Hormonal Contraceptive Use and the Effectiveness of Highly Active Antiretroviral Therapy

Jaclyn H. Chu1, Stephen J. Gange1, Kathryn Anastos2, Howard Minkoff3, Helen Cejtin4, Melanie Bacon5, Alexandra Levine6 and Ruth M. Greenblatt7

1 Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD
2 Montefiore Medical Center, New York, NY
3 Department of Obstetrics and Gynecology, Maimonides Medical Center and SUNY Health Sciences Center at Brooklyn, New York, NY
4 Cook County Hospital, Chicago, IL
5 Georgetown University Medical Center, Washington, DC
6 Keck School of Medicine, University of Southern California, Los Angeles, CA
7 Departments of Medicine and Epidemiology, University of California at San Francisco, San Francisco, CA

Reprint requests to Dr. Stephen J. Gange, Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, 615 North Wolfe Street, Room E-7638, Baltimore, MD 21205 (e-mail: sgange{at}jhsph.edu).

Received for publication January 27, 2004. Accepted for publication July 21, 2004.


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
The role of hormonal contraceptive use in the effectiveness of highly active antiretroviral therapy (HAART) was examined among participants in the Women's Interagency HIV Study who were followed from HAART initiation to 2001. Propensity score selection was used to match 77 hormonal contraceptive users with 77 nonusers on age, race, and pre-HAART CD4-positive T-lymphocyte (CD4+ cell) count and viral load. The authors compared hormonal contraceptive users and nonusers with regard to the CD4+ cell count and viral load responses to HAART upon initiation. Proportional hazards analyses were used to assess the effect of hormonal contraceptive use on times to increases in CD4+ cell count of 50 cells/mm3 and 100 cells/mm3 and achievement of an undetectable viral load. There were no statistically significant differences in CD4+ cell counts and log viral load responses by hormone use after HAART initiation, except in log viral load at the third visit after initiation (p = 0.047). Time-dependent hormonal contraceptive use was not a statistically significant predictor of achieving increases in CD4+ cell count of 50 cells/mm3 and 100 cells/mm3 or an undetectable viral load (p = 0.517, p = 0.751, and p = 0.218, respectively) after HAART initiation. In conclusion, the authors did not find substantial evidence that use of hormonal contraceptives strongly affected responses to HAART.

antiretroviral therapy, highly active; contraceptives, oral, hormonal; HIV; hormones; levonorgestrel; medroxyprogesterone 17-acetate


Abbreviations: HAART, highly active antiretroviral therapy; HIV, human immunodeficiency virus; NNRTI, nonnucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; WIHS, Women's Interagency HIV Study


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Since the advent of highly active antiretroviral therapy (HAART) in 1996, numerous studies have proven the effectiveness of these regimens in reducing mortality and morbidity among human immunodeficiency virus (HIV)-infected persons in the United States (1Go–7Go). However, the degree of clinical success experienced by persons initiating HAART varies at the individual level and may be explained by a wide variety of biologic and behavioral factors that influence response to these drugs. While the immunologic changes associated with HAART have been increasingly characterized (8Go–14Go), the role that hormones may play in response to HAART is not as well understood.

The female sex hormones, estrogen and progesterone, may influence immune responses to HIV infection and disease progression (15Go, 16Go). Numerous studies have found that estrogen can stimulate both antibody- and cell-mediated immune responses, by increasing and/or suppressing certain levels of cytokine expression (17Go–20Go). Various studies have also suggested that progesterone may induce antibody-mediated responses (21Go, 22Go), and one study involving HIV-infected pregnant women suggested that progesterone may inhibit HIV replication by enhancing the efficacy of zidovudine (23Go).

