2. HPV Tajossadat Allameh Associated Profeesor of Ob& Gyn
Fellowship of Gynecology Oncology

3. Papillomaviruses are double-stranded DNA viruses
(HPV) infect only humans.
There are more than 200 types of HPV
cutaneous or mucosal

4. Papillomaviruses are double-stranded DNA viruses that constitute the Papillomavirus genus of the Papillomaviridae family. These viruses are highly species specific; human papillomaviruses (HPV) infect only humans. There are more than 200 types of HPV, which can be subdivided into cutaneous or mucosal categories based upon their tissue tropism.

5. There are over 40 HPV types that infect the anogenital area.

6. HPV GENOTYPES AND RISK OF CANCER

7. Cervical cancer
●High-risk – This includes HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68
●Low-risk – 6, 11, 40, 42, 43, 44, 53, 54, 61, 72, 73, and 81
Types 16 and 18 are the most commonly isolated HPV types in cervical cancer, with type 16 found in approximately 50 percent of patients.

8. مجله دانشكده پزشكي اصفهان مقاله پژوهشي سال بيست و نهم/شماره /163هفته سوم دي ماه 1390تاريخ دريافت: 90 /5/ 14تاريخ پذيرش: 90
بررسي شيوع يو روس پاپيلوماي انساني در زنان متأهل 18-60ساله با پاپ اسمير طبيعي مراجعه كننده به كلينيكهاي تخصصي زنان وابسته به دانشگاه علوم پزشكي اصفهان دكتر تاج السادات علامه ،1دكتر شراره مقيم ،2دكتر فريناز فرهبد

9. چكيده
مقدمه: سرطان دهانهي رحم دومين علت مرگ و مير در اثر سرطان در بين زنان ميباشد. تيپهاي پر خطر ويروس پاپيلوماي انساني ) HPVيا (Human papillomavirusعامل اصلي سرطان سرويكس هستند. اين مطالعه با هدف تعيين شيوع تيپ ياه 16 ،11 ،6و HPV 18در زنان متأهل ساله با پاپ اسمير طبيعي انجام شد. روشها: در اين مطالعهي توصيفي-تحليلي 180نفر از زنان متاهل 18-60ساله كه در سالهاي به كلينيك تخصصيهاي زنان وابسته به دانشگاه علوم پزشكي اصفهان مراجعه كرده بودند، به روش در دسترس بررسي شدند. پس از بررسي سيتولوژي در پاپ اسمير از كليهي نمونههاي طبيعي يك نمونه تهيه گرديد. سپس با انجام PCRابتدا ويروس HPVبا استفاده از پرايمرهاي + GP5و + GP6شناسايي شد. نمونههاي حاوي HPVبراي تعيين ژنوتيپ با استفاده از پرايمرهاي اختصاصي براي تيپهاي 16 ،11 ،6و PCR 18مجدد شدند.

10. يافته ها: بر اساس مرحلهي اول (Polymerase chain reaction) PCRاز بين 180نمونه ويروس HPVدر 46نمونه ) 25/55درصد( يافت شد. از 46نمونهي مثبت 7نمونه )15/21درصد( تيپ 6 ،16نمونه ) 13/04درصد( تيپ 10 ،18نمونه ) 21/74درصد( تيپهاي 11يا 6و 23نمونه ) 50درصد( از ساير تيپهاي اين ويروس بود. در ميان 180نمونهي مورد مطالعه در 13نمونه ) /7 22درصد( حداقل يكي از تيپهاي پر خطر 18و 16 يافت شد. نتيجه گيري: با توجه به شيوع بالاي اين ويروس در مطالعهي ما و ساير مطالعات انجام شده در منطقه، انجام اقدامات پيشگيري از بروز اين مشكل ضروري به نظر ميرسد. يكي از روشهاي پيشگيري استفاده از واكسن گارداسيل است كه تأثير مناسب آن در مطالعات نشان داده شده است. واژگان كليدي: پاپ اسمير طبيعي، ويروس پاپيلوماي انساني، ،PCRسرطان سرويكس

11. Arch Gynecol Obstet. 2011 Dec;284(6):1509-13. doi: 10
Arch Gynecol Obstet Dec;284(6): doi: /s Epub 2011 Mar 9.
A survey on the prevalence of high-risk subtypes of human papilloma virus among women with cervical neoplasia in Isfahan University of Medical Science. Allameh T1, Moghim S, Asadi-Zeidabadi M.

