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Human Papillomavirus (HPV)
Human papillomavirus (HPV) is the most common sexually transmitted infection affecting more than 20 million people in the United States with an estimated six million new HPV infections occurring annually (CDC, 2010a). The HPV virus is found in approximately 70% of all cervical cancers, 90% of genital warts, and 90% in HPV associated cancers (National Cancer Institute, 2012). HPV infection is highest among the adolescent and young adult population with a prevalence rate of 64%; and by the age of 50, nearly 80 % of women will be infected by the HPV virus (National Cervical Cancer Coalition, 2013). HPV is transmitted through sexual contact, contact with infected genital skin, mucous membranes, or bodily fluids from an infected partner (Myrth & Dollin, 2007). Most people who become infected with HPV do not develop symptoms and do not know they have it as our immune system generally rids itself of the infection within two years, yet HPV lies dormant. Unprotected sex and multiple sexual partners are the greatest risk factors for contracting HPV infection.
There are over 100 different types of HPV; more than 40 HPV types can infect the genital area; and over 13 HPV types are related to HPV associated cancers involving the cervix, vulva, anus/rectal, penile, and throat (CDC, 2013). HPV types can be classified into high risk and low risk. HPV low risk types 6 and 11 are the causative factor for genital warts, while high risk type 16 and 18 are strongly linked to HPV associated cancers (Bosch, Qiao, & Castellsague, 2006). Type 16 is the cause of approximately 50% of cervical cancers worldwide, and types 16 and 18 together account for over 70% of all cervical cancers (National Cancer Institute, 2012).
History of HPV
One of the most important discoveries in the last 25 years has been the demonstration that cervical cancer is caused by certain types of the Human Papilloma Virus (Castellsague, 2008). In 1972, the association between the human papilloma virus and skin cancer was proposed by the Polish scientist Stefania Jablonska who later discovered the HPV strain 5 was directly related to skin cancers. Based off of her research and much research before him, German scientist Harald zur Hausen proposed a hypothesis in 1976 that HPV caused cervical cancer. Through many years of research, he discovered HPV had hundreds of different types. In 1984, he discovered HPV type 16 was present in cervical cancer tumors, and a year later, associated HPV type 18 was also present in cervical cancer tumors (Zur Hausen, 2009).

Harald zur Hausen is also credited with the discovery of the HPV type 6, one of the causative factors of genital warts. The other is HPV type 11. In 2008, Harald zur Hausen was awarded the 2008 Nobel Prize for his research on HPV. His research has lead to the development of two HPV vaccinations currently on the market aimed at reducing and preventing the occurrences of HPV associated cancers.

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Morphology of hpv:
Previously we found differences in the distribution of the individual human papillomavirus types in cervical cancers and high-grade squamous intraepithelial lesions. This suggested that there were differences in risk for progression of high-grade squamous intraepithelial lesions that were related to human papillomavirus type within the category of oncogenic genotypes. In this work, we add additional cases including low-grade squamous intraepithelial lesions. ThinPrep® samples from 282 squamous intraepithelial lesions and invasive cervical cancers were categorized morphologically by consensus interpretation and genotyped for 27 individual human papillomavirus types by polymerase chain reaction-based reverse line blot analysis using PGMY09/PGMY11 consensus primers for the L1 open reading frame. The 27 human papillomavirus types were divided into three categories: high risk 16, 18, 31, 45; intermediate risk 33, 35, 39, 51, 52, 56, 58, 59, 68, 73, 82, 83; and low risk: 6, 11, 26, 40, 42, 53, 54, 55, 57, 66, and 84. Of the 282 cases of cancer and squamous intraepithelial lesions, 95.7% were positive for one or more of 27 human papillomavirus types and 38.7% had two or more genotypes. Three major categories of squamous intraepithelial lesions were identified based upon the combination of consensus diagnosis and human papillomavirus category: (1) high-grade squamous intraepithelial lesions associated with high-risk human papillomavirus types that appear to be at increased risk for progression to carcinoma; (2) squamous intraepithelial lesions (typically low-grade intraepithelial lesions and high-grade lesions consistent with moderate dysplasia) associated with intermediate risk human papillomavirus types with limited or indeterminate risk for progression; (3) low-grade squamous intraepithelial lesions associated with low-risk human papillomavirus types with little or no risk for progression. Only a subset of human papillomavirus genotypes commonly considered to be oncogenic were closely associated with invasive cervical cancer and high-grade squamous intraepithelial lesions classed as severe dysplasia. Other oncogenic types were closely associated with high-grade squamous intraepithelial lesions of moderate dysplasia and low-grade squamous intraepithelial lesions. This suggests that risk for progression to invasion in squamous intraepithelial lesions is closely related to human papillomavirus genotype. Knowledge of the associated human papillomavirus type in women with morphologic squamous intraepithelial lesions may help to clarify risk for progression ADDIN EN.CITE <EndNote><Cite><Author>Antonsson</Author><Year>2002</Year><RecNum>29</RecNum><DisplayText>(Antonsson and Hansson, 2002)</DisplayText><record><rec-number>29</rec-number><foreign-keys><key app=”EN” db-id=”zzzt99s5yfps5zes9daxevzydxse0va5avt9″ timestamp=”1525215515″>29</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Antonsson, Annika</author><author>Hansson, Bengt Göran</author></authors></contributors><titles><title>Healthy skin of many animal species harbors papillomaviruses which are closely related to their human counterparts</title><secondary-title>Journal of Virology</secondary-title></titles><periodical><full-title>Journal of Virology</full-title></periodical><pages>12537-12542</pages><volume>76</volume><number>24</number><dates><year>2002</year></dates><isbn>0022-538X</isbn><urls></urls></record></Cite></EndNote>(Antonsson and Hansson, 2002).

Classification of hpv ADDIN EN.CITE <EndNote><Cite><Author>Antonsson</Author><Year>2002</Year><RecNum>29</RecNum><DisplayText>(Antonsson and Hansson, 2002)</DisplayText><record><rec-number>29</rec-number><foreign-keys><key app=”EN” db-id=”zzzt99s5yfps5zes9daxevzydxse0va5avt9″ timestamp=”1525215515″>29</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Antonsson, Annika</author><author>Hansson, Bengt Göran</author></authors></contributors><titles><title>Healthy skin of many animal species harbors papillomaviruses which are closely related to their human counterparts</title><secondary-title>Journal of Virology</secondary-title></titles><periodical><full-title>Journal of Virology</full-title></periodical><pages>12537-12542</pages><volume>76</volume><number>24</number><dates><year>2002</year></dates><isbn>0022-538X</isbn><urls></urls></record></Cite></EndNote>(Antonsson and Hansson, 2002):

