Human papillomavirus (HPV)

MICROBIOLOGY

• Non-enveloped DNA virus.
• HPV widespread worldwide.
• >100 types recognized as capable of causing human infection with specific clinical manifestations.
• Papillomaviruses use skin or mucosal linings (such as oral, genital, anal or respiratory) to replicate.
• Some types have oncogenic potential.

CLINICAL

• Anogenital warts (condylomata acuminatum): see separate module on anogenital warts.
• Uterine cervical infection without visible warts:
  • Usually no clinical signs of infection.
  • While "high risk" (oncogenic) virus types are responsible for 99.7% of all cervical cancer, most infections do not lead to cervical cancer.
  • Liquid-based cytology (e.g., ThinPrep®) and conventional Pap smear screening are both acceptable for cervical cancer screening.
  • Liquid-based cytology permits testing for HPV, which may be useful in guiding management of women whose Pap smear reveals ASCUS or LSIL, as well as women ≥30y with normal Pap smears.
• Perianal and intra-anal HPV infection without visible warts:
  • Oncogenic HPV types account for most cases of anal intraepithelial neoplasia (AIN) and squamous cell carcinoma of ano-rectal area.
  • Cellular transition zone of anal verge at higher risk of infection than other mucosal surfaces in the perirectal area.
  • Annual screening for anal neoplasia using anal Pap smears in high risk groups (e.g., MSM) not currently recommended but may be of use and under study.
  • Anal Pap smears are weakly recommended for HIV-infected MSM, HIV-infected women with a history of anal receptive intercourse and/or an abnormal cervical Pap smear, and all HIV-infected patients with genital warts
• Cutaneous warts: common, plantar, flat
  • Mostly seen in children/adolescents but may be occupational hazard in butchers, fish handlers and meat packers.
  • Caused by non-oncogenic HPV types (HPV-1, -2, -4, -27, and -57 most commonly).
  • Usually asymptomatic except at weight-bearing or frequent friction site.
  • Spontaneous resolution of 50-90% within 1-5 years.
  • Patients with warts lasting >18 months despite treatment are more likely to be HLA-type DQA1*0301.
  • Common warts (verruca vulgaris):
    • Most common type of cutaneous wart.
    • Most prevalent in young children.
    • Usually on the hands.
    • Typical lesion is brown, exophytic, hyperkeratotic papule.
  • Plantar warts (verruca plantaris):
    • Second most common type of wart.
    • Most common in adolescents/young adults.
    • Thrombosed capillaries upon paring down distinguish from callus.
  • Flat warts (verruca plana):
    • Most commonly seen in children.
    • Occurs on face, neck, chest, flexor surfaces of forearms and legs.
• Recurrent respiratory papillomatosis: HPV-driven disease primarily of larynx.
  • Two forms:
    • Juvenile-onset: transmitted from HPV-infected mother during passage through birth canal.
    • Adult-onset: believed to be an STD.
  • Detection usually following complaints of changes in voice or, in rapidly growing lesions, secondary to difficulty breathing.
  • Complications include obstructive, life-threatening respiratory compromise in infants/children.
  • Adult form usually less aggressive than that seen in infants/children.
  • Caused by non-oncogenic HPV genotypes, most frequently HPV-6 and HPV-11.
• Other uncommon forms:
  • Buschke-Lowenstein tumors (giant condylomas, GCBL)
    • Slow growing verrucous lesion highly destructive to contiguous tissue. Metastases uncommon.
    • Most commonly located on the glans penis in (usually uncircumcised) men > other anogenital mucosal surfaces, including the vulva, vagina, rectum, scrotum, and bladder.
    • HPV suspect cause with types 6 and 11 commonly found and types 16 and 18 occasionally found; type 54 rarely found.
    • In U.S., accounts for 5-24% of penile cancers and 0.3-0.5% of all male malignancies.
    • Bladder lesions have been associated with schistosomiasis (e.g., Schistosoma haematobium).
    • Patients with suspect GCBL should be referred to dermatology for diagnosis and treatment.
  • Bowenoid papulosis
    • Flesh-colored to reddish papules outside the anogenital area.
    • HPV (usually type 16)-induced papules with distinctive histopathology (called Bowen’s disease when occurring outside the anogenital region and also seen in erythroplasia of Queyrat) of focal epidermal hyperplasia and dysplasia and evidence of squamous cell carcinoma (SCC) in situ.
    • No racial, gender preferences; found in sexually active young adults with mean age of 31 yrs.
  • Bowen’s disease (BD)
    • Gradually enlarging, well-demarcated, usually solitary [multiple in 10–20%] erythematous plaque with an irregular border and surface crusting or scaling, often of the lower leg (60-85% of cases).
    • May occur at any age in adults but is rare before the age of 30 years (sixth and seventh decades most common).
    • Women account for up to 85% of cases.
    • Patients with suspect BD should be referred to a dermatologist for management.
    • HPV is suspected but not proven as the etiological agent of some or all of the cases.
  • Epidermodysplasia verruciformis
    • Rare, probably autosomal recessive (sex-linked also reported).
    • Disseminated (trunk, hands, upper and lower extremities, and face characteristic) flat to warty eruptions and reddish-brown pigmented plaques beginning early in life with frequent malignant transformation to squamous cell carcinomas (SCC) after age 30 years, first on sun-exposed areas.
    • Multiple HPV types often present simultaneously. HPV-5 and HPV-8 have been isolated in more than 90% of associated SCC.
    • Ddx includes SCC, common warts, flat warts, tinea versicolor, benign papillomas.
    • Patients with suspect disease should be referred to an oncologic dermatologist for definitive diagnosis and management.
  • Erythroplasia of Queyrat
    • Lesions on the glans penis (similar in morphology to Bowen’s disease lesions) have oncogenic potential.
    • Occur on glans penis and under prepuce, almost exclusively in uncircumcised men.
    • Histopathology is intraepithelial neoplasia.
    • HPV is suspected but not proven as the etiological agent of some or all of the cases.
    • Suspect cases should be referred to a dermatologist for management.

