Dhivya Project

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INTRODUCTION Human Papilloma Virus (HPV) is the etiological agent of cervical cancer, the second-most common malignant tumour in the world. In India, cervical cancer is a leading cancer among women, with an annual incidence of approximately !",### and mortality rates of approximately $%,###. HPV infection is the most common genital infection of female&s particularly afflicting adolescents and women in their early "#s. 'ost young women are infected within the first few years of (ecoming sexually active, and the lifetime ris) of HPV infection is $#*$+,. -dolescent females har(oring infections with high ris) HPV seem to (e most vulnera(le to develop histological lesions of the cervix that may (ecome precancerous and potentially invasive cancer. .he ma/or reason for high mortality from cervical cancer is late stage of diagnosis owing to the lac) of a cervical cancer screening program. 'oreover, most genital HPV infections are asymptomatic and unapparent. 0ince -dolescents are more vulnera(le to HPV infection, early detection in this age group at appropriate time is essential (1ari 2raaten et al., "##34 'arc 0te(en et al., "##$4 5avid Hager, "##+). Human Papilloma Virus (HPV) contains a circular, dou(le-stranded 56genome, and more than %# HPV types can infect the genital area and result in genital lesions. -s the most common sexually transmitted virus, HPV is commonly transmitted through direct s)in-to-s)in contact, most often during penetrative genital contact, followed (y contact with infected cutaneous or mucosal surfaces, including the anogenital epitheliu (7iang 8ang et al., "# !). .he prevalence of HPV infection among promiscuous and sexually active adults has (een studied in many countries, and different geographic distri(utions of various HPV types have (een found. 9or example, HPV- : and HPV- 3 are the prevalent types among sexually active adults in the ;nited 0tates, 2ra<il, and 0pain (5el -mo et al., "##+, 1outs)y ++$). 8hereas HPV-=", followed (y HPV- : and HPV-=3, are the most common types in the Philippines ('iyashita et al., "##+). 9emale 0ex 8or)ers (908s) are at a particularly high ris) of HPV infection. (7iang 8ang et al., "# !) Hpv is the main ris) factor for cervical cancer and the third most common cause of cancer-related death among women. It can (e categori<ed into low-ris)
Prevalence of Human Papilloma Virus (HPV) infection among college going girls using self collected urine sample from >rode district, .amil 6adu.
and high-ris) types (Par)in et al., "##=) the latter of which there are !, including HPV:, HPV- 3, HPV-! , HPV-!!, HPV-!=, HPV-!+, HPV-%=, HPV-= , HPV-=", HPV-=:, HPV-=3, HPV-=+ and HPV-:3. -lthough most HPV infections are transient and disappear without treatment within " years (2ierman et al., ++3). ?ervical infections caused (y Human Papilloma Virus (HPV) cause preinvasive and invasive cervical neoplasia. 8omen infected with HIV are at higher ris) for genital HPV infection (9erenc<y et al., "##!). 8ith advances in our understanding of HPV (iology and with the development of technologies for HPV detection, there is a growing interest in the potential use of HPV 56- testing as a screening tool for cervical cancer (@atnam et al., "###4 0ellors et al., "###4 ?lavel et al., "## 4 1ulasingam et al., "##"). .he detection of HPV 56- in the urine of HIV-positive women could identify women at ris) for HPV disease in a routine manner that is less invasive to the patient (Aoeli 2rin)man et al., "##"). HPV types : and 3 account for approximately $#, of cervical cancer cases worldwide with other high-ris) types such as HPV-%=, HPV-! , HPV-!! and HPV-=" accounting for the ma/ority of the remaining cervical malignancies (Veldhui/<en et al., "# #) HPV Blow-ris)C types (D@-HPV), mainly HPV-: and HPVwarts ('iddleton et al., "##!). -n understanding of HPV, ris) factors, modes of transmission, and the virus& role in cervical cancer is generally low or nonexistent in many populations. - national survey in "### found that less than one third of -mericans had heard of HPV and only ", of -mericans were a(le to identify HPV as a sexually transmitted disease (9riedman and 0hepeard, "##$). In Aune of "##:, .he 9ood and 5rug -dministration (95-) approved the use of 'erc)&s vaccine Eardasil, which protects against HPV types :, :, and 3. .ypes : and ?o, "##3). -lthough HPV infection is considered a sexually transmitted infection, HPVs can also (e transmitted (y non-sexual routes including casual physical contact and perinatal
are rarely detected in high grade cervical lesions (ut cause the ma/ority of anogenital
are low ris) strains that cause +#, of genital warts cases and
types : and 3 are high-ris) strains that cause $#, of cervical cancer cases ('erc) F
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vertical transmission (0inal and 8oods, "##=4 0yr/anen and Puranen, "##"). HPV is epitheliotropic, resulting in infection and replication in (asal epithelial cells. .he virus is 0pecies- and tissue type-specific, infecting the s)in or mucous mem(ranes. (2artholomew, "##%4 1ahn and Hillard, "##%). .here have (een more than ## different types of HPV identified, with !#-%# that are )nown to infect the genital tract. However, most HPV infections spontaneously regress and only in a small percentage of cases the infection persists, Dow-grade Intraepithelial Desions (D0ID) progress to High-grade Intraepithelial Desions (H0ID) and, ultimately, develop into invasive cervical carcinoma (8oodman et al., "##$). 0everal studies have reported that self-o(tained samples from the anogenital tract were accurate and suita(le for HPV-56testing and have shown a similar correlation to clinically o(tained samples (Petignat et al., "##$4 Ho((s et al., "##3). 'ost HPV infections are asymptomatic and are efficiently controlled (y the immune system, therefore, the outcome of HPV infection is varia(le, the infection is usually transient, and complete resolution is generally common within "*"% months (Ho gye et al., ++34 'oscic)i et al., "## )..he prevalence of HPV infection, overall and (y age, varies (y country, region within country, and population su(group. .o compare HPV prevalence (etween geographic areas or countries, data on age-specific or age-ad/usted prevalence using sensitive HPV detection methods are needed. -ge-specific data on HPV prevalence among female adolescents would also (e useful (in con/unction with data on age at first intercourse) to inform future policies to maximi<e the potential (enefits of HPV prophylactic vaccination. (Aennifer et al., "##3). 0tudies of adolescence represents uniGue opportunity to examine HPV infected in HIV-infected individuals with a more limited history of sexual activity and relatively recent HIV and HPV infections (-nna-2ar(ara 'oscic)i et al., "###).?ervical cancer is one of the leading causes of mortality (y cancer with approximately %+= ### women newly diagnosed each year (9erlay et al., "##%). In Portugal, cervical cancer is the %th most freGuent cancer with +=# new diagnosis and !$3 deaths per year, and the second most freGuent among women (etween the age of = and %% (Pinheiro et al., "##%).
-dolescents and young-adult women are more vulnera(le to HPV infection. .hese o(servations are (ased on (iologicalH physiological differences in the cervical epithelium. 8hile in adults the predominant cell type is sGuamous, in adolescents the predominant cell type is columnar and metaplastic ('oscic)i et al., +++)..he use of nucleic acid (6-) pro(es in the detection of human pathogens has (ecome increasingly important (6orval et al., +3$; .enover et al., +33). .he purification of 6- from specimens li)e serum, urine, or (acterial cultures, however, has (een la(orious and time-consuming. 'oreover, the many steps involved in the purification of 6- from such specimens (y classical procedures (involving detergentmediated lysis, proteinase treatment, extractions with organic solvents, and ethanol precipitation) increase the ris) of transmission of 6- from sample to sample. 8hen the extremely sensitive polymerase chain reaction (P?@) (0ai)i et al., ++3; 0ai)i et al., +3=) or the transcription-(ased amplification system is used for the detection of a few 6- molecules of a pathogen, the transmission of 6- might easily lead to false-positive results. -ssociation (etween HPV infection and urinary tract tumors is still under investigation. Here we show a case of urethral condyloma acuminatum and concomitant multiple (ladder papillomas, and existence of HPVs in each of the tumors was assessed (y the P?@. (6atsu)o 6a)a<a)i et al., "# "). In the genital tract, HPV is primarily transmitted (y s)in-to-s)in contact, and certain genotypes are trophic in (oth men and women. .his can result in su(clinical infection of the s)in over the entire genital region, which can (e detected (y HPV 56- testing. - small proportion of those infected will manifest either (enign or malignant disease. .his chapter will review the epidemiologic aspects of HPV infection and the natural history of HPV disease, primarily in the female genital tract. (5e(orah et al., "##$). .o test the Guality of 56- o(tained from exfoliated cells, a polymerase chain reaction on the human genomic I-glo(in gene was performed. HPV 56- detection and genotyping was performed, amplified using the 0P9 # primer and HPV amplimers tested on agaroses gels (1leter et al., +++). Human papillomavirus (HPV) 56- screening seems to (e an attractive alternative to cytology screening. .his was first supported (y
split sample studies in which more high-grade ?ervical Intraepithelial 6eoplasia (?I6) was detected with HPV 56- screening than with cytology screening (?u<ic) et al., "##3). Human papilloma virus is a small non enveloped lcosahedral 56- virus that replicates in the nucleus of sGuamous epithelial cells (Par)in et al., "##:). .hey are called papilloma virus (ecause certain strains may cause warts or papilloma which are (enign (non-cancerous) tumors (1umar et al., "##$).?ancer of the cervix is the second most common cancer among women worldwide (J(ure et al., "##+). In India it is the ma/or cause of cancer in women and a leading cause of deaths due to cancer. >very year, more than !#,### new cases and a(out $#,### deaths were recorded. .he persistent infection (y specific High @is) Human Papilloma Viruses (H@-HPVs) is essential for the progression of cervical lesion and women who are infected with H@-HPVs are li)ely to develop cancer. ?ancerous HPV types are associated with cervical cancer, and noncancerous HPV types are associated with warts of the genital areas and low grade disease of the cervix ('arais et al., "##3). Human Papilloma Virus (HPV) prevalence, age-specific prevalence, and type of distri(ution differ su(stantially (etween populations (?lifford et al., "##=4 9ranceschi et al., "##:) and HPV 3 has a greater role in cervical cancer in Indonesia than in the rest of the world. HPV 3 was found as freGuently as HPV : in cervical cancer (0chelle)ens et al., "##%) or even more freGuently than HPV : (2osch et al., ++=). In Jcto(er +++, we initiated a cluster-randomi<ed, controlled trial to evaluate the effectiveness of a single round of HPV testing, cytologic testing, or VI- in reducing the incidence of cervical cancer, as compared with a control group that received usual care in a previously unscreened, high ris) population in the Jsmana(ad district in the state of 'aharashtra, India. - highly efficacious prophylactic vaccine against HPV types :, , :, and 3 to "
was licensed in Aune "##: and recommended for routine use in females aged
years in the ;nited 0tates.(1outs)y et al., "##"4 Villa et al., "##=,etc.,).?ancer of the cervix is the second most common cancer among women worldwide (J(ure et al., "##+). In India it is the ma/or cause of cancer in women and a leading cause of deaths due to
cancer. >very year, more than !#,### new cases and a(out $#,### deaths were recorded. .he persistent infection (y specific High @is) Human Papilloma Viruses (H@-HPVs) is essential for the progression of cervical lesion and women who are infected with H@HPVs are li)ely to develop cancer. ?ancerous HPV types are associated with cervical cancer, and non-cancerous HPV types are associated with warts of the genital areas and low grade disease of the cervix ('arais et al., "##3).
Elo(ally it is estimated that of =##,### women develop cervical cancer and almost "$%,### of them die from the disease per year (8HJ, P-.H, and the ;nited 6ations Population 9und, "##+). It is the second most common cancer in women worldwide and the most common in women in under-developed and developing countries, which (ear more than 3#, (8HJ, "# #) of the glo(al (urden of the disease. .his reveals the lac) of effective control measures in these countries.
.he sensitivity for high-grade lesions in these studies, which have used urine, vaginal swa( or tampon specimens, has ranged from ::, to +%,. -lthough these findings appear promising, the studies have had limitations (ecause of test insensitivity, small sample si<es and methodological flaws, such as verification (ias. .he primary o(/ective of the study reported here was to determine the sensitivity and specificity of self-sampling for HPV in detecting H0ID (?I6 " or !) (Aohn et al., "###). 'ost of these HPV infections are found to (e transient and only women who har(or persistent high ris) HPV infection are at ris) of developing cervical lesions. High ris) HPV infections (hrHPV) seem to persist longer than infections with low ris) HPVs (9ranco et al., +++4 8oodman et al., "## 4 Euiliano et al., "##"4 @ichardson et al., "##!4 'uno< et al., "##%4 2rown et al., "##=). .he HPV- :H 3 fraction was found to account for $3.+ per cent of I??, : .= per cent with High-grade 0Guamous Intraepithelial Desions (H0ID), !#.3 per cent with Dow-grade 0Guamous Intraepithelial Desions (D0ID) and !.+ per cent in women with normal cytologyHhistology. .he most prevalent HPV types associated with cervical cancer were HPV- :, - 3, -%=, -!!, -!=, =3, -=+ and -! . (?lifford et al., "##!). It is estimated that over =##,### new cases and more than "=#,### deaths occur every year due to this preventa(le disease. In .ur)ey, ?? is the ninth most common cancer in women with a mortality ris) of more than =# , and is the cause of =.! , of all
malignancies affecting women (J<gul, "##$). ?ancer of cervix is preventa(le, yet approximately %+!, ## new cases and more than "$!,### deaths occur each year among women worldwide (9erlay et al., "##") India, which accounts for the one-sixth of the world&s population also (ears the one-fifth of the world&s (urden of cervical cancer (0an)aranaryanan et al., "## ). ?ervical cancer is a leading form of cancer among women living in low resource regions of the world and often )ills women at young age when they are still raising families (8al(oomers et al., +++). .he Human Papilloma Virus (HPV) is a non-enveloped, dou(le-stranded 56virus infecting deeper layers of s)in and the inner mucosal lining of organs. Jf the over ## )nown HPV types, %# preferentially infect the stratified sGuamous epithelium of the mucosa and genital s)in of the cervix, vagina, vulva, penis, and perianal areas. HPV infection is very common and, in most cases, transient or self-limiting. However, #*"#, of HPV-infected women develops a persistent infection and continues to shed HPV 56from the genital tract for "% or more months ('oscic)i et al., "##:). However, 56- detection in urine also implies a num(er of challenges. 9irst, it is a diluted sample and contains (oth )nown, such as urea and nitrites, and un)nown Polymerase chain reaction (P?@) inhi(itors (1han et al., ++ ). 9urther, the 56- can (e deteriorated (y contaminating (acteria andHor endonucleases ('ilde et al., +++4 ?arder et al., +++) If HPV 56- detection in urine is to (e used in a cervical cancer screening program, additional disadvantages are that the sample is not collected at the original disease site and only contains spontaneously exfoliated cells. 9urthermore, the presence of HPV 56- may also (e indicative of an HPV infection of the urinary tract or the lower genital tract. .wo HPV vaccines, a Guadrivalent vaccine protecting against HPV types :H H :H 3 and a (ivalent one directed against HPV types :H 3, have (ecome availa(le for the primary prevention of HPV :H 3-related cervical cancer. 0elf-sampling has several advantages compared with physician-collected samples for detection of HPV genital infection. 0elf-sampling is a less costly and non-invasive collection procedure. 0elf-collected samples can (e more easily o(tained in settings with limited resources or in populations difficult to reach. 6umerous studies have reported lately that self-o(tained
samples of the anogenital tract in women were accurate and suita(le for 56- testing (Petignat et al., "##=4 Harper et al., "##"4 Harper et al., "##"4 8right et al., "###4 ?outlee et al., ++$). .he International -ssociation for @esearch in ?ancer (I-@?), the most prevalent reported high-ris) HPV types, which infect the uterine cervix, areK HPV- : (=!,), HPV3 ( =,), HPV-%= (+,), HPV-! (:,), and HPV-!! (!,) ('uno<, "###). Dower prevalence of other phylogenetically related types is also found ('eyer et al., ++3). 0ince HPV cannot (e cultured and the clinical performance of serological assays is poor, diagnosis of HPV infection is almost entirely (ased on molecular tools, including liGuid hy(ridi<ation (e.g. Hy(rid ?apture"4 5igene 5iagnostics, 0ilver 0prings, ;0-) (?ox et al., ++=). .he HPV virion has a dou(le-stranded, circular 56- genome of approximately $+## (p, with eight overlapping open reading frames, comprising early (>), and late (D) genes and an untranslated long control region. .he D and D" genes encode the ma/or and minor capsid proteins. .he capsid contains $" pentamers of D , and approximately " molecules of D". .he early genes regulate viral replication and some have transformation potential (0teen(ergen et al., "##=). HPV :, which is one of the more common types among cytologically normal women, is also the most common type among cervical cancer cases (9ranco et al., +++4 Ho et al., ++34 Diaw et al., +++4 'uno< et al., "##!4 @ichardson et al., "##!4 0chiffman ++"4 8oodman et al., "## ). BHigh-ris)C HPV infection is asymptomatic, invisi(le, and may not (e expressed in cervical tissue dysplasia for years (-merican 0ocial Health -ssociation, "##"). It will not (e detected, except when cervical tissue is examined (y microscope in routine pelvic examination. >mploying Papanicolaou (Pap) testing4 when viral 56- is identified in cervical cells (6ational ?ancer Institute, "##%)4 or when invasive cancer produces symptoms. 'ore than ## HPV types are )nown to occur that are categori<ed into three (road categories depending upon their oncogenic potentialK high ris) types including HPV- :, - 3, -! , -!!, -!=, -!+, -%=, -= , -=", -=:, -=3, -=+, -:3, -$! and -3"4 intermediate
types including HPV-":, -=!, -:: and low-ris) types including HPV-:, -
, -%#, -%", -%!,
-%%, -=%, -: , -$#, -$", -3 and -?P: #3 ('uno< et al., "##!). Eenital Human Papilloma Virus (HPV) is the most common 0.I in the ;nited 0tates and, perhaps, the most common 0.I among sexually active youth. 5uring "##!-"##%, nearly a Guarter of females aged = to + years and %= percent of those aged "# to "% had a HPV infection (?enters for 5isease ?ontrol and Prevention. "##"-"##$). -lthough Human Papilloma Virus (HPV) is )nown to (e strongly associated with the development of cervical cancer, most HPV infections in young women are transient. 0eventy to ninety percent of adolescents and young women appear to eliminate HPV within "*%# months, as demonstrated (y repeated testing for HPV infection (Ho et al., ++34 'oscic)i et al., ++3)..he women with persistent infection appear to have a higher ris) of developing significant precancer even as adolescents ('oscic)i et al., ++34 1outs)y et al., ++"4 0chlecht et al., "## 4 1onno et al., ++"). -lthough factors that influence persistence of HPV are not yet well understood, several studies suggest that alterations in cell-mediated immune responses play a large role in persistence of HPV. Human Papilloma Virus (HPV) is a member of the Papoviridae family of viruses. There are over 100 distinct types of HPV that all infect different epithelial surfaces, from the hands and feet to the genital region. ome HPV types are the causative agent of !arts and condyloma acuminata (genital !arts), !hile others have been sho!n to be the causative agent of cervical cancer (;niversity of 2ristol, "##%). HPV 56- test is now accepted as a useful ad/unctive method that increases the sensitivity of the conventional cervical cytology. Perhaps the use of urine sample for the detection of HPV could provide a preliminary screening for a cervical cancer and thus circumvent the need for an annual Pap smear for women who are negative for HPV 56-. -lternatively, detection of HPV 56- in urine can function as a secondary screening techniGue for cervical cancer in triage for women with atypical sGuamous cells of undetermined significance. (Prusty et al., "##=4 Aaco(son et al., "###4 Vossler et al., ++=).
0ince ++= we have (een studying HPV infection in a cohort of approximately :=# HIV-infected women, with the aim of identifying early mar)ers of cervical disease. (;(erti-9oppa et al., ++3). 'ethods for the detection of 56- in patient urine have recently (een used to diagnose other common 0.5s that affect the cervix, such as Chlamydia trachomatis and Neisseria gonorrhoeae infections (?rotchfelt et al., ++$) the success of these screening programs provides a good preliminary endorsement of attempts to monitor cervical pathology (y detecting HPV 56- in urine specimens. Jne advantage to the detection of these organisms and the detection of HPV from urine specimens may (e that a single specimen could perhaps (e used to detect all three of these infectious agents simultaneously. 0everal investigators have attempted to use urine sampling for HPV 56- detection (9orslund et al., +++4 Aaco(son et al., "###4 0ellors et al., "###4 0trauss et al., +++4 Vossler et al., ++=) however4 no study to date has addressed the a(ility to detect HPV 56- in the urine of human immunodeficiency virus (HIV)-positive women. HPV is a relatively small, non-enveloped, dou(le-stranded circular 56- virus of Papillomaviridae family with a genome of 3###(p. .he genome consists of three ma/or regions Dong ?ontrol region, early regions (> , >", >%, >=, >: and >$) and late region (D and D"). .hese viruses are epitheliotropic in nature, infect the (asal cells of the stratified sGuamous epithelium and the metaplastic cells of the transformation <one of the cervical sGuamocolumnar /unction and preferentially locali<e to the ano*genital tract. HPV is enormously diverse, with over # HPV types have (een identified on the (asis of variations in genotype homology. -mong these approximately !#*%# HPV types infect the epithelial lining of the ano-genital tract (genital HPVs), of which =*"# types are oncogenic (5avid Hager, "##+4 -manda .ristram et al., "##$). 2ased on their potential to lead to cervical cancer, HPV has (een (roadly classified in to high ris) and low-ris) types. HPV infection, including infection with the high-ris) types associated with cervical cancer and there are = high ris)-HPV types ( :, 3, ! , !!, !=, !+, %=, = , =", =:, =3, =+, ::, :3, $! and 3"). Jn the other hand, different HPV types that have (een mainly associated with genital warts and (enign cervical lesions such as condylomata accuminata and dysplasias are termed as Llow-ris)& HPV types. .hese include HPV types :, , %#, %", %!, %%, =%, : , $#, 3 and ?P: #3.
#
Jf the = high-ris) oncogenic types, HPV : and 3 account for a(out $=, of all cervical cancers, adenocarcinoma in-situ of the cervix, cervical intraepithelial neoplasiaIII (severe dysplasia), as well as vulvar and vaginal intraepithelial neoplasia- II and III (moderate and severe dysplasia). -mong low-ris) types, HPV: and HPV approximately +#, of genital warts (5avid Hager, "##+4 >li<a(eth et al., "##=). -cGuisition of HPV is especially common among young sexually active adolescents with !-year cumulative incidence estimated at more than %#,. .he ?enters for 5isease ?ontrol and Prevention (?5?) estimates that one in every two people will acGuire a genital HPV infection in their lifetimes4 =#, of sexually active women will acGuire a cervical HPV infection within =-$ years of initiating vaginal intercourse and (y the age of =#, this proportion reaches 3#,. - longitudinal study of HPV in adolescent and young adult women su(seGuently showed that having a new sexual partner resulted in a #-fold increased ris) for acGuiring HPV (-nna-2ar(ara 'oscic)i, "##=)..he 8HJ has estimated that "= to !#, of women younger than "= years of age are infected with high-ris) HPV. -lthough HPV point prevalence is very high, most clear spontaneously, especially among young women4 however, persistent infection with high-ris) HPV (H@HPV) types is considered the crucial step in the development of cervical carcinoma ('ah(oo(eh 0afaeian et al., "##3). Infection may progress from residential to episomal and finally, to an integrated form. @esidential infection typically occurs a minimum of : wee)s from exposure, can persist without detection for decades, and can (e low ris) or high ris). In the episomal state, virally active HPV is located in the cell nucleus, separate from the human 56whereas in the integrated form, the HPV 56- circle has opened and /oined the human 56-. HPV is typically found in episomal form in cervical lesions and integrated form in cervical cancer. 5uring integration > and >" are freGuently disrupted whereas >: and >$ viral oncogenes are retained ('ichael Pichichero, "##$). Progression from initial HPV infection to invasive cervical cancer may ta)e =-"# years and is typically associated with persistent HPV infection ('elissa Dawson, "##:). 'ost HPV infections occur during the teenage years or early twenties, whereas cervical cancer typically presents in women != years and older ('ohammed -)htar, "##%). cause
.o initiate progression specific changes in cellular control functions including genetic mutations should occur in host cells. Inactivation of these cellular control functions permits deregulated transcription of the early viral genes >: and >$, and that triggers cell proliferation, inhi(ition of apoptosis, reprogramming of differentiation, and chromosomal insta(ility. .hese changes could support the integration of episomal HPV genomes into chromosomes of the host cell and contri(ute to further over expression of the viral genes >: and >$ (Irene 1raus et al., "##:4 0igrun @essler et al., "##$). .he clinical manifestations of HPV infection in adolescent are usually appear as either genital condylomatous lesions (HPV warts) or cytological a(normalities. Jnly a minority (roughly -",) of young adults infected with HPV will develop genital warts. Viral proteins expressed during active infection induce pathologic changes including (asal cell proliferation, nuclear enlargement, )oilocytosis, and a(normal mitotic figures. >ach of these changes is a defining feature of 0Guamous Intraepithelial Desions (0ID). -s such, the development of (oth Dow-grade 0Guamous Intraepithelial Desions (D0ID) and High-grade 0Guamous Intraepithelial Desions (H0ID) can (e considered the pathologic conseGuences of HPV infection. .he ma/ority of infections and su(seGuent corresponding cytological a(normalities are transient and of minimal significance (low-grade sGuamous intraepithelial lesions) in terms of oncogenic potential. D0IDs will regress in +", to +%, of adolescents and young women. In addition, a high proportion of H0IDs will also regress in young women, (ut the actual rates are un)nown. - smaller percentage of adolescents will have persistent infections with higher ris) su(types and manifest high grade cytological a(normalities (-nna-2ar(ara 'oscic)i, "##=4 .eresa >r( et al., "##3). In natural history studies of adolescents with newly acGuired HPV infection, the average length of infection of detecta(le HPV is ! months. 9ortunately HPV infection in adolescent is generally a transient infection that is cleared (y the immune system and undetecta(le in most people within "% months with only =- #, persisting. - study of college going girls showed that approximately $#, of girls with HPV infection (ecame HPV negative within year and as many as + , of them (ecame HPV negative within " years, with a mean duration of infection of 3 months.
