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The effect of highly active antiretroviral therapy on cervical cytologic changes associated with oncogenic Howard Minkoff, Linda Ahdieha, L. Stewart Massadb, Kathryn Anastosc, D. Heather Wattsd, Sandra Melnicke, Laila Muderspachf, Robert Burkg Objective Cervical intraepithelial neoplasia (CIN), a common condition among HIV- infected women, has been linked to HIV load and immune status. Highly active antiretroviral therapy (HAART) improves immunologic and virologic status. This study was undertaken to determine the relationship between HAART use and CIN.
Design Cohort study. The Women's Interagency HIV Study (WIHS) in ®ve cities in the USA (Bronx/Manhattan, New York; Brooklyn, New York; Chicago, Illinois; Los Angeles, California; San Francisco Bay area, California; Washington, District of Columbia).
Methods HIV-infected women were followed every 6 months with Papanicolaou smears and cervicovaginal lavage for human papillomavirus (HPV) DNA testing. To characterize exposures that changed over time and to capture the dynamic nature of cytologic changes, Papanicolaou smear ®ndings from each participant's consecutive visits were de®ned as a pair. We determined the proportion of all pairs that exhibited either regression or progression, according to HAART exposure, HPV results and Papanicolaou smear status. As participants could contribute multiple pairs, inferences were based on robust methods to adjust for correlated observations.
Results Women with persistent HPV infection were more likely to have progression of their lesions. After adjustment for CD4 cell count and Papanicolaou smear status, women on HAART were 40% (95% con®dence interval, 4±81%) more likely to demonstrate regression and less likely (odds ratio, 0.68; 95% con®dence interval, 0.52±0.88) to demonstrate progressionConclusions HAART altered the course of HPV disease in HIV-infected women, reducing progression and increasing regression. As HPV disease is a common sex- speci®c manifestation of HIV disease this effect of HAART would be a major additional bene®t from this modality of therapy.
& 2001 Lippincott Williams & Wilkins Keywords: HAART, HIV, human papillomavirus, squamous intraepithelial lesions From the departments of Obstetrics and Gynecology, Maimonides Medical Center and State University of New York Health Sciences at Brooklyn, New York, the aDivision of Epidemiology, Johns Hopkins School of Public Health, Baltimore, Maryland, bDepartment of Obstetrics and Gynecology, Cook County Hospital and Rush Medical College, Chicago, Illinois, cDepartment of Medicine, Monte®ore Medical Center and Lincoln Medical and Mental Health Center, Bronx, New York, the dNational Institute of Child Health and Human Development, the eNational Cancer Institute, Bethesda, Maryland, the fDepartment of Obstetrics and Gynecology, University of Southern California, the gDepartment of Pediatrics, Microbiology & Immunology and Social Medicine, Albert Einstein College of Medicine, and the hDepartment of Medicine, University of California at San Francisco, San Francisco, California, USA.
Requests for reprints to: H. Minkoff, Maimonides Medical Center, 967 48th Street, Brooklyn, New York 11219, USA.
Received: 26 January 2001; revised: 28 June 2001; accepted: 3 July 2001.
ISSN 0269-9370 & 2001 Lippincott Williams & Wilkins been described previously In brief, participants undergo visits every 6 months that include an inter- With the introduction of more effective antiretroviral view-administered questionnaire, a physical examina- therapy, the spectrum of disease in the AIDS epidemic tion, and the collection of plasma, Papanicolaou has been shifting. It is projected that 20±40% of HIV- smears, and cervicovaginal lavages for HPV testing. T- infected individuals will be diagnosed with a malig- cell subsets were determined using ¯ow cytometry in nancy One malignancy that is unique to women is laboratories participating in the AIDS Clinical Trials cervical cancer, the end stage of human papillomavirus Quality Assurance Program. Plasma HIV RNA levels (HPV)-associated cervical intraepithelial lesions. Nu- were measured using a nucleic acid sequence-based merous studies have shown that HIV-infected women, ampli®cation technique (Organon Teknika, Durham, particularly those with advanced disease, have a greatly North Carolina, USA) with a lower threshold of increased risk for the precursors to cervical cancer, both those measured by histology [cervical intraepithelial neoplasia (CIN)] and by cytology [squamous intrae- The protocol for collection of cervicovaginal lavage pithelial lesions (SIL)] Recent data have sug- specimens involved spraying 10 ml of sterile normal gested that as many as one in ®ve HIV-infected saline against the cervical os and the exocervix and women with no evidence of cervical disease will then aspirating ¯uid from the posterior vaginal fornix.
