Prevention and Management of HPV and Risk for Other Sexually Transmitted Infections JEAN M. KELLER, PAC ASSISTANT PROFESSOR JOHNS HOPKINS UNIVERSITY GYNECOLOGY AND OBSTETRICS

Learning Objectives  Understand the incidence, prevalence and natural history of Human Papilloma infection  Discuss current HPV vaccine guidelines  Understand the risk and prevention strategies of other Sexually transmitted infections.  Discuss how HPV can be prevented and prevented

Sexually Transmitted Infection Overview  CDC defines STDs as various clinical syndromes/infections caused by pathogens that can be acquired through sexual activity  Viral  Bacterial  Protozoan

Prevention of STDs Overview  Accurate risk assessment  Education and counseling of at risk persons  Pre-exposure vaccination  Identification of asymptomatic and symptomatic persons  Effective diagnosis, treatment, counseling and follow up  Evaluation, treatment, and counseling of Sex partners

STD/HIV Risk Assessment  Primary prevention of STDs  Behavioral and biologic risk  Routine sexual histories  Effective interviewing and prevention counseling  STD screening of all STDs  STDs are biologic markers of risk for HIV acquisition and transmission  Identifies asymptomatic infection

STD Prevention Counseling  USPSTF recommends high-intensity behavioral counseling for SA adults and adolescents at increased risk for HIV and STDs  Client centered STD/HPV Prevention counseling  Tailor the discussion of risk reduction to the individual situation.  Motivational interviewing  Achievable risk reduction goals.

Prevention Methods  Pre-exposure Vaccines  HPV, HAV and HBV  Abstinence and Reduction of Number of Sex Partners  Male condoms (available in latex and polyurethane)  Female condom (polyurethane)- available globally  FC2 Female Condom, Reddy condom, Cupid female condom, and Woman’s condom.  Although limited data on effectiveness - advantage is female controlled  Also been used during receptive anal intercourse (unknown efficacy)

Prevention Methods  Male circumcision-  Reduces risk for HIV and Some STDs in heterosexual men  Not effective  Topical microbicides and spermicides  Diaphragm  Non barrier contraception  Important to discuss with patient that these methods offer no STI or HIV protection

Prevention Methods  Retesting after treatment to detect Repeat Infections  Gonorrhea, chlamydia and trichomoniasis Repeat tests 3 months to assess for re-infection  Syphilis- follow-up with serologic syphilis testing  HIV prevention  PEP- Post exposure prophylaxis  Identification and treatment of persons with HIV-use of ARV to suppress HIV  PReP- use of TDF and FTC  Guidelines for use available  Safe conception with discordant couples

HPV Prevalence and Incidence  U.S.  Estimated that most every sexually active man and women will acquire HPV at some point in their lives.  79 million currently infected with HPV  14.1 million new infections each year (incidence of Chlamydia is 2.9 million)  50% occur in youth and young adults years old  Women incidence peaks in 20’s, decreasing  Studies in men show incidence relatively constant over a wide age range.  Cost of treatment in US about $1.7 billion Prevalence date based on NHANES (National Health and Nutrition Examination survey) Females only from self collected swabs and other clinical studies CDC Treatment guidelines web site ACIP HPV vaccine guidelines

HPV Natural History  Most infection occurs w/n a few years of SA  Most HPV infection (regardless of type) is transient- median duration of 12 month  Prevalence declines with increasing age  Peak prevalence years  Gradual decline to about 40-45, but may increase slowly again  Multiple infections  13-14% (more than one HPV type)  52% in immuno-compromised patients  HIV positive- increased persistence /recurrence

Source: tter/jul06/Cervical_Cancer_fig 1.jpg

HPV  Over 300 HPV sub-types (strains) identified  2 major branches: cutaneous or mucosal  40 mucosal or urogenital types  Transmissible through sexual contact  Infects the ano-genital and other mucosal tissue  Most classified as :  Low risk or non-oncogenic types  Genital warts  Benign/low grade cervical cellular changes  High risk or oncogenic types (ie. 16 and 18)  Associated with cancers of vulva, vagina, anus, penis and oropharynx