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.hus ma/ority of these infections will (e resided spontaneously (1ari 2raaten et al., "##3). 'ost infections are asymptomatic, with cell changes on the Pap smear a(normalities seen in only a(out #, of women who are positive for HPV. 0imilarly, (oth low- and high-grade lesions caused (y HPV can regress in adolescent and young adult women. .his study confirms the transient nature of HPV infection in most adolescent ('elissa Dawson, "##:4 'arcia 0hew et al., "##=4 -nna-2ar(ara 'oscic)i, "##=4 'ichael Pichichero, "##$). -lthough HPV infection is freGuently transient in adolescent and young adult women and the natural history of HPV infection and cytologic a(normalities is still (eing defined, this population has a relatively high incidence of a(normal Papanicolaou (Pap) smears. 'ount and Papillo reported that the incidence of Pap smears with sGuamous intraepithelial lesion was higher in adolescents # to + years of age than in adult women, and other investigators have proposed that the prevalence of a(normal pap smears and cervical dysplasia is increasing worldwide in young women (Aessica 1ahn et al., "##"). 'oreover, High- and low-ris) type HPV is reported to (e a common genital infection in adolescents, with prevalence ranging from +, to :, in different countries (9ran) DMdic)e et al., "## ). - recent study showed that =* +-year-old women had a rate of 0Guamous Intraepithelial neoplasia (0ID), second only to "#*"%-year-old women and #* %-year-olds, had a higher rate of 0ID than women over !# years (9rega et al., "##!). .he host&s immune response to HPV infection is initially the innate response, primarily interferon-(ased, which then triggers circulating humoral and cell-mediated responses at local lymph nodes. - cell-mediated immune response is reGuired for HPV containment and lesion regression. In addition to the immune evasion permitted (y the intracellular and epithelial location of the virus, HPV can induce a local immune deficiency (y depletion of intraepithelial lymphocytes, Dangerhan&s cells, and ?5%N cells with down-regulation of cyto)ine production (-manda .ristram et al., "##$4 5e(orah 'oney et al., "##$). 6evertheless, the more presence of a high-ris) form of HPV is not in itself sufficient to trigger the carcinogenic process. It is clear that other ris) factors are associated with acGuisition and retention of the virus and viral associated oncogenesis.
0everal factors including host cell factors are necessary for progression of HPV-infected precursor lesions to cancer. In particular, adolescent girls seem to exhi(it a num(er of factors that increase their suscepti(ility to HPV infection. .he (ehavioral and (iological ris) factors associated with the acGuisition of HPV in adolescents and young adult women include poor genital hygiene, early age of first sexual intercourse, num(er of lifetime sexual partners, alcohol and drug a(use, and lac) of condom use, hormonal and dietary factors and immunosuppression and the (iologic vulnera(ility of the adolescent cervix. Jther factors may play a role in increasing adolescent&s vulnera(ility. Chlamydia trachomatis, a common infection and ?igarette smo)ing may also enhance persistence and progression of HPV infection. However, in adolescents, the immune response to HPV exposure is greater than in adults. .his is why cervical cancers are rare in adolescents (O " years) ('ichael Pichichero, "##$4 9rega et al., "##!4 'elissa Dawson, "##:4 Hauwers, "##+4 0ara, "##+). .ransmission of HPV primarily occurs through direct genital contact, most commonly (y sexual intercourse. 2ut, other types of sexual and non-sexual contacts can transmit HPV in self reported BvirginsC. .ransmission via inanimate o(/ects such as (ed clothing, toilets is thought to (e unli)ely, (ut the true ris) is un)nown (1ari 2raaten et al., "##3). ;ntil recently Papanicolaou-stained (Pap) smear cervical cytology was the only traditional morphological screening method which detects early HPV infection and should (e done only in asymptomatic women. ?ellular changes were classified (y the pathologists according to the 2ethesda classification system as negative (normal), -typical 0Guamous ?ells of ;ndetermined 0ignificance (-0?;0), Dow-grade 0Guamous Intraepithelial Desion (D0ID), High-grade 0Guamous Intraepithelial Desion (H0ID), or suggestive of cancer (-ndrea 9uessel et al., "##%). 2ut Pap testing in adolescents is particularly not feasi(le (ecause of the vast ma/ority of cytological a(normalities in adolescents regress or does not represent cervical intraepithelial neoplasia (?I6) "H! or carcinoma in 0itu (Aessica 1ahn et al., "##=). ?olposcopy permits visuali<ation of the lesions and is performed for women with a(normal smears or with signs or symptoms suggestive of cancer. HPV 56- testing recently has (een incorporated into guidelines for primary cervical cancer screening in women older than !# years of age, and follow-up of
adolescent and adult women with a(normal cervical cytology and cervical dysplasia (?aitlin 8et<el et al., "##$). 5iagnosis of HPV infection has relied primarily on detection of the viral genome due to the in-(orn difficulties associated with the culturing of this virus. 0everal molecular (iology techniGues have (een used in detecting HPV infection, in particular P?@ and Hy(rid capture II test etc. In adult women HPV-56--P?@ on cervical scrapes, cervical (iopsies, vaginal swa( etc are used to identify the HPV-type responsi(le for the infection. 2iopsy is needed for women with high grade cervical lesions or any cancerous growth. -lternatively, detection of HPV 56- in urine can function as a secondary screening techniGue for cervical cancer in triage for women with atypical sGuamous cells of undetermined significance (-0?-;0). It has (een reported that women with cytological a(normalities are li)ely to have detecta(le HPV 56- in urine as in cervical swa(s (>un-0eop 0ong et al., "##$). ?ompare to the P?@ urine screen with conventional molecular assays that reGuires cervical swa( specimens, researchers found that positive urine and cervical swa( results had similar correlations with a(normal Pap smear results. It appears to (e a useful way of determining which types of HPV are present in the cervix and would (e an ideal sample for screening large populations and as well as for monitoring adolescents, children and adults. 2eing a(le to use urine HPV as an indicator of cervical infection is particularly important in developing countries that lac) the trained personnel needed for pelvic exams. ;rinary HPV-56- reflects the presence of infected cells shed from the epithelium of the urethral meatus. >specially, the first part of voided urine contains most of the exfoliated cells4 delayed catching of the first voided urine specimens or collecting a larger amount of urine will adversely affect the amount of collected cells. -lso some inhi(itory components li)e white urea, heparin, proteins or iron present in urine can (e impair urine HPV-56- detection. .hese inhi(itory components can (e removed (y (oiling the specimen, (y phenol-chloroform extraction, (y diluting or (y dialysis, or (y pre-treating the samples with glass (eads etc., In women urine HPV-56- detection can (e somewhat (etter, pro(a(ly (ecause of the close proximity of the urinary tract to the vagina, vulva and cervix (Hauwers et al., "##+4 5e(orah 'oney et al., "##$). .herefore in the present
study we proposed to investigate the prevalence of HPV among the adolescent girls using urine HPV-56- detection. Persistent infection with High-@is) Human Papillomavirus (H@-HPV) has (een demonstrated to (e the necessary causal factor for developing cervical cancer. .o )now the most prevalent H@-HPV in different geographical areas is important to design diagnostic tests and implementation of vaccines. .he prevalence of H@HPV in a total of ## patients, +3 with normal cytology results, %+3 with Dow-grade 0Guamous Intraepithelial Desion (D0ID), and "#= with High-grade 0Guamous Intraepithelial Desion (H0ID) who attended our gynaecology department for opportunistic screening of HPV infection. ('aria Dusia 'ateos Dindemann et al., "# #). Infection (y Human Papilloma Virus (HPV) is one of the primary causes of mortality (y cancer in northern 2ra<il. 0exually active women from 'anaus, -ma<onas, without cytological alterations and women with pre-malignant and malignant cytological alterations were examined for HPV virus, identified via P?@ and seGuencing. .he target region for this study was part of the D capsid gene of HPV. .wenty-three samples that were P?@-positive were seGuenced. -nalysis of !!: (p demonstrated a high incidence of high-ris) HPV types in the population of 'anaus, identified as HPVs :, !!, =3, ::, :3. HPV type : was the most prevalent, presenting two variants similar to the -sian-merican (--) and >ast--sian type (-s) variants. - rare HPV type ! related to BHec)&s diseaseC was also detected. .his preliminary provides important information a(out the HPV circulating in -ma<onas 0tate (?astro et al., "# ).
High-@is) Human Papilloma Viruses (H@-HPVs) are the causative agents of cervical cancer and prophylactic HPV vaccination has (een recommended for adolescents (ut no data are availa(le on the prevalence of HPV infection among adolescents in India. 0elf-collected midstream urine samples from +%# healthy school children, aged 3* $ years, from " different schools in and around 6oida and 5elhi, India, were collected for HPV detection (y P?@. Jf %=3 girls, = (!.",) were positive for HPV and # (::.:,) were positive for High-@is) Human Papilloma Virus (H@-HPV) type : and " ( !.!,) for HPV 3. Jf !%" (oys, $ (". ,) were HPV positive, of which = ($ .%,) had HPV type : (ut interestingly, none were positive for H@-HPV types : or 3. -mong HPV
positive girls, ! (::.:,) were P ! years and the rest were O ! years (P Q #.##%), while all seven HPV positive (oys were P ! years (P Q #.##$). .he ma/ority of HPV positive adolescents (3#*3:,) (elonged to the Hindu and related communities, whereas only a(out %*"#, (elonged to the 'uslim community. - significant association (P O #.## ) was o(served (etween the parent&s education and the awareness of cervical cancer, which was significantly higher among adolescent girls from India, there(y exerting an immense psychosocial impact on vaccination programs. - lower prevalence of H@-HPV infection among adolescent girls will have significant positive effect on HPV vaccination and cancer control programs in India where education and awareness should go hand in hand. (0how)et Hussain et al., "# ").
AIM &OBJECTIVES .he present study was designed to meet the following (road o(/ectivesK .o study the prevalence of HPV infection in adolescent girls in >rode district. .o estimate the prevalence of high-ris) HPV :, (y using highly sensitive polymerase chain reaction (P?@). .o assess the socio demographic factors associated with HPV positive study su(/ects. .o assess the sign and symptoms associated with HPV positive study su(/ects. .o assess the ris) factors associated with HPV positive study su(/ects. ?omparative analysis of two 56- extraction protocol in order to ascertain their relative effectiveness for non-invasive urine samples. >fficiency of D P?@ analysis with 'R#+H'R primers HPV :. consensus primers and specific
2. REVIEW OF LITERATURE ?ancer of the uterine cervix is the second most common cancer among women worldwide with an estimated = #,### newly diagnosed cervical cancer cases and "33,### deaths. In India, cervical cancer is a leading cancer among women, with an annual incidence of approximately !",### and mortality rates of approximately $%,###. >pidemiological estimates suggest that the worldwide prevalence of HPV infection is (etween + and !,, which eGuates to approximately :!# million infected women. .he cancers that develop from uterine cervix are of two typesK (i) sGuamous cell carcinomas, which develop from sGuamous epithelium, cover mostly visi(le part of cervix4 and (ii) adenocarcinomas, which arise from glandular lining of endocervical canal. -(out 3=, to +#, of cervical cancers are sGuamous cell carcinomas, and the rest #* =, are adenocarcinomas. 0Guamous ?ell ?arcinoma (0??) is preceded (y well-recogni<ed epithelial changes, the precancerous lesions, which develop through several gradesK cervical intraepithelial neoplasia (?I6) I to III4 or Dow grade 0Guamous Intraepithelial Desions (D0ID) to high grade 0ID or a mild, moderate and severe dysplasia leading to ?arcinoma-In-Situ (?I0). .hese lesions may progress to malignancy, or persist, or regress (-lo) 2harti et al., "# #4 2hudev 5as et al., "###). High-ris) Human Papilloma Viruses (H@-HPVs) are the causative agents of cervical cancer and prophylactic HPV vaccination has (een recommended for adolescents (ut no data are availa(le on the prevalence of HPV infection among adolescents in India. 0elf-collected midstream urine samples from +%# healthy school children, aged 3* $ years, from " different schools in and around 6oida and 5elhi, India, were collected for HPV detection (y P?@. Jf %=3 girls, = (!.",) were positive for HPV and # (::.:,) were positive for High-@is) Human Papilloma Virus (H@-HPV) type : and " ( !.!,) for HPV 3. Jf !%" (oys, $ (". ,) were HPV positive, of which = ($ .%,) had HPV type : (ut interestingly, none were positive for H@-HPV types : or 3. -mong HPV positive girls, ! (::.:,) were P ! years and the rest were O ! years (P Q #.##%), while all seven HPV positive (oys were P ! years (P Q #.##$). .he ma/ority of HPV positive adolescents (3#*3:,) (elonged to the Hindu and related communities, whereas only a(out %*"#, (elonged to the 'uslim community. - significant association (P O #.## ) was o(served (etween the parent&s education and the awareness of cervical cancer, which was significantly higher among adolescent girls from India, there(y exerting an immense
psychosocial impact on vaccination programs. - lower prevalence of H@-HPV infection among adolescent girls will have significant positive effect on HPV vaccination and cancer control programs in India where education and awareness should go hand in hand. (0how)et Hussain et al., "# "). 2.1 ROLE OF HPV Human Papilloma Virus (HPV) infection is the cause of cervical cancer in almost ##, of the cases. .he association (etween HPV infection and cervical neoplasm was esta(lished after the lin) (etween genital HPV infections and cervical cancer was first demonstrated in the early +3#s (y Harold <ur Hausen and a num(er of molecular and epidemiologic studies have since demonstrated a strong co-relation (etween human papillomavirus (HPV) infection and this disease (Hoenil Ao et al., "##=). HPV infection can also lead to genital warts, recurrent respiratory papillomatosis, and vaginal, vulval, anal and penile cancers. HPV types : and 3 are responsi(le for more than $#, of HPVrelated cervical cancers whilst HPV types : and cause approximately +#, of the cases of genital warts. HPV infection is most common among young, sexually active individuals, and it is so prevalent that approximately $=, to 3#, of sexually active individuals will (ecome infected in their lifetime. ?linical, su(-clinical and latent HPV infections are the most common sexually transmitted viral diseases today, with a pea) in prevalence among young women soon after the onset of sexual activity. Datent genital HPV infection can (e detected in =, to %#, of sexually active women of reproductive age. In most cases, genital HPV infection is transient or intermittent (-lo) 2harti et al., "# #4 Aha ;rvashi Prasad et al., "##34 2ethany weaver et al., "##:). Human Papilloma Virus (HPV) is the main cause of cervical cancer. (8al(oomers et al., +++4 Harold <ur Hausen et al., ++:) 'ore than != HPV types have (een identified in the genital tract, and HPV : and 3 are responsi(le for approximately $#, of cervical cancer.('uno< et al., "##!4 2osch et al., "##!).wo HPV vaccines, a Guadrivalent vaccine that protects against HPV:, , :, and 3 and a (ivalent vaccine that protects against HPV : and 3, have (een developed and approved (y the ;nited 0tates 9ood and 5rug -dministration (95-) for females +*"= years and +*": years of age, respectively. (-ult et al., "##$).
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Human Papillomavirus (HPV) : and
are the aetiological agents responsi(le for
@ecurrent @espiratory Papillomatosis (@@P). .here is general consensus that HPV results in more aggressive disease compared to HPV:. .here are numerous su(-types or variants of (oth HPV: and HPV . .hese su(-types have different activities at least invitro. .he num(ers of different HPV types within @@P tissue may (e more extensive than initially appeared. .his depends specifically upon the HPV types tested. .he clinical differences (etween HPV: and HPV disease may not (e accurately predicta(le as these viruses exist in numerous su(-types. -lso, @@P tissue may contain more than one su(type or even (e co-infected with other viruses that may influence outcome. In-vitro studies upon cell lines are a reasona(le starting point for evaluation of these differences. (5onne et al., "# #). .he role of inflammation in HPV infection and disease is complex since it involves responses capa(le of preventing initial infections, clearing those ongoing as well as promoting persistence and progression of associated lesions. -voiding the immune response has (een considered a )ey aspect of HPV persistence which is the main factor leading to HPV-related neoplasia. HPVs have evolved different ways of targeting immune signaling pathways. 'oreover, host inflammatory response may promote lesion progression and affect tumor fate (y diverse mechanisms including the direct participation of inflammatory cells. In this review we discuss the interplay (etween HPV oncogenic proteins and an array of inflammatory responses that ultimately may lead to cancer. (httpKHHwww.nc(i.nlm.nih.govHpu(medH"#3 +$$+, "# !). Human Papilloma Virus (HPV) is the main cause of cervical cancer, and many countries now offer vaccination against HPV to girls (y way of government-funded national immuni<ation programs. 'onitoring HPV prevalence in adolescents could offer a near-term (iological measure of vaccine impact, and urine sampling may (e an attractive large-scale method that could (e used. (>spen >nerly et al., "# !). 2.2 BIOLOGY OF HPV .he Papilloma Viruses (PV) (elongs to the family Papillomaviridae and is highly species-specific with a tropism for epithelial cells. .he Papillomaviruses are found among many species, and pro(a(ly occur in most mammals and (irds (Villers, "##%). .he first
"
Papillomavirus was identified in +!!, and causes warts in cottontail ra((its (0hope, +!!). .his particular virus, cottontail ra((it papillomavirus (?@PV), later induces malignant transformation (@ous, +!=). Harald Sur Hausen proposed in the late seventies that Human Papilloma Virus (HPV) can cause cervical cancer (Hausen, +$:). Human Papillomavirus is a mem(er of the Papillomaviridae family, designated (y the International ?ommittee on .axonomy of Viruses (I?.V) that infects only humans (I?.V Virus .axonomy "##+). Di)e all Papilloma Viruses, HPV esta(lishes productive infections only in the epithelium of the s)in or mucosa. 'olecular (iology has made it possi(le to study the interactions of viral gene expression and replication with the host cell phenotype (I-@? 'onographs "##$). 'a/or (rea)throughs in the understanding of the viral oncoprotein, most nota(ly in the >=H:H$ proteins, activities of H@-HPV types to the integrity of cellular 56- and cell-cycle control were made already in the ++#&s. Jne hundred eighteen Papilloma Virus (PV) types have (een completely descri(ed, and a yet higher num(er of presumed new types have (een detected (y preliminary data such as su(genomic amplicons. .he classification of this diverse group of viruses, which include Important human pathogens, has (een de(ated for three decades. .his article descri(es the higher-order PV taxonomy following the general criteria esta(lished (y the International ?ommittee on the .axonomy of Viruses (I?.V), reviews the literature of the lower order taxa, lists all )nown LLPV types&&, and interprets their phylogenetic relationship. PVs are a taxonomic family of their own, Papillomaviridae, unrelated to the polyomaviruses. Higher-order phylogenetic assem(lages of PV types, such as the LLgenital human PVs&&, -re considered a genus, the latter group, for example, the genus LL-lpha-Papillomavirus&&. Dower-order assem(lages of PV types within each genus are treated as species (ecause they are phylogenetically closely related, (ut while they have distinct genomic seGuences, they have identical or very similar (iological or pathological properties. .he taxonomic status of PV types, su(types, and variants remains unchanged and is (ased on the traditional criteria that the seGuence of their D genes should (e at least #,, "* #,, and maximally ", dissimilar from one another.(>thel-'ichele de Villiers et al., "##%).
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?lassification of HPV in this data(ase was taxonomic scheme developed (y International ?ommittee on .axonomy of Viruses. Class ! "a# $% $! H&'a% Pa( ll$'a) *&s V *&s+s 2.2.1 H&'a% Pa( ll$'a V *&s (HPV) is a 56- virus from the papilloma virus family that is capa(le of infecting humans. Di)e all papilloma viruses, HPVs esta(lish productive infections only in )eratinocytes of the s)in or mucous mem(ranes. 8hile the ma/ority of the )nown types of HPV cause no symptoms in most people, some types can cause warts (verrucae), while others can in a minority of cases lead to cancers of the cervix, vulva, vagina, penis, oropharynx and anus.( Eenital HPV Infection, "##+). 2., MORPHOLOGY AND GENOME ORGANISATION HPV is a relatively small (==nm diameter) non-enveloped virus and contain a dou(le-stranded closed-circular 56- genome of approximately $"## (p*3### (p. It has an icosahedral capsid composed of $" capsomers, which contain at least two capsid proteins, D and D" replicating as an episome in the nucleus of host cells. .he HPV genome can (e divided into three regions, the noncoding Dong ?ontrol @egion (D?@), or
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the upper regulatory region (;@@), and the early (>) and late (D) gene region (protein encoding). .he D?@H;@@ constitutes a(out #, of the genome, varying (etween 3## (p and +## (p. ;@@ forms a 6on-protein-?oding @egion (6?@) of the viral genome, (ut it contains many cis-acting elements. Viral gene expression is generally regulated (y several viral and host-cell transcription factors, which (ind to the ;@@. .hese factors include nuclear factor- (69- ), activator protein- (-P- ), octamer- (inding factor(Jct- ), progesterone receptor, Rin and Rang factorglucocorticoid receptor, etc. 5uring HPV 56- integration, the viral genome usually (rea)s in the > H>" region. .he (rea) usually leads to the loss of the > and >" regions. .he loss of >", which encodes proteins including one that inhi(its the transcription of the >: and >$ regions, has (een )nown to result in uncontrolled and increased expression of >: and >$ oncogenic proteins. Increased expression of >: and >$, meanwhile, has (een o(served to lead to the malignant transformation of the host cells and to tumor formation (2osch et al., ++"4 5oor(ar et al., ++ 4 Phelps et al., ++3). HPV viral integration into the host genomic 56- is associated with progression from polyclonal to monoclonal status in ?I6, and these events play a fundamental role in the progression from low-grade to high grade cervical neoplasia (;eda et al., "##!) .he D?@ regulates transcription from the early and late regions, and therefore controls the production of viral proteins and particles. .he early region is downstream of the D?@ and contains six open reading frames, > , >" and >%*>$, and is involved in viral replication and oncogenesis. .hese encode all viral proteins except for the viral capsid proteins, which are encoded in the late region. .he D and D" genes in the late region encode the ma/or and minor capsid proteins, (oth of which are reGuired late in the viral life cycle to encapsulate the virus (-manda .ristram et al., "##$4 Hoenil Ao et al., "##=4 2hudev 5as et al., "###). (RR- ), 0P- , 1@9and
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>na(les > protein to (ind to the viral origin of replication located within the D?@ >ncodes a D?@-(inding protein that regulates transcription of the early region >ncodes a protein that interacts with cyto)eratin >xpressed in later stages of infection, when complete virions are (eing assem(led -ugment cellular proliferation and 56- synthesis in a context of cell mem(rane receptors, such as >E9 and P5E9 Induces an increase in mitogen-activated protein )inase activity 2inds to p=! and targets it for rapid degradation via a cellular u(iGuitin ligase Induces telomerase activation 2inds to the hypophosphorylated @( proteins and li(erate >"9, which results in 0 phase entry Interacts with inhi(itors of cyclin dependent )inases Induces a(normal centrosome duplication resulting in aneuploidy
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2.1 HPV TYPES Human papilloma virus types are recogni<ed (ased on their genetic seGuence and are num(ered in order of their discovery. 0eGuence differences showing less than +#, homology to any of the )nown types on the (asis of the >:, >$, D regions are consider as a new HPV type and seGuence difference of more than #, in the D region are
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recogni<ed as another type, whereas variations of less than ", are recogni<ed as variants of currently num(ered types. HPVs can (e grouped as cutaneous or mucosal types. .he cutaneous types are Guite numerous and are associated with common hand and foot warts as well as a rare genetic disorder characteri<ed (y widespread warts and freGuent s)in cancer, erythrodermoplasia verruciformis. .he cutaneous types are (eing investigated as ris) factors for actinic )eratoses, psoriasis, (asal cell carcinomas, and sGuamous cell carcinomas. .he mucosal types are those most commonly found in the anogenital region, (ut that may (e found elsewhere, including the nail (eds and oropharyngeal epithelium. 'ore than 3# types of Human Papilloma Viruses (HPVs) are )nown today, and they are generally classified according to their potential to induce malignant transformation. HPVs :, 3, ! , !!, !=, !+, %=, =#, = , =!, ==, =:, =3, =+, :% and :3 are considered Bhigh ris)C types (ecause they are detecta(le in carcinomas and dysplasias 3, "!. HPVs ! , !!, !=, = and =" are sometimes regarded as Bintermediate ris)sC (ecause they are more common in mild or severe dysplastic lesions than in carcinomas. -mong the high-ris) strains, HPV : and 3 are the most closely associated with cervical carcinoma. .he HPV : 56- has (een found in more than =#, of sGuamous cell carcinomas, while the HPV 3 56- has (een found in more than =#, of adenocarcinomas 2'ilde-Dangosch et al., ++!). .o date, more than # human and animal papillomavirus genotypes have (een
characteri<ed and seGuenced. Jf the approximately !# HPVs that infect the ano*genital tract, = HPV types (HPV types :, 3, ! , !!, !=, !+, %=, = , =", =:, =3, =+, :3, $! and 3") have (een found to (e associated with high grade lesions and invasive cervical cancer and hence are classified as Lhigh-ris)& types. HPV types : and 3 are the two most common highly oncogenic HPV types found in invasive cervical cancer and high-grade ?ervical Intraepithelial 6eoplastic (?I6) lesions. Jn the other hand, different HPV types that have (een mainly associated with genital warts and (enign cervical lesions such as condylomata accuminata and dysplasias are termed as Llow-ris)& HPV types. .hese include HPV types :, HPV: and HPV , %#, %", %!, %%, =%, : , $#, 3 and ?P: #3. -mong these, cause approximately +#, of genital warts (-lo) 2harti et al., "# #).
