Epidemiology and Social: Editorial Comment
Human papillomavirus genotypes among women with HIV: implications for research and prevention
Chaturvedi, Anil K; Goedert, James J
Viral Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA.
Received 19 July, 2006
Accepted 27 July, 2006
Women with HIV infection have a high prevalence, incidence, and persistence of genital human papillomavirus (HPV) infection and consequently are at high risk for epithelial dysplasia and cancer of the cervix [1–8]. In several recent studies, HIV-positive women have also been show to carry a wide diversity of HPV genotypes as well as multiple concurrent HPV genotypes [1,2,9–13], but the relationship of these to cervical disease has been unclear. In this issue of AIDS, Clifford et al.  report results from a meta-analysis that describes the diversity of HPV genotypes among HIV-positive women by severity of cervical cytological abnormities and compares the HPV genotype distribution in high-grade squamous intraepithelial lesions (HSIL) between HIV-positive women and women in the general population. As expected, Clifford et al.  found that HPV16 was the predominant type across lesions of varying severity among HIV-positive women. Paradoxically, among those with HSIL, HIV-positive women were significantly less likely to harbor HPV16, the type that is responsible for 50% of all cervical cancer worldwide . Furthermore, HIV-positive women with HSIL were more likely than women with HSIL in the general population to be infected with HPV types 11, 18, 33, 51, 52, 53, 58, and 61, and with multiple HPV genotypes . Further research into these differences in the epidemiology of HPV genotypes between HIV-positive women and the general population would help to clarify the ecology of HPV types, effects of immune perturbations, and value of approaches to prevent cervical cancer.
Infection prevalence is a function of both incidence and duration . A wider range of HPV genotypes and infection with multiple types occurs among HIV-positive women partially because of increased incidence arising from high-risk sexual behavior and partly because of reactivation of latent infections and increased persistence of HPV infections in immunosuppression [11,15]. Clifford et al.  clearly show that HIV-positive women with HSIL were approximately nine-fold more likely than the general population to harbor multiple HPV types. This raises the question whether coinfecting HPV genotypes can act synergistically to increase the risk of cervical dysplasia and progression to HSIL [16–18]. However, the association of multiple HPV infections with HSIL may be confounded by the level of immunosuppression (CD4 cell count), because the prevalence of both multiple infections and HSIL increases with worsening immunosuppression [2,19,20].
By retrieving most of their data from the published literature, the meta-analysis by Clifford et al.  is limited by the inability to characterize individual HPV genotypes as occurring in single or multiple infections. This limitation precludes the interpretation of individual genotype associations with HSIL, particularly for low-risk HPV types such as 11, 53, and 61, because the association of these genotypes with HSIL may be confounded by coinfection with other high-risk types. Confounding by coinfection with high-risk types seems particularly likely because, among HIV-positive women, only the major high-risk types (16, 18, 31, and 33) were overrepresented in HSIL compared with lower grade lesions (atypical squamous cells of undetermined significance/low-grade squamous intraepithelial lesions) .
Despite the increased prevalence, incidence, and persistence of HPV infections, cervical cancer rates among HIV-positive women, while substantially increased, have not reached epidemic proportions [8,15,21,22]. The observation by Clifford et al.  that HPV16, the most carcinogenic type, was significantly underrepresented in HSIL among HIV-positive women may explain, in part, the modest elevations in cervical cancer rates among HIV-positive women. Perhaps, this underrepresentation of HPV16 among HIV-positive women with HSIL arises from the relatively weaker effect of HIV-induced immunosuppression on prevalence and incidence of HPV16 compared with other HPV genotypes . Further, HIV-induced immunosuppression may enhance the carcinogenicity of non-HPV16 high-risk genotypes, leading to the association of a range of genotypes with HSIL.
The wide diversity of HPV types among HIV-positive women noted by Clifford et al.  raises important questions about how prophylactic vaccines should be used to reduce cervical cancer risk in HIV-positive women [23–25]. In general, the vaccines are reported to be about 95% effective against primary infection with the targeted high-risk HPV types (16 and 18) that together account for about 70% of cervical cancers [24,25]. The overrepresentation of other high-risk types (33, 51, 52, and 58) among HIV-positive women that are not targeted by the current generation of vaccines implies that the vaccines could be less effective in reducing cancer risk in this group compared with the general population. However, the wide diversity of HPV genotypes among HIV-positive women also presents opportunities to clarify the impact of type-specific vaccination on untargeted HPV genotypes, such as the recently reported cross-protection for HPV31 and HPV45 .
