HPV: Factual Analysis

From Annual Review in Family Medicine, sponsored by the
University of California, San Francisco, School of Medicine

Michael S. Policar, MD, MPH, Associate Clinical Professor of Obstetrics, Gynecology, and Reproductive Sciences at the University of California, San Francisco, School of Medicine, and Medical Director, UCSF Family PACT Program Support, California Office of Family Planning

Educational Objectives

The goal of this program is to improve management of HPV infection and increase familiarity with current clinical guidelines for Papanicolaou (Pap) testing and HPV typing. After hearing and assimilating this program, the clinician will be better able to:

1.   Review the human papillomavirus (HPV) DNA types and their oncogenic potential.

2.   Describe the timing of HPV infection, risk factors associated with infection, and the natural history of disease progression.

3.   Summarize current guidelines for screening for cervical cancer using the Papanicolaou test.

4.   State current guidelines for management of cervical abnormalities, including appropriate use of colposcopy.

5.   Discuss appropriate timing of HPV testing and guidelines for use of the HPV vaccine.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the plan­ning committee to disclose relevant financial relationships within the past 12 months that might create any personal con­flicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. Dr. Policar and the planning committee reported nothing to disclose. Dr. Policar presents information in his lecture that is related to off-label or investigational use of a therapy, product, or device.

Acknowledgements

Dr. Policar spoke at the Annual Review in Family Medicine, Controversies and Challenges in Primary Care, held April 19, 2009, in San Francisco, CA, and presented and sponsored by the Department of Family and Community Medicine of the University of California, San Francisco, School of Medicine. The Audio-Digest Foundation thanks Dr. Policar and the Uni­versity of California, San Francisco, School of Medicine, for their cooperation in the production of this program.

Controversies in Human Papillomavirus (HPV) Screening  and Vaccination

HPV DNA types: >100 DNA types of HPV; types 6 and 11  —primary cause of genital warts; account for 30% to 50% of low-grade squamous intraepithelial lesions (LSIL) of cervix; types 6 and 11 do not progress to carcinoma in situ (CIN) II or higher; no nuclear integration of viral DNA into host DNA; types 16 and 18  —  viral DNA splices into host DNA; cause »30% of LSIL and »70% of high-grade dysplasia (HSIL) and cancer; all HPV vaccines pro­tect against 16 and 18, but not only these oncogenic types of HPV; other HPV types  —intermediate-risk groups ac­count for 30% of HSIL and invasive cancers; high-risk and intermediate-risk types differ in progression to CIN III or invasive cancer

Risk for progression: study over 10 yr, 20% of women with HPV 16 developed CIN III lesions; 15% of women with HPV 18 developed HSIL; only 3% of women with intermediate-risk HPV developed HSIL; <1% of women nega­tive for HPV infection at beginning of study developed HSIL; most focus on HPV 16 and 18

Incidence of HPV: most sexually active individuals infected with one type of HPV and possibly multiple types; in study of thousands of sexually active adults, 15% of adults had direct evidence of HPV infection; 60% had anti-HPV antibodies from previous infection; only 25% of participants had no evidence of HPV infection; every study shows similar proportion depending on age of cohort; older cohorts more likely infected; ubiquity of HPV  —  marker for sexual activity; most common sexually transmitted disease (STD); from public health point of view, considered ubiquitous but preventable, viral infection among sexually active people

Timing of HPV infection: study  —  virginal women starting college checked every 4 mo for shedding of HPV; within 1 yr, 30% of women positive for HPV; within 2 yr, 40% of women positive for HPV; by study end at 4.5 yr, close to 60% of women positive for HPV; accumulate infection with new types of HPV over time; greatest rate of infection with HPV within first 2 yr after sexual debut;

Associated risk factors: sexual activity patterns; lifetime number of partners; frequency of intercourse; whether part­ner has infection (eg, genital warts); condom use  —controversial; condoms moderately protective against HPV in­fection for men; less so for women (inconclusive data); pregnancy  —increased incidence of HPV infection and genital warts; immunocompromised patients  —  unable to fight off HPV infection well; patients with human immu­nodeficiency virus (HIV) infection more likely to have genital warts or abnormal Papanicolaou (Pap) tests; patients on anti-rejection drugs after organ transplantation, on long-term steroid therapy, or on chemotherapy for malig­nancy more likely to have genital warts, HSIL, and invasive cervical cancers; cigarette smoking  —women who smoke have double risk for HSIL and triple risk for invasive cervical cancer; even uncoupled from sexual activity and other risk factors, women smokers have increased risk of developing HSIL and invasive cancers, due to con­centration of contents of cigarette smoke in cervical mucus

