treatment is the removal of the wart(s) not the eradication of HPV. If left untreated, the warts may resolve on their own, remain unchanged, or continue to grow.
A specific treatment regimen should be chosen with consideration given to anatomic site, size and number of warts, and pregnancy status, as well as the expense, efficacy, convenience, and potential for adverse effects.
Chemical agents such as podofilox and trichloracetic acid are moderately successful. Podofilox is a purified form of podophyllin and an extract of the May Apple plant. It can be applied by the patient and is recommended for external/urethral meatal warts only. It causes local tissue to necrotize. Generally, it is applied twice a day for three days, followed by four days of no therapy, repeating this cycle up to four times. It should not be used in cases of pregnancy. Trichloracetic acid ( TCA) 80 – 90% is another caustic agent that is applied directly to the warts. The surrounding area should be powdered with talc or baking soda to remove unreacted acid. It is safe to use in cases of pregnancy, but treatment can be painful and cause scarring.
Cryotherapy (freezing with super cold liquid or gas nitrogen) is a popular treatment for both internal and external warts that is relatively inexpensive, does not require anesthesia, and does not result in scarring if performed properly. Cryotherapy can be used with pregnant clients.
Electrosurgery (using an electric current to remove warts) is another relatively effective treatment requiring local and sometimes general anesthesia depending on the site of being treated. This procedure is safe during pregnancy.
Surgical excision (literally cutting off the warts) is used in many cases. However, patients often believe that this is definitive therapy and they should be counseled that there is no guarantee that the warts will not return.
Laser surgery can be an effective method, but is very expensive and requires a skilled operator. Many physicians prefer to use it when other methods have failed.

64. Papillomavirus Patient-applied
Podofilox (Condylox) 0.5% solution or gel
Apply 2x/day for 3 days, followed by 4 days of no therapy.
Repeat as needed, up to 4x or
Imiquimod (Aldara) 5% cream
Apply bedtime 3x/week for up to 16 weeks
Sinecatechins 15% ointment*,**
Apply ointment 3 times daily for up to 16 weeks.
Do not wash off post-application
*Safety not established in pregnancy
**Safety not established in HIV- or HSV-co-infected individuals
Podofilox cream or gel (Condylox) is a self-applied treatment for external genital warts. It doesn’t cost much, is easy to use and is safe, but it must be used for about 4 weeks.
Imiquimod cream (Aldara) is a self-applied treatment for external genital warts. It is safe, effective and easy to use. This cream is different than any other treatments. Other treatments work by destroying the wart tissue, but Aldara actually boosts the immune system to fight HPV.
Podophyllin should be applied to the affected area and washed off at a later point in time.
Podofilox should be applied to the affected area, but not washed off.

65. Provider-administered
Cryotherapy (liquid nitrogen) *repeat every 1-2 weeks or
Podophyllin resin 10-25% *thoroughly wash off in 1-4 hrs
Trichloroacetic or
Bichloroacetic acid 80-90%
*can be repeated weekly

66. Papillomavirus Vaginal warts Cryotherapy or TCA/BCA 80-90%
Urethral meatal warts
Cryotherapy or podophyllin 10-25%
Anal warts

67. Papillomavirus
Therapy choice needs to be guided by preference of patient, experience of provider, and patient resources (time and/or money)
No evidence exists to indicate that any one regimen is superior
An acceptable alternative may be to do nothing but watch and wait; possible regression/uncertain transmission

68. Warts can and often do recur after treatment.
HPV is INCURABLE
Warts can and often do recur after treatment.
Virus can remain in surrounding tissue after warts have been destroyed.
Important points to remember are: “HPV is incurable”.
Warts can and often do recur after treatment.
The virus can remain in surrounding tissue after warts have been destroyed.
When warts are present, the virus is considered “active”.
When warts are gone, the virus is latent (and may or may not be contagious)
A healthy immune system appears to help fight the virus.

