Prevention and Management of Human Papillomavirus Infection in Adults With HIV

Purpose of This Guideline

Reviewed and updated: Meera Shah, MD, MPH, MS, AAHIVS; November 4, 2022
Writing group: Steven M. Fine, MD, PhD; Rona M. Vail, MD; Joseph P. McGowan, MD, FACP, FIDSA; Samuel T. Merrick, MD; Asa E. Radix, MD, MPH, PhD; Charles J. Gonzalez, MD; Christopher J. Hoffmann, MD, MPH
Committee: Medical Care Criteria Committee
Date of original publication: May 2013

This guideline on human papillomavirus (HPV) in individuals with HIV was developed by the New York State Department of Health AIDS Institute (NYSDOH AI) to inform primary care providers and other practitioners in New York State about HPV prevention, screening methods, diagnosis and presentation, and treatment in adults with HIV. This guideline aims to achieve the following goals:

• Increase the number of New York State residents with HIV who are screened and effectively treated for HPV-related dysplasia. 
• Support the NYSDOH Prevention Agenda 2019-2024 by educating care providers on the importance of HPV vaccination and increasing the rate of 3-dose HPV immunization among individuals with HIV.
• Reduce the morbidity and mortality associated with HPV in people with HIV through early identification and treatment of potentially precancerous and cancerous lesions, when treatment is most likely to be effective.

HPV-Associated Cancers

Reviewed and updated: Meera Shah, MD, MPH, MS, AAHIVS, with the Medical Care Criteria Committee; November 4, 2022

HPV-associated cancers: Cervical cancer rates have decreased because of a robust screening system in the United States that has been in place since the 1960s [NCI(a) 2022]. The incidence of anal cancer persists, particularly among men who have sex with men (MSM) with or without HIV and among women with HIV [Islami, et al. 2017; Palefsky 2017; Hessol, et al. 2013], and approximately 91% of anal cancers are thought to be caused by human papillomavirus (HPV) [CDC(b) 2022].

This Committee has recommended anal screening for specific subpopulations of individuals with HIV since 2007 and recently expanded the recommendation to include anal cytology screening for MSM, cisgender women, transgender women, and transgender men who have HIV and are ≥35 years old (see the NYSDOH AI guideline Screening for Anal Dysplasia and Cancer in Adults With HIV). Anal Cancer HSIL Outcomes Research (ANCHOR) study investigators announced by press release in October 2021 that treatment of precancerous lesions reduced anal cancer risk among people with HIV [ANCHOR 2021]. Although screening tests are available for oropharyngeal cancers, the utility and benefits have not been established; therefore, screening other than visual inspection is not yet recommended (see American Dental Association > Evaluation of Potentially Malignant Disorders in the Oral Cavity Clinical Practice Guideline [2017] for more information). There are no routine screening tests or procedures for vulvar, vaginal, or penile cancers.

HPV types: There are many HPV types, some of which cause cancer (oncogenic) and others of which cause noncancerous disease (nononcogenic verruca vulgaris and condyloma acuminata). Approximately 30 different HPV types infect cells in the anus and genital tract, including the cervix, and may cause asymptomatic infection, condylomata acuminata (genital warts), squamous intraepithelial lesions (SILs), glandular cell abnormalities, and anal and cervical cancer or other genital carcinomas. HPV is also associated with oropharyngeal cancer [CDC(a) 2022; CDC(b) 2022]. HPV infection is often asymptomatic, and the time course from initial infection to the presence of lesions has not been determined, preventing a reliable method for determining the source and time of acquisition.

In the general U.S. population, HPV types 16 and 18 are responsible for approximately 70% of cases of cervical and anal SILs and cervical and anal cancers [Lowy and Schiller 2012; Steinbrook 2006] in addition to most oropharyngeal, vaginal, vulvar, and penile cancers [Saraiya, et al. 2015; Forman, et al. 2012; Grulich, et al. 2010; Bouvard, et al. 2009]. Nononcogenic HPV types 6 and 11 cause >90% of genital warts [CDC(a) 2021; Workowski, et al. 2021]. A wider range and higher prevalence of HPV types responsible for oncogenic and nononcogenic disease have been documented in people with HIV [Massad, et al. 2016; Kojic, et al. 2011; Clifford, et al. 2006]. HPV-associated cancers occur more often among people with HIV than in the general population [Liu, et al. 2018; Jemal, et al. 2013], and the distribution of HPV types responsible for SILs and warts also differs between these populations [Clifford, et al. 2006].

High-risk HPV types that are related to anogenital cancers include types 16, 18, 26, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 67, 68, 69, 70, 73, and 82 [Guan, et al. 2012; Hariri, et al. 2012]. Although high-risk HPV types are detected in 99% of cervical cancers, types 16 and 18 are the most oncogenic [Clifford, et al. 2017; Keller, et al. 2015] and account for nearly 70% of all cervical cancers in the general population [CDC(a) 2021]. HPV type 16 is the most common high-risk type among individuals with or without HIV [Lin, et al. 2018]. Among individuals with HIV, cervical cancer is associated with types 16 and 18 and high-risk types 51, 52, 53, 56, 58, and 59 [McKenzie, et al. 2010]. High-risk HPV types other than type 16 are more common and are more frequently associated with anal cancer among MSM with HIV than MSM without HIV [Poynten, et al. 2021]. Infection with more than one HPV type occurs more frequently among individuals with HIV, and these individuals can be at risk of cervical and anal SILs and nonmalignant disease simultaneously [Castilho, et al. 2015; Clifford, et al. 2006].

