HPV Infection and Cervical Cancer

1. HPV Infection and Cervical Cancer

2. Introduction • Human papillomavirus (HPV) is the most common sexually transmitted infection in the United States; an estimated 14 million persons are newly infected every year • Although most infections cause no symptoms and are self-limited, persistent HPV infection can cause cervical cancer in women as well as other anogenital cancers, oropharyngeal cancer, and genital warts in men and women. • Persistentoncogenic HPV infection is the strongest risk factor for development of HPV-associated precancers and cancers.

3. How many types of HPV are there? • Which types of HPV are most likely to cause disease?

4. More than 184HPV types have been identified, including approximately 40 that infect the genital area. • Genital HPV types are categorized according to their epidemiologic association with cervical cancer. • Low-risk types (e.g., types 6 and 11) can cause benign or low-grade cervical cell changes, genital warts, and recurrent respiratory papillomatosis . • High-risk types (e.g., types 16 and 18) can cause low-grade cervical cell abnormalities, high-grade cervical cell abnormalities that are precursors to cancer, and cancers. • Essentially all cervical cancers are attributable to high-risk HPV types, and approximately 70% of cervical cancer cases worldwide are caused by types 16 and 18.

5. What are the low risk and high risk types?

6. "Low-risk" types of HPV There are about 12 types of HPV that are called "low risk" because they cannot cause cervical cancer. They can, however, cause genital warts or very minor cell changes on the cervix. These low-risk types of HPV are known by the numbers 6, 11, 40, 42, 43, 44, 53, 54, 61, 72, 73 and 81. Types 6 and 11 – which are linked to about 90 percent of  genital wart – are the most common. • "High-risk" types of HPV There are more than a dozen types of "high-risk" HPV that can cause abnormal cells to form on the cervix. These abnormal cell changes may gradually develop into cervical cancer if not removed. The 13 types of high-risk HPV that are of most concern are known by the numbers 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 and 68. Types 16 and 18 are the most dangerous, since they cause about 70 percent of cervical cancers.

7. What diseases dose HPV infection cause? • Can HPV cause any other kinds of cancer besides cervical cancer?

8. In addition to cervical cancer, HPV infection also is the cause of some other anogenital cancers such as cancer of the vulva, vagina, penis, and anus, as well as cancer of the oropharynx, esophagus and larynx.

9. HPV-Associated Oropharyngeal Cancers Chaturvedi, 2011, J Clin Oncol- data from SEER Prevalence increased from 16.3% (1984-89) to 71.7% (2000-04) Population-level incidence of HPV-positive cancers increased by 225% while HPV-negative cancers declined by 50% If trends continue, the annual number of HPV-positive oropharyngeal cancers is expected to surpass the annual number of cervical cancers by the year 2020

10. How is HPV infection spread? • Can HPV be transmitted by nonsexual transmission routes?

11. Transmission • Genital HPV infection is transmitted primarily by genital contact, usually through sexual intercourse but also through other intimate contact (e.g., oral-genital or genital-genital). • Intercourse is not necessary for infection • Nonsexual routes of genital HPV transmission are less common and can include intrapartum transmission from mother to infant

12. In virtually all studies of HPV prevalence and incidence, the most consistent predictors of infection have been measures of sexual activity, most importantly the number of sex partners (lifetime and recent). • Transmission is very common between sex partners, and likely more frequent from females to males than from males to females.

13. What are the signs and symptoms of HPV infection?

14. Most HPV infections are transient and asymptomatic and cause no clinical problems; 70% of persons with new cervical HPV infection will clear the infection within 1 year, and approximately 90% within 2 years. • The median duration of new infections is about 8 months for genital infection among both females and males. • The risk for persistence and progression to cancer precursor lesions varies by HPV type as well as host factors (including those with HIV infection). HPV 16 is more likely to persist and progress to cancer than other high-risk HPV types.Theusual time between initial HPV infection and development of cervical cancer is decades but more rapid progression has occurred. • Women persistently infected with high risk HPV strains are at risk of the development of high grade cervical intraepithelial neoplasia (CIN) and invasive cervical cancer (CC).

