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In this issue of Cancer, Leitao and colleagues1 have made an important contribution toward informing the clinical and epidemiological patterns of cervical cancer in human immunodeficiency virus (HIV)-infected women and its place as an acquired immunodeficiency syndrome (AIDS)-defining cancer. Somewhat typical of small case–control studies, the importance of this work is not restricted to its absolute findings but, rather, its ability to inform key directions for clinical care and research and illumination of broader social correlates of disease. The fortuitous timeliness of this report is difficult to over emphasize: The emerging health disparities illustrated by the changing epidemiological features of the HIV/AIDS epidemic highlights the need to reassess cervical cancer's third-place conceptual setting in the triad of AIDS-defining cancers.

The onset of the AIDS epidemic in the early 1980s was heralded by a sudden departure from the previously known epidemiology of certain infectious diseases and cancers. Kaposi sarcoma (KS) was 1 of the early and striking conditions that defined AIDS. Previously observed mainly in older individuals of Mediterranean descent, KS was thought of as an indolent, angioproliferative, mucocutaneous lesion primarily involving the extremities. Suddenly, it began appearing with uncharacteristic lethality involving both skin and visceral organs almost exclusively among young gay men in large cities on both coasts of the United States. Subsequently it was clear that aggressive B-cell lymphomas (ARL) were increasing among those affected by the epidemic, again with markedly altered clinical aggressiveness and disturbing epidemiological features. Only after 13 years into the epidemic, in 1993, was cervical cancer added as an AIDS-defining condition. The inclusion of this cancer was controversial to some extent, reflecting the somewhat less visible impact of this tumor in the AIDS epidemic. Indeed, partly because of uncertainty of its link to immune suppression, some have questioned whether cervical cancer should be considered an AIDS-defining condition at all. In addition, there has not been uniform evidence that its occurrence or clinical presentation is altered in the setting of HIV. In their well conducted case–control study, Leitao and colleagues have demonstrated a strong association between invasive cervical cancer and immunodeficiency. Also, their study calls attention to the emerging health disparities in HIV/AIDS.

For their analysis, the researches used virologic and immunologic parameters that previously were associated with HPV infection, high-grade intraepithelial neoplasia, and AIDS. This type of approach is well established in AIDS research and has formed the basis of defining the risk of specific AIDS complications, as predicted by the degree of immune suppression. In the case of ARL, for example, not only is the absolute CD4 cell count associated strongly with the risk of developing the tumor, but the degree of CD4 cell depletion is highly predictive of which specific lymphoma histopathologic type is most likely to occur.2 Also, the risk of developing AIDS malignancies associated with oncogenic viruses generally increases with advancing immune depletion.3 For that study, the authors defined immunosuppression as a CD4 cell count <200/μL and an HIV viral load ≥10,000 copies/mL. Women with cervical cancer were more likely to be immunosuppressed by these criteria compared with control cases of HIV-infected women without cervical cancer (see Leitao et al1). It is noteworthy that the cases also were less likely to receive effective combination antiretroviral therapy (cART), also known as highly active antiretroviral therapy or HAART.

This latter point is particularly relevant clinically for both cancer management and HIV management in these patients. Patients who are naive to cART have favorable prospects for successful long-term HIV therapy. Also, because a substantial subset of those defined as immunodeficient by the study criteria had only moderate immune suppression in terms of HIV disease itself, it is quite likely that most would benefit from cervical cancer therapy equivalent to and appropriate for HIV noninfected women.4 However, the cases demonstrate the well known consequences that can ensue when HIV infection and HPV-related cervical dysplasia go undetected or untreated. It is of concern, however, that, although the study was small, it provides a warning of potentially much greater public health developments.

The epidemiologic shift in the American HIV/AIDS epidemic increasingly has involved minorities, especially heterosexual women.5 These women largely are monogamous with a partner whose HIV-seropositive status is unknown to them. Of the over 1.1 million Americans infected with HIV, it is estimated that 25% are unaware of their HIV-seropositive status. In 2004, black Americans accounted for 50% of all new HIV/AIDS cases diagnosed and had the highest HIV/AIDS infection rate with 69.3 cases per 100,000 in the population, which was 8.5 times the rate for whites. Twenty-seven percent of new adolescent and adult AIDS cases were in women. HPV generally is transmitted sexually. Cohort studies have demonstrated that more than half of college-age women will become infected with HPV in their first 2 years of sexual activity. Most women are unaware of the HPV infection, because it generally is asymptomatic and self-limiting. An increasing proportion of women at risk for dual HIV and HPV infection, unaware of their increased risk of AIDS and cervical cancer, thus, may pose a significant emerging public health concern. Moreover, the women at highest risk of these infections also appear to be at highest risk for suboptimal routine health screening, including screening for cervical dysplasia (see Leitao et al1).

Most of the women with cervical cancer were naive to cART, as mentioned above; thus, their prospects for successful, long-term anti-HIV therapy are likely to be quite good. This is important, because, at least for women with early-stage, HIV-unrelated cervical cancer, the median survival surpasses 10 years, and it is not unusual for women to survive for decades after standard therapy for cervical cancer.6 Recent treatment advances in AIDS malignancies have demonstrated that patients with HIV infection can have favorable outcomes comparable to patients who are not infected with HIV, and this is particularly the case when the underlying treatment prospects for HIV are favorable.3, 7 Moreover, prospective data from the Women's Interagency HIV Study, with a 10-year follow-up, confirm that >80% of participants who were recruited and enrolled in HIV studies were retained on study, demonstrating the feasibility and success in research efforts aimed at this population of individuals.8 Thus, the inclusion of women at risk for AIDS-related cervical cancer into research studies can be very successful. Collaborations should be formed to facilitate the inclusion of those with favorable HIV disease status and invasive cancer into cancer clinical trials that recruit HIV-negative women.9 The emergence of AIDS-related cervical cancer as an increasingly important public health concern is potentially an issue for which health disparities exist not, only in the United States but worldwide. The Cancer Health Disparities Progress Review Group, which was formed by the United States Department of Health and Human Services, has recommended the mobilization of national resources to address these issues.10 The National Cancer Institute clinical trials infrastructure forms an important part of the national resources that can be leveraged toward improving health for these underserved communities.