12. Abstract
AIM: Given the importance of epidemiological studies on the prevalence of human papilloma virus (HPV) and its subtypes to plan more effective strategies for cervical cancer prevention, the aim of this study was to determine the prevalence of HPV in women with cervical intraepithelial neoplasia and cancer in Isfahan. METHODS: In this descriptive cross-sectional study, women referred to oncology clinic of Shahid Beheshti Hospital because of abnormal cytology of their cervices within the last year were studied. The 2001 Bethesda system was used for histologic classification. The distribution of different pathologies was as follows: squamous cell carcinoma (SCC) 34.7%, low- grade squamous intraepithelial lesions (LSIL) 30.5%, high-grade squamous intraepithelial lesions (HSIL) 22.8%, atypical squamous cell of undetermined significance (ASCUS) 8.4%, and adenocarcinoma (AC) 3.3%. There was no case of atypical glandular of undetermined significance or cases of adenocarcinoma associated with an early lesion. The presence of HPV infection and its subtypes including HPV 16, 18, 6 and 11 was assessed in different cytological categories of cervical neoplasia, by using polymerase chain reaction method.

13. RESULTS:
During this study, 130 patients were studied. Their median age was 52 years (range years). HPV was detected in 118/130 patients (90.8%) with abnormal cervical cytology. The prevalence of positive HPV samples was 97.6, 80, 93.1, 92.3, and 66.6% in cases with SCC, AC, HSIL, LSIL, and ASCUS, respectively (P < 0.05 between SCC and ASCUS, HSIL and ASCUS, and LSIL and ASCUS). Out of 118 cases with positive HPV, 98 (83.1%) were positive for multiple HPV types 16, 18, and 11 or 6. The distribution of studied HPV subtypes among women with positive HPV was as follows: 49.1% for both types 16 and 18, 10.1% for type 16, 1.69% for type 18 and 22% for type 11 or 6. The prevalence of HPV type 16 was not significantly different in various cytological categories of cervical neoplasia (P > 0.05). The prevalence of HPV type 16 and 18 was significantly higher than the HPV type 11 or 6 in cervical neoplastic lesions (P < 0.05).

14. CONCLUSION:
The results of this research indicated the high prevalence of HPV infection in all categories of cervical neoplasia. This emphasizes the importance of HPV screening and vaccination programs. In order to assess more effective screening programs in Isfahan and evaluate the cost-effectiveness of vaccination programs, further population-based prospective studies are required.
PMID:
DOI: /s
[Indexed for MEDLINE]

15. Head and neck cancer
HPV infection is associated with some forms of oral squamous cell cancers, particularly those of the oropharynx. There is an approximately two to fourfold increased risk for cancers of the oral cavity and oropharynx in patients infected with high-risk (oncogenic) HPV types

16. Anal cancer
 HPV types in the anal canal is similar to that described in the cervix .
HPV 16 is the most commonly detected HPV type associated with anal cancer

17. MOLECULAR PATHOGENESIS
●HPV DNA is commonly present in anogenital precancer and invasive cancers, as well as oropharyngeal cancers ●Expression of the viral oncogenes E6 and E7 is consistently demonstrated in lesional tissue

18. Role of p53 protein
 In the normal cell, the p53 protein is a negative regulator of cell growth,
E6 binding of p53, p53 is degraded in the presence of E6-associated protein . This allows unchecked cellular cycling, and has an anti-apoptotic effect, permitting the accumulation of chromosomal mutations without DNA repair .
In contrast to the E6 protein, E7 protein sensitizes wild-type p53-containing cells to apoptosis, but exerts an anti-apoptotic effect in cells with mutated p53. The possible significance of this finding is discussed in the next section.