Genus Biological properties Genome organization
Alpha-papillomavirus Mucosal and cutaneous lesions in humans and primates Conserved with an E5 ORF within the ELR HYPERLINK “https://www.sciencedirect.com/science/article/pii/S004268220400220X” l “TBLFN1” a (ca. 300–500 bp)
High- and low-risk classification based on molecular biological data—high-risk types (pre- and malignant lesions) immortalize human keratinocytes; low-risk types (benign lesions) do not. ORFs in ELR from different species may be divided into three groups:
Recent compilations of epidemiological data demonstrate more frequent association of specific species as high-risk types. –classical E5 ORF
–closer related to the ungulate E5 ORF
–putative ORF with distinct conserved motives HYPERLINK “https://www.sciencedirect.com/science/article/pii/S004268220400220X” l “TBLFN2” bBeta-papillomavirus Cutaneous lesions in humans ELR is generally less than 100nt in length
Infections exist in latent form in general population, activated under conditions of immune suppression E5 ORF absent
Also referred to EV-HPV types due to close association with disease Epidermodysplasia verruciformis (EV) Gamma-papillomavirus Cutaneous lesions in humans—histologically distinguishable by intracytoplasmic inclusion bodies specific for type species ELR is generally less than 100 nt in length. E5 ORF absent
Delta-papillomavirus Lesions in ungulates ORFs located in ELR have transforming properties
Induces fibropapillomas in the respective host Trans-species transmission occurs inducing sarcoidsEpsilon-papillomavirus Bovine papillomavirus cutaneous papillomas in cattle Zeta-papillomavirus Cutaneous lesions in horses Undefined ORF overlapping with L2 ORF
Eta-papillomavirus Avian papillomaviruses E4 and E5 ORFs absent
Cutaneous lesions in host No typical E6 ORF, but an ancestral E7 ORF with partial E6 characteristics
Theta-papillomavirus Avian papillomaviruses E4 and E5 ORFs absent
Cutaneous lesions in host No typical E6 ORF, but an ancestral E7 ORF with partial E6 characteristics
Iota-papillomavirus Rodent papillomaviruses E5 ORF absent
Cutaneous lesions E2 ORF considerably larger then in other genera
Kappa-papillomavirus Isolated from rabbits E6 ORF larger than in other papillomaviruses.

Cutaneous and mucosal lesions Harbors an uncharacterized E8 ORF within the E6 ORF region
Lambda-papillomavirus Animal papillomaviruses ELR region exceptionally large (1500 bp and 1271 bp in 2 known species)
Benign mucosal and cutaneous lesions Mu-papillomavirus Human papillomaviruses URR relatively large (982 bp and 558 bp for two known species)
Cutaneous lesions—histologically distinguishable by intracytoplasmic inclusion bodies specific for type species Nu-papillomavirus Human papillomavirus Several larger uncharacterized ORFs scattered throughout genome.

