Of 669 women (612 HIV-seropositive, 57 HIV-seronegative) diagnosed with warts during follow-up extending up to 14 years, 77 treatments were used for 63 (9%) women (57 [9%] HIV-seropositive; six [10%] –seronegative; P=.81). These treatments included excision by scalpel or electrosurgical loop (23 [30%]); laser or other ablation (24 [31%]); combined laser and excision (two [3%]); and topical therapies including trichloroacetic acid (17 [22%]), imiquimod (five [6%]), 5-fluorouracil (four [5%]), and podophyllin (two [3%]). Among these women, 51 had one treatment, 10 had two treatments, and two had three treatments.
After excluding two women with inadequate documentation of wart status, 39 (64%) of the remaining 61 treated women were free of warts at the next visit (34 of 56 [61%] among HIV-seropositive women and five of five [100%] among HIV-seronegative women; P=.15). Among the 39 women whose lesions had cleared by the first posttreatment visit, treatment effects were durable in 100% among HIV-seronegative women but waned with time among HIV-seropositive women with same-site wart-free survival of 88% at 12 months, 65% at 3 years, and 56% at 5 years. However, long-term follow-up was not available for many women, and rates did not differ by HIV serostatus at any of these time points.
Of 373 vulvar biopsies from 213 women (199 HIV-seropositive, 14 HIV-seronegative), results for two biopsies from two women were missing. Multiple biopsies from the same visit were assessed according to the most severe result, leaving 332 results from the 213 women with two excluded for missing result.
Women with HIV were more likely to have vulvar lesions biopsied: the vulvar biopsy rate was 0.79 (95% CI 0.66–0.94) per 100 person-years for HIV-seropositive women with HIV and 0.17 (0.08–0.32) for HIV-seronegative women (P<.001). In multivariable analysis, risk factors for biopsy included HIV serostatus and CD4 lymphocyte count (compared with HIV-seronegative women, hazard ratio, 2.3, 95% CI 1.1–4.9 for women with HIV and CD4 counts greater than 500/cm3, hazard ratio 4.0, 95% CI 2.0–8.0 for those with CD4 counts 200–500/cm3, hazard ratio 10.0, 95% CI 5.0–20.0 for those with CD4 counts less than 200/cm3, P for trend <.001) and vulvar treatment within 6 months (hazard ratio, 9.38, 95% CI 1.3–67.8, P=.03).
The higher vulvar biopsy rate among women with HIV appeared to be the result of a truly higher risk for lesions rather than to a lower threshold for biopsy, because the distribution of the histologic severity of biopsies did not differ by HIV status. Table 4 shows the results of the highest grade biopsy for each woman.
Table 1 shows the demographic and medical characteristics at the time of diagnosis for 116 women (111 with and five without HIV) found to have VIN or cancer; HIV-seropositive women had fewer sexual partners than HIV-seronegative women.
Incident VIN of any grade occurred more frequently among HIV-seropositive than HIV-seronegative women: 0.42 (0.33–0.53) compared with 0.07 (0.02–0.18) per 100 person-years (P<.001). In multivariable analysis, only HIV serostatus and CD4 lymphocyte count were correlated with incident VIN (compared with HIV-seronegative women, hazard ratio, 3.7, 95% CI 1.2–11.4 for women with HIV and CD4 counts greater than 500/cm3, hazard ratio, 5.4, 95% CI 1.9–15.7 for those with CD4 counts 200–500/cm3, hazard ratio, 16.3, 95% CI 5.6–47 for those with CD4 counts less than 200/cm3, P for trend <.001).
Positivity for VIN 2 was found in 58 women (55 with and three without HIV, P<.001). Demographic factors from the time of diagnosis are presented in Table 1; no significant differences in VIN 2 positivity were evident between HIV-seropositive and HIV-seronegative women, although the small number of HIV-seronegative women may have been limiting.
Incident VIN 2 positivity was much less common than VIN of any grade but was more frequent among HIV-seropositive than HIV-seronegative women. The incidence of VIN 2 positivity was 0.18 per 100 person-years (95% CI 0.12–0.26) for women with HIV and 0.03 per 100 person-years (95% CI 0.004–0.12) for HIV-seronegative women (P=.01).
