1. HUMAN PAPILLOMAHUMAN PAPILLOMA
VIRUSVIRUS
(HPV)(HPV)
Prof. M.C. Bansal.Prof. M.C. Bansal.
MBBS.MS. MICOG.FICOG.MBBS.MS. MICOG.FICOG.
Founder Principal & Controller;Founder Principal & Controller;
Jhalawar Medical College And HospitalJhalawar.Jhalawar Medical College And HospitalJhalawar.
Ex. Principal & Controller;Ex. Principal & Controller;
Mahatma Gandhi Medical college and hospital,Mahatma Gandhi Medical college and hospital,
Sitapura, JaipurSitapura, Jaipur
DR. AAKANKSHA AGARWALDR. AAKANKSHA AGARWAL

2. HUMAN PAPILLOMA VIRUSHUMAN PAPILLOMA VIRUS
►Papillomaviruses are small, non enveloped,Papillomaviruses are small, non enveloped,
double-stranded DNA viruses encased in adouble-stranded DNA viruses encased in a
72-sided icosahedral protein capsid.72-sided icosahedral protein capsid.
The HPV genome consists of circular,The HPV genome consists of circular,
double-stranded DNA of approximatelydouble-stranded DNA of approximately
7,900 nucleotide base pairs.7,900 nucleotide base pairs.

3. HPV StructureHPV Structure
Non Enveloped Double Stranded DNA VirusNon Enveloped Double Stranded DNA Virus
Small DNA viruses with
about 7900 base pairs
6 early (E) and 2 late (L)
proteins
L1-capsid protein
**E6 and E7 are
oncogenic
!
Each type has less than
90% base pair
homology with any
other type

4. Noble Prize Winner 2008Noble Prize Winner 2008
Detected HPV DNA in CancerDetected HPV DNA in Cancer
cellscells
Structure
of HPV
Prof. Harald zur Husen

5. HPVHPV
5
► INCIDENCEINCIDENCE
 MOST PREVALENT STD IN COLLEGE WOMENMOST PREVALENT STD IN COLLEGE WOMEN
► CLINICAL IMPRESSIONCLINICAL IMPRESSION
 VISIBLE GENITAL WARTS CALLEDVISIBLE GENITAL WARTS CALLED
CONDYLOMA ACUMINATACONDYLOMA ACUMINATA
► CONDYLOMA = “KNUCKLES”, ACUMINATA =CONDYLOMA = “KNUCKLES”, ACUMINATA =
“POINTED”“POINTED”
 SMOOTH OR FINGERLIKE FLESH-COLOREDSMOOTH OR FINGERLIKE FLESH-COLORED
PROJECTIONSPROJECTIONS  ROUGHROUGH
 MULTIPLE PAPULES MAY BECOMEMULTIPLE PAPULES MAY BECOME
CONFLUENT, OR MULTILOBED MASSESCONFLUENT, OR MULTILOBED MASSES
 CAN BE PAINFUL, FRIABLE &/OR PRURITICCAN BE PAINFUL, FRIABLE &/OR PRURITIC
► INVASIVE CANCERINVASIVE CANCER

6. 6
33%
Estimated 24 to 40 million cases today,
with 1 million NEW cases per year,
mostly in people under 25 years old.
Several studies have shown that
about one third (33%) of sexually
active females carry this virus
FASTEST GROWING STD IN USA

7. HUMAN PAPILLOMA VIRUSHUMAN PAPILLOMA VIRUS
►More than 100 different kinds are I denified,More than 100 different kinds are I denified,
but only 30 types of them cause genitalbut only 30 types of them cause genital
HPV infection.HPV infection.
►Infection spreads by sexual contact and orInfection spreads by sexual contact and or
from mother to baby(trans placental).from mother to baby(trans placental).
►Genital warts appear 6 weeks to 8 monthsGenital warts appear 6 weeks to 8 months
aftersexual contact with an HPV infectedaftersexual contact with an HPV infected
person.person.

8. HPV TYPESHPV TYPES
►The common HPV types can be divided intoThe common HPV types can be divided into
three major categories based on theirthree major categories based on their
oncogenic potential:oncogenic potential:
1.Low risk HPV-6,11,42,43,441.Low risk HPV-6,11,42,43,44
►
2.Intermediate risk HPV-33,35,39,52,582.Intermediate risk HPV-33,35,39,52,58
►
3.High risk HPV-16,18,31,453.High risk HPV-16,18,31,45

9. ►Low risk types most commonly causeLow risk types most commonly cause
genital warts.genital warts.
HPV-6 is the most common type associatedHPV-6 is the most common type associated
with genital warts.with genital warts.
Seventy-five percent cases of cervicalSeventy-five percent cases of cervical
cancer are infected with high risk types.cancer are infected with high risk types.

10. HPV-16 is the predominant type inHPV-16 is the predominant type in
pathogenesis of squamous cell cancer.pathogenesis of squamous cell cancer.
HPV-18 is the predominant pathogen inHPV-18 is the predominant pathogen in
adenocarcinoma of cervix.adenocarcinoma of cervix.
Multiple infections are common withMultiple infections are common with
prevalence ranging from 2 to 20 percent.prevalence ranging from 2 to 20 percent.
All types can cause subclinical infection.All types can cause subclinical infection.

18. APPEARANCE OF HPVAPPEARANCE OF HPV

19. MECHANISM OF INFECTIONMECHANISM OF INFECTION
►All HPV exhibit extreme specificity forAll HPV exhibit extreme specificity for
infection on epithelial cells.infection on epithelial cells.
►The papillomavirus epitheliotrophy residesThe papillomavirus epitheliotrophy resides
in the interaction of specific transmissionin the interaction of specific transmission
factors with the viral regulatory regionfactors with the viral regulatory region
LCR.LCR.
►The infection normally results inThe infection normally results in
hyperproliferation of the host cell and mayhyperproliferation of the host cell and may
lead to transformation and immortalization.lead to transformation and immortalization.

20. LIFE CYCLELIFE CYCLE

21. HPV GENOMICHPV GENOMIC
ORGANIZATIONORGANIZATION
 Upstream regulatory region (URR)Upstream regulatory region (URR)
 Early regionEarly region
 Late regionLate region
► URR regulates viral replicationURR regulates viral replication
► Early region- Transcribes proteins that isEarly region- Transcribes proteins that is
helpful to program the host cell tohelpful to program the host cell to
produce new viral DNAproduce new viral DNA
► Late region- encodes proteins for theLate region- encodes proteins for the
capsid that surround like DNA core tocapsid that surround like DNA core to
produce the complete viron molecule.produce the complete viron molecule.
► With all these mechanisms, the virusWith all these mechanisms, the virus
takes over the control of infectedtakes over the control of infected
epithelial cells.epithelial cells.
► The virus then entirely controls the hostThe virus then entirely controls the host
cell mechanism to produce new viralcell mechanism to produce new viral
DNA and viral proteins.DNA and viral proteins.

22. Host Immune ResponseHost Immune Response
HumoralHumoral
► There isThere is developmentdevelopment of HPV specific neutralizingof HPV specific neutralizing
antibodies either of immunoglobulin IgA and IgGantibodies either of immunoglobulin IgA and IgG
► These antibodies prevent infection of anogenitalThese antibodies prevent infection of anogenital
mucosal surface.mucosal surface.
► These are detected against L1 & L2 HPV capsidThese are detected against L1 & L2 HPV capsid
protein.protein.