Tobacco use: Tobacco use is an established contributor to the oncogenic potential of HPV and is an independent risk factor for acquisition and progression of cervical SILs [Collins, et al. 2010], anal neoplasia [Daling, et al. 2004], oropharyngeal cancer [NCI(b) 2022], and vulvar cancer in individuals with HIV [ACS 2018; Kutlubay, et al. 2013]. Some data suggest that HIV-related immune suppression can contribute to relapse and progression of HPV disease, and antiretroviral therapy-mediated immune reconstitution can lead to regression of SILs associated with HPV infection [Blitz, et al. 2013]. Other studies do not support this finding [Piketty, et al. 2013; Adler 2010].

References

ACS. Risk factors for vulvar cancer. 2018 Jan 16. https://www.cancer.org/cancer/vulvar-cancer/causes-risks-prevention/risk-factors.html [accessed 2022 Oct 17]

Adler DH. The impact of HAART on HPV-related cervical disease. Curr HIV Res 2010;8(7):493-497. [PMID: 20946095] 

ANCHOR. Press release: treating anal cancer precursor lesions reduces cancer risk for people with HIV. 2021 Oct 7. https://iansoc.org/resources/ANCHOR%20press%20release_07OCT2021.pdf [accessed 2022 Oct 17]

Blitz S, Baxter J, Raboud J, et al. Evaluation of HIV and highly active antiretroviral therapy on the natural history of human papillomavirus infection and cervical cytopathologic findings in HIV-positive and high-risk HIV-negative women. J Infect Dis 2013;208(3):454-462. [PMID: 23624362] 

Bouvard V, Baan R, Straif K, et al. A review of human carcinogens–Part B: biological agents. Lancet Oncol 2009;10(4):321-322. [PMID: 19350698] 

Castilho JL, Levi JE, Luz PM, et al. A cross-sectional study of high-risk human papillomavirus clustering and cervical outcomes in HIV-infected women in Rio de Janeiro, Brazil. BMC Cancer 2015;15:478. [PMID: 26100400] 

CDC(a). Epidemiology and prevention of vaccine-preventable diseases: Human papillomavirus. 2021 Aug 18. https://www.cdc.gov/vaccines/pubs/pinkbook/hpv.html [accessed 2022 Oct 17]

CDC(a). How many cancers are linked with HPV each year? 2022 Oct 3. https://www.cdc.gov/cancer/hpv/statistics/cases.htm [accessed 2022 Oct 17]

CDC(b). HPV-associated cancer diagnosis by age. 2022 Oct 3. https://www.cdc.gov/cancer/hpv/statistics/age.htm [accessed 2022 Oct 17]

Clifford GM, Goncalves MA, Franceschi S. Human papillomavirus types among women infected with HIV: a meta-analysis. AIDS 2006;20(18):2337-2344. [PMID: 17117020] 

Clifford GM, Tully S, Franceschi S. Carcinogenicity of human papillomavirus (HPV) types in HIV-positive women: a meta-analysis from HPV infection to cervical cancer. Clin Infect Dis 2017;64(9):1228-1235. [PMID: 28199532] 

Collins S, Rollason TP, Young LS, et al. Cigarette smoking is an independent risk factor for cervical intraepithelial neoplasia in young women: a longitudinal study. Eur J Cancer 2010;46(2):405-411. [PMID: 19819687] 

Daling JR, Madeleine MM, Johnson LG, et al. Human papillomavirus, smoking, and sexual practices in the etiology of anal cancer. Cancer 2004;101(2):270-280. [PMID: 15241823] 

Forman D, de Martel C, Lacey CJ, et al. Global burden of human papillomavirus and related diseases. Vaccine 2012;30 Suppl 5:F12-23. [PMID: 23199955] 

Grulich AE, Jin F, Conway EL, et al. Cancers attributable to human papillomavirus infection. Sex Health 2010;7(3):244-252. [PMID: 20719211] 

Guan P, Howell-Jones R, Li N, et al. Human papillomavirus types in 115,789 HPV-positive women: a meta-analysis from cervical infection to cancer. Int J Cancer 2012;131(10):2349-2359. [PMID: 22323075] 

Hariri S, Unger ER, Powell SE, et al. Human papillomavirus genotypes in high-grade cervical lesions in the United States. J Infect Dis 2012;206(12):1878-1886. [PMID: 23045628] 

Hessol NA, Holly EA, Efird JT, et al. Concomitant anal and cervical human papillomavirusV infections and intraepithelial neoplasia in HIV-infected and uninfected women. AIDS 2013;27(11):1743-1751. [PMID: 23803793] 

Islami F, Ferlay J, Lortet-Tieulent J, et al. International trends in anal cancer incidence rates. Int J Epidemiol 2017;46(3):924-938. [PMID: 27789668]

Jemal A, Simard EP, Dorell C, et al. Annual Report to the Nation on the Status of Cancer, 1975-2009, featuring the burden and trends in human papillomavirus(HPV)-associated cancers and HPV vaccination coverage levels. J Natl Cancer Inst 2013;105(3):175-201. [PMID: 23297039] 