Human Papilloma Virus (HPV) and Cervical Cancer 1990’s Epidemiologic studies Molecular technologies  Certain types established as a central cause of ICC  Using the most sensitive detection assays, 99.7% of ICC found to be HPV (+) - Clifford, et al, Br J Cancer, Walboomers, et al, J Pathol, 1999 Source: images/hpv.jpg Photo of HPV

HPV Types and Lower Genital Tract Neoplasia- Relative Risk

HPV and Cervical Cancer

HPV Cancer  HR HPV (types 16,18)  Anogenital cancers  Cervix:66%  Vagina:55%  Anal:79%  Oro-pharyngeal62%  HPV 16 linked with oro-pharyngeal cancer  Each year 26,000 new cancers are attributable to HPV

HPV infection  HPV cervical cancer disproportionately higher among minorities than whites including:  Hispanics  Blacks  American Indians  Alaskan natives  HPV vaginal cancer rates higher in blacks  HPV vulva cancer rates higher in whites  HPV oropharyngeal increasing frequency males >females in all racial groups except blacks

CIN and Invasive Risk Co-factors in the development of Cervical Cancer  Epidemiologic  Early Sexual Experience  # of sexual partners  Male partner factors (# sex partners, hx/o STI’s)  Smoking  Nutritional  Carotenoids, vitamin A, retinoids  Vitamins C, E, and folate

System Failures leading to Cervical Cancer Diagnosis Women do not come in for screening Health care providers do not screen women at visits Evaluation of Abnormal screen Not done Patient does not get Appropriate therapy Patient gets Cervical cancer Source: P Pronovost

Prevention - HPV Vaccine  Three licensed prophylactic vaccines are available  Bivalent*, Quadrivalent and 9-valent HPV vaccines  Each protects against HPV 16 and 18.  Quadrivalent additional protection for 6 and 11 Prevents 90% of genital warts  9-valent- additional protection for HPV 31,33,45,52, and 58)

HPV Vaccine 9-valent  HPV 9-Valent Vaccine (Gardasil-9)  Additional protection against cervical cancer (15%)  Protect against vaginal and vulvar cancers  Anal cancer in females and men  Protects against genital warts

HPV Vaccine- Treatment vaccines  Safety, Efficacy and Immunogenicity of VGX-3100  Randomized treatment vaccine for CIN 2/3 with HPV 16 and HPV 18  167 patients randomized to Vaccine (125) or placebo (42)  Primary efficacy endpoint- CIN1 or normal pathology 36 weeks after the first dose  Findings  Vaccine group 53/107 (49.5%) vs. 11/36 (30.6%) showed regression (p=0.034)  VGX-3100 is the first therapeutic vaccine to show efficacy against CIN 2/3

Other HPV Vaccine Information  ACIP: recommends MSM/Bisexual men be vaccinated through age 26 years.  Can continue with the 9-valent HPV vaccine if the series is started with a different HPV vaccine  oads/9vHPV-guidance.pdf

Pap Smears  Widespread introduction of Pap smear began in 1949  Mortality from cervical cancer in US decreased from approximately 10/100,000 in 1950 to <3/100,000 in 1994  93% of cervical cancers could be prevented by Screening and HPV vaccination

Role of Cervical Cancer Screening (Pap smear)  Significant reduction of Cervical ca in U.S.  13,000 new cases each year  Cervical ca mortality- 4,400  Counsel patients on the purpose and importance of routine pap smears  External warts are not an indication for more frequent pap smears

Liquid-based Collection and Thin-Layer Processing  Minimal cell loss with immediate fixation  Decreased unsatisfactory rate 63%  Decreased ASCUS/AGCUS %  SIL detection increased by %  Enhanced sensitivity  No loss in specificity Lee. Obstet Gynecol 1997; 90:278 Papillo. Acta Cytol 1998; 42:203 Guidos. Diagn Cytopathol 1999; 20:70

Cervical Cancer Screening  Cervical cancer screening should begin at age 21 years.  Women under 21 should not be tested  Women between 21 and 29  HPV testing should not be used for screening in this age group  Women between 30 and 65  Cervical pap every 3 years  With HPV (co-testing) every 5 years (preferred)  Women over 65 years  If past regular screening tests normal stop screening (ACOG recommendation)  If history of serious dysplasia continue for 20 years after the diagnosis regardless of age.