Cervical environment and HPV infection: at menarche  —columnar epithelium surrounds cervical os and produces cervical mucus; surrounding tissue composed of squamous epithelium; as vaginal fluids become acidic, columnar epithelium damaged; epithelium repairs itself through squamous metaplasia, converting columnar cells to squa­mous ones; 20 yr after menarche  —squamocolumnar junction has moved up into cervical canal; metabolically ac­tive metaplasia of cervical epithelium during teen years and into early 20s uniquely susceptible to infection with HPV

Natural history of HPV progression: develops over decades; median age of first sexual intercourse 16 yr; find HPV in first years after sexual debut; peak of curve for CIN III early- to mid-30s; peak incidence of invasive cervical cancer in 40s; Pap test strategies based on this long timeline; progression of HPV lesions  —  previously assumed preinvasive lesions always worsened; when LSIL followed over 2 yr, »60% resolve spontaneously, »30% remain after 2 yr but have not worsened, and »11% progress and need treatment; for HSIL, likelihood of progression greater, and more aggressive treatment indicated, particularly in women >21 yr of age

Case presentation: woman 18 yr of age presents for annual well woman visit; reports first vaginal intercourse 18 mo before; 3 lifetime sex partners; serially monogamous; smokes one-half pack cigarettes per day; Chlamydia tracho­matis screen last year and 1 follow-up both negative; Pap test last year normal; wants refill of oral contraceptive prescription; in past, Pap test always performed in such cases; however, guidelines changed in 2002

Cervical Cancer Screening Guidelines

Guidelines: current guidelines from American Cancer Society (ACS), United States Preventive Services Task Force (USPSTF), American College of Obstetricians and Gynecologists (ACOG), and American Academy of Family Physi­cians (AAFP); delineate when to start and stop, and intervals for testing

When to start Pap tests: 3 yr after first vaginal intercourse or 21 yr of age, whichever comes first; earliest HSILs ap­pear 3 yr after first sexual intercourse; alternatively, at 21 yr of age, as some patients do not disclose sexual histo­ries, and some providers do not ask; guidelines assume every woman sexually active by 18 yr of age and therefore needs first Pap by 21 yr of age; explain benefits and risks of Pap test screening to virginal women and leave deci­sion to them; if patient never had penetrative intercourse, risk for cervical cancer near zero

When to stop Pap tests: if woman had total hysterectomy for benign condition and if cervical pathology results neg­ative, she never needs another Pap test; if HSIL present on cervix at time of hysterectomy, stop after 3 negative cer­vical cuff Pap tests; discontinue at 65 (USPSTF) or 70 yr of age (ACS) if 3 consecutive benign Pap tests in previous 10 yr; no change in recommendation if woman has new sexual partner(s) because cervix metabolically inactive; ab­normal Pap test result after age 65 yr secondary to infection acquired years earlier

How often to do Pap tests: if using liquid-based cytology, test every 1 or 2 yr until age 30; if Pap tests normal until age 30, go to 2- to 3-yr intervals; if using glass slide Pap tests, annual testing recommended until 30 yr of age, then at 2- to 3-yr intervals; if woman immunocompromised, continuation of annual Pap testing advised

Pap test during adolescence: American Society for Colposcopy and Cervical Pathology (ASCCP) guidelines state little benefit for Pap tests in younger women, particularly if <3 yr after onset of sexual intercourse; earliest HSILs start 3 yr after onset of sexual intercourse; earliest invasive cancers »5 yr after sexual debut; study followed cohort of younger women with LSIL, and only 3% of cases progressed to HSIL; HSIL uncommon in adolescents

Risks of over-screening: findings of atypical squamous cells of uncertain significance (ASC-US) and LSIL lead to unnecessary evaluation, treatment, and anxiety; in first 3 yr after sexual debut, harms of screening with Pap test al­most certainly greater than benefits

