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HAART Reduces HPV - Influence of Adherent and Effective Antiretroviral Therapy Use on Human Papillomavirus Infection and Squamous Intraepithelial Lesions in Human Immunodeficiency Virus-Positive Women
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The Journal of Infectious Diseases March 1 2010;201:681-690
"In summary, we found that effective and adherent HAART use was significantly associated with a reduced burden of HPV infection and SILs among HIV-positive women. These protective effects may help explain why age-specific cervical cancer rates have not increased despite the greater survival of HIV-positive women during the HAART era. However, the overall public health burden of cervical cancer in HIV-positive patients could grow as this population increasingly enters older age groups, which have higher cervical cancer rates......The average prevalence of oncogenic HPV infection decreased 36% in adherent women (from 22% before to 14% after HAART initiation) and 12% in nonadherent individuals (from 24% before to 21% after HAART initiation)....adherent women had a highly significant reduction in oncogenic HPV prevalence following their initiation of HAART (odds ratio [OR] [after vs before], 0.60 [95% confidence interval {CI}, 0.44-0.81]; p=.001), whereas nonadherent HAART use was not significantly associated with a change in oncogenic HPV prevalence (Table 2). A direct comparison of rates in adherent women versus nonadherent women after HAART initiation suggested an about 30% reduction in oncogenic HPV prevalence related to adherence (OR [adherent vs nonadherent], 0.70 [95% CI, 0.48-1.01]; p=.06)......Adherent HAART use was also associated with a reduction in the incident detection rate of oncogenic HPV infection. Specifically, the rate of incident detection decreased 33%......Our major end point was oncogenic HPV-positive SILs (oncHPV+ SILs), lesions that are thought to have the potential to result in tumors. Adherent users had a significant reduction in oncHPV+ SIL prevalence after HAART initiation.....there was a significant relationship between adherent HAART use and the rate of oncHPV+ SIL clearance...which was significantly greater than the oncHPV+ SIL clearance rate observed among nonadherent women.....The average prevalence of oncogenic HPV infection decreased 20% in patients using effective HAART, from 20% before to 14% after HAART initiation, and did not decrease but actually increased slightly in those using ineffective HAART, from 22% before to 24% after HAART initiation."
Howard Minkoff,1 Ye Zhong,2 Robert D. Burk,2 Joel M. Palefsky,4 Xiaonan Xue,2 D. Heather Watts,6 Alexandra M. Levine,5 Rodney L. Wright,3 Christine Colie,8 Gypsyamber D'Souza,7 L. Stewart Massad,9 and Howard D. Strickler2
1Department of Obstetrics and Gynecology, Maimonides Medical Center and State University of New York Downstate, Brooklyn, and Departments of 2Epidemiology and Population Health, and 3Obstetrics and Gynecology, Albert Einstein College of Medicine, Bronx, New York; 4Department of Medicine, University of California, San Francisco, and 5Department of Medicine, University of Southern California School of Medicine, Los Angeles; 6Pediatric, Adolescent, and Maternal AIDS Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development and National Institutes of Health, Bethesda, and 7Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland; 8Department of Medicine, Georgetown University School of Medicine, Washington, D.C.; 9Department of Obstetrics and Gynecology, Washington University School of Medicine, St Louis, Missouri
ABSTRACT
Background. The impact of highly active antiretroviral therapy (HAART) on the natural history of human papillomavirus (HPV) remains uncertain following conflicting reports. Prior studies, however, did not consider patients' adherence to their regimens or HAART effectiveness (viral suppression).
Methods. Human immunodeficiency virus (HIV)-positive women (n=286) who initiated HAART during follow-up in a prospective cohort were assessed semiannually for HPV infection (by polymerase chain reaction) and squamous intraepithelial lesions (SILs). Adherence was defined as use of HAART as prescribed >95% of the time, and effective HAART was defined as suppression of HIV replication. The prevalence, incident detection, and clearance of HPV infection and/or SILs before versus after HAART initiation were compared (using women as their own comparison group).
