HPV-Associated Neoplasms and Other Lesions in Human Immunodeficiency Virus Infection - Infectious Disease Advisor

HPV-Associated Neoplasms and Other Lesions in Human Immunodeficiency Virus Infection

Slideshow

  • HPV Vaccine

    HPV Vaccine

    Gardasil® 9 is the only HPV vaccine available for use in the United States due to low demand for the two previously approved vaccines (Gardasil 4and Cervarix™).24 Gardasil 9 protects against HPV serotypes 6, 11, 16, 18, 31, 33, 45, 52, and 58. It is indicated for male and female patients age 9 to 26 to protect against various HPV-related anogenital neoplasms and lesions.25 There are no contraindications to vaccinating patients who are HIV-positive with Gardasil 9, although it is most efficacious if given before an individual becomes sexually active. Nevertheless, some benefit has been observed in older patients who are co-infected with HIV and HPV. In a study of adults age ≥27 who infected with HIV, Gardasil 4 showed efficacy in preventing persistent oral HPV infections, although it did not prevent new anal HPV infections or improve anal HSIL outcomes.26 In another recently published study, Gardasil 9 decreased the burden of high-risk HPV infection in women (median age, 38) who are HIV-positive.27

  • Role of Highly-Active Antiretroviral Therapy

    Role of Highly-Active Antiretroviral Therapy

    Data regarding the impact of HAART on HPV infection and subsequent dysplasia and neoplasia are conflicting.3 Anal cancer has been reported to be increased in patients who are HIV-positive despite treatment with combination antiretroviral therapy.28 In contrast, the incidence of cervical cancer has not increased in the HAART era, although no benefit has been observed in reducing progression to high-grade cervical or anal intraepithelial neoplasia.3 A rise in HPV-related oral lesions has been reported in patients who are HIV-positive, with prevalence increased with longer HAART use, but it is unclear whether this is a direct effect of HAART.29 Although HAART may not decrease the incidence of HPV-related lesions, these lesions are more difficult to treat in patients with low CD4 nadirs; thus, effective HAART remains essential. Further high-quality studies are needed to better elucidate the relationship between HAART, HPV infections, and associated lesions.21

  • In patients who are HIV-positive, HPV infection is common but prevalence varies based on many factors, such as geographic location, patient sex and sexual orientation, and anatomical site. In Asia and the United States, HPV co-infection has been reported in 31% of women who are HIV-positive, whereas in Central/South America and Africa, HPV co-infection has been reported in up to 57% of women who are HIV-positive.1 In a 2017 study by Italian researchers, HPV coinfection was identified in 48% of women in Central and Eastern Italy who were HIV-positive.2 This is almost twice the rate observed in the HIV-negative population (28%), which is consistent with other literature. In a 2013 cross-sectional study of men and women who are HIV-positive treated at a hospital in Milan, Italy, men had an anal HPV prevalence of 81%, and women had a cervical HPV prevalence of 58%.3 In bisexual and homosexual men who are HIV-positive, HPV prevalence has been reported to reach 93%.4 Photo Credit: Gopal Murti

    Prevalence of HIV and HPV Co-infection

    In patients who are HIV-positive, HPV infection is common but prevalence varies based on many factors, such as geographic location, patient sex and sexual orientation, and anatomical site. In Asia and the United States, HPV co-infection has been reported in 31% of women who are HIV-positive, whereas in Central/South America and Africa, HPV co-infection has been reported in up to 57% of women who are HIV-positive.1


    In a 2017 study by Italian researchers, HPV coinfection was identified in 48% of women in Central and Eastern Italy who were HIV-positive.2 This is almost twice the rate observed in the HIV-negative population (28%), which is consistent with other literature.


    In a 2013 cross-sectional study of men and women who are HIV-positive treated at a hospital in Milan, Italy, men had an anal HPV prevalence of 81%, and women had a cervical HPV prevalence of 58%.3 In bisexual and homosexual men who are HIV-positive, HPV prevalence has been reported to reach 93%.4


    Photo Credit: Gopal Murti

  • HPV Classification and Malignant Potential

    HPV Classification and Malignant Potential

    HPV is a group of DNA viruses with >200 known genotypes.5 HPV is classified as belonging to one of five genera based on sequence relatedness: alpha, beta, gamma, mu, or nu.6 Alpha-HPVs infect mucosal tissue, most commonly the vagina, mouth, and gut, whereas beta-, gamma-, nu-, and mu-HPVs infect cutaneous sites, most often the hands and feet.5 HPV strains are further categorized according to their malignant potential. High-risk strains include HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 667; low-risk strains include HPV 6, 11, 40, 42, 43, 44, 54, 61, 70, 72, and 81.7


