Affiliation of authors: Department of Pathology, School of Medicine, University of Washington, Seattle
Correspondence to: Nancy B. Kiviat, MD, Department of Pathology, University of Washington, 1914 N 34th St., Ste. 300, Seattle, WA 98103 (e-mail: nbk{at}u.washington.edu)
Previous studies have clearly demonstrated that human immunodeficiency virus (HIV)-infected women, especially those with low CD4+ T-cell counts, are at increased risk for infection with human papillomaviruses (HPVs) (1,2), the etiologic agent for the development of cervical cancer. Furthermore, HIV infection has been shown to increase a woman's risk of cervical cancer and of cervical cancer precursor lesions (3), including high-, and especially, low-grade squamous intraepithelial lesions (SIL) (47). The mechanism by which HIV increases the risk of HPV infection and cervical neoplasia is believed to be related, in part, to HIV-induced immunodeficiency and the resulting inability to control HPV infection (8). Given this potential mechanism, it has been proposed that highly active antiretroviral therapy (HAART), which is known to lead to clinically significant immunologic reconstitution (9,10), might alter the course of HPV-related cervical lesions in HIV-infected women. At least seven studies (1117) have examined the effects of HAART on the course of cervical lesions, but it is still unclear whether HAART substantially affects the natural history of SIL. Although some studies (1114), including one by the Women's Interagency HIV Study (WIHS) Group (14), reported an association of HAART with regression of cervical lesions, others did not (1517). Indeed, recent data from the HIV Epidemiology Research Study, a multicenter American study of HIV infection, failed to show any beneficial effect of HAART on regression of cervical lesions in 774 HIV-positive women followed at 6-month intervals for an average of 5.5 years (17). The inconsistent findings among studies likely reflect small numbers of study participants, different study outcome definitions, a focus on prevalent cervical lesions, and differences in the timing and duration of the therapy in each study.
The effect of HAART therapy on cervical neoplasia has been further evaluated in a study by the WIHS Group and their results are reported in this issue of the Journal (18). Previously, the WIHS Group found that, among HIV-positive women infected with at least one high-risk HPV type, women on HAART were 40% more likely to experience regression of prevalent and incident cytologic abnormalities, primarily atypical squamous cells of undetermined significance, than were women who did not receive HAART (14). The WIHS Group now examines the effects of HAART on regression of incident SIL by comparing the rate of regression of incident SIL in the pre- and post-HAART periods among HIV-infected women who received HAART at some time during the study period, as well as among HIV-infected women who never received HAART. Overall, 45% of incident SIL, primarily low-grade SIL, among HIV-infected women regressed, with a median time to regression of 2.7 years. Women with more advanced HIV disease at the time of diagnosis of SIL were less likely to have a lesion regress than women with less advanced HIV disease. Thus, because administration of HAART is associated with more advanced HIV disease status, it was not surprising that the WIHS Group found that incident SIL was less likely to regress among HIV-positive women who had received HAART than among HIV-positive women who never received HAART or women who were HIV-negative. Most importantly, in analyses among women who received HAART at some time during the study period, none of the incident SIL lesions was noted to regress in the pre-HAART group (i.e., in women who did not receive HAART), whereas a regression rate of 12.5 per 100 person-years was noted in the post-HAART group. Furthermore, the likelihood of regression was dose-dependently associated with CD4+ T-cell count for both women who received HAART during the study period and women who never began HAART.
The results of the study by Ahdieh-Grant et al. (18) help answer the question of whether HAART alters the natural history of SIL among HIV-infected women because the WIHS Group limits analyses to women who had incident SIL and to women who were followed regularly every 6 months for more than 7 years. Importantly, given the fact that women who do and do not receive HAART may differ in important ways with regard to their immune status, the main analyses addressing the effect of HAART on regression of incident SIL were limited to women who received HAART at some time during the study period. Such a restriction reduced potential bias. In addition, CD4+ T-cell counts were monitored over time, permitting the modeling of CD4+ T-cell counts in a time-dependent fashion, and Pap smears from all six participating sites were evaluated at one laboratory by cytopathologists who were blinded to the participants HIV infection status. Furthermore, individuals who reported treatment for cervical lesions were censored at the time of treatment, and although outcomes were based on cytology rather than biopsy, misclassification was minimized by defining regression as having two consecutive normal Pap smears 6 months apart.
Although the study by the WIHS Group (18) provides evidence that HAART therapy will have at least a modest benefit for HIV-infected women at risk for cervical neoplasia, several concerns remain. In the study, the average length of follow-up time per person in the pre-HAART group was considerably shorter than that in the post-HAART group (1.6 years [163/102] versus 3.1 years [694/221] per person). Because regression was defined as having two negative Pap smears 6 months apart, the relatively short period of follow-up among the pre-HAART group may have limited the number of women who might have achieved the study end point. Furthermore, biases may have been introduced, given that the median time to regression in the overall cohort was 2.7 yearsfar longer than the average length of follow-up for women in the pre-HAART groupand given that the pre-HAART study period was more likely to include women with more recently developed SIL than the post-HAART study period.
A number of important questions concerning the effect of HAART therapy on cervical neoplasia remain. The WIHS Group (18) and others provide data suggesting that HAART therapy likely increases the rate of regression of some low-grade SIL in HIV-infected women. However, whether HIV-infected women on HAART therapy are at decreased risk of progression to high-grade SIL and to carcinoma in situ, the immediate precursor of invasive cervical cancer, has not been resolved. From a clinical point of view, few low-grade SIL lesions are believed to contain the molecular changes necessary for progression to invasive cancer, whereas 30%40% of carcinoma in situ lesions are believed to contain such changes necessary for progression to invasive cervical cancer if the lesion is left untreated in HIV-negative women. Data from the WIHS Group (18) and other studies suggest that, although HIV-infected women receiving HAART therapy will live longer and will likely have better control over cervical HPV infection and some low-grade SIL, HAART therapy does not appear likely to lead to a complete reconstitution of normal control of HPV. Rates of regression among HIV-infected women receiving HAART remained lower than rates seen in HIV-infected women never on HAART or in HIV-negative women (18). Thus, HIV-infected women who live longer as a result of HAART therapy might be at increased risk for prolonged exposure to HPV oncoproteins and thus be at increased risk for the acquisition of the molecular changes characteristic of carcinoma in situ that are necessary for progression to invasive cervical cancer. A similar situation appears to be present in women with HIV-2, an HIV infection (3) that is characterized by substantially lower HIV viral loads, slower CD4+ T-cell count decline, and longer life expectancy than seen with HIV-1 infection. Nevertheless, although the host immune response appears to be able to better control HIV-2 than HIV-1, HIV-2-infected women have been found to be at greater risk of high-grade SIL, carcinoma in situ, or invasive cervical cancer than HIV-1-infected women or HIV-negative women, perhaps as a result of many years of mild immunosuppression with a long-term exposure to HPV oncoproteins (19). HIV-1-infected women receiving HAART in many ways resemble HIV-2-infected women. Future studies will need to determine whether treatment with HAART or treatment with therapeutic or prophylactic HPV vaccines can be used to decrease risk of development of high-grade SIL among HIV-infected women. Thus, although the current study by the WIHS Group (18) suggests that HAART likely affects regression of some low-grade cervical lesions, all HIV-positive women, including those on HAART, need to be encouraged to participate in cervical cancer screening programs.
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