develop SIL within 3 years. These data suggest a need All specimens were frozen in aliquots at À708C. HPV to assess determinants of cytologic progression and to testing was performed in two laboratories by PCR using MY09/MY11/HB01 L1 consensus primers and a control primer set which simultaneously ampli®ed a Highly active antiretroviral therapy (HAART) regi- mens have been in clinical use since late 1995. These positive using the generic probe were re-probed to regimens have been shown to reduce HIV viral loads.
identify speci®c HPV types. For analysis, we de®ned The salutary effects of HAART on morbidity and oncogenic types as HPV-16, 18, 31, 33, 35, 39, 45, mortality and on immunologic and virologic markers 51, 52, 56, 58, 59, 68, and 73 At the time of this of HIV disease progression have been well documented analysis, HPV data was available from the ®rst three associated malignancies, particularly cervical lesions, has Papanicolaou smears were collected using a plastic Ayre spatula and an endocervical brush. Both specimens HAART has the potential to in¯uence the relationship were smeared onto a single slide and ®xed immediately.
between HIV and cervical cancer precursors in two Cervical cytology samples from all sites were centrally contrasting ways. First, by prolonging lives it may interpreted at Kyto Meridien Laboratories (New York, lengthen exposure to HPV, thereby allowing the USA) using the Bethesda System criteria for cytologic accumulation of genetic somatic mutations that increase diagnosis All smears were read by two cytotech- the likelihood of cervical disease. Conversely, because nologists who were blinded to the participants' status HAART can decrease HIV viral load, and can partially (there were also HIV-uninfected women in the WIHS restore immune competence, HAART may mitigate who are not included in this analysis). Ten percent of the effect of HIV on the course of HPV disease. To all negative smears and all abnormal smears were date, these possibilities have been assessed only in small con®rmed by a cytopathologist. Diagnoses were re- case series and the implications of antiretroviral ported as normal or benign, atypical squamous cells of therapy for cervical neoplasia are unclear. Therefore, to uncertain signi®cance (ASCUS), low-grade SIL, mod- determine if HAART can in¯uence the course of HPV erate or high-grade SIL, and cancer. Glandular ab- disease the following study was undertaken.
normalities were not included. Patients were excluded if the cervix was surgically absent.
The primary goal of our analysis was to identify whether exposure to HAART impacted rates of short- term (6 month) cytologic regression and progression.
The Women's Interagency HIV Study (WIHS) is a Given that the study assesses each participant's Papani- prospective study of the natural and treated history of colaou smear status at regularly spaced 6 month inter- HIV infection in women that enrolled 2059 HIV- vals, we were able to group consecutive smears from seroprevalent participants at six clinical consortia each individual into pairs of smears, de®ned by an (Bronx, New York; Brooklyn, New York; Chicago; index smear (at Papt) and a follow-up smear (at Los Angeles; San Francisco; Washington) between Papt‡1). We chose to utilize this analytic approach October 1994 and November 1995. The recruitment because it allowed for the full characterization of methods and data collection procedures for WIHS have exposures that change over time and as such could HAART and cervical disease Minkoff et al.
capture the dynamic nature of cytologic change individuals who had an oncognenic HPV infection (de®ned above). In addition, we compared short-term cytological progression and regression rates between There were three possible outcomes for each pair: those with and without an oncogenic HPV infection.
regression, if Papt‡1 was a lower grade abnormality Those with at least one oncogenic infection were than Papt; no change, if Papt‡1 was the same as Papt; further characterized as having 1/3, 2/3 or 3/3 onco- or progression, if Papt‡1 was a higher grade abnorm- ality than Papt. For the ®nal analysis, we compared rates of both regression and progression, prior to and subsequent to the initiation of HAART.
After determining the proportion of all pairs that exhibited 6 month cytologic change, we used logistic Papanicolaou smears that were included in the analysis regression to model the two outcomes of interest, i.e., were obtained at visits subsequent to the visits at which regression and progression, according to HAART the HPV tests were performed. We deleted pairs for exposure. As each participant could contribute more which treatment for cervical abnormalities was reported than one pair of smears, inferences were based on at the follow-up visit. At the time of the analysis, robust statistical methods that adjust for the correlation Papanicolaou smear ®ndings were available for the inherent in such repeated measures Multivariate study's initial eight biannual visits.
models accounted for CD4 cell count at well as Papanicolaou smear abnormality at the index visit (t), At each visit, participants were asked which antiretro- such that pairs of measurements were comparable with viral medications they had used since their last visit.
