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American Journal of Epidemiology Advance Access originally published online on June 14, 2006
American Journal of Epidemiology 2006 164(2):176-183; doi:10.1093/aje/kwj165
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American Journal of Epidemiology Copyright © 2006 by the Johns Hopkins Bloomberg School of Public Health All rights reserved; printed in U.S.A.

Original Contribution

Smoking and Time to Clearance of Human Papillomavirus Infection in HIV-Seropositive and HIV-Seronegative Women

Jill Koshiol1, Jane Schroeder1, Denise J. Jamieson2, Stephen W. Marshall1, Ann Duerr3, Charles M. Heilig4, Keerti V. Shah5, Robert S. Klein6, Susan Cu-Uvin7, Paula Schuman8,9, David Celentano10 and Jennifer S. Smith1

1 Department of Epidemiology, School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC
2 Division of Reproductive Health, Women's Health and Fertility Branch, National Center for Chronic Disease Prevention and Health Promotion, Atlanta, GA
3 HIV Vaccine Trials Network, Seattle, WA
4 Office of the Chief Science Officer, Centers for Disease Control and Prevention, Atlanta, GA
5 Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD
6 Montefiore Medical Center and Albert Einstein College of Medicine, Bronx, NY
7 Department of Obstetrics and Gynecology, Brown Medical School, Brown University, Providence, RI
8 Department of Infectious Disease and Quality Health Care, School of Medicine, Virginia Commonwealth University, Richmond, VA
9 Department of Medicine, Division of Infectious Diseases, School of Medicine, Wayne State University, Detroit, MI
10 Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD

Correspondence to Dr. Jill Koshiol, National Cancer Institute, 6120 Executive Blvd., MSC 7236, Bethesda, MD 20892-7236 (e-mail: koshiolj{at}mail.nih.gov).

Received for publication August 16, 2005. Accepted for publication January 20, 2006.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Persistent human papillomavirus (HPV) infection seems central to cervical carcinogenesis. Smoking is associated with cervical cancer in HPV DNA-positive women, but its association with HPV persistence is unclear, particularly with respect to human immunodeficiency virus (HIV) serostatus. The authors evaluated smoking and HPV clearance by HIV serostatus among 801 women from the HIV Epidemiology Research Study (United States, 1993–2000). Type-specific HPV duration was defined as the interval between initial MY09/11 polymerase chain reaction positivity and the first of two consecutive HPV-negative study visits. Hazard ratios adjusted for study site and risk behaviors (sexual activity or injection drug use) were estimated using Cox regression. This analysis included 522 HIV-seropositive and 279 HIV-seronegative women (median follow-up, 4.4 years). Ever smoking was associated with reduced clearance of high-risk HPV in HIV-seronegative women (hazard ratio (HR) = 0.51, 95% confidence interval (CI): 0.30, 0.88) but not in HIV-seropositive women (HR = 0.96, 95% CI: 0.65, 1.42); similar results were found for current smoking. Current smoking was not associated with clearance of any type-specific HPV in HIV-seropositive (HR = 0.99, 95% CI: 0.82, 1.20) or HIV-seronegative (HR = 0.93, 95% CI: 0.68, 1.26) women. HPV clearance did not appear to vary by amount or duration of smoking. Smoking did not modify overall clearance but was associated with lower high-risk HPV clearance in HIV-seronegative women.

HIV; papillomavirus, human; smoking; women

Abbreviations: CI, confidence interval; HERS, HIV Epidemiology Research Study; HIV, human immunodeficiency virus; HPV, human papillomavirus; HR, hazard ratio


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Invasive cervical cancer is the second most common cancer in women worldwide (1Go). High-risk types of human papillomavirus (HPV) are a central cause of cervical carcinogenesis (2Go). An estimated 70 percent or more of sexually active women may acquire HPV during their lifetime (3Go), but most HPV infections are transient (4Go, 5Go). Persistent HPV infection is considered a central risk factor for high-grade cervical dysplasia and cancer development (6Go, 7Go). Thus, the identification of risk factors for HPV persistence may facilitate efforts to prevent cervical cancer.