SITES OF INFECTION

• Cutaneous surfaces: plantar warts, common warts, flat warts; other rare manifestations noted above.
• Mucosa: genitalia in areas of coital friction, perianal/anal area, mouth, cervix
• Larynx/trachea: respiratory papillomatosis

TREATMENT

OTHER INFORMATION

• Subclinical genital HPV infection without exophytic warts: routine use of 3-5% acetic acid to identify these areas is not recommended. In absence of coexistent SIL, treatment is not recommended.
• Cervical cancer screening guidelines:
  • Begin screening at age 21 years.
  • Screen women 21-29 with cervical cytology (CC) alone every 3 years.
  • Screen women ≥30 with either CC + testing for high-risk HPV (co-testing) every five years OR with CC every three years.
    • If co-testing done and CC negative but hrHPV positive, either repeat co-testing in 12 months or perform hrHPV genotyping.
    • Refer for colposcopy if hrHPV found or if repeat co-testing shows abnormalities ≥ASC-US or if HPV again positive
  • Stop screening at age 65 years (assuming adequate negative prior screening results).
  • Similar guidelines offered by 3 groups: American Cancer Society, American College of Obstetricians and Gynecologists, and the U.S. Public Health Service Prevention Guidelines. (http://www.uspreventiveservicestaskforce.org; www.acog.org; www.cancer.org). Comparison of the guidelines can be found at: http://www.cdc.gov/cancer/cervical/basic_info/screening.htm.

Basis for recommendation

1. Meites E, Kempe A, Markowitz LE. Use of a 2-Dose Schedule for Human Papillomavirus Vaccination - Updated Recommendations of the Advisory Committee on Immunization Practices. MMWR Morb Mortal Wkly Rep. 2016;65(49):1405-1408.  [PMID:27977643]

   Comment: This 2016 report provides further detail regarding the revised HPV vaccine recommendations, to include use only of the 9vHPV vaccine.
   

2. Petrosky E, Bocchini JA, Hariri S, et al. Use of 9-valent human papillomavirus (HPV) vaccine: updated HPV vaccination recommendations of the advisory committee on immunization practices. MMWR Morb Mortal Wkly Rep. 2015;64(11):300-4.  [PMID:25811679]

   Comment: 9-valent vaccine as of 2017 only form available. See 2016 ACIP recommendations for 2 dose schedule for 9 - 14 yr olds.
   