While many studies have evaluated the impact of oral contraceptive use on the risk of HIV infection, the published literature on exogenous hormone use and HIV transmission has been inconsistent (20Go, 24Go–34Go). The effects of contraceptives containing estrogen and/or progesterone on disease progression and the host response to HAART have been far less well examined, and the specific biologic interactions of these hormones with the immune system are still unclear. A study by Clark and Bessinger (35Go) found that hormone replacement therapy was marginally associated with a lowered risk of death from all causes among a small number of older women with HIV infection (relative risk = 0.28; p < 0.06). While these findings may be related to better access to health care, they also suggest that hormones influence the immunologic response to HIV infection.

Our specific aim in this study was to determine whether there is an association between hormonal contraceptive use and immunologic and virologic responses to HAART. We evaluated these responses to HAART using data from the Women's Interagency HIV Study (WIHS), a large, ongoing prospective cohort study of HIV-infected and high-risk HIV-negative women in the United States.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Study population
The methods used in the WIHS have been described in detail previously (36Go), and only methods relevant to this analysis are presented here. The WIHS protocol was approved by the Committee on Human Research at the Johns Hopkins Bloomberg School of Public Health. The original recruitment of WIHS participants occurred between October 1994 and November 1995. A total of 2,059 HIV-positive women and 569 HIV-negative women were enrolled through six US clinical consortia (23 sites). Women selected for this analysis included HIV-seropositive WIHS participants who initiated HAART during enrollment in the WIHS. HAART was defined using 1997 US Department of Health and Human Services guidelines and includes any one of the following therapies: 1) two or more nucleoside reverse transcriptase inhibitors (NRTIs) in combination with at least one protease inhibitor or one nonnucleoside reverse transcriptase inhibitor (NNRTI); 2) one NRTI in combination with at least one protease inhibitor and at least one NNRTI; 3) a regimen containing ritonavir and saquinavir in combination with one NRTI and no NNRTIs; or 4) an abacavir-containing regimen of three or more NRTIs in the absence of both protease inhibitors and NNRTIs (37Go).

WIHS visits are structured around a calendar-based system, in which participants are scheduled for one visit during each 6-month calendar period (April–September and October–March). Women who reported being pregnant or who had a positive urine pregnancy test during the study period were censored from the analysis after the reported pregnancy. Women who reported menopause, ovarian surgery, bilateral oophorectomy, hysterectomy, or having had no menstrual period for 12 consecutive months were also censored from the analysis after the corresponding event was first reported. Women with missing visits were allowed to contribute data for the visits attended, which were classified according to the corresponding WIHS visit number. After all of the selection criteria were applied, 1,112 women were eligible to contribute data to the analysis.

Data collection and study variables
Biologic specimens were collected at 6-month intervals, along with the administration of a standardized and detailed interview at each visit. Quantification of plasma HIV type 1 (HIV-1) RNA was performed using an isothermal nucleic acid sequence-based amplification method (NASBA/Nuclisens; Organon Teknika, Durham, North Carolina) with a lower limit of detection of 80 copies/ml from a 1.0-ml sample input. Levels of CD4-positive T-lymphocytes (CD4+ cells) were measured using standard flow cytometry in participating laboratories of the National Institute of Allergy and Infectious Diseases Flow Cytometry Quality Assessment Program (38Go).

Exposure to hormonal contraceptives was defined as any reported use of an oral contraceptive, depo-medroxyprogesterone acetate, or levonorgestrel subcutaneous implants during the pre-HAART time period, which was defined as the visit of first reported HAART use and the two visits prior to that. Additional baseline variables included race, age at HAART initiation, prior pregnancy, time of the first HAART visit, HIV transmission risk, hepatitis C virus infection, prior use of non-HAART antiretroviral therapy, acquired immunodeficiency syndrome status, illicit drug use, HIV-1 viral load, CD4+ cell count, education, income, and use of health-care services.

Baseline HIV-1 RNA levels and CD4+ cell counts were identified as the maximum value that was reported among the three visits of the defined pre-HAART time period. Drug use was defined as any reported use of marijuana/hashish, crack, cocaine, heroin, methadone, or amphetamines during the pre-HAART period, even if inconsistent use was reported across visits. Baseline education was defined as the maximum reported level of educational achievement, and baseline income was defined as the lowest reported level of annual monetary earnings during the pre-HAART period. Reported number of visits to a doctor's office, hospital clinic, emergency room, prison, drug treatment clinic, nursing home, mobile clinic, and/or other clinic was used as a surrogate marker for access to health-care services at baseline.