19. Role of retinoblastoma protein
 The Rb protein inhibits the effect of positive growth regulation and halts cell growth or induces cell apoptosis in response to DNA damage
The interaction of E7 with Rb may permit cells with damaged DNA to bypass the G1 growth arrest normally induced by wild-type p53

20. RISK FACTORS FOR HPV INFECTION
 Genital HPV infections are considered to be spread by unprotected penetrative intercourse or close skin-to-skin physical contact involving an infected area
Fomite, digital/anal, and digital/vaginal contact probably may also potentially spread the virus, although the evidence for this is not definitive

21. DETECTING HPV
HPV DNA testing - HPV DNA testing to cervical cytology improved the sensitivity for detection of cervical cancer precursors, such as cervical intraepithelial neoplasia (CIN) 2 and 3.
HPV ribonucleic acid (RNA) testing – HPV RNA testing, looking for expression of E6 and/or E7 RNA, may be performed with the expectation that active HPV oncogene expression would provide equivalent sensitivity and better specificity than HPV DNA testing. improves the specificity of detecting cervical intraepithelial neoplasia grade 2 and above (CIN2+), thereby decreasing the number of "false-positive" HPV tests compared with HPV DNA testing.
Detection of cellular markers – High-grade CIN lesions contain high levels of p16, and pathologists often immunostain cervical biopsies to help distinguish between high-grade CIN and immature squamous metaplasia, which is not associated with HPV and is not precancerous.

22. DETECTING HPV PCR-based Cobas 4800 test. Cervista test
FDA-approved RNA-based test.

23. Cervical Cancer Screening
as a single, primary screening test among women aged 25 years or older, or as cotesting with a Pap test. The Cobas 4800 test is currently the only test that is FDA-approved for primary HPV testing.

26. Other cancers
Head and neck cancer – There is no role for HPV testing of oral rinse or salivary specimens as a screening test for oropharyngeal cancer.
Anal cancer – The role for HPV testing in anal swab or brush testing in screening for anal cancer, or anal high-grade squamous intraepithelial lesions, the precursor to anal cancer, is not clear. There are no recommendations for anal HPV testing of populations at high risk of anal cancer. These data are discussed separately.
Penile cancer – There are no clinically available tests to screen for penile HPV infection for detection of penile cancer or precancerous lesions. In addition, HPV testing for men with penile cancer has no impact on decision-making regarding treatment and is not routinely performed.

27.  Human papillomavirus (HPV) is a sexually transmitted pathogen that causes anogenital and oropharyngeal disease in males and females.
The high-risk HPV genotypes (or "types") 16 and 18 cause approximately 70 percent of all cervical cancers worldwide, and types 31, 33, 45, 52, and 58 cause an additional 20 percent.
HPV types 16 and 18 also cause nearly 90 percent of anal cancers and a significant proportion of oropharyngeal cancer, vulvar and vaginal cancer, and penile cancer.
HPV types 6 and 11 cause approximately 90 percent of anogenital warts.

28. AVAILABLE VACCINES
Quadrivalent HPV vaccine (Gardasil) targets HPV types 6, 11, 16, and 18.
9-valent vaccine (Gardasil 9) targets the same HPV types as the quadrivalent vaccine (6, 11, 16, and 18) as well as types 31, 33, 45, 52, and 58.
Bivalent vaccine (Cervarix) targets HPV types 16 and 18.

29. HPV types 16 and 18, which are targeted by all three HPV vaccines, cause approximately 70 percent of all cervical cancers worldwide, and HPV types 31, 33, 45, 52, and 58, which are additionally targeted by the 9-valent vaccine, cause an additional 20 percent.
HPV types 16 and 18 also cause nearly 90 percent of anal cancers and a substantial proportion of vaginal, vulvar, and oropharyngeal cancers.
Vaccination with the quadrivalent or 9-valent HPV vaccine also protects against anogenital warts (90 percent of which are caused by HPV types 6 and 11)
The adverse effects of HPV vaccination are generally limited to mild local reactions.

30. Males
HPV types 16 and 18 cause nearly 90 percent of anal cancers and substantial proportion of oropharyngeal and penile cancers. Vaccination with 9-valent or quadrivalent vaccine also protects against anogenital warts (90 percent of which are caused by HPV types 6 and 11).