23. Cell Mediated Immunity-Cell Mediated Immunity-
► Whenever the pathogens enter the human cell-CellWhenever the pathogens enter the human cell-Cell
Mediated immunity ( CMI) mechanism is switched on inMediated immunity ( CMI) mechanism is switched on in
following way.--------following way.--------
► Specific CD8 +, cytotoxic T lymphocytes , CD4 and HelperSpecific CD8 +, cytotoxic T lymphocytes , CD4 and Helper
T lymphocytes are activated and play important role,T lymphocytes are activated and play important role,
required to clear the infected cells.required to clear the infected cells.
► Cytotoxic T lymphocytes (CTL) recognise the earlyCytotoxic T lymphocytes (CTL) recognise the early
proteins in the infected cells in conjuction with host majorproteins in the infected cells in conjuction with host major
histocompatibility complex (MHC) class I molecule.histocompatibility complex (MHC) class I molecule.
► Helper T cells recognise longer peptide fragmentsHelper T cells recognise longer peptide fragments
complexed with MHC class II molecules.complexed with MHC class II molecules.
► Both these cytotoxic T lymphocytes and Helper TBoth these cytotoxic T lymphocytes and Helper T
lymphocytes promote specific antibody production throughlymphocytes promote specific antibody production through
cytokines induction.cytokines induction.

24. About 80% of Women
will be infected with
HPV in their lifetime
HPV and Cervical CancerHPV and Cervical Cancer
Source: Gynecologic Cancer Foundation

25. About 9-25
per100,000
Women (per year
in India) will
develop cervical
cancer
HPV and Cervical CancerHPV and Cervical Cancer

26. HPV AND CERVICALHPV AND CERVICAL
NEOPLASIANEOPLASIA
► Infections with HPV cause approximately 5% of the globalInfections with HPV cause approximately 5% of the global
burden of human cancers and at least 500,000 deathsburden of human cancers and at least 500,000 deaths
annually .annually .
Infection with specific HPV (16,18) types is necessary forInfection with specific HPV (16,18) types is necessary for
the development of the vast majority of cervical cancersthe development of the vast majority of cervical cancers
(>99.7%) and the immediate precursor lesion (CIN 3) .(>99.7%) and the immediate precursor lesion (CIN 3) .
The magnitude of the association between HPV andThe magnitude of the association between HPV and
cervical cancer is higher than the association betweencervical cancer is higher than the association between
smoking and lung cancer.smoking and lung cancer.

28. ► The four major steps in the development of cervical cancerThe four major steps in the development of cervical cancer
are-are-
(i) infection of the metaplastic epithelium of the(i) infection of the metaplastic epithelium of the
transformation zone with one or more carcinogenic HPVtransformation zone with one or more carcinogenic HPV
types;types;
(ii) viral persistence rather than clearance reflecting the host(ii) viral persistence rather than clearance reflecting the host
immune response;immune response;
(iii) clonal progression of persistently infected epithelium to(iii) clonal progression of persistently infected epithelium to
cervical precancer (CIN 3); and progression tocervical precancer (CIN 3); and progression to
(iv) clinical cancer (macro and micro invasion).(iv) clinical cancer (macro and micro invasion).

29. Model of CervicalModel of Cervical
CarcinogenesisCarcinogenesis
Latent InfectionLatent Infection
Productive Viral InfectionProductive Viral Infection
Cellular TransformationCellular Transformation
Transformation to MalignancyTransformation to Malignancy

30. HPV – PATHOGENISIS OFHPV – PATHOGENISIS OF
CERVICAL CANCERCERVICAL CANCER
The HPV genome is usually maintained as a stable viral episome, independentThe HPV genome is usually maintained as a stable viral episome, independent
of the host cell genome, in the nucleus of infected cells.of the host cell genome, in the nucleus of infected cells.
It codes for only eight genes .It codes for only eight genes .
In some high-grade CIN lesions, and more frequently in cervical cancer, HPVIn some high-grade CIN lesions, and more frequently in cervical cancer, HPV
genomes are covalently bonded or integrated into the host chromosomes .genomes are covalently bonded or integrated into the host chromosomes .
This integration event occurs at random within the host cell genome but isThis integration event occurs at random within the host cell genome but is
highly specific in relation to the viral genome, involving the E1 and E2 genes,highly specific in relation to the viral genome, involving the E1 and E2 genes,
with important consequences for regulation of viral gene expression .with important consequences for regulation of viral gene expression .
This integration of the HPV genome into the host genome is associated withThis integration of the HPV genome into the host genome is associated with
invasive cancer and might serve as an important biomarker to distinguish HPVinvasive cancer and might serve as an important biomarker to distinguish HPV
infection from precancer .infection from precancer .

31. ►The late genes, L1 and L2, the sequencesThe late genes, L1 and L2, the sequences
of which are highly conserved among allof which are highly conserved among all
papilloma viruses, encode the commonpapilloma viruses, encode the common
capsid proteins.capsid proteins.
These viral proteins reflect late viral geneThese viral proteins reflect late viral gene
expression and are exclusively present inexpression and are exclusively present in
well-differentiated keratinocytes .well-differentiated keratinocytes .
Both proteins play an important role inBoth proteins play an important role in
mediating efficient virus infectivity.mediating efficient virus infectivity.

32. The proteins encoded by the E6 and E7 genes of high-risk HPV types,The proteins encoded by the E6 and E7 genes of high-risk HPV types,
particularly HPV 16 (clade A9) and 18 (clade A7), are directly involvedparticularly HPV 16 (clade A9) and 18 (clade A7), are directly involved
in cellular transformation in the presence of an active oncogene .in cellular transformation in the presence of an active oncogene .
E6 and E7 are the primary HPV oncoproteins with numerous cellularE6 and E7 are the primary HPV oncoproteins with numerous cellular
targets .targets .
Both E6 and E7 proteins can immortalize primary keratinocytes fromBoth E6 and E7 proteins can immortalize primary keratinocytes from
cervical epithelium and can influence transcription from viral andcervical epithelium and can influence transcription from viral and
cellular promoters .cellular promoters .
The activity of these viral oncoproteins results in genomic instability,The activity of these viral oncoproteins results in genomic instability,
leading to the malignant phenotype.leading to the malignant phenotype.
E6 proteins of high-risk HPV types bind the tumor suppressor proteinE6 proteins of high-risk HPV types bind the tumor suppressor protein
p53 .p53 .
This induces ubiquitination and degradation of p53, removing the p53-This induces ubiquitination and degradation of p53, removing the p53-
dependent control of the host cell cycle.dependent control of the host cell cycle.

33. ► E6 also increases telomerase activity in keratinocytesE6 also increases telomerase activity in keratinocytes
through increased transcription of the telomerase catalyticthrough increased transcription of the telomerase catalytic
subunit gene (hTERT) through induction of c-myc .subunit gene (hTERT) through induction of c-myc .
Telomerase activity is usually absent in somatic cells,Telomerase activity is usually absent in somatic cells,
leading to shortening of telomeres with successive cellleading to shortening of telomeres with successive cell
divisions and to eventual cell senescence. E6 mediation ofdivisions and to eventual cell senescence. E6 mediation of
telomerase activity may predispose to long-term infectiontelomerase activity may predispose to long-term infection
and the development of cancer.and the development of cancer.
Recently E6 and E7 viral oncogenes have been shown toRecently E6 and E7 viral oncogenes have been shown to
antagonize BRCA-mediated inhibition of the hTERTantagonize BRCA-mediated inhibition of the hTERT
promoter .promoter .
►

34. ► The E7 gene product is a nuclear phosphoprotein that associates withThe E7 gene product is a nuclear phosphoprotein that associates with
the product of the retinoblastoma gene (pRb), which is a tumorthe product of the retinoblastoma gene (pRb), which is a tumor
suppressor gene important in the negative control of cell growth .suppressor gene important in the negative control of cell growth .
E7 is the primary transforming protein.E7 is the primary transforming protein.
Degradation of p53 by E6 and the functional inactivation of pRb by E7Degradation of p53 by E6 and the functional inactivation of pRb by E7
represent the main mechanisms whereby expression of HPV E6 andrepresent the main mechanisms whereby expression of HPV E6 and
E7 oncoproteins subverts the function of the negative regulators of theE7 oncoproteins subverts the function of the negative regulators of the
cell cycle .cell cycle .
Deregulated expression of the viral oncogenes is a predisposing factorDeregulated expression of the viral oncogenes is a predisposing factor
to the development of HPV-associated cancers.to the development of HPV-associated cancers.