Benign and malignant cutaneous lesions E2 binding sites in URR all modified
Xi-papillomavirus Bovine papillomaviruses Characteristic E6 ORF absent
Induce true papillomas in host. E8 ORF (located in E6 ORF region) with properties similar to E5 ORF of BPV 1
Cutaneous or mucosal lesions Omikron-papillomavirus Isolated from genital warts in cetaceans E7 ORF absent
Several larger unidentified ORFs located in L1 ORF region
Pi-papillomavirus Isolated from hamsters ELR absent with E2 and L2 ORFs partially overlapping
Mucosal lesions
Pathogenesis – HPVs are ubiquitous in the human population, and occasionally infection leads to cervical cancer Although the body is working to get the infection under control, HPVs infect and disturb cutaneous and mucosal epithelial cells of the anogenital tract, hands or feet which can lead to a variety of diseases with a range of severities depending on the types of HPV infection ADDIN EN.CITE <EndNote><Cite><Author>Ashrafi</Author><Year>2016</Year><RecNum>30</RecNum><DisplayText>(Ashrafi and Salman, 2016)</DisplayText><record><rec-number>30</rec-number><foreign-keys><key app=”EN” db-id=”zzzt99s5yfps5zes9daxevzydxse0va5avt9″ timestamp=”1525215819″>30</key></foreign-keys><ref-type name=”Book Section”>5</ref-type><contributors><authors><author>Ashrafi, G Hossein</author><author>Salman, Nadia Aziz</author></authors></contributors><titles><title>Pathogenesis of human papillomavirus–immunological responses to HPV infection</title><secondary-title>Human Papillomavirus-Research in a Global Perspective</secondary-title></titles><dates><year>2016</year></dates><publisher>Intech</publisher><urls></urls></record></Cite></EndNote>(Ashrafi and Salman, 2016).- The type HPV family is divided into two categories
low-risk HPVs and high-risk HPVs (HR-HPVs) ADDIN EN.CITE <EndNote><Cite><Author>Ashrafi</Author><Year>2016</Year><RecNum>30</RecNum><DisplayText>(Ashrafi and Salman, 2016)</DisplayText><record><rec-number>30</rec-number><foreign-keys><key app=”EN” db-id=”zzzt99s5yfps5zes9daxevzydxse0va5avt9″ timestamp=”1525215819″>30</key></foreign-keys><ref-type name=”Book Section”>5</ref-type><contributors><authors><author>Ashrafi, G Hossein</author><author>Salman, Nadia Aziz</author></authors></contributors><titles><title>Pathogenesis of human papillomavirus–immunological responses to HPV infection</title><secondary-title>Human Papillomavirus-Research in a Global Perspective</secondary-title></titles><dates><year>2016</year></dates><publisher>Intech</publisher><urls></urls></record></Cite></EndNote>(Ashrafi and Salman, 2016). The low-risk HPV types such as HPV 6 and HPV 11 commonly cause benign genital warts (condylomas) ADDIN EN.CITE <EndNote><Cite><Author>Ashrafi</Author><Year>2016</Year><RecNum>30</RecNum><DisplayText>(Ashrafi and Salman, 2016)</DisplayText><record><rec-number>30</rec-number><foreign-keys><key app=”EN” db-id=”zzzt99s5yfps5zes9daxevzydxse0va5avt9″ timestamp=”1525215819″>30</key></foreign-keys><ref-type name=”Book Section”>5</ref-type><contributors><authors><author>Ashrafi, G Hossein</author><author>Salman, Nadia Aziz</author></authors></contributors><titles><title>Pathogenesis of human papillomavirus–immunological responses to HPV infection</title><secondary-title>Human Papillomavirus-Research in a Global Perspective</secondary-title></titles><dates><year>2016</year></dates><publisher>Intech</publisher><urls></urls></record></Cite></EndNote>(Ashrafi and Salman, 2016). These lesions can regress even without treatment ADDIN EN.CITE <EndNote><Cite><Author>Nasiell</Author><Year>1986</Year><RecNum>31</RecNum><DisplayText>(Nasiell et al., 1986)</DisplayText><record><rec-number>31</rec-number><foreign-keys><key app=”EN” db-id=”zzzt99s5yfps5zes9daxevzydxse0va5avt9″ timestamp=”1525216057″>31</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Nasiell, KAREN</author><author>Roger, VIVI</author><author>Nasiell, MAGNUS</author></authors></contributors><titles><title>Behavior of mild cervical dysplasia during long-term follow-up</title><secondary-title>Obstetrics and gynecology</secondary-title></titles><periodical><full-title>Obstetrics and gynecology</full-title></periodical><pages>665-669</pages><volume>67</volume><number>5</number><dates><year>1986</year></dates><isbn>0029-7844</isbn><urls></urls></record></Cite></EndNote>(Nasiell et al., 1986), due to cell-mediated immune responses ADDIN EN.CITE <EndNote><Cite><Author>Coleman</Author><Year>1994</Year><RecNum>32</RecNum><DisplayText>(Coleman et al., 1994)</DisplayText><record><rec-number>32</rec-number><foreign-keys><key app=”EN” db-id=”zzzt99s5yfps5zes9daxevzydxse0va5avt9″ timestamp=”1525216231″>32</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Coleman, Nicholas</author><author>Birley, Humphrey DL</author><author>Renton, Adrian M</author><author>Hanna, Nashat F</author><author>Ryait, Balvinder K</author><author>Byrne, Micheline</author><author>Taylor-Robinson, David</author><author>Stanley, Margaret A</author></authors></contributors><titles><title>Immunological events in regressing genital warts</title><secondary-title>American journal of clinical pathology</secondary-title></titles><periodical><full-title>American journal of clinical pathology</full-title></periodical><pages>768-774</pages><volume>102</volume><number>6</number><dates><year>1994</year></dates><isbn>1943-7722</isbn><urls></urls></record></Cite></EndNote>(Coleman et al., 1994). While the high-risk types of HPV which include HPV 16, 18, 31, 35 and 45 are associated with the development of anogenital cancers and found in up to 99% of all cervical carcinomas ADDIN EN.CITE <EndNote><Cite><Author>Walboomers</Author><Year>1999</Year><RecNum>33</RecNum><DisplayText>(Walboomers et al., 1999)</DisplayText><record><rec-number>33</rec-number><foreign-keys><key app=”EN” db-id=”zzzt99s5yfps5zes9daxevzydxse0va5avt9″ timestamp=”1525216835″>33</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Walboomers, Jan MM</author><author>Jacobs, Marcel V</author><author>Manos, M Michele</author><author>Bosch, F Xavier</author><author>Kummer, J Alain</author><author>Shah, Keerti V</author><author>Snijders, Peter JF</author><author>Peto, Julian</author><author>Meijer, Chris JLM</author><author>Muñoz, Nubia</author></authors></contributors><titles><title>Human papillomavirus is a necessary cause of invasive cervical cancer worldwide</title><secondary-title>The Journal of pathology</secondary-title></titles><periodical><full-title>The Journal of pathology</full-title></periodical><pages>12-19</pages><volume>189</volume><number>1</number><dates><year>1999</year></dates><isbn>1096-9896</isbn><urls></urls></record></Cite></EndNote>(Walboomers et al., 1999) , ADDIN EN.CITE <EndNote><Cite><Author>Muñoz</Author><Year>2003</Year><RecNum>34</RecNum><DisplayText>(Muñoz et al., 2003)</DisplayText><record><rec-number>34</rec-number><foreign-keys><key app=”EN” db-id=”zzzt99s5yfps5zes9daxevzydxse0va5avt9″ timestamp=”1525216898″>34</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Muñoz, Nubia</author><author>Bosch, F Xavier</author><author>de Sanjosé, Silvia</author><author>Herrero, Rolando</author><author>Castellsagué, Xavier</author><author>Shah, Keerti V</author><author>Snijders, Peter JF</author><author>Meijer, Chris JLM</author></authors></contributors><titles><title>Epidemiologic classification of human papillomavirus types associated with cervical cancer</title><secondary-title>New England Journal of Medicine</secondary-title></titles><periodical><full-title>New England Journal of Medicine</full-title></periodical><pages>518-527</pages><volume>348</volume><number>6</number><dates><year>2003</year></dates><isbn>0028-4793</isbn><urls></urls></record></Cite></EndNote>(Muñoz et al., 2003).-The lifecycle, oncogenic characteristics and molecular-based evidence of HR-HPVs are suggestive of a causal role for cancer. HPV infections are normally cleared by the immune system; however, the persistence of HPV could trigger a progression to malignant lesion in the presence of other risk factors ADDIN EN.CITE <EndNote><Cite><Author>Ashrafi</Author><Year>2016</Year><RecNum>35</RecNum><DisplayText>(Ashrafi and Salman, 2016)</DisplayText><record><rec-number>35</rec-number><foreign-keys><key app=”EN” db-id=”zzzt99s5yfps5zes9daxevzydxse0va5avt9″ timestamp=”1525217126″>35</key></foreign-keys><ref-type name=”Book Section”>5</ref-type><contributors><authors><author>Ashrafi, G Hossein</author><author>Salman, Nadia Aziz</author></authors></contributors><titles><title>Pathogenesis of human papillomavirus–immunological responses to HPV infection</title><secondary-title>Human Papillomavirus-Research in a Global Perspective</secondary-title></titles><dates><year>2016</year></dates><publisher>Intech</publisher><urls></urls></record></Cite></EndNote>(Ashrafi and Salman, 2016).-HPV facilitates this mechanism using early oncoproteins, E5, E6 and E7, which have the ability to interfere and actively participate to the downregulation of host immune system ADDIN EN.CITE <EndNote><Cite><Author>Ashrafi</Author><Year>2016</Year><RecNum>35</RecNum><DisplayText>(Ashrafi and Salman, 2016)</DisplayText><record><rec-number>35</rec-number><foreign-keys><key app=”EN” db-id=”zzzt99s5yfps5zes9daxevzydxse0va5avt9″ timestamp=”1525217126″>35</key></foreign-keys><ref-type name=”Book Section”>5</ref-type><contributors><authors><author>Ashrafi, G Hossein</author><author>Salman, Nadia Aziz</author></authors></contributors><titles><title>Pathogenesis of human papillomavirus–immunological responses to HPV infection</title><secondary-title>Human Papillomavirus-Research in a Global Perspective</secondary-title></titles><dates><year>2016</year></dates><publisher>Intech</publisher><urls></urls></record></Cite></EndNote>(Ashrafi and Salman, 2016).-E5 oncoprotein downregulates surface MHC class I by retaining it in the Golgi apparatus ADDIN EN.CITE <EndNote><Cite><Author>Ashrafi</Author><Year>2005</Year><RecNum>36</RecNum><DisplayText>(Ashrafi et al., 2005)</DisplayText><record><rec-number>36</rec-number><foreign-keys><key app=”EN” db-id=”zzzt99s5yfps5zes9daxevzydxse0va5avt9″ timestamp=”1525217397″>36</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Ashrafi, G Hossein</author><author>Haghshenas, Mohammad R</author><author>Marchetti, Barbara</author><author>O&apos;Brien, Philippa M</author><author>Campo, M Saveria</author></authors></contributors><titles><title>E5 protein of human papillomavirus type 16 selectively downregulates surface HLA class I</title><secondary-title>International journal of cancer</secondary-title></titles><periodical><full-title>International journal of cancer</full-title></periodical><pages>276-283</pages><volume>113</volume><number>2</number><dates><year>2005</year></dates><isbn>1097-0215</isbn><urls></urls></record></Cite></EndNote>(Ashrafi et al., 2005).-The role of E6 and E7 is to inhibit the production of IFN in natural killer (NK) cells or the expression of transporter associated with antigen processing (TAP) ADDIN EN.CITE <EndNote><Cite><Author>Barnard</Author><Year>1999</Year><RecNum>37</RecNum><DisplayText>(Barnard and McMillan, 1999)</DisplayText><record><rec-number>37</rec-number><foreign-keys><key app=”EN” db-id=”zzzt99s5yfps5zes9daxevzydxse0va5avt9″ timestamp=”1525217546″>37</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Barnard, Paula</author><author>McMillan, Nigel AJ</author></authors></contributors><titles><title>The human papillomavirus E7 oncoprotein abrogates signaling mediated by interferon-?</title><secondary-title>Virology</secondary-title></titles><periodical><full-title>Virology</full-title></periodical><pages>305-313</pages><volume>259</volume><number>2</number><dates><year>1999</year></dates><isbn>0042-6822</isbn><urls></urls></record></Cite></EndNote>(Barnard and McMillan, 1999) , ADDIN EN.CITE <EndNote><Cite><Author>Nees</Author><Year>2001</Year><RecNum>38</RecNum><DisplayText>(Nees et al., 2001)</DisplayText><record><rec-number>38</rec-number><foreign-keys><key app=”EN” db-id=”zzzt99s5yfps5zes9daxevzydxse0va5avt9″ timestamp=”1525217600″>38</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Nees, Matthias</author><author>Geoghegan, Joel M</author><author>Hyman, Tehila</author><author>Frank, Stephan</author><author>Miller, Lance</author><author>Woodworth, Craig D</author></authors></contributors><titles><title>Papillomavirus type 16 oncogenes downregulate expression of interferon-responsive genes and upregulate proliferation-associated and NF-?B-responsive genes in cervical keratinocytes</title><secondary-title>Journal of virology</secondary-title></titles><periodical><full-title>Journal of Virology</full-title></periodical><pages>4283-4296</pages><volume>75</volume><number>9</number><dates><year>2001</year></dates><isbn>0022-538X</isbn><urls></urls></record></Cite></EndNote>(Nees et al., 2001).- E5 contribute to cell transformation through interaction with several cellular proteins, including the epidermal growth factor receptor (EGF-R), the human receptor for colony stimulating factors (CSF-1). E5 may also reduce the processing and presentation of viral antigen ADDIN EN.CITE <EndNote><Cite><Author>Venuti</Author><Year>2011</Year><RecNum>39</RecNum><DisplayText>(Venuti et al., 2011)</DisplayText><record><rec-number>39</rec-number><foreign-keys><key app=”EN” db-id=”zzzt99s5yfps5zes9daxevzydxse0va5avt9″ timestamp=”1525217742″>39</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Venuti, Aldo</author><author>Paolini, Francesca</author><author>Nasir, Lubna</author><author>Corteggio, Annunziata</author><author>Roperto, Sante</author><author>Campo, Maria S</author><author>Borzacchiello, Giuseppe</author></authors></contributors><titles><title>Papillomavirus E5: the smallest oncoprotein with many functions</title><secondary-title>Molecular cancer</secondary-title></titles><periodical><full-title>Molecular cancer</full-title></periodical><pages>140</pages><volume>10</volume><number>1</number><dates><year>2011</year></dates><isbn>1476-4598</isbn><urls></urls></record></Cite></EndNote>(Venuti et al., 2011).