Statistical analysis
Propensity scoring.
The propensity score method was developed by Rosenbaum and Rubin (39Go) as a means of combining the effects of all observed covariates into one composite score and determining the probability of exposure with respect to these background characteristics (40Go). This method is statistically valid and is particularly useful in observational studies, where the number of naturally occurring demographic and behavioral differences between the exposed and unexposed groups might be large, relative to the sample size (41Go). The use of propensity score matching in this analysis to determine the independent effect of exposure (hormonal contraceptive use) on the observed outcomes was considered to be a robust method of balancing and thus adjusting for observed covariates, given the large number of observed covariates, the limited number of participants in our analysis, and the desire to avoid bias introduced by incomplete covariate matching.

Persons with missing baseline data were dropped from the analysis; this resulted in a total of 695 eligible women. Given the large number of variables used in generating the propensity scores, this considerable drop in the number of eligible participants was anticipated. Propensity scores were constructed using multiple logistic regression methods to estimate the probability of exposure to hormonal contraceptives on the basis of values for selected baseline covariates, which included: age, race, prior pregnancy, time of first HAART visit, HIV transmission risk, hepatitis C infection, prior use of non-HAART antiretroviral therapy, acquired immunodeficiency syndrome status, illicit drug use, viral load, CD4+ cell count, education, income, and use of health-care services.

Hormonal contraceptive users and nonusers were matched on propensity scores using a stratification method, in which four strata were created based on propensity score distributions. Stratum-specific t tests were performed to determine any statistically significant differences in propensity scores between hormonal contraceptive users and nonusers. On the basis of the p values from these tests, the mean propensity scores within each stratum were found to be statistically similar, except in stratum 1 (p = 0.001), which included propensity scores ranging between 0.01 and 0.15. A nearest-neighbor approach was used for this stratum, whereby we selected the unexposed persons with the propensity score that was closest to the score of each exposed individual. Random sampling was used for the statistically similar strata.

The baseline demographic characteristics of hormonal contraceptive users and the two unexposed groups (all nonusers, propensity score-selected nonusers) were compared using t tests, {chi}2 tests for heterogeneity, and nonparametric median tests.

Evaluation of HAART effectiveness.
We performed t tests to compare mean CD4+ cell counts and (geometric) mean log viral loads between hormone users and nonusers at the visit of HAART initiation and at each visit after HAART initiation. Because of smaller numbers of observations at each subsequent visit after HAART initiation, these values were reported up to the sixth visit after HAART initiation. Varying observation numbers at each visit reflect missing or uncollected data among various study participants at those respective visits. To control for any initial discrepancies in the baseline values between exposure groups, we performed t tests to compare the mean changes in CD4+ cell count and log viral load between hormone users and nonusers, from the closest visit prior to HAART initiation to each post-HAART visit. Similar comparisons were made using mean percent changes in these outcome markers, because the significance of absolute differences in markers may vary according to the baseline level.

Twenty women were excluded from the time-to-event analyses because of lack of follow-up data after HAART initiation; however, 65 exposed women and 69 unexposed women were still observed. The measured outcomes for this analysis included the times to 1) an increase in CD4+ cell count of at least 50 cells/mm3, 2) an increase in CD4+ cell count of at least 100 cells/mm3, and 3) an undetectable viral load. Kaplan-Meier survival curves and univariate Cox proportional hazards models were used to assess the impact of hormonal contraceptive use on the three outcomes. Deviations from proportionality were checked using standard methods (i.e., interactions of exposure variables with time).

Secondary analysis was performed to determine whether the study group made significant changes in hormonal contraceptive use throughout the observation period. Subsequently, hormonal contraceptive use was assessed as a time-dependent exposure using a Cox proportional hazards model for each of the three outcome variables. Time-varying HAART use after initiation was also accounted for in the models.