Results. HAART initiation among adherent women was associated with a significant reduction in prevalence (odds ratio, 0.60 [95% confidence interval {CI}, 0.44-0.81]; p=.001), incident detection of oncogenic HPV infection (hazard ratio [HR], 0.49 [95% CI, 0.30-0.82]; p=.006), and decreased prevalence and more rapid clearance of oncogenic HPV-positive SILs (HR, 2.35 [95% CI, 1.07-5.18]; p=.03). Effects were smaller among nonadherent women. The associations of HPV infection and/or SILs with HAART effectiveness were fairly similar to those with HAART adherence.
Conclusion.Effective and adherent HAART use is associated with a significantly reduced burden of HPV infection and SILs; this may help explain why rates of cervical cancer have not increased during the HAART era, despite greater longevity.
Rates of cervical cancer and its precursors are significantly elevated in women with human immunodeficiency virus (HIV) infection and/or AIDS, compared with the general population [1-4]. It has been speculated that these rates might increase further as HIV-positive women live longer through the use of highly active antiretroviral therapy (HAART) [5]. By prolonging the lives of HIV-positive women, HAART may increase cumulative exposure to oncogenic human papillomavirus (HPV), the viral cause of cervical cancer, as well as permit longer HPV persistence and the accumulation of somatic mutations and epigenetic changes that contribute to cervical carcinogenesis. Furthermore, HIV-positive women are entering, for the first time in sizeable numbers, the age groups in which cervical cancer rates reach their peak [6].
Conversely, HAART can partially restore immune competence. The host's immune status is strongly associated with the incident detection and persistence of oncogenic HPV infection, as well as with precancerous cervical neoplasia, in HIV-positive women [7, 8]. It is of clinical and public health significance, therefore, to determine whether and to what degree HAART mitigates the effects of HIV infection on the course of HPV-related disease. Unfortunately, prior studies of HAART and HPV infection and/or cervical neoplasia have had conflicting results [9-16].
A clearer understanding of the relationship between HAART and HPV-related disease may have been obscured by the failure of prior studies to account for variations in patient adherence with HAART and variations in the effectiveness of the HAART regimen being used (eg, suppression of HIV replication). Furthermore, prior studies were often limited by concerns regarding "selection by indication"; that is, women who receive HAART from their physicians may be different in various ways (including being more infirm and less vigorous) from those who do not receive HAART, even after controlling for laboratory values, such as CD4+ T cell counts [17].
Because of the challenges in capturing factors related to the initiation of therapy, and in an attempt to minimize selection by indication, the current investigation involved a direct comparison of HPV infection and/or squamous intraepithelial lesion (SIL) rates before and after HAART initiation in women who started HAART during follow-up (using these women as their own comparison group). We then conducted formal analyses to assess the impact of patient adherence and HAART effectiveness on these outcomes.
Discussion
The effects of HAART on HPV infection and cervical neoplasia in HIV-positive women have remained uncertain [9-16]. The current study, therefore, used several design features intended to help accurately measure the changes in the natural history of HPV and cervical neoplasia that are related to HAART use. Most notably, our investigation focused on a single group of women enrolled in a long-term cohort, all of whom started HAART during follow-up (instead of using the more common practice of comparing 2 separate groups, HAART users and nonusers), and then assessed rates of HPV infection and cervical neoplasia before and after HAART initiation. By using HAART initiators as their own comparison group, the study could more directly estimate the effects of HAART (ie, by comparing results in the same women in the presence and absence of HAART) while minimizing concerns regarding selection by indication, that is, the possibility of bias due to the fact that women who receive HAART from their physicians are often sicker than those who do not receive HAART. Furthermore, the current study was the first, to our knowledge, to consider whether participants were adherent with their HAART regimens and whether their HAART regimens were effective in suppressing HIV replication.