31. Vaccine indication
Females – HPV vaccine is recommended at 11 to 12 years. It can be administered starting at 9 years of age, and catch-up vaccination is recommended for females aged 13 to 26 years who have not been previously vaccinated or who have not completed the vaccine series.
Males – HPV vaccine is recommended at 11 to 12 years. It can be administered as starting at 9 years of age, and catch-up vaccination is recommended for males aged 13 to 21 years who have not been previously vaccinated or who have not completed the vaccine series.
Among males 22 to 26 years old, catch-up HPV vaccination is recommended if they are men who have sex with men or immunocompromised (including HIV-infected males). Otherwise, "permissive use" of HPV vaccination is recommended for this age range.

32. Vaccine indication
HPV vaccination is immunogenic, efficacious, and safe in older women
primary target of HPV vaccination programs be females aged 9 to 14 years and that local public health programs should recommend vaccination of older females only if it is affordable and cost effective and does not divert resources from vaccinating the primary target population or screening for cervical cancer [30]. ASCO recommendations for resource-limited settings are similar

33. Optimal timing
 Within the recommended age range, the optimal time for HPV immunization is prior to an individual's sexual debut.
A history of an abnormal Papanicolaou test, genital warts, or HPV infection is NOT a contraindication to HPV immunization

34. Choice of vaccine we recommend the 9-valent vaccine.
In the United States only the 9-valent vaccine is available (since 2017).
The greater HPV-type coverage provided by the 9-valent compared with the quadrivalent and bivalent vaccines protects against additional cervical cancers.

35. Immunization schedule
●Individuals initiating the vaccine series before 15 years of age – Two doses of HPV vaccine should be given at 0 and at 6 to 12 months. If the second dose was administered less than five months after the first, the dose should be repeated a minimum of 12 weeks after the second dose and a minimum of five months after the first.
●Individuals initiating the vaccine series at 15 years of age or older – Three doses of HPV vaccine should be given at 0, 1 to 2 (typically 2), and 6 months. The minimum intervals between the first two doses is four weeks, between the second and third doses is 12 weeks, and between the first and third dose is five months. If a dose was administered at a shorter interval, it should be repeated once the minimum recommended interval since the most recent dose has passed.
●Immunocompromised patients – Three doses of HPV vaccine should be given at 0, 1 to 2, and 6 months regardless of age.

36. Missed doses — Patients often do not follow up for their immunizations on schedule . The ACIP recommends that if the vaccination series is interrupted for any length of time, it can be resumed without restarting the series.
Postvaccination instructions — Because of a potential for syncope with any vaccine, and particularly with the HPV vaccine, a routine 15-minute waiting period in a sitting or supine position following HPV vaccination is recommended . This may decrease the risk of syncope with subsequent injury.

37. Unnecessary evaluation
Prevaccination assessment — HPV vaccination can be administered without special evaluation. Serologic or HPV DNA testing is not warranted prior to immunization . Pregnancy testing is also not necessary.
Postvaccination serology — There is no evidence that the measurement of postvaccination antibody titers to monitor immunity is useful for determining who is protected against infection by the vaccine-targeted types.

38. SPECIAL POPULATIONS
Pregnant or breastfeeding females — HPV vaccination during pregnancy is not recommended because of limited information about safety
Lactating females can receive the immunization series since subunit vaccines do not affect the safety of infant breastfeeding.
Preexisting HPV-associated disease — A history of genital warts, a positive HPV test result, or abnormal cervical, vaginal, vulvar, or anal cytology all indicate a prior HPV infection but not necessarily with the HPV types included in the vaccines. Vaccination is still recommended in individuals within the recommended age range who have evidence of prior HPV infection, as it can still provide protection against infection with HPV vaccine types not already acquired .