Keller MJ, Burk RD, Massad LS, et al. Cervical precancer risk in HIV-infected women who test positive for oncogenic human papillomavirus despite a normal pap test. Clin Infect Dis 2015;61(10):1573-1581. [PMID: 26187020] 

Kojic EM, Cu-Uvin S, Conley L, et al. Human papillomavirus infection and cytologic abnormalities of the anus and cervix among HIV-infected women in the study to understand the natural history of HIV/AIDS in the era of effective therapy (the SUN Study). Sex Transm Dis 2011;38(4):253-259. [PMID: 20966828] 

Kutlubay Z, Engin B, Zara T, et al. Anogenital malignancies and premalignancies: facts and controversies. Clin Dermatol 2013;31(4):362-373. [PMID: 23806153] 

Lin C, Franceschi S, Clifford GM. Human papillomavirus types from infection to cancer in the anus, according to sex and HIV status: a systematic review and meta-analysis. Lancet Infect Dis 2018;18(2):198-206. [PMID: 29158102] 

Liu G, Sharma M, Tan N, et al. HIV-positive women have higher risk of human papilloma virus infection, precancerous lesions, and cervical cancer. AIDS 2018;32(6):795-808. [PMID: 29369827]

Lowy DR, Schiller JT. Reducing HPV-associated cancer globally. Cancer Prev Res (Phila) 2012;5(1):18-23. [PMID: 22219162] 

Massad LS, Xie X, Burk RD, et al. Association of cervical precancer with human papillomavirus types other than 16 among HIV co-infected women. Am J Obstet Gynecol 2016;214(3):354.e351-356. [PMID: 26433170]

McKenzie ND, Kobetz EN, Hnatyszyn J, et al. Women with HIV are more commonly infected with non-16 and -18 high-risk HPV types. Gynecol Oncol 2010;116(3):572-577. [PMID: 19906410]

NCI(a). Cancer stat facts: cervical cancer. 2022 Oct 27. https://seer.cancer.gov/statfacts/html/cervix.html [accessed 2022 Oct 17]

NCI(b). Oral cavity, oropharyngeal, hypopharyngeal, and laryngeal cancers prevention (PDQ®)–Health professional version. 2022 Jun 23. https://www.cancer.gov/types/head-and-neck/hp/oral-prevention-pdq [accessed 2022 Oct 17]

Palefsky J. Human papillomavirus-associated anal and cervical cancers in HIV-infected individuals: incidence and prevention in the antiretroviral therapy era. Curr Opin HIV AIDS 2017;12(1):26-30. [PMID: 27828801] 

Piketty C, Cochand-Priollet B, Lanoy E, et al. Lack of regression of anal squamous intraepithelial lesions despite immune restoration under cART. AIDS 2013;27(3):401-406. [PMID: 23079803] 

Poynten IM, Jin F, Garland SM, et al. HIV, immune dysfunction, and the natural history of anal high-risk human papillomavirus infection in gay and bisexual men. J Infect Dis 2021;224(2):246-257. [PMID: 33220687] 

Saraiya M, Unger ER, Thompson TD, et al. US assessment of HPV types in cancers: implications for current and 9-valent HPV vaccines. J Natl Cancer Inst 2015;107(6):djv086. [PMID: 25925419] 

Steinbrook R. The potential of human papillomavirus vaccines. N Engl J Med 2006;354(11):1109-1112. [PMID: 16540608] 

Workowski KA, Bachmann LH, Chan PA, et al. Sexually transmitted diseases treatment guidelines, 2021. MMWR Recomm Rep 2021;70(RR-4):1-187. [PMID: 26042815] 

HPV Prevention

Lead authors: Maria Teresa (Tess) Timoney, MS, RN, CNM, and Jessica M. Atrio, MD, MSc, with the Medical Care Criteria Committee; March 25, 2022 > Screening for Cervical Dysplasia and Cancer in Adults With HIV

HPV Vaccine

In 2006, the U.S. Food and Drug Administration (FDA) approved a 9-valent vaccine that protects against nononcogenic HPV types 16, 18, 31, 33, 45, 52, and 58 (Gardasil 9). Because it offers broader coverage of HPV types, the 9-valent vaccine is the only HPV vaccine available in the United States (see the Centers for Disease Control and Prevention [CDC] supplemental information and guidance for vaccination providers regarding use of 9-valent HPV for more information). The HPV vaccine is approved by the FDA for preventive but not therapeutic use.

Extrapolating data from the demonstrated effectiveness of the quadrivalent HPV vaccine in older individuals [Wilkin, et al. 2018], the FDA expanded the age range for recommended HPV vaccination in the United States from ages 9 to 26 years to ages 27 to 45 years [FDA 2020]. There is no specific mention of HIV infection in the updated FDA recommendation. Although 1 study demonstrated lower efficacy of the quadrivalent vaccine in individuals with HIV [Wilkin, et al. 2018], other research linked HIV viral suppression to vaccine efficacy [Money, et al. 2016]. Given the increased lifetime burden of persistent HPV infection, disease, and morbidity, proactive vaccination among individuals with HIV is a strategic means of primary prevention and potential disease mitigation that should be strongly considered and encouraged [Di Donato, et al. 2021; Karimi-Zarchi, et al. 2020; Lichter, et al. 2020].

