Highly Active Antiretroviral Therapy and Cervical Squamous Intraepithelial Lesions in Human Immunodeficiency Virus–Positive Women

JNCI: Journal of the National Cancer Institute, Jul 2004

Background: Women infected with human immunodeficiency virus (HIV) have an increased risk of persistent squamous intraepithelial lesions (SILs) of the cervix. We assessed the association between use of highly active antiretroviral therapy (HAART) and regression of SIL in HIV-infected women enrolled in the Women's Interagency HIV Study, a large, multicenter, prospective cohort study. Methods: Of 2059 HIV-infected participants, 312 HIV-infected women had normal cervical cytology at baseline and were subsequently diagnosed during 7 years of follow-up with incident SIL. Pap smears, CD4+ T-cell counts, and information regarding use of HAART were obtained every 6 months. The outcome of interest was lesion regression, defined as two consecutive normal Pap smears 6 months apart. Incidence rates of SIL regression were computed among person-years at risk, both before and after HAART initiation. All statistical tests were two-sided. Results: Of 312 women, 141 had lesions that regressed to normal cytology, with a median time to regression of 2.7 years. Overall, the incidence of regression increased ( Ptrend = .002) over time after HAART was introduced. At incident SIL, median CD4+ T-cell counts were lower in women whose lesions did not regress than in women whose lesions regressed (230 versus 336 cells/ μ L; P <.01). Before HAART was introduced, the rate of lesion regression was 0.0% (95% confidence interval [CI' = 0.0% to 2.4%). After HAART was introduced, the rate was 12.5% (95% CI = 9.9% to 15.1%) and was related to post-HAART CD4+ T-cell counts ( Ptrend = .002). Conclusions: HAART use was associated with increased regression of SIL among HIV-infected women, and among women who used HAART, increased CD4+ T-cell counts were associated with a greater likelihood of regression. However, the majority of cervical lesions among HIV-infected women, even among individuals who used HAART, did not regress to normal.

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Highly Active Antiretroviral Therapy and Cervical Squamous Intraepithelial Lesions in Human Immunodeficiency Virus–Positive Women

Journal of the National Cancer Institute Highly Active Antiretroviral Therapy and Cervical Squamous Intraepithelial Lesions in Human Immunodeficiency Virus-Positive Women Linda Ahdieh-Grant 0 Rui Li 0 Alexandra M. Levine 0 L. Stewart Massad 0 Howard D. Strickler 0 Howard Minkoff 0 Michael Moxley 0 Joel Palefsky 0 Henry Sacks 0 Robert D. Burk 0 Stephen J. Gange 0 0 Affiliations of authors: Johns Hopkins Bloomberg School of Public Health , Baltimore, MD (LAG, RL , SJG); University of Southern California School of Medicine, Los Angeles (AML); Southern Illinois University School of Medicine, Springfield (LSM); Albert Einstein College of Medicine , Bronx, NY (HDS , RDB); Maimonides Medical Center/State University of New York Health Sciences at Brooklyn, Brooklyn, NY (HM); Georgetown University Medical Center , Washington , DC (MM); University of California at San Francisco, San Francisco (JP); Mount Sinai School of Medicine , New York, NY (HS). School of Public Health, Department of Epidemiology , Rm. E-7014, Baltimore, MD 21205 , USA Background: Women infected with human immunodeficiency virus (HIV) have an increased risk of persistent squamous intraepithelial lesions (SILs) of the cervix. We assessed the association between use of highly active antiretroviral therapy (HAART) and regression of SIL in HIV-infected women enrolled in the Women's Interagency HIV Study, a large, multicenter, prospective cohort study. Methods: Of 2059 HIV-infected participants, 312 HIV-infected women had normal cervical cytology at baseline and were subsequently diagnosed during 7 years of follow-up with incident SIL. Pap smears, CD4 T-cell counts, and information regarding use of HAART were obtained every 6 months. The outcome of interest was lesion regression, defined as two consecutive normal Pap smears 6 months apart. Incidence rates of SIL regression were computed among person-years at risk, both before and after HAART initiation. All statistical tests were two-sided. Results: Of 312 women, 141 had lesions that regressed to normal cytology, with a median time to regression of 2.7 years. Overall, the incidence of regression increased (Ptrend .002) over time after HAART was introduced. At incident SIL, median CD4 T-cell counts were lower in women whose lesions did not regress than in women whose lesions regressed (230 versus 336 cells/ L; P<.01). Before HAART was introduced, the rate of lesion regression was 0.0% (95% confidence interval [CI] 0.0% to 2.4%). After HAART was introduced, the rate was 12.5% (95% CI 9.9% to 15.1%) and was related to post-HAART CD4 T-cell counts (Ptrend .002). Conclusions: HAART use was associated with increased regression of