There are no data on HPV vaccine efficacy, or safety, among HIV-positive women. Consequently, our views must be based on extrapolations from the general population and the consequences of HIV-related immunodeficiency. Studies are needed to assess the benefits from vaccinating the current generation of HIV-positive women. The majority of HIV-positive women may have been previously infected with vaccine-targeted HPV genotypes. Current estimates of vaccine efficacy in the general population come from trials conducted in women naive for vaccine-targeted HPV types [23–26]. Recent studies among women seropositive for vaccine HPV types at baseline indicate that the quadrivalent HPV vaccine (16/18/6/11) is well tolerated and induces anamnestic response . It remains to be seen whether these encouraging results will hold for HIV-positive women, given that their humoral immunity, which is required for HPV vaccine efficacy, may be impaired .
Efficacy of the HPV vaccine appears to persist for more than 4 years . It is not known whether similar persistent efficacy will be found among HIV-positive women. HPV vaccination of girls would almost certainly ameliorate the risk of cervical neoplasia in future generations of young women, including those who do become infected with HIV. Even so, because the first-generation vaccines do not target several high-risk types (31, 33, 45, 52, 58 and others) and thus provide coverage for only 70% of the HPV types that cause cervical cancer, regular repeated screening for and treatment of HSIL will continue to be needed for the foreseeable future, especially in HIV-positive women.
1. Ahdieh L, Klein RS, Burk R, Cu-Uvin S, Schuman P, Duerr A, et al
. Prevalence, incidence, and type-specific persistence of human papillomavirus in human immunodeficiency virus (HIV)-positive and HIV-negative women. J Infect Dis 2001; 184:682–690.
2. Palefsky JM, Minkoff H, Kalish LA, Levine A, Sacks HS, Garcia P, et al
. Cervicovaginal human papillomavirus infection in human immunodeficiency virus-1 (HIV)-positive and high-risk HIV-negative women. J Natl Cancer Inst 1999; 91:226–236.
3. Ellerbrock TV, Chiasson MA, Bush TJ, Sun XW, Sawo D, Brudney K, et al
. Incidence of cervical squamous intraepithelial lesions in HIV-infected women. JAMA 2000; 283:1031–1037.
4. Sun XW, Kuhn L, Ellerbrock TV, Chiasson MA, Bush TJ, Wright TC Jr. Human papillomavirus infection in women infected with the human immunodeficiency virus. N Engl J Med 1997; 337:1343–1349.
5. Frisch M, Biggar RJ, Engels EA, Goedert JJ. Association of cancer with AIDS-related immunosuppression in adults. JAMA 2001; 285:1736–1745.
6. Delmas MC, Larsen C, van Benthem B, Hamers FF, Bergeron C, Poveda JD, et al
. Cervical squamous intraepithelial lesions in HIV-infected women: prevalence, incidence and regression. European Study Group on Natural History of HIV Infection in Women. AIDS 2000; 14:1775–1784.
7. Massad LS, Ahdieh L, Benning L, Minkoff H, Greenblatt RM, Watts H, et al
. Evolution of cervical abnormalities among women with HIV-1: evidence from surveillance cytology in the women's interagency HIV study. J Acquir Immune Defic Syndr 2001; 27:432–442.
8. 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; 92:1500–1510.
9. Shah KV, Solomon L, Daniel R, Cohn S, Vlahov D. Comparison of PCR and hybrid capture methods for detection of human papillomavirus in injection drug-using women at high risk of human immunodeficiency virus infection. J Clin Microbiol 1997; 35:517–519.
10. Jamieson DJ, Duerr A, Burk R, Klein RS, Paramsothy P, Schuman P, et al
. Characterization of genital human papillomavirus infection in women who have or who are at risk of having HIV infection. Am J Obstet Gynecol 2002; 186:21–27.
11. Broker TR, Jin G, Croom-Rivers A, Bragg SM, Richardson M, Chow LT, et al
. Viral latency: the papillomavirus model. Dev Biol (Basel) 2001; 106:443–451.
12. Cappiello G, Garbuglia AR, Salvi R, Rezza G, Giuliani M, Pezzotti P, et al
. HIV infection increases the risk of squamous intra-epithelial lesions in women with HPV infection: an analysis of HPV genotypes. DIANAIDS Collaborative Study Group. Int J Cancer 1997; 72:982–986.
