Risk factors associated with inadequate Pap testing in the general population include older age,^15–21 white vs. Hispanic or black race/ethnicity,^15,16,19,21 obesity,^17,22 lower income,^15,19,20,23 lower education level,^{15,17,19–21,23,24} unemployment,²⁴ unmarried status,^15,16,18,21 lack of health insurance,^{15,18,19,21,23} and no usual source of medical care.^15,16,23 The data on the relationship between cigarette smoking and Pap screening are mixed.^{15–17,19,23}

Risk factors for inadequate Pap testing in HIV-infected women are less clear. Receiving gynecologic care at the same location as HIV care,^13,14 recent pregnancy,¹³ and history of abnormal Pap testing^13,25 have been associated with increased odds of recent Pap testing. Lower education,^25–27 younger²⁵ or older^13,26,27 age, obesity or low body weight,²⁶ intravenous drug use,^26,28 cigarette smoking,²⁶ depression,²⁷ and receiving primary care from a private infectious disease physician²⁶ have all been associated with less frequent gynecologic care. Data on the association between race/ethnicity and adequate gynecologic care in HIV-infected women are mixed.^14,26,28 CD4 count <200 cells/mm³ has been associated with decreased odds of Pap testing in multiple studies,^13,25,29 although the relationship between HIV viral load and Pap testing is unclear.^26,27,30

A dedicated nurse practitioner was available at Center for Infectious Diseases (CID) for routine gynecologic care, and patients were generally referred by their HIV providers to her for Pap tests, which were not required to occur on the same day as an HIV provider visit. Patients could also self-refer to the nurse practitioner. The primary exposure of interest was a clinic systems issue: the proportion of CID visits that occurred on Mondays, Tuesdays, and Fridays—the days when the gynecologic nurse practitioner was available for Pap test appointments. This variable was based on the percentage of visits that occurred on these days: >75%, >50% but ≤75%, >25% but ≤50%, and ≤25%. After preliminary review of the data, these categories were dichotomized to >50% vs. ≤50% of visits on days when the nurse practitioner was available. We hypothesized that women who had the majority of HIV clinic visit on days when the gynecologic nurse practitioner was available would be more likely to be adherent with Pap testing compared to women who were seen predominantly on days when she was not available.

Covariates of interest were divided into demographic and medical patient variables and provider-related variables. Demographic information collected included age, race/ethnicity, language, country of birth, employment status, marital status, education level, cigarette smoking, and any type of illicit substance abuse. Cigarette smoking and illicit substance abuse were collected from documentation in the medical record and dichotomized to active/former vs. never use. The electronic medical record was reviewed for subjects with missing race/ethnicity, country of birth, employment status, and education level. Race/ethnicity was inferred based on country of birth. Because information about immigrant status as an HIV risk factor is routinely collected, women with no documentation of immigration status and missing country of birth information were assumed to be U.S. born. ZIP code was used to approximate distance from home to clinic. Medical variables included baseline and final CD4 count and HIV viral load defined as first value during the study period, mental health diagnoses documented on the problem list of the medical record (including mood, psychotic, and cognitive disorders), prescription of antiretrovirals (ARVs) as ordered in the medical record, documentation of cervical dysplasia or cervical cancer and documentation of opportunistic infection (OI). The result of each Pap test during the study period was recorded.

Because subjects contributed up to 4½ years of follow-up, many women saw multiple providers, and, therefore, we were unable to analyze at an individual provider level for association with affected Pap testing adherence. Instead, provider gender and training were assessed. These variables were calculated as attending most visits (≥75%) with a provider of one gender or training method (general internist vs. infectious diseases trained) compared to a more mixed provider visit pattern. Participation in the Healthcare for the Homeless Program (HCH) was also recorded. Because clinic patients could potentially be homeless, at least transiently, and not enrolled in the program, this was defined as a system issue and not a demographic characteristic. The Boston University Medical Center Institutional Review Board approved the study protocol.

The mean age of included subjects was 39.3 years (Table 1). Fewer than half of the subjects were born in the United States, and 71% were black. Eighty-four women (15.3%) had no Pap test documented, and 293 (53.4%) had a Pap test during every 18 months of follow-up; 397 women (72.3%) were followed for at least 36 months. There were 31 women with Pap testing documented at an outside institution. The overall model results did not change when a sensitivity analysis was performed; therefore, these women are included in all results presented. Of 464 women (38.6%) who had at least one Pap test during the study, 179 had an abnormal Pap test result, a rate of 19.2 abnormal Pap tests per 100 person-years of follow-up.