SIL among HIV-infected women, and among women who used HAART, increased CD4 T-cell counts were associated with a greater likelihood of regression. However, the majority of cervical lesions among HIV-infected women, even among individuals who used HAART, did not regress to normal. [J Natl Cancer Inst 2004;96:1070 - 6] - Infection with the human immunodeficiency virus (HIV) and its related immunosuppression are associated with an increased risk of prevalent, incident, and persistent squamous intraepithelial lesions (SILs) of the cervix ( 1,2 ). Cervical infection and persistence of human papillomavirus (HPV) infection, the major etiologic agent in most cervical neoplasms (3), is also increased in HIV-infected women ( 4 ). It is well established that the use of highly active antiretroviral therapy (HAART) in HIV-infected individuals has a profound effect on immune status and greatly reduces the risk of acquired immunodeficiency syndrome (AIDS) and death ( 5–11 ). However, only a few small studies with short follow-up times have examined the effects of HAART on regression of SIL in HIV-positive women, with the majority primarily evaluating the effects of HAART on prevalent cervical lesions. Because the date of onset of a prevalent lesion could not be known, it was not possible to adequately estimate the duration of the lesion. Thus, it is not surprising that the results reported to date have been equivocal regarding whether HAART increases the probability of regression of SIL. To more comprehensively study the long-term effects of HAART on the regression of incident cervical SIL, we analyzed data from the Women’s Interagency HIV Study (WIHS), a large, multicenter, prospective cohort of HIV-infected women who, at the time of this analysis, had been followed every 6 months for more than 7 years. Two important strengths of this study are the analysis of only incident SIL and the availability of data from before and during the HAART era. SUBJECTS AND METHODS Study Design Participants of the WIHS were recruited from October 1994 through November 1995, during which time 2059 HIVseropositive and 569 HIV-seronegative women were enrolled at six sites (Bronx/Manhattan, NY; Brooklyn, NY; Chicago, IL; Los Angeles, CA; San Francisco Bay Area, CA; Washington, DC, metropolitan area). The study protocol has been described previously ( 12 ). All participants gave written informed consent, and the study was approved by institutional review boards at all sites. In brief, after an initial baseline visit, WIHS participants were evaluated every 6 months. Each evaluation consisted of administering a structured questionnaire and performing a physical and gynecologic examination. Blood specimens were collected to determine levels of CD4 T cells and plasma HIV RNA. T-cell subsets were determined by flow cytometry in laboratories participating in the AIDS Clinical Trials Quality 1070 ARTICLES Assurance Program. Plasma HIV RNA levels were measured using a nucleic acid sequence-based amplification technique (Organon Teknika, Durham, NC) according to the manufacturer’s recommended protocol. Assessment of Cervical SIL and HPV Infection Pap smears were collected using a plastic Ayre spatula and an endocervical brush, and the cells were spread onto a single slide. Cytology samples from all six participating sites were centrally evaluated at Kyto Meridien Laboratories (New York, NY) using the 1994 Bethesda System criteria for cytologic diagnosis ( 13 ). Two cytotechnologists, who were blinded to participants’ HIV infection status, read all smears. All abnormal smears and a randomly selected sample of 10% of all negative smears were confirmed by a cytopathologist. The cytopathologist’s diagnosis was considered final. Diagnoses were reported as normal or benign, atypical squamous cells of undetermined significance (ASCUS), low-grade SIL (LSIL), moderate or high-grade SIL (HSIL), or cancer. HPV infection was determined from cells collected by cervicovaginal lavage. This protocol involved rinsing the cervical os and the exocervix with 10 mL of sterile normal saline and then aspirating the fluid from the posterior vaginal fornix. A comparison of cervicovaginal lavage and cytobrush methods for the detection of HPV found that both methods provided similar estimates of the prevalence of HPV ( 14 ). All specimens were stored in aliquots at –70 °C. Two laboratories performed HPV testing on samples collected at the baseline visit by using a polymerase chain reaction with MY09/MY11/HB01 L1 consensus primers, which are generic but not HPV-type–specific, and a control primer set that simultaneously amplifies a beta-globin DNA fragment, as described ( 15 ). Samples that were positive using the consensus probe were re-probed to identify the following specific HPV types: HPV6, HPV11, HPV13, HPV16, HPV18, HPV26, HPV31, HPV35, HPV39, HPV40, HPV42, HPV45, HPV51, HPV59, HPV61, HPV62, HPV64, HPV66, HPV73, HPV81, HPV85, HPV89, AE9, and AE10. Use of HAART