– While E6 and E7 are presented throughout the course of the HPV infection, their functions are necessary for the maintenance of a transformed status ADDIN EN.CITE <EndNote><Cite><Author>Ashrafi</Author><Year>2016</Year><RecNum>40</RecNum><DisplayText>(Ashrafi and Salman, 2016)</DisplayText><record><rec-number>40</rec-number><foreign-keys><key app=”EN” db-id=”zzzt99s5yfps5zes9daxevzydxse0va5avt9″ timestamp=”1525217895″>40</key></foreign-keys><ref-type name=”Book Section”>5</ref-type><contributors><authors><author>Ashrafi, G Hossein</author><author>Salman, Nadia Aziz</author></authors></contributors><titles><title>Pathogenesis of human papillomavirus–immunological responses to HPV infection</title><secondary-title>Human Papillomavirus-Research in a Global Perspective</secondary-title></titles><dates><year>2016</year></dates><publisher>Intech</publisher><urls></urls></record></Cite></EndNote>(Ashrafi and Salman, 2016).

Laboratory Diagnosis
HPV has not been cultured by conventional methods. Infection is identified by detection of HPV DNA from clinical samples. Assays for HPV detection differ considerably in their sensitivity and type specificity, and detection is also affected by the anatomic region sampled as well as the method of specimen collection. Several HPV tests have been approved by the Food and Drug Administration (FDA) and detect 13-14 high-risk types (HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68). Test results are reported as positive or negative for any of the types; some tests specifically identify HPV 16 and 18. These tests are approved for triage of Papanicolaou (Pap) test results (ASC-US, atypical cells of undetermined significance) and in combination with the Pap test for cervical cancer screening in women 30 years of age and older. The tests are not clinically indicated nor approved for use in men. Epidemiologic and basic research studies of HPV generally use nucleic acid amplification methods that generate type-specific results. The polymerase chain reaction (PCR) assays used most commonly in epidemiologic studies target genetically conserved regions in the L1 gene.

Epidemiologic and basic research studies of HPV generally use nucleic acid amplification methods that generate type-specific results. The polymerase chain reaction (PCR) assays used most commonly in epidemiologic studies target genetically conserved regions in the L1 gene.

The most frequently used HPV serologic assays are virus-like particle (VLP)-based enzyme immunoassays. However, laboratory reagents used for these assays are not standardized and there are no standards for setting a threshold for a positive result ADDIN EN.CITE <EndNote><Cite><Author>Obstetricians</Author><Year>2010</Year><RecNum>41</RecNum><DisplayText>(Obstetricians and Gynecologists, 2010)</DisplayText><record><rec-number>41</rec-number><foreign-keys><key app=”EN” db-id=”zzzt99s5yfps5zes9daxevzydxse0va5avt9″ timestamp=”1525218018″>41</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>American College of Obstetricians</author><author>Gynecologists</author></authors></contributors><titles><title>Human papillomavirus vaccination. committee opinion No. 467</title><secondary-title>Obstet Gynecol</secondary-title></titles><periodical><full-title>Obstet Gynecol</full-title></periodical><pages>800-3</pages><volume>116</volume><number>3</number><dates><year>2010</year></dates><urls></urls></record></Cite></EndNote>(Obstetricians and Gynecologists, 2010) , ADDIN EN.CITE <EndNote><Cite><Author>Markowitz</Author><Year>2014</Year><RecNum>42</RecNum><DisplayText>(Markowitz et al., 2014)</DisplayText><record><rec-number>42</rec-number><foreign-keys><key app=”EN” db-id=”zzzt99s5yfps5zes9daxevzydxse0va5avt9″ timestamp=”1525218066″>42</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Markowitz, Lauri E</author><author>Dunne, Eileen F</author><author>Saraiya, Mona</author><author>Chesson, Harrell W</author><author>Curtis, C Robinette</author><author>Gee, Julianne</author><author>Bocchini Jr, Joseph A</author><author>Unger, Elizabeth R</author></authors></contributors><titles><title>Human papillomavirus vaccination: recommendations of the Advisory Committee on Immunization Practices (ACIP)</title><secondary-title>Morbidity and Mortality Weekly Report: Recommendations and Reports</secondary-title></titles><periodical><full-title>Morbidity and Mortality Weekly Report: Recommendations and Reports</full-title></periodical><pages>1-30</pages><volume>63</volume><number>5</number><dates><year>2014</year></dates><isbn>1057-5987</isbn><urls></urls></record></Cite></EndNote>(Markowitz et al., 2014).

Epidemiology
Occurrence HPV infection occurs throughout the world.

Reservoir Viruses in the papillomavirus family affect other species. Humans are the only natural reservoir of HPV.

Transmission HPV is transmitted by direct contact, usually sexual, with an infected person. Transmission occurs most frequently with sexual intercourse but can occur following nonpenetrative sexual activity.

Genital HPV infection also may be transmitted by nonsexual routes, but this appears to be uncommon. Nonsexual routes of genital HPV transmission include transmission from a woman to a newborn infant at the time of birth
Temporal Pattern There is no known seasonal variation in HPV infection.
Communicability HPV is presumably communicable during the acute infection and during persistent infection. This issue is difficult to study because of the inability to culture the virus. Communicability can be presumed to be high because of the large number of new infections estimated to occur each year.