The time-to-event analyses were reassessed using a different method to define hormonal contraceptive exposure, which accounted for the duration of hormone use during the pre-HAART time period. The duration of exposure was defined categorically as 1) no reported pre-HAART hormonal contraceptive use, 2) reported hormone use at only one of the three pre-HAART visits, 3) reported hormone use at two visits, and 4) reported hormone use throughout the entire pre-HAART time period. Kaplan-Meier and Cox proportional hazards analyses were performed using this exposure variable.


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
A total of 695 women, 77 hormonal contraceptive users and 618 nonusers, were compared prior to propensity score matching. Of the 77 hormonal contraceptive users, 64 percent used oral contraceptives, 27 percent used depo-medroxyprogesterone acetate, 4 percent used levonorgestrel subcutaneous implants, and 4 percent used a combination of oral contraceptives and depo-medroxyprogesterone acetate during the pre-HAART period. Table 1 displays the distributions of baseline demographic characteristics by hormonal contraceptive use, including p values from comparison tests. In this study, the majority (79 percent) of women initiated HAART with a regimen that included a protease inhibitor and no NNRTIs; there was no significant difference between hormonal contraceptive users and nonusers. Because of the statistically significant differences in race, age, HIV transmission risk, hepatitis C infection, and baseline CD4+ cell levels between hormonal contraceptive users and nonusers, selection by propensity scores was used to generate similar distributions of, and thus a means of controlling for, these baseline characteristics by the exposure of interest. The resulting distributions of propensity scores by hormonal contraceptive use are displayed in figure 1. The mean propensity score value was 0.100 among all nonusers, 0.196 for hormonal contraceptive users, and 0.198 among propensity score-selected nonusers. Furthermore, there were no statistically significant differences among any of these observed covariates after propensity score selection (table 1).


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TABLE 1. Demographic and pre-HAART* characteristics of HIV*-infected women with known dates (±6 months) of HAART initiation, by hormonal contraceptive use before and after propensity score selection of nonusers, Women's Interagency HIV Study, HAART initiation to 2001

 


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FIGURE 1. Propensity score distributions of human immunodeficiency virus (HIV)-infected women initiating highly active antiretroviral therapy (HAART), by hormonal contraceptive use and propensity score selection, Women's Interagency HIV Study, HAART initiation to 2001. Boxes represent the interquartile range (25th to 75th percentiles), with the horizontal line inside the box representing the median value. The upper and lower T-shaped lines represent upper and lower adjacent values, respectively. Dots represent outliers.

 
The mean changes (from the pre-HAART values) in CD4+ cell count and log viral load are displayed in figures 2 and 3, respectively. The trend in CD4+ cell response to HAART initiation among users and nonusers illustrates an overall positive increase, despite fluctuations in the mean values across consecutive visits (figure 2). There were no statistically significant differences in the mean CD4+ cell count or the mean change in CD4+ cell count at or after HAART initiation between hormonal contraceptive users and nonusers. No statistically significant differences in mean changes in CD4+ cell count at any visit after HAART initiation were seen in a separate analysis of only those women who had values for all observed visits, indicating that the changing sample size at each visit did not notably influence the initial results. Additionally, no significant differences were seen when assessing the mean percent changes in CD4+ cell count by hormonal contraceptive use and post-HAART visits.



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FIGURE 2. Mean increase in CD4-positive T-lymphocyte (CD4+) count for hormonal contraceptive users and nonusers who initiated highly active antiretroviral therapy (HAART), Women's Interagency HIV Study, HAART initiation to 2001. Increases in CD4+ count were calculated by subtracting the value at the most recent visit prior to HAART initiation from the value at visit k.

 


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FIGURE 3. Mean decrease in human immunodeficiency virus type 1 (HIV-1) viral load for hormonal contraceptive users and nonusers who initiated highly active antiretroviral therapy (HAART), Women's Interagency HIV Study, HAART initiation to 2001. Decreases in log HIV-1 viral load were calculated by subtracting the value at the most recent visit prior to HAART initiation from the value at visit k.