The prospects that cervical cancer may emerge as a major public health concern in those with HIV infection speaks to the important issues of screening at-risk patients. Successful screening efforts have led to a decrease >of 70% in the mortality rate from this tumor since 1940 in the background population.11 The identification of those at risk for HIV infection and appropriate screening also may translate into risk reduction for both HIV and HPV infection. The identification and appropriate medical monitoring and care of those already infected with HIV also may result in improved control of HPV-related cervical disease. Although the data are somewhat mixed, when cART results in sufficient immune reconstitution, intraepithelial dysplastic lesions are more likely to resolve, and there is a reduction in the recurrence of cervical intraepithelial neoplastic lesions (CIN) after conisation.12–15 Decades of successful screening and treatment of CIN have produced the resultant decrease in cervical cancer incidence in areas where such screening is widely available. The benefits of screening and appropriate therapy for HIV infection and HPV-related cervical disease suggest that the inclusion of women into the network of AIDS-related care benefits should be prioritized to include those with early precursor disease so that these successes can be directed to high-risk populations. Cervical cancer is one of the few tumors in which there are clear cancerous precursor lesions that can be detected and treated with a consequent reduction in the risk of invasive cancer. Although most women with cervical dysplasia do not go on to develop invasive cancer, the risk of persistent dysplasia is greater among women with HIV infection compared with the background population, and the persistence of dysplasia increases the risk of developing invasive cervical cancer.16 These features are amenable to successful therapeutic intervention.

Data from the Women's Interagency HIV Study and other findings suggest that cART favorably impacts HPV-related disease.16 This provides evidence that a variety of preventive efforts can be combined effectively to reduce the cervical cancer burden in HIV-infected women. The use of HPV testing can identify patients who are at risk for and with CIN.17 HPV vaccine strategies can be incorporated into HIV screening in the research setting with an objective of assessing the ability of HPV vaccines to alter the risk of infection in women with HIV infection. It also is possible that the prevention of HPV infection may help protect against HIV infection through preservation of the mucosal protective surfaces. In addition, currently, data are insufficient to guide standards of care for AIDS-related cervical cancer; thus, research is needed to inform this lack of knowledge.

The concern for a hidden and emerging rise in cervical cancer incidence and prevalence should not be dismissed. Since the introduction of cART in 1997, the incidence of AIDS and deaths from AIDS has decreased by >50%.18 However, as individuals are living longer, the prevalence of those living with HIV/AIDS has more than doubled. The denominator of at-risk individuals with HIV/AIDS continues to increase and increasingly affects minority women, and the disparities in healthcare are likely to continue to unfold in additional cases of preventable deaths from cervical cancer. Indeed, in the study by Leitao et al,1 all of the cases were among black women who were substantially less likely to be taking anti-HIV therapy or to have had recent gynecologic examinations. Although this can be explained away as a study artifact because of where the patients were treated and, thus, where the study was conducted, a broad view of the national data compels serious contemplation that these findings are illustrative of a wide gap in access to health systems that extends to a substantial and increasing population of women.

Tremendous strides have been made in the treatment of AIDS-related KS and ARL.7, 19–23 In the past, before the availability of cART, the median survival after an ARL diagnosis was on the order of 4 to 18 months. Currently, a substantial proportion of patients affected by ARL are cured of lymphoma; and, with successful anti-HIV therapy, the median survival reported in studies of certain subsets is not yet reached even with years of follow-up, just like in the non-AIDS setting. The data presented by Leitao et al. suggest that similar advances can be made in AIDS-related cervical cancer. However, this will be achieved much as it was in the non-AIDS setting: effective screening, prevention, and identification of early-stage disease. Expanded epidemiological and clinical research efforts are needed to address these important issues. The communities in which the AIDS epidemic is now growing frequently are characterized by individuals of marginal economic means without routine access to health benefits. The existing disparities can be addressed in part through HIV and HPV surveillance programs for minority women and should be introduced with ongoing education and sequential screening. Adolescents of both sexes are at risk for HPV infection. Research opportunities to define the epidemiology, the optimal use and timing of prophylactic HPV vaccines, the potential for therapeutic HPV vaccines in HIV-seropositive and HIV-seronegative individuals, and the best treatment of HPV-associated neoplasia and invasive cervical cancer will provide scientific information and will support and inform needed public health services.

It is important to note that an AIDS diagnosis can make additional resources available to those who are disadvantaged economically; and, by bringing existing social programs to bear, substantial infrastructure already exists to promote successful work in HIV/AIDS research. Because cervical cancer is clearly a disease continuum that begins with HPV infection and progresses with known pathologic features, efforts to optimize access to clinical research for at-risk populations is fundamental to the successful study and preventive intervention of this tumor. The work by Leitao et al helps to illuminate these issues and raises the question of whether the best medical and social policy would be to include women with HIV and HPV infection in the larger network of treatment assistance programs that an AIDS diagnosis provides. This is likely to be essential toward stemming the threat of this emerging health problem. These investigators have helped to point the way: The larger clinical cancer research community now must follow the lead and reverse this emerging problem. HIV-related HPV disease claims a major response on the part of researches to address this issue.

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