When to Vaccinate

HPV vaccination may be scheduled at the same time as standard adolescent vaccines offered at ages 9 to 12 years. If possible, the vaccine series should begin at age 9 years [Glidden, et al. 2016]. The 3-dose vaccine regimen is recommended for all patients with HIV who are 9 to 45 years old. The 9-valent HPV vaccine should be administered according to the CDC standard schedule for immunocompromised adults, children, and adolescents (a 3-dose regimen over a 6-month period at 0, 2, and 6 months) and should be offered regardless of CD4 cell count.

HPV vaccination provides high levels of neutralizing antibody for at least 5 years and is protective in individuals ≤26 years old who do not have HIV, regardless of history of sexual activity; however, the full length of its protection has not been established. In an observational study conducted in England that examined the effectiveness of a national HPV immunization program, the reduction in cervical cancer was greatest in individuals who received the vaccine at ages 12 to 13 years [Falcaro, et al. 2021]. Although data are limited, the immunogenicity of the quadrivalent HPV vaccine has been demonstrated in individuals with HIV [Wilkin, et al. 2018; Kojic, et al. 2014].

HPV testing and vaccination: HPV testing is not recommended before vaccine administration. It is unlikely that an individual will have been infected with all the HPV types covered by the 9-valent vaccine; therefore, it is expected that the 9-valent HPV vaccine will be effective against any of the 9 HPV types or any HPV types to which the individual has not been exposed. There also may be beneficial prevention due to cross-reactivity with other HPV types not included in the 9-valent vaccine [Wheeler, et al. 2012].

Revaccination with the 9-valent HPV vaccine is not currently recommended for individuals previously immunized with the bivalent or quadrivalent HPV vaccine [ACOG 2020; Petrosky, et al. 2015]. Vaccination with the quadrivalent HPV vaccine has demonstrated cross-protection against other oncogenic HPV types [Kemp, et al. 2011]. There is no maximum interval between vaccine doses; as long as all 3 doses are given, there is no need to repeat doses if a scheduled vaccination is not given on schedule [CDC(b) 2021].

Other Forms of HPV Prevention

HPV infection is the most common sexually transmitted infection (STI) in the United States, and many individuals become infected with multiple types of HPV during their lives [CDC(c) 2021]. Most HPV infections resolve, become latent, or are not detectable on clinical assays within a few years of exposure and infection [Ho, et al. 1998; Moscicki, et al. 1998; Evander, et al. 1995]. HPV is transmitted via skin-to-skin contact, so barrier methods such as condoms offer some but not full protection. Because prior identification of HPV infection in a sexual partner is unlikely, limiting the number of sexual partners may reduce but not eliminate an individual’s exposure to HPV [Workowski, et al. 2021].

References

ACOG. Human papillomavirus vaccination: ACOG committee opinion, number 809. Obstet Gynecol 2020;136(2):e15-e21. [PMID: 32732766] 

CDC(b). HPV vaccine schedule and dosing. 2021 Nov 1. https://www.cdc.gov/hpv/hcp/schedules-recommendations.html [accessed 2022 Oct 17]

CDC(c). Sexually transmitted infections prevalence, incidence, and cost estimates in the United States. 2021 Jan 25. https://www.cdc.gov/std/statistics/prevalence-2020-at-a-glance.htm [accessed 2022 Oct 17]

Di Donato V, Caruso G, Petrillo M, et al. Adjuvant HPV vaccination to prevent recurrent cervical dysplasia after surgical treatment: a meta-analysis. Vaccines (Basel) 2021;9(5). [PMID: 33919003] 

Evander M, Edlund K, Gustafsson A, et al. Human papillomavirus infection is transient in young women: a population-based cohort study. J Infect Dis 1995;171(4):1026-1030. [PMID: 7706782] 

Falcaro M, Castanon A, Ndlela B, et al. The effects of the national HPV vaccination programme in England, UK, on cervical cancer and grade 3 cervical intraepithelial neoplasia incidence: a register-based observational study. Lancet 2021. [PMID: 34741816] 

FDA. Gardasil 9. 2020 Aug 21. https://www.fda.gov/vaccines-blood-biologics/vaccines/gardasil-9 [accessed 2022 Oct 17]

Glidden DV, Amico KR, Liu AY, et al. Symptoms, side effects and adherence in the iPrEx open-label extension. Clin Infect Dis 2016;62(9):1172-1177. [PMID: 26797207] 

Ho GY, Bierman R, Beardsley L, et al. Natural history of cervicovaginal papillomavirus infection in young women. N Engl J Med 1998;338(7):423-428. [PMID: 9459645] 

Karimi-Zarchi M, Allahqoli L, Nehmati A, et al. Can the prophylactic quadrivalent HPV vaccine be used as a therapeutic agent in women with CIN? A randomized trial. BMC Public Health 2020;20(1):274. [PMID: 32106837] 

Kemp TJ, Hildesheim A, Safaeian M, et al. HPV16/18 L1 VLP vaccine induces cross-neutralizing antibodies that may mediate cross-protection. Vaccine 2011;29(11):2011-2014. [PMID: 21241731] 

Kojic EM, Kang M, Cespedes MS, et al. Immunogenicity and safety of the quadrivalent human papillomavirus vaccine in HIV-1-infected women. Clin Infect Dis 2014;59(1):127-135. [PMID: 24723284] 

Lichter K, Krause D, Xu J, et al. Adjuvant human papillomavirus vaccine to reduce recurrent cervical dysplasia in unvaccinated women: a systematic review and meta-analysis. Obstet Gynecol 2020;135(5):1070-1083. [PMID: 32282601] 