Self-reported history of smoking has been associated with an increased risk of cervical cancer and precursor lesions (8Go, 9Go), but the potential influence of smoking on the natural history of HPV infection is unclear. In theory, smoking could increase the incidence and persistence of cervical HPV infections by suppressing local immune function (10Go). Conversely, smoking may up-regulate specific cytokines that could protect against HPV and other viral infections in the cervix (11Go), thus lowering a woman's risk of persistent HPV infection and associated cervical neoplasia.

Previous studies have found negative (4Go, 12Go), positive (13Go), or null (14Go–17Go) associations between smoking and HPV infection over time. Investigators from two recent studies reported conflicting results. In a US-based study of 346 women, Giuliano et al. (13Go) found that ever smoking was associated with a lower risk of clearance of high-risk types of HPV. In another US-based study of 1,797 HIV-seropositive women and 496 HIV-seronegative women, Minkoff et al. (17Go) found that current smoking was not associated with HPV clearance but was positively associated with persistent type-specific infections through increased incidence.

The duration of HPV infection also appears to vary by HPV type. For example, HPV16 infection appears to have a lower rate of clearance than infection with low-risk types of HPV (15Go). Although specific HPV types might modify any association between smoking and HPV persistence, previous studies have not stratified results by specific HPV type or phylogenetically related types.

HIV seropositivity is associated with an increased risk of persistent HPV infection (14Go, 18Go, 19Go). Thus, the association between smoking and HPV persistence could differ between HIV-seropositive and HIV-seronegative women. Because HIV-positive women have a higher risk of cervical lesions (20Go, 21Go), identifying risk factors for HPV persistence in these women may facilitate cancer prevention efforts and could help further clarify the role of immune function in cervical carcinogenesis.

Our primary aim in the current analysis was to evaluate the association between self-reported smoking and time to clearance of HPV infection using data from a multicenter US study, the HIV Epidemiology Research Study (HERS), stratified by HIV serostatus and HPV type.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 References
 
The HERS study enrolled 871 HIV-seropositive women and 439 HIV-seronegative women in four US cities (Baltimore, Maryland; Bronx, New York; Detroit, Michigan; and Providence, Rhode Island) from April 1993 to December 1995, as previously described (22Go). Approximately half of the women were current or past injection drug users, and approximately half engaged in high-risk sexual behaviors (having had five or more sexual partners within the past 5 years, exchanging sex for money or drugs, or having had sex with a male injection drug user or known/suspected HIV-positive male).

Women with AIDS-defining conditions according to the 1987 Centers for Disease Control and Prevention case definition (23Go) were ineligible. Local institutional review board approval and US Public Health Service certificates of confidentiality were obtained at all sites.

Women with no baseline HPV DNA data, no cervix at baseline, cervical treatment in the 6 months prior to study initiation, or baseline low- or high-grade squamous intraepithelial lesions or invasive cancer were excluded from the current study. Women who had made only one study visit or who became HIV-seropositive or pregnant during follow-up were also excluded, leaving 801 women. Subjects were censored upon hysterectomy or cervical treatment, leaving 6,061 visits.

Although HERS data collection continued through 2000, with a total of 15 possible study visits at 6-month intervals, follow-up for the current analysis continued through visit 10 (latest visit: August 1999), after which Papanicolaou tests became annual rather than semiannual. Cervicovaginal lavage specimens collected at each visit were assayed for HPV DNA using polymerase chain reaction with MY09/MY11/HMB0l primers (12Go). Type-specific HPV positivity was ascertained via hybridization with probes for 26 HPV types (12Go). Samples that were positive with the general probes for HPV DNA but negative for all type-specific probes were classified as untyped. Polymerase chain reaction amplification of a human ß-globin gene segment was used as an internal control for DNA quality. Samples that were ß-globin-negative were classified as having missing data on HPV status.