Subjects had no Pap testing documented in 27.8% of 18-month follow-up periods. The proportion of women with Pap testing performed remained relatively constant over time, with 27.1% of subjects with no Pap testing between October 1, 2003, and March 31, 2005; 28.1% with no Pap testing between April 1, 2005, and September 30, 2006; and 28.2% with no Pap testing between October 1, 2006, and March 31, 2008. In univariate analyses, older age, Hispanic ethnicity, white race (vs. black race), U.S.-born status, unemployment, current/former drug use or cigarette smoking, and baseline HIV viral load >10,000 copies/mL and CD4 count <200 cells/mm³ were associated with increased odds of no Pap testing during 18 months of follow-up (Table 2). Documentation of cervical dysplasia was associated with decreased odds of no Pap test during 18 months of follow-up (OR 0.5, 95% CI 0.4-0.8). History of OI was not associated with likelihood of Pap testing, even when stratified by CD4 count.

Because of the concern for possible effect measure modification by abnormal Pap test result during the study, the unadjusted results were stratified by whether an abnormal Pap test result was documented (results not shown). The two strata were generally similar; therefore, the nonstratified multivariate model is presented. There were 540 subjects (98%) contributing 1181 18-month follow-up periods included in the multivariate models. Older age, white race, U.S.-born status, drug use, and baseline CD4 count <200 cells/mm³ remained significantly associated with increased odds of no Pap testing in the multivariate model (Table 2). History of cervical dysplasia was associated with decreased odds of no Pap testing, and participation in the HCH Program trended toward decreased odds of no Pap testing. Fifty percent or fewer clinic visits on days when the gynecologic nurse practitioner was available was not associated with no Pap testing in all analyses. U.S.-born status and drug use showed evidence of confounding and interaction, and an analysis stratified by U.S.-born status was performed. The change in log rate of CD4 count was substituted for baseline CD4 count and was not statistically significant; therefore, baseline CD4 count was used in the final model.

The U.S.-born women had no Pap test performed in 36.1% of 18-month follow-up periods compared to 21.0% of 18-month follow-up periods for the non-U.S.-born women (p<0.001). In the U.S.-born group, white race, unemployment, cigarette smoking, drug use, living ≥5 miles from the clinic, baseline CD4 count <200 cells/mm³, and viral load >10,000 copies/mL were associated with increased odds of no Pap testing during 18 months of follow-up (Table 3). Farther distance from home to clinic, majority of clinic visits with a male provider, and baseline CD4 count between 200 and 499 cells/mm³ trended toward an association with no Pap testing. In the foreign-born group, aged ≥50 years, Hispanic ethnicity, drug use, CD4 count <200 cells/mm³, and viral load >10,000 copies/mL were associated with increased odds of no Pap testing. Foreign-born women with documentation of cervical dysplasia had 60% decreased odds of no Pap testing in 18 months of follow-up. In the foreign-born group, aged 40–49 years old, no prescription of ARV, non-English language, and mental health diagnosis trended toward increased odds of no Pap testing.

In multivariate models adjusted for age, for the 256 U.S.-born women included in the multivariate model, white women (vs. black) had 2 times the odds of no Pap test during 18 months of follow-up (OR 2.0, 95% CI 1.3-3.1, p=0.002). Women with a baseline CD4 count <200 cells/mm³ had 1.7 times the odds of no Pap testing (95% CI 1.0-2.9, p<0.05). Although drug use initially appeared to be associated with no Pap testing, it was removed when unemployment was entered in the model for U.S.-born women (OR 2.3, 95% CI 1.0-5.0, p=0.04). For the 284 foreign-born women included in the multivariate model, age ≥50 years (OR 3.9, 95% CI 1.7-9.0, p=0.002), non-English-speaking status (OR 1.6, 95% CI 1.0-2.4, p=0.03), and drug use (OR 5.8, 95% CI 2.5-13.9, p<0.0001) were associated with increased odds of no Pap testing (Table 4). History of cervical dysplasia was associated with decreased odds of no Pap testing (OR 0.5, 95% CI 0.3-1.0, p=0.04). CD4 count<200cells/mm³ trended toward increased odds of no Pap testing (OR 1.7, 95% CI 1.0-3.0, p=0.07). In both stratified models, ≤50% of clinic visits on days when the gynecologic nurse practitioner was available was not associated with likelihood of Pap testing. Substituting change in log rate of CD4 count for the baseline values was not statistically significant in either U.S.-born or foreign-born stratified modeling.