Money DM, Moses E, Blitz S, et al. HIV viral suppression results in higher antibody responses in HIV-positive women vaccinated with the quadrivalent human papillomavirus vaccine. Vaccine 2016;34(40):4799-4806. [PMID: 27544584] 

Moscicki AB, Shiboski S, Broering J, et al. The natural history of human papillomavirus infection as measured by repeated DNA testing in adolescent and young women. J Pediatr 1998;132(2):277-284. [PMID: 9506641] 

Petrosky E, Bocchini JA, Jr., 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):300-304. [PMID: 25811679] 

Wheeler CM, Castellsagué X, Garland SM, et al. Cross-protective efficacy of HPV-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by non-vaccine oncogenic HPV types: 4-year end-of-study analysis of the randomised, double-blind PATRICIA trial. Lancet Oncol 2012;13(1):100-110. [PMID: 22075170] 

Wilkin TJ, Chen H, Cespedes MS, et al. A randomized, placebo-controlled trial of the quadrivalent human papillomavirus vaccine in human immunodeficiency virus-infected adults aged 27 years or older: AIDS Clinical Trials Group Protocol A5298. Clin Infect Dis 2018;67(9):1339-1346. [PMID: 29659751] 

Workowski KA, Bachmann LH, Chan PA, et al. Sexually transmitted diseases treatment guidelines, 2021. MMWR Recomm Rep 2021;70(RR-4):1-187. [PMID: 26042815] 

Cervical and Anal Cancer Screening

Reviewed and updated: Meera Shah, MD, MPH, MS, AAHIVS, with the Medical Care Criteria Committee; November 4, 2022

Cervical cancer screening: Clinicians should perform cervical and anal cytologic screening for people with HIV according to the recommendations in the NYSDOH AI guidelines Screening for Cervical Dysplasia and Cancer in Adults With HIV and Screening for Anal Dysplasia and Cancer in Adults With HIV. HPV testing with cytologic screening enhances the identification of HPV-related cervical disease in individuals with HIV. Examination of the anogenital area of patients with HIV to assess for visible HPV lesions is necessary because HPV can also infect the urethra and the external genitalia [Ehrenpreis and Smith 2018; Leeds and Fang 2016; Tyerman and Aboulafia 2012; Weyers, et al. 2010]. Speculum examination of the vagina, neovagina, and cervix and anoscopic examination of the anus and lower rectum may also reveal lesions. There are currently no data on urethral screening and treatment, but referral to a urologist will facilitate appropriate assessment and management when this is a concern.

Anal cancer screening: Anal squamous intraepithelial lesions (SILs) have been associated with concurrent cervical SILs; however, they also occur independently. Anal cytology should be performed for all cisgender women with HIV [Gaisa, et al. 2017; Stier, et al. 2015; Hessol, et al. 2013; Kojic, et al. 2011], with or without cervical abnormalities, according to guidelines for adults with HIV. See the NYSDOH AI guideline Screening for Anal Dysplasia and Cancer in Adults With HIV. Although there are no specific data on transgender men or transgender women, anal screening is also recommended for these populations.

Transgender individuals: It is important that care providers and facilities establish a safe and welcoming environment for transgender patients [Deutsch 2016]. Approximately one-third of transgender or gender-diverse individuals assigned female sex at birth identify as nonbinary [James, et al. 2016]. Asking patients to provide details about all gender-affirming and gynecologic surgical procedures will help establish the need for screening for HPV-related cancers. See University of California San Francisco Gender-Affirming Health Program for terminology and definitions related to transgender care.

Sexual history: Discussion of sexual health, including a patient’s history of sexually transmitted infections (STIs), is an important component of the baseline and annual assessments and is an opportunity to discuss a patient’s concerns and questions. The frequency of the sexual health assessment is based on risk factors. It is particularly important to use nonjudgmental, sex-positive language in this discussion to establish a strong connection and facilitate open discussion. See the NYSDOH AI resource GOALS Framework for Sexual History Taking in Primary Care.

References

Deutsch MB. UCSF transgender care & treatment guidelines: Creating a safe and welcoming clinic environment. 2016 Jun 17. https://transcare.ucsf.edu/guidelines/clinic-environment [accessed 2022 Oct 17]

Ehrenpreis ED, Smith DG. Patients with newly diagnosed cervical cancer should be screened for anal human papilloma virus and anal dysplasia: Results of a pilot study using a STELLA computer simulation and economic model. Papillomavirus Res 2018;5:38-45. [PMID: 29272853] 

Gaisa M, Ita-Nagy F, Sigel K, et al. High rates of anal high-grade squamous intraepithelial lesions in HIV-infected women who do not meet screening guidelines. Clin Infect Dis 2017;64(3):289-294. [PMID: 27965301] 

Hessol NA, Holly EA, Efird JT, et al. Concomitant anal and cervical human papillomavirusV infections and intraepithelial neoplasia in HIV-infected and uninfected women. AIDS 2013;27(11):1743-1751. [PMID: 23803793] 

James SE, Herman JL, Rankin S, et al. The Report of the 2015 U.S. Transgender Survey. National Center for Transgender Equality. 2016 Dec. https://transequality.org/sites/default/files/docs/usts/USTS-Full-Report-Dec17.pdf [accessed 2022 Oct 17]