69. Perinatal complications

70. HPV and Pregnancy
No link with premature labor, miscarriage, or other complications
Low rate of transmission to baby
Range is generally from 0.4 to 1.1 cases/100,000 births
C-section is not recommended in most instances
Women with HPV may be relieved by the reassuring news that the virus appears to have no link with premature labor, miscarriage, or other types of pregnancy complications.
In fact, the virus should not be a hinderance to a woman planning a family except that it may be more practical to delay conception until after consulting a physician
Low rate of transmission from mother to baby.
Genital warts seem to grow more rapidly during pregnancy due to the expected decline in the normal immunity as well as increased hormones and blood supply. Depending on where they are located, they may cause obstruction of the urethra and/or vaginal opening causing obstruction during delivery.
Having genital warts is not a reason to have a C-section.

71. The large vulvar warts that may occur in HPV infected pregnant females, may occasionally lead to the obstruction of the birth canal. In these cases and when the warts are open and draining, C-section is recommended. Otherwise natural birth is the safest because the rate of infection is very low and several HPV cases in infants have been reported following Cesarean section. Therefore the risks involved in performing C-sections outweigh the benefits.

72. Treatment Regimens

73. Papillomavirus Treatment in Pregnancy
Imiquimod, podophyllin, and podofilox should not be used in pregnancy
Many specialists advocate wart removal due to possible proliferation and friability
HPV types 6 and 11 can cause respiratory papillomatosis in infants and children
Preventative value of cesarean section is unknown; may be indicated for pelvic outlet obstruction or if vaginal delivery would result in excessive bleeding
Imiquimod, podophyllin, and podofilox should not be used during pregnancy because they are absorbed by the skin and may cause birth defects.
Many specialists advocate wart removal due to possible proliferation and friability.

74. HPV in Neonates
Those who develop warts will usually do so within several weeks
First-born child
Juvenile onset recurrent respiratory papillomatosis (JO-RRP)
rare -- 1 per 100,000 births
types 6 and 11
occurs up to age four
Children born to infected mothers, who do develop warts in the throat, usually will do so within several weeks after birth.
The most serious form of HPV infection in children is juvenile onset of recurrent respiratory papillomatosis (JORRP) which involves lesions of the trachea, pharynx, and bronchi. The infection is apparently acquired when the child passes through the mother’s infected birth canal and aspirates contaminated cervical, vaginal or vulvar material.
50% of those with JORRP have symptoms which begin shortly after birth, during infancy or in the preschool years. There are currently an estimated 4.3/100,000 children under age 14 with JO-RRP.
The risk of papillomatosis is greatest from HPV types 6 & 11, so typing may be helpful in cases of pregnancy, at the same time, 95% of genital warts in the US are caused by one of these two types of HPV.
Symptoms of papillomatosis may appear:
shortly after birth, (50%)
during infancy,
during the preschool years.
Newly diagnosed cases may occur as last as years of age. It is unusual to diagnose new cases between years.
The initial symptom is hoarseness. In some children, the warts spontaneously resolve. For those that do not, the treatment of choice is surgical removal. Since the warts have a tendency to recur, repeat laser surgery (as often as weekly) may be necessary to prevent obstruction of the breathing passages. For the most severely affected persons, as many as 100+ surgical procedures may be necessary to maintain a safe and adequate airway.
Research on the use of interferon therapy in combination with laser surgery indicates this drug may show promise in slowing the course of disease.
JO-RRP is predominantly observed in the first-born child of a young, pregnant woman. There is only rare documentation of siblings having RRP.

75. HPV and Cervical Cancer
In 2006, it is estimated that there will be 9,710 new cases of cervical cancer and 3,700 deaths attributed to it in the US. Worldwide, cervical cancer is the second most common cancer in women; and it is estimated to cause over 470,000 new cases and 233,00 deaths per year.
About 50% of women who develop cervical cancer in the US have never had a Pap test and another 10% have not had a pap smear in the past 5 years.