Time to clearance of each type-specific HPV infection was measured as starting at the first visit positive for a specific HPV type and ending at the first of two consecutive visits that were negative for that specific type. Two consecutive HPV-negative tests were required to confirm clearance because of the possibility of false-negative test results and prior evidence that HPV negativity over a 12-month period may best identify true clearance of HPV infection (5Go). However, estimated time to clearance was based on the date of the first negative visit, which, when followed by a second HPV-negative visit, was assumed to represent a true negative result. HPV infections that became negative at a woman's last study visit were censored at the last visit. To ensure comparability of clearance assumptions for censored and noncensored infections, we added 6 months to the person-time contributed by HPV infections present at a woman's last study visit. Neither the 6-month addition nor an alternate assumption that clearance occurred halfway between visits appreciably changed results. Type-specific HPV status was assumed to remain unchanged across single missing visits. Infections spanning more than two consecutive missing visits were excluded (n = 55) because of the increased uncertainty regarding HPV status. HPV infection over time was plotted with Kaplan-Meier curves.

The association between smoking and time to clearance of individual HPV infections was evaluated using Cox proportional hazards models for the following categories: 1) all type-specific HPV infections (high-risk, low-risk, and untyped HPV infections combined), 2) high-risk infections, 3) low-risk infections, 4) HPV16 and phylogenetically related infections, 5) HPV18 and phylogenetically related infections, and 6) other high-risk infections (see footnotes to table 1). The high-risk and low-risk HPV groupings were derived from an international case-control analysis that classified HPV types in invasive cervical cancer (24Go) and from a recent study suggesting that HPV53 could be classified as a low-risk type (25Go). Hazard ratios less than 1.0 indicate lower clearance rates (i.e., longer durations of infection) in smokers than in nonsmokers. Hazard ratios for HPV18 and phylogenetically related infections and other high-risk infections are not presented for HIV-seronegative women because of few observations. Untyped HPV infections were included in analyses of the clearance of all HPV infections (group 1 above) but not in analyses stratified by HPV risk group (groups 2–6 above).


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  		TABLE 1. Baseline characteristics of 801 women included in an analysis of clearance of human papillomavirus infection, by human immunodeficiency virus (HIV) serostatus, HIV Epidemiology Research Study, 1993–2000

 
Smoking was classified as baseline ever smoking versus never smoking and as current smoking versus nonsmoking in the 6 months before HPV infection. Amount and duration of smoking were also considered. Past smokers who had smoked fewer than 10 cigarettes per day for less than 1 year were classified as never smokers (n = 18). A time-dependent smoking variable that allowed smoking status to change during HPV infection was examined but not included in the final analysis because most women (85 percent) maintained consistent smoking habits and results did not differ appreciably from models without this time-dependent variable.

All models included the HERS design variables for study site, risk classification (sexual risk behaviors or injection drug use), and HIV serostatus (as applicable). Potential confounders included baseline age, ethnicity, education, ever smoking, number of recent (last 6 months) male sexual partners, recent condom use, frequency of vaginal sex, recent use of hormonal contraceptives, pregnancy history, bacterial vaginosis positivity, Trichomonas vaginalis vaginal infection, hepatitis C virus serum antibody positivity, and herpes simplex virus types 1 and 2 serum antibody positivity. In models including HIV-seropositive women, CD4 cell count, HIV viral load, and antiretroviral therapy at the start of HPV infection were also evaluated. Covariate data were obtained through interviews and blood and cervical samples collected at study visits (22Go). Confounding was considered important if removing a covariate changed the hazard ratio for smoking by at least 10 percent in comparison with the full model. No covariate met this criterion. Departures from multiplicative joint effects of HIV serostatus and smoking on clearance of all HPV types were evaluated using likelihood ratio tests for interaction terms (26Go). Hazard ratio modification by high-risk (vs. low-risk) HPV in all women was similarly evaluated. In light of potential underestimation of the duration of HPV infections that were present at baseline (prevalent HPV infections), hazard ratios were also estimated on the basis of "incident" (newly acquired or nonprevalent) HPV infections alone.