Risk Factors Risk factors for HPV infection are primarily related to sexual behavior, including lifetime and recent sex partners. Results of epidemiologic studies are less consistent for other risk factors, including young age at sexual initiation, number of pregnancies, genetic factors, smoking, and lack of circumcision of male partner ADDIN EN.CITE <EndNote><Cite><Author>Markowitz</Author><Year>2007</Year><RecNum>43</RecNum><DisplayText>(Markowitz et al., 2007)</DisplayText><record><rec-number>43</rec-number><foreign-keys><key app=”EN” db-id=”zzzt99s5yfps5zes9daxevzydxse0va5avt9″ timestamp=”1525218164″>43</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Markowitz, Lauri E</author><author>Dunne, E</author><author>Saraiya, M</author><author>Lawson, H</author><author>Chesson, H</author><author>Unger, ER</author></authors></contributors><titles><title>Quadrivalent human papillomavirus vaccine</title><secondary-title>MMWR Morb Mortal Wkly Rep</secondary-title></titles><periodical><full-title>MMWR Morb Mortal Wkly Rep</full-title></periodical><pages>1-24</pages><volume>56</volume><number>2</number><dates><year>2007</year></dates><urls></urls></record></Cite></EndNote>(Markowitz et al., 2007) , ADDIN EN.CITE <EndNote><Cite><Author>Control</Author><Year>2010</Year><RecNum>44</RecNum><DisplayText>(Control and Prevention, 2010)</DisplayText><record><rec-number>44</rec-number><foreign-keys><key app=”EN” db-id=”zzzt99s5yfps5zes9daxevzydxse0va5avt9″ timestamp=”1525218210″>44</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Centers for Disease Control</author><author>Prevention</author></authors></contributors><titles><title>FDA licensure of bivalent human papillomavirus vaccine (HPV2, Cervarix) for use in females and updated HPV vaccination recommendations from the Advisory Committee on Immunization Practices (ACIP)</title><secondary-title>MMWR. Morbidity and mortality weekly report</secondary-title></titles><periodical><full-title>MMWR. Morbidity and mortality weekly report</full-title></periodical><pages>626</pages><volume>59</volume><number>20</number><dates><year>2010</year></dates><isbn>1545-861X</isbn><urls></urls></record></Cite></EndNote>(Control and Prevention, 2010).

Treatment ADDIN EN.CITE <EndNote><Cite><Author>Park</Author><Year>2015</Year><RecNum>45</RecNum><DisplayText>(Park et al., 2015)</DisplayText><record><rec-number>45</rec-number><foreign-keys><key app=”EN” db-id=”zzzt99s5yfps5zes9daxevzydxse0va5avt9″ timestamp=”1525218607″>45</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Park, Ina U</author><author>Introcaso, Camille</author><author>Dunne, Eileen F</author></authors></contributors><titles><title>Human papillomavirus and genital warts: a review of the evidence for the 2015 centers for disease control and prevention sexually transmitted diseases treatment guidelines</title><secondary-title>Clinical Infectious Diseases</secondary-title></titles><periodical><full-title>Clinical Infectious Diseases</full-title></periodical><pages>S849-S855</pages><volume>61</volume><number>suppl_8</number><dates><year>2015</year></dates><isbn>1537-6591</isbn><urls></urls></record></Cite></EndNote>(Park et al., 2015)

Future and advanced treatment
Treatment 0f HPV induced cancer was considered only on surgical resection, or chemo-radiation therapy, but due to many side effects due to chemo and radio therapy, scientist were trying to find another way to reduce side effects and treat HPV induced cancer ADDIN EN.CITE <EndNote><Cite><Author>Psyrri</Author><Year>2012</Year><RecNum>47</RecNum><DisplayText>(Psyrri et al., 2012)</DisplayText><record><rec-number>47</rec-number><foreign-keys><key app=”EN” db-id=”zzzt99s5yfps5zes9daxevzydxse0va5avt9″ timestamp=”1525218919″>47</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Psyrri, Amanda</author><author>Sasaki, Clarence</author><author>Vassilakopoulou, Maria</author><author>Dimitriadis, George</author><author>Rampias, Theodoros</author></authors></contributors><titles><title>Future directions in research, treatment and prevention of HPV-related squamous cell carcinoma of the head and neck</title><secondary-title>Head and neck pathology</secondary-title></titles><periodical><full-title>Head and neck pathology</full-title></periodical><pages>121-128</pages><volume>6</volume><number>1</number><dates><year>2012</year></dates><isbn>1936-055X</isbn><urls></urls></record></Cite></EndNote>(Psyrri et al., 2012).
Vaccination was the light in a dark tunnel, they started its use in 2006 then 2009, and there were two types ADDIN EN.CITE <EndNote><Cite><Author>Psyrri</Author><Year>2012</Year><RecNum>47</RecNum><DisplayText>(Psyrri et al., 2012)</DisplayText><record><rec-number>47</rec-number><foreign-keys><key app=”EN” db-id=”zzzt99s5yfps5zes9daxevzydxse0va5avt9″ timestamp=”1525218919″>47</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Psyrri, Amanda</author><author>Sasaki, Clarence</author><author>Vassilakopoulou, Maria</author><author>Dimitriadis, George</author><author>Rampias, Theodoros</author></authors></contributors><titles><title>Future directions in research, treatment and prevention of HPV-related squamous cell carcinoma of the head and neck</title><secondary-title>Head and neck pathology</secondary-title></titles><periodical><full-title>Head and neck pathology</full-title></periodical><pages>121-128</pages><volume>6</volume><number>1</number><dates><year>2012</year></dates><isbn>1936-055X</isbn><urls></urls></record></Cite></EndNote>(Psyrri et al., 2012):
**Prophylactic Vaccines:
Quadrivalent vaccine consisting of 4 different types of viral like particles from the 4 serotypes of HPV (types 6, 11, 16, and 18).

Bivalent HPV vaccine targeting HPV types 16 and 18.

But there was another problem, after testing efficacy on naiive patients, they found that its only effective on young patients at the time that the most susceptible population were elders.

**therapeutic Vaccines:
This type was formed to enhance the immune system as HPV is a virus that is removed by the action of immune system ADDIN EN.CITE <EndNote><Cite><Author>Psyrri</Author><Year>2012</Year><RecNum>47</RecNum><DisplayText>(Psyrri et al., 2012)</DisplayText><record><rec-number>47</rec-number><foreign-keys><key app=”EN” db-id=”zzzt99s5yfps5zes9daxevzydxse0va5avt9″ timestamp=”1525218919″>47</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Psyrri, Amanda</author><author>Sasaki, Clarence</author><author>Vassilakopoulou, Maria</author><author>Dimitriadis, George</author><author>Rampias, Theodoros</author></authors></contributors><titles><title>Future directions in research, treatment and prevention of HPV-related squamous cell carcinoma of the head and neck</title><secondary-title>Head and neck pathology</secondary-title></titles><periodical><full-title>Head and neck pathology</full-title></periodical><pages>121-128</pages><volume>6</volume><number>1</number><dates><year>2012</year></dates><isbn>1936-055X</isbn><urls></urls></record></Cite></EndNote>(Psyrri et al., 2012).

