Preventing HPV in Patients With HIV: New Guidelines

New Guidelines for HPV in HIV

The Medical Care Criteria Committee of the New York State Department of Health (NYSDOH) AIDS Institute recently released a new guideline, "Human Papillomavirus in Patients with HIV." These guidelines inform providers about HPV-related anogenital disease, focusing on evidence-based approaches to HPV prevention and vaccination, screening methods for HPV-associated precancerous lesions, and treatment of HPV-related lesions.

HIV and HPV

HIV-infected individuals experience substantially higher rates of cervical and anal squamous intraepithelial lesions (SIL) and cervical and anal cancer compared with the general population.^[1,2,3] Increased rates of cancer and SIL are seen in those with a history of AIDS and lower CD4 counts.^[1,2,4] The effect of long-term virologic suppression of HIV on cervical and anal SIL is unclear, but increasing data suggest that effective antiretroviral therapy (ART) lowers the risk for SIL and cancer.^[1,5,6,7] Approximately 70% of anal and cervical cancers are due to HPV types 16 and 18, whereas most genital warts are caused by HPV types 6 and 11.^[8,9] Most oropharyngeal, penile, vulvar, and vaginal cancers are caused by HPV infection as well.^[10] HPV infection is associated with increased risk for HIV acquisition.^[11]

Screening for precancerous lesions of the cervix, with subsequent treatment, has dramatically reduced the incidence of cervical cancer in areas of the world where such prevention programs are widely available. A similar approach for prevention of anal cancer in those living with HIV is the focus of the National Cancer Institute–sponsored ANCHOR study.^[12] No similar strategies for prevention of oropharyngeal cancer caused by HPV are currently available in clinical practice.^[13]

Prevention of HPV

Vaccination

The NYSDOH AIDS Institute guideline recommends that the 9-valent HPV (HPV-9) vaccine (Gardasil-9) series (administered at 0, 2, and 6 months) be offered to all individuals with HIV aged 9-26 years regardless of CD4 count and HPV status. Currently, the HPV-9 vaccine is the only available HPV vaccine in the United States. It is not necessary to revaccinate with the HPV-9 vaccine those who have previously completed vaccination with the bivalent or quadrivalent (qHPV) vaccines, although this approach can be considered.^[14] The two-dose series recommended for those aged 9-14 years has not been studied in immunocompromised populations.^[15] The US Food and Drug Administration recently expanded Gardasil 9’s indication to include both females and males 9-45 years of age, as the quadrivalent vaccine (Gardasil 4) significantly prevented persistent HPV infection, genital warts, and cervical dysplasia in a large vaccine cohort of HIV-uninfected women 24-45 years of age.^[16] However, current Advisory Committee on Immunization Practices recommendations for HPV vaccination have not yet been reconsidered on the basis of this approval. A recent randomized double-blind trial did not show benefit for prevention of anal HPV infection in people over age 26 living with HIV.^[17]

HPV vaccination has been shown to be highly immunogenic and efficacious in preventing SIL and warts in immunocompetent individuals,^[14] including HIV-negative men who have sex with men (MSM).^[18] In HIV-infected populations, the quadrivalent HPV vaccine induces long-term immunogenicity in children^[19] and in adult men.^[20] Given the lack of specific data for HPV vaccine efficacy in people with HIV, recommendations are based on the vaccine's demonstrated safety and immunogenicity in this population. The role of HPV vaccination in adjunctive treatment of HPV neoplasia is controversial.^{[18,21,22,23,24]} The NYSDOH AIDS Institute guideline reminds practitioners that prior HPV vaccination does not obviate the need for screening to prevent HPV-associated cancer.

Condom Use

Condoms do afford partial protection against HPV. Consistent use of male (penile) condoms reduces oncogenic HPV infection by 70% in women^[25] and about 50% of penile acquisition by heterosexual men.^[26,27] The guideline discusses the use of dental damns and female condoms as a means of increasing protection against HPV; however, there is a paucity of data on the efficacy of these barriers. Patients should be aware of the high risk for HPV exposure via sexual activity, given the incomplete protection offered by condoms, the asymptomatic nature of HPV infection, and high rates of background HPV infection in the population.^[28] Clinicians should continue to encourage condom use to prevent HIV and other sexually transmitted infections.