Cervical Cancer Screening  History of hysterectomy -  no screening if negative history of severe dysplasia or cervical cancer.  HPV vaccinated  Should still follow screening recommendations for her age group  APP for smart phone: Pap guide

Roles for HPV Testing in Cervical Screening Programs  Cervical cancer screening in conjunction with Pap  Negative HPV in women >30 can increase time between screening from 3-5 years  Triage of abnormal cervical cytology  ASCUS  Follow up after treatment of Cervical dysplasia (precancerous)  Future- Primary screening

HPV Testing  Several FDA approved HPV tests in the US  Available for women >30 years undergoing cervical cancer screening  Should not be used to  Screen men for HPV  In women <30 years  As a general STI screening test

AGCUS or AIS  > 35 years must be evaluated with endometrial biopsy  < 35 years  Endometrial biopsy should be performed if risk factors for endometrial neoplastic lesions  Unexplained vaginal bleeding  Chronic conditions suggesting anovulation

Recommendations for Screening for Other Anogenital HPV-related Disease  Careful examination of vulva, vagina, perinal region for possible HPV-related lesions  Biopsy atypical-appearing lesions  Routinely question about rectal bleeding or pain  Anal cytology: consider if resources are available to evaluate (high resolution anoscopy) and treat abnormal findings (Aberg 2009)

HPV Transmission  HPV is a double stranded DNA virus of the Papilomaviridae family and are obligatory intra- nuclear organisms.  Genital types have specific affinity for genital skin and mucosal surfaces.  Three possible events at entry into the cell  Viral DNA are intranuclear, but extra-chromosomal replicating with the cell establishing latent infection  Conversion from latent into productive infection with assembly of complete infective virions; or  Integration of the DNA into the host cellular genome seen in HPV infection associated with malignancies

HPV Transmission  Transmission can occur by auto- and hetero- inoculation from common skin warts  Fomites have been found on surfaces but only fully formed virion known to be infectious  Most frequent sites are those susceptible to micro trauma during intercourse  Introitus  peri-anal and intra-anal membranes  Increased risk of transmission  Hormonal contraception  Pregnancy  Impaired cell mediated immunity

HPV Diagnosis  Presumptive  Typical warts on skin  Detection of lesion by colposcopy  Detection of subclinical lesion by application of 5% acetic acid  Suggestive  Demonstration of typical cytologic changes on pap smear

HPV Diagnosis  Definitive  Identification of characteristic change on biopsy (koilocytosis)  Detection of HPV in smear material  HPV and Pap co-testing

HPV Spectrum of disease  Condyloma acuminata (genital warts)  Subclinical disease (cervical cellular abnormalities)  Some anogenital squamous cell carcinomas  Other types of cancers ( oropharyngeal cancers)  Recurrent respiratory papilomatosis  Latent/asymptomatic infection  No evidence of disease  Viral shedding and transmission possible

Differential Diagnosis Genital Warts  Normal anatomic structures  Pearly penile papules  Sebaceous Tyson’s glands  Micropapillomatosis or vestibular papillae (exaggerated version of physiologic vulvar skin)

Squamous papillomatosis Squamous Papillomatosis

Genital Warts Differential Diagnosis (Acquired conditions)  Bowenoid papules  Bushke-Lowenstein tumor ( Verrucous Carcinoma )  Lichen planus  Lichen nitidus  Melanocytic nevi  Pseudoverrucous papules  Molluscum contagiousum  seborrheic keratosis  Condyloma lata  Crohn’s disease  Skin tags  VIN

Lichen simplex chronicus

VIN 3

Breakdown Indurated mass Left Labial Lesion 2.5 x 7 x 5.7 cm lesion

Clinical Manifestations  Genital warts  Condylomata acuminata  Smooth papules  Flat papules  Keratotic warts (can resemble seborrheic keratosis)

Condyloma Accuminata (Genital Warts)  Incubation period 3weeks to 8 months  Usually asymptomatic but occasionally itching, burning, pain, or bleeding  Spontaneous regression and recurrence common  No increased prevalence HSIL  HPV type 6, % contain HPV 16

Condyloma Accuminata  Typically raised lesions with a warty granular appearance  May be flat or hyper-pigmented* *Most suspicious for VIN  Most often multifocal  Women located  introitus, labia minora, majora and perianal skin  Men located  distal half of the penis and the urethral meatus