At each visit, participants were asked for the names of the antiretroviral medications they had used since their previous visit. Photo-medication cards were provided to assist the participants in their recall. The primary exposure of interest for this analysis was the use of HAART. Women reporting use of one of the following combinations since the time of their last visit were considered as being on HAART: (a) two or more nucleoside reverse transcriptase inhibitors (NRTIs) in combination with at least one protease inhibitor or one non-nucleoside reverse transcriptase inhibitor (NNRTI); (b) one NRTI in combination with at least one protease inhibitor and at least one NNRTI; (c) a regimen containing ritonavir and saquinavir in combination with one NRTI and no NNRTIs; or (d) an abacavir-containing regimen of three or more NRTIs in the absence of both protease inhibitors and NNRTIs. Combinations of zidovudine and stavudine with either a protease inhibitor or an NNRTI were not considered HAART because of contraindications. The definition of HAART was based on the U.S. Department of Health and Human Services–Kaiser Panel guidelines ( 16 ) and the International AIDS Society–USA Panel ( 17 ). The date of HAART initiation was determined to be the midpoint between the first visit at which a participant reported using HAART and the preceding visit. Participants who began HAART were classified as HAART users from the date they first started HAART. Study Population and Outcome of Interest For this analysis, the study population consisted of all HIVinfected women enrolled in the WIHS who had a normal Pap smear at study enrollment (i.e., baseline) and subsequently developed a cytologic lesion during at least 7 years of follow-up. A cytologic lesion was defined as LSIL or worse. Our outcome of interest was cytologic regression, which was defined as two consecutive normal Pap smears 6 months apart. Pap smears were classified as normal when both squamous and endocervical cells were within normal limits. Participants were excluded from the study if they had a diagnosis of ASCUS at baseline. A diagnosis of ASCUS during follow-up after the incident SIL event was not considered an endpoint of interest. Because gynecologic treatment has an impact on the course of cervical SIL, individuals who reported treatment for cervical neoplasia were censored at the time of treatment. The following procedures were considered cervical disease treatments: interferon; 5-fluorouracil; cryotherapy; laser ablation; conization by diathermy loop, laser or scalpel; radiation; and hysterectomy. A report of cervical biopsy alone was not considered a treatment, and participants who reported such were included in the analysis. Statistical Methods We compared participants whose cervical lesions regressed with participants whose lesions did not regress to a normal Pap smear in terms of their demographic, immunologic, and virologic characteristics at the time of the incident cytologic lesion. Continuous variables were compared using Wilcoxon tests, and discrete variables were assessed using chi-squared tests. All statistical tests were two-sided. We characterized the rate of cytologic regression using a person-time approach. Specifically, follow-up time began with the first visit after the incidence of a cytologic lesion and continued until the event of interest (cytologic regression) or time of censoring. Three analyses of the incidence of regression were conducted using Poisson regression methods, and confidence intervals (CIs) were calculated using exact methods (StatXact; Cytel Software, Cambridge, MA). First, we examined time trends in regression rates of cytologic lesions among all HIV-infected women in sequential annual calendar periods. Second, we evaluated the trends around the time an individual began HAART. The usual method of investigating this factor would be to partition person-time by whether the individual began HAART. Thus, “no HAART” time would be a combination of pre-HAART visits among women who later began HAART and visits from women who never began HAART. Because HAART was administered by primary care providers rather than as part of this observational study, there are a number of key differences between women who began HAART and women who did not. Specifically, women who initiate HAART generally have more advanced disease than those who do not begin therapy ( 18 ). Because of the challenges in capturing factors relating to initiating therapy and to minimize the bias introduced by such selection by indication, we therefore restricted the primary analysis to a comparison of incidence rates pre- and post-HAART initiation among those women who began HAART at some time ARTICLES 1071 during follow-up. Third, we conducted analyses in which person-time was partitioned by quartiles of the overall CD4 T-cell count distribution. CD4 T-cell count measurements were incorporated as a time-dependent variable and, as such, are