Purpose of This Guideline
Date of current publication: November 4, 2022
Lead author: Meera Shah, MD, MPH, MS, AAHIVS
Contributors: Maria Teresa (Tess) Timoney, MS, RN, CNM, and Jessica M. Atrio, MD, MSc
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: July 10, 2018
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.
Note on “experienced” and “expert” HIV care providers: Throughout this guideline, when reference is made to “experienced HIV care provider” or “expert HIV care provider,” those terms are referring to the following 2017 NYSDOH AI definitions:
- Experienced HIV care provider: Practitioners who have been accorded HIV Experienced Provider status by the American Academy of HIV Medicine or have met the HIV Medicine Association’s definition of an experienced provider are eligible for designation as an HIV Experienced Provider in New York State. Nurse practitioners and licensed midwives who provide clinical care to individuals with HIV in collaboration with a physician may be considered HIV Experienced Providers as long as all other practice agreements are met (8 NYCRR 79-5:1; 10 NYCRR 85.36; 8 NYCRR 139-6900). Physician assistants who provide clinical care to individuals with HIV under the supervision of an HIV Specialist physician may also be considered HIV Experienced Providers (10 NYCRR 94.2)
- Expert HIV care provider: A provider with extensive experience in the management of complex patients with HIV.
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. 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  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.
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 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.
Cervical and Anal Cancer Screening
Cervical and Anal Cancer Screening
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. 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 UCSF 2016. Approximately one-third of transgender or gender-diverse individuals assigned female sex at birth identify as nonbinary National Center for Transgender Equality 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. For terminology and definitions related to transgender care, see University of California San Francisco Gender-Affirming Health Program.
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.
Presentation and Diagnosis of HPV Infection
Presentation and Diagnosis of HPV Infection
Abbreviations: HPV, human papillomavirus; HRA, high-resolution anoscopy.
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.
For images of the clinical manifestations of HPV, see the following:
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.
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 (for more information, see NYSDOH AI guideline Screening for Cervical Dysplasia and Cancer in Adults With HIV).
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.
Table 1, below, lists available treatment options for condyloma for patients with HIV.
|Table 1: Available Treatment Options for Anogenital Condyloma for Patients With HIV [a]|
|Abbreviations: BCA, bichloroacetic acid; TCA, trichloroacetic acid.
|Condyloma Type||Treatment [b,c]||Comments|
Patient self-administered treatments:
|Urethral meatus condyloma||
||Cryoprobe use in the vagina is not recommended because of the risk of vaginal perforation and fistula formation.|
||Management of intra-anal warts should include consultation with a colorectal specialist.|
|Neovaginal condyloma [f,g]||
Patient self-administered treatments:
|Imiquimod may weaken condoms and vaginal diaphragms.|
Partner Exposure to HIV and HPV
Partner Exposure to HIV and HPV
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 PEP and treatment for the STI as needed. 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 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 non-occupational PEP. 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.
|New York State Law||
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.
|ALL RECOMMENDATIONS: PREVENTION AND MANAGEMENT OF HUMAN PAPILLOMAVIRUS INFECTION IN ADULTS WITH HIV|
Cervical and Anal Cancer Screening
Presentation and Diagnosis of HPV Infection
Partner Exposure to HIV and HPV
Abbreviations: HPV, human papillomavirus; HRA, high-resolution anoscopy.
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Updates, Authorship, and Related Guidelines
|Updates, Authorship, and Related Guidelines|
|Date of original publication||July 10, 2018|
|Date of current publication||November 04, 2022|
|Highlights of changes, additions, and updates in the November 04, 2022 edition||
|Intended users||Clinicians in New York State who provide care to individuals with HIV|
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
|Author and writing group conflict of interest disclosures||There are no author or writing group conflict of interest disclosures|
|Developer and funder|
See Guideline Development and Recommendation Ratings Scheme, below.
Guideline Development and Recommendation Ratings
|Guideline Development: New York State Department of Health AIDS Institute Clinical Guidelines Program|
|Program manager||Clinical Guidelines Program, Johns Hopkins University School of Medicine, Division of Infectious Diseases. See Program Leadership and Staff.|
|Mission||To produce and disseminate evidence-based, state-of-the-art clinical practice guidelines that establish uniform standards of care for practitioners who provide prevention or treatment of HIV, viral hepatitis, other sexually transmitted infections, and substance use disorders for adults throughout New York State in the wide array of settings in which those services are delivered.|
|Expert committees||The NYSDOH AI Medical Director invites and appoints committees of clinical and public health experts from throughout New York State to ensure that the guidelines are practical, immediately applicable, and meet the needs of care providers and stakeholders in all major regions of New York State, all relevant clinical practice settings, key New York State agencies, and community service organizations.|
|Disclosure and management of conflicts of interest||
|Evidence collection and review||
|Review and approval process||
|Recommendation Ratings Scheme|
|Strength||Quality of Evidence|
|A||Strong||1||Based on published results of at least 1 randomized clinical trial with clinical outcomes or validated laboratory endpoints.|
|B||Moderate||*||Based on either a self-evident conclusion; conclusive, published, in vitro data; or well-established practice that cannot be tested because ethics would preclude a clinical trial.|
|C||Optional||2||Based on published results of at least 1 well-designed, nonrandomized clinical trial or observational cohort study with long-term clinical outcomes.|
|2†||Extrapolated from published results of well-designed studies (including nonrandomized clinical trials) conducted in populations other than those specifically addressed by a recommendation. The source(s) of the extrapolated evidence and the rationale for the extrapolation are provided in the guideline text. One example would be results of studies conducted predominantly in a subpopulation (e.g., one gender) that the committee determines to be generalizable to the population under consideration in the guideline.|
|3||Based on committee expert opinion, with rationale provided in the guideline text.|