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G+%$'+ $*0a% 3a# $% $! H&'a% Pa( ll$'a V *&s #/(+ 145 $%+ $! #-+ s&6#/(+s 7%$8% #$ "a&s+ "+*) "al "a%"+*. 2E19E: +a*l/ 0+%+s5 L19L2 la#+ 0+%+s; "a(s .) 2.< LIFE CYCLE OF HPV HPV are strictly host-specific and infects its host (y penetrating through mucosal tears in the (asal mem(rane. .he nature of the cell surface receptor used for viral attachment is not )nown, although heparin sulphate and sta(ili<ing proteoglycans have (een suggested to (e epithelial cell receptors for HPV. .he target cells for an initial HPV infection are the immature (asal cells of the epithelium, and HPV is thought to reach these cells through micro a(rasions or crac)s within the epithelium. Jnce in a host cell, the life cycle of HPV can (e separated into two stages, i.e., nonproductive and productive. In the nonproductive stage, the virus maintains its genome as a low copy num(er episome (y using the host&s 56- replication machinery to synthesi<e its 56- in (asal layer of the epithelium ..he pattern of viral gene expression in these cells is not well defined, (ut it is generally (elieved that the viral > and >" proteins are expressed in order to maintain the viral 56- as an episome and to facilitate the correct segregation of genomes during cell division. .he num(er of copies of the HPV genome, as a circular or episomal form, is thus low in the (asal cell&s nucleus, and virally encoded proteins are expressed at very low levels. -s a result, HPV-infected (asal cells show no specific cytologic or histologic changes and cannot (e distinguished from uninfected cells. .his stage of an HPV infection is referred to as a BlatentC or Bclinically unapparentC infection since the woman is HPV 56- positive, (ut no lesions can (e detected, even (y microscopy ('arc 0te(en et al., "##$= -nna-2ar(ara 'oscic)i, "##=). .he productive stage of the viral life cycle occurs in the terminally differentiating supra(asal layers of the epithelium. In these cells, the virus switches to a rolling-circle
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mode of 56- replication and amplifies its genome to higher copy num(er, expresses late genes encoding capsid proteins, and produces viral progeny (Hoenil Ao et al., "##=) Human papilloma virus is episomal in productive infections and in most lesions. Integration of the viral genome into host cellular 56- is found in essentially all cancers with HPV 3 and most of those with HPV :. Viral integration has not (een o(served in all cancers, (ut integration clearly has implications in the perpetuation of the transformed phenotype as well as in tumor progression. HPV integration appears to (e random with respect to the cellular chromosome, (ut nearly always occurs within the > H>" region of the HPV genome. Integration may (e an irreversi(le event as a conseGuence of host cell genomic insta(ility, or it may (e that integration initiates a chain of events including the impairment of tumor suppressor genes (e.g., .P=! and @2), which results in genomic insta(ility and cell immortali<ation. .he papillomavirus life cycle differs from that of all other virus familiesK infection reGuires the availa(ility of epidermal or mucosal epithelial cells that are still a(le to proliferate. In these cells, viral gene expression is largely suppressed, although the limited expression of specific BearlyC viral genes (such as >=, >:, and >$) results in enhanced proliferation of the infected cells and their lateral expansion.: 9ollowing entry into the supra(asal layers, BlateC viral gene expression is initiated4 the circular viral genome is then replicated, and structural proteins form. In the upper layers of the epidermis or mucosa, complete viral particles are assem(led and released (-manda .ristram et al., "##$).
L !+ "/"l+ $! 0+% #al H&'a% Pa( ll$'a V *&s.

"3
2.4 PATHOGENESIS OF CERVICAL CANCER - significant role for malignant transformation can (e assigned to the >: and >$ genes and their respective proteins. >: and >$ proteins are encoded (y high-ris) HPV such as : and 3 and in addition to having in vitro transforming activity, (oth >: and >$ are always actively transcri(ed in cervical cancer, suggesting that unregulated expression of these genes plays a significant role in carcinogenesis and maintenance of the malignant phenotype. .hese proteins interact with cellular proteins such as p=! and the product of retino(lastoma gene (p@(), which is normally responsi(le for controlling )ey steps in the cell cycle. P=! is a )ey cellular regulatory gene that acts as a transcriptional activator and has characteristics of a tumor suppressor gene. In non-infected cells, p=! levels increase in response to cellular or 56- damage or a(errant cellular proliferation signals. High levels of p=!, (y interacting with 8-9 Hcip and cd)-cyclin, induce the cell to undergo growth arrest in the E phase of the cell cycle, which provides an opportunity for the cell to either repair 56- damage or (e eliminated through programmed cell death (apoptosis). In HPV-infected cells >: protein from high-ris) HPVs (inds to p=! thus causing loss of its crucial role in controlling the cell cycle. = p@( also plays a crucial role in controlling the transition from E to the 0 phase of the cell cycle (y interacting with other cell cycle proteins including >"9, c-myc and n-myc. >$ encoded (y high-ris) HPVs (inds with p@(, (loc)ing its a(ility to interact with >"9 and unregulated proliferation occurs. Jn the other hand, >: and >$ from low-ris) HPVs have a lower affinity for p=! and p@2 and therefore is not oncogenic ('ohammed -)htar, "##%). .he >= gene product induces an increase in mitogen-activated protein )inase activity, there(y enhancing cellular responses to growth and differentiation factors. .his results in continuous proliferation and delayed differentiation of the host cell. .he inactivation of p=! and p@( proteins can give rise to an increased proliferation rate and genomic insta(ility. -s a conseGuence, the host cell accumulates more and more damage 56- that cannot (e repaired, leading to transformed cancerous cells. In addition to the effects of activated oncogenes and chromosome insta(ility, potential mechanisms contri(uting to transformation include methylation of viral and cellular 56-, telomerase activation, and hormonal and immunogenetic factors (>li<a(ath et al., "##=).
"+
2.: NATURAL HISTORY OF HPV INFECTION IN ADOLESCENTS -dolescents represent a uniGue population in terms of infectious disease suscepti(ility and associated mor(idity (ecause (iological and (ehavioral factors place them at particular ris) of acGuiring HPV. .he )ey period of sexual exploration and development occurs during adolescence. >vidence from around the world suggests that young, unmarried, adolescents are initiating intercourse at a younger age, having multiple sexual partners for a limited duration, having unprotected first intercourse and (eing more li)ely to report high ris) sexual (ehavior than do married adolescents and people in older age groups. 0uch (ehavior may also (e associated with very early HPV infection and an elevated ris) of cervical cancer development ('anop 1anato et al., "##:4 .eresa >r( et al., "###). 2.> ADOLESCENT BIOLOGICAL VULNERABILITY Roung age at first intercourse has long (een associated with ris) for invasive cancer. .he ris) of invasive cancer increases twofold in women who initiate sexual intercourse under the age of 3 years as compared with those initiating sexual intercourse after + years when controlling the num(er of lifetime sex partners. .his finding suggests that there is a certain (iological vulnera(ility of the cervix of young women to HPV infection. .he adolescent cervix is structurally different from the cervix of adult women. It freGuently has a mosaic appearance with different cellular components including relatively large areas of columnar and metaplastic sGuamous epithelium. >m(ryologically, the cervix is initially lined (y columnar epithelium in utero. ;rogenital sGuamous epithelium replaces the columnar epithelium4 however the replacement is incomplete with an a(rupt sGuamous-columnar /unction occurring on the ectocervix. .he adolescent enters pu(erty with relatively large areas of columnar epithelium compared to the adult women. 5ue to increased estrogenic activity and resulting acidity of the vagina, uncommitted generative cells of the columnar epithelium (egin to transform themselves into sGuamous epithelium. >ventually, columnar epithelium transforms into sGuamous epithelium with a new columnar /unction occurring well into the os. .he predominant cell type in adults is the mature sGuamous cell. 2oth columnar and metaplastic sGuamous cells are vulnera(le to HPV pro(a(ly for a variety of reasons of which thinness of the >pithelium may (e one factor ('elissa Dawson, "##:4 'arcia 0hew et al., "##=).
!#
.he transformation process is referred to as sGuamous metaplasia. 0ince the process of sGuamous metaplasia appears to (e most active during adolescence, it may represent a vulnera(ility to the esta(lishment of HPV infections. .riggers of sGuamous metaplasia include sexual activity. -lthough, the mature sGuamous epithelium provides more protective (arrier to HPV than the thin columnar epithelium, the process of transformation creates a fertile environment for HPV infection and development of 0ID. HPV replication and patterns of transcription are highly dependent on the differentiation program of )eratinocytes in the cervical sGuamous epithelium. .herefore, it is somewhat intuitive that sGuamous metaplasia is particularly favora(le to HPV survival. .he environment is conducive to viral replication, and possi(ly persistence. It is important to emphasi<e, however, that HPV detection in adolescents is most commonly associated with normal cytology. Jver three-Guarters of HPV-infected adolescents have normal cytology. - study of adolescent women showed that those large amounts of metaplastic change visi(le on colpopophotographs were more li)ely to develop D0ID if infected with HPV than adolescents with a relatively Guiescent cervix (-nna-2ar(ara 'oscic)i, "##$). 2.? INCIDENCE OF HPV IN ADOLESCENTS .he incidence of cancer of the cervix was !!.: per year per million in =- to "+year-olds4 this increased dramatically for those over !# years of age . Jver time, however, the incidence of cervical cancer declined slightly in the "#- to "%-year-old group, a trend that was also noted in older age groups. .his reduction in incidence is attri(uta(le to a decline in the incidence of sGuamous cell carcinoma of the cervix, although the incidence of adeoncarcinoma of the cervix actually increased. In general, the incidence of HPV in the general population varies (etween 3 and "#, per year and the incidence rates were higher for oncogenic HPV infections than for non-oncogenic HPV infections (-nna Eiuliano et al., "##"). In recent longitudinal studies conducted among young women, the annual incidence was (etween % and "%, and %!-==, over ! years. 0imilarly, in a study conducted in young -merican women aged :-"! over a period of up to %3 months5 the type-specific incidence and mean duration of HPV :, , : and 3 were o(served as +.!, (@alph et al., "##$).In a 3.%, 3.", and :.% months, respectively. .hat is, mean duration of incident HPV- :H HPV- 3 infections approximately twice that of HPV-:H HPVstudy reported in "## , approximately ==, of adolescents and young women acGuired a
cervical HPV infection within !: months after /oining the study ..his was approximately within =*$ years after initiating sexual intercourse. 2.1@ PREVALENCE OF HPV AMONG ADOLESCENTS .he prevalence of HPV infection varies (y country and studied populationK HPV is detected in the ?ervix of = to =#, of asymptomatic women of reproductive age. -lthough the pea) of HPV prevalence is reached in the first half of the third decade ( 3* "= years) of life, cervical cancer is found much later, usually after %# years, with a flatter pea) of incidence around age %= years. Interestingly, unli)e in the 8est, HPV infection is most common in Indian women a decade later, at around ":*!= years of age, (ut a very low freGuency (T!,) of HPV infection occurs during adolescence as the ma/ority are not sexually active at this age (+* ! years of age) in India and cancer arises much later, with a pea) at approximately %=*== years of age. .herefore, there is a long gap (etween infection and invasive cancer, and the phenomenon provides a suita(le window period for cancer control (-lo) 2harti et al., "# #4 -nna-2ar(ara 'oscic)i et al., 200 ). .he identification of HPV in almost all cases of cervical cancer has led to the development of prophylactic vaccines. .wo products are now licensed and availa(le for use. EardasilU and ?ervarixU target the two most common high-ris) HPV types : and 3, found in $#, of cervical cancers (8HJ and Institute types : and ?atalV d&Jncologia Information ?entre on HPV and ?ervical ?ancer "##$). EardasilU also targets HPV , which cause most cases of genital warts. 0hort-term data suggests that the vaccines offer protection against the development of cervical intraepithelial neoplasia and few side effects have (een o(served (8HJ "##$). - prospective follow-up study of sexually naive college students found that within " months of initiating sexual intercourse, !#, (ecame HPV positive4 within %3 months, =%, were HPV positive.! Jther follow-up studies of adolescents and young women have found that with repeated testing and long-term follow-up, HPV is detected in more than two-thirds over a several year period. In a study, the Prevalence of HPV infection was found to (e highest among females aged "# to "% years %%.3, (+=, ?I, !:.!,==.!,)..he overall prevalence among females aged % to "% years was !!.3. -mong sexually active females, HPV prevalence was found to much higher !+.:, (+=, ?I,
!"
!".+,-%$.3,) for % to + years, %+.!, (+=, ?I, %#.$,- =+.:,) for "# to "% years, (+=, ?I, "3.:,-%#.#,). .he overall prevalence of HPV among females aged % to "% years was !!.3,.In this study, HPV 56- was detected in =.", of females who reported never having had sex. .hey found that the prevalence of HPV infection increased from % years through "% years, and then decreased at older ages and prevalence of HPV- : to (e low and that other HPV types were more prevalent (>ileen 5unne et al., "##$).
-nother study was performed in a group of closely followed adolescent women to detect the HPV incidence, prevalence, type distri(ution, persistence, and associated dysplasia. In this study, adolescent women underwent very freGuent HPV testing, careful HPV typing, and prolonged follow- ;p. .he prevalence of detecta(le HPV infection of adolescent women in this study was in the range of "=,*%#, and .he cumulative prevalence was P3#,.Jncogenic or High-@is) (H@)-HPV types were detected in !3.:, and nononcogenic or Dow-@is) (D@) types were detected in +.:, of specimens. 5uring the entire study period, %+ of :# su(/ects tested positive for HPV (cumulative prevalence, 3 .$,). .he most freGuently detected H@ types were HPV types =", :, and =+ and D@ types were :: and :. Infections with multiple HPV types were common. .he median duration of persistence of a specific HPV type was :3 days, and H@ types were more persistent than D@ types. -(normal cervical cytological results occurred in !$, of the adolescent women and were significantly associated with H@ HPV infection (2rown et al., "##=). .he prevalence of high and intermediate-ris) type HPV infection and cervical dysplasia was analysed in an ur(an 0wiss adolescent population attending the local -dolescent ?linic, using a liGuid-(ased Pap test com(ined with ris) type HPV 56Prevalence of Human Papilloma Virus (HPV) infection among college going girls using self collected urine sample from >rode district, .amil 6adu.
!!
testing. Jf the !% specimens analy<ed for HPV,
= patients were negative and +
( %.",) were positive for HPV types :, 3, ! , !!, !=, !+, %=, = , =", =:, =3, =+, or :3. - significant association (etween HPV infection and having had more than one lifetime sexual partner was found (P O.#=). -(normal Pap test was related to HPV infection (odds ratio, %:."4 +=, confidence interval, $.% to "3$.%) and, inversely, to age at first sexual intercourse (odds ratio, #.+34 +=, confidence interval, .+$ to .#) (9ran) DMdic)e et al., "## ) In a survey conducted in male and female university students in south )orea(:$" female and !3 male) that included self-collected vaginal cells from females and, for males, physician-performed collection of exfoliated genital cells, found that HPV 56was detected more freGuently in female students ( =."#$o) than in male students (3.$#So)4 in (oth sexes, high-ris) HPV types were predominant. -mong sexually active students, HPV prevalence was !3.3, in females and #.:, in males 2Hai-@im 0hin et al., "##%). - study conducted among ,##: randomly selected women, ages 3 to "% years, living in 0icily (south Italy) assessed the prevalence of HPV infection and genotypes ..he overall HPV rate was "%. , (+=, confidence interval, " .=-":.+). .he most freGuent types were HPV- : (%.=,), HPV-=! (".$,), and HPV-3% (".:,) (Pietro -mmatuna et al., "##3)-nother study conducted in rural and su(ur(an female population (6W":!!) of ;0- found that the most prevalent genotype was HPV- : (nW=#4 +.:,), followed (y HPV-=" (nW"%4 +.%,). Jne novel HPV-!+ variant was also detected in repeat testing in a patient with persistent HPV infection (0in Hang Dee et al., "##+).In a study performed among "#:= unscreened women aged 3 to "+ years. 8omen returned a self-collected cervico-vaginal specimen and filled out a Guestionnaire. -ll HPV 56--positive samples ((y 0P9 # 5>I-) were genotyped using the I66J-DiP- HPV genotyping assay. HPV point prevalence in this sample was +,. Dow and high ris) HPV prevalence was +. , and .3,, respectively. - single HPV-type was detected in %.+, of all women, while multiple types were found in %. ,. HPV-types : (".3,) and 3 ( .%,) were found concomitantly in only ! women (#. ,). .here was an increase in HPV prevalence till "" years (?harlotte Denselin) et al., "##3). 9uture reduction in overall HPV prevalence and vaccine HPV type-specific prevalence and using urine testing as a monitoring method, care should (e ta)en when
!%
interpreting the data. Indeed the data may not necessarily mimic the true HPV distri(ution in the cervix nor estimate the expected reductions in cervical cancer and high-grade lesions, as indicated (y varia(le vaccine HPV type-specific (HPV :H 3) concordance (etween paired urine and cervical samples. .here is great scientific and political interest in monitoring the early effects of HPV vaccination in the general population. However, monitoring HPV prevalence as an early measurement of vaccine impact is only possi(le in a few countries as su(stantial financial and human resources are needed as well as a =* #-year commitment in order to demonstrate results. (8)ly >pidemiol @ec. "# #) prevalence study showed that other high-ris) HPV genotypes than - : and - 3 (i.e., HPV types -%=, -!!, -! , -=", -!=, -!+, -=3, - = , -=+, -=:, and -::) were associated with more than "#, of cervical carcinomas glo(ally (0an/ose et al., "# #4 I-@?,"# #). 'onitoring the prevalence of type-specific HPV-56- infections (efore and shortly after introduction of routine HPV vaccination offers the opportunity to evaluate early effects of the vaccination program. 8ith this aim a cohort study was set up of %- to :-year-old girls eligi(le for HPV vaccination in the 6etherlands. -nnually, HPV-56and anti(ody status in vaginal self-samples and in serum respectively, will (e studied among vaccinated (=3,) and unvaccinated girls (%",). Here we present (aseline data on vaginal HPV-56- status in relation to serum anti(odies. ('ollers et al., "# "). 2.11 TRANSMISSION AND ACAUISITION OF HPV AMONG ADOLESCENTS HPV is essentially sexually transmitted. .he mean incu(ation period is estimated to (e " to ! months, ranging from a few wee)s to eight months (Handsfield ++$, Jriel +$ ). .he rate of transmission to partners of infected individuals is estimated to (e =#$#, (Dawee ++#, Jriel +$ ). - study was conducted to evaluate the (ehaviour at ris) in the transmission of HPV infection among virgin adolescents. In those two groups of virgins with genital HPV lesions and their Partners were also examined. HPV lesions were detected in 33 virgins, who have never had sexual intercourse. .his can (e due to vertical transmission4 fomities and s)in-to-s)in contact (-ntonio 9rega et al., "##!). .he strongest evidence, however, that genital types of HPV are predominantly sexually transmitted is provided (y longitudinal studies of virgin women who initiated sexual activity during the study period. - 5anish population-(ased cohort study of ##
!=
virgins and #= monogamous women showed that all the women who remained virgins throughout the study period tested negative for (oth HPV 56- and serum HPV- : anti(odies at enrollment and at each visit thereafter. In that study, detection of serum HPV- : anti(odies and development of cervical lesions occurred only after HPV transmission, suggesting that sexual intercourse is a necessary step in (oth the acGuisition of infection with genital HPV and the development of cervical neoplasia (-nna-2ar(ara 'oscic)i et al., "##$4 7avier 2osch et al., "##:). .he evidence for the nonsexual transmission of genital types of HPV has (een reviewed (y several authors who concluded that ( ) genital HPV infections, including genital warts, may occur in sexually naive populations such as infants, children, and virgin adolescents and adults4 (") there is some evidence of hori<ontal transmission of low-ris) types of HPV4 (!) vertical and perinatal transmission of HPV from mother to child exists, although rates are low4 (%) high-ris) genital types of HPV have (een detected in nongenital mucosae, e.g., of the mouth and oropharynx as well as the con/unctiva, and they have (een associated with some cancers of the oral cavity and oropharynx and with con/unctival sGuamous cell carcinoma. .ransmission via (lood and (reast mil) has not (een documented. 2ut the possi(le role of sperm as a vector for HPV has (een explored in several studies (7avier 2osch et al., "##:)..he natural history of type-specific human papillomavirus (HPV) infections was examined in a cohort of !! women aged 3*!= years. In that, the rate of acGuisition of new HPV infections was ".+, per month. -cGuisition of new infections was highest for HPV- : (#.=+, per month), HPV- !+ (#.%:, per month), HPV-3% (#.%", per month), and HPV- = (#.!%, per month) (-nna Eiuliano et al., "##"). 2.12 PERSISTENCE AND CLEARENCE 5espite the high rates of anogenital infection, very few result in cellular changes, genital warts, intraepithelial neoplasia, or cancer. 'ost infections ($#-+#,) are contained (y host immune responses and (ecome undetecta(le within : to # months. Persistence of the virus (ie, continued detection of the virus for longer periods of time) is a necessary (ut not sufficient step for the development of (oth ?ervical Intraepithelial 6eoplasia (?I6) and cervical cancer. Persistence consistently is associated with high-ris) viral types, particularly HPV :. Persistence of the virus also has (een associated with having
!:
multiple sexual partners, cigarette smo)ing, immune suppression, and oral contraception. HPV viral persistence appears to (e a complex interaction of sexual (ehaviors, coexisting genital infections, and viral characteristics ('arcia 0hewet et al., "##=). .he ma/orities of HPV infections are self-limited and spontaneously clear within a several-year period as a result of cell-mediated immunity. In one study, two-thirds of adolescents infected with low ris) HPV types spontaneously cleared their infections (y " months, as did over half of those infected with high-ris) HPV types. 2y "! months, more than 3#, had cleared their HPV infections. In another follow-up study of adolescents and young women with D0ID, + , of HPV-infected individuals cleared their infections after !: months of follow-up. However, many women who spontaneously clear one specific type of HPV (ecome infected with another HPV type. .his is part of the reason that infection with multiple types of HPV is Guite common in sexually active adolescents and young women (.homas 8right, "##+). Persistence of Human Papilloma Virus (HPV) infection is necessary for the development of cervical cancer. -dditionally, infection with HPV is implicated in the ma/ority of cases of other genital tract malignancies including vulvar, penile, and vaginal cancer. HPV testing and vaccination are a routine part of o(stetricalHgynecological clinical practice. 8ith an enhanced pu(lic awareness of HPV infections, many patients turn to their o(stetriciansHgynecologists with Guestions a(out transmission, testing, and prevention. In this review, we will discuss the (iology of HPV, epidemiology of disease, methods and indications for testing, and vaccination strategies. (>ric)son et al., "# !). 2.1, DETERMINANTS OF HPV INFECTION -lthough HPV is a necessary factor for the causation of cervical cancer, it appears to (e insufficient. Various other factors including host cell factors are necessary for progression of HPV-infected precursor lesions to cancer. .he primary ris) factors for acGuiring HPV are generally associated with sexual activity. HPV is so common and transmissi(le that having /ust one sexual partner often results in infection. Indeed, cumulative prevalence rates are as high as 3", among adolescent women in select populations. -s such, nearly all sexually active adolescents are at high ris) for acGuiring HPV (-nna-2ar(ara 'oscic)i, "##=). .he main factors associated with HPV infection
!$
are sex, age, race, sociodemographic characteristics, prior sexually transmitted infections, parity, contraceptive methods, 5ietary factors and smo)ing (>liane 5uarte-9ranco, "##%) .he most significant ris) factor for HPV infection is sexual (ehaviour. .he total num(er of sexual partners and the num(er of recent partners appear to (e the most consistent factors, particularly for infections with carcinogenic HPVs. -ge at the time of the first sexual contact is a less constant factor of HPV infection ..here are several studies suggesting that the num(er of sexual partners is an important mechanism through which adolescent and young adult women acGuire HPV. - longitudinal cohort study of female university students (6 W:#3) proved that a prior coercive sexual experience was associated with a higher lifetime num(er of sexual partners ( p O.### ), which in turn associated with su(seGuent HPV infection (p! .### ) and 0ID (p O .### ). In logistic regression models, coercive sexual experience was associated significantly with HPV (odds ratio XJ@Y, .3%4 +=, confidence interval X?IY, . + *".3%) and at a marginal significance level with 0ID (J@, .+#4 +=, ?I, .+$*!.$#) (Aessica 1ahn et al., "##=). study conducted among randomly selected women aged 3 to "% years, living in 0icily (south Italy) found that .he only ris) factor for HPV infection was the num(er of sexual partners (women with "-! partners versus women with partnerK odds ratio, !.3:4 +=, confidence interval, ".%=-:.#+) ( Pietro -mmatuna et al., "##3) Jther factors, such as 0.I history, hormonal factors (oral contraceptives or pregnancy), condom use, and smo)ing are occasionally associated with HPV infection. 2.11 CLINICAL MANIFESTATION OF HPV AMONG ADOLESCENTS 0everal studies have indicated that the incidence of cervical cytologic a(normalities among adolescents is rising. .he dramatic increase in the incidence of cervical a(normalities among adolescents is li)ely multifactorial, related primarily to increasing rates of sexual activity and HPV infection in this age group. -dolescents with sGuamous intraepithelial lesions of the cervix are at su(stantial ris) for the development or persistence of high-grade cervical intraepithelial neoplasia. -mong adolescents, the rate of -0?-;0 ranges from $* :,, D0ID from !* !,, and H0ID from #."*!, -0?;0 cytology in girls and women aged was #* + years (etween ++= and +++ was performed. .he study group consisted of !+3 patients and the mean duration of follow-up + months. @epeated cytology and colposcopy of cervical (iopsies were done.