regard to the stage of HIV infection and of HPV- HAART was de®ned according to 1997 National associated disease. Our primary goal was to quantify Institutes of Health guidelines as two or more the impact of HAART on rates of cytologic progres- nucleoside reverse transcriptase inhibitors, with either a sion and regression. Given that the mechanism by protease inhibitor or a non-nucleoside reverse tran- which HAART operates is linked primarily to reduc- scriptase inhibitor. Those receiving two or more tions in HIV RNA levels and immune reconstitution, protease inhibitors were classi®ed as receiving it was more appropriate to include CD4 cell count in our multivariate models for the purpose of controlling for stage of disease and to determine the independent HAART usage was analyzed as the primary exposure effect of HAART on both the progression and the of interest. Pairs of Papanicolaou smears were categor- ized as off-HAART if the woman contributing those pairs never received HAART during her time in the study or, among those women who eventually were on HAART, those pairs contributed before the woman had started HAART. Pairs of Papanicolaou smears were categorized as being on-HAART if they were There were 741 women (41.6% of participants) with at obtained at any visits after HAART was ®rst given.
least one oncogenic HPV at visits one through three.
Among women who had HPV tests at all three baseline In order to be conservative, we used an intent-to-treat visits and who had at least one positive test (n ˆ 507), model. Therefore patients who at one point had been oncogenic HPV was detected at one, two, and three given HAART, and who subsequently discontinued its visits in 189 (37.3%), 145 (28.6%), and 173 (34.2%) use (n ˆ 64) were categorized as being on HAART at women respectively. Details regarding the types of any visits after HAART was ®rst given. We excluded HPV at baseline have been described previously from the analysis pairs associated with HAART initia- tion (i.e., no HAART at the start of the interval (t), but on HAART at the end of the interval (t‡1) to with and without any oncogenic HPV. The group keep the dichotomous exposure (no HAART versus with oncogenic HPV was younger and more likely to smoke, to report HIV treatment, to have SIL at baseline, to be younger at ®rst coitus, and to have more The study population for our analysis of the impact of sexual partners. This group also had lower CD4 cell HAART on short-term cytological regression and counts and higher HIV viral loads. None of these progression analysis was composed of 1779 HIV- variables were found to be associated with cytologic seropositive participants who had at least one study visit progression or regression. In addition, ethnicity and after 1 October 1995 (the approximate date at which report of a prior sexually transmitted disease were not HAART became available) and were tested for HPV infection during the 1 year following their enrollment.
The study's primary analyses were limited to those Table 1. Baseline comparison of HIV seropositive participants with and without oncogenic human papillomavirus (HPV) infection.
ASCUS, Atypical squamous cells of uncertain signi®cance; LGSIL, low-grade squamous intrae- pithelial lesion; HGSIL, moderate or high-grade squamous intraepithelial lesion; HAART, highly four categories of Papanicolaou smear status at the (39.4%) compared to pairs characterized by RNA levels index visit. As described previously, examination of of 4000±20 000 copies/ml (27.7%), 20 000±100 000 consecutive Papanicolaou smears allowed us to char- copies/ml (29.9%), and . 100 000 copies/ml (22.7%) acterize more fully the dynamic and short-term nature (P , 0.001). Cytological regression was also more likely among pairs characterized by CD4 cell counts those with and without any oncogenic HPV. Regres- . 500 3 106/l (40.7%) compared to pairs characterized sion was more frequent (P , 0.001) and progression by CD4 cell counts of 200±500 3 106/l (35.9%) and less common (P , 0.001) among women with no , 200 3 106/l (21.6%) (P , 0.001). Cytological pro- oncogenic HPV. Further, persistent HPV infection gression was less likely among pairs of measurements signi®cantly decreased regression rates and increased where the HIV RNA level at the index visit was progression rates. Among those with three measure- , 4000 copies/ml (16.4%) compared to RNA levels of ments, regression rates among those with 1/3, 2/3, and 4000±20 000 copies/ml (19.8%), 20 000±100 000 3/3 positive oncogenic HPV infections were 39.3%, copies/ml (23.4%) and . 100 000/ml (27.5%) (P , 30.7% and 24.7% respectively; overall progression rates 0.001). There was no association noted between CD4 were 16.2%, 23.6% and 24.6% respectively (P , cell count and progression; speci®cally, 17.9% of pairs with CD4 cell counts . 500 3 106/l progressed, as compared to 21.8% of pairs with CD4 cell counts Cytological regression was also more likely among pairs 200±500 3 106/l and 21.2% of pairs with , 200 3 characterized by HIV RNA levels , 4000 copies/ml HAART and cervical disease Minkoff et al.