To account for within-subject correlation associated with multiple HPV infections in the same woman, hazard ratio variance estimates were derived using a robust variance estimator based on the DFBETA statistic (27Go, 28Go). The proportional hazards assumption was evaluated with Cox p values and likelihood ratio tests for continuous and categorical time interactions (29Go). These analyses suggested no violation of the proportional hazards assumption overall, and thus no time interactions were included in the final models.

The analysis and interpretation of our results focused on the patterns of association between smoking and clearance of HPV infection as defined by the magnitude and precision of the hazard ratios.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 References
 
The study cohort included 522 HIV-seropositive women and 279 HIV-seronegative women with a mean age at enrollment of 35 years (table 1). Overall and individual risk-group HPV positivity was higher in HIV-seropositive women than in HIV-seronegative women. The mean duration of follow-up was 3.6 years (median, 4.4; range, 0.4–4.7), with an average of 7.6 visits (median, 9.0). Current and ever smoking were common overall (75–86 percent at baseline) and were similarly distributed by HIV serostatus. HIV-seropositive women had a lower level of educational attainment and fewer recent sexual partners than HIV-seronegative women. A total of 1,800 type-specific HPV infections were detected in 619 women, including 1,460 infections in HIV-seropositive women and 340 infections in HIV-seronegative women.

The mean amount of time between visits in the time-to-clearance analyses was 6.3 months (median, 6.0; range, 1.9–15.8). The mean observed duration of HPV infection was 1.2 years (median, 0.7); it was slightly longer in HIV-seropositive women than in HIV-seronegative women (mean, 1.3 vs. 1.0; median, 0.8 vs. 0.6). Prevalent HPV infections had a longer duration (mean, 1.8 years; median, 1.4) than incident infections (mean, 1.0; median, 0.6) in all women, as well as in HIV-seronegative women (median: 1.1 prevalent vs. 0.5 incident) and HIV-seropositive women (median: 1.4 prevalent vs. 0.6 incident). The percentage of all HPV infections that were incident was 72.7 (1,126/1,550) among ever smokers and 76.4 (191/250) among never smokers.

The hazard ratios for clearance of any HPV infection were 0.94 (95 percent confidence interval (CI): 0.77, 1.15) for ever smoking versus never smoking and 0.99 (95 percent CI: 0.84, 1.17) for current smoking versus nonsmoking. Lower clearance rates (i.e., longer infections) are reflected by hazard ratios below 1.0. Table 2 presents hazard ratios for smoking and estimated rates of HPV infection clearance by HIV serostatus and HPV risk group. Among HIV-seropositive women, there was no evidence of an association between ever smoking and clearance of all type-specific infections combined, clearance of high-risk HPV types, or clearance of HPV18 and related types. Hazard ratios for low-risk types and HPV16 and related types were slightly elevated, while the hazard ratio for other high-risk types of HPV was slightly below the null. However, the lack of coherence and imprecision associated with these estimates provided no firm evidence of an association.


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  		TABLE 2. Hazard ratios for clearance of human papillomavirus infection relative to ever smoking and current smoking, by human immunodeficiency virus (HIV) serostatus, HIV Epidemiology Research Study, 1993–2000

 
Among HIV-seronegative women (table 2), clearance of all type-specific HPV infections was somewhat reduced in HIV-seronegative ever smokers compared with never smokers. The clearance rate for high-risk HPV infections was notably lower in HIV-seronegative ever smokers than in never smokers (hazard ratio (HR) = 0.51, 95 percent CI: 0.30, 0.88).

In HIV-seropositive women, the hazard ratio magnitudes for current smokers versus nonsmokers were similar to those for ever smokers versus never smokers (table 2). In HIV-seronegative women, associations between current smoking and HPV clearance were somewhat weaker than those for ever smoking.