!3
Persistent -0?-;0 was identified in := ( :,), low-grade sGuamous intraepithelial lesionsHcervical intraepithelial neoplasia (?I6) was found in %% ( ,) and high-grade sGuamous intraepithelial lesionsH?I6 " or ! occurred in !: (+,) of the adolescents. 6o cases of invasive carcinoma were found (8right et al., "##%).similar HPV testing was done (etween Auly "##" and 9e(ruary "##% among adolescents. 8hen stratified (y age, $$, of the women aged younger than "# years were positive for high ris) su(types. .he rate of oncogenic HPV infection approached 3#, in adolescent women with -0?;0 (2oardman et al., "##=). - cytological diagnosis of D0ID or H0ID was done among :%: adolescents (etween ++$ and "##!. In that, 3, of teenagers with D0ID and = , with H0ID were eventually found with a high-grade lesion. .hus, adolescents with cytology reported as 0ID carry a similar ris) for underlying cervical intraepithelial neoplasia as adults (8right et al., "##=) the incidence of cervical intraepithelial neoplasia (?I6) was estimated in adolescents (ages %*" years)with a(normal cytology from ++" to "##%. -dolescents with a(normal cytology were found to have a high incidence of ?I6"H!, yet no cases of cancer were identified (-shley et al., "##:). 0imilarly a study was conducted to estimate the ris)s of cervical intraepithelial neoplasia (?I6) !among :"" adolescents aged ! to "% years with a(normal cytology. It showed that ?I6 ! is relatively rare in adolescents and young women referred for a(normal cytology. .hose with ?I6 ! appear to have an extremely low li)elihood of progression to cancer (ecause none was found in the time frame of this study. .he primary ris) for ?I6 " and ! in this age group remains HPV : and 3 infections (-nna-2ar(ara 'oscic)i et al., "##3) 2.1< PROGRESSION OF CERVICAL CANCER -lthough more than +#, of HPV infections are spontaneously cleared (y the immune system, some infections will cause D0ID, H0ID, or progress to cervical cancer (-nna-2ar(ara 'oscic)i, "##=). 9unctionally high-ris) HPV infection contri(utes to carcinogenesis and tumor progression predominantly through the actions of two viral oncogenes, >: and >$. .hese oncogenes are consistently expressed in cervical cell lines and in human cancers. 2oth of these oncogenes interact with and inhi(it the activities of critical components of cell cycle regulatory systems, in particular >: with p=! and >$ with @(. .he >$ protein interacts with p@2 and inactivates this cellular protein. -s a
!+
conseGuence, >"9 transcription factor is released from p@2->"9 complex, leading to transcriptional activation of several genes involved in cell proliferation. 2inding of the >: protein to the p=! promotes the degradation of the latter through a u(iGuitin -dependant proteolysis system. -lso of significance is that on completion of the degradation of p=! (y the u(iGuitin-dependant proteolysis system, the >: protein is free to interact again with remaining p=! molecules, leading to further degradation of the latter (0ree)ala 6air et al., "##=). 2.14 HPV E4 INTERACTIONS WITH BAB -poptosis, or programmed cell death, triggers a series of events that lead to the expeditious elimination of unwanted cells. In actively proliferating tissues, intrinsic apoptotic signaling is controlled (y mem(ers of the "cl-2 gene family, which are critical regulators of mitochondrial integrity and of mitochondria-initiated apoptosis. .his family contains (oth anti-apoptotic ("cl-2#"cl-$%) and pro-apoptotic species ("a&, "ad and "id). .hus, "a& promotes apoptosis whereas "cl-2 represses apoptosis. >: has (een shown to prevent apoptosis in (oth a p=!-dependent and a p=!-independent manner (Pan et al, ++=). P=! is one of the (est )nown inducers of apoptosis, (ut its activity in HPVinfected cells is countered (y viral >: protein. 'oreover, >: can damage p=! (y targeting it for u(iGuitin-mediated proteolysis. However, >: has (een shown to prevent apoptosis in (oth a p=!-independent and dependent manner. @ecent research into HPV >: oncogenic properties found that pro-apoptotic effect of 2a) is a target of anogenital HPV >: protein, and that this proceeds in a p=!-independent manner (.homas et al., ++3). >: proteins from HPV- 3, HPV- : and HPV, can all (ind 2a) in vitro and stimulate its degradation in vivo, and this 2a) down regulation was found to induce apoptosis via a >:-P-dependent process (.homas et al, ++3). In fact, 2a) was found to (ind >:associated protein (>:-P) in the a(sence of >: unli)e p=! (<ur Hausen, "###). .his terminology classifies the different types of o(served lesions. 0Guamous Intraepithelial Desions (0ID), also called ?ervical Intraepithelial 6eoplasia (?I6), represent precancerous cellular changes in the sGuamous epithelium of the uterine cervix (0uris, +++). .he D0IDHH0ID denominations are used mainly to express cytological results, while ?I6 -! represent histological diagnostics. ?ytological lesions are classified as low- and high-grade lesions (D0ID and H0ID), which correspond to histological diagnoses
%#
of ?I6
(D0ID) and ?I6 " and ! (H0ID), reflecting the increasingly a(normal
maturation of the affected epithelium. 2.1: IMMUNE RESPONSE .he immune response can (e divided into " typesK innate immunity and acGuired immunity. Innate immunityK In humans, innate immunity is the first line of defense against pathogens. .his nonspecific resistance is provided (y the s)in and a variety of other responses, including interferon-Z, cyto)ines, neutrophils and macrophages. A"C& *+. ''&% #/K -cGuired immunity is specific for each pathogen and can (e further divided into humoral and cell-mediated immunity. Humoral immunity involves the production of anti(odies (y the 2 lymphocytes. .hese anti(odies specifically (ind to the recogni<ed antigens ma)ing it easier for phagocytosis of pathogens or for lysis (y complement. 8ith cell-mediated immunity, speciali<ed cells are produced that react with the foreign antigens. .he reacting cells )ill the virus-infected cells (efore the occurrence of viral replication. Humoral responses are more important in the context of HPV vaccine (Aha ;rvashi Prasad et al., "##3). 2.1:.1 EVASION OF IMMUNE RESPONSE BY HPV .here are a num(er of mechanisms (y which HPV and its resulting neoplasia evade recognition (y the hostK HPV infects )eratinocytes, which are not good -P?s. .he virus is not lytic in its normal life cycle, and intraepithelial lesions are not necrotic, so no Ldanger& signals are produced to stimulate the immune system. ?apsid proteins are produced late in the life cycle, in superficial epithelium distant from normal immune surveillance and at low levels, compared with other viruses. HPV proteins have immunosuppressive actions. .here is no viraemic stage of infection and therefore little opportunity for systemic antigen presentation (-manda .ristram et al., "##$).
2.1> DIAGNOSIS Human papillomavirus testing is complicated (ecause of the nature of the virus. It cannot (e cultured, and anti(ody methods are relatively insensitive4 therefore, HPV detection reGuires some form of nucleic acid test. .he viral life cycle is restricted to differentiating epithelium4 therefore, a cellular sample collected from the site of infection is reGuired. 9urther, HPV is not a single virus (ut a family of more than ## closely related viral types. .he types are distinguished (ased on differences in their 56seGuence. -ssays must (e designed to handle the complexity introduced (y the large num(er of HPV types. Human papillomavirus testing has (een used to understand the epidemiology and natural history of the virus. .he nature of the sample and the assay will frame the view of infection. 5efinitions of occult, persistent, or recurrent infection are complicated (ecause of these issues. 'ethods for HPV testing include commercial tests, such as Hy(rid ?apture (H?4 5igene ?orporation, 0ilver 0pring, ;0-) and a variety of Polymerase ?hain @eaction (P?@) protocols. Hy(rid ?apture (H?) is a commercially availa(le solution hy(ridi<ation test and is the only HPV detection system that is approved (y the ;0 9ood and 5rug -dministration. It is relatively simple to use and therefore suita(le in a screening setting, (ut it does not provide information regarding individual HPV types present in a sample. Hy(rid ?apture " contains a coc)tail of pro(es for ! H@ ( :, 3, ! , !!, !=, !+, %=, = , =", =:, =3, =+ and :3) and = D@ (:, "##$). ?ervical cancer and genital warts are caused (y HPV. However, testing for the virus using standard techniGues can sometimes give a negative result -- in these cases, the condylomas are called [virus-negative[ warts. In a new study pu(lished in 'irology, researchers assessed the 56- found in samples ta)en from %# patients with [virusnegative[ genital warts. .hrough a general 56- seGuencing approach, the researchers showed that several of the negative samples did in fact contain HPV 56-. (Hanna Aohansson et al., "# !). , %", %! and %%) types. (-manda .ristram et al.,
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2.1>.1 TESTING METHODS FOR HPV DETECTION 0everal effective molecular diagnostic techniGues are availa(le for HPV infection. .he 0outhern 2lot method, 5ot 2lot method (ViraPap, Viratype), 9I0H method (filter in situ hy(ridi<ation), In situ hy(ridi<ation (I0H), Hy(rid captureII and P?@ (Polymerase ?hain @eaction). - new method for HPV detection and genotyping is the 56- ?hip. .his method, still under evaluation, uses P?@ amplification products and is a(le to identify "" HPV genotypes. HPV detection is strongly affected (y the Guality of the samples, in terms of cell Guantity. Jnly the P?@s include a control of the cells content of the sample. 2.1>.1 2a) THE HYBRID CAPTURE II ASSAY 2DIGENE) .he Hy(rid ?apture II assay (5igene) is commercially availa(le. It is a nucleic acid hy(ridi<ation assay with signal amplification that utili<es microplate , %", chemiluminescent detection. .he assay is highly sensitive and can detect 56- for ! High-@is) ( :, 3, ! , !!, !=, !+, %=, = , =", =:, =3, =+, :3) and five low-ris) (:, %!, %%) HPV types (?lavel et al., performance as a triage test it is not a sensitive or type-specific assay. 2.1>.1 26) PAP TEST .he Pap test is the gold standard for detecting a(normal cell changes in the uterine cervix due to HPV was developed (y Papanicolaou in the +"#s (?armichael, +$!). ?ells are collected from the outer opening of the cervix and the endocervix (transformation <one) using a speculum and Hor (rush and fixed on a glass followed (y examination under a microscope to loo) for a(normalities. .he test aims to detect potentially pre-cancerous changes, which could (e removed. It is the most widely used test in screening for cervical cancer worldwide. In -merica, the Pap test has reduced the incidence of cervical cancer from %#H ##,### to 3H ##,### women. In 9inland, 0weden, 2ritish ?olum(ia and ?anada, the incidence of cervical cancer has decreased up to $#3#, (Hristova and Ha)ama, ++$4 6ieminen et al., +++). It has (een o(served that the introduction of the Pap test in a population which has never (een screened for cervical cancer may reduce the ris) (y :#-+#, among women over "= years of age (I-@? "##=). -lthough the Pap test is a gold standard, if done once it has a sensitivity ranging from =#3#,. .he repeated sampling following an organi<ed programme is crucial.
++34 ?haudhary et al., "# #). 5espite its good
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2.1>.1 2") MULTIPLED HPV GENOTYPING 'ultiplex HPV genotyping is (ead-(ased Guantitative and high-throughput 56hy(ridi<ation method that uses the Duminex suspension array techniGue to simultaneously detect and genotype up to ## HPV types (0chmitt et al., "##:). .his method is (ased on the amplification of a seGuence of HPV 56- (in the D gene) identified (y the consensus primers EP=NH:N and the su(seGuent detection of the amplicons with type-specific oligonucleotide pro(es coupled with fluorescence-la(elled polystyrene (eads with a diameter of =.: \m that are internally dyed with various ratios of two spectrally distinct fluorophores, creating an array of ## different (ead sets with specific a(sorption spectra (Douvanto et al., "# #). It has a compara(le principle to that of 'ultiplex HPV serology. ,.>.2 METHODS OF HPV TYPING .he presently existing methods for identifying HPV types include type-specific P?@, line (lot methods and pyroseGuencing. @everse line (lot analysis is a Guic) and simple HPV typing procedure, (ased on EP=NHEP:N P?@ amplification products. .his method can analy<e %" samples per day per mem(rane, with a concordance of +:.=, for (oth single and multiple infections. 2.1>., SEROLOGY .he detection of HPV anti(odies is less used, due to the multitude of HPV genotypes and inconsistent immunological response. @oughly half of the cervical cancers are associated with HPV : and only half of these HPV : infections induce a seroconversion for un)nown reasons (H]pfl, "## ). -ccording to 5aling ( ++:), HPV seroprevalence is an unrelia(le measure of HPV exposure, its association with the presence of viral 56- demonstrating wea) sensitivity. -mong women with HPV : 56- detected, only %".$-%:, was seropositive. .he sensitivity of serology for detecting anti-HPV anti(odies is approximately =#, in (est case scenarios, may(e up to :=-$=,. 0pecificity is difficult to measure (ut is estimated at more than +3, (5illner, "###). HPV seropositivity is associated with the num(er of sexual partners, cytological lesions and previous HPV : infection.
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.he only HPV test approved (y the ;.0. 95- for clinical use is 5igene&s Hy(rid ?apture " HPV 56- test (H?"). .his test can (e applied to cervical cells collected with the 5igene ?ervical 0ampler (includes (rush and media), cervical cells collected for liGuid-(ased cytology, or with cervical (iopsies collected in 5igene 0pecimen .ransport 'edium. .he current assay format uses liGuid hy(ridi<ation in a microarray platform. 0amples are lysed to release nucleic acids and com(ined with the @6- pro(e mixture. .he high ris) pro(e mix includes ! types (HPV :, 3, ! , !!, !=, !+, %=, = , =", =:, =3, =+ and :3). .he @6- pro(es hy(ridi<e to the 56- targets in liGuid phase and are (ound to the wall (i.e., captured) (y anti(odies specific for 56-*@6- hy(rids. .he same anti(ody lin)ed to al)aline phosphatase is used to generate a signal after addition of chemiluminescent su(strate. ?utoff for a positive result is determined (y comparison of the intensity of sample to that of the testing. .ype-specific Polymerase ?hain @eaction (P?@) assays for HPV are availa(le and can (e particularly useful in Guantitative assessments of HPV. However, the large num(ers of types those are of interest limit their usefulness in most studies. P?@ assays that target seGuences that are highly conserved are called consensus assays. .hese assays will generate a product for nearly all HPV types. .ype-specific identification reGuires analysis using seGuencing, restriction fragment length polymorphism assays, or hy(ridi<ation. .he three most widely used consensus P?@ assays are PE'R#+H , EP=NH:N, and 0P9. -ll target the D region. .hey differ in the primer mix, the si<e of the amplified product, and the method for type identification. @esults differ slightly in terms of type-specific sensitivity and specificity. .yping assays using linear arrays or strips allow for efficient detection of multiple HPV types within a sample. Jther HPV assays include serology and in situ hy(ridi<ation. 0erologic assays use >DI0--(ased detection of type-specific anti(odies against D -VDPs (virus-li)e particles). - positive reaction indicates past or current infection (>li<a(eth et al., "##:) In the a(sence of genital samples, Human Papilloma Virus (HPV) serology may (e useful to assess HPV infection in young men and women. HPV seroprevalence and
pgHmD control. .he test has good interla(oratorys
comparisons and has (een widely used in trials determining the clinical utility of HPV
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determinants of seropositivity were assessed in 3 $ female and = 3 male university students in 2usan, 0outh 1orea, of whom $%, and %%,, respectively, reported never having had penetrative sexual intercourse. .ype-specific HPV 56- status, assessed (y a short P?@ fragment primer set, was availa(le from genital samples. 0eropositivity to D proteins of HPV types :, 3, ! , !!, %=, =", and =3 were assessed using multiplex HPV serology. -mong women, HPV seroprevalence was significantly higher among sexually active (":. ,) than nonsexually active students X . ,, odds ratio (J@) W ".+4 +=, confidence interval (+=, ?I), .3-%.$Y, although the association was wea)er than that for HPV 56- prevalence (J@, %4 +=, ?I, %.$-%"). 9urthermore, HPV seroprevalence was higher among HPV 56--positive ("%,) than HPV 56--negative women ( !,), and there was a positive correlation of type-specific seroprevalence with the presence of HPV 56- of the same type (Eary ?lifford, "# !). 2.1>.1 HPV DETECTION IN URINE SAMPLE In one study, the prevalence of and the ris) factors for human papillomavirus (HPV) infection and a(normal cytologic test results in ! " adolescent girls (mean age, :. years) were determined. 0u(/ects had a median of " years of sexual activity and % lifetime sex partners. ?ervical HPV was detected (y use of D -consensus polymerase chain reaction in :%, of su(/ects4 half of those with HPV had types, and $$, had high-ris) type. Independent ris) factors for HPV were lifetime num(er of sex partners, age of partner, and douching. ?ytologic a(normalities were common ("#.+, of su(/ects had atypical sGuamous cells of uncertain significance, and $.#, had high- or low-grade sGuamous intraepithelial lesions) and were significantly associated with detection of HPV4 however, most (= .:,) su(/ects with HPV had normal cytologic test results (.ar)ows)i et al., "##%). - study was conducted with self-collected urine samples from ## sexually
unexposed college going girls and cervical scrapes from #% normal healthy sexually active married women and a group of == women were recruited for collecting first urine and later scraped cervical cells to validate urine sampling (y directly comparing HPV positivity (etween the two types of (iological specimens. It was found that that urine can (e used for detection of genital HPV infection and convenient tool for noninvasive screening of healthy women and adolescent who may har(or oncogenic high-ris) HPVs
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(Prusty et al., "##=). -nother study demonstrated that the case (y case matching of HPV positivity and negativity (etween urine and cervicalHpenile scrapes or (iopsies o(tained from women with cervical cancer and their male partners demonstrated that the noninvasive urine sampling can (e relia(ly used for screening genital HPV infection in (oth men and women (-mita Eupta et al., "##:)..he same good results were o(served in 1orea when urine and cervical swa(s of women with cervical lesions were matchedK HPV-56- was found in $# H ## cervical samples and in %$ H +# urine samples (0ong et al., "##$). .ype-specific agreements were good for HPV :, 3, =", and =3. 0imilar results were seen in Ereece, in patients with HPV- :-infection, and in Sim(a(we, in women who had invasive cervical cancer (0tanc<u) et al., "##!). 9am(rini successfully used urine for the follow up of women after coni<ation of their cervical lesions4 this resulted in +:.:, concordance (etween cervical scrapes and urine (9am(rini et al., "##3). Powell found that young girls (children) with Dichen 0clerosus (D0) and non-D0-related vulvar pathology had a higher chance of intermediate and high-ris)-HPV than girls with no )nown vulvar disease (Powell et al., "##!). @ecent studies showed HPV prevalence in HIV positive-women&s urine and cervical smear samples, of %3-3 .= and = .+-=3,, respectively. ?oncordance (etween the samples was $ , in (oth studies. In a population of sexually unexposed college girls only six out of ## urine samples tested positive (Prusty et al., "##=). In the ;0- !":" sexually active women, aged 3 to "= years, were included in the 8-V> III 0tudy (6ational Dongitudinal 0tudy of -dolescent Health), and each produced a urine sample. Jverall, HPV prevalence was ":.+,, and %.!, in women with one lifetime partner. High-ris) types were detected in "#,, of which #, were infected with types covered (y the current vaccines ('anhart et al., "##:). Aaco(son found any HPV in +#, of cervical scrapes and in $=, of urine samples in a group of 3# sexually active -fro--merican adolescents (Aaco(son et al., "###). .hese last two studies show that urine may (e a good tool to screen a mass population. In one study, the clinical efficacy of urine-(ased Human Papilloma Virus (HPV) detection (y oligonucleotide 'icroarray was evaluated and the results of HPV test from
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matched cervical swa( specimens were compared. .he type specific agreement of HPV 56- tests (etween cervical swa(s and urine was good in HPV : ()appa indexW#.:% X+=, ?IK #.=#-#.$+Y), 3, =", and =3 and fair in HPV !! and !=. It was found that urine HPV test is a valua(le ad/unctive method for a conventional Pap smear and can (e used in population screening for cervical cancer in countries where it is difficult to o(tain colposcopic specimens for cultural or religious reasons (>un-0eop 0ong et al., "##$). 0amples yielding a positive result for the human I-glo(in gene were amplified for detecting HPV using three consensus primer sets (for detecting more infected women) as it has (een reported that using a single set might lead to underestimating viral prevalence compared to studies using more than one generic detection system (Iftner et al., "##!)..wo of the primers sets were directed to the region encoding late viral protein D K EP=NH:N and 'R#+H (5e @oda Husman et al., ++=). Infection, coinfection and type-specific Human Papilloma Virus (HPV) distri(ution was evaluated in human immunodeficiency virus (HIV)-positive women from paired cervical and urine samples. Paired cervical and urine samples (n W "#%) were ta)en from HIV-positive women for identifying HPV-56- presence (y using polymerase chain reaction (P?@) with three generic primer sets (EP=NH:N, 'R#+H and p; 'H"@). HPV-positive samples were typed for six high-ris) HPV (H@-HPV) (HPV- :, - 3, -! , -!!, -%= and -=3) and two low-ris) (D@-HPV) (HPV-:H ) types. -greement (etween paired sample results and diagnostic performance was evaluated. HPV infection prevalence was $#.:, in cervical and :!.", in urine samples. HPV- : was the most prevalent HPV type in (oth types of sample (::.$, in cervical samples and :".#, in urine) followed (y HPV-! (%$.",) in cervical samples and HPV-=3 (!=.$,) in urine samples. .here was ==.%, coinfection (infection (y more than one type of HPV) in cervical samples and %#.", in urine samples. -(normal Papanicolau smears were o(served in "=.!, of the women, presenting significant association with HPV-56(eing identified in urine samples. .here was poor agreement of cervical and urine sample results in generic and type-specific detection of HPV. ;rine samples provided the (est diagnosis when ta)ing cytological findings as reference. In conclusion including urine samples could (e a good strategy for ensuring adherence to screening programs aimed at reducing the impact of cervical cancer, since this sample is easy to o(tain and showed good diagnostic performance ('arina 'uno< et al., "# !).