76. HPV Linked to Cancer Cervical Cancer
10,000 new cases diagnosed/year in the US
3,000 deaths/year in the US
400, ,000 new cases internationally
300,000 deaths/year internationally, especially in developing countries
Single most important factor for cervical cancer
Virtually all squamous cell cervical cancer contain one of 18 types of HPV
The type of HPV that causes visible warts are not linked to cervical cancer
Associated with cancer of the penis, anus, vagina and vulva.
HPV has been linked with different types of genital cancer, especially cervical cancer which has been the cause of 3,000 known deaths each year in American women.
Vaginal cancer is diagnosed in 2,300/year and 600 die each year with vaginal cancer.
Vulvar cancer is diagnosed in 3,300/year and 900 die each year with vulvar cancer.
Penile cancer is diagnosed in 1,400 men each year; anal cancer is diagnosed in 3,000 men each year.
Anal dysplasia and anal cancer:
Anal cancer is a rare occurrence that has been strongly linked to "high-risk" types of HPV, especially type 16.
Abnormal cell changes in the anal area (anal dysplasia or anal neoplasia) are more common among individuals who engage in receiving anal sex.
However, anal dysplasia has also been reported in some females who have a history of severe cervical dysplasia
Treatment is available for anal dysplasia and anal cancer
More clinical and natural history research is needed before routine anal pap smears will be recommended for men at increased risk for HPV

77. HPV DNA Classification
Low Risk HPV Types: 6,11,40,42,43,44, 54, 61, 72, 73, 81
types 6 and 11 responsible for 95% of visible warts
High-Risk HPV Types: 31,33,35,39,45, 51, 52, 56, 58, 59, 68,82
High cancer risk: 16
Most common-50% of cervical cancer
High cancer risk: 18
10-12% of cervical cancer
*Risk not well established yet: 26, 53, 66, 73
HPV can be broken into FOUR classifications which are based on their potential to produce genital cancers:
1) low oncogenic ( cancer causing ) risk: Types 6, 11, 42, 43, 44
Types 6 and 11 are responsible for 95% of visible warts. All are associated with low grade cervical lesions, but no cervical cancer. All are associated with penile, vaginal/vulvar, and anal cancers, however.
Intermediate oncogenic risk: Types 31, 33, 35, 51, 52, 58
Higher prevalence in high grade lesions. Associated with some cervical cancer (17%), but due to long transition to malignancy, they are involved in fewer cancers than high risk types.
High oncogenic risk: Type 16
This type associated with over 50% of cervical cancer and 47% of high-grade precancerous lesions. Transition time to malignancy is 8 to 12 years.
High oncogenic risk: Type 18, 45, 56
These types associated with about 27% of cervical cancers, but only about 5% of high-grade neoplasias. Cancers with HPV 18 tend to occur at younger ages and may be more difficult to treat. Type 18 has an extremely short transition time to malignancy, allowing little time to screen for and treat the rapidly progressing disease.
Types 16 and 18 account for 70% of cervical cancers.
Sexually transmitted HPV is the single most important factor for cervical cancer and may be associated with cancer of the penis, anus, vagina, or vulva. As of 1994, the incidence of anal cancer was increasing among both men and women in the U.S., (in women at a rate of 2% per year and among men at a rate of 2.3% per year).

78. ANOGENITAL MALIGNANCIES
HPV IS ASSOCIATED WITH
ANOGENITAL MALIGNANCIES
HPV DNA is found in 50-98% of tumors depending
on location
Oncogenic genes (E6 and E7) of high-risk types are
expressed in tumors
E6 and E7 of high-risk types are oncogenic in-vitro
Support from many epidemiologic studies

79. 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.
The risk for re-infection with that specific type of HPV appears to be rare.
However, a person can be infected with more than one type of HPV

80. HPV and Cervical Cancer
Infection is generally indicated by the detection of HPV DNA
Routine Pap smear screening ensures early detection (and treatment) of pre-cancerous lesions
Only a small percentage of women infected with genital HPV develop persistent infections
Only women who develop persistent infections are at risk for developing high-grade pre-cancerous changes / cervical cancer
Most women with persistent HPV infection do NOT develop precancerous changes/cervical cancer
The most critical factor for developing cervical cancer is not having routine pap smears
A persistent infection is an infection that is not cleared by the immune system and is characterized by persistently detectable HPV DNA.
Factors associated with persistent infection include:
being 30 years of age or older
having high-risk HPV types
having a suppressed immune system