This study involved a diverse population of HIV-infected women: 71% of the subjects were black, 53% were not born in the United States, 29% were current or former drug users per the medical record, and the majority was followed for multiple years. At least one Pap test was performed during 72% of the 18-month follow-up periods, which suggests that most women in this population undergo Pap testing at least some of the time. Although the guidelines call for annual Pap tests, a longer period was used in this study to account for the fact that many women take somewhat longer than 1 year before returning for a repeat annual Pap test.

This study suggests an association between older age, white race, U.S.-born status, and drug use with no Pap testing in 18 months of follow-up. When the relationship between drug use and U.S. born status was assessed in greater detail, it appeared that the association between drug use and no Pap testing was present only for foreign-born women, although the same association was present in the U.S.-born population in the unadjusted analysis. Although drug use was included in the U.S.-born multivariate analysis, it appeared that the association between current or former drug use and no Pap testing was related to unemployment or disabled status. It is possible that the barriers of drug use and immigrating from another country work together against routine gynecologic care. As only 13 foreign-born women compared to 148U.S.-born women had a drug use history, these results are difficult to interpret. In general, however, foreign-born women were more likely to have a Pap test in 18 months of follow-up. This is in contrast to prior studies that have shown no relationship between U.S.-born status and cervical cancer screening^15,16 or decreased likelihood of Pap testing in immigrants.^34,35 It is unclear why white race predicted inadequate Pap screening in the U.S.-born group. It is possible, however, that unmeasured confounders partially explain this association. Some prior studies have also suggested that black women are more likely than white women to have a Pap test.^15,16,19,21

Baseline CD4 count <200 cells/mm³ was associated with increased odds of no Pap testing in both stratified and nonstratified analyses, with a trend toward significance in the non-U.S.-born multivariate model. This is a concern because lower CD4 count is associated with increased risk of cervical dysplasia,^4,7,8,36 and, therefore, Pap testing is particularly important for this group. Other studies have also shown a relationship between low CD4 count and lack of gynecologic care in a diverse group of women.^13,25,28,29 As we included women who were regularly coming for HIV care, it seems less likely that these women were simply too sick to have a Pap test, although this is one possible explanation. It seems more likely that women who had a low CD4 count at the start of the study may be less concerned with their overall health or may be different in other ways from women with higher baseline CD4 counts. In addition, we had access to only the first CD4 count documented after October 1, 2003, and not nadir CD4 count, so it is likely that some of the subjects with baseline CD4 counts >200 cells/mm³ had been in care before the study period and started with a much lower nadir CD4 count, which had improved over time. Although individuals who start ARVs at CD4 counts <200 cells/mm³ have worse outcomes than those starting at higher CD4 counts,³⁷ they can still have dramatic improvements in CD4 count over time when treated. Thus, cervical cancer screening is still an important issue for this high-risk group. Further studies on the relationship between CD4 count and adherence with Pap testing, including assessment of performance status and adherence to prescribed highly active antiretroviral therapy, as well as qualitative exploration of the reasons for nonadherence in this group, may provide better understanding of this issue. In addition, even if adherence to Pap screening guidelines improves among HIV-infected women, cervical cancer risk may remain higher because HIV-infected women have lower rates of adherence with colposcopy referral after an abnormal Pap result.³⁸

We hypothesized that a systems issue, namely, the availability of the single nurse practitioner in the HIV clinic performing the majority of Pap tests, would affect which women underwent a Pap test. However, this factor, as well as other issues, such as provider training or gender, did not appear to play a role in the adequacy of Pap testing, although the single center study design limits the ability to assess systems issues in great detail. There may be differences based on individual provider practice; however many of the subjects were seen by multiple providers over time, and, therefore, we were unable to examine individual provider practice in detail.

This study had several limitations. As with any retrospective study, we could not account for patient refusal of Pap tests, provider referral patterns, and the effect of separate gynecology appointments on adherence with Pap testing. The retrospective design may also be limited by inaccuracies in data recording, which may lead to misclassification of both exposures and outcomes. It is possible that women who received gynecologic care at an outside institution were misclassified, although records were reviewed in detail to limit this possibility. It seems particularly likely that sensitive issues, such as drug abuse, are underreported in the medical record; however, any exposure misclassification would likely be nondifferential, which would bias the results toward the null, thus underestimating the true effects. Although our study population is representative of the changing face of the HIV epidemic in women, it is important to remember that this study was conducted in a safety net HIV clinic providing care to predominantly low-income and minority women, which may limit generalizability of our findings to other HIV care settings.