13. Levi JE, Kleter B, Quint WG, Fink MC, Canto CL, Matsubara R, et al
. High prevalence of human papillomavirus (HPV) infections and high frequency of multiple HPV genotypes in human immunodeficiency virus-infected women in Brazil. J Clin Microbiol 2002; 40:3341–3345.
14. Clifford GM, Gonclaves MA, Franchesci S. Human papillomavirus types among women infected with human immunodeficiency virus: a meta-analysis. AIDS 2006; 20:000–000.
15. Strickler HD, Burk RD, Fazzari M, Anastos K, Minkoff H, Massad LS, et al
. Natural history and possible reactivation of human papillomavirus in human immunodeficiency virus-positive women. J Natl Cancer Inst 2005; 97:577–586.
16. Trottier H, Mahmud S, Costa MC, Sobrinho JP, Duarte-Franco E, Rohan TE, et al
. Human papillomavirus infections with multiple types and risk of cervical neoplasia. Cancer Epidemiol Biomarkers Prev 2006; 15:1274–1280.
17. Ho GY, Palan PR, Basu J, Romney SL, Kadish AS, Mikhail M, et al
. Viral characteristics of human papillomavirus infection and antioxidant levels as risk factors for cervical dysplasia. Int J Cancer 1998; 78:594–599.
18. Chaouki N, Bosch FX, Munoz N, Meijer CJ, El Gueddari B, El Ghazi A, et al
. The viral origin of cervical cancer in Rabat, Morocco. Int J Cancer 1998; 75:546–554.
19. Hawes SE, Critchlow CW, Sow PS, Toure P, N'Doye I, Diop A, et al
. Incident high-grade squamous intraepithelial lesions in Senegalese women with and without human immunodeficiency virus type 1 (HIV-1) and HIV-2. J Natl Cancer Inst 2006; 98:100–109.
20. Six C, Heard I, Bergeron C, Orth G, Poveda JD, Zagury P, et al
. Comparative prevalence, incidence and short-term prognosis of cervical squamous intraepithelial lesions amongst HIV-positive and HIV-negative women. AIDS 1998; 12:1047–1056.
21. Strickler HD, Palefsky JM, Shah KV, Anastos K, Klein RS, Minkoff H, et al
. Human papillomavirus type 16 and immune status in human immunodeficiency virus-seropositive women. J Natl Cancer Inst 2003; 95:1062–1071.
22. Mbulaiteye SM, Biggar RJ, Goedert JJ, Engels EA. Immune deficiency and risk for malignancy among persons with AIDS. J Acquir Immune Defic Syndr 2003; 32:527–533.
23. Koutsky LA, Ault KA, Wheeler CM, Brown DR, Barr E, Alvarez FB, et al
. A controlled trial of a human papillomavirus type 16 vaccine. N Engl J Med 2002; 347:1645–1651.
24. Harper DM, Franco EL, Wheeler C, Ferris DG, Jenkins D, Schuind A, et al
. Efficacy of a bivalent L1 virus-like particle vaccine in prevention of infection with human papillomavirus types 16 and 18 in young women: a randomised controlled trial. Lancet 2004; 364:1757–1765.
25. Villa LL, Costa RL, Petta CA, Andrade RP, Ault KA, Giuliano AR, et al
. Prophylactic quadrivalent human papillomavirus (types 6, 11, 16, and 18) L1 virus-like particle vaccine in young women: a randomised double-blind placebo-controlled multicentre phase II efficacy trial. Lancet Oncol 2005; 6:271–278.
26. Harper DM, Franco EL, Wheeler CM, Moscicki AB, Romanowski B, Roteli-Martins CM, et al
. Sustained efficacy up to 4.5 years of a bivalent L1 virus-like particle vaccine against human papillomavirus types 16 and 18: follow-up from a randomised control trial. Lancet 2006; 367:1247–1255.
27. Villa LL, Ault KA, Giuliano AR, Costa RL, Petta CA, Andrade RP, et al
. Immunologic responses following administration of a vaccine targeting human papillomavirus types 6, 11, 16, and 18. Vaccine 2006; 24:5571–5583.
28. De Milito A. B lymphocyte dysfunctions in HIV infection. Curr HIV Res 2004; 2:11–21.
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