35. ► The products of the E2 gene are involved in transcriptionalThe products of the E2 gene are involved in transcriptional
regulation of the HPV genome.regulation of the HPV genome.
The process of HPV integration into the cellular genome,The process of HPV integration into the cellular genome,
which occurs in some high-grade CIN lesions and mostwhich occurs in some high-grade CIN lesions and most
invasive cervical cancers, disrupts the E2 gene .invasive cervical cancers, disrupts the E2 gene .
This results in increased levels of E6 and E7 expression,This results in increased levels of E6 and E7 expression,
correlating with increased immortalization activity .correlating with increased immortalization activity .
Both E6 and E7 proteins are expressed at low levels in theBoth E6 and E7 proteins are expressed at low levels in the
process of HPV infectionprocess of HPV infection

36. ► Low-risk HPV types, particularly HPVs 6 and 11 (clade A10), areLow-risk HPV types, particularly HPVs 6 and 11 (clade A10), are
associated with condylomata acuminata of the genital tract in bothassociated with condylomata acuminata of the genital tract in both
sexes.sexes.
HPV 6 and 11 are also detected alone in low-grade cervical lesionsHPV 6 and 11 are also detected alone in low-grade cervical lesions
(exophytic condylomata acuminata, subclinical HPV infection, CIN 1(exophytic condylomata acuminata, subclinical HPV infection, CIN 1
and some CIN 2 lesion.and some CIN 2 lesion.
These viruses do not appear to induce malignant transformation; theyThese viruses do not appear to induce malignant transformation; they
are unable to integrate into the human genome.are unable to integrate into the human genome.
The E6 and E7 proteins of “lowrisk” HPV types only weakly bind p53The E6 and E7 proteins of “lowrisk” HPV types only weakly bind p53
and pRb and thus do not immortalize keratinocytes in vitro.and pRb and thus do not immortalize keratinocytes in vitro.

37. ►HPV- 16HPV- 16
Human papillomavirus 16 is the HPV type universallyHuman papillomavirus 16 is the HPV type universally
detected with greatest frequency in high-gradedetected with greatest frequency in high-grade
intraepithelial neoplasia and invasive cancers.intraepithelial neoplasia and invasive cancers.
HPV 16 is associated with 50% of cervical squamousHPV 16 is associated with 50% of cervical squamous
cancers and more than 30% of adenocarcinomas .cancers and more than 30% of adenocarcinomas .
It is present in more than 80% of high-grade cervical,It is present in more than 80% of high-grade cervical,
vaginal, vulvar, perianal, and penile preinvasive lesions.vaginal, vulvar, perianal, and penile preinvasive lesions.
It is detected in more than 25% of low-grade cervicalIt is detected in more than 25% of low-grade cervical
lesions, 40% of subclinical vulvar HPV infections, and 10%lesions, 40% of subclinical vulvar HPV infections, and 10%
of genital condylomata acuminata, particularly theof genital condylomata acuminata, particularly the
recalcitrant lesions .recalcitrant lesions .

38. ►HPV 18HPV 18  the second most common (25%)the second most common (25%)
HPV type in invasive cervical cancer, but isHPV type in invasive cervical cancer, but is
uncommon (5%) in preinvasive cervical lesions .uncommon (5%) in preinvasive cervical lesions .
The association of HPV 18 with aggressiveThe association of HPV 18 with aggressive
adenocarcinomas, particularly in younger women,adenocarcinomas, particularly in younger women,
and the underrepresentation of this viral type inand the underrepresentation of this viral type in
preinvasive lesions have raised concerns thatpreinvasive lesions have raised concerns that
HPV 18 may be associated with “rapid-transit”HPV 18 may be associated with “rapid-transit”
cancers that escape reliable cytologic detectioncancers that escape reliable cytologic detection

39. ► Although the true prevalence of cervical HPV infection isAlthough the true prevalence of cervical HPV infection is
unknown, it is the most common sexually transmittedunknown, it is the most common sexually transmitted
infection, with most sexually active women younger than 35infection, with most sexually active women younger than 35
years of age exposed.years of age exposed.
► HPV prevalence and incidence peak in women under 20HPV prevalence and incidence peak in women under 20
years of age and decline in women over 30, secondary toyears of age and decline in women over 30, secondary to
HPV clearance, with most women in the world exposed toHPV clearance, with most women in the world exposed to
one or more genital HPV types during their sexual lifeone or more genital HPV types during their sexual life

40. CLEARANCE OF HPVCLEARANCE OF HPV
►The median time to clearance of HPVThe median time to clearance of HPV
infection in an immunocompetent woman isinfection in an immunocompetent woman is
6 to 18 months (average of 12 months) with6 to 18 months (average of 12 months) with
90% of women clearing a specific HPV-type90% of women clearing a specific HPV-type
after 2 years of observationafter 2 years of observation

41. ►Viral clearance is not often associated withViral clearance is not often associated with
reappearance of the same HPV type.reappearance of the same HPV type.
Occasionally the same HPV type willOccasionally the same HPV type will
reappear.reappear.
It is unclear whether this representsIt is unclear whether this represents
reinfection or resurgence from a latent statereinfection or resurgence from a latent state
in the basal cells of the epithelium with veryin the basal cells of the epithelium with very
low viral copy numbers and without late virallow viral copy numbers and without late viral
expressionexpression

42. ►The longer a specific HPV type persists inThe longer a specific HPV type persists in
the epithelium, the lower the probability ofthe epithelium, the lower the probability of
clearance within a defined period, and theclearance within a defined period, and the
greater the risk of precancergreater the risk of precancer

43. 43

44. 44

46. ► Only persistent high-risk HPV infection of the cervical epithelium appears toOnly persistent high-risk HPV infection of the cervical epithelium appears to
trigger neoplastic progression.trigger neoplastic progression.
The risk factors for HPV persistence and progression to CIN 3 are not fullyThe risk factors for HPV persistence and progression to CIN 3 are not fully
understood. HPV type is the strongest factor affecting risk of viral persistence .understood. HPV type is the strongest factor affecting risk of viral persistence .
HPV 16 is highly carcinogenic with an absolute risk of CIN 3 approaching 40% atHPV 16 is highly carcinogenic with an absolute risk of CIN 3 approaching 40% at
3 to 5 years .3 to 5 years .
The risks of progression to CIN 3 with other HPV types are several-fold lower.The risks of progression to CIN 3 with other HPV types are several-fold lower.
Women infected with multiple HPV types have a further increased risk but it isWomen infected with multiple HPV types have a further increased risk but it is
not clear if the risk is equal to or greater than the cumulative risk associated withnot clear if the risk is equal to or greater than the cumulative risk associated with
each of the individual HPV types.each of the individual HPV types.
It is also unknown whether infection with multiple HPV types interferes withIt is also unknown whether infection with multiple HPV types interferes with
persistence of a given HPV type or with risk of progression to CIN 3 .persistence of a given HPV type or with risk of progression to CIN 3 .