HPV – Indications for biopsy anogenital lesions  Diagnosis uncertain  Lesions do not respond to therapy  Diagnosis worsens during therapy  Lesion atypical, indurated, pigmented, fixed, bleeding or ulcerated  Patient with compromised immunity (more likely to have anogenital dysplasia

Condylomata Accuminata

HPV Treatment of External Genital Warts  Cytotoxic agents and keratolytic agents: .5% podofilox (self treatment  liquid nitrogen  50-80% bichloroacetic or trichloroacetic acid  Podophylin  Cytodestructive techniques  CO2 laser vaporization  electroexcision/fulguration (LEEP)  Cryotherapy  Sinecatechin ointment (green tea extract)  Self applied TID up to 16 weeks

HPV Treatment of genital warts  Surgical excision  Immune-modulating agents  Imiquimod (Aldara)- interferon and cytokine inducer  5-Fluorouracil  Alpha-interferon- recalcitrant lesions  can be used in combination with laser or electro surgery  80% complete or partial response vs. placebo

HPV-(subclinical manifistations) Lower Anogenital Tract Neoplasias  More common than genital warts  Lower anogenital tract neoplasia- AIN, VIN, VAIN, CIN  Represents 60% & 90% of all HPV infections of the external anogenital tract and cervix respectively  Best seen with 5% acetic acid solution and colposcopic / anoscopic examination

AGCUS  17-34% associated intraepithelial or invasive lesions  Associated lesions:  Cervical adenocarcinoma  Endometrial adenocarcinoma  Metastatic Ca  Risk of HGSIL:  Premenopausal 30.4%  Postmenopausal 7.4% Kennedy. Gynecol Oncol 1996; 63:14 Korn. JRM 1998; 43:774 Duska. Obstet Gynecol 1998; 91:278

HPV Subclinical Manifestations  Histologic findings alone have little predicative value of HPV type  HPV typing determines whether low vs high risk for progression to invasive disease

HPV Subclinical Manifestations  Best appreciated with magnification & 5% acetic acid solution (colposcope)  Slightly elevated, well demarcated focal lesions with or without mosaic patterns or punctations  Commonly seen on labia minora, perianal, vestibular skin & cervical transformation zone

Cervical Ectopy

CINCIN 1 1

CIN 33

CIN 22

CIN 1 (higherCIN 1 magnification)

CIN 3- CA in situ (coarse punctation and coarse mosaic)

Leukoplakia

Numerous cysts in an established transformation zone

HPV Management of Subclinical Disease  Management determined by the location, severity and number of lesions  LSIL- Observation, 70% of low grade lesions will regress spontaneously  HSIL- 80% progression if untreated  Ablative or excisional dependent on the size and location of the lesion  Endocervical lesions should be managed with excisional therapy  Cervical, vulvar, vaginal ca- refer gyn oncologist

HPV Management of Subclinical Disease  Cervical, vaginal, and vulvar intraepithelial lesions (CIN, VAIN, VIN respectively)  Management usually based on colposcopic directed biopsy results and pap smear  Cervical lesions- cure rates related to size and distribution of lesions, not morphologic grade or HPV type

Treatment of Cervical Dysplasia  Excisional procedure recommended (LEEP or cervical conization)  Pathologic analysis, including margin status  Lesions may involve larger area of cervix

HPV Treatment of Cervical Warts  Dysplasia must be excluded before treatment is begun  Management should be carried out in consultation with an expert

HPV Subclinical Management Ablative vs. Excisional Treatment Ablative % effective but, may be used inadvertently in early invasive disease Excisional-Best for treatment of CIN, especially high grade endocervical lesions

HPV Subclinical Manifestations Advantages of LEEP/LLETZ  Low risk for missing invasive disease  Diagnosis and therapy in one session  Office procedure  Low cost of equipment  May be used for treatment of condylomata, intraepithelial lesions of the vagina & external anogenital epithelium

HPV Management of Sex Partners  Evaluation of sex partners is not necessary  Role of infection is minimal  No practical screening tests available for subclinical disease

Viral STIs HPV  There is no cure for HPV  Genital warts can be removed  Most HPV infection will go away on its own  However, persistent infection is more likely related to (high risk) cancer-types  Immunosuppressed individuals are more likely to have persistent infection