In multivariable analysis, being HIV-seropositive and having lower CD4 lymphocyte count was associated with VIN 2 positivity (compared with HIV-seronegative women, hazard ratio, 0.6, 95% CI 0.1–6.3, P=.64 for women with HIV and CD4 counts greater than 500/cm3, hazard ratio, 5.5, 95% CI 1.2–25.2, P=.03 for those with CD4 counts 200–500/cm3, hazard ratio, 16.3, 95% CI 3.6–73.4, P<.001 for those with CD4 counts less than 200/cm3). In a separate multivariable model, age, ethnicity, smoking, and the number of sexual partners in the 6 months before diagnosis did not distinguish women with VIN 2 positivity from those with genital warts and those with VIN 1 (not shown). In an additional multivariable model including only women with HIV, risk for VIN 2 positivity was higher among women with a clinical diagnosis of genital warts when CD4 counts were lower (compared with women with CD4 greater than 500/cm3, odds ratio for VIN 2 positivity compared with warts was 6.3, 95% CI 1.5–27.1, P=.01 when CD4=200–500/cm3 and 5.6, 95% CI 1.3–23.8, P=.02 when CD4 less than 200/cm3). Similarly, the likelihood that biopsies were diagnosed as VIN 2 positivity rather than VIN 1 was higher among HIV-infected women with lower CD4 counts (compared with women with CD4 greater than 500/cm3, odds ratio for VIN 2 positivity compared with VIN 1 was 21.5, 95% CI 2.5–185.5, P=.01 when CD4=200–500/cm3 and 21.8, 95% CI 2.4–195.1, P=.01 when CD4 less than 200/cm3).
Of 114 women with VIN, 41 (38 HIV-seropositive, three HIV-seronegative), had 54 vulvar treatments. Therapies included ablation (24 [44%]), excision (21 [39%]), topical therapies (seven [13%]), and both excision and ablation (two [4%]). Because repeat biopsy was often not performed, we could not define treatment success rates.
Two women in our HIV-seropositive group developed incident stage IB vulvar squamous cell cancers, the first in 1996 and the second in 2002. Both had prior Paps showing atypical or low-grade squamous cells. The former patient had a lesion detected several months before diagnosis. The latter had a wart excised in 1995 and was followed without lesions until 2000, when an ulcer was managed as infectious until biopsy the next year showed VIN 3 and local excision showed invasion. Both cancers were treated surgically without adjuvant therapy and although the first patient developed a recurrence in 2002 and later an anal carcinoma managed with resection, both were alive without vulvar cancer recurrence in 2010.
As we and others have shown, HIV infection increases women's risk for genital warts and VIN.1 – 7 In addition to providing longer follow-up, showing that one-third of HIV-infected women in our long-term cohort developed genital warts at some point during up to 13 years of observation, our results confirm and expand on prior work. We found a clear dose–response but no threshold CD4 count for risk, indicating that even marginal immunosuppression increases susceptibility to HPVs that cause warts. Nevertheless, HIV-seropositive women's experience of vulvar disease is dynamic. HIV infection delays spontaneous clearance and may impair the effectiveness of treatments for genital warts, although differences by HIV status did not reach significance. Most warts among these women resolve spontaneously or respond to therapy. Only the most profound immunosuppression (CD4 less than 200/cm3) had a detectable effect on the relatively high rate of spontaneous regression. Women with HIV and relatively high CD4 levels can be observed or treated with reasonable expectation of ultimate wart clearance, whereas women with lower CD4 counts may benefit from earlier, more aggressive, and repeated treatment. As reported by de Panfilis and colleagues,15 women with HIV and genital warts should be counseled that recurrence can be a troubling but manageable complication of HIV infection with 46% of women in their study who were treated for genital warts recurring within 5 years. In that study and ours, incidence rates fell with time and were lower among older women. Smoking is a modifiable risk factor for incident warts, and smoking cessation should be especially encouraged for HIV-seropositive smokers with genital warts.
Although we found that VIN 2 positivity was also more frequent in women with than those without HIV, it remained relatively uncommon. Intact immunity is important not only in the control of initial HPV infections that cause warts and VIN 1, but also in the control of precancers. There may be a threshold effect, because the incidence of VIN 2 positivity was increased only for women with CD4 counts less than 500/cm3.