There was little evidence of a dose-response pattern in the estimated hazard ratios for either amount of smoking or duration of smoking. Hazard ratios for time to clearance of any HPV infection for women who smoked 0–9 cigarettes/day, 10–19 cigarettes/day, 20–29 cigarettes/day, and ≥30 cigarettes/day versus never smokers were 0.9 (95 percent CI: 0.6, 1.2), 1.0 (95 percent CI: 0.8, 1.3), 0.9 (95 percent CI: 0.7, 1.1), and 1.1 (95 percent CI: 0.9, 1.4), respectively. Corresponding hazard ratios were also nonmonotonic and similar across levels of amount of smoking among HIV-seropositive women (range, 0.9 (95 percent CI: 0.6, 1.3) to 1.2 (95 percent CI: 0.9, 1.6)) and HIV-seronegative women (range, 0.7 (95 percent CI: 0.5, 1.1) to 0.8 (95 percent CI: 0.5, 1.3)). Hazard ratios for the clearance of any HPV infection for >0–9, 10–19, and ≥20 years of smoking versus never smoking were 0.9 (95 percent CI: 0.7, 1.2), 0.9 (95 percent CI: 0.8, 1.2), and 1.0 (95 percent CI: 0.8, 1.2), respectively (HIV-seropositive range, 1.0 (95 percent CI: 0.7, 1.4) to 1.0 (95 percent CI: 0.8, 1.3); HIV-seronegative range, 0.7 (95 percent CI: 0.5, 1.0) to 0.8 (95 percent CI: 0.5, 1.3)). Analyses stratified by HPV risk group (i.e., high-risk HPV) provided no evidence of dose-response for either number of cigarettes smoked per day or years of smoking (data available upon request).

Figure 1 illustrates the estimated time to clearance of all type-specific HPV infections, stratified by smoking status and HIV serostatus. HIV-seronegative never smokers had the fastest estimated time to type-specific HPV clearance (75 percent of infections cleared by 1.1 years), followed by HIV-seronegative ever smokers (75 percent cleared by 1.9 years). HIV-seropositive ever smokers and never smokers had similar rates of HPV clearance (75 percent cleared by 4.0 years and 3.9 years, respectively). The hazard ratio for never smoking versus ever smoking among HIV-seronegative women (i.e., the independent effect estimate for smoking alone) was 0.78 (95 percent CI: 0.59, 1.04). The hazard ratio for HIV-positive serostatus versus HIV-negative serostatus among never smokers (i.e., the independent effect estimate for HIV serostatus) was 0.54 (95 percent CI: 0.39, 0.74). The joint estimate for ever smoking and HIV seropositivity combined (relative to HIV-seronegative never smokers) was 0.54 (95 percent CI: 0.42, 0.69). Although the likelihood ratio test did not rule out multiplicative effects of smoking and HIV seropositivity (p = 0.27), the joint effect estimate was closer to the null than the expected joint hazard ratio assuming multiplicative effects (HR = 0.42). In particular, smoking did not appear to contribute to the likelihood of clearance beyond the effect of HIV-positive serostatus.


Figure 1
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  		FIGURE 1. Kaplan-Meier curves for the persistence of human papillomavirus (HPV) infection, by smoking status (ever smoking vs. never smoking) and human immunodeficiency virus (HIV) seropositivity, among 619 women from the HIV Epidemiology Research Study, 1993–2000. The inset shows hazard ratios (HRs) and 95% confidence intervals (in parentheses) for the independent and joint effects of ever smoking and HIV seropositivity. The reference category was HIV-negative never smokers.