Screening

All individuals with HIV should undergo regular cytologic analysis (Pap smear) of the cervix and/or anus. Cervical cytologic specimens should also be submitted for high-risk HPV testing in patients aged 30 years or older. The role for HPV testing in anal samples remains unclear. Please see the NYSDOH AIDS Institute guideline, "Cervical Screening for Dysplasia and Cancer in Patients With HIV," and corresponding Medscape commentary, "Cervical Cancer Screening in Patients With HIV: Updated Guidelines," for recommendations regarding cervical screening. While there is no consensus regarding frequency of anal cytology, the NYSDOH AIDS Institute "Anal Dysplasia and Cancer Guideline" recommends obtaining annual anal pap smears in a subset of people living with HIV, and the current HPV in HIV guideline expands this recommendation to all males and females living with HIV, as the prior guideline did not recommend screening for groups at appreciable risk for anal high-grade SIL (HSIL).^[3] Many clinicians begin screening patients at age 35 on the basis of cost-effectiveness models.^[29]

The guideline recommends performing regular complete anogenital exams (including digital rectal exams), because HPV can cause neoplasia near the urethra and external genitalia (penile shaft, vulva, scrotum). The anus, cervix, vagina, and/or neovagina should be examined. Screening recommendations are the same for transgender men and women. Sexual histories should focus on sexual behavior rather than sexual and gender identity^[30] to help optimize screening.

Diagnosis

The most easily recognized form of HPV-related dysplasia is genital warts (condyloma acuminata). However, the appearance of HPV-related neoplasia varies. Small external warts without atypia can be treated without biopsy by clinicians with appropriate expertise. Clinicians should consider biopsy of the following lesions in people living with HIV to exclude precancerous or cancerous disease:

Hypopigmented or hyperpigmented plaques or lesions;
Lesions that bleed;
Internal lesions;
Variegated lesions;
Rapidly growing lesions;
Condyloma with atypical appearance;
Typical lesions that fail to respond to standard treatment; and
Other genital lesions of uncertain etiology.

Patients may require expert evaluation, including colposcopy and/or high-resolution anoscopy (HRA). Certain penile or urethral lesions may require urologic evaluation. Colposcopy is recommended for all patients with HIV and atypical cervical cytology, including persistent squamous cells of undetermined significance (ASCUS) and/or high-risk HPV. HRA is recommended for all patients with HIV who have abnormal anal cytology, visible external anal lesions, or palpable lesions on digital anorectal exam.

Patients with poorly controlled HIV (viremia and low CD4 counts) are at higher risk for HPV-related neoplasia, with higher rates of condyloma and SIL, persistent HPV infection, extensive disease, decreased rates of spontaneous disease regression, and higher recurrence rates after treatment.^{[31,32,33,34]}

Treatment

Treatment of HPV-related lesions involves removing or destroying lesions using a variety of surgical options, such as cryotherapy, excision, or electrocautery, as well as clinician-applied compounds such as bichloroacetic acid (BCA) or trichloroacetic acid (TCA). Patient-applied topical therapies, such as podophyllotoxin or imiquimod, may also be used alone or in conjunction with surgical treatment. Treatment should be offered to all patients with precancerous or symptomatic lesions. The guideline recommends against the use of sinecatechins, given the paucity of safety and efficacy data in HIV-infected patients and despite the mention of off-label use in the Centers for Disease Control and Prevention/National Institutes of Health/HIV Medicine Association of the Infectious Diseases Society of America's "Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents." Podophyllotoxin, interferon, and cidofovir gel are not commonly used due to lack of efficacy, toxicity, and/or issues with availability and expense of these therapies. Use of sinecatechins, podophyllin, podophyllotoxin, and 5-FU should be avoided in pregnancy. Individuals having any of the following characteristics should be referred to specialists experienced in the treatment of HPV-related lesions in those with HIV:

Lesions with ulceration;
Irregularly shaped lesions;
Lesions with variegation;
Lesions with pigment changes;
Internal lesions; and
HSIL on histology

All cases of confirmed invasive squamous cell carcinoma should be referred to the appropriate specialist. Management options include surgical excision for superficially invasive squamous cell cancer or chemoradiation for more extensive lesions.^[35]

Partner Exposure

HPV infection is very common in the general population, with more than 80% of women and men acquiring HPV by age 45.^[28] And while condoms are equivocally recommended, they provide incomplete protection against HPV. The guidelines suggest that sex partners of patients with HPV-related disease may also benefit from counseling and examination to assess for the presence of HPV-related lesions. The authors of this commentary recommend that eligible unimmunized partners be offered vaccination as well. The guideline places emphasis on the importance of reducing transmission of other sexually transmitted infections, particularly HIV, through education, training, notification, and chemoprophylaxis.

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