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2.1? VACCINES .he development of HPV vaccines has ta)en many years, since there is no effective culture system to propagate HPV. .he pro(lem has (een solved (y using the D coat protein to produce Virus-Di)e Particles (VDPs), which contain no viral 56-. However, their outward close resem(lance to the actual virus activates a strong immune response. .here are = HPV genotypes which have carcinogenic potential4 so far, the vaccines contain VDPs against only two types. It appears that HPV gains entry through a micro a(rasion of the genital epithelium and enters )eratinocytes in the (asal epithelium (0tanley, "# #). HPV does not cause a viraemia and, therefore, there is no systemic infection to trigger anti(ody production, facilitating the persistence of the infection, and then transmission (y shed epithelial cells. .here may (e a local cell-mediated immune response, which results in clearance of the infection, (ut does not always result in the production of serum neutralising anti(odies. Jnly around half of those infected develop anti(odies to the virions, and even then the levels are usually too low to prevent reinfection, even with the same HPV type (0chwar<, "##34 0afaeian, "# #). 'erc) F ?o (Eardasil * mar)eted (y ?ommonwealth 0erum Da(oratories X?0DY in 6ew Sealand) and Elaxo 0mith 1line (E01 * ?ervarix) have (oth developed vaccines that have (een licensed in 6ew Sealand. Eardasil contains VDPs for HPV types :, , : and 3 and ?ervarix VDPs for HPV types : and 3. Eardasil is licensed in females aged + to %= years and males aged + to ": years (0exually .ransmitted Infection >ducation 9oundation "# ").Jn this (asis, two prophylactic vaccines containing type - : and- 3 specific antigens were recently developed4 to date, they have showed a $*+ year clinical efficacy of a(out ##, against cervical cytological a(normalities caused (y HPV- : and - 3 genotypes, with a varia(le cross-protective efficacy against cervical lesions associated with other high-ris) oncogenic types ('alago et al., "# "4 8heeler et al., "# "). .he arena of vaccination, which has (een adversely affecting so many children, is now a center point for documenting how 2ig Pharma has ta)en over so much of science, resulting in outright fraud that&s used to promote their products. 0cientists Duci/a .oml/enovic ?hristopher 0haw, Audy 8ilyman, >va Vanamee, and .oni 2ar) use the example of 'erc)&s Eardasil, Human Papilloma Virus (HPV) vaccine, to demonstrate the
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point that HPV vaccine activism is not (ased on science, (ut instead on misrepresentations of science. In a letter signed (y all five of these scientists, they point out several flaws in the claims 'erc)&s Eardasil and Pfi<er&s ?ervarix ma)e to sell their vaccineK . HPV vaccines have never (een shown to prevent cervical cancer. ". .he end-points used in the studies are (ased on infections and lesions that usually heal without !. Help, so how can they demonstrate efficacy in preventing cancer several years later^ %. .he trials are (iased to produce false negatives and therefore cannot accurately estimate the ris) of developing cancer. =. Passive methods of recording adverse effects cannot accurately reflect how prevalent they are. :. -ccurate estimates of the actual freGuency of HPV vaccine adverse effects cannot (e made when such effects are automatically dismissed as unrelated to the vaccine. $. 8omen are not informed that, in some instances the HPV vaccines may increase the rate at which existing a(normalities develop, thus causing the cancer from which they&re supposedly (eing protected. 3. 8hen information a(out HPV vaccine ris)s and limitations are not provided, women cannot possi(ly ma)e informed decisions a(out whether to have the vaccine. (Heidi 0tevenson, (reen med in)ormation, )e*, !). .here are currently two HPV vaccines on the mar)et, (ut if there was any regard for sound scientific evidence, neither would (e promoted as heavily as they are. .he first, Eardasil, was licensed (y the ;0 9ood and 5rug -dministration (95-) in "##:. It is now recommended as a routine vaccination for girls and women (etween the ages of +-": in the ;0. .he second HPV vaccine, ?ervarix, was licensed in "##+. ('ercola, !). .he study pointed out that HPV vaccine upta)e among young girls in the ;0 has (een low (ut concluded thatK +,ithin )our years o) vaccine introduction, the vaccine-type -P' prevalence decreased among females aged %* + years despite low vaccine upta)e. .he estimated vaccine effectiveness was high.C
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- new study loo)ing at the prevalence of Human Papilloma Virus (HPV) infections in girls and women (efore and after the introduction of the HPV vaccine shows a significant reduction in vaccine-type HPV in ;.0. teens. .he study, pu(lished in Xthe Aune issue ofY .he Aournal of Infectious 5iseases reveals that since the vaccine was introduced in "##:, vaccine-type HPV prevalence decreased =: percent among female teenagers %- + years of age. -(out $+ million -mericans, most in their late teens and early "#s, are infected with HPV. >ach year, a(out % million people (ecome newly infected. B.his report shows that HPV vaccine wor)s well, and the report should (e a wa)e-up call to our nation to protect the next generation (y increasing HPV vaccination rates,C said ?5? 5irector .om 9rieden. B;nfortunately only one third of girls aged !- $ have (een fully vaccinated with HPV vaccine. ?ountries such as @wanda have vaccinated more than 3# percent of their teen girls. Jur low vaccination rates represent =#,### preventa(le tragedies * =#,### girls alive today will develop cervical cancer over their lifetime that would have (een prevented if we reach 3# percent vaccination rates. 9or every year we delay in doing so, another %,%## girls will develop cervical cancer in their lifetimes.C(5ivision of 6ews F >lectronic 'edia, !). -ccording to ?5?, each year in the ;nited 0tates, a(out +,### cancers caused (y HPV occur in women, and cervical cancer is the most common. -(out 3,### cancers caused (y HPV occur each year in men in the ;nited 0tates, and oropharyngeal (throat) cancers are the most common. .he study (y 5r. Dauri 'ar)owit< and colleagues at the ?5? used the 6ational Health and 6utrition >xamination 0urvey (6H-6>0) data to compare prevalence or proportion of girls and women aged %-=+ years with certain types of HPV (efore the start of the HPV vaccination program ("##!-"##:) with the prevalence after vaccine introduction ("##$-"# #). .hrough these promising results, pu(lic health experts and clinicians loo) forward to more people getting vaccinated for HPV. @outine vaccination at age - " for (oth (oys and girls is recommended, (ut according to recent national immuni<ation surveys, only a(out half of all girls in the ;.0. and far fewer (oys received the first dose of HPV vaccine. - series of three shots is recommended over six months. HPV vaccination is
also recommended for older teens and young adults who were not vaccinated when younger (?5?, "# !). .he 9ood and 5rug -dministration (95-) has approved two vaccines that protect against HPV types : and 3, which cause $#, of cervical cancers. Jne of the vaccines also protects against types : and , which cause a(out +#, of genital warts. .he 95has approved (oth vaccines for use in girls and women + to ": years old, and the second vaccine for prevention of genital warts in (oys and men + through ": years old. .he vaccines are given in three doses over a period of six months. .he -merican -cademy of Pediatrics recommends that (oth girls and (oys receive HPV vaccines (etween ages and " and that those ages ! to " that haven[t had the vaccine (e immuni<ed. .he 95- says the vaccines are considered safe (ut are only effective if given (efore an initial exposure to the virus. --P recommends that young people who are sexually active still receive the vaccination as those already infected with one type of HPV infection may (enefit from the protection against other types included in the vaccine. 2.1?.1 ABOUT GARDASIL E-@5-0ID is approved for use in more than "= countries. -s of Auly "# ", more than += million doses of E-@5-0ID have (een distri(uted worldwide4 however, it is not )nown how many doses have (een administered. 'erc) is pursuing a systematic and thoughtful approach to improve access to E-@5-0ID in the developing world through four )ey pillarsK innovation, partnerships, pricing and implementation. .he initiative in ;ganda follows the launch in -pril "# of a comprehensive cervical cancer prevention program in @wanda incorporating (oth HPV vaccination and HPV testing, the first program of its )ind in -frica. In its initial year, an estimated +! percent of eligi(le girls " to = years of age in @wanda were vaccinated with three doses of E-@5-0ID. -lso, in "# # 'erc) partnered with the @oyal Eovernment of 2hutan and -ustralian ?ervical ?ancer 9oundation to launch a six-year national vaccination program with E-@5-0ID for appropriate girls and young women (etween the ages of " and 3 in 2hutan. (Heidi 0tevenson, "# !).
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2.1?.2 Va"" %+ S#$*a0+ a%. Ha%.l %0 HPV vaccines should (e stored continuously at !=_*%:_9 ("_*3_?) and should (e protected from light. .he vaccine should (e removed from refrigeration immediately (efore administration. .he vaccines must not (e exposed to free<ing temperature. Vaccine exposed to free<ing temperature should never (e administered. 2.1?., HPV Va"" %+ Is Ass$" a#+. 8 #- S+* $&s H+al#- R s7s5 I%"l&. %0 S&..+% D+a#'any women are not aware that the HPV vaccine Eardasil might actually increase your ris) of cervical cancer. Initially, that information came straight from 'erc) and was presented to the 95- prior to approval. -ccording to 'erc)&s own research, if you have (een exposed to HPV strains : or 3 prior to receipt of Eardasil vaccine, you could increase your ris) of precancerous lesions, or worse, (y %%.: percent. Jther health pro(lems associated with Eardasil vaccine include immune-(ased inflammatory neurodegenerative disorders, suggesting that something is causing the immune system to overreact in a detrimental way sometimes fatally.
2etween Aune
, "##: and 5ecem(er ! , "##3, there were
",%"% reported
adverse events following Eardasil vaccination, including !" deaths. .he girls, who were on average 3 years old, died within two to %#= days after their last Eardasil in/ection.
2etween 'ay "##+ and 0eptem(er "# #, : additional deaths after Eardasil vaccination were reported. 9or that timeframe, there were also $3+ reports of `serious` Eardasil adverse reactions, including " ! cases of permanent disa(ility and "= diagnosed cases of Euillain-2arre 0yndrome. 2etween 0eptem(er , "# # and 0eptem(er =, "# reported following HPV vaccination. , another ": deaths were
-s of 'ay !, "# !, V->@0 had received "+,:3: reports of adverse events following HPV vaccinations, including !: reports of death, as well as +"" reports of disa(ility, and ==# life-threatening adverse events.
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2.1?.1 Cas+ R+($*# $! a Ga*.as l D+a#- C$%! *'s P*+s+%"+ $! HPV DNA F*a0'+%#s >arlier this year, a la( scientist, who discovered HPV 56- fragments in the (lood of a teenage girl who died after receiving the Eardasil vaccine, pu(lished a case report in the peer reviewed /ournal .dvances in "ioscience and "iotechnology . .he otherwise healthy girl died in her sleep six months after receiving her third and final dose of the HPV vaccine. - full autopsy revealed no cause of death. 0in Hang Dee with the 'ilford 'olecular Da(oratory in ?onnecticut confirmed the presence of HPV- : D gene 56- in the girl&s postmortem (lood and spleen tissue. .hese 56- fragments are also found in the vaccine. .he fragments were protected from degradation (y (inding firmly to the particulate aluminum ad/uvant used in the vaccine. +/he signi)icance o) these -P' 0N. )ragments o) a vaccine origin )ound in post-mortem materials is not clear and 1arrants )urther investigation,2 he wrote. Dee suggests the presence of HPV 56- fragments of vaccine origin might offer a plausi(le explanation for the high immunogenicity of Eardasil, meaning that the vaccine has the a(ility to provo)e an exaggerated immune response. He points out that the rate of anaphylaxis in girls receiving Eardasil is far higher than normalareportedly five to "# times higher than any other school-(ased vaccination programb ('ercola, "# !).
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,. MATERIALS AND METHODS ,.1 STUDY POPULATION .he study population consists of "!# college going adolescent girls from various parts of >rode 5istrict. -ll the su(/ects were recruited (etween Aanuary "# ! to -ugust "# !. -ll the participants were volunteers who gave informed written consent. .he exclusion criteria include those who had prior malignancy, mental illness, and the participants those who had received anti(iotics in the previous month. -ll participants were provided self collected first voided urine in a =#ml collection tu(es and the samples were immediately transported to la( in icepac)s. .he samples were refrigerated until processing. 0u(/ects were entered the study providing signed informed consent form. .hey were interviewed with a structured Guestionnaire to o(tain information on their age, sex, residence, family income, and medical history. 'any of adolescent girls were uncomforta(le in giving urine samples for testing. 'any of those who were refused to give their personal history are not ta)en in to the study. 0o, a total of " # adolescent girls were included in this study. .he data and samples were unlin)ed and anonymous. ,.2 SAMPLE COLLECTION AND PROCESSING -(out =#ml of first voided urine sample were collected from each individual in a =#ml conical (ottomed centrifuge tu(e and stored at % ? (efore processing. >ach sample was thawed, then aliGuoted in to #ml and centrifuged at =###rpm for !#mins. .he supernatant was decanted and resulting cell pellet was resuspended in ml ice-cold 7 P20 and again centrifuged at !###rpm for =mins and resulting cell pellet was stored at -"#?. Jf the " # urine samples collected, pellet was not o(tained in $ samples and nearly ! samples were turned tur(id and cloudy while transporting, so excluded from analysis leaving a total of "## for further analysis. ,., DNA EDTRACTION METHODS .hree 56- isolation protocols were tested and compared in order to ascertain their relative effectiveness for extracting HPV-56- from urine samples.
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P*$#$"$l 1; B$$' +# al.5 1??@ '+#-$. . -(out #ml of urine sample was centrifuged for !#mins at !###rpm and the pellet was collected. ". .he pellets were washed twice with 7 P20. !. +##cl of D: lysis (uffer and %#cl of diatom suspension was added to each pellet, vortexed well and incu(ated for # mins at room temperature, then centrifuged for = mins at =###rpm. %. -fter centrifugation ml of D" wash (uffer was added and the suspension was transferred to a clean .=ml eppendroff tu(e, and then centrifuged at :###rpm for min. .he pellet was washed twice with D" wash (uffer. =. .hen the pellet was washed twice with $#, ethanol, centrifuged for :###rpm. 6. >ach pellet were washed once with ml acetone, vortexed well and centrifuged for min at :###rpm, dried at =:? for # mins. 7. 56- was eluted in "#cl of distilled water for # min at =: ? in presence of =cl of #mgHml Proteinase 1. 8. .he eluted 56- solution was (oiled for # mins at ##? and centrifuged for min at :###rpm. 9. .he supernatant was transferred to a fresh sterili<ed .=ml eppendroff tu(e and stored at -"#?. P*$#$"$l 2; B$ l %0 '+#-$. . -(out #ml of urine sample was centrifuged for !#mins at !###rpm and the pellet was collected. ". .he pellets were washed twice with 7 P20. !. "#cl of (oiling (uffer ( #m' .ris, pH-3.#, =m' >5.- and , triton ## wHv) was added to each pellet and mixed well (y vortexing. %. .he pellets were (oiled at ###? for #mins and centrifuged at !###rpm for =mins. 5. .he supernatant was transferred to a fresh sterili<ed .=ml eppendroff tu(e and stored at -"#?.
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,.1 DETECTION AND AUANTIFICATION OF DNA .he 56- isolated (y these two methods were detected on #.3, agarose gel and the purity of 56- extracted (y two method were compared (ased on readings at ":#H"3#nm a(sor(ance ratio to analy<e the Guality and Guantity of 56- extracted. ,.1.1 HPV DNA AMPLIFICATION AND DETECTION Initially all samples were su(/ected to I-glo(ulin primer amplification to determine the presence of cellular 56-. 0amples negative for I-glo(ulin were excluded from the study. -ll I-glo(ulin positive 56- samples were then screened (y 'R#+H'R consensus primer spanning the D region of the HPV genome. .hen further analysis of P?@ using type-specific primer for HPV- : was performed. .he primers used, their seGuence and amplicon si<e were given in ta(le . P?@ was performed in a "= cl reaction mix containing :cl of template, ".=m' 'g?l", #m'd6.P, #c' of each primer, ".=; of .aG polymerase. .he thermal cycling consisted of an initial denaturation step at +%o? for %mins, followed (y %# cycles of denaturation at +% o? for min, annealing at ==o? for min and extension $"o? for min respectively and terminated (y final extension $"o? for $mins. R+a"# $% s+#&( S#$"7 C$%"+%#*a# $% #7 #m' "=m' ##c' =;H cl W$*7 %0 C$%"+%#*a# $% 7 "##c' "m' #c' =;
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extension $"o? for min respectively and terminated (y final extension $" o? for $mins. second round of amplification with the general primer positioned inside of the 'R#+ and 'R primer was performed on cl of amplified 56- from the first round of P?@ added to %+ cl of P?@ master mix. -fter an initial denaturation step of +%_? for = min, the samples were su(/ected to %# reaction cycles of denaturation at += _? for min, primer-template annealing at %#_? for "min and primer extension at $"_? for " min. -t the end of the cycles a final extension step at $"_? for # min was performed. Ta6l+ 1 P* '+*s &s+. !$* .+#+"# $% $! HPV
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,.1.2 DETECTION OF AMPLIFIED PRODUCTS -fter P?@ amplification, 3cl of each single-step P?@ product were mixed with "cl of loading dye and were electrophoresi<ed through ", agarose gel at ## volts. 0u(seGuently =cl of the nested P?@ product was electrophoresed through ", agarose
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gel. -fter electrophoresis the gels were stained with ethidium (romide and examined and photographed under ultraviolet illuminator using Eel documentation system. .he (ands of appropriate si<e were identified (y comparison with )nown si<e ladder ( ## - ###(p ladder, 2io-@ad Da(.,). ,.< METHODS OF GEL ELECTROPHORESIS .he edges of a clean, dry glass plate were sealed with tape to form a mold and the mold was set on a hori<ontal section of the (ench. 0ufficient electrophoresis (uffer ( x .2>) was prepared to fill the electrophoresis tan) to cast the gel. .= gm of agarose powder was added to ##ml of x .2> (uffer solution in an >rlenmeyer flas). .he slurry was heated in a (oiling water (ath until the agarose dissolved completely. 8hen the gel had cooled to ==c,ethidium (romide to a final concentration of "#cl of #mgHml was added. .he gel solution was mixed thoroughly (y gentle swirling. .he com( was positioned #.=- .#mm a(ove the plate to form the sample slots in the gel. .he warm agarose solution was poured into the mold and the gel allowed to set completely (!#-%= minutes at room temperature), .hen poured a small amount of electrophoresis (uffer on the top of the gel, the comp was removed carefully. -gain electrophoresis (uffer was poured off and the tape was removed carefully. .he gel was mounted in the electrophoresis tan). -dded /ust enough electrophoresis (uffers to cover the gel to a depth of mm. #cl of P?@ product was mixed with "cl :x gel-loading (uffer and slowly loaded into the slots of the su(merged gel using a micropipette, ##(p 56ladder was used to detect the num(er of (ase pairs. .he lid of the tan) was closed and electrical leads were attached, so that the 56- migrates towards the positive anode. -pply a voltage of -=vHcm..he gel was run until the (romophenol (lue had migrated an appropriate distance thoroughly the gel.
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.hen the electrical current was turn off, the leads and the lid removed from the gel tan). .he gel was examined carefully (y ultraviolet (uv) transilluminator and the results were noted and photographed the gel. ,.4 STATISTICAL ANALYSIS .he t-test analysis was calculated to evaluate the purity of 56- extracted (y protocol (2oom et al., ++#) and protocol " ((oiling method) (ased on a(sor(ance ratio at ":#H"3#nm. Jdds ration and +=, ?onfidence Interval was calculated for determining the prevalence of HPV infection in rural and ur(an areas of adolescent girls included in this study.
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1. RESULTS .his chapter deals with analysis and results of data collected from the college going adolescent&s girls, >rode, .amilnadu. .he study was (ased on the sample of 2@@ s&6F+"#s in the study population. .he data regarding the HPV and other (ac)ground varia(les such as age, occupation, annual income, Height, 8eight, food ha(its, stomach ache, ;.I, Inflammation, Viral infection, 9ungal infection, irritation, itching, loss of (ody weight, (ac) ache, arthritis, lower a(dominal pain, vaginal discharge, Irregular menstruation, >xposure to 0.5, HPV :, screening test for cervical cancer, History of a(normal cell, -norexia, Vaccination etc., were elicited from the randomly selected su(/ects over the population. .he information&s were carefully screened and recorded from the collected samples. .he data were put into several statistical analysis to extensively explicate the prevalence of HPV over the study areas and to explore the results with various socio-demographic varia(les. -nalysis of the data focused on the following o(/ectives, 1.1 G+%+*al O6F+"# )+ .he Prevalence of HPV over the study populations of >rode 5istrict. 1.2 S&6 O6F+"# )+ .o examine the prevalence status of HPV Positive, High-@is) HPV- : in the study su(/ects. .o determine the sign and symptoms of HPV Positive, High-@is) HPV- : .o determine the ris) factors associated with HPV Positive, High-@is) HPV- :. 1., P$l/'+*as+ C-a % R+a"# $% 1.,.1 S %0l+ *$&%. PCR .o chec) the presence of HPV-56-, all samples were initially screened with Iglo(ulin primer and 1@ girls sample were found negative. .hese samples were excluded
from the study, leaving a total of "## urine samples for further analysis. Jnly the HPV56- positive for I-glo(ulin was further analy<ed (y P?@ for 'R#+H'R consensus primer, and two was positive for HPV- :. P?@ amplification of D region of HPV was shown in the Plate and the and typespecific primer HPV- :. Jut of "## urine samples, < were positive for 'R#+H'R
amplified products of HPV- : were shown in Plate ". 1.,.2 DNA EG#*a"# $% .he purity of 56- extracted (y protocol (2oom et al., ++#) and protocol " (2oiling method) was analy<ed using student-t-test. .he t-test analysis of purity of 56isolated (y a(ove mentioned two methods were shown in ta(le . .he P value was found to (e O #.### indicating there was a statistical significant difference (etween two methods employed. -s evidence from the picture and the t-test analysis, the Guantity and Guality of 56- extracted (y (oom et al., procedure was found to (e (etter. .he Guantity of 56- o(tained per urine sample was a(out : to #ng which was sufficient for P?@. .his indicates that protocol (2oom et al., ++#) was an effective method for extraction of HPV-56- from urine sample.
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.he association of socio demographic varia(les with HPV positive result was shown in ta(le-!. Prevalence (J@ for women with age group 3-"# vs." -"! W ."3=4 +=, ?IK #." #-$.3::). 3-"# years was slightly increased level with HPV positivity. Jccupation (J@ for women with rural vs. ur(an W +.%%34 +=, ?IW .#!!-3:.!:). High level HPV positivity was found to (e rural women. -nnual income (J@ for their income "=,### vs. "=,### W #." !4 +=, ?IK #.# -!.#"$) higher level HPV infection was more distri(uted to a(ove "=,### study su(/ects. Height (J@ for women, their height %===cms vs. =:- :=cms W %. 3 4 +=, ?IW #.%!#-%#.:) the height =:- :=cms was found to (e positive for HPV. 8eight (J@ for women, their weight !=-%=vs%:-$#)g- ".!!4 +=,?IW .3%-3".!) the weight %:-$# )g was found to (e positive for HPV. Ta6l+ I 1; Ass$" a# $% $! s$" $ .+'$0*a(- " )a* a6l+s 8 #- HPV 9 14 *+s&l#s C- sC&a*+ #+s# Class ! "a# $%s HPV I 14 T$#al P$s # )+ N$. H " # " # .3= # !. # # N+0a# )+ N$. H N$. H #3 ## .$" " -"! @ural O""&(a# $% ;r(an A%%&al I%"$'+ O"=,### !: =3 ##.# ## !: =3 ## ## #.3"= #.:!$$ #.%3#! #.#""$ #. =+3 +" :" ## +" +:.+ :% ## ## %.!$! #. "%: #.+"## #.= :: "!#.3%"! #.!%=" %.!%"$ #."#=3 + .:"" #: +3. = ?<H C$%! .+%"+ I%#+*)al U((+* l'# L$8+* l'#
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.he association of socio demographic varia(les with HPV - : positive results was shown in a(ove .a(le-$. -ge group ( 3-"# vs. " -"! W %.!%"$4 +=, ?I4 #."#-+ .:") the prevalence of age group 3-"# years was increased level with HPV : positivity. Jccupation, the HPV : positivity (!. ,) was found to (e in rural women. -nnual income ("=,### vs. "=,### W #.%3#4 +=, ?I W #.#""- #. =+. Height and weight, the prevalence of the HPV : positivity were found to (e the height =:- := cms and the weight !=-%= )g. .he unmarried women were more prone to the HPV : infection compared with married women.
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.he associations of symptoms with HPV : positive study su(/ects were resulted in ta(le 3..he prevalence of HPV : positive results were eGually distri(uted in symptoms such as stomach ache (J@W.#.%=4 +=, ?IK #.#"3-$.%#3), ;.I (J@W!3.:4 +=,?IK ". # $#3.+$), 2ac) ache (J5W".%$4 +=,?IK #. ="-%#.""3), a(dominal pain (J5W #.3:4 +=,?IK#.#=!=- %.#$).6one of the positive su(/ects were found to (e fungal infection, Itching, Vaginal discharge, loss of (ody weight, Irritation, arthritis, Inflammation, and viral infection were not much associated with prevalence of HPV infection in the study su(/ects.
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<. DISCUSSION Human Papilloma Virus infections (HPV) remain the most common 0.I of females& particularly afflicting adolescents and women in their early "#s. .he greatest ris) factors for infection are young age and num(er of sexual partners, with highest rates of infection in adolescents and women less than "= years of age ('anop 1anato et al.,
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"##:4 Aessica 1ahn et al., "##=4 'oscic)i et al., "## ). It is accepted that in young sexually active women the li)elihood of (eing exposed to HPV and su(seGuent infection is extremely high. In adolescents, the ma/ority of infections and su(seGuent corresponding cytological a(normalities are transient and of minimal significance in terms of oncogenic potential. Jnly a smaller percentage of adolescents will have persistent infections with higher ris) su(types and manifest high grade cytological a(normalities. In this small percentage of women who fail to clear these infections, persistent infection can predispose to the development of high-grade cancer precursor lesions and cervical cancer. .he Prevalence of HPV infection in pre-pu(ertal girls and college girls was also well documented in previous study (Eallo et al., "##!4 Powell et al., "##!). 0o, early detection of HPV infection and cervical cancer in this age group is reGuired. 'ost of HPV 56- detection uses cervical (iopsies, cervical swa( samples, and cervical scrapes as a 56- source, so patients might overcome the discomfort and the emotional stress of the colposcopic examination. -lso, in developing country li)e India, women and adolescents were rarely present for a routine pelvic exam if they were asymptomatic for disease. .herefore, a relia(le screening method which is non-invasive and comforta(le that could increase the participation rate and cervical cancer screening coverage in population with low compliance for pelvic exam is in need. ;rine sample is one such sample adopted for detection of HPV-56- and it has (een widely accepted. .he reason for using urine for detection of HPV is that the epithelial wall of the uterine cervix andHor vagina normally sheds exfoliated cells into the urine and if there are HPV infections, the shredded cells should contain viral genomes (Prusty et al., "##=). -nd also detection of HPV-56- in first voided urine sample from female urine sample is easier (ecause of the anatomical position of urethra to vagina, vulva and cervix. >arlier it was also demonstrated that HPV 56- could (e detected in urine samples of women with cervical precancer and cancer and the results showed a perfect match of HPV positivity (etween urine and cervical scrapes (2hudev 5as et al., ++"). In this study, first voided urine sample from sexually active married women with healthy cervix for the presence of HPV infection in adolescent girls in >rode, .amilnadu. - total of "## women were initially recruited in this study. .wo different 56- extraction
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protocol was evaluated to find a suita(le method for HPV- 56- extraction from urine and of that 56- isolated (y 2oom et al., ( ++#) method was found to (e of good Guality and presented in ta(le . "## study su(/ects Rielded sufficient 56- for the su(seGuent HPV analysis. I-glo(ulin 56- was not detected in = urine samples, suggesting scarcity or a(sence of cellular material. -mong the += study su(/ects HPV 56- was detected in =(".=,) after a single round amplification with D consensus primer, 'R#+H'R (Plate "). Jut of "## study su(/ects, = (".=,) were positive for HPV infection (y D consensus primer and H@-HPV particularly, HPV- : was detected only in "( ,) were recorded in ta(le age group. Pavani et al., ("##=) made similar o(servations4 the most prevalent HPV types found in the invasive cervical cancer in -ndra Pradesh were HPV- :(::.$,). - study from ?hennai reported ++.=, presence of high ris) in invasive. ?ervical cancer and "! different types were found although HPV- : was most common (9ranceschi et al., "##!). In comparison in our study to previous study performed (y other countries li)e 0rilan)a ##, (5e silva et al., "##:), 2ra<il +:, (>leuterio et al., "##:), India +=, (Peedicayil et al., "##:), 6orway +", (1raus et al., "##:), Dithuania +", (Eudleviciene et al., "##=), -ustralia +#, (Diu et al., "##%), 1orea 3=, (-n et al., "##=), Aapan 3$, (-sato et al., "##%), Italy 3=, (.ornesello et al., "##:), Erace $%, (1onidaris et al., "##$) and ?hina $=-3!, (diu et al., "##$) have shown higher HPV prevalence. .his may (e explained (y the difference in the num(er of samples the type of case group (high-ris) or low-ris) group) or cultural limitations. In present study, the age distri(utions of study su(/ects over the HPVD and HPV : prevalence were presented in ta(le " and figure ". - total of "## study su(/ects were tested for the present study, the prevalence of HPVD ! and " positive su(/ects were found in the age groups 3 * "# and " - "! respectively. .he maximum num(ers of positive su(/ects were found in the age group 3 - "#. In the case of HPV : two positive su(/ects were found in the age group 3-"# respectively. .he result revealed that the
(Plate
).Jn further analysis of type-specific HPV primer, only " were positive for HPV- :
and figure .
