Comparing subjects with or without HPV data at all visits, Hispanic subjects were much more likely (P = 0.004) to have all HPV data. There was no significant difference in other baseline demographic and health characteristics. A higher rate of high-risk HPV DNA detection at baseline was marginally associated (P = 0.089) with missing HPV data for at least 1 follow-up visit, whereas a higher rate of low-risk HPV DNA detection at baseline was significantly associated (P = 0.030) with missing follow-up data. Overall, it seemed that HPV-infected women had less complete HPV data. This indicated that we could not assume the missing data pattern as missing completely at random when assessing the trend of HPV prevalence over time. Likelihood-based logistic random effect mixed models for longitudinal exploration were therefore chosen to take into account the correlation between the repeated measures over time within 1 subject with appropriate assumptions.
After adjusting for age, sexual activity at baseline, cervical cytological abnormality at baseline, CD4 count, and plasma HIV-1 viral load at baseline, and current sexual activity, the duration of follow-up was found to be significantly associated with decreased detection of HPV DNA of any type [odds ratio (OR) = 0.87, 95% confidence interval (CI) (0.77 to 1.00), P = 0.043]; high-risk HPV type [OR = 0.83, 95% CI (0.74 to 0.94), P = 0.002]; multiple HPV types [OR = 0.87, 95% CI (0.78 to 0.97), P = 0.013]; and multiple high-risk HPV types [OR = 0.83, 95% CI (0.72 to 0.95), P = 0.009] (Table 3). The odds of detecting HPV DNA of any type were estimated to decrease by 13% after every 24 weeks of follow-up. The same model was applied to the subset of subjects who had specimens available at each time point (n = 72) and it yielded similar results except that the decrease for HPV DNA of any type was no longer significant (P = 0.113. Table 4).
The frequency of detecting DNA of nearly all individual HPV types also decreased with time of follow-up. The longitudinal detection of DNA of each HPV type is shown in Figure 2A. Because of the loss of subjects over time, these results are presented as the percentage of available specimens that were positive for DNA of each HPV type. All types showed a decrease in prevalence except for the high-risk types HPV 39 and 68 and the low-risk types HPV 42 and 54 that showed no change or a marginal increase in prevalence. Figure 2B shows similar data for the subset of subjects with specimens available at each time point. In this figure, the absolute number of each type is shown because the number of available specimens is the same at each time point. The result is similar, but the smaller numbers make detailed comparisons difficult.
Among the 106 subjects who did not have a cervical cytological abnormality at baseline and who had at least 1 follow-up visit, 21 had a cervical cytological abnormality subsequently detected. The pooled logistic models showed that the presence of HPV DNA of any type [OR = 6.74, 95% CI (2.09 to 21.81), P = 0.001] and HPV DNA from a high-risk type [OR = 10.69, 95% CI (3.40 to 33.62), P < 0.001] at baseline were positively associated with detection of a cervical cytological abnormality, after controlling for CD4 count, age, sexual activity, and plasma HIV-1 viral load at baseline, and the current CD4 count, plasma HIV-1 viral load, and sexual activity. The presence of HPV DNA from a low-risk type at baseline was found to be inversely associated with the detection of a cervical cytological abnormality [OR = 0.23, 95% CI (0.08 to 0.69), P = 0.008]. The presence of multiple HPV DNA types or multiple high-risk types at baseline was not found to be significantly associated with the detection of a cervical cytological abnormality. After adjustment for sexual activity, HPV DNA status (any type), CD4 count, plasma HIV-1 viral load at baseline, the current plasma HIV RNA, and sexual activity, the model showed that the current CD4 count [OR = 0.77 for every 50-cell increase, 95% CI (0.65 to 0.91) P = 0.002] and age >35 [OR = 0.35 95% CI (0.14 to 0.85) P = 0.020] were inversely associated with the detection of a cervical cytological abnormality.
Retrospective studies and small prospective studies have shown varying effects of HAART on HPV infection and on HPV-associated dysplasia and cancer. This study was designed to prospectively evaluate the impact of HAART on HPV infection and disease in previously untreated women.