The main drawbacks of these vaccines were :Limited species coverage: as HPV has many species ab0ut 200, and these vaccines c0ver maximally 4 species ADDIN EN.CITE <EndNote><Cite><Author>Harper</Author><Year>2004</Year><RecNum>48</RecNum><DisplayText>(Harper et al., 2004)</DisplayText><record><rec-number>48</rec-number><foreign-keys><key app=”EN” db-id=”zzzt99s5yfps5zes9daxevzydxse0va5avt9″ timestamp=”1525219038″>48</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Harper, Diane M</author><author>Franco, Eduardo L</author><author>Wheeler, Cosette</author><author>Ferris, Daron G</author><author>Jenkins, David</author><author>Schuind, Anne</author><author>Zahaf, Toufik</author><author>Innis, Bruce</author><author>Naud, Paulo</author><author>De Carvalho, Newton S</author></authors></contributors><titles><title>Efficacy of a bivalent L1 virus-like particle vaccine in prevention of infection with human papillomavirus types 16 and 18 in young women: a randomised controlled trial</title><secondary-title>The lancet</secondary-title></titles><periodical><full-title>The lancet</full-title></periodical><pages>1757-1765</pages><volume>364</volume><number>9447</number><dates><year>2004</year></dates><isbn>0140-6736</isbn><urls></urls></record></Cite></EndNote>(Harper et al., 2004) , ADDIN EN.CITE <EndNote><Cite><Author>Einstein</Author><Year>2009</Year><RecNum>49</RecNum><DisplayText>(Einstein et al., 2009)</DisplayText><record><rec-number>49</rec-number><foreign-keys><key app=”EN” db-id=”zzzt99s5yfps5zes9daxevzydxse0va5avt9″ timestamp=”1525219092″>49</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Einstein, Mark H</author><author>Schiller, John T</author><author>Viscidi, Raphael P</author><author>Strickler, Howard D</author><author>Coursaget, Pierre</author><author>Tan, Tina</author><author>Halsey, Neal</author><author>Jenkins, David</author></authors></contributors><titles><title>Clinician&apos;s guide to human papillomavirus immunology: knowns and unknowns</title><secondary-title>The Lancet infectious diseases</secondary-title></titles><periodical><full-title>The Lancet infectious diseases</full-title></periodical><pages>347-356</pages><volume>9</volume><number>6</number><dates><year>2009</year></dates><isbn>1473-3099</isbn><urls></urls></record></Cite></EndNote>(Einstein et al., 2009).

Absence of therapeutic role: as its 0nly effective at naiive patients whose age range fr0m 16-25 ADDIN EN.CITE <EndNote><Cite><Author>Roden</Author><Year>2004</Year><RecNum>50</RecNum><DisplayText>(Roden et al., 2004)</DisplayText><record><rec-number>50</rec-number><foreign-keys><key app=”EN” db-id=”zzzt99s5yfps5zes9daxevzydxse0va5avt9″ timestamp=”1525219144″>50</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Roden, Richard BS</author><author>Ling, Morris</author><author>Wu, T-C</author></authors></contributors><titles><title>Vaccination to prevent and treat cervical cancer</title><secondary-title>Human pathology</secondary-title></titles><periodical><full-title>Human pathology</full-title></periodical><pages>971-982</pages><volume>35</volume><number>8</number><dates><year>2004</year></dates><isbn>0046-8177</isbn><urls></urls></record></Cite></EndNote>(Roden et al., 2004).

Cost and affordability: as it is very expensive and only could be affordable by few people who are already live in area which there is little infection ADDIN EN.CITE <EndNote><Cite><Author>Kumar</Author><Year>2015</Year><RecNum>51</RecNum><DisplayText>(Kumar et al., 2015)</DisplayText><record><rec-number>51</rec-number><foreign-keys><key app=”EN” db-id=”zzzt99s5yfps5zes9daxevzydxse0va5avt9″ timestamp=”1525219236″>51</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Kumar, Sushil</author><author>Biswas, Manash</author><author>Jose, Tony</author></authors></contributors><titles><title>HPV vaccine: Current status and future directions</title><secondary-title>medical journal armed forces india</secondary-title></titles><periodical><full-title>medical journal armed forces india</full-title></periodical><pages>171-177</pages><volume>71</volume><number>2</number><dates><year>2015</year></dates><isbn>0377-1237</isbn><urls></urls></record></Cite></EndNote>(Kumar et al., 2015).

NEW VACCINES ADDIN EN.CITE <EndNote><Cite><Author>Psyrri</Author><Year>2012</Year><RecNum>52</RecNum><DisplayText>(Psyrri et al., 2012)</DisplayText><record><rec-number>52</rec-number><foreign-keys><key app=”EN” db-id=”zzzt99s5yfps5zes9daxevzydxse0va5avt9″ timestamp=”1525219289″>52</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Psyrri, Amanda</author><author>Sasaki, Clarence</author><author>Vassilakopoulou, Maria</author><author>Dimitriadis, George</author><author>Rampias, Theodoros</author></authors></contributors><titles><title>Future directions in research, treatment and prevention of HPV-related squamous cell carcinoma of the head and neck</title><secondary-title>Head and neck pathology</secondary-title></titles><periodical><full-title>Head and neck pathology</full-title></periodical><pages>121-128</pages><volume>6</volume><number>1</number><dates><year>2012</year></dates><isbn>1936-055X</isbn><urls></urls></record></Cite></EndNote>(Psyrri et al., 2012):
The objectives in developing second-generation vaccines will be to
1-broaden coverage to include protection against other genital oncogenic HPV types
2-induce long-term protection
3- make the vaccines more affordable and easily stored
4- Allow vaccines to be administered easily via non-injectable methods.

5-potentially provide therapeutic efficacy beside its prophylactic efficacy.
EXAMPLE:
Immune response to Human papillomavirus (HPV):
Immunity might be important against HPV virus to eliminate it. First of all the innate immunity response including macrophages, natural killer T-cells and natural killer cells as the first line of defense against HPV virus. Second of all, the adaptive immunity responses as the second line of defense including cytotoxic T-lymphocytes (CTLs) targeting some proteins (HPV16 E 0010 and E 0030) that help to eliminate the infected cells with HPV16. However the immune response can be evaded by the HPV. During viral replication, HPV does not kill host cells and therefore there isn’t viral antigen or inflammation. And there are some proteins like HPV16 E 0030 and E 0035 downregulate the expression of type-1 interferons in host cells. HPV16 E 0025 protein downregulate the expression of HLA-class 1 and then it can evade the CLT attack. All of these mechanisms of immune evasion may finally make persistent HPV infection leading to cervical cancer (Sasagawa et al., 2012).

SITUATION IN EGYPT
Human Papillomavirus and Related Cancers
Figure 1: Egypt and Northern Africa

Egypt has a population of 30.55 millions women ages 15 years and older who are at risk of developing
cervical cancer.
Current estimates indicate that every year 866 women are diagnosed with cervical cancer and 373 die from the disease.