Our results suggest that the burden of HPV infection and SILs is primarily decreased when patients are adherent with their HAART regimens or when there is strong evidence that HAART is effective against HIV infection. Specifically, HAART initiation among adherent women was associated with a significant reduction in the prevalent and incident detection of oncogenic HPV, as well as decreased prevalence and more rapid clearance of oncHPV+ SILs. Even in these adherent women, however, these associations were of moderate size, and perhaps because of this, it is notable that not every expected result was observed (eg, the incidence of SILs was not lower among adherent women compared with nonadherent women). However, the effects of HAART initiation were generally smaller and nonsignificant among nonadherent women. Fairly similar associations between HPV infection and/or SILs and effective versus ineffective HAART use were also observed.
The protective biologic effects of HAART against HPV infection and/or SILs could represent an important countervailing influence to the risk of cervical cancer that is related to longer patient survival with HAART. As mentioned above, by prolonging the lives of HIV-positive women, HAART may increase cumulative exposure to oncogenic HPV and allow accumulation of somatic mutations and epigenetic changes that can lead to cervical oncogenesis. Our data may help explain why, despite the greater survival of HIV-positive women, cancer registry data have so far failed to detect an increase in age-specific cervical cancer rates among women with HIV infection and/or AIDS during the HAART era [15, 16]. At the same time, the moderate strength of these protective effects may help explain why age-specific cervical cancer rates have also not discernibly decreased.
However, even if age-specific cervical cancer incidence rates remain stable, the overall burden of cervical cancer in the HIV-positive population is still likely to increase as this population continues to age, because older women have higher rates of cervical cancer. This could especially impact African American women because they represent a disproportionately high fraction of HIV-positive patients, and their age-specific cervical cancer rates are considerably higher than those of white women [10].
Finally, our results may help explain the variability in the findings between earlier studies of HAART and HPV infection and/or SILs. That is, HAART adherence and effectiveness should be considered in measuring the full biologic impact of HAART on HPV infection and cervical neoplasia. Differences in the results of prior studies, therefore, could reflect population differences in patient adherence and/or in HAART regimens and their effectiveness.
This investigation had several limitations that must be recognized. Although our results are most likely internally consistent (eg, reflective of the subcohort acting as its own comparison group), our data may not be entirely reflective of the WIHS or of women in other settings or countries. Also, an analysis that contrasted adherence and effectiveness by use of a composite exposure variable might have been informative by comparing, for example, pre-HAART results with those of adherent and effective, nonadherent and effective, adherent and ineffective, and nonadherent and ineffective HAART regimens. However, that was not feasible because of the sample size. Furthermore, intervention studies that compare participants before and after an intervention are susceptible to period effects, although, in the current study, this concern was mitigated by the fact that we largely observed the expected differences in HPV infection and/or SIL carriage between adherent and nonadherent women even though both groups had similar follow-up. Most importantly, although these data are strongly suggestive, we can not be completely sure how they relate to invasive cancer, because we only studied the natural history of HPV infection and SILs.
In summary, we found that effective and adherent HAART use was significantly associated with a reduced burden of HPV infection and SILs among HIV-positive women. These protective effects may help explain why age-specific cervical cancer rates have not increased despite the greater survival of HIV-positive women during the HAART era. However, the overall public health burden of cervical cancer in HIV-positive patients could grow as this population increasingly enters older age groups, which have higher cervical cancer rates.
Results
Table 1 shows participant characteristics at the visit just prior to HAART initiation, stratified by HAART adherence. No associations were observed between adherence and age, race, CD4+ cell count, number of sex partners in the past 6 months, or smoking. There were also no cross-sectional differences in the prevalence of HPV infection or cytologic abnormalities at the visit prior to HAART initiation.
We then compared oncogenic HPV prevalence rates before and after HAART initiation. The average prevalence of oncogenic HPV infection decreased 36% in adherent women (from 22% before to 14% after HAART initiation) and 12% in nonadherent individuals (from 24% before to 21% after HAART initiation). The changes related to HAART were more clearly and accurately reflected in our multivariate mixed-effects models, adjusted for covariates (see Materials and Methods). Specifically, adherent women had a highly significant reduction in oncogenic HPV prevalence following their initiation of HAART (odds ratio [OR] [after vs before], 0.60 [95% confidence interval {CI}, 0.44-0.81]; p=.001), whereas nonadherent HAART use was not significantly associated with a change in oncogenic HPV prevalence (Table 2). A direct comparison of rates in adherent women versus nonadherent women after HAART initiation suggested an about 30% reduction in oncogenic HPV prevalence related to adherence (OR [adherent vs nonadherent], 0.70 [95% CI, 0.48-1.01]; p=.06).