HPV- : are more commonly detected than non-
oncogenic HPV types as these women were sexually active and relatively of little higher
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sexually active age group was more prone to HPV infection. 0imilar results are also o(tained (y 9ranceschi et al., ("##=). In our present study the associations of socio demographic varia(les with HPV and HPV : positive results were illustrated in ta(le ! and ta(le-%. -ge group associated with HPV prevalence (J@ for women with age group 3 * "# vs. "# * " W ."3=4 +=,?IK #." #-$.3::) 3-"# years was slightly increased level with HPV positivity. Jccupation (J@ for women wor)ing in rural vs. ur(anW+.%%34 +=,?IK .#!!-3:.!:=) high level HPV positivity was found to (e rural women. -nnual income (J@ for women their income O"=###vsP"=###W#" !4 +=,?IK #.# -!.+"$) higher level HPV infection was seen only higher income group. Height (J@ for women, their height %===cmvs =:- :=cmW%. 3 4 +=,?IK #.%!#-%#.:%) the height =:- :=cm was found to (e positive for HPV. 8eight (J@ for women, their weight !=-%=)g vs. %:-$#)gW ".!!4 +=,?IK .3%:-3".!$) the weight %:-$# )g was found to (e slightly positive for HPV. .he unmarried women were more prone to the HPV infection compared with married women. -ge group associated with HPV : prevalence (J@ for women with age group 3-"# vs. " -"! W%.!%"4 +=,?IK .#."#=-+ .:""). .he HPV : positivity (!. ,) was found to (e in rural women. -nnual income (J@ for women their income O"=###vsP"=###W#.%3#!4 +=,?I4 .#.#""- #. =+) higher level HPV : infection was seen only higher income group. Height and weight, the prevalence of HPV : positivity were found to (e the height =::=cm and the weight !=-%=)g. Jur study was very close to the results o(servation (y -ggarwal et al., ("##:). .he prevalence of HPV positive and HPV : over the personal ha(its was recorded ta(le = and ta(le : .9ood ha(itat associated with HPV prevalence (J@K .=!:4 +=,?IK ."=#-+.%!3).-nd the positive su(/ects were found to (e ha(it of vegetarian. 6one of the positive su(/ects were found to (e ha(it of vegetarian (J@K #.%%$"4 +=, ?IK . #.#" -+.%=!) in HPV : respectively. .he a(ove mentioned personal ha(its were not much associated with prevalence of HPV infection in the study su(/ects. .he associations of symptoms with HPV positive and HPV : positive study su(/ects were presented in ta(le $ and ta(le 3..he stomach ache associated with HPV positive prevalence (J@ for women had symptom of stomach ache vs. without stomach
3#
ache W#.:3"4 +=,?IK#.
-%. + ).;rinary tract infection (J@ for women had ;.I vs. 3-"%:.#). -(dominal pain (J@ for women had
without ;.IW! .3!!4 +=,?IK %.
a(dominal pain vs. without a(dominal pain W .! "4 +=,?IK #." %-3.#"). .he (ac) ache (J@ for women had (ac) ache vs. without (ac) ache W #.:#4 +=,?IK #.#::-=.=!). .he itching (J@ for women had itching vs. without itching W !.#!4 +=, ?IK %.:%-!:=$.#) .he irritation (J@ for women had irritation vs. without irritation W "$.+" +=, ?IK ." :+=:.#). .he symptoms such as viral infection, vaginal discharge, fungal infection, Inflammation, arthritis and other complaints were not associated with HPV positive infection. .he prevalence of HPV : positive results were eGually distri(uted in symptoms such as stomach ache (J@W#.%==+4+=,?IK#.#"3#-$.%#3), 2ac) ache and ;.I (J@W":.!!!4+=,?IK". # :-$#3.+$$), (J@W".%$,+=,?IK#. =" -%#.""3), symptoms such as fungal
-(dominal pain (J@W#.3:4 +=,?IK#.#=!=- %.#$).Jther
infection ,Itching, Vaginal discharge, loss of (ody weight, inflammation, irritation, arthritis and viral infection were included (ut the corresponding J@s did not change materially. In the previous study the prevalence of HPV 56- higher in poor hygienic condition. It is colla(orated (y the o(servation that significant num(er i.e. =3, of positive women had vaginitis (-ggarwal et al., "##:). Poor hygiene was noted to (e associated with higher prevalence of HPV in women the control group (y (9ranceschi et al., "##=) women who did not toilet their genitals after intercourse or during menstruation have (een found to (e greater ris) (?haou)i et al., ++3). .he symptoms li)e pain in lower a(domen, history of discharge purities vulvae were common correlating with presence of genital after intercourse or during menstruation have (een found to (e at greater ris) (?haou)i et al., ++3). 8omen using homemade pads during menstruation have (een shown to have a ! to % fold increased ris) of cervical cancer (5uttagupta et al., "##%). .he prevalence of HPV positive and HPV : over the associated ris) factors were studied and presented in ta(le + and ta(le #. 6one of positive su(/ects were found in >7P to 0.5 HPV :, 0creening test for cervical cancer, history of a(normal cell, anorexia, and vaccination. Irregular menstruation (J@K =.3%!4 +=, ?IK #.=3%-=3.%%). .he prevalence of HPV :5 none of positive su(/ects were found in >7P to 0.5, 0creening test for cervical cancer, History of a(normal cell, Vaccination, anorexia. Irregular menstruation (J@K "!.$= +=, ?IK .!=+"-% =.##). .he previous study showed that HPV infections were
more pronounced in younger age ever used hormonal or contraceptives (p O#.#=for each) (Howayda et al., "##$). .he results of three hundred and eighty (!3#) of ,"$= ("+.3,) women were followed up for a median time of 3.= months (inter-Guartile range +.$-":.:). 0ixty-nine (:+) women had incident HPV infections during "": person-years of follow-up reflecting an incidence rate of !#.= per ## person-years. Incident HPV infections were marginally associated with HIV positivity (@@ W ".3, +=, ?IK #.+ - 3.!). ?learance for HPV typespecific infections was freGuent ranging (etween %".!,and ##.#, for high- and =#, and ##, for low-ris) types. Jnly ! .", of women cleared all their infections. ?learance was associated with HIV negativity (-d/usted clearance W #.", +=, ?IK #. #.$) (ut not with age at study entry, lifetime num(er of sexual partners and multiplicity of infections. .he prevalence of low-grade sGuamous intraepithelial lesions (D0IDs) was =!H!:= ( %.=,). 6one of the women had a high-grade cervical lesion (H0ID) or cancer. .wenty-two ("") of =# ( %.$,) HPV negative women at (aseline developed incident D0ID during follow-up. .he ris) for D0ID appeared to (e elevated among women with HPV 3-related types compared to women not infected with those types (@@ W !.=, +=, ?IK .# .3) (>lisa(ete weiderpass et al.,"# #).
.he results Jf ".!3 million adolescent girls aged " to $ years, !.:+ million ("+.$:,) were recommended to receive the HPV vaccine (y their health care provider. .he ma/ority who received the HPV vaccine recommendation were ! to $ years of age (3!,), were white ($ ,), and had one or more preventive visits (+%,). -mong those for whom the HPV vaccine was recommended, %3.$=, (+=, ?I %=.!$*=". !) received the vaccine. 'ultivariate logistic regression analysis of those who were recommended revealed that ena(ling and predisposing factors were significantly associated with the HPV vaccination. ?hildren living at # , to "##, of the 9ederal Poverty Devel (odds ratio #.=% X+=, ?I #.!#*#.+3Y) and children in households with two or more adults (#.= X#.!!*#.3#Y) were negatively associated with HPV vaccination, whereas children with any preventive medical care visit(s) ("."3 X .!:*!.3%Y) in the previous year were positively associated with HPV vaccination. (0wetha @ao palli et al., "# ").
3"
-ccording to several studies, the (ehavioral ris) factors associated with the HPV infection in adolescents and young adult women include early age of first sexual intercourse. However, due to restricted customs of the Indian population, the ;niversity girls& do not have sexual intercourses (efore marriage and hence low positivity among the study population has (een reported. Jur results also suggests that the age did not seem to (e a cofactor for HPV infection and nevertheless, sexual intercourse is an important factor for HPV infection and it hence more freGuent among sexually active married women than among virgin girls.(.hilagavathi et al., "# "). .ype-specific HPV-56- was detected in %.%, (n W $+) of the 3## girlsK ".$, (n W %+) concerned a high ris) HPV type (hrHPV-56-). .he three most common types were HPV type :, 3 and = (%#,). Jut of the hrHPV-56- positive girls, !", was seropositive vs. ", in HPV-56- negative girls (p O #.## ). @is) factors independently associated with hrHPV-56- infection among the sexually active girls were age P = years vs. %* = years (J@ W ".: ( ."*=.+)), age of sexual de(ut O % vs. a(ove % years (J@ W !.# ( . *3.")), total num(er of lifetime partners a(ove two vs. less than two partners (J@ W !." ( .!*3.#)) and age of partner P $ vs. under $ years (J@ W %." ( .=* !.#)). Dow hrHPV- 56- prevalence was found in the adolescent girls. .he o(served vs. expected age-related increase in HPV-56- prevalence in this cohort in the coming years (with increased sexual activity) will provide understanding of the effect of HPV vaccination. 9urthermore, this cohort study will offer the opportunity to improve )nowledge of anti(ody responses following natural infection and vaccination. ('ollers et al., "# "). Prevalence of cervical infection with HPV vaccine campaign in Viet 6am, it is important to note that one can (e infected with multiple types of HPV. Vaccination does not protected against all type of high ris) HPV types. 9uture vaccine campaigns should openly disclose this information to women receiving vaccines. High prevalence of infection with HPV high ris) types was o(served in this study. -s HPV infection has a high correlation with cervical cancer, this study emphasi<es the need for (oth primary prevention of cervical cancer with HPV vaccines as well as secondary prevention with screening. (Dan th vu et al., "# !).
3!
.wo hundred and forty five women (etween "# and $! years old, were enrolled in the study (mean ageK !3. years4 05 #.$ years). .wo hundred and thirty nine of the "%= cervical samples (+$.:,) were positive (y human I-glo(in amplification and "#3 of the "": urine samples (+".%,). 9ifty one women were not included in the statistical analysis due to their samples[ low 56- Guality (negative result for I-glo(in) or a lac) of either of the samples (cervical or urine). ('arina 'uno< et al., "# !) Jur findings confirm that HPV is shed into the urine and that P?@ performed on urine specimens is capa(le of detecting HPV 56- in the vast ma/ority of HPV infected individuals. .he result suggest that ;rine sample can (e used as an important tool for HPV-56- detection in large populations unwilling to undergo pelvic exam or unwilling to provide invasive specimens and screening of symptom-free normal adolescents and healthy women who may har(or oncogenic high-ris) HPVs or other HPV-related infections. .his will help in early detection and monitoring of adolescent and women at high ris) for developing cervical cancer. 9urther research on HPV infection in adolescent should focused on identification of (ehavioral and (iological ris) factors for HPV infection, persistence and progression to cervical cancer. In conclusion, the study found a prevalence of ".=, for HPV in study population. ?ervical cancer screening practices are inconsistent in India. .he prevalence is high in rural, low social economical, poor hygienic and sexually active women. It can (e controlled or prevented (y regular screening of cervical cytology (y similar Pap testing in every women started at the age a(ove "!. In another way health education, promotion of condom usage and need to follow healthy hygienic practices in during menstruation is the most cost effective approach in reducing the incidence of cervical cancer. Vaccination also availa(le to high ris) types : and 3, (ut not in other HPV types. Vaccination does not prevent the entire life. 0till (Viral li)e particle) is developed to prevent the all types of HPV and easy availa(le to all the women (less cost effective). Eovernment will ta)e the responsi(ility to the screening programmed and vaccination to the women and control the cervical cancer death in India.
3%
4. SUMMARY In the present study, a total of "## urine samples were collected from college going girls with healthy cervix to investigate the prevalence of HPV infection. .wo different 56- extraction protocol was evaluated to find suita(le method for HPV-56extraction from urine sample. 2y comparing the Guality and Guantity of 56- extracted (y two methods it was found that 2oom et al., ++# protocol was the (est method. 56isolated (y this method was ta)en for further analysis. -ll 56- were screened with IPrevalence of Human Papilloma Virus (HPV) infection among college going girls using self collected urine sample from >rode district, .amil 6adu.
3=
glo(ulin to assess the presence of cellular 56- and only I-glo(ulin positive samples were ta)en for P?@ analysis with consensus and type-specific primers. Jut of "## urine samples = were positive for D consensus primer, = for 'RHEP nested, and " for HPV- :. 6one of the samples showed positive for HPV- 3 .he overall prevalence of HPV positive and HPV were found to (e =(".=,) and "( ,) ta(le- and figure- . In age wise distri(ution, ! positive su(/ects were found in 3-"# age group and " su(/ects found to (e (elow " -"! age group. Prevalence of HPV positive over the socio-demographic varia(les of study su(/ects were analy<ed statistically and recorded in ta(le-!. HPV prevalence in varia(les among married women were also compared and statistically analy<ed to calculate J@ and +=, ?I. .hough there was no statistical significant association, HPV prevalence was higher in su(/ects from rural areas, age group 3-"#, annual income a(ove "=, ### Prevalence of HPV positive and HPV : over the personal ha(its of study su(/ects were analysed statistically and recorded in ta(le = and ta(le :. 6one of the positive su(/ects were found in the varia(les of (oth HPV : and positive su(/ects were found in HPV positive. Jut of ! symptoms, 9ive symptoms were positively associate with HPV positive and .wo su(/ect was positively associate with HPV :, the positive su(/ects were statistically significant @is) factors of positive and negative cases were assessed statistically (.a(le+F.a(le #). Irregular menstruation was positively associated with (oth HPV positive and HPV prevalence. .he study revealed that the following points are the most pro(a(le mode of HPV transmission among the study su(/ects. Poor hygiene condition Premarital and extramarital sexual ha(its ;nsafe sexual practices Dac) of medical facilities
3:
Dac) of awareness on health care S&00+s# $%s; - large scale study may (e conducted (y Eovernments or some other sponsoring agencies to assess the prevalence of HPV among the study su(/ects. - red alert should (e rounded powerfully to promote the )nowledge on health care. Health care personnel to (e activated to promote the )nowledge on signs, symptoms and ris) of HPV. 9reGuent pap screening should (e implemented. HPV typing is an important factor for cervical cancer diagnosis and P?@ F @9DP methods are used for detection of HPV types. .he prophylactic trial HPV vaccination (E-@5-0ID) should (e insisted among the study population. -wareness programmes should (e conducted (y the Eovernment through media, stages.., etc. Eovernment should ta)e the responsi(ilities to provide the screening programme and vaccination to the women and to control the cervical cancer death in India
:. CONCLUSION In ?onclusion, the present study showed that even in adolescent girls HPV infection of the uterine cervix is common. -lthough the prevalence of high ris) HPV infection is lesser in adolescent girls than married women, they do act as carrier of HPV infection and at ris) for cervical cancer as there are studies indicating that oncogenic
3$
HPVs particularly HPV- : contri(ute to the development of cervical cancer. .he adolescent girls with healthy cervix had the advantage of ena(ling prevalence of HPV infection using non-invasive urine HPV-56- detection. .hese findings confirm that HPV is shed into the urine and that P?@ performed on urine specimen is capa(le of detecting HPV 56- in the vast ma/ority of HPV infected individuals. .he result suggest that ;rine sample can (e used as an important tool for HPV-56- detection in large population unwilling to undergo pelvic exam or unwilling to provide invasive specimens and screening of symptom-free normal adolescents and healthy women who may har(or oncogenic high-ris) HPVs or other HPV-related infections. .his will help in early detection and monitoring of adolescent at high ris) for developing cervical cancer. 9urther research on HPV infection in adolescent should focused on identification of (ehavioral and (iological ris) factors for HPV infection, persistence to cervical cancer.
33
BIBLIOGRAPHY Al.$ Ca'(a%a, "## . High and Intermediate @is) Human Papilloma virus Infection in 0exually -ctive -dolescent 9emales. 3 Pediatr .dolesc (ynecd. %K $ - $%. Al$7 B-a*# C.5 S- * s- S-&7la5 S&#a(a Ma-a#a5 S&*+s- H+.a& a%. B-&.+) D+s C., "# #. Human papilloma virus and control of cervical cancer in India. 4&pert 5eu 6*stet. (ynecd. =(!)K!"+-!%:. A'a%.a D+'(s+/ F.5 A"-a'/+l+- G+6*+'a* a'5 La&*a B$&#s7/5 a%. L sa Ma%-a*#, "##3. 2ehavior in >arly -dolescence and @is) of Human Papillomavirus Infection as a Roung -dultK @esults from a Population- 2ased study. P40I./5ICS. "" ( ). A'a%.a T* s#*a' a%. Al s$% F a%.+*, "##$. Human papillomavirus (including vaccines). A'+* "a% Ass$" a# $% !$* Cl % "al C-+' s#*/, ("# !). Hpv test. -vaila(le online at httpKHHwww.cdc.govH std HHPVH0.5 . 9act-HPV. htm through httpKHHwww.cdc.gov. A'+* "a% S$" al H+al#- Ass$" a# $%5 ("##"). HPV Guestions and answers. @esearch .riangle Par), 6?K -0H- @esource ?enter. @etrieved Aune httpKHHwww.ashastd.orgHhpvHhpvref.htm A' #a G&(#a5 Ra7s-a A*$*a5 Sa%Fa/ G&(#a5 B-&(+s- B.5 P*&s#/ a%. B-&.+) Das C., "##:. Human papilloma virus 56- in urine samples of women with or without cervical cancer and their male partners compared with simultaneously collected cervicalHpenile smear or (iopsy specimens. 3oumal o) Clinical 'irology.!$K +#- +%. A%%a G &l a%$ R.5 R$6 % Ha** s5 R+6+""a S+.F$ L.5 S&s + Bal.8 %5 a%. D+% s+ R$+5 "##". Incidence, Prevalence, and clearance of .ype- 0pecific Human Papillomavirus InfectionsK .he Roung 8omen&s Health 0tudy 3I0. 3:K%:"-%:+. A%%a9Ba*a6a*a M$s" "7 M.D.5 Y !+ M.S.5 a%. C-a*l+s W 66+ls'a% M.D.5 "##3. @is)s for ?ervical Intraepithelia 6eoplasia ! among -dolescents and Roung 8omen with -(normal ?ytology. 6*stet (ynecol. "!K ""+-"!%. A%%a9Ba*6a*a M$s" "7 M.D.5 J$as H.5 Ell+%6+*05 S#+% H. V+*'&%.5 C-* s# + A.5 H$lla%.5 T+*+sa Da**a0-5 P+00/ A.5 C*$8l+/9N$8 "75 L %.a L+) % 5 "*a 0 M.8 ls$%5 "###. Prevalence of and ris)s for cervical human papilloma virus
Prevalence of Human Papilloma Virus (HPV) infection among college going girls using self collected urine sample from 6ama))al district, .amil 6adu.
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"K !!=-%".
A%%a9Ba*a6a*a M$s" "7 M.D., "##$. HPV infections in adolescents, 0isease 7ar8ers
infection and sGuomous intraepithelial lesions in adolescenct girls. -rch pediatr adolesc medivol =% . A%%a9Ba*6a*a M$s" "7 MD.5 "##=. Impact of HPV infection in adolescent populations, 3ournal o) .dolescent -ealth. !$K!-+. A%#$% $ F*+0aa5 Ma* a C+%" 65 Pa#* 3 a S#+%#+llaa5 L&"a C (* a%$a5 A%.*+a D+I$* sa5 Ma&*$ Al.+* s $65 Al.$ V+""- $%+, "##!. Human a papilloma virgins and (ehavior at ris). Cancer %etters. +%K" -"%. As-l+/ Cas+ S.5 R$.%+/ R$""$% P.5 a%. M "-a+l S#*a&0-% J.5 "##:. ?ervical Intraepithelial 6eoplasia in -dolescent 8omen. 6*stet (ynecol. #3K !:+-$%. A&l# B.A., "##$. >ffect of prophylactic human papillomavirus D virus-li)e-particle vaccine on ris) of cervical intraepithelial neoplasia grade ", grade !, and adeno carcinoma in situK a com(ined analysis of four randomised clinical trials. Dancet. !:+(+=$:)K 3: * 3:3. XPu('edY Ba*#-$l$'+8 D.A., "##%. Human papilloma virus infection in adolescentsK a rational approach. -dolesc 'ed 4 =K=:+-+=. B$s"- F.D.5 D+ Sa%F$s+ S., "##!. ?hapter K Human papillomavirus and cervical cancer (urden and assessment of causality. A 6atl ?ancer Inst 'onogr. ! K!* !. XPu('edY. B$s"- F.D.5 Ma%$s M.M.5 M&%$3 N.5 S-+*'a% M.5 Ja%s+% A.M.5 P+#$ J.5 S"- !!'a% M.H.5 M$*+%$ V.5 B&*'a% R.5 S-a- B.V.5 ( ++=). Prevalence of human papillomavirus in cervical cancerK a worldwide perspective. International (iological study on cervical cancer (I20??) 0tudy Eroup. A 6atl ?ancer Inst 3$K $+:*3#". B$s"- F.D.5 M&K$3 N.5 S-a- B.V.5 a%. M+-+&s A. I%# J Ca%"+*5 papillomavirus. <2K $ - $!. B* ## 7. E* "7s$%5 R$%al. D. A )*a*+35 Wa**+* B.H&- . 209:. -uman Papilloma 'irus; ,hat every provider should 8no1, .merican <ournal o) o*stetrics and gynecology. 0epartment o) o*stetrics and gynecology, 0ivision o) gynecological oncology, university o) .la*ama at "irmingham. 'olume 20 , Issue :, 7arch, pages 9=>-9?@. B*/a% H$l"$'65 J$a%%+ M$# % Ba l+/ O., "##%. -dults& 1nowledge and 2ehaviors @elated to Human Papillomavirus Infection. 3."AP. $ ( ).