reflective of the ongoing heterogeneity in the effectiveness of HAART. RESULTS At study enrollment there were 1243 individuals with a normal Pap smear. Of these women, 343 had an incident cytologic lesion, of which 312 had subsequent follow-up during which regression could be examined. This group of 312 women constituted the study population for this analysis. There were no differences in characteristics between the 312 women with subsequent follow-up and the remaining 31 women (data not shown). Among the 312 women, 299 had LSILs and 13 had HSILs. Cytologic regression was observed in 141 (45.2%) women, and the median time to regression was 2.7 years (interquartile range 1.0 year to more than 4.6 years). A total of 33 women were censored because they received a gynecologic treatment. A comparison of the characteristics of women whose lesions regressed and women whose lesions did not regress is shown in Table 1. At the time of detection of incident SIL there was no difference between groups by race/ethnicity, but women whose lesions regressed were younger than women whose lesions did not (36.8 versus 39.2 years; P .02). Compared with women whose lesions regressed, women whose lesions did not regress had more advanced HIV disease, including statistically significantly lower CD4 T-cell counts and higher HIV RNA levels at the time of their incident SIL (both P .001). Furthermore, a greater proportion of women whose lesions did not regress had prior ASCUS findings than women whose lesions did regress (64.9% versus 51.1%, respectively; P .02). Because the women included in our analysis had normal Pap smears at study enrollment and developed incident LSIL or worse during followup, the women with prior ASCUS had this diagnosis made subsequent to baseline. There were no statistically significant differences between the two groups of women in the prevalence of baseline HPV infection (P .15). The median time from baseline to incident cytologic lesion was 2.9 years, with no statistically significant difference between women whose lesions regressed and women whose lesions did not (P .65; data not shown). Among the 312 women in our study population, 221 began HAART during study follow-up. At the time of their incident cytologic lesion, 193 women had never used HAART. Of these women, 91 never began HAART and 102 began HAART subsequent to their incident lesion. The component classes of initial HAART regimens, which were similar to those reported by the WIHS population overall (data not shown), did not differ among women whose lesions regressed and women whose lesions did not. Among women who began HAART, 94.6% of all regimens consisted of two or more NRTIs in combination with at least one protease inhibitor or one NNRTI, 3.2% of all regimens consisted of one NRTI in combination with at least one protease inhibitor and at least one NNRTI, and 2.3% of all regimens consisted of ritonavir and saquinavir in combination with one NRTI and no NNRTIs. Changes in the incidence of regression among the HIVinfected women over calendar time are shown in Fig. 1. Using this population-level approach, we found that, before July 1, 1996, the incidence of cytologic regression was 3.8% per 6-month period (five events out of 133 person-visits). After July 1, 1996, the incidence of cytologic regression increased over time, concomitant with the increased use of HAART among the cohort (Fig. 1). An unadjusted test for linear trend of these rates was statistically significant (Ptrend .002). Moreover, after adjustment for CD4 T-cell counts at each visit, the linear trend remained statistically significant (Ptrend .002). However, the rates of regression in HIV-positive women, even in the latter time periods, remained lower than the overall rate of regression among the 27 HIV-negative women (i.e., 16 events out of 84 person-visits, 19.0% per 6-month period). Incidence rates of cytologic regression per year before and after beginning HAART are shown in Table 2. The denominator for these rates is the respective number of person-years contributed before and after beginning HAART. Overall, there were no instances of cytologic regression in the pre-HAART period (i.e., before HAART initiation), although more than 160 person-years were contributed. However, the rate of cytologic regression among women in the post-HAART period (i.e., after HAART initiation) was 12.5% (95% CI 9.9% to 15.1%), and the likelihood of regression was dose-dependently associated with CD4 T-cell count (Ptrend .002). This statistically significant trend for increasing regression rates with higher CD4 T-cell counts persisted after adjusting for age at incident SIL. For example, the regression rate was 7.9% (95% CI 5.3% to 11.7%) among women with CD4 T-cell counts of less than 200 cells/ L and 17.0% (95% CI 10.9% to 26.5%) among women with CD4 T-cell counts of greater than or equal to 500 cells/ L. Similar results were noted when we limited the analysis to individuals with