Table 2. Changes in cervical cytologic status in consecutive pairs of Table 3. The association of highly active antiretroviral therapy measurements of HIV-seropositive participants according to initial (HAART) exposure and changes in cervical cytologic status in con- > smear ®ndings among those with and without oncogenic HPV secutive pairs of measurements according to initial Papanicolaou infection at visits one through three.
smear ®nding among HIV-seropositive participants with at least one oncogenic HPV infection at visits 1 through 3.
aAmong 1653 patients with abnormal Papanicolaou at index meas- aPercent of pairs that regress (total number of pairs). bAdjusted for urement. bAmong 951 patients with abnormal Papanicolaou at index CD4 cell count and Papanicolaou smear status at index visit. ASCUS, measurement. HPV, Human papillomavirus; ASCUS, Atypical squa- Atypical squamous cells of uncertain signi®cance; LGSIL, low-grade mous cells of uncertain signi®cance; LGSIL, low-grade squamous squamous intraepithelial lesion; HGSIL, moderate or high-grade intraepithelial lesion; HGSIL, moderate or high-grade squamous squamous intraepithelial lesion; NA, not applicable.
intraepithelial lesion; NA, not applicable.
cytological regression and decreased cytological pro- shows cytologic progression and regression gression, after controlling for stage of HIV disease and rates for each category of initial Papanicolaou smear severity of cytological disease. We also con®rmed measurement strati®ed by HAART use among women previous reports that found high rates of HPV carriage, with an oncogenic HPV detected at least once. Odds which were often persistent, among HIV-infected ratios are adjusted for CD4 cell count and Papanicolaou women. Ho reported that persistence of infection with smear status at the index visit (t). Overall, pairs of HPV was related to the risk of persistent cervical measurements were 1.4 times [95% con®dence interval dysplasia using similar methods We found that (CI), 1.04±1.82] more likely to demonstrate regression among HIV-infected women persistent carriage of on HAART. A bene®cial effect of HAART was HPV and high viral load were associated with cytologic observed on progression. Pairs of visits on HAART progression and that low viral load and high CD4 cell demonstrated a 0.68 times (95% CI, 0.52±0.8) like- count were associated with regression.
lihood of progression of disease, i.e., pairs contributed off HAART were 1.5 times (95% CI, 1.3±1.9) more HAART has been shown in clinical trials and likely to progress as compared to pairs contributed on cohort studies to be effective in lowering viral loads. These agents' antiviral effects have been shown also to be associated with clinically signi®cant bene®ts.
However, relatively little attention has been paid to the relationship of HAART to malignancies in general or to cervical disease in particular. Since the introduction of HAART, some studies have shown stable levels of Patients with HIV are at increased risk of malignancy.
non-Hodgkin's lymphoma and other cancers, and The risk of non-Hodgkin's lymphoma is more than declining rates of Kaposi's sarcoma and primary brain one hundred-fold greater and the risk of Kaposi's sarcoma several hundred-fold greater among HIV- Individual cases in which human herpes virus type 8 infected individuals Cervical cancer, the end stage (HHV-8) was cleared from peripheral blood mono- of HPV-associated squamous intraepithelial neoplasia, nuclear cells following initiation of antiretroviral ther- has also been associated with AIDS Cytologic apy have also been reported Conversely, at least screening monitors the precursors of these lesions.