    Worldwide, 5.2% of all cancers have been associated with HPV, with up to 3.5% of these being attributed to HPV 16.5 In patients with normal immune systems, most HPV infections become undetectable within 1 to 2 years, but immunosuppression in individuals who are HIV-infected can lead to persistent infections that increase the risk for dysplasia and subsequent malignancy.8


    Photo Credit: Medical Images/ISM/Dr. A Gaillot

  • Approximately 95% of anal cancers are caused by HPV.9 A recently published comprehensive systematic review and meta-analysis showed that HPV 16 is the strain most commonly associated with anal cancer in men and women who are HIV-positive. 9 HPV 16 positivity was found to increase between high-grade lesions and anal cancer, while other high-risk HPV strains (HPV18, 31, 33, 45, 52, and 58) were associated with a high percentage of low- or high-grade lesions, but the prevalence was decreased in anal cancer. Overall, however, HPV 16 infection was found to be less frequent in patients with anal cancer who were HIV-positive vs HIV-negative.10 There are currently no formal screening guidelines for anal cancer in individuals who are HIV-positive. Because anal cancer is similar to cervical cancer, with high-grade squamous intraepithelial lesions (HSIL) preceding malignancy, some experts have recommended routinely screening patients who are HIV-positive, particularly high-risk individuals such as homosexual men, for anal HSIL.11,12</sup Photo Credit: Medical Images/ Garry DeLong

    Anal Cancer

    Approximately 95% of anal cancers are caused by HPV.9 A recently published comprehensive systematic review and meta-analysis showed that HPV 16 is the strain most commonly associated with anal cancer in men and women who are HIV-positive. 9 HPV 16 positivity was found to increase between high-grade lesions and anal cancer, while other high-risk HPV strains (HPV18, 31, 33, 45, 52, and 58) were associated with a high percentage of low- or high-grade lesions, but the prevalence was decreased in anal cancer.


    Overall, however, HPV 16 infection was found to be less frequent in patients with anal cancer who were HIV-positive vs HIV-negative.10


    There are currently no formal screening guidelines for anal cancer in individuals who are HIV-positive. Because anal cancer is similar to cervical cancer, with high-grade squamous intraepithelial lesions (HSIL) preceding malignancy, some experts have recommended routinely screening patients who are HIV-positive, particularly high-risk individuals such as homosexual men, for anal HSIL.11,12</sup


    Photo Credit: Medical Images/ Garry DeLong

  • Almost all cervical cancers have been attributed to HPV, with HPV serotypes 16 and 18 associated with approximately 70% of all cases.9 However, evidence suggests other high-risk strains may play an equally prominent role in certain geographic areas. For example, HPV 45 has been strongly associated with invasive cervical cancers in women in Africa who are HIV-positive.13 Although chronic HPV 16 infection plays a major role in the development of many cervical cancers, the strain alone may not determine cancer risk.14 An analysis of the HPV 16 genome found thousands of variations among samples taken from women in the same geographic area, with subsequent cancer risk depending on the variation. Cancerous lesions were more likely with strains containing the viral gene E7, enabling a new treatment target.14 Research also suggests that HPV strains might not be a single viral entity with slow genetic drift, but that each HPV isolate might be a separate virus with different carcinogenic potential.15 Photo Credit: CDC

    Cervical Cancer

    Almost all cervical cancers have been attributed to HPV, with HPV serotypes 16 and 18 associated with approximately 70% of all cases.9 However, evidence suggests other high-risk strains may play an equally prominent role in certain geographic areas. For example, HPV 45 has been strongly associated with invasive cervical cancers in women in Africa who are HIV-positive.13


    Although chronic HPV 16 infection plays a major role in the development of many cervical cancers, the strain alone may not determine cancer risk.14 An analysis of the HPV 16 genome found thousands of variations among samples taken from women in the same geographic area, with subsequent cancer risk depending on the variation. Cancerous lesions were more likely with strains containing the viral gene E7, enabling a new treatment target.14 Research also suggests that HPV strains might not be a single viral entity with slow genetic drift, but that each HPV isolate might be a separate virus with different carcinogenic potential.15