 
Table 3 presents hazard ratios for smoking and HPV clearance for incident (nonprevalent) HPV infections only (n = 1,317). Estimates based on incident infections only were broadly similar to those based on incident and prevalent infections combined, without consistent differences between the two. Estimates based on prevalent infections alone were unstable but suggested that the association between smoking and lower clearance of high-risk HPV infections among HIV-negative women (ever smoking vs. never smoking: HR = 0.51, 95 percent CI: 0.30, 0.88) was more pronounced for prevalent infections than for incident infections (prevalent infection: HR = 0.23, 95 percent CI: 0.09, 0.59; incident infection: HR = 0.71, 95 percent CI: 0.35, 1.42). The association between smoking and reduced clearance of HPV16 and related infections among HIV-negative women (ever smoking vs. never smoking: HR = 0.50, 95 percent CI: 0.24, 1.03) appeared to be driven by prevalent infections alone (prevalent infection: HR = 0.22, 95 percent CI: 0.05, 0.93; incident infection: HR = 0.96, 95 percent CI: 0.37, 2.46).


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  		TABLE 3. Hazard ratios for clearance of incident human papillomavirus infection relative to ever smoking and current smoking, by human immunodeficiency virus (HIV) serostatus, HIV Epidemiology Research Study, 1993–2000

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
References
 
To our knowledge, this was the first study to examine the association between women's smoking habits and time to clearance of HPV infection according to both HIV seropositivity and HPV risk group. The results for clearance of all HPV infections in HIV-seropositive and HIV-seronegative women combined suggested no association between past or current smoking status and clearance of cervical HPV infection. No notable evidence of an effect of ever or current smoking was seen in HIV-seropositive women. Stratum-specific estimates in HIV-seronegative women suggested a lower clearance rate in ever smokers versus never smokers with high-risk HPV infections (HR = 0.51, 95 percent CI: 0.30, 0.88) and HPV16 and related infections (HR = 0.50, 95 percent CI: 0.24, 1.03), although estimates were based on small numbers of observations.

Prevalent HPV infections had a longer mean duration than incident HPV infections among HERS participants despite likely underestimation of prevalent infection duration. This longer duration suggests that prevalent HPV infections may have included a larger proportion of persistent infections than incident HPV infections. However, hazard ratios for smoking and clearance of incident infections alone were similar to those for incident and prevalent infections combined. We were not able to evaluate the effect of smoking separately for clearance of prevalent HPV infections because of few observations in this group.

The inconsistency in results for smoking and HPV persistence reported in previous studies (4Go, 12Go–17Go) may be partially due to differences in definitions of HPV persistence used across studies, as well as lack of precision due to relatively small sample sizes. When HIV serostatus and HPV risk group are taken into account, our results are generally consistent with those of studies that used time to clearance of HPV infection as the outcome (13Go, 15Go, 17Go). The overall hazard ratio of 0.99 (95 percent CI: 0.84, 1.17) for time to clearance of any HPV infection in current smokers versus nonsmokers in our study was similar to the hazard ratio of 0.97 (95 percent CI: 0.80, 1.16) for current smokers versus nonsmokers in the Women's Interagency HIV study, a comparable US cohort study of HIV-seropositive and HIV-seronegative women (17Go). In a population-based study of largely HIV-seronegative Colombian women, Molano et al. (15Go) reported a hazard ratio of 0.98 (95 percent CI: 0.74, 1.30) for clearance of any HPV infection among ever smokers versus never smokers. In another US-based study carried out among young women without a history of chronic illness, Giuliano et al. (13Go) reported a hazard ratio of 0.55 (95 percent CI: 0.31, 0.97) for clearance of high-risk HPV infections in ever smokers versus never smokers; this is similar to our findings for high-risk HPV clearance among HIV-seronegative women (HR = 0.51, 95 percent CI: 0.30, 0.88).

Smoking may increase a woman's likelihood of developing a persistent HPV infection by causing immunosuppression in the cervix. One study of colposcopy clinic patients found significantly lower Langerhans cell counts in biopsy specimens obtained from smokers than in specimens obtained from nonsmokers (10Go). Because Langerhans cells are involved in presenting viral antigens to T cells (30Go), lower Langerhans cell counts might reduce the detection and clearance of HPV infections, thus increasing HPV persistence. Given that HIV infection may cause substantial immunosuppression (31Go), a weak-to-modest effect of smoking on immune function might be apparent only among HIV-seronegative women. Our study supported this hypothesis, as smoking was only associated with decreased HPV clearance in HIV-seronegative women.

