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To describe the incidence and risk factors for verrucae in HIV-infected and uninfected women.
A prospective study of 1,790 HIV-infected and 772 uninfected women. Skin examinations and interviews were performed every six months over an 8-year study period. Data collected at each visit included antiretroviral therapy use since the prior visit, CD4 counts, HIV RNA loads, and location, description, and diagnosis of verrucae. Incidence rates of cutaneous and anogenital warts were determined.
Unadjusted cumulative incidence of cutaneous warts for HIV-uninfected women was 6.6%, 6.7% for HIV-infected women who initiated HAART, and 8.4% for HIV-infected, HAART-naïve women. The unadjusted cumulative incidence of anogenital verrucae for HIV-uninfected women was 9.3%, 28.4% for HIV-infected women who initiated HAART, and 25.1% for HIV-infected women who were HAART-naïve. Multivariate proportional hazard models revealed the following significant factors for the development of cutaneous verrucae among HIV-infected women: Black race (RH=0.50) and Hispanic ethnicity (RH=0.38), compared to White race. Risk factors for anogenital verrucae were: more recent recruitment (RH=0.63), HPV infection at baseline (RH=1.85), decade of age (RH=0.82), current smoker (RH=1.40), lowest CD4 count (per 100 cells/mm3) in the past 4 years (RH=0.85), and log10 higher HIV viral load at the prior visit (RH=1.34).
HIV-infected women had a significantly increased cumulative incidence of anogenital verrucae compared to HIV-uninfected women. Although HAART did not alter the risk of developing skin or anogenital warts, those with higher CD4 cell counts and lower HIV RNA had a lower risk of developing anogenital warts.
Patients with HIV-1 infection have an increased frequency and concomitance of dermatological diseases [1-4]. Among HIV-infected women, there is a 59% prevalence of nongenital skin disease [2, 5]. Previous studies of participants in the Women’s Interagency HIV Study (WIHS) reported no significant difference in the baseline prevalence of cutaneous verrucae among HIV-infected and uninfected women  while the prevalence of both oral and anogenital verrucae were found to be significantly higher among HIV-infected women [6-8].
Unlike Kaposi’s sarcoma and eosinophilic folliculitis that improve with increased host immunity and highly active antiretroviral therapy (HAART) [9-14], cutaneous warts have been observed to be clinically recalcitrant to increasing CD4 counts and improved immunity [1, 15]. However, no cohort studies have evaluated the effects of HAART on cutaneous warts.
HAART has been shown to reduce the incidence of genital warts . Although there has been conflicting data regarding treatment with HAART and HPV infections in anogenital locations, particularly regarding the persistence of HPV infection, and the regression and progression rates of cervical and anal dysplasia [17-19].
Our study objectives were to describe the incidence and risk factors, including the effect of HAART, for the development of cutaneous and anogenital verrucae in the WIHS.
The WIHS is a prospective study of HIV-1 infection in women, conducted in New York City, Washington D.C., Chicago, Southern California and the San Francisco Bay Area. The WIHS methods and baseline cohort characteristics have been previously described . Briefly, between October 1994 and November 1995, 2056 HIV-1 infected and 569 uninfected women were enrolled. A second enrollment between October 2001 and September 2002, added 737 HIV-infected and 406 HIV-uninfected women. For the second wave of enrollees, medical record abstraction was performed for participants reporting HAART use at enrollment, to determine their pre-HAART CD4 and HIV RNA counts, and to verify date of HAART initiation and regimen . Study protocols were reviewed and approved by the institutional review boards and informed consent was obtained from the participants.
Every six months, WIHS participants were interviewed and received a physical examination. Multiple gynecologic and blood specimens were collected at each visit. Interviewers assessed self-reported HAART use during the period prior to the study visit. Clinicians performed participants’ skin examinations, including genital and oral exams. The location, description, and diagnosis of verrucae were based on clinical appearance. Beginning in October 2002, the recording of oral warts changed. Due to the change in reporting method and the overall low number of events, we did not examine predictors of incidence for oral warts.
Baseline characteristics examined included HIV status, age, race/ethnicity, marital status, parity, and lifetime number of male partners. Race/ethnicity was categorized as white, African-American, Hispanic or other ethnicity. The definition of HAART was guided by the DHHS/Kaiser Panel guidelines  and categorized as ever initiated HAART use or currently on HAART. The CD4+ cell count, per 100 cells/mm3, and HIV RNA viral load, rescaled to log10 copies, were obtained from the visit prior if it occurred within 270 days. Exfoliated cells for HPV DNA testing were obtained using cervicovaginal lavage (CVL) fluid [23, 24]. HPV DNA was detected with L1 consensus primer polymerase chain reaction assays. Details of these laboratory methods have been published previously , and the results were shown to have high reproducibility, sensitivity, and specificity [24, 26, 27]. Additional variables examined for each study visit included: cigarette use, and incident self-reported diagnosis of clinical AIDS.