3. Aberg JA, Gallant JE, Ghanem KG, et al. Executive Summary: Primary Care Guidelines for the Management of Persons Infected With HIV: 2013 Update by the HIV Medicine Association of the Infectious Diseases Society of America. Clin Infect Dis. 2014;58(1):1-10.  [PMID:24343580]

   Comment: This updated guide to the primary care of HIV-infected persons includes a summary of the limited data in support of screening HIV-infected persons with anal cytology to permit early detection of and precursors to anal cancer.
   

4. Markowitz LE, Dunne EF, Saraiya M, et al. Human Papillomavirus Vaccination. MMWR Recomm Rep. 2014;63(RR-05):1-30.  [PMID:25167164]

   Comment: August 2014 HPV vaccine recommendations from ACIP and CDC. Includes review of efficacy, immunogenicity, and safety data from clinical trials of HPV4 vaccine.
   

References

5. Stefanaki C, Lagogiani I, Kouris A, et al. Cryotherapy versus imiquimod 5% cream combined with a keratolytic lotion in cutaneous warts in children: A randomized study. J Dermatolog Treat. 2016;27(1):80-2.  [PMID:25886088]

   Comment: Small study in children demonstrated that imiquimod 5% + salicylic acid 15% was superior to cryotherapy in eradicating plantar warts at three months. There were no differences in rates of eradication for common and plane warts between the two groups.
   

6. Olguin-García MG, Jurado-Santa Cruz F, Peralta-Pedrero ML, et al. A double-blind, randomized, placebo-controlled trial of oral isotretinoin in the treatment of recalcitrant facial flat warts. J Dermatolog Treat. 2015;26(1):78-82.  [PMID:24547881]

   Comment: Placebo-controlled study of 31 adults with treatment-refractory facial flat warts showed a significant benefit of treatment with isotretinoin 30 mg/d for twelve weeks.
   

7. Joura EA, Giuliano AR, Iversen OE, et al. A 9-valent HPV vaccine against infection and intraepithelial neoplasia in women. N Engl J Med. 2015;372(8):711-23.  [PMID:25693011]

   Comment: This randomized, international, double-blind study in 14,215 women showed the 9vHPV vaccine prevented cervical, vulvar, and vaginal disease and persistent infection associated with HPV-31, 33, 45, 52, and 58. Antibody responses to HPV-6, 11, 16, 18 were noninferior to those among participants who received the 4vHPV vaccine, and the incidence of disease related to HPV-6, 11, 16, and 18 was similar in the two vaccine groups.
   

8. Panagiotou OA, Befano BL, Gonzalez P, et al. Effect of bivalent human papillomavirus vaccination on pregnancy outcomes: long term observational follow-up in the Costa Rica HPV Vaccine Trial. BMJ. 2015;351:h4358.  [PMID:26346155]

   Comment: Observational long-term follow-up data obtained from women who received bivalent HPV vaccination showed no risk of miscarriage for pregnancies conceived less than 90 days from vaccination. Among pregnancies conceived at any time from bivalent HPV vaccination, exposure was not associated with an increased risk of miscarriage overall or in subgroups, except for miscarriages at weeks 13-20 of gestation (relative risk 1.35), suggesting a need for further study.
   

9. Sterling JC, Gibbs S, Haque Hussain SS, et al. British Association of Dermatologists' guidelines for the management of cutaneous warts 2014. Br J Dermatol. 2014;171(4):696-712.  [PMID:25273231]

   Comment: Nice guideline document that lists the many therapeutics that have been utilized to manage cutaneous warts. Only salicylic acid gets an "A" recommendation, based in part upon studies referenced in the 2012 Cochrane review listed above.
   

10. Massad LS, Einstein MH, Huh WK, et al. 2012 updated consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precursors. Obstet Gynecol. 2013;121(4):829-46.  [PMID:23635684]

    Comment: ACOG guideline statement including recommendations for cervical cancer screening as well as the management of abnormal findings. In average risk women, beginning screening at age 21 is recommended. For women 30-65, screening with either (a) cytology every three years, or (b) cytology + HPV DNA testing every five years is recommended.
    

