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HPV-Related Diseases in HIV-Infected Individuals (18HH01)

Debra Chew, MD, MPH, Clinical Assistant Professor, Division of Infectious Diseases, Department of Medicine, Rutgers New Jersey Medical School, Lisa Dever, MD, Vice Chair for Faculty Development in the Department of Medicine, Clinical Chief of Infectious Diseases and the Director of the Infectious Disease Fellows, Rutgers New Jersey Medical School, and Shobha Swaminathan, MD, Assistant Professor, Division of Infectious Diseases, Department of Medicine, Rutgers New Jersey Medical School

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Infection with human papillomavirus (HPV), a DNA virus, is the most common sexually transmitted infection in the United States (US).1 The clinical spectrum of diseases associated with HPV ranges from anogenital and oral warts, anogenital cancer precursors (cervical, anal, vulvar and vaginal squamous intraepithelial neoplasia), and squamous cell cancers of the anogenital tract and oropharynx. HPV causes essentially all cervical cancers, and is linked to about 90% of anal cancers, 60% of oropharyngeal (excluding laryngeal), 35% of penile, 60% of vaginal, and 50% of vulvar cancers in the US.2 Of these, rates of anal and oropharyngeal cancers continue to rise.3-4 It is well documented that individuals with HIV/AIDS have higher prevalence of oral and anogenital HPV infection, anogenital cancer and oropharyngeal cancers compared to the general population.5-7 In this review, we discuss the epidemiology, pathogenesis, and management of HPV-related diseases in HIV-infected individuals, underscoring the need to optimize screening and treatment of HPV-associated precancerous lesions and prevention of HPV-associated cancers among persons living with HIV.


Condyloma acuminatum, wartlike growths on the mucosa of the mouth caused by human papilloma virus (HPV).

Credit: Aubert / Phanie

HPV infection in the General Population

It is estimated that up to 80% of sexually active adults will acquire a genital tract HPV infection before the age of 50.8 Although the incidence of HPV infection is high, the majority of infections, including those caused by high-risk types, are transient and asymptomatic, and up to 90% clear and become undetectable by HPV DNA PCR within 2 years.9-11 In women, genital HPV infection is most common in young sexually active women, with the highest prevalence among females aged 20-24 years old (45% in the National Health and Nutrition Examination Survey [NHANES]).12 Among men who have sex with men (MSM), HPV prevalence typically remains high (50-60%) and is constant throughout life, likely from acquisition of other HPV types from new sexual partners over time.13 Oral HPV infection is much less common than genital infection, but time to clearance of infection appears to be similar.14-15

Other than host factors, the major risk factor for persistence and progression to a cancer precursor lesion is HPV type. Twelve HPV types are currently classified as high-risk oncogenic types, and include predominantly types 16 and 18, and less frequently types 31, 33, 35, 39, 45, 51, 52, 56, and 68. HPV 16 and 18 account for approximately 50% and 20% of all cervical cancers in the United States, respectively. Low-risk HPV types (mostly types 6 and 11) are responsible for 90% of benign genital warts or condyloma accuminata.26 High-risk HPV types have a predilection for mucous membrane infection whereas low-risk types have a predilection for cutaneous epithelium and are found in plantar and nongenital warts.

The oncogenic potential of HPV is attributed to 2 oncoproteins, E6 and E7, expressed during the early stages of the HPV lifecycle, which bind to and inactivate host-tumor suppressor proteins p53 and pRB. Both E6 and E7 are consistently expressed in HPV-carrying anogenital tumors.17-18

Cervical HPV infection progresses with increasing dysplasia before invasive cancer develops, and other anogenital HPV infections are presumed to do so as well. Cellular changes associated with cervical or anal HPV infection and dysplasia that are seen on Papanicolaou (Pap) smears are currently classified as squamous intraepithelial lesions (SIL). In cervical and anal HPV infection, low-grade SIL corresponds to histologic diagnoses of flat condylomas and cervical intraepithelial neoplasia (CIN) 1 or anal intraepithelial neoplasia (AIN) 1 whereas high-grade SIL corresponds to the histologic diagnoses of CIN/AIN 2 and 3.19 In general, low-grade SIL usually does not progress to invasive disease, and often regresses without treatment, whereas high-grade SIL is considered a cancer precursor. High-risk oncogenic types of HPV increase in frequency with severity of histologic lesion. The development of initial HPV infection to CIN 2-3 typically occurs in less than 5 years, whereas progression of CIN 2-3 to invasive cancer may take several decades.20 The lag between HPV infection and development of invasive cancer allows for routine Pap screening to detect dysplastic changes before significant invasion occurs. Anal cancer progression is assumed to occur similarly to cervical cancer, though data is limited showing direct progression of AIN 2-3 to invasive anal cancer.

HPV-associated cervical and anal cancers typically develop at sites of squamous metaplasia. The transition zones at the cervical and anorectal squamous columnar junction are vulnerable to high-risk HPV infection,21 and are the areas targeted for cytologic cervical and anal cancer screening.

HPV Infection in HIV-Infected Individuals

HPV is transmitted primarily by close contact, usually through sexual contact. HIV-induced immunosuppression contributes to the greater prevalence and persistence of HPV infection and progressive disease among those infected with HIV. HIV-infected individuals have higher HPV viral loads, more frequent infections with concomitant multiple HPV oncogenic types, and less HPV clearance than HIV-uninfected individuals.22-27 Considerable data demonstrate that HPV infection and cancer risk are directly related to degree of immunosuppression, as reflected by CD4+ cell count. The degree of immunosuppression also predicts the severity of HPV disease (e.g., extent of lesions and multisite involvement)26, 28-33 and response to treatment.34-36 Additionally, HIV itself promotes carcinogenesis at the molecular level. It has been shown that HIV-encoded tat protein may enhance expression of the HPV E6 and E7 oncogene proteins.37 HPV and HIV also interact in a complex bidirectional manner, and several studies have shown that HPV infection, like other sexually transmitted diseases, may be a risk factor for HIV acquisition. 38-40

Cervical HPV Infection in HIV-Infected Women


The risk of cervical cancer among HIV-infected women is 5 to 8-fold the risk for HIV-uninfected women,5-6,41-43 and invasive cervical cancer is a Centers for Disease Control and Prevention (CDC) AIDS defining illness.44 It is well-established that HPV infection and high-grade CIN are significantly more prevalent among HIV-infected women than HIV-uninfected women.22-26,31-33,45-46 In the Women’s Interagency HIV Study (WIHS), the largest study on cervical-vaginal HPV infection, presence of HPV DNA was 2 times greater among HIV-infected women than HIV-uninfected women, with the highest prevalence of HPV DNA among infected women with a CD4+ count less than 200 cells/μL.31 The HIV Epidemiologic Research Study (HERS) also found that HPV prevalence was not only greater (64% vs 28%), but HPV persistence was nearly double in those with a CD4+ count less than 200 cells/uL.33 Ellerbrock et al. found that HIV-infected women were 4.5-fold more likely than HIV-uninfected women to develop CIN at 54 months of follow-up.24

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