    Photo Credit: CDC

  • Approximately 70% of oropharyngeal cancers are associated with HPV, with >50% attributed to HPV 16.9 As with anal and cervical cancers, patients with HIV are at increased risk for developing HPV-related oropharyngeal cancers compared with the general population, although the risk increase for this cancer vs others appears more modest.16,17 Risk is greatest in individuals who are HIV-positive with a higher number of lifetime sexual partners (>8), including >4 oral sexual partners; current high tobacco and/or alcohol use; and increased immunosuppression.16,17 There is currently no validated screening method for detecting HPV-associated oropharyngeal cancer, and some evidence suggests screening might only be beneficial in symptomatic patients.16 Nevertheless, preventing chronic HPV infections in patients who are HIV-positive is important in reducing cancer risk and improving quality of life; thus, many clinicians have advocated for prophylactic HPV vaccination. Photo Credit: Science Source/Dr P Marazzi

    Oropharyngeal Cancers

    Approximately 70% of oropharyngeal cancers are associated with HPV, with >50% attributed to HPV 16.9 As with anal and cervical cancers, patients with HIV are at increased risk for developing HPV-related oropharyngeal cancers compared with the general population, although the risk increase for this cancer vs others appears more modest.16,17 Risk is greatest in individuals who are HIV-positive with a higher number of lifetime sexual partners (>8), including >4 oral sexual partners; current high tobacco and/or alcohol use; and increased immunosuppression.16,17


    There is currently no validated screening method for detecting HPV-associated oropharyngeal cancer, and some evidence suggests screening might only be beneficial in symptomatic patients.16 Nevertheless, preventing chronic HPV infections in patients who are HIV-positive is important in reducing cancer risk and improving quality of life; thus, many clinicians have advocated for prophylactic HPV vaccination.


    Photo Credit: Science Source/Dr P Marazzi

  • Other Cancers

    Other Cancers

    Although HPV is known to cause anal, cervical, and oropharyngeal cancers, it has also been implicated in a variety of other cancers, including 65% of vaginal cancers, 50% of vulvar cancers, and 35% of penile cancers.9 More recently, an association between HPV and certain skin cancers has been reported.18


    A 2010 study found a relationship between beta-HPV infection and squamous cell carcinoma of the skin, but not basal cell carcinoma, with a pronounced risk in individuals who are immunosuppressed.18 Unlike with anal and cervical cancers, which are caused by high-risk alpha-HPV strains, no high-risk serotypes of beta-HPV were identified, but risk appears to hinge on the number of beta-HPV strains to which individuals tested positive. These findings indicate that infection with multiple HPV strains may play an important role in the development of beta-HPV-related skin cancer.18


    Photo Credit: Medical Images/ Dr A Gaillot

  • Epidermodysplasia verruciformis (EV) is a rare, inherited disorder that increases susceptibility to beta-HPV infection, with oncogenic HPV 5 and 8 being the most frequently implicated.19 Patients with EV can develop wart-like lesions all over their bodies, although sun-exposed areas are particularly vulnerable.19 Immunosuppressed individuals are at higher risk for EV manifestations. In a small study of 11 patients with EV who were HIV-positive, 10 developed their first EV lesions a median of 9 years following their HIV diagnosis.19 All patients had extensive flat warts and associated pityriasis-like macules and lichenoid papules were also common. Almost all patients (73%) had a history of another cutaneous or mucosal infection, such as palmar/plantar warts, anogenital bowenoid papulosis, condylomas, or high-grade cervical intraepithelial neoplasia. Approximately 25% of the patients developed non-melanoma skin cancers. HAART was ineffective in preventing or clearing lesions despite immunity being restored.19 Photo Credit: Science Source/ Dr Harout Tanielian

    Epidermodysplasia Verruciformis

    Epidermodysplasia verruciformis (EV) is a rare, inherited disorder that increases susceptibility to beta-HPV infection, with oncogenic HPV 5 and 8 being the most frequently implicated.19 Patients with EV can develop wart-like lesions all over their bodies, although sun-exposed areas are particularly vulnerable.19 Immunosuppressed individuals are at higher risk for EV manifestations. In a small study of 11 patients with EV who were HIV-positive, 10 developed their first EV lesions a median of 9 years following their HIV diagnosis.19