++". 0econd
International 8or)shop on the epidemiology of cervical cancer and human
ii
Ca #l % W+#3+l A66 0a l T ss$# M.A.5 L %.a B$lla* M., "##$. 5evelopment of HPV >ducational Protocol for -dolescents. 3 pediatr .dolesc (ynecol. "#K"3 -"3$. Ca*.+* C.5 R$6 %s$% A.J.5 B*$&0-#$% C.5 S#+(-+%s$% J.M.5 R .08a/ G.L.5 ( +++). >valuation of self-ta)en samples for the presence of genital ?hlamydia trachomatis infection in women using the ligase chain reaction assay. Int A 0.5 -I50 #( ")K$$:*$$+. Ca*la V #$la G$%"al)+s5 S l)a%a Ma* a A& %#a%a5 Al+ss%a.a*a "* s# %a Ma*"$l %5 G+*al.$ D&a*#+5 J&)+%al S$a*+s D as a%. M$% a S#+ 0l+.+* B a%"- 5 "##+. 'icro invasive carcinoma of the uterine cervix in a %- year-old adolescentK case report and literature review. Sao Paulo 7ed 3. "$(")K #=-$. C+%#+*s !$* D s+as+ C$%#*$l a%. P*+)+%# $% . "##$. 0exual and reproductive health of persons aged #-"%a;nited 0tates. C+%#+*s !$* D s+as+ C$%#*$l, "##$. duadrivalent Human Papillomavirus Vaccine. @ecommendations of the -dvisory ?ommittee on Immuni<ation Practices (-?IP). ''8@. =: (6o. @@#")4 -"%. C-a*l$##+ L+%s+l %7 H.5 W ll+' M+l"-+*s J.G.5 W ' A& %# G.V.5 a%. R&&. B+77+*s L.M., "##%. 0exual 2ehaviour and HPV Infections in 3 to "+ Rear Jld 8omen in the Pre-Vaccine >ra in the 6etherlands. P%os 6N4.! ( )K"-3. Cla)+l C.5 Mas&*+ M.5 B$*/ JP.5 "## . Human papilloma virus testing in primary screening for the detection of high-grade cervical lesionsK a study of $+!" women. 2r A ?ancer 4 3%K : :*"!. Cl !!$*. G.M.5 Gall&s S.5 H+**+*$ R.5 M&%$3 N.5 S% F.+*s P.J.5 Va""a*+lla S.5 A%P.T.5 F+**+"" $ C.5 H +& N.T.5 Ma#$s E.5 M$la%$ M.5 RaF7&'a* R.5 R$%"$ G.5 .+ Sa%F$s+ S.5 S- % H.R.5 S&7) *a"- S.5 T-$'as J.O.5 T&%sa7&l S.5 M+ F+* C.J.5 F*a%"+s"- S.5 ("##=). 8orldwide distri(ution of human papillomavirus types in cytologically normal women in the International -gency for @esearch on ?ancer HPV prevalence surveysK a pooled analysis. Dancet !::K ++ *++3. Cl !!$*. G.M.5 S' #- J.S.5 Pl&''+* M.5 M&%$3 N.5 F*a%"+s"- S ., "##!. Human papilloma virus types in invasive cervical cancer worldwideK a meta-analysis. "r 3 Cancer ; :!-$!. C$&#l++ F.5 Ha%7 %s C.5 La($ %#+ N., ++$. .he ?anadian 8omen[s HIV 0tudy Eroup. ?omparison (etween vaginal tampon and cervicovaginal lavage specimen
iii
collection for detection of human papillomavirus 56- (y the polymerase chain reaction. A 'ed Virol , = K%"*$. C$G J.T.5 L$* %"3 A.T.5 S"- !!'a% M.H.5 S-+*'a% M.E.5 C&ll+% A.5 B&*'a% R.J.5 ++=. Human papillomavirus testing (y hy(rid capture appears to (e useful in triaging women with a cytologic diagnosis of atypical sGuamous cells of undetermined significance. -m A J(stet Eynecol , $"K +%:*+=%. C*$#"-!+l# B.A.5 W+ls- L.E.5 D+B$%) ll+ D.5 R$s+%s#*a&s M.5 a%. A& %% T.C.5 ++$. 5etection of Neisseria gonorrhoeae and Chlamydia trachomatis in genitourinary specimens from men and women (y a coamplification P?@ assay. A. ?lin. 'icro(iol. ,<; =!:* =%#. C&s"- +* B.5 Na%.8a% R.5 M"G$&0- P ., "# 3!( )K +3!* +3$. XPu('edY . ;rine testing as a surveillance tool to 4 monitor the impact of HPV immuni<ation programs. A 'ed Virol. "#
C&3 "7 J.5 A*6/% M.5 Sa%7a*a%a*a/a%a% R.5 T3& V.5 R$%"$ G.5 Ma/*a%. M.H.5 D ll%+* J.5 M+ F+* C.J.5 ("##3). Jverview of human papillomavirus-(ased and other novel options for cervical cancer screening in developed and developing countries. Vaccine ":(0uppl #)K 1"+*1% . Da**$% B*$8% R.5 Ma*" a S-+8 L.5 a%. B*a- ' Aa.a.* , "##=. - longitudinal 0tudy of Eenital Human Papillomavirus Infection in a ?ohort of ?losely 9ollowed -dolescent 8omen, Eenital HPV in -dolescent 8omen 3I0. + ( =)K 3"- +". Da) . Ha0+* W., "##+. Human Papilloma Virus Infection and Prevention in the -dolescent Population. 3 Pediatr .dolescent (ynecd. ""K +$-"#%. D+ R$.a H&s'a% A.M.5 Wal6$$'+*s J.M.5 )a% .+% B*&l+ A.J.5 M+ F+* C.J.5 S% F.+*s P.J.5 ( ++=). .he use of general primers EP= and EP: elongated at their !e ends with ad/acent highly conserved seGuences improves human papillomavirus detection (y P?@. A Een Virol $: Pt %K #=$* #:". XPu('edY D+ Sa%F$s+ S.5 A& %# W.G.5 Al+'a%/ L.5 G+*a+#s D.T.5 Bla&s#+*'+ +* J.E.5 et al., ("# #). @etrospective International 0urvey and HPV .ime .rends 0tudy Eroup. Human papilloma virus genotype attri(ution in invasive cervical cancerK a retrospective cross-sectional worldwide study. Dancet Jncol >pidemiology and 6atural History of HPV Infection ./ogc.
)K #%3* #=:.
D+6$*a- M.5 M$%+/5 Va%"$&)+* B.C.5 D a%+ M.5 P*$)+%"-+*.5 M$%#*+al A.C ., "##$.
iv
D+6$*a- M$%+/ M.5 Va%"$&)+* M "-+l R$/ B.".5 a%. A&+6+" C #/ A.C. , "##$. >pidemiology and 6atural History of HPV Infection. 36(C9K"+(3)K!. D+l A'$ J.5 G$%3Ll+3 C.5 B+l.a J.5 F+*%L%.+3 E.5 Ma*#M%+3 R.5 GN'+3 I.5 et al., "##+. Prevalence and ris) actors of high-ris) human papillomavirus in female sex wor)ers in 0painK differences (y geographical origin. A. 8omens Health (Darchmt) 3( ")K "#=$-:%. D ) s $% $! N+8s & El+"#*$% " M+. a5 22@1,). 6ew study shows HPV vaccine helping lower HPV infection rates in teen girls. O!! "+ $! C$''&% "a# $% 21@1) 4,?9 ,2>4. D$%%+ A.J.5 Ha'(s$% L.5 Ha'+* J.J.5 Ha'(s$% I.N.5 "# #. .he role of HPV type in recurrent respiratory papillomatosis. International /ournal of pediatric otorhindaryngology.$%K$- %. D$$*6a* J.5 El/ S.5 S#+*l %0 J.5 M"L+a% C.5 a%. C*a8!$*. L.5 epithelial cell intermediate filament networ). ,<2K3"%-3"$. D&%%+ E.F.5 N +ls$% C.M.5 S#$%+ B.M.5 Ma*7$8 #3 L.E.5 G &l a%$ A.R ., "##:. Prevalence of HPV infection among menK - systematic review of the literature. A Infect 5is. +% (3)K #%%* #=$. XPu('edY E l++% D&%%+ F., "##$. Prevalence of HPV Infection among 9emales in the ;nited 0tates. 3.7.. "+$ (3). El a%+ D&a*#+9F*a%"$ a%. E.&a*.$ L F*a%"$ , "##%. ?ancer of the ;terine ?ervix . "7C ,omenBs -ealth. % (0uppl )K0 !. El 3a6+#- U%0+* R.5 Ma"7 R&!! % T.5 a%. C$%"+(# $% D a39A**as# a, "##=. Human Papillomaviruses (yneocologic in)ectious diseases. !("") !#=-! %. Es(+% E%+*l/5 C+" l a Ol$!ss$%5 Ma* N/0O*.5 22@1,). 'onitoring human papillomavirus prevalence in urine samplesK a review. Cl % E( .+' $l. <; 4:I:?. E#-+l9M "-+l+ .+ V ll +*s5 Cla&.+ Fa&C&+#5 T-$'as R.5 B*$7+*5 Ha%s9Ul* "B+*%a*.5 a%. Ha*al. 3&* Ha&s+%a. ("##%). ?lassification of papilloma viruses Virology !"%, availa(le at science direct.com, $* "$. E&%9S+$( S$%05 H&% Fa+ L++ a%. Ta+ S$$7 H8a%0 , "##$. ?linical >fficacy of Human Papillomavirus 56- 5etection in ;rine from Patients with Various ?ervical Desions. 3 Corean 7ed Sci.""K++- #%. ++ . 0pecific interaction (etween HPV : > ->% and cyto)eratins results in collapse of the
Fa'6* % M.5 P+%%a C.5 P +*all A.5 B&ssa% C.5 Falla% M.G.5 A%.+*ss$% B.L.5 et al., "##3. P?@ detection rates of high ris) human papillomavirus 56- in paired selfcollected urine and ?ervical scrapes after co" ioni<ation for High - grade cervical intraepithelial neoplasia. (ynecol 6ncol. #+K=+-:%. F+*+%"3/ A.5 C$&#l+P+ F.5 F*a%"$ E.L.5 Ha%7 %s C ., "##!. HIV and HPV coinfection and lower genital tract neoplasiaK review of recent developments .?'-A4 :+K%! *%. F+*la/ J.5 B*a/ F.5 P sa% P.5 et al.5 "##=. ?ancer Incidence, 'ortality and Prevalence 8orldwide International -gency for @esearch on ?ancer. I-@? "##". ?- ?ancer A ?lin.4 ==K$%* #3. F+*la/ J.B.F.5 P sa% P5 a%. Pa*7 %5 "lobocan D.M., "##". HPV types in cervical carcinomas in Aa)arta, Indonesia. Eynecol Jncol +!K %+*=! , Cancer Incidence 7ortality and Prevalence ,orld1ide I.5C Cancer*ase no. @, version 2.0 , I-@? Press, Dyon, 9rance, "##%. F$$. a%. D*&0 A.' % s#*a# $%. "##$. Eardasil (Guadrivalent human papillomavirus Xtypes :, , :, 3Y recom(inant vaccine) Xpac)age insertY. 8hitehouse 0tation, 6AK 'erc) F ?o4 "##:. F$*sl&%. O.5 Ha%ss$% B.G.5 R/'a*7 P.5 a%. BF+**+ B.5 ++!. Human papillomavirus 56- in urine samples compared with that in simultaneously collected urethra and cervix samples. A. ?lin. 'icro(iol. >; +$=* +$+. F*a%"+s"- S.5 H+**+*$ R.5 Cl !!$*. G.M.5 S% F.+*s P.J.5 A*sla% A.5 A%- P.T.5 B$s"F.D.5 F+**+"" $ C.5 H +& N.T.5 La3"a%$9P$%"+ E.5 Ma#$s E.5 M$la%$ M.5 A a$ Y.L.5 RaF7&'a* R.5 R$%"$ G.5 .+ Sa%F$s+ S.5 S- % H.R.5 S&7) *a"- S.5 T-$'as J.O.5 M+ F+* C.J.5 M&%$3 N.5 ("##:). Variations in the age-specific curves of human papillomavirus prevalence in women worldwide. Int A ?ancer +K ":$$* ":3%. F*a%"$ E.L.5 V lla L.L.5 S$6* %-$ J.P.5
1>@, % =-!. et al.5 ( +++). >pidemiology of acGuisition and clearance of cervical human papilloma virus infection in women from a high-ris) area for cervical cancer. 3 In)ect 0is,
F*a%"$ E.L.5 V lla L.L.5 S$6* %-$ J.P.5 P*a.$ J.M.5 R$&ss+a& M.C.5 D+s/ M.5 et al., +++. >pidemiology of acGuisition and clearance of cervical human papillomavirus infection in women from a high-ris) area for cervical cancer. A Infect 5is4 3#(=)K % =*"!.
vi
F*a%7 l&. "7+5 A%%+ S#al6+*05 P +**+ Vass la7$5 A## la MaF$* L.5 a%. Al.$ Ca'(a%a, "## . High-and Intermediate-@is) Human Papillomavirus Infection is 0exually -ctive -dolescent 9emales. 3 pediatr .dolescent gyneocol . %4 $ $%. F* +.'a% A.L.5 S-+(+a*. H., "##$. >xploring the )nowledge, attitudes,(eliefs, and communication preferences of the general pu(lic regarding HPVK findings from ?5? focus group research and implications for practice. -ealth 4duc "ehav4 !%K %$ *%3=. Gall$ G.5 B 66$ M.5 Ba0+lla L.5 Ea'(a*+ll A.5 Sa%+)+* %$ F.5 G $)a0%$l M.R.5 et al. "##!. 0tudy of viral integration of HPV- : in Roung patients with 0ID. 3 Clin Pathol.=:K=!"-:. G+% #al HPV I%!+"# $% Q CDC Fa"# S-++#R , "##+. ?enters for 5isease ?ontrol and Prevention. (?5?). G &l a%$ A.R.5 Ha** s R.5 S+.F$ R.L.5
et al., ("##"). Incidence, prevalence, and clearance of typespecific human papilloma virus infectionsK the Roung 8omen&s Health 0tudy. 3 In)ect 0is, 1>4, %:"-+.
G &l a%$ A.R.5 N +ls$% C.M.5 Fl$*+s R.5 et al., "##$. .he optimal anatomic sites for sampling heterosexual men for human Papilloma Virus (HPV) detectionK the HPV detection in men study. A Infect 5is. "##$4 +:(3)K %:* =". XPu('edY Ha 9R ' S- %5 S l) a F*a%"+s"- 5 a%. Sal)a#$*+ Va""a*+lla5 "##%. Prevalence and 5eterminats of Eenital Infection with Papillomavirus, In 9emale and 'ale ;niversity 0tudents in 2usan, 0outh 1orea. +#K!" - 3I0!"=. Ha%%a J$-a%ss$%5 Da) # B3-$llalla5 J$-a%%a E7s#*a'5 E' l + H&l# %5 J$a7 ' D ll%+*5 Ola F$*sl&%., 209:. 7etagenomic seDuencing o) +-P'-Negative2 condylomas detects novel putative -P' types. 'irology, EE0F9); 9 0ol; 90.909=#3. 'irol. Ha*(+* D.M.5 N$ll W.W.5 B+ll$% D.R.5 C$l+ B.F ., "##". @andomi<ed clinical trial of P?@-determined human papilloma virus detection methodsK self-sampling versus clinician-directed (iologic concordance and women[s preferences. -m A J(stet Eynecol 4 3:K!:=*$!. Ha*(+* D.M.5 Ra/'$%. M.5 N$ll W.W.5 B+ll$% D.R.5 D&%"a% L.T.5 C$l+ B.F. , .ampon samplings with longer cervicovaginal cell exposures are eGuivalent to two consecutive swa(s for the detection of high-ris) human papillomavirus. 0ex .ransm 5is "##" 4"+K:"3*!:.
vii
Ha&8+*s D.B.W.5 TFal'a WA., "##+. 0creening for human papillomavirusK Is urine useful^ Indian 3aumal o) Cancer. %:(!)K +#- +!. H+ . S#+)+%s$%5 ("# !). 0cientists Point out ?orruption in Vaccine&s Promotion. Volume 3, issue !. H$ E.R., 2ierman @., 2eardsley D., ?hang ?.A., 2ur) @.5., ++3. 6atural history of cervicovaginal papillomavirus infection in young women. 6 >ngl A 'ed 4 !!3K%"!-3. ?ross @ef 'edline 8e( of 0cience. H$ G.Y.5 B +*'a% R.5 B+a*.sl+/ L.5 C-a%0 C.J.5 B&*7 R.D ., ++3. 6atural history of cervicovaginal papilloma virus infection in young women. 6 >ngl A 'ed4 !!3($)K%"!-3. H$ GYF.5 B +*'a% R.5 B+a*.sl+/ L.5 C-a%0 C.J.5 B&*7 R.D.5 ( ++3). 6atural history of cervicovaginal papilloma virus infection in young women. .he 6ew >ngland Aournal of 'edicine !!3K%"!* %"3. H$66s M.M.5 Va% D+* P$l B.5 T$##+% P.5 ("##3). 9rom the 6IHK proceedings of a wor)shop on the importance of self-o(tained vaginal specimens for detection of sexually transmitted infections. 0ex .rans 5is !=K3* !. H$+% l J.O.5 a%. W+$% B ', "##=. Implications of HPV infection in ;terine cervical ?ancer. Cancer /herapy. !K% +-%!%. IARC M$%$0*a(-s $% #-+ E)al&a# $% $! Ca*" %$0+% " R s7s #$ H&'a%s V$l&'+ 1@@B5 ("# "). - @eview of Human ?arcinogensK 2iological -gents. -vaila(leK mono ##2.pdf. I!#%+* T.5 V lla L.L.5 ("##!). ?hapter "K Human papillomavirus technologies. A 6atl ?ancer Inst 'onogr 3#*33. XPu('edY I$a%% s Ma''as N.5 & G+$*0+ S$&* ) %$&s , "##+. Human papilloma virus (HPV) infection in children and adolescents. 4ur 3 pediatr. :3K":$-"$!. Ja"$6s$% D. L.5 W$'a"7 S.D.5 P+*al#a L.5 E+% l'a% J.M.5 F+*$l B.5 Ma+-* J.5 R. Da% +l R.W.5 a%. S-a- B.V.5 "###. ?oncordance of human papilloma virus in the cervix and urine among inner city adolescents. Pediatr. Infect. 5is. A. 1?;$""* $"3. Ja"$6s$% D.L.5 W$'a"7 S.D.5 P+*al#a L.5 E+% l'a% J.M.5 F+*$l B.5 Ma+-* J.5 et al., "###. ?oncordance of human papillomavirus in the cervix and urine among inner city adolescents. Pediatr In)ect 0is 3. +K$""-3.
viii
Ja"$6s$% D.L.5 W$'a"7 S.D.5 P+*al#a L.5 E+% l'a% J.M.5 F+*$l B.5 Ma+-* J.5 Da% +l R.W.5 S-a- B.V.5 "###. Concordance o) human papilloma virus in the cervi& and urine among inner city adolescents. Pediatr In)ect 0is 3; 9>; ?22- . Jas$% W* 0-# D.5 A% l P %#$ B.5 a%. Ma##-+8 A.5 "##%. Powell -typical 0Guamous cells of ;ndetermined 0ignificance in Eirls and 8omen. 6*stet (ynecol. #!.:!"-:!3. Jas$% W* 0-# D.5 R$sa Da) la M.5 a%. Ba*+% P %#$ R. , "##=. ?ervical 5ysplasia in -dolescents. 6*stet (ynecol. #:K =- "#. J+%% !+* S.5 S' #-5 A'/ M+l+%./ D.V.M.5 Ras- .a B.5 Ra%a M.S.B.5 a%. J+a%%+ M.5 P '+%#a5 "##3. -ge-0pecific Prevalence of Infection with Human Papilloma virus in 9emalesK - Elo(al @eview Aournal of -dolescent Health %! ,0=*0"=. J+ss "a Ba-% A.5 B+*%#+ % D.I.5 R$s+%#-al S.L.5 H&a%0 B.5 a%. G*$+% P. , "##=. -ccepta(ility of Human Papillomavirus self testing in female adolescents Se& transm In)ect. 3 K%#3-% %. J+ss "a Ba-% A.5 B % H&a%05 S&sa% R$s+%#-al L.5 A66 0a l T ss$# M.5 a%. R$6+*# B&*7 D5 "##=. ?oercive 0exual experiences and su(seGuent Human papillomavirs infection and sGuamous intraepithelial lesions in adolescent and young adult women. 3ournal o) .dolescent -ealth. !:K!:$-!$ . J+ss "a Ba-% A.5 S&sa% R$s+%#-al L.5 Pa&l S&""$( A.5 Gl$* a HO Y.F.5 a%. R$6+*# B&*7 D, "##". 'ediators of the association 2etween -ge of 9irst 0exual Intercourse and 0u(seGent Human Papillomavirus Infection. P40I./5ICS. #+( ). J-a U*)as- P*asa.5 a%. S8as# 5 "##3. HPV vaccination to prevent cervical cancerF HPV related 5iseases. 3 6*stet (ynecol. =3(:)K %3%-%+%. J$+l A.5 B* %7'a%5 El 3a6+#- J$%+s W.5 A%% Ga!!0a M.5 J$%a#-a% A.5 Sa%.+*s.5 A% l B.5 C-a#&*)+. 5 J$s+(- Sla) %s7/5 J$-% L.5 Cla/#$%5 J+a%%+ D&'+s#*+5 a%. M "-a+l E.5 Ha0+%s++5 "##". 5etection of Human Papillomavirus 56- in ;rine 0pecimens from Human Immunodeficiency Virus-Positive 8omen. AJ;@6-D J9 ?DI6I?-D 'I?@J2IJDJER, Vol. %#, 6o. + p. ! ==*! : . J$+l A.5 B* %7'a%5 El 3a6+#- J$%+s W.5 Ga!!0a M.5 J$%a#-a% A.5 Sa%.+*s5 A% l B.5 C-a#&*)+. 5 J$s+(- Sla) %s7/5 J$-% L.5 Cla/#$%5 J+a%%+ D&'+s#*+5 a%. M "-a+l E.5 Ha0+%s++5 "##". 5etection of Human Papillomavirus 56- in ;rine
ix
0pecimens from Human Immunodeficiency Virus-Positive 8omen. AJ;@6-D J9 ?DI6I?-D 'I?@J2IJDJER, Vol. %#, 6o. + p. ! ==*! : . J$-% W.5 S+ll$*s5 A## la T.5 L$* %"35 Ja'+s B.5 Ma-$%/5 I8$%a M +l3/%s7a5 Al "+ L/#8/%5 Pa&la R$#-5 M "-+ll+ H$8a*.5 S/l) a C-$%05 D+a% Da/a5 W ll a' C-a('a%5 MaG C-+*%+s7/5 "###. ?omparison of self-collected vaginal, vulvar and urine samples with physician-collected cervical samples for human papilloma virus testing to detect high-grade sGuamous intraepithelial lesions. ?'-A, :! (=). Ba-% J.A.5 H lla*. P.A., "##%. Human papillomavirus and cervical cytology in adolescents. -dolesc 'ed. %4 = (")K!# - !" . B-a% G.5 Ba%0*$ H.O.5 C$a#+s P.J.5 H+a#- R.B.5 ++ . Inhi(itory effects of urine on the polymerase chain reaction for cytomegalovirus 56-. A ?lin Pathol %%(=)K!:#* !:=. Bl+#+* B.5 )a% D$$*% L.J.5 S"-*a&8+% L.5 M$l F% A.5 Sas#*$8 F$#$ S.5 T+* S"-+00+# J.5 L %.+'a% J.5 T+* Ha*'s+l B.5 B&*0+* M.5 A& %# W.5 +++. 5evelopment and clinical evaluation of a highly sensitive P?@-reverse hy(ridi<ation line pro(e assay for detection and identification of anogenital human papillomavirus. A ?lin 'icro(iol !$K "=#3* "= $. B$%%$ R.5 Sa#$ S.5 YaF 'a A.5 ++". Progression of sGuamous cell carcinoma of the uterine cervix from cervical intraepithelial neoplasia infected with human papillomavirusK a retrospective follow-up study (y in situ hy(ridi<ation and polymerase chain reaction. Int A Eynecol Pathol4 0cience. B$&#s7/ L.A.5 A&l# B.A.5 W-++l+* C.M.5 et al., "##". Proof of Principle 0tudy Investigators. - controlled trial of a human papilloma virus type : vaccine. N 4ngl 37ed. "##"4!%$K :%=- := . B$&#s7/ L.A.5 H$l'+s B.B.5 C* #"-l$8 C.W.5 et al., ++". - cohort study of the ris) of cervical intraepithelial neoplasia grade " or ! in relation to papillomavirus infection. 6 >ngl A 'ed4 !"$K "$"-3. 'edline 8e( of 0cience. B&las %0a' S.L.5 H&0-+s J.P.5 B ) a# N.B., et al., "##". >valuation of human papilloma virus testing in primary screening for cervical a(normalitiesK comparison of sensitivity, specificity, and freGuency of referral. A-'-4 "33K $%+*=$. K #=- ". 'edline 8e( of
B&'a* V.5 A6as+ A.B.5 Fa&s#$ N.5 a%. M #"-+ll+ R ., ("##$). 2asic Pathology (3ed) Philadelpia 0aunders. La% T-& V&5 D +& B& a%. H& TT L+5 2@1,. Prevalence o) cervical in)ection 1ith -P' type 9= and 9 'ietnam; implication )or vaccine campaign."7C Cancer 9:;@:. L a8 B.L.5 Glass A.G.5 Ma%$s M.M.5 G*++* C.E.5 S"$## D.R.5 S-+*'a% M.5 et al., +++. 5etection of human papilloma virus 56- in cytologically normal women and su(seGuent cervical sGuamous intraepithelial lesions. A 6atl ?ancer Inst +++4 + ( )K+=%*:#. L (('a% S.A.5 S&"&( *a M.C.5 J$%+s H.E.5 L&(( C.G.5 Pal+!s7/ J.5 )a% .+ W F0+*# J.H.5 et al., "##". Prevalence, distri(ution and correlates of endocervical human papilloma virus types in 2ra<ilian women. Int A 0.5 -I504 " (")K #=-+. L$* B$a*.'a% A.5 Ca*a S#a%7$ S.5 S-+**/ W+ #3+% P.5 a%. Ja'+s S&%0 C.5 "##=. -typical 0Guamous ?ells of ;ndetermined 0ignificanceK Human Papillomavirus .esting in -dolescents.6*stet (ynecol #=K$% -:. Ma-6$$6+- Sa!a+ a%5 M$-a''a. B ..&0a)&, "##3. 5eterminants of Incidence and ?learance of High-@is) Human Papillomavirus Infections in @ural @a)ai, ;ganda cancer 4pidemiol "iomar8ers Prev. $(:). Mala0$P% T.5 D*$l+# M.5 B$ l/ MC.5 F*a%"$ EL.5 J # M. , et al., ("# ") ?ross protective efficacy of two human papilloma virus vaccinesK a systematic review and metaanalysis. Dancet Infect 5is "( #)K $3 *$3+. Ma%-a*# L.E.5 H$l'+s B.B.5 B$&#s7/ L.A.5 W$$. T.R.5 B+%%+/ D.l.5 F+%0 A.5 et al., "##:. Human papilloma virus Infection among sexually active young women in the ;nited 0tatesK Implications 9or developing a vaccination strategy. Se& /ransom 0is !!K=#"". Ma%$( Ba%a#$5 a%. B+s %++ Sa*a'* ## "- , "##:. >arly >xperience of 0exual Intercourse- - @is) 9actor for ?ervical ?ancer @eGuiring 0pecific Intervention for .eenagers. . Sian Paci)ic 3 cancer Pure $K = - =!. Ma*a s D.J.5 C$%s#a%# D.5 Alla% B.5 Ca**a*a H.5 H$!!'a% M.5 S-a( *$ S.5 M$**$% C.5 W ll a's$% A.L.5 ?ervical Human Papilloma virus (HPV) Infection and HPV .ype : -nti(odies in 0outh -frican 8omen. A ?lin 'icro(iol. "##34 %:(")K $!"*$!+. Ma*a s D.J.5 C$%s#a%# D.5 Alla% B.5 Ca**a*a H.5 H$!!'a% M.5 S-a( *$ S.5 M$**$% C.5 W ll a's$% A.L.5 ?ervical Human Papillomavirus (HPV) Infection and HPV
xi
.ype : -nti(odies in 0outh -frican 8omen. A ?lin 'icro(iol. "##34 %:(")K $!"* $!+. Ma*" S#+6+% a%. El a%+ D&a*#+9F*a%"$, "##$. Human papillomavirus infectionK >pidemiology and pathophysiology. (ynecologic 6ncology. #$K0"-0=. Ma*" a S-+8 L.5 a%. D+%% s D+%% s F$*#+%6+**/ J. , "##=. HPV Infection in -dolescentsK 6atural History, ?omplications, and Indicators for Viral .yping Semin Pediatr In)ect 0is. :K :3- $%. Ma* %a M&%$35 M l+%a Ca'a*0$5 Sa*a C.5 S$#$9D+ L+$%5 R "a*.$ Sa%"-+35 D a%a Pa**a5 A%.*+a C.5 P %+.a5 O##$ S&ss'a%%5 A%#$% $ P+*+39P*a.$s5 Ma%&+l E.5 Pa#a**$/$5 a%. Ma%&+l A.5 Pa#a**$/$5 ("# !). Human Papillomavirus 5etection from Human Immunodeficiency Virus-Infected ?olom(ian 8omen[s Paired ;rine and ?ervical 0amples. PL$S O%+. = >22); +<4<@?. M+l ssa La8s$% M.D., "##:. Human Papillomavirus (HPV) in -dolescents. .dolsecent 7edicine.3 (:). M+*"7 & C$. "##:. httpKHHwww.gardasil.comH. -ccessed Aan !#, "##3. M+*"$la, "# !. Jncology 5ietitian >xposes 9raud in ?5?&s HPV Vaccine >ffectiveness 0tudy, 2:>5:41 ) +8s. M+/+* T.5 A*%.# R.5 C-* s#$(-+*s E.5 ++3. -ssociation of rare papillomavirus types with genital premalignant and malignant lesions. 3 In)ect 0is 9? K "="-"==. M "-a+l P "- "-+*$ E., "##$. 8ho should get the HPV vaccine^ .he <oumal o) )amily Practice =: (!). M ..l+#$% B.5 P+- W.5 S$&#-+*% S.5 G* !! % H.5 S$#la* B.5 Na7a-a*a T.5 El9S-+* ! A.5 M$** s L.5 S+#- R.5 H 6'a M.5 J+%7 %s D.5 La'6+*# P.5 C$l+'a% N.5 D$$*6a* J.5 "##!.Jrgani<ation of human papilloma virus productive cycle during neoplastic progression provides a (asis for selection of diagnostic mar)ers. A Virol , $$( +)K # 3:-"# . M l.+ A.5 Haas9R$"--$l3 H.5 Baa#s"- H.J.5 ( +++). Improved 56- typing of human urine (y adding >5.-. Int A Degal 'ed " (!)K"#+*" #. M l.+9La%0$s"- B.5 S"-*+ 6+* C.5 B+"7+* G.5 LS% %0 T.5 a%. S#+0%+* HE.5 ++!. Human papilloma virus detection in cervical adenocarcinoma (y polymerase chain reaction. 21K=+#-=+%.