47. ►The modal time from HPV infection to CIN 3The modal time from HPV infection to CIN 3
is 7 to 15 years, with infection occurring inis 7 to 15 years, with infection occurring in
the late teens or early twenties and CIN 3the late teens or early twenties and CIN 3
diagnosis peaking at 25 to 30 years .diagnosis peaking at 25 to 30 years .
The average age of diagnosis of CIN 3The average age of diagnosis of CIN 3
depends on average societal age of firstdepends on average societal age of first
intercourse, a proxy for initial HPVintercourse, a proxy for initial HPV
exposure, and age of onset and intensity ofexposure, and age of onset and intensity of
screeningscreening

48. ►CIN 3 lesions are a homologous populationCIN 3 lesions are a homologous population
of aneuploid lesions, mostly associated withof aneuploid lesions, mostly associated with
oncogenic HPVs, and are genuine canceroncogenic HPVs, and are genuine cancer
precursors.precursors.
► The transit time to invasive cancer isThe transit time to invasive cancer is
variable, taking as little as 12 to 18 monthsvariable, taking as little as 12 to 18 months
or as long as several decades. Mostor as long as several decades. Most
cervical abnormalities do not transform tocervical abnormalities do not transform to
invasive cancerinvasive cancer

51. Persistent infection critical for development ofPersistent infection critical for development of
neoplastic changeneoplastic change

52. ► Cervical neoplasia can be viewed as the result of a complex interplay betweenCervical neoplasia can be viewed as the result of a complex interplay between
a “seed,” that is, high-risk HPV types, and a “soil,” that is, the immature,a “seed,” that is, high-risk HPV types, and a “soil,” that is, the immature,
metaplastic epithelium of the cervical transformation zone.metaplastic epithelium of the cervical transformation zone.
Exposure to specific high-risk HPV types, in the presence of cofactor activity,Exposure to specific high-risk HPV types, in the presence of cofactor activity,
may deviate the metaplastic process along a neoplastic pathway.may deviate the metaplastic process along a neoplastic pathway.
Disease expression begins at the new squamocolumnar junction. The initialDisease expression begins at the new squamocolumnar junction. The initial
abnormality produced is usually a low-grade cervical lesion. Such lesionsabnormality produced is usually a low-grade cervical lesion. Such lesions
represent a heterologous mixture of genuine cancer precursors and benignrepresent a heterologous mixture of genuine cancer precursors and benign
HPV infections . The most critical step in cervical carcinogenesis is notHPV infections . The most critical step in cervical carcinogenesis is not
acquisition of an HPV infection but progression to CIN 3.acquisition of an HPV infection but progression to CIN 3.
HPV infection alone is necessary but not sufficient to induce carcinoma in anHPV infection alone is necessary but not sufficient to induce carcinoma in an
immunocompetent host.immunocompetent host.
HPV infection with oncogenic viral types is much more common than cervicalHPV infection with oncogenic viral types is much more common than cervical
neoplasia, indicating the necessity of cofactors in the process of cervicalneoplasia, indicating the necessity of cofactors in the process of cervical
carcinogenesis .carcinogenesis .

55. Co-factor Interaction with HumanCo-factor Interaction with Human
PapillomavirusPapillomavirus
►Plausible cofactors in cervical and lowerPlausible cofactors in cervical and lower
genital tract carcinogenesis include the usegenital tract carcinogenesis include the use
of tobacco products, infection by otherof tobacco products, infection by other
microbial agents, specific vitaminmicrobial agents, specific vitamin
deficiencies, hormonal influences, anddeficiencies, hormonal influences, and
immunosuppression.immunosuppression.

56. Cigerrate smokingCigerrate smoking
►Cigarette smoking has been demonstratedCigarette smoking has been demonstrated
to be a risk factor for cervical and vulvarto be a risk factor for cervical and vulvar
carcinoma.carcinoma.
An increased risk of developing a high-An increased risk of developing a high-
grade squamous intraepithelial lesiongrade squamous intraepithelial lesion
(HSIL) has been demonstrated among high-(HSIL) has been demonstrated among high-
risk HPV positive women who smoke orrisk HPV positive women who smoke or
who are passive smokerswho are passive smokers

57. ►Cigarette smoking influences epithelialCigarette smoking influences epithelial
immunity by decreasing the numbers ofimmunity by decreasing the numbers of
antigen-presenting Langerhans cells in theantigen-presenting Langerhans cells in the
genital epithelium .genital epithelium .
Cervical HPV infection and CIN areCervical HPV infection and CIN are
associated with diminished numbers ofassociated with diminished numbers of
intraepithelial Langerhans cells. Such localintraepithelial Langerhans cells. Such local
immunologic depletion could favor viralimmunologic depletion could favor viral
persistence, contributing to malignantpersistence, contributing to malignant
transformationtransformation

58. Infection by Other MicrobialInfection by Other Microbial
AgentsAgents
► Genital HPV infection and cervical neoplasia are moreGenital HPV infection and cervical neoplasia are more
common among individuals who have had multiple sexualcommon among individuals who have had multiple sexual
partners or whose partner has had multiple sexual partnerspartners or whose partner has had multiple sexual partners
..
An increased incidence of other sexually transmittedAn increased incidence of other sexually transmitted
diseases has been reported in association with genital HPVdiseases has been reported in association with genital HPV
infection and cervical neoplasia .infection and cervical neoplasia .
Disruption of epithelial integrity and reparative metaplasiaDisruption of epithelial integrity and reparative metaplasia
associated with acute cervicitis that is due to Chlamydiaassociated with acute cervicitis that is due to Chlamydia
trachomatis, Neisseria gonorrhoeae, herpes simplex virustrachomatis, Neisseria gonorrhoeae, herpes simplex virus
(HSV), or Trichomonas vaginalis may increase(HSV), or Trichomonas vaginalis may increase
susceptibility to genital HPV infection.susceptibility to genital HPV infection.

59. Dietary FactorsDietary Factors
►Dietary deficiencies of vitamin A or beta-Dietary deficiencies of vitamin A or beta-
carotene may increase the risk of CIN andcarotene may increase the risk of CIN and
cervical cancercervical cancer

60. Sex Hormonal InfluencesSex Hormonal Influences
►Epidemiologic studies have shown anEpidemiologic studies have shown an
increased risk of CIN in long-term oralincreased risk of CIN in long-term oral
contraceptive pill (OCP) users, rising tocontraceptive pill (OCP) users, rising to
twofold for 5 or more years of OCP use.twofold for 5 or more years of OCP use.
OCP-induced folate deficiency with reducedOCP-induced folate deficiency with reduced
metabolism of mutagens is a proposedmetabolism of mutagens is a proposed
mechanism for increased risk.mechanism for increased risk.

61. Exogenous and EndogenousExogenous and Endogenous
ImmunosuppressionImmunosuppression
► The risk of CIN and cervical cancer is increased in humanThe risk of CIN and cervical cancer is increased in human
immunodeficiency virus (HIV)-infected women, and failureimmunodeficiency virus (HIV)-infected women, and failure
rates of treatment for preinvasive lesions are increased.rates of treatment for preinvasive lesions are increased.
HPV prevalence and persistence are increased in HIV-HPV prevalence and persistence are increased in HIV-
positive women.positive women.
Systemic immune suppression from diseases such asSystemic immune suppression from diseases such as
Hodgkin's disease, leukemia, and collagen vascularHodgkin's disease, leukemia, and collagen vascular
diseases are associated with an increased incidence anddiseases are associated with an increased incidence and
recalcitrancy of HPV-associated disease.recalcitrancy of HPV-associated disease.

62. MODES OF TRANSMISSIONMODES OF TRANSMISSION
► 11. Sexual transmission-. Sexual transmission- Genital HPV infection are primarily through sexualGenital HPV infection are primarily through sexual
contact. Infectivity rate is approximately 65%.contact. Infectivity rate is approximately 65%.
The risk factors for transmision are:The risk factors for transmision are:
- Number of lifetime sexual partners- Number of lifetime sexual partners
-younger age group-younger age group
-cigarette smoking-cigarette smoking
-use of oral contraceptive pills-use of oral contraceptive pills
2. Extragenital skin transmission2. Extragenital skin transmission: Skin to skin or genital to skin transmission: Skin to skin or genital to skin transmission
has been observed in periungal and congenital warts.has been observed in periungal and congenital warts.
3.Formites:3.Formites: Transmission through formites is arare documentation, eg. Gloves,Transmission through formites is arare documentation, eg. Gloves,
surgical instruments.surgical instruments.
4.4. Genital HPV types appear to be uncommonly transmitted in neonatal period.Genital HPV types appear to be uncommonly transmitted in neonatal period.
The only clinically expressed HPV disease that is acquired at birth is laryngealThe only clinically expressed HPV disease that is acquired at birth is laryngeal
papillomatosis. This is mainly caused by HPV-6 and 11.papillomatosis. This is mainly caused by HPV-6 and 11.