one study suggested that few anal SIL regress in In this large cohort of HIV-infected women with high-risk HPV DNA, we found that the use of With particular regard to cervical disease, Heard re- HAART was associated with signi®cantly increased ported on Papanicolaou smear changes among 49 women on combination antiretroviral therapy, includ- progression was signi®cantly greater than among unin- ing a protease inhibitor Five months after therapy, fected women Massad, in an analysis of women in three out of 13 women with high-grade lesions showed this cohort has shown that progression of SIL was regression, as did nine out of 21 with low-grade linked to HIV serostatus and to viral load and CD4 cell lesions. Although these results were encouraging, the count As noted, we have also found that progres- failure to include a group with similar Papanicolaou sion and regression may be linked to immune status smear ®ndings, HPV ®ndings and HIV status who were not on therapy makes interpretation dif®cult. Orlando, in another small (n ˆ 15) observational series, noted One possible explanation for the linkage of both serostatus and immune status to malignancies may be that HIV-associated products up-regulate cell prolifera- In our cohort, the regression rate among women with tion Reduction of viral load and restoration of high-grade and low-grade lesions who did not receive host immunity thus might retard the progression of HAART were similar to, or greater than, those seen these neoplasias. This ®nding is supported by the fact among women receiving protease inhibitors in the Heard study. However, when the rates of progression presented in the odds ratios for progression and regression among women with high-risk HPV and regression decreased towards 1. It is impossible, who were on HAART were contrasted with changes however, to be certain that the association between the among similar women not on HAART, the bene®cial use of HAART and a less aggressive course of HPV effect of antiretroviral therapy became clear. These disease is mediated simply by a reduced HIV viral load results are particularly striking as women in both groups that results in less up-regulation of HPV. That were comparably at risk in terms of the presence of HAART could have a direct antiviral effect on HPV oncogenic HPV. These results were also supported by has been suggested as a possibile explanation of the lack multivariate analysis that included markers of HIV of correlation between decreases in HIV viral load and disease stage as well as other factors linked to changes regression of cytologic abnormalities in women on posited as an explanation for the clearance of HHV-8 The association between HIV disease and both HPV infections and SIL has been widely noted Sun system of the treated woman might also be better able detected HPV at an initial examination in 56% of to `control' HPV infections. Burk has shown a reduced HIV-seropositive women and 31% of HIV-seronega- rate of HPV as women age, even when controlling for tive women Minkoff reported a prevalence of the number of lifetime sexual partners suggesting oncogenic HPV in 32.5% of HIV-infected and 17.0% that there might be `acquired immunity to HPV from past exposure' This mechanism has been proposed correlation between HPV detection and low CD4 cell to explain the loss of cytomegalovirus (CMV) viremia counts and high HIV viral loads in an earlier report of following HAART therapy, even in the absence of baseline data from this cohort Other authors have speci®c anti-CMV therapy Similarly, Ahdieh, reported a similar inverse association between immune who reported that the likelihood of chronic carriage of HPV is linked to immune status, has suggested that `the reversal of immunosuppression possible in the current Several investigators have demonstrated that in addition era of potent antiretroviral therapy may reduce HPV to an increased frequency of HPV infection, there is an persistence and consequently the increased risk for increased frequency and severity of HPV-associated cervical lesions among HIV-infected women. Massad found that rates of SIL were ®ve times greater among A few limitations of this study should be acknowl- HIV-infected than uninfected women Mandelblatt, edged. The outcome measure that we used was cy- in a review of 15 studies comparing the association tology rather than histology. However, there is no between HIV, HPV and CIN found that the odds ratio reason to believe that any discordance between histol- for CIN was eight times greater for HPV-infected ogy and cytology would be linked to a patient's use of women and that there was an interaction between antiretroviral therapy (none was seen among women undergoing biopsy in this sample; data not shown).
Further, the Papanicolaou smear is the standard test The clinical course of CIN has been noted to be used to screen for cervical disease in the USA. In marked by more progression and less regression among addition, all slides were read centrally by blinded HIV-infected women Ellerbrock has recently technicians. Another limitation was including ASCUS reported that among 328 HIV-infected women with- smears in the analysis. An ASCUS result may not be a out SIL at baseline 20% developed SIL during approxi- reproducible ®nding, leading at times to spurious diag- mately 30 months of follow-up. That rate of nosis of progression or regression (e.g., a woman with a HAART and cervical disease Minkoff et al.
normal Papanicolaou that at a subsequent visit has a The authors thank M. Silverberg for technical assistance Papanicolaou read as ASCUS may not, in reality, have had a change in status). However, this would bias ®ndings toward the null; our ®ndings of signi®cant Sponsorship: The WIHS is funded by the National differences based on HAART exposure would there- Institute of Allergy and Infectious Diseases, with addi- fore be reinforced. We also recognize the possibility of tional supplemental funding from the National Cancer selection by indication In this study, however, Institute, the National Institute of Child Health and that bias would relate to the fact that women who Human Development, the National Institute on Drug were most likely to manifest progression of their HPV Abuse, the National Institute of Dental Research, the Agency for Health Care Policy and Research , and the disease would also be those most likely to be put on Centers for Disease Control and Prevention. U01-AI- HAART. If this were to occur, it would also result in 35004, U01-AI-31834, U01-AI-34994, AI-34989, U01- a bias toward the null and therefore would again HD-32632 (NICHD), U01-AI-34993, U01-AI-42590, increase con®dence in our ®nding that women receiv- ing HAART had less progression of HPV disease. A ®nal concern is misclassi®cation bias related to HAA- RT, mediated by poor patient adherence. Here again, we have bias toward the null (i.e., if a patient is categorized as taking HAART but in fact takes little or none of her medication, it would tend to dilute any 1. Goedert JJ, Cote TP, Vergo P, et al. Spectrum of AIDS-associated effect size related to therapy). That we did see a malignant disorders. Lancet 1998, 351:1833±1839.
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