    All patients had extensive flat warts and associated pityriasis-like macules and lichenoid papules were also common. Almost all patients (73%) had a history of another cutaneous or mucosal infection, such as palmar/plantar warts, anogenital bowenoid papulosis, condylomas, or high-grade cervical intraepithelial neoplasia. Approximately 25% of the patients developed non-melanoma skin cancers. HAART was ineffective in preventing or clearing lesions despite immunity being restored.19


    Photo Credit: Science Source/ Dr Harout Tanielian

  • Condyloma acuminata, or anogenital warts, are generally attributed to HPV 6 and 11; however, in patients who are HIV-positive, they have also been associated with high-risk serotypes 16, 18, 31, 33, and 35.20,21 Approximately 630 million new cases of HPV occur annually worldwide, and 30 million of these individuals develop anogenital warts, with the risk being especially elevated in patients who are HIV-positive and individuals who are immunocompromised.22 In a Brazilian cross-sectional study, 31% of men who were HIV-positive had anogenital warts.22 Irregular antiretroviral treatment and co-infection with herpes simplex virus were associated with a higher risk for developing anogenital warts.22 More severe anogenital wart presentation has been reported in patients who are HIV-positive, with lesions being larger, more numerous, treatment-resistant, and prone to recurrence, even in the setting of effective HAART.21 Nevertheless, treatment remains the same in this population as in non-immunocompromised individuals.23 Photo Credit: Medical Images/Dr Isabelle Cartier/ISM

    Condyloma Acuminata

    Condyloma acuminata, or anogenital warts, are generally attributed to HPV 6 and 11; however, in patients who are HIV-positive, they have also been associated with high-risk serotypes 16, 18, 31, 33, and 35.20,21 Approximately 630 million new cases of HPV occur annually worldwide, and 30 million of these individuals develop anogenital warts, with the risk being especially elevated in patients who are HIV-positive and individuals who are immunocompromised.22 In a Brazilian cross-sectional study, 31% of men who were HIV-positive had anogenital warts.22 Irregular antiretroviral treatment and co-infection with herpes simplex virus were associated with a higher risk for developing anogenital warts.22 More severe anogenital wart presentation has been reported in patients who are HIV-positive, with lesions being larger, more numerous, treatment-resistant, and prone to recurrence, even in the setting of effective HAART.21 Nevertheless, treatment remains the same in this population as in non-immunocompromised individuals.23


    Photo Credit: Medical Images/Dr Isabelle Cartier/ISM

Immunosuppression increases the risk for human papillomavirus (HPV) infection in patients infected with human immunodeficiency virus (HIV). It is thought that the HIV-compromised immune system is unable to control the expression and replication of HPV, increasing susceptibility to HPV infection upon exposure and possibly facilitating reactivation of latent HPV infection.1

As HPV exposure persists, patients are at increased risk for developing a variety of neoplasms and other lesions. Because highly active antiretroviral therapy (HAART) has enabled patients who are HIV-positive to achieve a normal lifespan, early detection of these lesions is essential in order to improve patients’ quality of life, reduce the risk for complications, and ensure maximum lifespan.