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M /as- #a M.5 A0.a'a0 D.M.5 Sasa0a8a T.5 Ma#s&s- #a B.5 Sal&. L.M.5 Sal&. CO , et al., "##+. High-ris) HPV types in lesions of the uterine cervix of female commercial sex wor)ers in the Philippines. A 'ed Virol4 3 (!)K=%=-= . M$-a''+. A7-#a* MD., "##%. Human papillomavirusK .he disease and prevention strategies. .nn Saudi 7ed. "% ( ). M$ll+*s M.5 S"-+*(+% ss+ M.5 Va% .+* 7 lls F.R.M.5 B %0 A. J.5 Va% R$ss&' T.G.J.5 Va% L$0"-+% E.M.5 F+l# Ba'( M.C.5 M+FF+* M.5 S% F.+*s P.J.F.5 B$$# H.J.5 D+ M+l7+* H.E.5 2092. Prevention o) genital -P' in)ection and -P' serology in adolescent girls, Prior to 'accination. Cancer 4pidemiology 'olume :=, Issue =, Pages @9>-@2E. M$% #$* %0 #-+ "$)+*a0+ a%. '(a"# $! -&'a% (a( ll$'a) *&s )a"" %+5 2@@?. R+($*# $! WHO '++# %0.5 W7l/ E( .+' $l R+". 2@1@=><22<);2,:I21,. M$s" "7 A.B.5 H lls N.5 S- 6$s7 S.5 ("## ). @is)s for incident human papilloma virus infection and low-grade sGuamous intraepithelial lesion development in young females. A -m 'ed -ssoc "3=K"++=*!##". M$s" "7 A.B.5 H lls N.5 S- 6$s7 S.5 et al., "## . @is)s for incident human papillomavirus infection and low-grade sGualors intraepithelial lesion development in young females. 3.7.."3=K"++=-!##". M$s" "7 A.B.5 S"- !!'a% M.5 BFa+* S.5 V lla L.L.5 ("##:). ?hapter =K ;pdating the natural history of HPV and anogenital cancer. Vaccine "%(0uppl !)K0!H%"*0!H= . M$s" "7 A.B.5 S- 6$s7 S.5 B*$+* %0 J.5 et al., ++3. .he natural history of human papillomavirus infection as measured (y repeated 56- testing in adolescent and young women. A Pediatr4 !"K"$$-3%. ?ross @ef 'edline 8e( of 0cience. M$s" "7 B.V.5 G*&66s B&*#5 Ba%$8 #3 S.5 Da**a0- T.5 a%. S- 6$s7 S. , +++.B.he significance of sGuamous metaplasia in the development of low grade sGuamous intraepithelial lesions in young women,C Cancer, vol. 3=, no. =, pp. !+* %%. M&%$3 N.5 B$s"- F.D.5 D+ Sa%F$s+ S.5 H+**+*$ R.5 Cas#+llsa0&+ D.5 S-a- B.V.5 S% F.+*s P.J.F.5 a%. M+ F+* CJLM.5 "##!. International -gency for @esearch on ?ancer 'ulticenter cervical ?ancer 0tudy Eroup. >pidemiologic classification of human papillomavirus types associated with cervical cancer. 6ew >ngl. A. 'ed. !%3 = 3*="$.
xiii
M&%$3 N.5 B$s"- FD.5 D+ Sa%F$s+ S.5 "##!. >pidemiologic classification of human papilloma virus types associated with cervical cancer. 6 >ngl A 'ed4 !%3(:)K= 3* ="$. XPu('edY M&K$3 N.5 MT%.+3 F.5 P$ss$ H.5
"#$$-$. et al., ("##%). Incidence, duration, and determinants of cervical human papilloma virus infection in a cohort of ?olom(ian women with normal cytological results. 3 In)ect 0is, 1?@,
Na# $%al Ca%"+* I%s# #&#+ ("##%). .-uman papilloma virus and cancer. Na#s&7$ Na7a3a7 5 Maa/$s- Ea #s&5 B$F M 7a' 5 S-&%s&7+ Y& 5 A/&' Ba%a#a% 5 N$*)al M.5 a%. B %0-a' R.W., +3$. -dvances in the use of nucleic acid pro(es in diagnosis of viral disease of man. -rch. Virol. +$K = - :=. O6&*+ J.5 Ol$la O.5 S8a B.5 Mla/ P.5 Mas+%0a G.5 Wal'+* D ., "##+. Prevalence and severity of cervical sGuamous intraepithelial lesion in a tertiary hospital in northern .an<ania, .an<an. A Health @es4 (%)K :!- :+. O6&*+ J.5 Ol$la O.5 S8a B.5 Mla/ P.5 Mas+%0a G.5 Wal'+* D ., "##+. Prevalence and severity of cervical sGuamous intraepithelial lesion in a tertiary hospital in northern .an<ania, .an<an. A Health @esK (%)K :!- :+. O30&l 6., "##$. .he condition of cervix cancer in .ur)ey and cervical cancer screening programes. InK .uncer -' (ed) ?ancer control in .ur)ey. 'inistry of Health of .ur)ey, -n)ara, pp !%+*!=3. Pa% H.5 a%. G* (+ A.E.5 ++=. .emporally distinct patterns of P=! * dependent and P=! independent apoptosis during mouse lens development. (enes 0eu +K" =$-:+. Pa*7 % D.M.5 B*a/ F.5 F+*la/ J.5 P sa% P ., "##=. Elo(al cancer statistics, "##". ??ancer A ?lin4 ==(")K$%* #3. Pa*7 % D.M.5 P sa% P.5 B*a*/ F.5 ("##:). .he glo(al health (urden of infection associated cancer in the year "##". International 3ournal Cancer %. P+# 0%a# P.5 Fal# % D.L.5 B*&"- ' I.5 T*a'+* M.R5 F*a%"$ E.L.5 C$&#l++ F.5 ("##$). -re self-collected samples compara(le to physician- collected cervical specimens for human papilloma virus 56- testing. - systematic review and meta-analysis. Eynecologic Jncol #=K=!#*=!=. P+# 0%a# P.5 Ha%7 %s C.5 Wal'sl+/ S.5 et al., "##=. 0elf-sampling is associated with increased detection of human papillomavirus 56- in the genital tract of HIV-sero positive women. ?lin Infect 5is4 % K="$*!%. 3 ( ") !#!#-
xiv
P-+l(s W.C.5 Y++ C.L.5 M&%0+* B.5 a%. H$8l+/ P.M.5 papillomavirus type functions similar to adenovirus > -. <>K=!+-=%$.
+33. .he human
: >$ gene encodes transactivation and transforming
P +#*$ A''a#&%a5 L&" a G $)a%%+ll 5 D$'+% "a Ma#*a%0a5 Sa)+* $ C * ' %%a5 a%. A%#$% $ P+* %$, "##3. Prevalence of Eenital Human Papilloma Virus Infection and Eenotypes among Rong 8omen in 0icily, 0outh Italy. Cancer 4pideniol "iomar8ers Preu $ (3). P %-+ *$ P.S.5 T/"3/%Ps7 J.E.5 B*a/ F.5 A'a.$ J.5 Ma#$s E.5 a%. Pa*7 % D.M.5 "##!.B?ancer incidence and mortality in Portugal,C 4uropean 3ournal o) Cancer, vol. !+, no. $, pp. "=#$*"="#. P$8+ll J5 S#*a&ss S5 G*a/ J.5 W$F%a*$8s7a F.5 "##!. Eenital carriage of human papillomavirus (HPV) 56- in prepu(ertal Eirls with and without vulval disease. Pediatr 0ermatol."#K + -%. P*&s#/ B.B.5 B&'a* A.5 A*$*a R.5 Ba#*a S.5 Das BC ., "##=. -uman papilloma virus F-P') 0N. detection in sel)-collected urine. Int (ynecol 6*stet; >0; 22:-?. Ral(- I%s %0a P.5 E* 7 Das6a"- J.5 Ela' % El6as-a H.5 Ba 9L L a85 a%. El a) Ba**5 "##$. Incidence and 5uration of ?ervical Human Papillomavirus :, and Perspectives. Cancer 4pidemiol "iomar8ers Preu : (%). Ra#%a' S.5 F*a%"$ E.L.5 F+*+%"3/ A., "###. Human papilloma virus testing for primary screening of cervical cancer precursors. ?ancer >pidemiol 2iomar)ers Prev "###4 +K+%=*= . R "-a*.s$% H.5 B+lsall G.5 T+ll +* P.5
et al., ("##!). .he natural history of type-specific human papilloma virus infections in female university students. Cancer 4pidemiol "iomar8ers Prev, 12, %3=-#.
, :,
3 Infections in Roung 8omenK -n >valuation from 'ultiple -nalytic
R "-a*.s$% H.5 B+lsall G.5 T+ll +* P.5 V$/+* H.5 A6*a-a'$8 "3 M.5 F+*+%"3/ A.5 et al., "##! .he natural history of type-specific human papillomavirus infections in female university students. ?ancer >pidemiol 2iomar)ers Prev4 "(:)K%3=*+#. Sa 7 R.B.5 S"-a*! S.5 Fal$$%a F.5 M&ll s B.B.5 H$*% G.T.5 E*l "- H.A.5 a%. A*%-+ ' N.5 +3=. >n<ymatic amplification of I-glo(in genomic seGuences and restriction site analysis for diagnosis of sic)le cell anemia. 0cience "!#K !=#!=%. Sa 7 5 R. B.5 G+l!la%. D.H.5 S#$!!+l S.5 S"-a*! S.J.5 H 0&"- R.5 H$*% G.T.5 M&ll s B.B.5 a%. E*l "- H.A., +33. Primer directed en<ymatic amplification of 56with a thermosta(le 56- polymerase. 0cience "!+K%3$-%+ .
xv
Sa%7a*a%a*a/a%a% R.5 N+%+ B.M.5 D %s-a8 B.A. , et al., - cluster randomi<ed controlled trial of visual, cytology and human papilloma virus screening for cancer of the cervix in rural India. Int A ?ancer "##=4 :K: $-"!. Sa%7a*a%a*/a%a% R.5 B&.&7 A.M.5 RaF7&'a* R., >ffective screening programmes for cervical cancer in low and middle income developing countries. 2ull 8orld Health Jrgan. "## 4 $+K+=%*:". Sa*a B.5 R "-a*. C*$s6/ A.5 a%. G*+0$*/ M$$*+ R5 "##+. Pap 0mear 1nowledge -mong Roung 8omen 9ollowing the Introduction of the HPV Vaccine. 3 Pediatr .dolesc (yneod.""."= -"=:. S"-+ll+7+%s M.C.5 D F7'a% A.5 A3 3 MF.5 S *+0a* B.5 C$*%a % S.5 B$l7'a%9UlF++ S.5 P+#+*s LA.5 Fl+&*+% G.J.5 ("##%). Prevalence of single and multiple. S"- !!'a% M.H., @ecent progress in defining the epidemiology of human papillomavirus infection and cervical neoplasia. A 6atl ?ancer Inst ++"43% (:)K!+%*3. S"-l+"-# N.F.5 B&la0a S.5 R$6 #a ll+ J.5 et al., "## . Persistent human papilloma virus infection as a predictor of cervical intraepithelial neoplasia. A-'- "## 4 "3:K! #:- %. S+-0al A.5 G&(#a S.5 Pa*as-a* A.5 S$.-a% P.5 S %0- V ., "##+. ;rine HPV-56detection for cervical cancer screeningK prospects and pre/udices. A J(stet Eynaecol. "+($)K=3!*=3+. XPu('edY S+ll$*s J.W.5 L$* %"3 A.T.5 Ma-$%/ J.B.5 M +l3/%s7a I.5 L/#8/% A.5 R$#- P.5 H$8a*. M.5 C-$%0 S.5 Da/a D.5 C-a('a% W.5 a%. C-+*%+s7/ M.5 "###. ?omparison of self-collected vaginal, vulvar and urine samples with physiciancollected cervical samples for human papilloma virus testing to detect high-grade sGuamous intraepithelial lesions. ?an. 'ed. -ssoc. A. 14,;= !*= 3. S+ll$*s J.W.5 Ma-$%/ J.B.5 Ba"3$*$8s7 J.5 et al., "###. Prevalence and predictors of human papillomavirus infection in women in Jntario, ?anadaK survey of HPV in Jntario 8omen (0HJ8) Eroup. ?'-A4 :!K =#!*3. S 0*&% R+ssl+*.5 R+%+ S"-+ .+%.5 B+*s# % D*+ +*.5 A%.*+as La "-.5 a%. Ha%s9P+#+* V +*#l+*, "##$. 0exually .ransmitted Infection >ducation 9oundation, $th >dition High-ris) Human Papillomavirus >$ Jncoprotein 5etection in ?ervical 0Guamous ?ell ?arcinoma. Clin Cancer 5es. !("!).
xvi
S % Ha%0 L++5 V+*$% "a V 0l $## % S.5 a%. S&* Pa((& , "##+. HPV infection among women in a representative rural and su(ur(an population of the ;0-. International 3oumal o) (ynecology and 6*stetrics. #=K" #-" %. S %al S.H.5 W$$.s C.R.5 ("##=). Human papilloma virus infections of the genital and respiratory tracts in young children. 0emin Pediatr Infect 5is :K!#:*! :. doiK #. #=!H/.spid."##=.#:.# #. S$%0 E.5 L++ H.J.5 H8a%0 T.J ., "##$ ?linical efficacy of Human papillomavirus 56detection in urine from patients with various cervical lesions. 3 Corean med Sci.""K++- #%. S*++7ala Na * a%. M Ra.-a7* s-%a P lla , "##=. Human Papilloma Virus, ?ellular Eenetics and 0uscepti(ility to ?ervical ?ancer. Int 3 -um (enet. =( )K - $. S#a%"3&7 GA.5 Ba/ P.5 Alla% B.5 C- *a*a M.5 Ts8a%a SA.5 B+*0s#*$' S.5 et al., "##!. 5etection of Human papillomavirus in urine and cervical swa(s from patients with invasive cervical. 3 7ed 'irol. $ K #-%. S#++%6+*0+% RDM.5 D+ W l.+ J.5 W l# %0 S.M.5 B* %7 AATP.5 S% F.+*s PJF.5 M+ +* ?AD', "##=. HPV-mediated transformation of the anogenital tract. A ?lin Virol, S#*a&ss S.5 J$*.+%s J.E.5 M"B* .+ D.5 S$%%+G C.5 E.8a*.s S.5 D+ss+l6+*0+* U.5 Wa## P.5 a%. G*a/ J.J.5 +++. 5etection and typing of human papilloma virus 56- in paired urine and cervical scrapes. >ur. A. >pidemiol. 4;=!$*=%!. S/*Fa%+% S.5 P&*a%+% M.5 ("##"). Human papilloma virus infections in childrenK the potential role of maternal transmission. ?rit @ev Jral 2iol 'ed K"=+*"$%. Ta7&s- Na7a#a% 5 A7 7$ I#$5 Y&#a Ta7+s- 'a5 A7 7$ T$%$$7a5 H .+a7 O7a5 T+%$)+*5 F. C., +33. 5iagnostic deoxyri(onucleic acid pro(es for infectious diseases. ?lin. 'icro(iol. @ev. K3"- # . T+*+sa E*6 MD.5 a%. R "-a*. B+ 0 H.5 "##3. ;pdate on Infectious 5iseases in -dolescent Eynecology. 3 Pediatr .dolesc (ynecol. " K !=- %!. .he role of inflammation in hpv carcinogenesis. "# !. >5. +th Jcto(er. 2ioportifoioK I006K %:#- " 3 #4 @efK httpKHHwww.nc(i.nim.nih.gov.govHpu(medH"#3 +$$+. T-$'as M.5 a%. Ba%7s L., ++3. Inhi(ition of (a) -induced apoptosis (y HPV- 3>: 6ncogene. $K"+%!-=%. T-$'as W* 0-# C., "##+. 6atural History of HPV Infection. /he 3ournal o) Aamily practice. =3 (+).
xvii
T$'$7$ M 7 a%. Ta7&' Ta7+&"- 15 "# ". ?oincidence of HPV
-Positive ;rethral
?ondyloma -cuminatum and HPV- 6egative 'ultiple 2ladder Papilloma in a 9emale. ?ase @eports in 'edicine Volume, -rticle I5 :#"3 +, ! pages. U6+*# 9F$((a C.5 O* 0$% M.5 Ma lla*. M.5 et al., >valuation of the detection of human papilloma virus genotypes in cervical specimens (y hy(rid capture as screening for precancerous lesions in HIV-positive women. A 'ed Virol ++34 =:K !!*$. U+.a Y.5 E%$'$#$ T.5 M /a#a7+ T.5 O3a7 B.5 Y$s- 3a7 T.5 Ba%a$ H.5 U+%$ Y.5 Na7as- 'a R.5 S-*$/+* BR.5 M&*a#a Y.5 La6 I%)+s#5 "##!. 'onoclonal expansion with integration of high-ris) type human papilloma virus is an essential step for cervical carcinogenesisK association of clonal status and human papilloma virus infection with clinical outcome in cervical intraepithelial neoplasia. >,K = $="$. US C+%#+*s !$* D s+as+ C$%#*$l a%. P*+)+%# $% . "##$. -?IP provisional recommendations for the use of Guadrivalent HPV vaccine. httpKHHwww.cdc.govHnip HrecsHprovisionalfrecsHhpv.pdf. -ccessed 9e(ruary 3. V+l.-& F3+% N.J.5 S% F.+*s P.J.5 R+ ss P.5 M+ F+* C.J.5 )a% .+ W F0+*# J.H.5 "# #. 9actors affecting transmission of mucosal human papilloma virus. Dancet Infect 5is "# #, #( ")K3:"-$%, @eview. V lla L.L.5 C$s#a R.L.5 P+##a C.A.5 et al., "##=. Prophylactic Guadrivalent human papilloma virus (types :, , :, and 3) D virus-li)e particle vaccine in young womenK a randomised dou(le-(lind place(o-controlled multicentre phase II efficacy trial. %ancet 6ncol 4 :K "$ -"$3. V$*s#+*s A.5 M "al+ss I.5 B l"7+ J.5 I+)+% M.5 B$0+*s J.5 Va% Da''+ P., "# ". 5etection of human papilloma virus 56- in urine. - review of the literature. >ur A ?lin 'icro(iol Infect 5is. 4! (=)K:"$*:%#. XPu('edY V$ssl+* J. L.5 F$*6+s B.A.5 a%. A.+ls$% M.D.5 ++=. >valuation of the polymerase chain reaction for the detection of human papillomavirus from urine. A. 'ed Virol. 1<;!=%*!:#. V$ssl+* J.L.5 F$*6+s B.A.5 A.+ls$% M.D ., ++=. 4valuation o) the polymerase chain reaction )or the detection o) human papilloma virus )rom urine. 3 7ed 'irol; E@; :@E-=0. Wal6$$'+*s J.M.5 Ja"$6s M.V.5 Ma%$s M.M., et al., +++. Human papilloma virus is a necessary cause of invasive cervical cancer worldwide. A Pathol.4 3+K "*+.
xviii
Wal6$$'+*s JM.5 Ja"$6s MV., +++. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. A Pathol. 3+( )K "* +. XPu('edY W-++l+* C.M.5 H&%# W.C.5 J$s#+ N.E.5 B+/ C.R.5 A& %# W.G.V.5 a%. Cas#l+ P.E., BHuman papilloma virus genotype distri(utionsK implications for vaccination and cancer screening in the ;nited 0tates,C 3ournal o) the National Cancer Institute , vol. # , no. $, pp. %$=ss*%3$, "##+ W-++l+* CM.5 Cas#+llsa0&+P D.5 Ga*la%. SM.5 S3a*+8s7 A.5 Paa)$%+% J.5 et al., ("# ") ?ross-protective efficacy of HPV- :H 3 -0#%-ad/uvanted vaccine against cervical infection and precancer caused (y non-vaccine oncogenic HPV typesK %year end-of-study analysis of the randomised, dou(le-(lind P-.@I?I- trial. Dancet Jncol !( )K ##* #. W$$.'a% C.B.5 C$ll %s S.5 W %#+* H.5 Ba l+/ A.5 Ell s J.5 P* $* P.5 et al., "## . 6atural history of cervical human papilloma virus infection in young womenK a longitudinal cohort study. Dancet4 !=$(+"$ )K 3! . W$$.'a% CB5 C$ll %s S5 W %#+* H5
et al., ("## ). 6atural history of cervical human papillomavirus infection in young womenK a longitudinal cohort study. %ancet, ,<:, 3! -:.
W$$.'a% CBJ.5 C$ll %s S.I.5 Y$&%0 L.S.5 ("##$). .he natural history of cervical HPV infectionK unresolved issues. 6at @ev ?an $K *"". W* 0-# TC.5 D+%%/ L.5 B&-% L.5 P$lla"7 A.5 L$* %"3 A ., "###. HPV 56- testing of self-collected vaginal samples compared with cytologic screening to detect cervical cancer. A-'- "###4 "3!K3 *:. Da) +* B$s"- F.5 Y$&9L % A a$5 a%. Da) +* Cas#+lla0&+, "##:. .he epidemiology of human papillomavirus infection and its association with cervical cancer. International <ournal o) gynecology and 6*stetrics. +%Ks3-0" . D a%0 Wa%0 5 D$%0-&a G& 5 B % L$& 5 B % D& 5 F&"-& A a% 5 Y& C-+%5 "# !. Hospital-(ased prevalence of high-ris) cervical HPV types infecting the general population and female sex wor)ers in Hu<hou, ?hina. International Aournal of Eynecology and J(stetrics "# K !$*% . D a$"-+%0 W&%7 D.5 G*$)+s C$ll++% C.5 M"La&0-l %5 A-'+. % J+'al5 J ' Ma*# % &V ) +% C-+% W., "##=. ?ancer incidence patterns among adolescents and young adults in the ;nited 0tates. Cancer Causes and Control. :K!#+-!"#. E&* Ha&s+% H., ++:. Papillomavirus infections a a ma/or cause of human cancers.2iochim 2iophys -cta. "33(")K9==*9$3. XPu('edY.
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