low-grade lesions and excluded the 13 individuals whose incident lesion was considered high-grade or above. Furthermore, there was also an inverse dose–response association between HIV RNA levels and the likelihood of regression; specifically, regression rates associated with viral loads of less than 400 copies/mL, 400 –20 000 copies/mL, and greater than or equal to 20 000 copies/mL were 17.2% (95% CI 11.9% to 24.6%), 13.3% (95% CI 9.6% to 18.5%), and 8.3% (5.4% to 12.6%), respectively. Only a small subset of women did not begin HAART during study follow-up. It is not surprising that this number is relatively low because cytologic abnormalities are often associated with levels of immunosuppression that fall within the guidelines of HAART initiation. The median CD4 T-cell count was 204 cells/ L for women who began HAART and 326 cells/ L for women who did not (data not shown). Among the latter group, the rate of cytologic regression per year was 23.2% (95% CI 17.6% to 30.6%). There was an association between CD4 T-cell count and regression, with regression rates ranging from 11.1% (95% CI 4.7% to 26.0%) for women with CD4 T-cell counts of less than 200 cells/ L to 33.3% (95% CI 21.3% to 52.1%) for women with CD4 T-cell counts of greater than or equal to 500 cells/ L (Table 3). It is of note that regression rates for these women were higher than rates for those in the postHAART era, supporting our previous observations ( 18 ) of a major selection by indication for HAART initiation, i.e., individuals who were selected to remain HAART-naive were the healthiest, with the least advanced HIV disease in our study population. Moreover, when we collapsed person-years contributed by women who never began HAART with pre-HAART time contributed by women who began HAART, regression rates were similar to those of women in the post-HAART period. This result is likely due to the strong association between CD4 T-cell count and both HAART initiation and the incidence of an abnormal Pap smear. DISCUSSION HIV-related immunosuppression has been shown to alter the clinical course of HPV and SIL by increasing the likelihood of viral persistence and lesion progression, respectively ( 19 –21 ). Although HAART has lowered the incidence of various opportunistic diseases associated with immunosuppression, its possible impact on cytologic lesions is unclear and, to date, has been addressed in only a few studies ( 22–24 ). In this study, which was based on a large cohort of HIVinfected women followed prospectively since 1994, we found that, after controlling for level of immunosuppression, the probability of cytologic regression was greater after HAART initiation than before HAART initiation. In fact, whereas there were no instances of cytologic regression before HAART initiation, regression rates were higher than 10% after beginning HAART. These data suggest that the duration of a cytologic lesion is shorter for women who take HAART than for women who do not, although it is essential to note that, even in the post-HAART period, the majority of lesions did not regress. Among those lesions that did regress to normal cytology, the average duration of cytologic abnormalities was nearly 3 years. By comparison, the likelihood of regression among HIV-negative women was high, with 16 (approximately 59%) of the 27 women with incident LSIL or worse regressing to normal. ARTICLES 1073 Because the WIHS continues to ascertain longitudinal CD4 T-cell count measurements, we were able to incorporate the heterogeneity of the effect of HAART by modeling CD4 T-cell counts in a time-dependent fashion and examining sequential person-visits contributed at different levels of immunosuppression. We applied an “intent to remain on treatment” assumption; thus, our estimate of the effect of HAART may be an underestimate because some women discontinued therapy or were noncompliant with their HAART regimen. Indeed, it should be noted that between October 1996 and September 1999, only a minority of women switched to a non-HAART regimen (10.0%) or discontinued HAART (6.7%) ( 25 ). The frequency of switching among HAART regimens, however, was very common ( 26 ). Models that use post-HAART initiation data and allow for switching or discontinuing HAART regimens are complicated by biases inherent in the fact that individuals who alter therapies after initiation are different from those who remain on prescribed regimens ( 25,26 ). Because such selection biases are an inherent challenge to using observational data to understand treatment effects (27), one active field of investigation is focused on using more comprehensive models, such as causal models ( 28 ). We took a different approach in which we examined trends at the population level and linked such trends to changes in exposures (Fig. 1). Although this approach is subject to ecologic distortion, the observation that SIL regression rates decreased as the use of HAART increased is highly suggestive of an