63. HISTOLOGYHISTOLOGY
► Infected cells exhibit nuclear atypia. Koilocytosis ,Infected cells exhibit nuclear atypia. Koilocytosis ,
described as acombination of perinuclear halo withdescribed as acombination of perinuclear halo with
pyknotic or shrunken nucleus is a charateristic feature ofpyknotic or shrunken nucleus is a charateristic feature of
papilloma virus infection .papilloma virus infection .
► Other features include dyskeratosis, atypical basal cells,Other features include dyskeratosis, atypical basal cells,
acanthosis and multinucleation. Koilocytosis is the mostacanthosis and multinucleation. Koilocytosis is the most
specific marker except in HPV-16 and 18 where it is oftenspecific marker except in HPV-16 and 18 where it is often
absent.absent.

64. CLINICAL FEATURESCLINICAL FEATURES
► Infection with HPV disease presents with a wide variety ofInfection with HPV disease presents with a wide variety of
clinical findings. The spectrum of HPV disease include:clinical findings. The spectrum of HPV disease include:
1.1.SUBCLINICAL HPV INFECTED OF CERVIX ,SUBCLINICAL HPV INFECTED OF CERVIX ,
VAGINA, VULVA PERINEUM AND ANUS:VAGINA, VULVA PERINEUM AND ANUS:
HPV trnamission also occurs in absence of lesion duringHPV trnamission also occurs in absence of lesion during
latent phase. Subclinical HPV infection may be 10 to 30latent phase. Subclinical HPV infection may be 10 to 30
times more common than cytologically apparenttimes more common than cytologically apparent
infections.Latent infection may persist;progress to clinicalinfections.Latent infection may persist;progress to clinical
disease or resolve.disease or resolve.

65. ►2.GENITAL WARTS2.GENITAL WARTS::
Genital warts can be divided into four morphological types:Genital warts can be divided into four morphological types:
a.Condyloma acuminataa.Condyloma acuminata – They are cauliflower – shaped– They are cauliflower – shaped
warts usually present initially at forchette and adjacent labia, thenwarts usually present initially at forchette and adjacent labia, then
spread to other parts of vulva.spread to other parts of vulva.
b.Papular warts-b.Papular warts- Dome shaped (usually skin coloured)Dome shaped (usually skin coloured)
c.Keratotic genital warts-c.Keratotic genital warts- They are thick horny warts.They are thick horny warts.
d.Flat-topped papulesd.Flat-topped papules – May be present on cervix.– May be present on cervix.
Morphological appearance of all warts involving different sites isMorphological appearance of all warts involving different sites is
similar. External genital warts are frrequently multifocal (present as onesimilar. External genital warts are frrequently multifocal (present as one
or more lesion at asingle anatomic site) or multicentric (present as oneor more lesion at asingle anatomic site) or multicentric (present as one
or more lesion on different anatomic sites).or more lesion on different anatomic sites).

66. ►Condylomata acumlnata, also called genitalCondylomata acumlnata, also called genital
warts ,is induced by papillomaviruswarts ,is induced by papillomavirus
►��Pathogen:Pathogen:
Papillomavirus, has above 80 kinds ofPapillomavirus, has above 80 kinds of
antigens. Type 6�11�40�44�51 areantigens. Type 6�11�40�44�51 are
belong to low danger tpye andbelong to low danger tpye and
►16�18�31�33�35�39�45�55�5616�18�31�33�35�39�45�55�56
are belong to high danger tpye which haveare belong to high danger tpye which have
close relationship with cancerationclose relationship with canceration
66

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

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

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

72. Genital Wart –Vulva AndGenital Wart –Vulva And
PerineumPerineum
72

73. Condyloma acuminata, vaginalCondyloma acuminata, vaginal
wallwall
73

74. Penile Genital WartPenile Genital Wart
74

75. Condyloma acuminata, penileCondyloma acuminata, penile
75

76. CLINICAL FEATURESCLINICAL FEATURES
► LOWENSTIEN-BUSCHKELOWENSTIEN-BUSCHKE tumor or “gianttumor or “giant
condylomata” are extremely large genital warts seen incondylomata” are extremely large genital warts seen in
patient with impaired cell mediated immunity due to HIV ,patient with impaired cell mediated immunity due to HIV ,
immuosuppressive therapy, lymphoma or pregnancy .immuosuppressive therapy, lymphoma or pregnancy .
These lesions can become locally invasive and destructiveThese lesions can become locally invasive and destructive
but do not metastasize and are usually infected by HPV-6but do not metastasize and are usually infected by HPV-6

77. ►3. INTRAEPITHELIAL NEOPLASIA OF3. INTRAEPITHELIAL NEOPLASIA OF
CERVIX , VULVA , PERINEUMCERVIX , VULVA , PERINEUM, VAGINA ,, VAGINA ,
PENIS AND ANUS: High risk HPV are found to be morePENIS AND ANUS: High risk HPV are found to be more
common cause of intraepithelial lesion. Lesions withcommon cause of intraepithelial lesion. Lesions with
persistent HPV tend to progress more to invasive cancer.persistent HPV tend to progress more to invasive cancer.
►4. JUVENILE REPIRATORY (LARYNGEAL)4. JUVENILE REPIRATORY (LARYNGEAL)
PAPILLOMATOSIS:PAPILLOMATOSIS: In infants it is caused by HPVIn infants it is caused by HPV
-6 and HPV-11. The mode of tranmission is not-6 and HPV-11. The mode of tranmission is not
compeletely understood. Potential routes includecompeletely understood. Potential routes include
tranplacental, intrapartum in birth canal or postnatal. Thetranplacental, intrapartum in birth canal or postnatal. The
estimated risk of infection from infected mothers toestimated risk of infection from infected mothers to
neonates ranges from 1 per 100 to 1 per 1000 cases.neonates ranges from 1 per 100 to 1 per 1000 cases.

78. DIAGNOSISDIAGNOSIS
1.Genital warts-1.Genital warts- They can be visualised by grossThey can be visualised by gross
inspectioninspection
2- Subclinical HPV infection2- Subclinical HPV infection is diagnosed byis diagnosed by
colposcopy.colposcopy.
After application of 3-5 percent acetic acid , subclinicalAfter application of 3-5 percent acetic acid , subclinical
HPV has shiny- white colour with irregular borders andHPV has shiny- white colour with irregular borders and
satellite lesions.satellite lesions.
Vaginal subclinical infection may exibit reverse punctation.Vaginal subclinical infection may exibit reverse punctation.
3- Squamous intraepithelial lesion(SIL) of cervix:3- Squamous intraepithelial lesion(SIL) of cervix:
They are detected mainly by routine cytological screeningThey are detected mainly by routine cytological screening
test Paps smear.test Paps smear.

79. HPV DETECTIONHPV DETECTION
TECHNIQUESTECHNIQUES
► PAP SMEARPAP SMEAR
► Developed by Dr. George N. Papanicolaou in 1940’sDeveloped by Dr. George N. Papanicolaou in 1940’s
► Most common cancer screening testMost common cancer screening test
► Key part of annual gynecologic examinationKey part of annual gynecologic examination
► Has greatly reduced cervical cancer mortality in U.SHas greatly reduced cervical cancer mortality in U.S
This cytology test has excellent specificity but only fairThis cytology test has excellent specificity but only fair
sensitivity.sensitivity.

