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.
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