association between HAART and the course of cytologic lesions. Our findings confirm and extend our previous observations that linked HAART use to the likelihood of short-term, 6-month cytologic regression ( 22 ). In our previous study, the odds of regression to any lower grade lesion were 40% greater among individuals using HAART than among individuals not using HAART. This pattern of higher regression rates for women using HAART was also observed when high-grade lesions were examined separately. Since the publication of these findings, two additional studies ( 23,24 ) have examined longitudinal patterns of HPV infection and cytologic lesions in the context of women who use HAART. Heard et al. (23) found that 67 (39.9%) of 168 women had low-grade SIL that regressed to a lower grade abnormality and that the likelihood of regression was doubled for women receiving HAART. Similar to the results reported by Minkoff et al. ( 22 ), regression rates increased in individuals who used HAART, regardless of lesion grade. A major strength of the analysis by Heard et al. ( 23 ) was the availability of histologic specimens to ascertain cervical disease status. Unlike our results and those of Minkoff et al. ( 22 ) and Heard et al. ( 23 ), a recent Italian study of 163 women found no association between HAART and the regression of cytologic lesions ( 24 ). Furthermore, HAART affected neither the persistence of high-risk HPV infection nor the incidence of higher grade lesions, defined as either a new lesion or progression. Participants in the study were followed for 15.4 months, and the outcomes of interest were assessed at baseline and at a single follow-up visit. The sample size for the analysis of cytologic regression was, however, relatively small. Only 43 subjects had a cytologic lesion at baseline and could subsequently be evaluated for regression, and only 74 subjects used HAART among all 163 participants. Additional studies are needed to fully resolve questions regarding the role of HAART on cervical disease. HAART has dramatically changed the outcome of HIV infection and the clinical course of many of its commonly associated conditions. Analyses of data from the WIHS ( 29 ) and a large international collaborative study involving more than 45 000 individuals ( 30 ) evaluated the risk of specific cancers before and after the introduction of HAART and found statistically significant declines in the risk for Kaposi’s sarcoma (P .03) and, to a lesser extent, for non-Hodgkin lymphoma (P .06), although not for cervical cancer. Much attention is currently focused on gaining a better understanding of the mechanisms leading to these reduced incidence rates, with immunosuppression believed to play an important role. Our study has several limitations. We used longitudinal cytologic specimens to assess cervical disease rather than colposcopy and histologic samples. We cannot exclude the possibility that negative cytology may mask persistent histologic disease or that abnormal cytology may reflect non-neoplastic changes. It should be emphasized, however, that all smears were read by two trained cytotechnologists with expertise in cervical cytology at a well-established central laboratory. The cytotechnologists were blinded to any identifying information from participants. Therefore, there is no reason to believe that any misclassification that occurred was differential according to HAART use. Furthermore, random misclassification of cervical disease status would only dilute estimates of the effect of HAART. To address potential non-differential misclassification, we applied a conservative outcome measure, i.e., regression was defined by two consecutive normal Pap smears rather than only one. Despite the use of incident SIL to measure duration of lesions, there is evidence that even these estimates are imprecise, as suggested by the very high incidence of ASCUS before diagnosis of SIL, indicating that at least some lesions may have occurred earlier than estimated using a diagnosis of SIL, given the limitations of cytopathology. Finally, because the majority of abnormal smears in our analysis were low-grade and we had no concomitant biopsy results, it is possible that our results reflect an effect of HAART on HPV expression rather than on oncogenic or premalignant processes. However, an effect of HAART on viral persistence would be meaningful in itself because the persistence of HPV is generally recognized as the first and most crucial step in cervical oncogenesis. Notwithstanding these challenges in using cytologic specimens to study questions of cervical disease, a core advantage to their use is that Pap smears are routinely obtained from all subjects at all visits and on the same day that other biologic specimens and patient data are collected. This temporality is an important concern in the WIHS. Cervical lesions are often transient and, especially in the era of HAART, the immune status of a patient may change, making