39. Immunogenicity
 seroconversion rates of 93 to 100 percent in females and 99 to 100 percent in males
With each of the three vaccines, the geometric mean titers (GMT) of postvaccination antibodies among females aged 9 to 15 years were generally twofold higher than those observed in females aged 16 to 26 for all targeted HPV types
In a head-to-head comparison of the immunogenicity of quadrivalent and bivalent HPV vaccines in females ages 18 to 45 years, immunization with the bivalent vaccine induced GMT of serum neutralizing antibodies 2.3- to 4.8-fold higher for HPV 16 and 6.8- to 9.1-fold higher for HPV 18 across all age strata compared with the quadrivalent vaccine . However, whether the induction of higher serum titers against HPV 16 and 18 has any impact on the degree and duration of protection is unknown.

40. Efficacy
Cervical, vaginal, and vulvar disease — HPV vaccination is effective in preventing cervical disease, including cervical intraepithelial neoplasia (CIN2 or 3) and adenocarcinoma in situ.
quadrivalent and 9-valent HPV vaccines have been demonstrated to reduce the incidence of vaginal and vulvar intraepithelial neoplasia (VAIN and VIN 1-3). Vaccine efficacy is greatest in those who do not have prior HPV infection.

41. Quadrivalent HPV vaccine
•97 to 100 percent among HPV-naïve populations
•44 percent among the overall population
Efficacy for preventing VIN2 or 3 and VaIN2 or 3 was similarly 100 percent among HPV-naïve populations and 62 percent among the overall population.

42. 9-valent HPV vaccine •97 percent among the HPV-naïve population
the rates of high-grade cervical, vaginal, and vulvar disease were the same among women who received the 9-valent vaccine and those who received the quadrivalent vaccine (14 cases/1000 person-years in both groups).

43. Bivalent HPV vaccine females aged 15 to 25 years
•93 percent among the HPV-naïve population
•53 percent among the overall population
HPV vaccination also appears to be safe and effective in preventing subsequent infection and cervical disease in older women, but the overall benefit is less than in younger females

44. Anal disease
 Data informing the impact of HPV vaccine on anal intraepithelial neoplasia (AIN) and anal cancers are more limited than that for cervical disease but suggest efficacy in males and expected efficacy in females.

45. Oral disease
prevention of oral HPV infection was estimated to be 93 percent. Whether HPV vaccination can prevent the development of HPV-related oropharyngeal cancer has not yet been evaluated.

46. Anogenital warts
In a large randomized trial among females aged 16 to 24 years, quadrivalent HPV vaccine efficacy for preventing vulvar and vaginal condylomata was 100 percent among HPV-naïve participants (without evidence of HPV vaccine types at enrollment) and 70 to 78 percent among the overall population

47. Duration of protection
Continued protection against high-grade cervical, vaginal, and vulvar neoplasia has been observed through at least 84 months following vaccination among female trial participants
Persistent antibody levels and protection against HPV infection have been reported up to 10 years following vaccination

48. VACCINE SAFETY
 All vaccines use virus-like particles (VLPs)which mimic the viral capsid.
VLPs do not contain genetic material and are produced in biologic systems, which have well-established safety records

49. Quadrivalent vaccine (Gardasil)
vaccine is safe and well tolerated apart from mild injection site reactions. Postvaccination syncopal events have emerged as a potential serious adverse effect
VTE
Anaphylaxis

50. 9-valent vaccine (Gardasil 9)
 Fewer post-licensure safety data are available for the 9-valent vaccine than the quadrivalent vaccine. The overall safety profile appears similar, although the frequency of mild local reactions might be higher with the 9-valent vaccine.
pain, erythema, and swelling, headache, fever, nausea, dizziness

51. Bivalent vaccine (Cervarix)
Data from large placebo-controlled randomized trials indicate that bivalent HPV vaccine is safe.

52. Behavioral impact
   not supported an increase in risky sexual behavior following vaccination .

53. Cervical screening
HPV immunization is not effective in clearing HPV infection, genital warts, or cervical intraepithelial neoplasia that is already present, and the vaccine does not protect against 100 percent of types known to cause cervical cancer. Thus, HPV vaccination status does not impact cervical cancer screening recommendations.
The optimal approach to cervical cancer screening in HPV-naïve females who have received the 9-valent vaccine and are thus protected against 90 percent of cervical cancer is unclear.

54. Anal screening 
some specialists recommend anal cytologic screening for HIV-infected males and females and other populations known to be at increased risk of anal cancer