80. ►.. In 1988, the first National Cancer InstituteIn 1988, the first National Cancer Institute
(NCI) workshop held in Bethesda, Maryland,(NCI) workshop held in Bethesda, Maryland,
Classification resulted in the development ofClassification resulted in the development of
the Bethesda System for cytologicthe Bethesda System for cytologic
reporting .reporting .
A standardized method of reporting cytologyA standardized method of reporting cytology
findings was needed to facilitate peer reviewfindings was needed to facilitate peer review
and quality assurance. The terminology wasand quality assurance. The terminology was
refined in the Bethesda III System (2001).refined in the Bethesda III System (2001).

82. ► Cellular changes associated with HPV (ie, koilocytosis and CIN 1) areCellular changes associated with HPV (ie, koilocytosis and CIN 1) are
incorporated within the category of LSIL because the natural history,incorporated within the category of LSIL because the natural history,
distribution of various HPV types, and cytologic features of both ofdistribution of various HPV types, and cytologic features of both of
these lesions are the same .these lesions are the same .
Long-term follow-up studies have shown that lesions properlyLong-term follow-up studies have shown that lesions properly
classified as koilocytosis progress to high-grade intraepithelialclassified as koilocytosis progress to high-grade intraepithelial
neoplasia in 14% of cases and that lesions classified as mild dysplasianeoplasia in 14% of cases and that lesions classified as mild dysplasia
progress to severe dysplasia or CIS in 16% of cases.progress to severe dysplasia or CIS in 16% of cases.
Thus, on the basis of clinical behavior, molecular biologic findings, andThus, on the basis of clinical behavior, molecular biologic findings, and
morphologic features, HPV changes and CIN 1 appear to be the samemorphologic features, HPV changes and CIN 1 appear to be the same
diseasedisease

83. ► The Pap test has been successful in reducing the incidence of cervical cancerThe Pap test has been successful in reducing the incidence of cervical cancer
by 79% and the mortality by 70% since 1950 .by 79% and the mortality by 70% since 1950 .
Unfortunately, 20% of women in theUnfortunately, 20% of women in the
United States do not undergo regular screening and have not had a Pap test inUnited States do not undergo regular screening and have not had a Pap test in
the previous three years.the previous three years.
In three recent reviews of the accuracy of cervical cytology assessment, theIn three recent reviews of the accuracy of cervical cytology assessment, the
sensitivity of the Pap test in detecting CIN 2and3 ranged from 47% to 62% andsensitivity of the Pap test in detecting CIN 2and3 ranged from 47% to 62% and
the specificity ranged from 60% to 95% .the specificity ranged from 60% to 95% .
Approximately 30% of new cancer cases each year result from women whoApproximately 30% of new cancer cases each year result from women who
have undergone Pap testing, but errors of sampling, fixation, or interpretationhave undergone Pap testing, but errors of sampling, fixation, or interpretation
occur previous 3 years.occur previous 3 years.

84. New Liquid Pap TestsNew Liquid Pap Tests
►More accurate testMore accurate test
 Thin, uniform layer of cellsThin, uniform layer of cells
 Screening errors reduced by halfScreening errors reduced by half
►Screening needed less oftenScreening needed less often
►Can test for HPV with same specimen ifCan test for HPV with same specimen if
abnormal cells foundabnormal cells found
►ExpensiveExpensive

85. COLPOSCOPYCOLPOSCOPY
►Colposcopy directed biopsies are oftenColposcopy directed biopsies are often
considered 100 percent accurate.considered 100 percent accurate.
This leads to the opinion that “goldThis leads to the opinion that “gold
standard” for disease detection isstandard” for disease detection is
colposcopy.colposcopy.

88. ► Colposcopy is ideally suited to help accurately evaluateColposcopy is ideally suited to help accurately evaluate
lesion severity so that an appropriate treatment plan can belesion severity so that an appropriate treatment plan can be
instituted.instituted.
► Historically, most practitioners recommended colposcopyHistorically, most practitioners recommended colposcopy
for all women with Papanicolaou test findings of HGSIL orfor all women with Papanicolaou test findings of HGSIL or
worse.worse.
► In 2001, the Bethesda conference provided consensusIn 2001, the Bethesda conference provided consensus
guidelines for the evaluation of women with lower-gradeguidelines for the evaluation of women with lower-grade
findings.findings.
► This expert panel recommended that all women with LGSILThis expert panel recommended that all women with LGSIL
or ASCH Papanicolaou test findings also undergoor ASCH Papanicolaou test findings also undergo
colposcopy.colposcopy.
►
They further recommended that women with ASCUSThey further recommended that women with ASCUS
findings can be evaluated by colposcopy, repeatfindings can be evaluated by colposcopy, repeat
Papanicolaou test, or HPV DNA analysis.Papanicolaou test, or HPV DNA analysis.

89. Women with ASCUS smears with negative HPVWomen with ASCUS smears with negative HPV
testing were recommended to return to annualtesting were recommended to return to annual
Papanicolaou test screening.Papanicolaou test screening.
These recommendations were based largely onThese recommendations were based largely on
evidence-based information obtained from theevidence-based information obtained from the
ASCUS-LSIL Triage Study (ALTS).ASCUS-LSIL Triage Study (ALTS).
The data from this trial indicate that HPV triage inThe data from this trial indicate that HPV triage in
patients with ASCUS is at least as sensitive aspatients with ASCUS is at least as sensitive as
colposcopy in detecting cervical intraepithelialcolposcopy in detecting cervical intraepithelial
neoplasia (CIN) while concomitantly referring half asneoplasia (CIN) while concomitantly referring half as
many women to colposcopy.many women to colposcopy.
Immediate HPV typing for ASCUS is nowImmediate HPV typing for ASCUS is now
recommended as the preferred triage by the Americanrecommended as the preferred triage by the American
Society for Colposcopy and Cervical Pathology.Society for Colposcopy and Cervical Pathology.

90. A special circumstance not discussed in the ALTS trialA special circumstance not discussed in the ALTS trial
specifically is ASCUS management in postmenopausalspecifically is ASCUS management in postmenopausal
women with evidence of atrophy.women with evidence of atrophy.
If a woman has no contraindication to estrogen therapy,If a woman has no contraindication to estrogen therapy,
an acceptable option is a trial of intravaginal estrogenan acceptable option is a trial of intravaginal estrogen
therapy with repeat cytology 1 week after completion oftherapy with repeat cytology 1 week after completion of
therapy.therapy.
It is also acceptable, however, to treat postmenopausalIt is also acceptable, however, to treat postmenopausal
women with ASCUS by performing HPV testing.women with ASCUS by performing HPV testing.

91. Finally, the ALTS trial also evaluated management of LSIL.Finally, the ALTS trial also evaluated management of LSIL.
The data suggest that because of the risk of CIN and theThe data suggest that because of the risk of CIN and the
high prevalence of high-risk HPV types (more than 85%) inhigh prevalence of high-risk HPV types (more than 85%) in
LSIL cases, no efficient triage for LSIL exists.LSIL cases, no efficient triage for LSIL exists.
Expedient colposcopy for LSIL is therefore indicatedExpedient colposcopy for LSIL is therefore indicated
because only a small percentage of patients would bebecause only a small percentage of patients would be
triaged differently if HPV DNA testing were performed.triaged differently if HPV DNA testing were performed.

92. NUCLEIC ACID DETECTIONNUCLEIC ACID DETECTION
TESTSTESTS
► As only certain types of HPV is primarily associated with cervicalAs only certain types of HPV is primarily associated with cervical
cancer, HPV typing becomes nnecessary. The following nucleic acid-cancer, HPV typing becomes nnecessary. The following nucleic acid-
based tests have been used for detecting and typing HPV inbased tests have been used for detecting and typing HPV in
specimens:specimens:
► 1.Polymerase chain reaction1.Polymerase chain reaction
2.Hybrid capture 2 procedure2.Hybrid capture 2 procedure
3.In situ hybridisation technique3.In situ hybridisation technique
The median sensitivity of HPV testing for routine screening of womenThe median sensitivity of HPV testing for routine screening of women
with CIN2, CIN3 and cervical cancer is 93 % compared to 75 % forwith CIN2, CIN3 and cervical cancer is 93 % compared to 75 % for
Pap smear. Paps smear is slightly more specific than HPV DNAPap smear. Paps smear is slightly more specific than HPV DNA
testing when the presence of high grade cervical diesease istesting when the presence of high grade cervical diesease is
considered.considered.
ISH is less – sensitive than PCR or hc2 but is abetter confirmatory test.ISH is less – sensitive than PCR or hc2 but is abetter confirmatory test.