The 66% prevalence of HPV DNA detection at baseline was similar to that reported in previous studies that used HPV DNA detection methods of similar sensitivity.1,2,33 The distribution of HPV types detected also was similar to other reports in comparable populations,33-35 although there were small differences of uncertain significance. Although HPV 16 and 18 cause the majority of cervical cancers11 and are targeted by current HPV vaccines,36,37 there were other HPV types that were detected more commonly than HPV 16 and 18. This could have implications if HPV immunization is offered to HIV-infected women in the future or if women who previously received an HPV vaccine are subsequently infected with HIV.38 However, the purpose of the vaccine is to prevent high-grade dysplasia and cancer; the relative importance of these additional HPV types compared with HPV 16 and 18 in advanced disease (especially cancer) in this patient population has not been conclusively established. One study suggested that even though types other than HPV 16 and 18 were commonly detected in HIV-infected women, HPV 16 and 18 were associated with about 65% of invasive cervical cancer, a prevalence similar to that of matched control subjects.39
As with most persons initiating antiretroviral therapy, the subjects in this study responded well to treatment with improvements in CD4 counts and declines in HIV-1 viral load. A variety of different antiretroviral regimens were used, but there was no adjustment for regimen. The proportion of subjects with undetectable plasma HIV-1 viral loads at 48 and 96 weeks (67% and 63%, respectively) was somewhat lower than expected. For example, some subjects in this study were coenrolled in ACTG protocol 5095 that had rates of undetectable viral loads of approximately 80% at 48 and 96 weeks.40 However, many of the subjects in the current study were on treatment by prescription, and women have been found to have somewhat higher failure rates in nonclinical trial settings.41
Any prospective study relies on longitudinal data that are as complete as possible, so we were concerned about subject loss. Our analysis suggested that subjects were not lost at random. A logistic random effect mixed model accounts for the association of loss with covariates. Although this is a valid approach, there is still some uncertainty because the exact nature of the missing data is unknown. Using this model, we demonstrated a decline of detection of any HPV type of 13% for every 24 weeks on study. The decline was most evident among the high-risk HPV types and was seen for nearly every individual HPV type detected. An analysis of 2 large cohorts of HIV-infected women (Women's Interagency HIV Study and HIV Epidemiology Research Study) suggested that detection of HPV 16 was less closely related to immunosuppression as measured by CD4 count than detection of other HPV types.33 Based on that observation, the authors predicted that HAART would have relatively less impact on HPV 16 detection than on detection of other HPV types. Although the numbers in the current study are relatively small, there was no suggestion that there was a differential effect of HAART on HPV 16 compared with other high-risk HPV types. There was no significant effect of HAART on the detection of low-risk HPV types. The reasons for this are not certain. It may be that our relatively small sample size and lower prevalence of low-risk HPV types were insufficient to detect a difference.
There are inherent methodologic limitations in this study design. Detection of HPV DNA at 2 time points could reflect persistence of HPV or clearance and reinfection. Detection of DNA of a new HPV type could reflect a new infection or reactivation of a previously acquired HPV. Similarly, loss of detection could represent clearance, sampling variability, or other technical problems. Despite these limitations, the steady decline of HPV detection after initiation of HAART is consistent with a treatment effect. The impact of HAART on HPV infection seems to be limited mostly to the high-risk HPV types. In addition, the observation that the detection of cervical cytological abnormalities was inversely associated with current CD4 count at follow-up visits also suggests a treatment effect.
Further studies will be needed to confirm and extend these observations. Few women in this study developed high-grade dysplasia, and there were no cases of cervical cancer. It will be important to measure the impact of HAART on key end points of HPV infection, high-grade dysplasia, and cervical cancer. Some such studies have been initiated in developing countries where cervical cancer is more prevalent.42
The authors would like to thank Linda Naini for her assistance in the preparation of this article and Brahim Qadadri for technical assistance with the HPV assays. We would also like to thank Dr. Anna-Barbara Moscicki for helpful comments on the article.