Kojic EM, Cu-Uvin S, Conley L, et al. Human papillomavirus infection and cytologic abnormalities of the anus and cervix among HIV-infected women in the study to understand the natural history of HIV/AIDS in the era of effective therapy (the SUN Study). Sex Transm Dis 2011;38(4):253-259. [PMID: 20966828] 

Leeds IL, Fang SH. Anal cancer and intraepithelial neoplasia screening: A review. World J Gastrointest Surg 2016;8(1):41-51. [PMID: 26843912] 

Stier EA, Sebring MC, Mendez AE, et al. Prevalence of anal human papillomavirus infection and anal HPV-related disorders in women: a systematic review. Am J Obstet Gynecol 2015;213(3):278-309. [PMID: 25797230] 

Tyerman Z, Aboulafia DM. Review of screening guidelines for non-AIDS-defining malignancies: evolving issues in the era of highly active antiretroviral therapy. AIDS Rev 2012;14(1):3-16. [PMID: 22297500] 

Weyers S, De Sutter P, Hoebeke S, et al. Gynaecological aspects of the treatment and follow-up of transsexual men and women. Facts Views Vis Obgyn 2010;2(1):35-54. [PMID: 25206965] 

Presentation and Diagnosis of HPV Infection

Reviewed and updated: Meera Shah, MD, MPH, MS, AAHIVS, with the Medical Care Criteria Committee; November 4, 2022

Diagnosis of external condylomata acuminata is often made based on clinical appearance. The appearance of warts varies. Condylomata acuminata (genital warts) can be smooth and skin-colored or hyperpigmented papules or plaques that may be flat, hyperkeratotic, nodular, or exophytic. Symptoms may be absent or may include itching, bleeding, burning, and discomfort. Warts on the external genitalia and the cervix are commonly flat, plaque-like lesions but may also be exophytic and visible to the naked eye. Cervical lesions are best visualized by colposcopy. Penile lesions can occur along the shaft but may also occur along the penile urethra and be hidden from view.

Small external lesions are often treated without biopsy. Lesions that are atypical or variegated in color or shape require biopsy to exclude squamous intraepithelial lesions (SILs) or cancer. Clinicians should maintain a low threshold for obtaining biopsies of the following, which may indicate precancerous or cancerous lesions: atypical-appearing lesions; pigmented, internal, or condylomatous lesions; rapidly growing lesions; or lesions that fail to respond to standard treatment.

Manifestations of HPV infection in individuals with HIV infection may include the following [Wang and Palefsky 2019; Liu, et al. 2018; Clifford, et al. 2017; Palefsky 2017; Lillo, et al. 2001; Minkoff, et al. 2001; Palefsky(a), et al. 2001; Palefsky(b), et al. 2001; Frisch, et al. 2000; Palefsky, et al. 1998]:

• Condylomata acuminata, anal SILs, anal intraepithelial neoplasia, cervical SILs, and cervical intraepithelial neoplasia have all been reported to occur more frequently in people with HIV.
• With increased immunosuppression, there is evidence for increased risk of persistent and recurrent HPV infection and disease of the anal and genital tracts; decreased rates of spontaneous disease regression; increased severity of HPV disease; anal SILs and cervical SILs; and development of condylomata acuminata.
• HPV infection may be more difficult to treat and more likely to recur with advanced immunosuppression.
• Patients with more advanced immunosuppression have an increased relative risk of developing HPV-related invasive anogenital cancers.

Data are mixed regarding the contribution of HIV-related immune suppression to the relapse and progression of HPV disease and whether antiretroviral therapy (ART)-mediated immune reconstitution can lead to regression of SIL associated with HPV infection [Blitz, et al. 2013; Piketty, et al. 2013; Adler 2010]. Although there are cases of involution of mucocutaneous warts after initiation of ART, the prevalence or course of anogenital HPV disease is not altered significantly by ART [Lofgren, et al. 2015; Adler 2010].

References

Adler DH. The impact of HAART on HPV-related cervical disease. Curr HIV Res 2010;8(7):493-497. [PMID: 20946095] 

Blitz S, Baxter J, Raboud J, et al. Evaluation of HIV and highly active antiretroviral therapy on the natural history of human papillomavirus infection and cervical cytopathologic findings in HIV-positive and high-risk HIV-negative women. J Infect Dis 2013;208(3):454-462. [PMID: 23624362]

Clifford GM, Tully S, Franceschi S. Carcinogenicity of human papillomavirus (HPV) types in HIV-positive women: a meta-analysis from HPV infection to cervical cancer. Clin Infect Dis 2017;64(9):1228-1235. [PMID: 28199532] 

Frisch M, Biggar RJ, Goedert JJ. Human papillomavirus-associated cancers in patients with human immunodeficiency virus infection and acquired immunodeficiency syndrome. J Natl Cancer Inst 2000;92(18):1500-1510. [PMID: 10995805] 

Lillo FB, Ferrari D, Veglia F, et al. Human papillomavirus infection and associated cervical disease in human immunodeficiency virus-infected women: effect of highly active antiretroviral therapy. J Infect Dis 2001;184(5):547-551. [PMID: 11494160] 

Liu G, Sharma M, Tan N, et al. HIV-positive women have higher risk of human papilloma virus infection, precancerous lesions, and cervical cancer. AIDS 2018;32(6):795-808. [PMID: 29369827] 