 
Nonusers of hormonal contraceptives experienced a greater drop in mean log viral load during the first two visits after HAART initiation than did users (figure 3). At the third visit after HAART initiation, the mean drop in log viral load became greater among hormone users than among nonusers. The nonusers experienced a sharp increase in viral load at the third visit after HAART initiation. Concurrently, the users experienced the largest decline in log viral load at this visit. Overall, however, there were no statistically significant differences in mean changes in log viral load between hormonal contraceptive users and nonusers, except at the isolated third visit after HAART initiation (p = 0.047). Similar results were seen when evaluating the mean percent changes in log viral load. No statistically significant differences in mean changes of log viral load were seen among only those women who had values for all visits.

Figure 4 shows the Kaplan-Meier estimates of the probabilities of achieving increases in CD4+ cell count of 50 cells/mm3 and 100 cells/mm3 and an undetectable HIV-1 RNA level. Over the study follow-up period, 69 percent of hormonal contraceptive users (n = 45) and 81 percent of nonusers (n = 56) obtained an increase in CD4+ cell count greater than or equal to 50 cells/mm3 after HAART initiation (p = 0.109). Over the entire follow-up period, 74 percent of nonusers (n = 51) and 58 percent of hormonal contraceptive users (n = 38) obtained an increase in CD4+ cell count greater than or equal to 100 cells/mm3 after HAART initiation (p = 0.058). Overall, 58 percent of hormone users (n = 38) and 64 percent of nonusers (n = 44) achieved an undetectable viral load during the observed period after HAART initiation (p = 0.529).



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FIGURE 4. Percentages of subjects achieving a) an increase in CD4-positive T-lymphocyte count of 50 cells/mm3, b) an increase in CD4-positive T-lymphocyte count of 100 cells/mm3, and c) an undetectable human immunodeficiency virus type 1 (HIV-1) RNA level after initiation of highly active antiretroviral therapy (HAART), according to use of hormonal contraceptives (HC), Women's Interagency HIV Study, HAART initiation to 2001.

 
As table 2 illustrates, the relative hazards of achieving the observed outcomes showed that hormonal contraceptive use was not a statistically significant predictor of HAART response. While hormonal contraceptive use was not a significant predictor of achieving an increase in CD4+ cell count of 50 cells/mm3 or 100 cells/mm3, the hazards estimates were qualitatively consistent with the Kaplan-Meier curves, showing that hormonal contraceptive users were slightly less likely than nonusers to achieve both CD4+ outcomes. There was no evidence that the data violated the proportional hazards assumption of the Cox model (p > 0.1 for all three outcomes).


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TABLE 2. Relative hazards for time to increases in CD4-positive T-lymphocyte (CD4+) count of 50 cells/mm3 and 100 cells/mm3 and an undetectable viral load among 134 HIV*-infected women initiating HAART* with a known date (±6 months) of initiation, Women's Interagency HIV Study, HAART initiation to 2001

 
By the fourth visit after HAART initiation, 65 percent of defined users had stopped taking hormonal contraceptives, while only 4 percent of defined nonusers had switched to taking hormonal contraceptives. Because of the extent of switching among exposure groups, we assessed time-dependent hormonal contraceptive use to determine whether the switching of exposure status altered any previous findings. After additional adjustment for time-varying HAART use, there remained no statistically significant differences in achieving an increase in CD4+ cell count of 50 cells/mm3 (p = 0.517) or 100 cells/mm3 (p = 0.751) or an undetectable viral load (p = 0.218) between hormonal contraceptive users and nonusers (table 2). As would be expected, women who continued to use HAART were almost three times more likely to experience a CD4+ cell-count increase of 50 cells/mm3 (p = 0.004), over 3.5 times more likely to achieve a CD4+ cell-count increase of 100 cells/mm3 (p = 0.001), and approximately 2.7 times more likely to achieve an undetectable viral load (p = 0.008) than nonusers.