Participants who HIV-seroconverted during the study (N=16) were excluded from analysis. An incident event was defined as the first occurrence of either a cutaneous or anogenital wart after the baseline study visit. The time to event was the time from baseline until the visit date when the incident event occurred. Women with oral, skin or anogenital warts at baseline were excluded from incident events. Women who had multiple incident events in the same location were counted at the time of first occurrence only. The development of a verruca in one location did not exclude a participant from contributing to an incident event in another location.
For women in the original cohort, we defined a participant’s baseline visit (time=0) as the first visit that occurred post-January 1, 1996, to correspond to HAART availability. For the 2001-02 recruits, the baseline visit occurs between October 1, 2001 and September 30, 2002. Time to event in years was calculated from time=0 to presentation of an event or last date seen (maximum date March 31, 2004) for participants who did not develop warts. Unadjusted incidence rates for skin and anogenital warts were calculated using the Nelson-Aalen estimate, stratified into one of three groups: HIV-uninfected women; HIV-infected HAART-naïve women; and HIV-infected HAART initiators.
To examine predictors of incidence, univariate and multivariate Cox proportional hazard models with time-dependent covariates were used. Multivariate models were constructed by including all covariates that were considered of clinical interest.
For analyses that assessed risk factors for skin or anogenital warts, we restricted the study sample to those women who were HIV-infected. Because women with the strongest indication for antiretroviral therapy use are more likely to use it , we examined the association with therapy using a version of the marginal structural proportional hazards model . The weights were constructed at each visit by using pooled logistic regression models to estimate the probability of HAART initiation using both time-fixed and time-varying covariates, including a quadratic polynomial to model the effect of time. HAART initiation can be predicted much more reliably than current use; once a participant initiates HAART, she is treated as always exposed.
The time-varying predictors used to construct the weights for the marginal structural model were: visit, development of clinical AIDS, number of hospitalizations, crack, cocaine and/or heroin (CCH) use, HIV RNA at the prior visit, CD4+ cell count at the prior visit, and, in the prior 4 years, CD4 nadir and highest HIV RNA. The following time-fixed predictors were also used: phase of cohort enrollment, race, and baseline measurements of HPV infection, number of sex partners, smoking status (current/other) at baseline and age. The final, weighted model included only the time fixed covariates and a time-varying variable for initiation of HAART.
The covariates in these models were chosen on the basis of their ability to predict HAART initiation. Participants reporting use of CCH during the previous four years were indicated to have used CCH. Injection drug use (IDU) was coded in a similar way. The highest HIV RNA measurement (rescaled to log10) and the lowest CD4+ cell count (per 100 cells/mm3) from the past four years were also included.
By construction the marginal structural model is focused on the estimation of the effect of HAART initiation, and not useful to examine the effects of other predictors of outcome. For this purpose we used an additional conventional proportional hazards model, including an additional time-varying covariate for injection drug use, an additional risk factor for incidence of skin warts.
A total of 1,790 (70%) HIV-infected and 772 (30%) HIV-uninfected women were evaluated for verrucae over 8 years of study follow-up. Baseline characteristics for each analytic group are provided in Table 1.
The unadjusted cumulative incidence of cutaneous warts over the 8-year study period for HIV-uninfected women was 6.6% (95% confidence interval [CI] 3.8-9.3%), 6.7% (95% CI 4.6-8.8%) for HIV-infected women who initiated HAART, and 8.4% (95% CI 4.5-12.3%) for HIV-infected women who were HAART-naive.
In both the weighted univariate model and the marginal structural model, the HAART initiator variable was highly non-significant for risk of skin warts. Results from the conventional proportional hazard model, which was run as a check, also found the HAART exposure variable to be non-significant, whether HAART was classified as current HAART use or HAART initiation.
The effects of the remaining covariates were examined in a conventional (non-weighted) proportional hazards regression model. Both black and Hispanic women had significantly less risk than whites (Table 2), and there was a suggestion that CCH use during the last four years was also a risk factor.
After 8 years of follow-up, the unadjusted cumulative incidence of anogenital verrucae for HIV-uninfected women was 9.3% (95% CI 6.3-12.2%), 28.4% (95% CI 21.7-34.5%) for HIV-infected women who initiated HAART, and 25.1% (95% CI 18.4-31.2%) for HIV-infected women who were HAART-naive.
For the marginal structural model and the conventional proportional hazard model assessing the risk of anogenital warts, HAART initiation was not significant. The HAART exposure variable was also non-significant for the univariate model and for the conventional model with current HAART use as the exposure variable.
In the conventional proportional hazards model (Table 2), HPV infection was a highly significant predictor of incident anogenital warts. There was some evidence that more than 50 sex partners was also a risk factor. Increasing age was protective, while current smoking was an additional risk factor. Finally, nadir CD4 cell count, and current viral load were highly significant risk factors.