Lofgren SM, Tadros T, Herring-Bailey G, et al. Progression and regression of cervical pap test lesions in an urban AIDS clinic in the combined antiretroviral therapy era: a longitudinal, retrospective study. AIDS Res Hum Retroviruses 2015;31(5):508-513. [PMID: 25693769]

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):2157-2164. [PMID: 11684935] 

Palefsky JM. Human papillomavirus-associated anal and cervical cancers in HIV-infected individuals: incidence and prevention in the antiretroviral therapy era. Curr Opin HIV AIDS 2017;12(1):26-30. [PMID: 27828801] 

Palefsky JM, Holly EA, Hogeboom CJ, et al. Virologic, immunologic, and clinical parameters in the incidence and progression of anal squamous intraepithelial lesions in HIV-positive and HIV-negative homosexual men. J Acquir Immune Defic Syndr Hum Retrovirol 1998;17(4):314-319. [PMID: 9525431] 

Palefsky(a) JM, Holly EA, Ralston ML, et al. Effect of highly active antiretroviral therapy on the natural history of anal squamous intraepithelial lesions and anal human papillomavirus infection. J Acquir Immune Defic Syndr 2001;28(5):422-428. [PMID: 11744829] 

Palefsky(b) JM, Holly EA, Ralston ML, et al. Prevalence and risk factors for anal human papillomavirus infection in human immunodeficiency virus (HIV)-positive and high-risk HIV-negative women. J Infect Dis 2001;183(3):383-391. [PMID: 11133369] 

Piketty C, Cochand-Priollet B, Lanoy E, et al. Lack of regression of anal squamous intraepithelial lesions despite immune restoration under cART. AIDS 2013;27(3):401-406. [PMID: 23079803] 

Wang CJ, Palefsky JM. HPV-associated anal cancer in the HIV/AIDS patient. Cancer Treat Res 2019;177:183-209. [PMID: 30523625] 

HPV Treatment

Reviewed and updated: Meera Shah, MD, MPH, MS, AAHIVS, with the Medical Care Criteria Committee; November 4, 2022

The standard therapeutic approach to treating HPV-related nonmalignant lesions (condyloma/warts) and dysplasia (squamous intraepithelial lesions or above) in individuals with HIV is the same as that for individuals without HIV. Treatment of condyloma is aimed at removing symptomatic visible warts. However, some untreated warts may resolve spontaneously. There has been no evidence that any available treatment regimen eradicates HPV infection. Comparative efficacy trials of the different treatment options for patients with HIV have not been conducted. Treatment of precancerous lesions includes ablation, using cryotherapy or laser, and surgical or laser excision. These procedures should be performed only by experienced clinicians (see the NYSDOH AI guideline Screening for Cervical Dysplasia and Cancer in Adults With HIV for more information).

Cryotherapy, electrocautery, podophyllotoxin, interferon, imiquimod, cidofovir gel, trichloroacetic acid, and bichloroacetic acid have all demonstrated efficacy treating anogenital warts in patients without HIV. In a systematic review and meta-analysis, electrocautery and imiquimod were shown to be efficacious in treating anogenital warts in people with HIV [Werner, et al. 2017]. Controlled studies of other HPV interventions in people with HIV have not been done. Interferon, 5-fluorouracil, and podophyllotoxin are no longer preferred HPV treatments in the primary care setting because of low efficacy and toxicity that may limit their routine use [Lacey, et al. 2013]. The safety and efficacy of sinecatechins have not been evaluated in individuals with HIV and therefore should not be used [FDA 2007].

There are limited data on imiquimod use in pregnancy, but animal data suggest low risk of harm [Workowski, et al. 2021]. This drug can be used during pregnancy if no other options, including waiting until after delivery, are available. Because of a lack of safety data, podophyllin should not be used during pregnancy. Podofilox (podophyllotoxin) is contraindicated in pregnancy [Briggs, et al. 2017].

Data on treating HPV lesions of the neovagina, whether penile or colonic in origin, are limited to case reports and small case series. Standard, care provider-applied approaches to treatment should be used [Labanca and Mañero 2017; van der Sluis, et al. 2016; Matsuki, et al. 2015; Wasef, et al. 2005; Liguori, et al. 2004; Fiumara and Di Mattia 1973].

Clinicians often report poor clearance rates after therapy in patients with HIV [Richel, et al. 2013]. More than one application of therapy, more than one method of treatment (e.g., topical imiquimod followed by cryotherapy), or longer duration of treatment is often needed. Treatment length may vary, and frequent visits (as often as biweekly) are necessary to assess lesion regression and adverse effects. Topical treatments may cause adverse effects such as irritation and a burning sensation, which may affect treatment adherence. The response to treatment and its adverse effects should be evaluated throughout the course of therapy. The treatment approach may need to be changed if a patient has not improved substantially after standard therapy. There are no data available regarding effects of HPV treatment on HPV transmissibility.

When deciding whether to treat a patient with HIV for anogenital warts or refer the patient to a specialist, clinicians should consider their own experience and available resources, diagnostic certainty, anatomic site of lesions, potential adverse effects of treatment, and the patient’s ability to adhere to treatment.

The below table lists available treatment options for condyloma for patients with HIV.