Lastly, we assessed the duration of hormonal contraceptive use during the pre-HAART time period to determine whether there was an effect of exposure duration on the response to HAART. The relative hazards of achieving increases in CD4+ cell counts of 50 cells/mm3 and 100 cells/mm3 and an undetectable viral load indicated that duration of hormonal contraceptive use during the pre-HAART time period was not a statistically significant predictor of response to HAART (p = 0.804, p = 0.875, and p = 0.765, respectively).


    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
This study showed that HIV-infected hormonal contraceptive users and nonusers did not differ significantly in their immunologic and virologic responses to HAART. There were no statistically significant differences found when assessing exposures by baseline use of hormonal contraceptives and by time-dependent use of hormonal contraceptives. The achievement of increases in CD4+ cell count of 50 cells/mm3 and 100 cells/mm3 and an undetectable viral load after HAART initiation was found to be similar among both users and nonusers through time, which suggests that the overall effectiveness of HAART was not altered by hormonal contraceptive exposure among the women in this cohort.

The assessment of mean changes in CD4+ cell count and viral load at visits after HAART initiation revealed an aberrant response among nonusers at the third visit after that at which HAART was first reported. The sharp decline in immunologic and virologic improvement among nonusers at this visit may mask a significantly slower response to HAART among users. Although nonsignificant, the results of the Cox proportional hazards analyses support these findings, suggesting that users were less likely to achieve immunologic improvements after HAART initiation. However, the time-dependent analysis using Cox proportional hazards modeling revealed a directional difference in the relative hazard of achieving increases in CD4+ cell count of 50 cells/mm3 and 100 cells/mm3 (table 2). This suggests that, based on current and not baseline use of hormonal contraceptives, users in fact did not experience poorer improvements in immunologic response to HAART. Similarly, the relative hazard estimate of viral load from the time-dependent analysis indicates that there was no statistically significant difference in virologic response between users and nonusers upon HAART initiation.

The use of hormonal contraceptives among women in the WIHS cohort was rather limited. One suspected reason for the modest degree of hormonal contraceptive use is that women who are using condoms to prevent HIV transmission may be reluctant to use an additional method of birth control, as well as add to their already burdensome HAART regimen. Another explanation for the low use of hormonal contraceptives may be that the WIHS cohort as a whole is slightly older than the typical population of hormonal contraceptive users. The relatively modest number of hormonal contraceptive users in this cohort also has implications in limiting our statistical power and ability to rule out very small effects. We estimate that with 77 hormonal contraceptive users and nonusers and an exponential time-to-event distribution (relevant to the analysis in table 2), we would have 80 percent power to detect a relative risk of 1.6.

The use of this cohort of women may limit the generalizability of our findings to younger HIV-infected populations, in which hormonal contraceptive exposure may be more prevalent among HAART users. The fact that many WIHS participants were dropped from the analysis because of missing baseline data may have also limited the generalizability of our findings, given that injection drug use was found to be slightly higher in these women. However, the women dropped from the analysis were similar to our cohort in terms of other important characteristics, such as age, racial distribution, and education (36Go).

Unlike in a randomized study, assessment of the effect of hormonal contraceptive use on HAART effectiveness using this longitudinal study cohort required that significant measures be taken to control for various demographic and behavioral characteristics. The propensity scores were successful in matching hormonal contraceptive users and nonusers by observed baseline demographic and behavioral characteristics that were selected on the basis of published studies of factors associated with HAART effectiveness and/or hormonal contraceptive use in the WIHS (42Go, 43Go). The success of matching was also confirmed in multivariate Cox proportional hazards models, in which the relative hazard estimates for all three outcomes were not significantly altered by the inclusion of any observed covariates, including baseline CD4+ count and viral load, in the model.