Cervical cancer ranks as the 13th most frequent cancer among women in Egypt and the 10th most frequent cancer among women between 15 and 44 years of age.
Data is not yet available on the HPV burden in the general population of Egypt. However, in Northern Africa, the region Egypt belongs to, about 2.7% of women in the general population are estimated to harbour cervical HPV-16/18 infection at a given time, and 78.9% of invasive cervical cancers are attributed to HPVs 16 or 18 ADDIN EN.CITE ;EndNote;;Cite;;Author;Serrano;/Author;;Year;2017;/Year;;RecNum;53;/RecNum;;DisplayText;(Serrano et al., 2017);/DisplayText;;record;;rec-number;53;/rec-number;;foreign-keys;;key app=”EN” db-id=”zzzt99s5yfps5zes9daxevzydxse0va5avt9″ timestamp=”1525219851″;53;/key;;/foreign-keys;;ref-type name=”Journal Article”;17;/ref-type;;contributors;;authors;;author;Serrano, Beatriz;/author;;author;Brotons, María;/author;;author;Bosch, Francesc Xavier;/author;;author;Bruni, Laia;/author;;/authors;;/contributors;;titles;;title;Epidemiology and burden of HPV-related disease;/title;;secondary-title;Best Practice ;amp; Research Clinical Obstetrics ;amp; Gynaecology;/secondary-title;;/titles;;periodical;;full-title;Best Practice ;amp; Research Clinical Obstetrics ;amp; Gynaecology;/full-title;;/periodical;;dates;;year;2017;/year;;/dates;;isbn;1521-6934;/isbn;;urls;;/urls;;/record;;/Cite;;/EndNote;(Serrano et al., 2017).Demographic and socioeconomic factors ADDIN EN.CITE ;EndNote;;Cite;;Author;Bruni;/Author;;Year;2014;/Year;;RecNum;54;/RecNum;;DisplayText;(Bruni et al., 2014);/DisplayText;;record;;rec-number;54;/rec-number;;foreign-keys;;key app=”EN” db-id=”zzzt99s5yfps5zes9daxevzydxse0va5avt9″ timestamp=”1525220224″;54;/key;;/foreign-keys;;ref-type name=”Journal Article”;17;/ref-type;;contributors;;authors;;author;Bruni, L;/author;;author;Barrionuevo-Rosas, L;/author;;author;Albero, G;/author;;author;Aldea, M;/author;;author;Serrano, B;/author;;author;Valencia, B;/author;;/authors;;/contributors;;titles;;title;Human papillomavirus and related diseases report;/title;;secondary-title;L;apos;Hospitalet de Llobregat: ICO Information Centre on HPV and Cancer;/secondary-title;;/titles;;periodical;;full-title;L;apos;Hospitalet de Llobregat: ICO Information Centre on HPV and Cancer;/full-title;;/periodical;;dates;;year;2014;/year;;/dates;;urls;;/urls;;/record;;/Cite;;/EndNote;(Bruni et al., 2014)

Burden of HPV related cancers
HPV is the cause of almost all cervical cancer cases and is responsible for an important fraction of other
anogenital and head and neck cancer. Here, we present the most recent estimations on the burden of
HPV-associated cancer

Prevention ways
Hpv vaccines
In vitro, HPV virus-like particles (VLP) can be produced via the synthesis and self-assembly of the major virus capsid protein L1. Because these HPV L1 VLPs exhibit morphological and antigenic properties that are virtually identical to native virons, this has been utilized in the development of HPV L1 VLP subunit vaccines 11. The mechanisms by which VLPs elicit protection are not completely understood. At present, all women receiving the HPV vaccine have seroconverted. As a result, there are no immune correlates which denote protection 11. However, VLPs are highly immunogenic and anti-VLP antibody responses in VLP-immunized women are markedly greater than that identified in natural infections. Both bivalent and quadrivalent vaccines have been shown to be safe, immunogenic and effective against type-specific HPV infection ADDIN EN.CITE ;EndNote;;Cite;;Author;Psyrri;/Author;;Year;2012;/Year;;RecNum;55;/RecNum;;DisplayText;(Psyrri et al., 2012);/DisplayText;;record;;rec-number;55;/rec-number;;foreign-keys;;key app=”EN” db-id=”zzzt99s5yfps5zes9daxevzydxse0va5avt9″ timestamp=”1525220467″;55;/key;;/foreign-keys;;ref-type name=”Journal Article”;17;/ref-type;;contributors;;authors;;author;Psyrri, Amanda;/author;;author;Sasaki, Clarence;/author;;author;Vassilakopoulou, Maria;/author;;author;Dimitriadis, George;/author;;author;Rampias, Theodoros;/author;;/authors;;/contributors;;titles;;title;Future directions in research, treatment and prevention of HPV-related squamous cell carcinoma of the head and neck;/title;;secondary-title;Head and neck pathology;/secondary-title;;/titles;;periodical;;full-title;Head and neck pathology;/full-title;;/periodical;;pages;121-128;/pages;;volume;6;/volume;;number;1;/number;;dates;;year;2012;/year;;/dates;;isbn;1936-055X;/isbn;;urls;;/urls;;/record;;/Cite;;/EndNote;(Psyrri et al., 2012).

Bivalent vaccine
Cervarix™, developed by GlaxoSmithKline Biologicals, Rixensart, Belgium, is a bivalent HPV-16/18 L1 VLP vaccine. The L1 protein of each HPV type is expressed by a recombinant baculovirus vector, and the VLPs are generated separately and then combined 11. Cervarix™ consists of purified L1 VLPs of HPV types 16/18 at 20/20 ?g/dose, respectively, formulated on an ASO4 adjuvant consisting of aluminum hydroxide 500 ?g and 3-deacylated monophosphoryl lipid A 50 ?g. It is administered as a 0.5 mL intramuscular injection in a threedose immunization protocol at 0, 1 and 6 months. Cervical cancer Clinical trial data indicate that vaccine protection is maintained over a period of 4.5 years with the Cervarix™ bivalent vaccine 6. A multicenter, randomized follow-up trial (n= 776) demonstrated that N98% seropositivity was maintained for HPV-16/18 antibodies at 4.5 years. The bivalent vaccine was 96.9% effective against incident HPV-16/18 infection and 100% effective against 12-month persistent infection (Table 1). A combined analysis of the initial and follow-up studies showed 100% vaccine efficacy against cervical intraepithelial neoplasia (CIN) lesions associated with HPV16/18 ADDIN EN.CITE ;EndNote;;Cite;;Author;Psyrri;/Author;;Year;2012;/Year;;RecNum;55;/RecNum;;DisplayText;(Psyrri et al., 2012);/DisplayText;;record;;rec-number;55;/rec-number;;foreign-keys;;key app=”EN” db-id=”zzzt99s5yfps5zes9daxevzydxse0va5avt9″ timestamp=”1525220467″;55;/key;;/foreign-keys;;ref-type name=”Journal Article”;17;/ref-type;;contributors;;authors;;author;Psyrri, Amanda;/author;;author;Sasaki, Clarence;/author;;author;Vassilakopoulou, Maria;/author;;author;Dimitriadis, George;/author;;author;Rampias, Theodoros;/author;;/authors;;/contributors;;titles;;title;Future directions in research, treatment and prevention of HPV-related squamous cell carcinoma of the head and neck;/title;;secondary-title;Head and neck pathology;/secondary-title;;/titles;;periodical;;full-title;Head and neck pathology;/full-title;;/periodical;;pages;121-128;/pages;;volume;6;/volume;;number;1;/number;;dates;;year;2012;/year;;/dates;;isbn;1936-055X;/isbn;;urls;;/urls;;/record;;/Cite;;/EndNote;(Psyrri et al., 2012).