Adherent HAART use was also associated with a reduction in the incident detection rate of oncogenic HPV infection. Specifically, the rate of incident detection decreased 33% from a mean of 5.4/100 person-visits to 3.4/100 person-visits in adherent women, whereas in nonadherent women it decreased 9% from 6.1/100 person-visits to 5.6/100 person-visits. In multivariate frailty models, adherent HAART use (hazard ratio [HR] [after vs before], 0.49 [95% CI, 0.30-0.82]; ) but not nonadherent HAART use was associated with reduced incident oncogenic HPV detection, and the difference in incident detection rates between the 2 groups was significant (OR [adherent vs nonadherent], 0.49 [95% CI, 0.28-0.86]; ).
For analysis of HPV clearance the data proved too limited to study oncogenic HPV infection alone. Therefore, we studied clearance of any HPV (oncogenic and/or nononcogenic HPV types) and found that adherent users had marginally greater clearance of any HPV after HAART compared with before HAART (HR [after vs before], 1.28 [95% CI, 0.99-1.66]; p=.06), whereas there was no relationship with nonadherent HAART use (HR [after vs before], 1.05 [95% CI, 0.86-1.29]; p=.63).
Table 2 also shows the relationship between adherent HAART use and SILs. Our major end point was oncogenic HPV-positive SILs (oncHPV+ SILs), lesions that are thought to have the potential to result in tumors. Adherent users had a significant reduction in oncHPV+ SIL prevalence after HAART initiation (OR [after vs before], 0.40 [95% CI, 0.18-0.88]; p=.02), which was not significantly greater than the reduction observed among nonadherent patients (OR [adherent vs nonadherent], 0.68 [95% CI, 0.25-1.80]; p=.40). Although incident detection of oncHPV+ SILs was not significantly associated with HAART use, there was a significant relationship between adherent HAART use and the rate of oncHPV+ SIL clearance (HR [after vs before], 2.35 [95% CI, 1.07-5.18]; p=.03), which was significantly greater than the oncHPV+ SIL clearance rate observed among nonadherent women (HR [adherent vs nonadherent], 3.75 [95% CI, 1.43-9.88]; p=.07).
Table 3 shows the characteristics of the subcohort at the visit just prior to HAART initiation, stratified by HAART effectiveness (ie, whether HIV RNA levels were reduced >90% or to undetectable levels). The sample size is slightly smaller (n=254) than that used for the analysis of HAART adherence because of missing data. No significant differences were observed in this cross-sectional comparison. However, those with effective HAART (65%) were, on average, more likely than those with ineffective HAART (35%; p<.001) to report having been adherent during follow-up (and vice versa-in 65% of those who were adherent users, HAART was effective).
The average prevalence of oncogenic HPV infection decreased 20% in patients using effective HAART, from 20% before to 14% after HAART initiation, and did not decrease but actually increased slightly in those using ineffective HAART, from 22% before to 24% after HAART initiation. In multivariate models, effective HAART was marginally associated with reduced oncogenic HPV prevalence (OR [after vs before], 0.71 [95% CI, 0.50-1.02]; p=.06) and significantly associated with the prevalence of any HPV infection (OR [after vs before], 0.72 [95% CI, 0.60-0.88]; p=.002) (Table 4). The incident detection of oncogenic HPV infection (HR [after vs before], 0.62 [95% CI, 0.38-1.02]; p=.06) and that of any HPV infection (HR [after vs before], 0.64 [95% CI, 0.46-0.92]; p=.005) were also very similar in their associations with effective HAART use.
In contrast, although ineffective HAART had a marginal association with oncogenic HPV prevalence in multivariate models (OR [after vs before], 0.79 [95% CI, 0.50-1.02]; p=.06), it had no associations with incident detection of oncogenic HPV infection or with prevalent and/or incident detection of any HPV infection. Clearance of any HPV was not associated with either effective HAART or ineffective HAART.