it essential that HIV status, CD4 T-cell count, HIV RNA level, and HAART data be collected concurrently with diagnoses of cervical pathology. The use of cytologic endpoints for epidemiologic research purposes is consistent with another large, well-established, prospective cohort study of HPV and cervical disease ( 31 ). Although histology is the clinical gold standard from a research perspective, cytology and histology both present problems regarding diagnostic accuracy, because it has been repeatedly demonstrated that inter-rater agreement is only fair to good with either approach, even among expert pathologists ( 32 ). It should be noted that HPV infection is another important endpoint of interest with respect to cervical disease. Additional studies to 1074 ARTICLES elucidate the effect of HAART on HPV natural history will necessitate the inclusion of the larger subset of women who did not have incident SIL and will also require a different analytic approach that accounts for the fact that multiple, concurrent type-specific infections are common, especially among HIVinfected women. We believed that it was most appropriate to address the question of the effect of HAART on HPV infection separately and therefore focused this study on the clinically relevant consideration of the effect of HAART on cervical disease because it has a unique epidemiology that is of interest. Because HAART was introduced relatively soon after WIHS recruitment, there was limited follow-up time from the preHAART era. Consequently, it is possible that there was insufficient observed follow-up during which an incident lesion could resolve and that, with extended follow-up, additional preHAART regressions would have been noted. To investigate whether this was the case, we examined regression rates among the 275 women with prevalent LSIL or worse at baseline (data not shown). Consistent with the observations for incident cases, there were no regression events before the introduction of HAART. In summary, we found that individuals who began HAART during follow-up had a higher risk of cytologic regression than individuals who did not. These findings underscore the importance of ensuring that women who are immunosuppressed have full access to antiretroviral therapy. It should be emphasized, however, that HIV-infected women on HAART must still receive careful gynecologic follow-up and close routine monitoring. Furthermore, additional studies are needed to comprehensively examine how HAART impacts the incidence of cervical abnormalities and the persistence of high-risk HPV infections. ARTICLES 1075 NOTES Data in this manuscript were collected by the Women’s Interagency HIV Study (WIHS) Collaborative Study Group with the following centers (principal investigators): New York City/Bronx Consortium (Kathryn Anastos); Brooklyn, NY (Howard Minkoff); Washington DC Metropolitan Consortium (Mary Young); The Connie Wofsy Study Consortium of Northern California (Ruth Greenblatt, Phyllis Tien); Los Angeles County/Southern California Consortium ARTICLES (1) Massad LS , Riester KA , Anastos KM , Fruchter RG , Palefsky JM , Burk RD , et al. Prevalence and predictors of squamous cell abnormalities in Papanicolaou smears from women infected with HIV-1. Women's Interagency HIV Study Group . J Acquir Immune Defic Syndr 1999 ; 21 : 33 - 41 . (2) 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 . 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Interobserver reproducibility of cervical cytologic and histologic interpretations: realistic estimates from the ASCUSLSIL Triage Study . JAMA 2001 ; 285 : 1500 - 5 . (Alexandra Levine); Chicago Consortium (Mardge Cohen); Data Coordinating Center (Stephen J. Gange , Alvaro Mu n˜oz) . The WIHS is funded by Public Health Service Grants U01 -AI- 35004 , U01 -AI- 31834 , U01 -AI- 34994 , U01 -AI- 34989 , U01 -AI- 34993 , and U01-AI42590 from the National Institute of Allergy and Infectious Diseases; U01- HD-32632 from the National Institute of Child Health and Human Development; and M01-RR00079 and M01-RR00083 from the National Center for Research Resources; by supplemental funding from the National Cancer Institute, the National Institute on Drug Abuse, and the National Institute of Dental and Craniofacial Research, National Institutes of Health; and by the Centers for Disease Control and Prevention; all from the Department of Health and Human Services . Manuscript received May 1 , 2003; revised May 5 , 2004 ; accepted May 18, 2004 .


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Ahdieh-Grant, Linda, Li, Rui, Levine, Alexandra M., Massad, L. Stewart, Strickler, Howard D., Minkoff, Howard, Moxley, Michael, Palefsky, Joel, Sacks, Henry, Burk, Robert D., Gange, Stephen J.. Highly Active Antiretroviral Therapy and Cervical Squamous Intraepithelial Lesions in Human Immunodeficiency Virus–Positive Women, JNCI: Journal of the National Cancer Institute, 2004, 1070-1076, DOI: 10.1093/jnci/djh192