With only two incident vulvar cancers, we could not study invasive cancers. However, Simard and colleagues found that vulvovaginal cancer risk does not appear to rise until years after HIV diagnosis, suggesting that immunosuppression must be prolonged to allow progression of preinvasive lesions to cancer.16 Dedes and coworkers found that vulvar cancers developed despite therapy in two of 20 (10%) HIV-seropositive women with VIN 2 positivity followed at least 2 years.17 Ongoing surveillance for recurrent VIN and new cancer is important for early diagnosis, and the finding that both our cancers were preceded for months to years by visible lesions underscores the importance of liberal biopsy. Given the high regression rate of warts in our study, the finding that these diagnoses were delayed despite a protocol requiring biopsy of all lesions except apparent warts suggests persistent warts merit biopsy.
We have previously shown in this cohort that some cervicovaginal HPV infections in women with HIV reflect reactivation of latent HPV rather than new infections.18 In this study, the number of recent sexual partners did not affect the incidence of new genital warts. This also suggests that new warts in HIV-infected women may represent not new HPV infections, but rather activation of extant HPV infections, possibly from immunosuppression, from sexual or other trauma, or from these and other factors in combination.
Our study was limited by several factors. Our results should be generalizable to most women with HIV, although lesions found after less regular follow-up may be more advanced, more likely VIN 2 positivity, and less likely to regress. Although a studywide protocol recommended biopsy for persistent lesions, this did not occur in all cases owing both to patients declining biopsy and to clinicians with a low index of suspicion. However, 75% of women who had biopsies done were found to have either no VIN or VIN 1, which has minimal neoplastic potential, and only two incident cancers developed throughout follow-up, suggesting that failure to detect high-grade VIN was uncommon. In addition, diagnosis of genital warts was by clinical inspection alone; some skin tags, keratoses, and other abnormalities might have been misdiagnosed as genital warts. The effect of this would have been to weaken observed associations; colposcopy surveillance and more liberal biopsy might have identified additional risk factors and trends. Furthermore, although participants were asked about genital treatments at each visit, faulty recall might have caused us to misclassify some treatment-based regression as spontaneous if treatments outside Women's Interagency HIV Study were not reported. Similarly, we relied on biopsy to confirm VIN, and because repeat biopsy was often not performed, we could not define successful treatment rates. The small number of women with VIN 2 positivity, especially in the HIV-seronegative group, precluded multivariable analysis of factors potentially contributing to development of VIN 2 positivity. We lacked sufficient numbers to compare the efficacy of various treatments for warts and VIN. We did not have access to reasons why some women with warts were treated and others followed. A lower regression rate for warts in HIV-seropositive women may in part reflect undiagnosed VIN. Finally, HPV typing of wart and VIN specimens was not performed, and we could not assess HPV type distribution or the role of HPV type in determining regression and response to treatment among women with genital warts and VIN.
Although many vulvar lesions resolve, Conley and associates have reported that vulvar cancers can develop despite surveillance and treatment of VIN.19 Vulvar inspection should be a routine part of interval examination for women with HIV, because surveillance and treatment of VIN 2 positivity is an important component of cancer control. All lesions except typical warts should be biopsied, and high-grade VIN should be treated unless terminal comorbid conditions mean life expectancy is less than the potential 1- to 2-year transition time to cancer.17 Although most genital warts are caused by HPV types 6 and 11, which usually do not progress to cancer, a substantial minority of warts are associated with high-risk HPV types and may pose a risk for cancer.20 Persistent warts should be biopsied. The 82% spontaneous regression rate for warts in HIV-seropositive women, with a lower rate of regression after 1 year, suggests that apparent genital warts in women with HIV can be followed without biopsy or treatment for at least 12 months before biopsy or excision, which both treats warts and identifies unsuspected VIN. Our finding that only two cases of incident invasive vulvar cancer developed in our HIV-infected cohort during up to 13 years of observation despite an increased risk for VIN 2 positivity suggests that vulvar surveillance and treatment can be effective in preventing vulvar cancer among women with HIV. Women who develop invasive vulvar cancer should receive standard therapy, which can be curative.
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© 2011 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.
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