11. Kwok CS, Gibbs S, Bennett C, et al. Topical treatments for cutaneous warts. Cochrane Database Syst Rev. 2012;9:CD001781.  [PMID:22972052]

    Comment: This lengthy review of topical therapies for cutaneous warts finds that only salicylic acid is found to be superior to placebo, despite the many remedies that have been pursued.
    

12. Whitlock EP, Vesco KK, Eder M, et al. Liquid-based cytology and human papillomavirus testing to screen for cervical cancer: a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med. 2011;155(10):687-97, W214-5.  [PMID:22006930]

    Comment: This revised document details the evidence in support of the cervical cancer screening guidelines summarized above.
    

13. Sturgis EM, Cinciripini PM. Trends in head and neck cancer incidence in relation to smoking prevalence: an emerging epidemic of human papillomavirus-associated cancers? Cancer. 2007;110(7):1429-35.  [PMID:17724670]

    Comment: This paper synthesizes and reviews head and neck cancer incidence and smoking prevalence over the past 70 years. Notably, squamous cell carcinoma of the head and neck (SCCHN) have declined in response to decreased smoking rates. However, certain HN cancers have not shown a similar decline, particularly among young adults <45 years of age. These include cancer of the tongue and pharynx (including tonsil with a 4% increase per year over the past 30 years). This trend is thought to reflect the increase in HPV 16/18 associated cancers with the likely exposures via oral sex. Current recommendations for immunizing only females with the current HPV vaccine are noted and note the need to study vaccine safety and efficacy in males.
    Rating: Important
    

14. Castle PE, Schiffman M, Glass AG, et al. Human papillomavirus prevalence in women who have and have not undergone hysterectomies. J Infect Dis. 2006;194(12):1702-5.  [PMID:17109342]

    Comment: Prevalence study report from the National Cancer Institute of NIH examining the prevalence of HPV among age-matched women enrolled in a large northwest U.S. HMO stratified by hysterectomy history (n=573 with hysterectomy [WH] and n=581 with no hysterectomy [WNH[). Routine pelvic examinations were conducted and ethanol-fixed Pap smears collected (cuff smears collected on WH) and a vaginal lavage using 10 mL of normal saline was conducted and the wash sample used for HPV testing. There was no significant difference in HPV infection status between the 2 groups [WH=86.2% HPV negative vs WNH=84.0%] nor a difference of HPV genotype distribution among the 2 groups [WH=1.4% with HPV-16 vs WNH=1.6% and WH=9.2% non-oncogenic types vs WNH=9.5%] Notably, however, in the absence of a cervix, WH women are at lower risk of cancer in the presence of HPV-16 than those women with a cervix in place (WNH)..
    Rating: Important
    

15. Villa LL, Costa RL, Petta CA, et al. High sustained efficacy of a prophylactic quadrivalent human papillomavirus types 6/11/16/18 L1 virus-like particle vaccine through 5 years of follow-up. Br J Cancer. 2006;95(11):1459-66.  [PMID:17117182]

    Comment: This Merck Research Laboratories funded study reports on data collected during its multicenter phase II/III RCTs (used to support their now licensed vaccine) examining the efficacy of prophylactic quadrivalent HPV 6/11/16/18 L1 VLP vaccine during up to 5 years of follow-up. 552 women (age 16-23 years) were enrolled in the trial from Brazil, Finland, Sweden, Norway, and USA; 276 entered the vaccination arm of the trial and 275 into the placebo arm. After vaccination on day 0, 2m, and 6 m, 256 women entered follow-up for months 7-36 and 260 similarly were followed in the placebo arm. After 3 years the non-USA participants were eligible for further follow-up that continued for 2 more yrs. At the 5-year point, the overall incidence of infection with vaccine-containing genotypes was reduced 96% in the vaccine vs the placebo group. There were no vaccine genotype related precancerous lesions or genital warts in the vaccinated group compared with 6 in the placebo arm (95% CI = 12-100%). The anti-HPV geometric mean titers in sera remained significantly higher among vaccinees than among women who became infected with one or more of the 4 vaccine genotypes during the follow-up period.
    Rating: Important
    

16. Arain S, Walts AE, Thomas P, et al. The Anal Pap Smear: Cytomorphology of squamous intraepithelial lesions. Cytojournal. 2005;2(1):4.  [PMID:15715910]