93. ► INDICATIONS OF DNA TESTINGINDICATIONS OF DNA TESTING
1. To aid the diagnosis of sexually transmitted HPV1. To aid the diagnosis of sexually transmitted HPV
infections.infections.
►
2.To screen patients with ASCUS pap smear and2.To screen patients with ASCUS pap smear and
determine the need for colposcopy.determine the need for colposcopy.
►
3. To aid risk assessment of women with LSIL or HSIL3. To aid risk assessment of women with LSIL or HSIL
before colposcopy.before colposcopy.
►
HPV screening for all women is not recommended as it isHPV screening for all women is not recommended as it is
not cost effective.not cost effective.

95. Human Papillomavirus VaccineHuman Papillomavirus Vaccine
DevelopmentDevelopment
The development of a vaccine for HPV could lead to aThe development of a vaccine for HPV could lead to a
potential reduction in the incidence of cervical cancer andpotential reduction in the incidence of cervical cancer and
its precursor lesions, other associated cancers (anal,its precursor lesions, other associated cancers (anal,
penile, vaginal, vulvar), and genital warts .penile, vaginal, vulvar), and genital warts .
Recently three separate trials have been performed to testRecently three separate trials have been performed to test
the efficacy of various HPV vaccines.the efficacy of various HPV vaccines.
Each trial was able to show that the vaccine they wereEach trial was able to show that the vaccine they were
using was efficacious in preventing persistent HPVusing was efficacious in preventing persistent HPV
infectioninfection

96. The quadrivalent HPV vaccine is currently licensed in overThe quadrivalent HPV vaccine is currently licensed in over
80 countries and the bivalent vaccine in 2 countries.80 countries and the bivalent vaccine in 2 countries.
Vaccination is approved for young women up to the age ofVaccination is approved for young women up to the age of
26 years.26 years.
The greatest public health benefit is achieved byThe greatest public health benefit is achieved by
vaccination of girls and young women prior to sexualvaccination of girls and young women prior to sexual
initiation as the vaccines are prophylactic .initiation as the vaccines are prophylactic .
The U.S. Advisory Committee on Immunization PracticesThe U.S. Advisory Committee on Immunization Practices
(ACIP) recommends routine vaccination with the(ACIP) recommends routine vaccination with the
quadrivalent HPV vaccine of all 11- to 12-year-old girls,quadrivalent HPV vaccine of all 11- to 12-year-old girls,
“catch-up” vaccination of all 13- to 26-year-old girls and“catch-up” vaccination of all 13- to 26-year-old girls and
womenwomen

97. ► Vaccination of young sexually active women may stillVaccination of young sexually active women may still
provide some protection.provide some protection.
Routine performance of Pap smears or HPV DNA testingRoutine performance of Pap smears or HPV DNA testing
prior to vaccination is not recommended, although suchprior to vaccination is not recommended, although such
screening may be appropriate for sexually active women.screening may be appropriate for sexually active women.
Cervical cancer screening should continue for theCervical cancer screening should continue for the
immunized population to screen for disease caused byimmunized population to screen for disease caused by
nonvaccine HPV types, to monitor the continued efficacy ofnonvaccine HPV types, to monitor the continued efficacy of
the vaccination program (which may not be 100%), and tothe vaccination program (which may not be 100%), and to
screen HPV infected women as the vaccine is notscreen HPV infected women as the vaccine is not
therapeutic.therapeutic.

98. ► The optimal vaccine dosing schedule is three doses at 0, 2,The optimal vaccine dosing schedule is three doses at 0, 2,
and 6 months. Accelerated delivery schedules over 4 monthsand 6 months. Accelerated delivery schedules over 4 months
are being used in some countries.are being used in some countries.
The U.S. Advisory Committee on Immunization PracticesThe U.S. Advisory Committee on Immunization Practices
(ACIP) recommends :(ACIP) recommends :
► First and second doses must be separated by at least 4First and second doses must be separated by at least 4
weeks.weeks.
► Second and third doses must be separated by at least 12Second and third doses must be separated by at least 12
weeks.weeks.
► If the dosing schedule is interrupted, the vaccine series is notIf the dosing schedule is interrupted, the vaccine series is not
restarted but the required dose is given as soon as possible.restarted but the required dose is given as soon as possible.

99. Current HPVL1 VLPCurrent HPVL1 VLP
vaccinesvaccines
► Two HPVL1VLP vaccines have been developed commerciallyTwo HPVL1VLP vaccines have been developed commercially
► Both the vaccine development programmes began on the basis of theBoth the vaccine development programmes began on the basis of the
discovery by several academic groups that the L1 coat protein ofdiscovery by several academic groups that the L1 coat protein of
papillomavirus could assemble into apapillomavirus could assemble into a virus like particle (VLP)virus like particle (VLP)
when expressed as a recombinant protein in a heterogeneouswhen expressed as a recombinant protein in a heterogeneous
eukaryotic system.eukaryotic system.
► VLP are highly immunogenic andVLP are highly immunogenic and
► VLP immunized individuals have made anti VLP antibody responsesVLP immunized individuals have made anti VLP antibody responses
substantially greater than that identified and natural infections.substantially greater than that identified and natural infections.

100. ►HPV4 (Gardasil)HPV4 (Gardasil)
 contains types 16 and 18 (high risk) and types 6contains types 16 and 18 (high risk) and types 6
and 11 (low risk)and 11 (low risk)
►HPV2 (Cervarix)HPV2 (Cervarix)
 contains types 16 and 18 (high risk)contains types 16 and 18 (high risk)
►Both vaccines are supplied as a liquid in aBoth vaccines are supplied as a liquid in a
single dose vial or syringesingle dose vial or syringe
►Neither vaccine contains an antibiotic or aNeither vaccine contains an antibiotic or a
preservativepreservative

101. Composition of the HPV vaccineComposition of the HPV vaccine
►HPV – 16,18 plus/minus 6,11HPV – 16,18 plus/minus 6,11
►L1 protein VLPs from the capsid, no viralL1 protein VLPs from the capsid, no viral
DNA &DNA & hence non-infectivehence non-infective
►Produced by recombinant DNA technologyProduced by recombinant DNA technology
►Adjuvant- ASO4 or simply AluminiumAdjuvant- ASO4 or simply Aluminium
hydroxidehydroxide

102. Bivalent Human PapillomavirusBivalent Human Papillomavirus
VaccineVaccine
Cervarix composition- 1 dose(0.5ml)Cervarix composition- 1 dose(0.5ml)
► HPV type 16 L1 protein -20HPV type 16 L1 protein -20µµgg
► HPV type 18L1 protein-20HPV type 18L1 protein-20 µµgg
► Adjuvanted by ASO4 containing 500Adjuvanted by ASO4 containing 500 µµgg
► MPL-monophosphoryl lipid-50MPL-monophosphoryl lipid-50 µµgg
► Adsorbed on aluminium hydroxideAdsorbed on aluminium hydroxide
► Bivalent recombinant vaccineBivalent recombinant vaccine
► 0, 1, 6-month dosing regimen0, 1, 6-month dosing regimen

103. Adjuvant technology: AS04Adjuvant technology: AS04
► Originating from the Latin wordOriginating from the Latin word adjuvareadjuvare, meaning “to help”, meaning “to help”
► Adjuvants are added to a vaccine to improve the immune response toAdjuvants are added to a vaccine to improve the immune response to
the Antigensthe Antigens
► AS04 consists of an immunostimulant - Monophosphoryl Lipid A (MPL)AS04 consists of an immunostimulant - Monophosphoryl Lipid A (MPL)
► Adsorbed onto aluminium hydroxide (Al(OH)Adsorbed onto aluminium hydroxide (Al(OH)33))
► CervarixCervarix®®
adjuvanted with AS04 has been shown to induce both highadjuvanted with AS04 has been shown to induce both high
and Sustained antibody levels compared to the same antigensand Sustained antibody levels compared to the same antigens
adjuvanted with aluminium hydroxide alone.adjuvanted with aluminium hydroxide alone.