Table 4 also shows the relationship between HAART effectiveness and SILs. The findings were fairly similar for both oncHPV+ SILs and any SILs, but only the results for any SILs, with its greater number of end points, reached statistical significance. Specifically, effective HAART was not significantly associated with reduced prevalence of oncHPV+ SILs (OR [after vs before], 0.47 [95% CI, 0.19-1.16]; p=.10) and was significantly associated with any SILs (OR [after vs before], 0.45 [95% CI, 0.25-0.80]; p=.007), whereas ineffective HAART use was not associated with prevalence of any SILs or with prevalence of oncHPV+ SILs. The data were more limited for the analysis of incident SILs (see Materials and Methods), and whereas the observed HRs were in the expected (inverse) direction, only the relationship between ineffective HAART and the incident detection of any SILs reached significance. SIL clearance, however, like SIL prevalence, had a significant association with effective HAART (HR [after vs before], 2.48 [95% CI, 1.10-5.61]; ) but not with ineffective HAART (HR [after vs before], 1.26 [95% CI, 0.53-2.99]; p=.60).
Materials and Methods
Study participants.
The Women's Interagency HIV Study (WIHS) is an ongoing prospective cohort of HIV-positive women (n=2800) and HIV-negative women (n=973) enrolled through similar sources at 6 sites (Bronx, NY; Brooklyn, NY; Chicago, IL; Los Angeles, CA; San Francisco, CA; and Washington, DC). Enrollment was initially conducted between October 1994 and November 1995, and a second recruitment cycle occurred in 2002. Details of the WIHS data collection and recruitment methods have been reported elsewhere [18]. In brief, participants underwent a semiannual visit that involved an interviewer-administered questionnaire, including a photo-assisted history of medication use, and a physical and gynecologic examination with specimen collection, including a cervicovaginal lavage for HPV DNA testing. Our current study was limited to the subset of HIV-positive women who initiated HAART during their enrollment in the WIHS and who had adequate HPV DNA data before and after starting HAART (see the statistical methods below).
Laboratory methods.
The HPV DNA assays have been described in detail elsewhere [19]. Briefly, HPV DNA was detected using L1 degenerate primer MY09/MY11/HMB01 polymerase chain reaction assays [20], which could identify >40 individual HPV types. HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 82, and 73 were defined as oncogenic, and other HPV types were considered nononcogenic [21].
Specimens for papanicolaou tests were collected using an Ayre spatula and an endocervical brush. All cervical cytologic analysis was centrally interpreted at Kyto Meridien Laboratories (New York, NY) using the 1991 Bethesda System criteria for cytologic diagnosis [22].
Statistical methods.
The data set consisted of semiannual follow-up of all HIV-seropositive women who initiated HAART while in the WIHS. Because participants acted as their own comparison group, however, the analysis was limited to individuals with adequate data before and after initiation of HAART. Specifically, the analysis was conducted among women who had at least 2 semiannual visits during the 2.5 years just prior to HAART initiation and at least 2 semiannual visits during the 2.5 years immediately following HAART initiation, with censoring once a woman missed more than a single visit. Women who did not contribute adequate data to both periods were excluded.
These criteria restricted the number of women eligible for this study, and it was understood that the subcohort would not be representative of all women in the WIHS. The goal was internal consistency-to carefully assess the same women over time in the presence and absence of HAART. Indeed, 650 HAART initiators entered the WIHS fairly close in time to when HAART became widely available in 1996 and, by definition, had insufficient "before HAART" data (ie, <2.5 years). Among those with earlier enrollment dates, only 286 (37%) of the 783 HAART initiators had adequate data both before and after starting HAART to be included in the analysis of adherent and nonadherent HAART use. More specifically, compared with all other women who initiated HAART during follow-up, the 286 women we assessed were slightly older (median age, 39 vs 37 years), more likely to be African American (61% vs 51%), and had a higher median CD4+ cell count (320 vs 262 cells/mL), on the basis of data gathered at the visit prior to HAART initiation. Nonetheless, because women acted as their own control group, the effect estimates should be an unbiased measure of the biologic impact of HAART on the burden of HPV infection and/or SILs within the subcohort.