    Comment: Report of a study to determine the usefulness and limitations of anal pap smears in screening for anal squamous intraepithelial lesions (ASIL) among 198 of 200 consecutively liquid media-based collected smears. The findings from these slides were correlated with surgical biopsies. Subsequently, the authors examined the findings at 6 months -- follow-up testing (smears and biopsies)-- among men (n = 71) who returned for evaluation by their usual providers. Liquid-based anal smears had a high sensitivity (98%) for detection of ASIL but a low specificity (50%) for predicting the severity of the abnormality in subsequent biopsy. Patients with cytologic diagnoses of atypical squamous cells of undetermined significance (ASC-US) and low grade SIL (LSIL) had a significant risk (46-56%) of HSIL at biopsy. These data suggest 1) liquid collection media is more sensitive than slide Pap smear results reported in the literature and 2) all patients with a diagnosis of ASC-US and above be recommended for biopsy.
    Rating: Important
    

17. Rubin MA, Kleter B, Zhou M, et al. Detection and typing of human papillomavirus DNA in penile carcinoma: evidence for multiple independent pathways of penile carcinogenesis. Am J Pathol. 2001;159(4):1211-8.  [PMID:11583947]

    Comment: A study of histological subtypes of penile condylomata, dysplasia, and carcinoma using PCR applied to formalin-fixed, paraffin-embedded tissue samples from US and Paraguay. HPV DNA in 42% of penile CA; 90% of dysplasia; 100% condyloma. Keratinizing SCC and verrucous CA were much less likely to be positive for HPV than basaloid and warty tumor subtypes of CA suggesting that there may be different pathogenetic mechanisms for penile cancer.
    Rating: Important
    

18. Minkoff H, Ahdieh L, Massad LS, et al. The effect of highly active antiretroviral therapy on cervical cytologic changes associated with oncogenic HPV among HIV-infected women. AIDS. 2001;15(16):2157-64.  [PMID:11684935]

    Comment: The Women's Interagency HIV study conducted in 5 US cities among HIV-infected women using q6mo Pap smear and cervicovaginal lavage for HPV DNA testing stratified by HAART exposure. Women w/ persistent HPV more likely to have lesions progress. CD4 cell count and Pap smear status adjusted data found women on HAART 40% more likely to have regression of lesions.
    Rating: Important
    

19. Woodman CB, Collins S, Winter H, et al. Natural history of cervical human papillomavirus infection in young women: a longitudinal cohort study. Lancet. 2001;357(9271):1831-6.  [PMID:11410191]

    Comment: A very important contribution to our understanding of the natural hx of genital HPV in women. A 3-yr cohort study of 1075 15-19 y/o women who were cytologically WNL and HPV neg at start. Cumulative incidence of HPV infection over 3 years was 44% w/HPV type 16 the most common type. Among 246 w/ abnormal Pap, 28 progressed to high-grade. High viral load appeared to be associated with a higher cumulative risk of having an abnormal Pap smear.
    

20. Kjaer SK, Chackerian B, van den Brule AJ, et al. High-risk human papillomavirus is sexually transmitted: evidence from a follow-up study of virgins starting sexual activity (intercourse). Cancer Epidemiol Biomarkers Prev. 2001;10(2):101-6.  [PMID:11219765]

    Comment: This was an outstanding clinical study conducted by these Danish investigators to determine the role of sexual intercourse in HPV transmission, examine the determinants for seroconversion, and the correlation between HPV DNA, abnormal cervical cytology, and serological response to HPV 16. 100 virgins and 105 monogamous women were randomly selected from a population-based cohort in Denmark. Only virgins who initiated sexual activity became HPV DNA positive. The most important determinant for acquisition was the number of sexual partners between the 2 examinations conducted during 2-yr study.
    