Other questions about Pap test intervals: use of hormonal contraception or postmenopausal hormone therapy does not alter Pap test intervals; pregnancy does not change intervals; for women who have sex with women and never had male partner, HPV and SIL risk very low; however, if woman ever had male partner, risk similar to that of het­erosexual women

Management Guidelines for Cervical Cytology

Cervical abnormalities under 21 yr of age: ASCCP guidelines recommend repeat Pap test in 1 yr for management of ASC-US and LSIL; if Pap test result less than HSIL, then repeat after one more year; no role for HPV reflex test­ing, even if biopsy-proven CIN I or II present; continue with follow-up only (no treatment)

When to do colposcopy: women with highly abnormal Pap tests (ASC-H, HSIL, or suspicion for cancer); women ³21 yr of age with LSIL; any woman with atypical glandular cells (AGC); women ³21 yr of age with ASC-US and positive HPV test, or if subsequent testing shows ASC-US or worse; women <21 yr of age with ASC-US, LSIL, or HSIL with > 1 abnormal repeat test, or if concerned that patient might not return for follow-up; if leukoplakia pres­ent and unable to biopsy, refer for colposcopy, regardless of Pap test result; refer women with unexplained or per­sistent cervical bleeding, particularly if bleeding postcoital

Case presentation continued: 6 mo later, with new partner for 4 mo; requests STD screening, specifically HPV hy­brid capture test; asymptomatic external genital warts noted on examination; topical treatment prescribed; STD screening negative; does she need HPV screening?

HPV Testing and Vaccination

Tests for HPV: hybrid capture 2  —  reflexively checks for HPV if Pap test result shows ASC-US; looks for high-risk types of HPV; HPV DNA genotyping  —  distinguishes betweeen all high- and low-risk types (except HPV 6 and 11)

When to do HPV testing: ASCCP guidelines allow HPV testing with Pap test as primary screening in women ³30 yr of age; if woman has Pap test with ASC-US or AGC result, and ³21 yr of age; if woman has negative Pap test but positive HPV, then do genotyping; sometimes done in lieu of Pap test to follow women after treatment

When HPV testing should not be done: never on woman <21 yr of age (ASCCP guidelines); if ordered inadver­tantly, ignore result; do not perform in women with previous ASC-H, LSIL, or HSIL; do not routinely couple with Pap test in women <30 yr of age; do not perform in patient considering HPV vaccination, for STD screening, or for patients with genital warts; not recommended for evaluation of sex partners or as part of sexual assault evaluation

Case presentation continued: patient now 20 yr of age, home from college; with current boyfriend for 1 yr; total of 6 lifetime sexual partners; no recurrence of genital warts; wants to know if HPV vaccination appropriate

HPV vaccine: virion with HPV DNA (6, 11, 16, 18); created by splicing viral genome and inserting into yeast cell; yeast produces capsid proteins, which self-assemble into protein envelopes resembling original HPV minus DNA; genetically engineered “virus-like” particle vaccine

Gardasil: only HPV vaccine approved by Food and Drug Administration (FDA); quadrivalent vaccine with antigens for types 6, 11, 16, and 18; initial study of 21,000 women in 20 countries followed over 4-yr period; studies now at 6 yr, and plan to follow cohort 15 yr

Immunogenicity bridging study: women 9 to 15 yr of age, usually virginal, without exposure to HPV; vaccinated with Gardasil and quality of antibody response evaluated; antibody titers slightly higher than in women 16 to 26 yr of age; FDA based recommendation for vaccinating very young women on robust antibody response in age group (not because of reduced dysplasia)

Effectiveness of vaccine: best case scenario (per protocol)  —women not previously infected with HPV 6, 11, 16, 18, who received all 3 injections; prevention outcome showed protection extremely high as long as no previous expo­sure; average population  —  eg, women exposed to HPV before vaccination, those with previous abnormal Pap tests, those who did not receive all 3 injections, somewhat less protection; however, did have »40% reduction in HSIL, »70% decrease in vulvar and vaginal lesions, and »70% reduction in genital warts; conclusions  —  vaccine effective in sexually active women, but less so than in HPV-naive women; intent of vaccination prophylactic, not therapeutic; give before sexual debut; if given later, protects against types of HPV not yet encountered

Safety issues: generally safe, as not injecting virus, just protein coat;  injection site pain most common complaint; for some, pain more severe than with other vaccines; vasovagal syncope reported, sometimes resulting in falls; obser­vation for 15 min after injection recommended; pregnancy category B (no evidence yet of increase in congenital anomalies, but question under study)