104. HUMAN PAPILLOMA VIRUSHUMAN PAPILLOMA VIRUS
VACCINESVACCINES
► HPV4 vaccine is approved forHPV4 vaccine is approved for
 females 9 through 26 years of age for the prevention of cervicalfemales 9 through 26 years of age for the prevention of cervical
cancers, precancers and genital wartscancers, precancers and genital warts
 males 9 through 26 years of age for the prevention of genital wartsmales 9 through 26 years of age for the prevention of genital warts
► HPV2 vaccine is approved forHPV2 vaccine is approved for
 females 10 through 25 years of age for the prevention of cervicalfemales 10 through 25 years of age for the prevention of cervical
cancers and precancerscancers and precancers
 not approved for males or for the prevention of genital wartsnot approved for males or for the prevention of genital warts

105. ►Correct and consistent condom(male &Correct and consistent condom(male &
female)female)
use may have a protective effectuse may have a protective effect
on HPV acquisition, reduce theon HPV acquisition, reduce the
risk for HPV-associated diseases,risk for HPV-associated diseases,
and mitigate the adverseand mitigate the adverse
consequences of infectionconsequences of infection
with HPV.with HPV.

106. HPV Vaccine RecommendationsHPV Vaccine Recommendations
► Recommended age for routine HPV vaccination is 11 or 12Recommended age for routine HPV vaccination is 11 or 12
yearsyears
► Vaccination is recommended for females 13 through 26Vaccination is recommended for females 13 through 26
years of age not previously vaccinated or who have notyears of age not previously vaccinated or who have not
completed the full 3-dose seriescompleted the full 3-dose series
► The 3 dose series of HPV4 may be administered to malesThe 3 dose series of HPV4 may be administered to males
9 through 26 years of age to reduce their likelihood of9 through 26 years of age to reduce their likelihood of
acquiring genital wartsacquiring genital warts

107. HPV Vaccine Special SituationsHPV Vaccine Special Situations
► Females 26 years of age or younger with equivocal orFemales 26 years of age or younger with equivocal or
abnormal Pap test, positive HPV DNA, or genital wartsabnormal Pap test, positive HPV DNA, or genital warts
may be vaccinatedmay be vaccinated
 vaccine will have no effect on existing disease orvaccine will have no effect on existing disease or
infectioninfection
► Females 26 years of age or younger who are lactating andFemales 26 years of age or younger who are lactating and
breastfeeding, or are immunocompromised may bebreastfeeding, or are immunocompromised may be
vaccinatedvaccinated
► Vaccination not recommended for pregnant womenVaccination not recommended for pregnant women
 pregnancy testing is not needed before vaccinationpregnancy testing is not needed before vaccination

108. HPV VaccineHPV Vaccine
Contraindications andContraindications and
PrecautionsPrecautions
►Severe allergic reaction to a vaccineSevere allergic reaction to a vaccine
component or following a prior dosecomponent or following a prior dose
 yeast (HPV4)yeast (HPV4)
 latex (HPV2 prefilled syringe)latex (HPV2 prefilled syringe)
►Moderate or severe acute illnessModerate or severe acute illness

109. HPV VaccineHPV Vaccine
Adverse ReactionsAdverse Reactions
►Local reactionLocal reaction 20% - 90%20% - 90%
(pain, redness, swelling)(pain, redness, swelling)
►Temperature 100°FTemperature 100°F 10% - 13%10% - 13%
or higheror higher
►Serious adverse events NoneSerious adverse events None

110. HPV Vaccine and CervicalHPV Vaccine and Cervical
Cancer ScreeningCancer Screening
► Cervical cancer screening recommendations have NOTCervical cancer screening recommendations have NOT
changed for females who receive HPV vaccinechanged for females who receive HPV vaccine
► Females who are vaccinated could subsequently beFemales who are vaccinated could subsequently be
infected with a high-risk HPV type not in either vaccineinfected with a high-risk HPV type not in either vaccine
► Females who were sexually active prior to vaccinationFemales who were sexually active prior to vaccination
could have been infected with a vaccine-type HPV beforecould have been infected with a vaccine-type HPV before
vaccinationvaccination
► Healthcare providers who administer HPV vaccine shouldHealthcare providers who administer HPV vaccine should
educate women about the importance of cervical cancereducate women about the importance of cervical cancer
screeningscreening

111. HPV TREATMENTHPV TREATMENT
► Genital warts can be treated byGenital warts can be treated by
a doctor and by differenta doctor and by different
methods.methods.
► Podofilox gel:Podofilox gel: A patient-A patient-
applied treatment for externalapplied treatment for external
genital warts.genital warts.
► Imiquimod cream:Imiquimod cream: A patient-A patient-
applied treatment.applied treatment.
► Chemical treatments (includingChemical treatments (including
trichloracetic acid andtrichloracetic acid and
podophyllin), which must bepodophyllin), which must be
applied by a trained health careapplied by a trained health care
provider to destroy warts.provider to destroy warts.
► Cryotherapy:Cryotherapy: Uses liquidUses liquid
nitrogen to freeze off the warts.nitrogen to freeze off the warts.
► Laser therapy:Laser therapy: Uses a laserUses a laser
beam or intense lights tobeam or intense lights to
destroy the warts.destroy the warts.
► Electrosurgery:Electrosurgery: Uses andUses and
electric current to burn off theelectric current to burn off the
warts.warts.
► Surgery:Surgery: Can cut away theCan cut away the
wart in one office visit .wart in one office visit .
► Interferon:Interferon: an antiviral drug,an antiviral drug,
which can be injected directlywhich can be injected directly
into warts.into warts.

112. CURECURE
►There is currently no cure for humanThere is currently no cure for human
papillomavirus.papillomavirus.
►Once an individual is infected, he or sheOnce an individual is infected, he or she
carries the virus for life even if genital wartscarries the virus for life even if genital warts
are removed.are removed.
►The development of a vaccine against HPVThe development of a vaccine against HPV
is under way, but is still not available.is under way, but is still not available.
►If left untreated, some genital warts mayIf left untreated, some genital warts may
regress on their own.regress on their own.

113. HPV Vaccine And MaleHPV Vaccine And Male
►Like adolescent girls Poly valant HPVLike adolescent girls Poly valant HPV
vaccine should be advised to boys betweenvaccine should be advised to boys between
the age of 13-22 years of age before thethe age of 13-22 years of age before the
indulge in any sexual activity.indulge in any sexual activity.
►It will help in controlling genital warts ,It will help in controlling genital warts ,
anorectal cancer and cervical cancer intheiranorectal cancer and cervical cancer intheir
life partner.life partner.

114. SOURCESSOURCES
►http://cinvestav.mx/genetica/MyFiles/Papillomahttp://cinvestav.mx/genetica/MyFiles/Papilloma
►http://www.life.umd.edu/classroom/bsci424/BSChttp://www.life.umd.edu/classroom/bsci424/BSC
►WWW.STDSERVICES.ON.NET/STD/WARTSWWW.STDSERVICES.ON.NET/STD/WARTS
►http://www.ashastd.org/stdfaqs/hpv.htmlhttp://www.ashastd.org/stdfaqs/hpv.html
►http://www.niaid.nih.gov/factsheets/stdhpv.hhttp://www.niaid.nih.gov/factsheets/stdhpv.h
tmtm