HPV prevalence was defined as the fraction of positive results among women with adequate HPV tests (demonstrated by the amplification of ß-globin in the assay). Incident HPV detection was defined as a positive result for an HPV type that was not present at earlier visits. HPV persistence was measured as the time to clearance of an HPV type following its initial detection, with clearance defined as the first subsequent negative result. A more stringent definition of clearance based on 2 sequential negative results could not be used because of the limited data, but several prior WIHS studies [7, 23, 24] found that results were unchanged using either definition. Our analyses did, however, distinguish between HPV persistence following incident detection versus prevalent detection, which our group and others have found to be an important variable.
Consistent with prior studies [25, 26], "adherence" to the HAART regimen was defined as self-reported use of HAART as prescribed >95% of the time. More specifically, adherent women were those who reported 95% adherence for at least 2 sequential visits starting within 12 months of HAART initiation, with censoring at the visit prior to a report of a lower degree of adherence. "Effective HAART" was defined, as in other studies [27], as a reduction in HIV RNA level by >90%, or to undetectable levels, in a woman who had detectable plasma HIV RNA levels prior to HAART initiation. The change in CD4+ cell count could not be incorporated in our definition of effective HAART because these levels can have high intraindividual variability during short follow-up periods [28, 29], which, in our small data set, would have made it difficult to study temporal relationships. We considered effective HAART users to be women meeting the above definition for at least 2 sequential visits starting within 12 months of HAART initiation, with censoring at the visit prior to a report of an HIV RNA level that no longer met our definition. Using a more restrictive definition of effective HAART-namely, only undetectable HIV RNA levels-did not alter the findings (data not shown).
All women who were not categorized as adherent HAART users were considered nonadherent, and all participants who were not categorized as using effective HAART were considered to be using ineffective HAART. We did not study additional intermediate levels of adherence or effectiveness because the size of the subcohort limited our ability to further stratify our data.
To assess the effects of adherent and effective HAART use on the prevalence of HPV infection and/or SILs, we used random effects models. Incorporation of a random effect in our models controlled for the fact that the data involved repeated observations of the same women over time, as well as multiple different HPV types, and allowed estimation of the difference of interest (ie, HPV infection and/or SIL prevalence rates before and after HAART initiation) within an individual. Random effects models are 1 of the 2 types of models commonly used to analyze repeated observations of the same participants over time. The other type of models, called marginal models, assess between individual differences (eg, between women using HAART and those not using HAART-a comparison of 2 separate groups) instead of the type of within-individual comparisons of interest in the current study. Thus, random effects models are most appropriate for analysis of the current data set.
Incident detection of HPV (time to event) and time to clearance were assessed using frailty models. These models were used instead of standard Cox proportional hazards models for time-to-event analyses, because frailty models incorporate a random effect to adjust for within-participant correlation; they are the most commonly used time-to-event method that permits the comparison of women with themselves (ie, before and after HAART initiation). The time-to-event data in these models were most limited for analyzing incident SILs, because those analyses were, by definition, limited to individuals without prevalent lesions, and unlike the incident detection of HPV (which involved multiple HPV types), incident SILs had a single end point. The application of frailty models and mixed-effects models to the study of HPV natural history data was recently reviewed [30].
All models were adjusted for treatment of cervical neoplasia, using a time-dependent variable, and the CD4+ cell count at the start of each period (before HAART and during HAART). Adjustment for additional covariates had no impact on any of the findings in our study, including adjustment for variables that were associated with risk of HPV infection and SILs in prior analyses-that is, age, number of sex partners within the past 6 months, cigarette smoking, and race or ethnicity (data not shown).
Initial analyses were restricted to just the 5-year period (2.5 years before and 2.5 years after HAART initiation) that was used to select the subcohort, but this restriction did not change any of the findings in our study. Therefore, the results shown throughout this report include data from all visits of the subcohort (a total of 2,097 person-years of data).
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