There is evidence that the level of adherence to HAART is a strong indicator of the success of antiretroviral therapy in reducing viral load (44Go–46Go). We were not able to assess adherence to HAART, because these data were not initially recorded in the WIHS and only began to be collected at study visit 9. However, a study by Wilson et al. (47Go) of adherence data collected from October 1998 to March 1999 in the WIHS cohort indicated that 76.4 percent of the women who participated in the study during this time period reported adherence levels above 95 percent. Wilson et al. noted that women with lower levels of adherence were more likely to be younger, to be drug users, and to have detectable viral loads (47Go). We controlled for age, substance abuse, and baseline viral load through propensity scoring methods, which may have controlled for some potential differences in adherence between hormonal contraceptive users and nonusers. Adherence to hormonal contraceptives was also not assessed, which may have introduced some exposure misclassification bias, because of potential changes in exposure status between visits. However, changes in reported hormonal contraceptive use were accounted for using a time-dependent exposure variable in the relative hazards analysis, which revealed no statistically significant differences among any of the models.

We were unable to assess HAART regimen as a covariate, since most women during this period of the study initiated HAART with a protease inhibitor and no NNRTI. This is potentially an important confounder that should be studied further, given the varying potencies between regimens and the corresponding indications for their use. We were also unable to account for viral resistance to HAART, which has been shown to be associated with virologic failure (48Go). However, we may have partially controlled for differences in viral resistance between hormonal contraceptive users and nonusers through the inclusion of antiretroviral use prior to HAART initiation in the propensity scores, which may have placed the two groups at a similar predisposition for developing viral resistance. While we also did not assess changes in HAART regimen in this study, we did examine models with time-varying HAART and hormonal therapy use. In one study of the WIHS cohort, Kirstein et al. (49Go) reported a relatively high rate (75.9 percent) of HAART switching throughout the entire study period, indicating the importance of assessing this factor in future studies.

Our analysis was also limited by the absence of data on concurrent opportunistic infections, which may affect responses to therapy. Because of the nature of the WIHS data collection instruments, little information is collected on the clinical course of infections once they are identified. Overall, we feel that the propensity score model included most of the important factors that influence response to HAART, but we acknowledge the possibility of residual confounding by unobserved predictors.

The effect of duration of hormonal contraceptive use prior to HAART initiation on the response to HAART was shown to be negligible in this study. This may indicate that exposure to hormonal contraceptives does not have a cumulative or lasting effect on response to therapy. However, follow-up data collected over a greater number of years will be required to more adequately assess the effects of long-term exposure to hormonal contraceptives.

In summary, this study revealed an absence of association between hormonal contraceptive use and changes in both CD4+ cell count and viral load after initiation of HAART. From a public health perspective, these findings may alleviate some concerns regarding suspected negative effects of hormonal contraceptive use on the response to HAART. This information may be useful for the clinical management of sexually active HIV-infected women who wish to use hormonal contraceptives to prevent pregnancy. Health-care providers should be vigilant in counseling these women to use condoms as well, in an attempt to prevent the transmission of HIV.


    ACKNOWLEDGMENTS
 
Data in this manuscript were collected by the Women's Interagency HIV Study (WIHS) Collaborative Study Group, with the following centers and Principal Investigators: New York City/Bronx Consortium (Kathryn Anastos); Brooklyn, New York (Howard Minkoff); Washington, DC, Metropolitan Consortium (Mary Young); Connie Wofsy Study Consortium of Northern California (Ruth Greenblatt); Los Angeles County/Southern California Consortium (Alexandra Levine); Chicago Consortium (Mardge Cohen); and Data Analysis Center (Stephen Gange).

The WIHS is funded by the National Institute of Allergy and Infectious Diseases, with supplemental funding from the National Cancer Institute and the National Institute on Drug Abuse (grants UO1-AI-35004, UO1-AI-31834, UO1-AI-34994, UO1-AI-34989, UO1-AI-34993, and UO1-AI-42590). Funding is also provided by the National Institute of Child Health and Human Development (grant UO1-HD-32632) and the National Center for Research Resources (grants MO1-RR-00071, MO1-RR-00079, and MO1-RR-00083).


    References
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 

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