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Appendix I: AIDS Clinical Trials Group Protocol A5029
A5029 sites and contributing personnel include: Hannah Edmondson-Melancon, RN, MPH, and Lorraine Sanchez-Keeland, PA-C, University of Southern California (A1201) Clinical Trials Unit (CTU) Grant # AI27673; Elizabeth Livingston, MD, and Joan Riddle, RN, Duke University Medical Center (A1601) CTU Grant # AI69684; Mary Albrecht, MD, Beth Israel Deaconess Med Ctr (A0103) and Sigal Yawetz, MD, Brigham and Women's Hospital (A0107) CTU Grant # AI069472; AI060354; Margie Vasquez, RN and Judith A. Aberg, MD, New York University/NYC HHC at Bellevue (A0401) CTU Grant # AI069532 and GCRC Grant # RR00096; Donna McGregor, NP, and Oluwatoyin Adeyemi, MD, Northwestern University (A2701) and Cook County CORECenter (A2705) CTU Grant # AI 69471; Laura Bachmann, MD, MPH, and Angela Rivers, RN, University of Alabama at Birmingham (A5801) CTU Grant # AI069452-01, GCRC Grant # RR-00032, and CFAR Grant # AI027767; Helen Grubbs, RN, MSN, Indiana University (A2601) CTU Grant # AI25859 and GCRC Grant # RR000750; Jane Reid, RNc, MS, ANP, and Carol Greisberger, RN, University of Rochester (A1101) CTU Grant # AI69411 and GCRC Grant # RR00044; Michelle V. Lisgaris, MD, and Barbara Philpotts, RN, Case Western Reserve University (A2501) CTU Grant # AI069501; Anneris Delgado, PA, and Margaret A. Fischl, MD, University of Miami AIDS Clinical Research Unit (A0901) CTU Grant # AI069477; Sharon Riddler, MD, MPH, and Barbara Rutecki, MSN, MPH, CRNP, University of Pittsburgh (A1001) CTU Grant # AI 69494; Karen T. Tashima, MD, and Deborah K. Perez, RN, The Miriam Hospital (A2951) CTU Grant AI46381; Charles Davis and Barbara Glick, University of Maryland, Institute of Human Virology (A4651); Rodrigo Díaz-Velasco, MD, BC, Antonio Rodríguez- Mimoso, MD, Elvia Pérez-Hernández, BS, MEd, MA, MPH, and Lourdes Angeli-Nieves, RN, BSN, MPH, San Juan City Hospital (Westat/NICHD 5031) Contract # HD33345; Sharon Nachman, MD, Paul Ogburn, MD, and Jennifer Griffin, NP, SUNY at Stony Brook School of Medicine, Division of Pediatric Infectious Diseases (Westat/NICHD 5040) Contract # HD33345; Irma L. Febo, MD, and Hazel Ayala, RN, University of Puerto Rico, Childrens Hospital (P6601); Mykyelle Crawford, RN, BSN, and Madeline Torres, RN BSN, Columbia Collaborative HIV/AIDS Clinical Trials Unit (A7802) CTU Grant # AI069470; Esmine Leonard, RN, and Ana M. Puga, MD, North Broward Hospital District, Children's Diagnostic and Treatment Center, Inc (Westat/NICHD 5055) Contract # HD33345; Kristin Mondy, MD, and Michael K. Klebert, RN-CS, MSN, ANP, Washington University in St. Louis (A2101) CTU Grant # AI069495; Donna Mildvan, MD, and Gwendolyn Costantini, FNP, Beth Israel Medical Center (A2851) CTU Grant # AI46370; Vicki Bailey, RN, Beverly Byram, MSN, FNP, Vanderbilt AIDS Clinical Trials Center (A3652) CTU Grant # AI069439; Cris Milne, RN, CNP, and Marilou Marcelo Gonzalez, BS, University of Hawaii at Manoa (A5201) CTU Grant # AI34853; Douglas Watson and Sally Snader, University of Maryland Medical Center, Division of Pediatric Immunology and Rheumatology (P3702); Daniel Johnson and Dominika Kowalski, Mount Sinai Hospital Medical Center, Womens and Childrens HIV Program (P4005); Alice Stek, MD, and Ana Melendrez, RN, # 5048 Los Angeles County/University of Southern California Pediatric AIDS Clinical Trials Unit/Maternal-Child-Adolescent HIV Center (Westat/NICHD 5048) NICHD Contract # HD33345, Westat Subcontract Grant # 7735-S042, GCRC Grant # RR000043; N. Jeanne Conley, RN, and Ann C. Collier, MD, University of Washington (A1401) CTU Grant # AI27664 and AI 069434; Susan Pedersen, RN, and Kristine Patterson, MD, University of North Carolina at Chapel Hill (A3201) CTU Grant # AI69423-01, CFAR Grant # AI50410, GCRC Grant # RR00046; and Mobeen H. Rathore, MD, and Ana Alvarez, MD, University of Florida/Jacksonville (Westat/NICHD 5051) Contract # HD33345.