15. Studies have shown that the virus does not "ping-pong" back and forth. This means that a couple cannot re-infect each other within their own relationship. After exposure to HPV and subsequent clearance of the virus, a person probably has immunity to that type. He or she cannot be re-infected, but could be exposed to a new type of HPV. If a person enters a new relationship, he or she could put a new partner at risk for HPV. A person can be exposed to a new viral type of HPV with a new partner. 

16. Can a person be re-infected with HPV?

17. There appears to be humoral and probably cellular immunity that develops to a specific type of HPV after a person has been infected with it and “has cleared” it. • However, a person can be infected with more than one type of HPV. • The risk for re-infection with that specific type of HPV appears is rare.

18. Re-detection of the same HPV type is relatively common, occurring in at least 10–20% of women observed to have “cleared” the virus. Furthermore, convincing data from multiple studies of immune compromised, sexually abstinent, older, less sexually active populations and adolescents with long-term intensive follow-up support the phenomena of immunologically controlled re-detection or reactivation of a previously acquired type-specific HPV infection. • An important consideration, however, is that reactivation of previously acquired, latent HPV infection, rather than re-infection, may explain the apparent lack of protection against re-infection from natural antibodies in the older age group. • These results suggest that, in the presence of naturally acquired antibodies, reactivation or intermittent viral shedding of a previously acquired infection is a more probable source of new HPV detection than new acquisition.

20. No HPV test can determine which HPV infection will clear and which will progress. • Having HPV does not mean that a person or his/her partner is having sex outside the relationship. • Having HPV does not make it harder for a woman to get pregnant or carry a pregnancy to term. However, some of the precancers or cancers that HPV can cause, and the treatments needed to treat them, might lower a woman’s ability to get pregnant or have an uncomplicated delivery. Treatments are available for the conditions caused by HPV, but not for the virus itself.

21. HPV is found in virgins

22. Study examined the frequency of vaginal HPV and the association with non-coital sexual behavior in longitudinally followed cohort of adolescent women without prior vaginal intercourse • HPV was detected in 46% of women prior to first vaginal sex • 70% of these women reported non-coital behaviors that may in part explain genital transmission Shew, J Infect Dis. 2012

23. Wart • The average incubation period of visible warts is 3 weeks to one year. • Latency periods of years have been reported before the emergence of warts or cervical abnormalities. This can be quite confusing and stressful for partners in long term relationships. An example of this is the person whose immune system, on its own, keeps HPV under control or latent for so many years and then a long-delayed symptom may appear which seems to come from nowhere.

24. Women with genital warts do not need Pap tests more often than other women. • Condoms might lower the chances of transmitting genital warts if used consistently and correctly; however, HPV can infect areas that are not covered by a condom and might not fully protect against HPV. • Time of HPV acquisition cannot be definitively determined. Genital warts can develop months or years after getting HPV. HPV types that cause genital warts can be passed on to another person even in the absence of visible signs of warts. Sex partners tend to share HPV, even though signs of HPV (e.g., warts) might occur in only one partner or in neither partner. • Although genital warts can be treated, such treatment does not cure the virus itself. For this reason, it is common for genital warts to recur after treatment, especially in the first 3 months

25. Because genital warts can be sexually transmitted, patients with genital warts benefit from testingforotherSTDs. Sexual activity should be avoided with new partners until the warts are gone or removed. • HPV might remain present and can still be transmitted to partners even after the warts are gone. Virus can remain in surrounding tissue after warts have been destroyed.