Compiled by Christina Loguidice

References

  1. Denny LA, Franceschi S, de Sanjosé S, et al. Human papillomavirus, human immunodeficiency virus and immunosuppression. Vaccine. 2012;30(Suppl 5):F168-F174.
  2. Tartaglia E, Falasca K, Vecchiet J, et al. Prevalence of HPV infection among HIV-positive and HIV-negative women in Central/Eastern Italy: strategies of prevention. Oncol Lett. 2017;14(6):7629-7635.
  3. Marchetti G, Comi L, Bini T, et al. HPV infection in a cohort of HIV-positive men and women: prevalence of oncogenic genotypes and predictors of mucosal damage at genital and oral sites. J Sex Transm Dis. 2013;2013:915169.
  4. Palefsky JM, Holly EA, Ralston ML, Jay N. 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):361-367.
  5. Bacik LC, Chung C. Human papillomavirus-associated cutaneous disease burden in human immunodeficiency virus (HIV)-positive patients: the role of human papillomavirus vaccination and a review of the literature. Int J Dermatol. 2018;57(6):627-634.
  6. Schmitt M, de Koning MNC, Eekhof JAH, et al. Evaluation of a novel multiplex human papillomavirus (HPV) genotyping assay for HPV types in skin warts. J Clin Microbiol. 2011;49(9):3262-3267.
  7. Haedicke J, Iftner T. Human papillomaviruses and cancer. Radiother Oncol. 2013;108(3):397-402.
  8. Gravitt PE, Winer RL. Natural history of HPV infection across the lifespan: role of viral latency. Viruses. 2017;9(10):267.
  9. National Cancer Institute. HPV and cancer. Reviewed February 19, 2015. www.cancer.gov/about-cancer/causes-prevention/risk/infectious-agents/hpv-fact-sheet. Accessed July 23, 2018.
  10. 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.
  11. Kaplan JE, Benson C, Holmes KK, et al. Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. MMWR. 2009;58:1-198.
  12. Wells JS, Holstad MM, Thomas T, Bruner DW. An integrative review of guidelines for anal cancer screening in HIV-infected persons. AIDS Patient Care STDS. 2014;28(7):350-357.
  13. 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.
  14. Mirabello L, Yeager M, Yu K, et al. HPV16 E7 genetic conservation is critical to carcinogenesis. Cell. 2017;170(6):1164-1174.
  15. Science Daily. Human papillomavirus 16 infections may pose variable cancer risk [press release]. September 7, 2017. www.sciencedaily.com/releases/2017/09/170907142654.htm. Accessed July 13, 2018.
  16. Wang CC, Palefsky JM. Human papillomavirus-related oropharyngeal cancer in the HIV-infected population. Oral Dis. 2016;22(Suppl 1):98-106.
  17. Beachler DC, D’Souza G. Oral HPV infection and head and neck cancers in HIV-infected individuals. Cur Opin Oncol. 2013;25(5):503-510.
  18. Karagas MR, Waterboer T, Li Z, et al; New Hampshire Skin Cancer Study Group. Genus beta human papillomaviruses and incidence of basal cell and squamous cell carcinomas of skin: population-based case-control study. BMJ. 2010;341:c2986.
  19. Jacobelli S, Laude H, Carlotti A, et al. Epidermodysplasia verruciformis in human immunodeficiency virus-infected patients: a marker of human papillomavirus-related disorders not affected by antiretroviral therapy. Arch Dermatol. 2011;147(5):590-596.
  20. Orlando G, Fasolo MM, Beretta R, et al. Diagnosis and management of genital warts in HIV disease. AIDS Read. 2000;10(1).
  21. US Department of Veterans Affairs. HIV/AIDS. Published 2009. www.hiv.va.gov/provider/manual-primary-care/dermatologic-table7.asp. Accessed July 23, 2018.
  22. de Camargo CC, Tasca KI, Mendes MB, Miot HA, de Souza Ldo R. Prevalence of anogenital warts in men with HIV/AIDS and associated factors. Open AIDS J. 2014;8:25-30.
  23. Centers for Disease Control and Prevention (CDC). 2015 Sexually Transmitted Diseases Treatment Guidelines. Updated January 25, 2017. www.cdc.gov/std/tg2015/default.htm. Accessed July 19, 2018.
  24. American Academy of Pediatrics. HPV vaccine implementation guidance. Updated February 2017. www.aap.org/en-us/Documents/immunization_hpvimplementationguidance. Accessed July 23, 2017.
  25. Kojic EM, Conley L, Bush T, et al. Prevalence and incidence of anal and cervical high-risk human papillomavirus (HPV) types covered by current HPV vaccines among HIV-infected women in the SUN study. J Infect Dis. 2018;217(10):1544-1552.
  26. Gardasil® 9 [package insert]. Whitehouse Station, NJ: Merck & Co., Inc; 2018.
  27. Wilkin TJ, Chen H, Cespedes MS, et al. A randomized, placebo-controlled trial of the quadrivalent HPV vaccine in HIV-infected adults age 27 years or older: AIDS Clinical Trials Group protocol A5298 [published online April 5, 2018]. Clin Infect Dis. doi:10.1093/cid/ciy274
  28. Kojic EM, Conley L, Bush T, et al. Prevalence and incidence of anal and cervical high-risk human papillomavirus (HPV) types covered by current HPV vaccines among HIV-infected women in the SUN study. J Infect Dis. 2018;217(10):1544-1552.
  29. Piketty C, Selinger-Leneman H, et al; FHDH-ANRS CO 4. Marked increase in the incidence of invasive anal cancer among HIV-infected patients despite treatment with combination antiretroviral therapy. AIDS. 2008;22(10):1203-1211.
  30. Anaya-Saavedra G, Flores-Moreno B, et al. HPV oral lesions in HIV-infected patients: the impact of long-term HAART. J Oral Pathol Med. 2013;42(6):443-449.