There was little evidence of dose-response for amount or duration of smoking in either HIV-seropositive women or HIV-seronegative women. A noncausal explanation is that the observed associations between smoking and HPV clearance in HIV-seronegative women were due to uncontrolled confounding. Alternatively, a biologic rationale for this result is that the threshold for the effect of smoking on HPV clearance is low. It is also possible that the absence of a trend is due to low statistical power or imprecise measurement of amount and duration of smoking.

The small number of never smokers (13.9 percent overall and 12.5 percent of HIV-seronegative women) resulted in imprecise estimates of association between smoking and time to clearance of HPV infection, particularly among HIV-seronegative women. Power was also limited for stratification by HPV risk group, especially in HIV-seronegative women. Furthermore, we did not have data on age at smoking initiation.

This study was based on extensive follow-up data (up to 4.7 years), with sensitive polymerase chain reaction-based detection of a wide range of HPV types. It provided new information through its examination of the effect of smoking on HPV natural history in HIV-seropositive and HIV-seronegative women. To our knowledge, this study is the first to have considered the association between smoking and HPV clearance in finer HPV risk groupings (e.g., HPV16 and related types).

In conclusion, self-reported smoking history was not associated with the estimated rate of clearance of HPV infection in HIV-seropositive women, but in HIV-seronegative women smoking was associated with lower estimated clearance rates, particularly for high-risk types of HPV. These results suggest that HIV serostatus may modify the association between potential cofactors, such as smoking, and HPV persistence. Further studies are needed to evaluate risk factors for HPV persistence by HIV serostatus and to clarify whether the association between smoking and HPV clearance varies by specific HPV type.


   ACKNOWLEDGMENTS
 
The HIV Epidemiology Research Study (HERS) was funded through Centers for Disease Control and Prevention cooperative agreements U64/CCU106795, U64/CCU206798, U64/CCU306802, and U64/CCU506831. Dr. Jill Koshiol was supported through a National Cancer Institute National Research Service Award (CA09330-22) and is a Cancer Prevention Fellow in the Cancer Prevention Fellowship Program (Division of Cancer Prevention, National Cancer Institute). Dr. Jennifer Smith was supported through the Centers for AIDS Research, National Institute of Allergy and Infectious Diseases (grant 5 P30 AI050410-07).

The authors thank Pangaja Paramsothy for assisting with HERS data, Dr. Andrew Olshan for assisting in project design and review, Dr. Linda Ahdieh Grant for discussing previous analyses of persistence and providing feedback, and Dr. Charles Poole for preliminary involvement and methodological expertise. The authors also thank additional members of the HERS Study Group: Drs. Julia Arnsten, Robert D. Burk, Chee Jen Chang, Penelope Demas, Andrea Howard, and Ellie Schoenbaum, Montefiore Medical Center and Albert Einstein College of Medicine, Bronx, New York; Dr. Jack Sobel, Wayne State University School of Medicine, Detroit, Michigan; Drs. Anne Rompalo and David Vlahov, Johns Hopkins University School of Hygiene and Public Health, Baltimore, Maryland; Drs. Charles Carpenter, Timothy Flanigan, Joseph Hogan, Kenneth Mayer, Josiah Rich, Valerie Stone, and Karen Tashima, Brown University School of Medicine, Providence, Rhode Island; Dr. Lytt I. Gardner, Dr. Scott D. Homberg, Dr. Janet S. Moore, Ruby M. Phelps, Dr. Dawn K. Smith, and Dr. Dora Warren, Centers for Disease Control and Prevention, Atlanta, Georgia; and Katherine Davenny, National Institute of Drug Abuse, Rockville, Maryland.

Conflict of interest: none declared.


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 

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