26. What is primary goal for treatment of visible warts?

27. Wart Treatment • Primary goal for treatment of visible warts is the removal of symptomatic warts • Therapy may reduce but probably does not eradicate infectivity • Difficult to determine if treatment reduces transmission • No laboratory marker of infectivity • Variable results utilizing viral DNA

28. What are HPV Treatment Options?

29. Chemical agents • Cryotherapy • Electrosurgery • Surgical excision • Laser surgery • Imiquimod (Aldara) • Natural therapies

30. Updates on Pap Smear Guidelines 2015

31. What are risk factors for Cervical Cancer?

32. HPV infection (16/18) • Early onset of sexual activity (<16) • High number of sexual partners (>4) • Hx of genital warts • HIV seropositive • Immunosuppresive therapy • Active/passive Cigarette Smoking • Chronic inflammation associated with other STDs • Long term use of oral contraceptives • High number of live births LACK OF SCREENING IS THE MOST IMPORTANT FACTOR

33. How does cervical cancer occur?

34. HPV • Most young women have an effective immune response that clears the infection in an avg of 8 months. • CIN 1 is a manifestation of acute HPV and has a high rate of regression to normal cells. • CIN 2 is a mix of low-grade and high-grade lesions (70% regression in 3 years in some papers) • CIN 3 and AIS are cancer precursors • HSIL is associated with a persistent and transforming infection and cancer risk.

35. HPV and the Development of Cancer

36. What is the role of Colposcopy?

37. With directed bx remains the standard for disease detection • Technique of choice for treatment decisions • Endocervical sampling

38. Screening Today • When to start? • When to stop? • How often? • HR HPV testing • Continue in patients after hysterectomy? • No change in women vaccinated against HPV

39. Possible harms of screening • Anxiety over a positive test • Stigma of an STI • Pain/bleeding from procedures • Number of colposcopies is a marker for harms

40. Principles in Interpreting Guidelines • Current strategies cannot eliminate the risk of developing cancer. No screening test has 100% sensitivity. • Attempts to eliminate often result in unanticipated harm from excessive evaluation and treatment.

41. Start screening at age 21 • 0.1% of cervical cancer cases • 1-2 cases/1 million females age 15-19 • US and UK studies demonstrated that earlier screening did NOT decrease cervical cancer rates in this population. • Testing can be performed using either conventional or liquid-based cytologic tests (i.e., Pap tests)

42. Liquid-based cytology is an acceptable alternative to conventional Pap tests, as it has similar test-performance characteristics. • In the presence of cervical friability, liquid-based cytology should be used; conventional pap testing might need to be deferred in the presence of heavy bleeding until cervicitis is treated.

43. Cervical cancer screening should begin at age 21 • Women <21 should not be screened regardless of age of sexual contact. • Prevalence of oncogenic HPV types are high among adolescents aged <21 years, and oncogenic HPV and squamous intraepithelial lesions caused by HPV in adolescent girls are more likely to regress than those in older women. 

44. Screening 21 - 29 • Every 3 years • Co-testing with HPV should NOT be performed (HPV frequent in this population and >90% will spontaneously clear within 2 yrs)

45. Rational for Avoiding HPV tests among women ages 21-29 • Prevalence of carcinogenic HPV approaches 20% in teens and early 20s • Most carcinogenic HPV infections resolve without intervention • Identifying carcinogenic HPV that will resolve leads to repeated call-back, anxiety and interventions without benefits.

46. Screening 30 - 65 • Every 5 yrs • Co-testing of HPV 16/18

47. Rational for cotesting, ages 30-64 • Increased detection of prevalent CIN3 • Decreased CIN3 in subsequent screening rounds • Achieves risk of CIN3 equal to cytology alone 1-3 year intervals • Enhances detection of adenocarsinoma/AIS • Minimizes the increased number of colposcopies thus it reduces harm

48. What are Risk Factors for Continued Annual Screening?

49. Hx of CIN2/3/cervical cancer within the past 20 yrs • HIV infection or immunosuppression (transplant recipients)

50. When to stop screening?