Centers for Disease Control and Prevention vaccination guidelines: recommend routine vaccination with 3 doses of quadrivalent HPV vaccine for girls 11 to 12 yr of age; can start at 9 yr of age; recommend catch-up vaccination for women 13 to 26 yr of age not previously vaccinated, or to finish series

Vaccine schedule: identical to that for hepatitis B; give at 0, 2, and 6 mo; can give with other vaccines; contraindi­cated in patients with hypersensitivity to yeast

Other vaccine candidates: women who had abnormal Pap test, positive HPV DNA test, or genital warts; lactating women; immunocompromised women (robustness of immune response unclear); women seen for other minor acute illness; not recommended in pregnancy

American Cancer Society vaccination guidelines: evidence-based; target population 9 to 12 yr of age; recom­mended for women 13 to 18 yr of age; not recommended for women >26 yr of age or men; insufficient data to rec­ommend for or against in women 19 to 26 yr of age (category C) because only 40% reduction in CIN II for this age group

Remaining questions about HPV vaccination: durability and long-term safety of vaccine not yet known, as longest cohort currently at 6 yr; no data on whether women discontinue Pap tests after vaccination; debatable whether men should receive vaccine; debatable whether mandating vaccine advisable and whether insurance should cover cost

Suggested Reading

American Academy of Pediatrics Committee on Infectious Diseases:  Prevention of human papillomavirus infection: provi­sional recommendations for immunization of girls and women with quadrivalent human papillomavirus vaccine. Pediatrics 120:666, 2007; American College of Obstetricians-Gynecologists: ACOG Committee Opinion. Evaluation and management of abnormal cervical cytology and histology in the adolescent. Obstet Gynecol 107:963, 2006; Campbell FN, Lara-Torre E: Fol­low-up compliance of adolescents with cervical dysplasia in an inner-city population. J Ped Adol Gyne 22:3, 2009; Castellsagué X et al: Male circumcision, penile human papillomavirus infection, and cervical cancer in female partners. N Engl J Med 346:1105, 2002; Chan BK et al: Posttreatment human papillomavirus testing for recurrent cervical intraepithelial neoplasia: a systematic review. Am J Obstet Gynecol 200:422, 2009; Chesson HW et al:  The estimated direct medical cost of sexually trans­mitted diseases among American youth, 2000. Perspect Sex Reprod Health 36:11, 2004; Cottier O et al: Clinical follow-up of women infected with human papillomavirus-16, either alone or with other human papillomavirus types: identification of different risk groups. Am J Obstet Gynecol 200:3, 2009; Cox JT: Human papillomavirus testing in primary cervical screening and abnor­mal Papanicolaou management. Obstet Gynecol Surv 61:S15, 2006; Einstein MH et al: Clinician's guide to human papillomavi­rus immunology: knowns and unknowns. Lancet Infect Dis 9:347, 2009; Kim JJ, Goldie SJ: Health and economic implications of HPV vaccination in the United States. N Engl J Med 359:821, 2008; Koutsky L: Epidemiology of genital human papillomavi­rus infection. Am J Med 102:3, 1997; Markowitz LE et al: Quadrivalent human papillomavirus vaccine: recommendations of the advisory committee on immunization practices (ACIP). MMWR Recomm Rep 56:1, 2007; Nichols JR et al: Human papillomavi­rus infection: the role of vaccination in pediatric patients. Clin Pharmacol Ther 81:607, 2007; Ragin CC et al: Knowledge about human papillomavirus and the HPV vaccine  —  a survey of the general population. Infect Agent Cancer 1:S10, 2009; Saslow D et al: American Cancer Society Guideline for human papillomavirus (HPV) vaccine use to prevent cervical cancer and its precur­sors. CA Cancer J Clin 57:7, 2007; Warren JB et al: Cervical cancer screening and updated Pap guidelines. Prim Care 36:131, 2009; Winer RL et al: Genital human papillomavirus infection: incidence and risk factors in a cohort of female university stu­dents. Am J Epidemiol 157:218, 2003; Zsemlye M: High-grade cervical dysplasia: pathophysiology, diagnosis, and treatment. Obstet Gynecol Clin North Am 35:615, 2008.