81. Cofactors for Cervical Cancer
Weakened immune system
Multiple sex partners
Sex at an early age
Nutritional deficiencies
Mother who took DES
Lack of circumcision of male partner(s)
Active/passive Cigarette Smoking
Chronic inflammation associated with other STDs
Long term use of oral contraceptives
High number of live births*
Cofactors have also been linked to cancer development. To use a simple analogy, one might consider the cervix as the soil, the high risk HPV type as the seed, and “other factors” (sometimes called “cofactors”) as a kind of fertilizer. Some of the most common cofactors for cervical cancer are similar to those for STDs, including:
Smoking. Consistently shown to be an independent risk factor.
2) Presence of other infection
3) History of STDs, especially chlamydia and HSV2
4) Oral contraceptives and high number of live births-Some studies indicate long-term use of oral contraceptives and having a high number of live births may be risk factors
5) Weakened immune system
6) Multiple sex partners
7) Sex at an early age, and
8) Poor diet/nutritional deficiencies
Several studies have shown that women who smoke are two times as likely as non-smokers to have precancerous cervical cell changes or invasive cervical cancer.
Up to 60% of cervical cancer cases in the US occur among women who have never been screened or who have rarely been screened.
LACK OF SCREENING IS THE MOST IMPORTANT FACTOR

82. What is the difference between the Pap test, a biopsy and an HPV test?
Pap test finds abnormal cell changes on the cervix
Biopsy is when a cluster of cells is removed from the cervix to confirm earlier Pap smear results and rule out cancer
HPV test looks for genetic material (DNA) of HPV within cells.
What's the difference between a Pap test, a biopsy and a HPV test?
A Pap test, or Pap smear, is a screening to find abnormal cell changes on the cervix (cervical dysplasia ) before they ever have a chance to develop into cancer. During a pelvic exam, a small brush or cotton tipped applicator will be used to take a swab of cervical cells. These cells are then put either on a glass slide or in a container with liquid, and sent to the laboratory for evaluation. The most common commercially available liquid-based Pap test is called ThinPrep®, manufactured by Cytyc.
A biopsy is similar to a Pap test, but a larger cluster of cells is removed from the cervix to see if there are abnormal cell changes. It is a good way to confirm the earlier Pap smear result and to rule out cancer. If a biopsy is done, it will be performed at the same time as the colposcopy.
An HPV test is different than a Pap test or biopsy. This test checks directly for the genetic material (DNA) of HPV within cells, and can detect the types connected with cervical cancer. The test is done in a laboratory, usually with the same cell sample taken during the Pap test. The only commercially available test for HPV is called Hybrid Capture II™, produced by Digene. It is most convenient if the HPV test is done in the laboratory from a cervical cell sample that was taken using a liquid-based Pap test.

83. When Is an HPV Test Used?
As a follow-up test if the Pap result is “borderline”
In combination with a Pap test in women at the age of 30 and older
False positive results can occur
When is a HPV test used? Currently, the HPV test called Hybrid Capture II™, is approved by the U.S. Food and Drug Administration (FDA) for use in two different situations:
(1)     As a follow-up test if the Pap result is borderline between "normal" and "abnormal." This is usually called "atypical squamous cells" or "ASC-US." The HPV test is then used in the lab to determine if women with the borderline result are more likely to have precancerous changes on their cervix, (HPV positive), and which are more likely to just have normal cells (HPV negative). Basically, the test helps to rule out whether HPV is causing the borderline abnormal cells.
(2)     As a cervical cancer screening test in combination with a Pap test in women at or over age 30 (rather than just having the Pap test alone). Research shows that the combination test can increase the effectiveness of detecting any problems early on. A preliminary recommendation by the American Cancer Society state that if the combination Pap - HPV DNA test (Digene’s DNA with Pap™ test) result is normal/negative, then the next screening would not have to be for three years. However, if one of the tests in the DNA with Pap comes back abnormal/positive, then follow-up will be needed.
HPV testing can also be done on a cell sample taken during your Pap test if a technique called the liquid-based pap test was used. In the liquid-based pap test, the cells are collected by rotating a plastic brush on the cervix. The samples are then placed in a jar of solution and sent to the lab for examination.
HPV testing done during a liquid-based Pap test eliminates the need to have HPV testing done at a later time.