Verrucae were diagnosed more frequently and the 8-year unadjusted incidence rate of anogenital verrucae was higher in HIV-infected participants compared to HIV-uninfected participants.
We applied a statistical approach that only recently has been used for controlling confounders in studies of HIV/AIDS. We were able to reduce bias due to selection by indication by constructing weights (also known as propensity scores) based on prediction of HAART initiation at each visit for each individual, and including this information in a marginal structural model.
As noted in previous studies, the effect of HAART and the development of verrucae are not well understood. We found that HIV-infected women who reported initiating HAART were neither more nor less likely to develop cutaneous or anogenital verrucae when compared to those women who did not initiate HAART therapy [2, 30].
Previous studies showed a reduction in the incidence of genital warts and a favorable response of genital verrucae to HAART [8, 16]. We found no change in the risk of anogenital warts and the use of HAART. We could not comment on whether individual verrucae responded favorably or unfavorably to antiretroviral therapy, or detect if verrucae persisted or erupted in relation to HAART initiation.
Our findings suggest that increased CD4 cell counts and decreased HIV RNA independently reduce the risk of developing anogenital verrucae. Although HAART use was not significant for risk of anogenital warts, these changes in immunologic and virologic parameters are very likely due to use of effective HIV therapy and suggest that HAART responders (rather than all HAART users) have a decreased risk of disease.
As with incidence data based on periodic physical examinations, a detection bias exists for our outcome variables. Verrucae that may have occurred between study visits and were successfully treated or resolved on their own would have been missed.
In summary, HIV-infected women were more likely to develop anogenital verrucae than uninfected women. Although HAART did not alter the risk of developing skin or anogenital warts, those with higher CD4 cell counts and lower HIV RNA had a lower risk of developing anogenital warts. This study also confirmed the strong association with HPV infection, cigarette smoking and younger age and risk of anogenital warts.
Data in this manuscript were collected by the Women‘s Interagency HIV Study (WIHS) Collaborative Study Group with centers (Principal Investigators) at New York City/Bronx Consortium (Kathryn Anastos); Brooklyn, NY (Howard Minkoff); Washington DC Metropolitan Consortium (Mary Young); The Connie Wofsy Study Consortium of Northern California (Ruth Greenblatt); Los Angeles County/Southern California Consortium (Alexandra Levine); Chicago Consortium (Mardge Cohen); Data Coordinating Center (Stephen Gange). The WIHS is funded by the National Institute of Allergy and Infectious Diseases (UO1-AI-35004, UO1-AI-31834, UO1-AI-34994, UO1-AI-34989, UO1-AI-34993, and UO1-AI-42590) and by the National Institute of Child Health and Human Development (UO1-HD-32632). The study is co- funded by the National Cancer Institute, the National Institute on Drug Abuse, and the National Institute on Deafness and Other Communication Disorders. Funding is also provided by the National Center for Research Resources (MO1-RR-00071, MO1-RR-00079, MO1-RR-00083). We would also like to acknowledge Dr. Howard D. Strickler (Albert Einstein College of Medicine, Bronx, NY) for providing HPV baseline data (5R01CA085178-05).
We are deeply grateful to the women who consented to be part of this study.
Jacqueline C. Dolev contributed to the design of the project and data analyses, and drafting/completion of the manuscript. Toby Maurer contributed to the design of the project and data analyses, and drafting/completion of the manuscript. Gayle Springer contributed to the data management and analyses, and drafting/completion of the manuscript. Marshall J. Glesby contributed to the design of the project and drafting/completion of the manuscript. Howard Minkoff contributed to the design of the project and drafting/completion of the manuscript. Casey Connell contributed to the design of the project and drafting/completion of the manuscript. Mary Young contributed to the design of the project and drafting/completion of the manuscript. Karlene Schowalter contributed to the design of the project and drafting/completion of the manuscript. Christopher Cox contributed to the design of the project, led the statistical analyses and interpretation of results, and contributed to drafting/completion of the manuscript. Nancy A. Hessol was the lead investigator of this project, conceived of the design, and contributed to the analyses, interpretation, and writing of the manuscript.
Research support: The National Institute of Allergy and Infectious Diseases fund the WIHS, with supplemental funding from the National Cancer Institute, the National Institute of Child Health & Human Development, the National Institute on Drug Abuse, the National Institute of Dental Research, the Agency for Health Care Policy and Research, and the National Center for Research Resources. Grant numbers U01-AI-35004, U01-AI-31834, U01-AI-34994, U01-AI-34989, U01-HD-32632, U01-AI-34993, U01-AI-42590, MO1-RRR00071, MO1-RR00079, and MO1-RR00083.
The authors have no conflicts of interest to disclose.