Quadrivalent vaccine
Gardasil®, a quadrivalent HPV-16/18/6/11 L1 VLP vaccine, has been developed by Merck ; Co. Inc. 10 For each HPV VLP, the L1 protein is expressed via a recombinant Saccharomyces pombe vector and the vaccine is comprised of purified L1 VLPs of HPV types 6/11/16/18 at 20/40/40/20 ?g/dose, respectively, formulated on a proprietary alum adjuvant 11. Gardasil® is available as a 0.5 mL intramuscular injection Fig. 1. Papillomavirus capsid (A); papillomavirus particles (B); human papillomavirus-16 L1 virus-like particles (C). (Reprinted with permission of Elsevier.) 11. Table 1 Bivalent HPV vaccine efficacy in a cohort of 776 women followed for 4.5 years (per-protocol population) Endpoint Vaccine (n= 350) Placebo (n= 344) Vaccine efficacy (%; P-value) Incident HPV infections: women reporting ?1 HPV-16/18 event 1 28 96.9 (b0.0001) Persistent HPV infections: 6 months 1 16 94.3 (b0.0001) Persistent HPV infections: 12 months 0 7 100 (0.0062) Reprinted with permission from Elsevier 6. HPV= human papillomavirus. Table 2 Efficacy of the bivalent vaccine in a cohort of women followed for 4.5 years (per-protocol population) Endpoint a Vaccine (n= 350) Placebo (n= 344) Vaccine efficacy (%; P-value) ASCUS 2 44 b0.0001 LSIL 2 26 b0.0001 CIN1+ 0 8 0.0035 CIN2+ 0 5 0.0292 Reprinted with permission from Elsevier 6. ASCUS= atypical squamous cells of undetermined significance; CIN = cervical intraepithelial neoplasia; LSIL =low-grade squamous intraepithelial lesions. a Includes data from the initial efficacy study (27 months) plus the blinded ongoing extended follow-up study (44 to 53 months). S20 M. Stanley / Gynecologic Oncology 107 (2007) S19–S23 administered in a three-dose immunization protocol at 0, 2 and 6 months. Cervical cancer Data from a phase II randomized, multicenter study (n= 552) that followed women aged 16 to 23 years for up to 5 years demonstrated that vaccination of adolescents and young adults with Gardasil® at 0, 2 and 6 months resulted in 100% vaccination coverage and effectively prevented persistent infection and disease caused by HPV types 6/11/16/18 7. Relative to placebo, at 5 years, there was a 96% reduction in the combined incidence of HPV-related 6/11/16/ 18 persistent infection or disease. At this time point there were no cases of precancerous cervical dysplasia or genital warts in the vaccinated women (versus six cases in the placebo arm) and the vaccine-induced anti-HPV geometric mean titers remained at or above those observed with natural infection 7. These findings were confirmed in the randomized, doubleblind Females United To Unilaterally Reduce Endo/Ectocervical Disease (FUTURE II) study (n= 12,167) which demonstrated a significant reduction in the incidence of high-grade CIN related to either HPV-16 or -18 in women vaccinated with the quadrivalent HPV vaccine at 0, 2 and 6 months compared with those receiving placebo 8. Over an average follow-up of 3 years, vaccine efficacy in the per-protocol susceptible population (n= 10,565) which included women aged 15 to 26 years with no previous HPV-16 or -18 infection was 98%. CIN grade 2 or 3 or adenocarcinoma in situ developed in 1 woman receiving the HPV vaccine and 42 placebo recipients (Table 3). An immunogenicity substudy confirmed that 99% of vaccinated women demonstrated seroconversion to the relevant HPV type 8. Pooled data from four studies in 20,583 women aged 16 to 26 years, who were followed for a mean of 3 years, indicate that the quadrivalent vaccine has the potential to substantially reduce the incidence of HPV-16 and -18-related cervical precancers and cancers 12. In the per-protocol analysis women who were negative for HPV-16 or -18 (n= 17,129) demonstrated 99% vaccine efficacy for the primary endpoint of the combined incidence of HPV-16 and -18-related CIN 2/3, adenocarcinoma in situ, or cervical cancer. In the intention-to-treat analysis, which included women who were infected with HPV-16 and/or -18 at day 1, vaccine efficacy for the primary endpoint was 44%. Genital warts The phase III FUTURE I trial employing the 0, 2 and 6- month quadrivalent HPV vaccination schedule showed that over a 3-year follow-up period vaccination significantly reduced the incidence of HPV-associated anogenital diseases compared with placebo in 5455 women aged 16 to 24 years 9. Vaccine efficacy was 100% in the per-protocol group; in the vaccinated women there were no reported cases of vaginal, vulvar, perianal and perianal intraepithelial lesions or warts related to the HPV vaccine types compared with 60 cases in women receiving placebo. For the primary composite endpoint of anogenital warts, vulvar or vaginal intraepithelial neoplasia grades 1 to 3, or cancer regardless of causal relation to vaccine-type HPV, vaccination was associated with a 34% reduction relative to placebo. For each of the vaccine subtypes (6/11/16/18), ?99.5% of women in the per-protocol immunogenicity cohort had seroconversion 1 month after the third dose ADDIN EN.CITE ;EndNote;;Cite;;Author;Psyrri;/Author;;Year;2012;/Year;;RecNum;55;/RecNum;;DisplayText;(Psyrri et al., 2012);/DisplayText;;record;;rec-number;55;/rec-number;;foreign-keys;;key app=”EN” db-id=”zzzt99s5yfps5zes9daxevzydxse0va5avt9″ timestamp=”1525220467″;55;/key;;/foreign-keys;;ref-type name=”Journal Article”;17;/ref-type;;contributors;;authors;;author;Psyrri, Amanda;/author;;author;Sasaki, Clarence;/author;;author;Vassilakopoulou, Maria;/author;;author;Dimitriadis, George;/author;;author;Rampias, Theodoros;/author;;/authors;;/contributors;;titles;;title;Future directions in research, treatment and prevention of HPV-related squamous cell carcinoma of the head and neck;/title;;secondary-title;Head and neck pathology;/secondary-title;;/titles;;periodical;;full-title;Head and neck pathology;/full-title;;/periodical;;pages;121-128;/pages;;volume;6;/volume;;number;1;/number;;dates;;year;2012;/year;;/dates;;isbn;1936-055X;/isbn;;urls;;/urls;;/record;;/Cite;;/EndNote;(Psyrri et al., 2012).

Prevention
HPV Infection HPV transmission can be reduced but not eliminated with the use of physical barriers such as condoms. Recent studies demonstrated a significant reduction in HPV infection among young women after initiation of sexual activity when their partners used condoms consistently and correctly..Abstaining from sexual activity (i.e., refraining from any genital contact with another individual) is the surest way to prevent genital HPV infection. For those who choose to be sexually active, a monogamous relationship with an uninfected partner is the strategy most likely to prevent future genital HPV infections ADDIN EN.CITE ;EndNote;;Cite;;Author;Psyrri;/Author;;Year;2012;/Year;;RecNum;55;/RecNum;;DisplayText;(Psyrri et al., 2012);/DisplayText;;record;;rec-number;55;/rec-number;;foreign-keys;;key app=”EN” db-id=”zzzt99s5yfps5zes9daxevzydxse0va5avt9″ timestamp=”1525220467″;55;/key;;/foreign-keys;;ref-type name=”Journal Article”;17;/ref-type;;contributors;;authors;;author;Psyrri, Amanda;/author;;author;Sasaki, Clarence;/author;;author;Vassilakopoulou, Maria;/author;;author;Dimitriadis, George;/author;;author;Rampias, Theodoros;/author;;/authors;;/contributors;;titles;;title;Future directions in research, treatment and prevention of HPV-related squamous cell carcinoma of the head and neck;/title;;secondary-title;Head and neck pathology;/secondary-title;;/titles;;periodical;;full-title;Head and neck pathology;/full-title;;/periodical;;pages;121-128;/pages;;volume;6;/volume;;number;1;/number;;dates;;year;2012;/year;;/dates;;isbn;1936-055X;/isbn;;urls;;/urls;;/record;;/Cite;;/EndNote;(Psyrri et al., 2012).

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