84. An HPV test is different than a Pap test or biopsy
An HPV test is different than a Pap test or biopsy. This test checks directly for the genetic material (DNA) of HPV within cells, and can detect the types connected with cervical cancer. The test is done in a laboratory, usually with the same cell sample taken during the Pap test. The only commercially available test for HPV is called Hybrid Capture II™, produced by Digene. It is most convenient if the HPV test is done in the laboratory from a cervical cell sample that was taken using a liquid-based Pap test.

85. When Is an HPV Test NOT Used?
If the Pap result shows dysplasia or pre-cancerous changes
In women under age 30unless they have had an ASC-US Pap test result
Not on malesThe HPV test cannot be used on males. It is only FDA approved to be used on the female's cervix.
When is a HPV test NOT used?
If the Pap result shows dysplasia or precancerous changes. This is because it is automatically assumed that the HPV is the cause.
In women under age 30,.
The HPV test cannot be used on males. It is only FDA approved to be used on the female's cervix. The use of the test is currently being researched in males.

86. HPV Good News
70% of new HPV infections spontaneously clear within one year, and as many as 91% clear within 2 years. The median duration of new infections is typically 8 months.
The gradual development of an effective immune response is thought to be the likely mechanism for HPV DNA clearance.
Women who develop high risk lesions only have a 5% to 15% chance of developing cancer in the absence of treatment.
Millions of women in the US are known to be infected with HPV, yet only about 15,700 new cases of cervical cancer are diagnosed annually. This is due in part to two reasons:
Most women with high risk types of HPV that rid themselves of the virus within two years (immune response suppresses/eliminates virus)
Women who develop high risk lesions only have about a 5% to 15% chance of developing cancer in the absence of treatment.
A study of college students found 30% still had the detectable presence of HPV after 12 months and an additional 9% still had detectable presence of HPV after 24 months.
The longer that HPV persists, the more likely it will cause pre-cancerous/cancer changes. Only about 10% of women infected with HPV develop persistent HPV infections.
HPV 16 is more likely to persist than other HPV types, but in most cases, even with HPV 16, infection becomes undetectable within 2 years

87. Non-detectable HPV
Currently it is unclear whether genital HPV infections that become “non-detectable” using standard molecular tests have completely cleared or whether they remain latent in basal cells with the potential for later reactivation
Reactivation may explain why some older women in a mutually monogamous relationship can begin to shed genital HPV
HPV more likely to be detected in persons with immune system disorders

88. Key Educational Messages
HPV infection is very common, few will develop cervical cancer
HPV is not a reliable indicator of a woman’s sexual behavior or that of her partner
Most HPV infections are transient, harmless, have no signs/symptoms, and are cleared by the immune system
Persistent HPV infection over many years is necessary but not sufficient for the development of cervical cancer
Cervical cancer can be prevented by vaccination and early detection-regular Pap smears

89. Important Notes
Women should continue to receive regular cervical cancer screening (pap smears)
The vaccine will NOT protect against all types of genital HPV
Women may not have completed the full series of vaccinations
If they had been exposed to one or more types prior to vaccination, there is still a risk for cervical abnormalities and/or genital warts to develop
Women should continue to practice protective sexual behaviors since the vaccine will not prevent all cases of genital HPV or other STDs, including HIV
Women should still continue to practice protective sexual behaviors
-Abstinence
-Monogamy
-Limiting number of partners
-Using condoms (may have a protective effect on HPV acquisition, reduce the risk for HPV-associated diseases, and mitigate the adverse consequences of infection with HPV) since the vaccine will not protect against all cases of genital HPV nor will it prevent other STDs, including HIV.

90. HPV Prevention Abstinence Monogamy Condoms Removal of warts
Vaccine (Females aged 9-26)
The only way you can prevent getting an HPV infection is to avoid direct contact with the virus, which is transmitted by skin-to-skin contact. Avoid contact until all the warts are treated and gone.
Studies have not confirmed that male latex condoms prevent transmission of HPV itself, since they may not cover the area that has the warts. But results do suggest that condom use may reduce the risk of developing diseases linked to HPV, such as genital warts and cervical cancer.

91. Thank you for your attention