References

Briggs GG, Freeman RK, Yaffe SJ. 2017. Drugs in pregnancy and lactation: A reference guide to fetal and neonatal risk. Williams & Wilkins. https://books.google.com/books?id=o3ymMgEACAAJ

FDA. Veregen (sinecatechins) ointment, 15%. 2007 Dec. https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/021902s002lbl.pdf [accessed 2022 Oct 17]

Fiumara NJ, Di Mattia A. Gonorrhoea and condyloma acuminata in a male transsexual. Br J Vener Dis 1973;49(5):478-479. [PMID: 4270635] 

Labanca T, Mañero I. Vulvar condylomatosis after sex reassignment surgery in a male-to-female transsexual: Complete response to imiquimod cream. Gynecol Oncol Rep 2017;20:75-77. [PMID: 28349118] 

Lacey CJ, Woodhall SC, Wikstrom A, et al. 2012 European guideline for the management of anogenital warts. J Eur Acad Dermatol Venereol 2013;27(3):e263-270. [PMID: 22409368] 

Liguori G, Trombetta C, Bucci S, et al. Condylomata acuminata of the neovagina in a HIV-seropositive male-to-female transsexual. Urol Int 2004;73(1):87-88. [PMID: 15263800] 

Matsuki S, Kusatake K, Hein KZ, et al. Condylomata acuminata in the neovagina after male-to-female reassignment treated with CO2 laser and imiquimod. Int J STD AIDS 2015;26(7):509-511. [PMID: 24970474] 

Richel O, de Vries HJ, van Noesel CJ, et al. Comparison of imiquimod, topical fluorouracil, and electrocautery for the treatment of anal intraepithelial neoplasia in HIV-positive men who have sex with men: an open-label, randomised controlled trial. Lancet Oncol 2013;14(4):346-353. [PMID: 23499546] 

van der Sluis WB, Buncamper ME, Bouman MB, et al. Symptomatic HPV-related neovaginal lesions in transgender women: case series and review of literature. Sex Transm Infect 2016;92(7):499-501. [PMID: 27013740] 

Wasef W, Sugunendran H, Alawattegama A. Genital warts in a transsexual. Int J STD AIDS 2005;16(5):388-389. [PMID: 15949073] 

Werner RN, Westfechtel L, Dressler C, et al. Anogenital warts and other HPV-associated anogenital lesions in the HIV-positive patient: a systematic review and meta-analysis of the efficacy and safety of interventions assessed in controlled clinical trials. Sex Transm Infect 2017;93(8):543-550. [PMID: 28637906] 

Workowski KA, Bachmann LH, Chan PA, et al. Sexually transmitted diseases treatment guidelines, 2021. MMWR Recomm Rep 2021;70(RR-4):1-187. [PMID: 26042815] 

Partner Exposure to HIV and HPV

Reviewed and updated: Meera Shah, MD, MPH, MS, AAHIVS, with the Medical Care Criteria Committee; November 4, 2022

Treatment of lesions solely for the prevention of future transmission cannot be recommended because the value of treatment in reducing infectivity is not known. However, sex partners of patients who have genital lesions might benefit from counseling and examination to assess the presence of genital warts and HPV-related dysplasia. Sex partners should also be evaluated for other sexually transmitted infections (STIs), including HIV, because HPV disease is transmitted sexually [Workowski, et al. 2021].

Clinicians should inform patients that any sex partner who does not have confirmed HIV infection should have routine HIV testing for early identification of HIV acquisition. If a patient with an HIV exposure presents within 36 hours, evaluation for non-occupational post-exposure prophylaxis (PEP) should occur. When possible, onsite availability of HIV testing and STI treatment for partners is ideal because it may increase the likelihood that partners will receive timely access to HIV testing and appropriate treatment, including HIV post-exposure prophylaxis and treatment for the STI as needed (see the NYSDOH AI guideline PEP to Prevent HIV Infection). Such strategies may also increase identification of individuals who require ongoing medical care. Partner education about reducing high-risk sexual behaviors, including counseling about the use of male/insertive and female/receptive condoms and making condoms visibly available in the clinic, may help further decrease the risk of transmission of both HIV and other STIs. Patients who remain at high risk of exposure after completing a course of non-occupational PEP (nPEP) and who are negative for HIV at the time of the 4-week test should be offered pre-exposure prophylaxis (PrEP), to begin immediately after the last dose of nPEP (see the NYSDOH AI guideline PrEP to Prevent HIV and Promote Sexual Health). Patient education about undetectable=untransmittable (U=U) as an HIV prevention strategy should stress that an undetectable HIV viral load prevents only the sexual transmission of HIV (see the NYSDOH AI resource U=U Guidance for Implementation in Clinical Settings). 

The NYSDOH Partner Services program provides assistance to individuals with HIV and care providers who would like help notifying a patient’s sex partner(s) of possible exposure to HIV, chlamydia, gonorrhea, or syphilis. Available options for partner notification include anonymous notification from the local health department, dual disclosure (patient disclosure with the help of Partner Services staff), and self-disclosure. Partner Services staff within local health departments work with patients to develop a plan to notify their partners, whether that plan includes staff notifying potentially exposed partners anonymously or helping patients who choose to tell their partners on their own develop a notification plan and strategy.

Reference

Workowski KA, Bachmann LH, Chan PA, et al. Sexually transmitted diseases treatment guidelines, 2021. MMWR Recomm Rep 2021;70(RR-4):1-187. [PMID: 26042815] 

All Recommendations

Reviewed and updated: Meera Shah, MD, MPH, MS, AAHIVS, with the Medical Care Criteria Committee; November 4, 2022

Guideline Information and Updates