21. Schlecht NF, Kulaga S, Robitaille J, et al. Persistent human papillomavirus infection as a predictor of cervical intraepithelial neoplasia. JAMA. 2001;286(24):3106-14.  [PMID:11754676]

    Comment: A landmark cohort study examining the natural history of HPV in 1611 Brazilian women with no cytological lesions on enrollment and HPV test results from the 1st 2 study visits. Repeated measurements taken over a 24 month period. Incidence of SILs was 0.73/1000 women-months among those free of HPV at initial 2 visits; 8.68 among women w/ HPV type 16 or 18 persisting over both visits. RR of incident SIL was 10.19 for persistence with any oncogenic type; higher among those with HPV 16 and 18. Supports use of an algorithm that incorporates HPV testing if ASCUS identified.
    Rating: Important
    

22. Rousseau MC, Pereira JS, Prado JC, et al. Cervical coinfection with human papillomavirus (HPV) types as a predictor of acquisition and persistence of HPV infection. J Infect Dis. 2001;184(12):1508-17.  [PMID:11740725]

    Comment: Examination of a cohort of 1400 Brazilian women for an association between an index HPV infection and its effect on acquisition and persistence of other types. This question is important to vaccine development if only certain types of virus are being targeted. Persistence of HPV infection appeared to be independent of the presence of coinfection with multiple types, including type 16, the type that is associated with approx 50% of cervical cancers.
    

23. Palefsky JM, Holly EA, Ralston ML, et al. Prevalence and risk factors for human papillomavirus infection of the anal canal in human immunodeficiency virus (HIV)-positive and HIV-negative homosexual men. J Infect Dis. 1998;177(2):361-7.  [PMID:9466522]

    Comment: This is a report of a study to characterized anal HPV among MSM with (n=346) and without (n=262) HIV infection recruited from enrollees among 3 San Francisco cohorts groups. Polymerase chain reaction (PCR) detected HPV DNA in anal specimens collected using dacron swabs placed in transport media in 93% of HIV-positive (H-Pos) and 61% of HIV-negative (H-Neg) men. The detected HPV genotype spectrum was similar in both groups with HPV-16, an oncogenic genotype, the most common detected. Coinfection with multiple HPV types: H-Pos=73%, H-Neg=23%. A first-generation hybrid capture assay on unamplified collected material was used to examine oncogenic genotype (16/18/31/33/35/39/45/51/52/56/58) and non-oncogenic (6/11/42/43/44) spectra of infection among H-Pos men. Lower CD4 count was associated with higher levels of oncogenic types compared with non-oncogenic type Among HIV-positive men who were positive by hybrid capture for group B HPV type (p<0.005.
    Rating: Important
    

24. Ho GY, Bierman R, Beardsley L, et al. Natural history of cervicovaginal papillomavirus infection in young women. N Engl J Med. 1998;338(7):423-8.  [PMID:9459645]

    Comment: 608 women were followed at 6-mo intervals over 3 yrs. the cumulative 36 month incidence of HPV infection was 43% (C.I. 36-49%). Avg annual incidence was 14%. Median duration of new infections was 7 to 10 mo. Persistence of HPV for >6 mo related to older age, type of HPV associated w/cervical CA, and infection w/multiple types of HPV. Risk factors for infection: younger age, Hispanic ethnicity, black race, increase number of vaginal sex partners, high freq of vaginal sex, alcohol consumption, anal sex, partner with a high number of lifetime sex partners and who was not in school.
    Rating: Important
    

25. Marrazzo JM, Koutsky LA, Stine KL, et al. Genital human papillomavirus infection in women who have sex with women. J Infect Dis. 1998;178(6):1604-9.  [PMID:9815211]

    Comment: Genital HPV, determined by polymerase chain reaction (PCR) detection of HPV DNA (genotypes 6, 11, 16, 18, 31, 33, 35, 39, and 45) and prevalence of HPV-6 and -16 serum antibodies, was investigated in 149 women who were sexually active with women. HPV DNA was detected in 30% of subjects; of these, 20% had type 31/33/35/39, 18% had type 16, and 2% had type 6/11. 21 subjects reporting no prior sex with men; HPV DNA was detected in 19% and squamous intraepithelial lesions in 14%. Current smoking status correlated with detectable HPV DNA.
    Rating: Important
    

26. MASSING AM, EPSTEIN WL. Natural history of warts. A two-year study. Arch Dermatol. 1963;87:306-10.  [PMID:13933441]

    Comment: Old study that assessed the natural history of warts by following 1000 institutionalized children for two years. Source of the oft-repeated statement that two-thirds of warts spontaneously resolve in two years.