Of the 3766 women in WIHS (2791 HIV seropositive, 975 seronegative), we excluded 22 HIV seroconverters and 127 women missing data on baseline wart status. Women with HIV were more likely than uninfected women to have data on wart status missing (109 (3.9%) vs 18 (1.9%), P = 0.003). Of the remaining 3617 women, 160 (142 HIV seropositive, 18 seronegative) had genital warts at enrollment, for a prevalence rate of 4.4/100 women (5.3/100 for HIV seropositive women and 1.9/100 for seronegative women, P < 0.0001). The baseline prevalence in the 1994–5 subcohort was 4.9/100 women (5.6/100 for HIV seropositive and 2.4/100 for seronegative women). Baseline prevalence in the 2001–2 subcohort was lower at 3.4/100 women (P = 0.04) with 4.5 cases/100 women for HIV seropositive and 1.3/100 for seronegative women. For both subcohorts and overall, differences in wart prevalence between HIV seronegative and seropositive women were significant (all P < 0.005). Demographic and medical characteristics of women with warts are presented in .
Table 1 Demographic and medical characteristics characteristics at the time of first diagnosis with vulvar warts, vulvar intraepithelial neoplasia (VIN) of any grade, VIN 2 or a more severe lesion (VIN2+). All P-values by Fisher exact test except where noted. (more ...)
After excluding these prevalent cases and 310 women (223 HIV seropositive, 87 seronegative) with no follow-up, 3147 women (2317 HIV seropositive, 830 seronegative) were included in an analysis of the incidence of vulvar warts. These included 2145 (1673 HIV+, 472 HIV−) recruited in 1994–5 and 1002 (644 HIV+, 358 HIV−) recruited in 2001–2. Of these, 479 women (15%) were diagnosed with incident vulvar warts, including 441 (19%) HIV seropositive and 38 (5%) seronegative women..
The annual incidence of warts per 100 person-years was 3.1 (95% C.I. 2.8, 3.5) for HIV seropositive women and 0.6 (95% C.I. 0.4, 1.0) for seronegative women in the 1994–5 cohort (P < 0.0001) and 2.5 (95% C.I 2.0, 3.2) and 0.6 (95% C.I. 0.3, 1.1) for seropositive and seronegative women in the 2001–2 cohort (P < 0.0001). Incidence rates fell over time for women in both cohorts (P < 0.0001 for the combined cohorts). In addition, shows the cumulative risk of genital warts in the combined cohorts. After up to 13 years of follow-up in the 1994–5 cohort, the cumulative incidence of genital warts was 33% (95% C.I. 30, 36%) in HIV seropositive and 9% (95% C.I. 6, 12%) in seronegative women (P < 0.0001). After up to 6 years of follow-up in the 2001–2 cohort, the cumulative incidence of genital warts was 17% (95% C.I. 14, 20%) in HIV seropositive and 5% (95% C.I. 3, 7%) in seronegative women (P < 0.0001).
Cumulative risk of genital warts among human immunodeficiency virus (HIV) seropositive and seronegative women in the original cohort. P < .001 for differences between groups across all visits.
In multivariable analysis, lower CD4 lymphocyte count, younger age, and current but not former smoking were strongly correlated with incident genital warts (). The number of recent sexual partners was not significantly associated with wart incidence.
Results of multivariable analysis of risk factors for diagnosis of incident genital warts.
We also examined trends in the burden of warts over time. As shown in , the visit-specific prevalence of genital warts was higher among HIV seropositive women at all visits (P < 0.0001). also shows that for both HIV seropositive and seronegative women, prevalence fell over time (P < 0.0001).
Visit-specific point prevalence of genital warts among human immunodeficiency virus (HIV) seropositive and seronegative women. P < .001 for differences between groups across all visits.
We explored the likelihood of spontaneous regression among 669 women (612 HIV seropositive, 57 seronegative) with prevalent and incident warts. After excluding 65 women (59 HIV seropositive, 6 seronegative) whose warts were treated and 60 women (52 HIV seropositive, 8 seronegative) with inadequate follow-up, among the remaining 544 women (501 HIV seropositive, 43 seronegative) followed for up to five years, 451 (83%) regressed (410 (82%) HIV seropositive, 41 (95%) seronegative, P = 0.02). As shown in , most regression occurred in the first year after diagnosis in both groups, although regression continued to occur with ongoing follow-up, especially among women with HIV. In multivariable analysis including both incident and prevalent lesions (), wart regression was less likely in HIV seropositive women, especially those with lowest CD4 counts and higher HIV RNA levels (P for trend in stratum with CD4 counts <200/cmm < 0.0001). Regression was not linked to smoking or number of sexual partners (data not shown). When the multivariable analysis was carried out distinguishing prevalent from incident warts, prevalent warts were less likely to clear than incident warts (P < 0.0001), though the effects of CD4 count and HIV viral load were similar for both prevalent and incident warts.
Cumulative likelihood of spontaneous regression of vulvar warts over time after excluding treated women (P = .004 for human immunodeficiency virus [HIV]-positive compared with HIV-negative women).
Results of multivariable analysis of risk factors for regression of genital warts.
Of 669 women (612 HIV seropositive, 57 seronegative) diagnosed with warts during follow-up extending up to 14 years, 77 treatments were used for 63 (9%) women, (57 (9%) HIV seropositive; 6 (10%) seronegative, P = 0.81). These treatments included excision by scalpel or electrosurgical loop (23, 30%); laser or other ablation (24, 31%); combined laser and excision (2, 3%); topical therapies including trichloroacetic acid (17, 22%), imiquimod (5, 6%), 5-fluorouracil (4, 5%), and podophyllin (2, 3%). Among these women, 51 had one treatment, 10 had two treatments, and two had three treatments.
After excluding 2 women with inadequate documentation of wart status, 39 (64%) of the remaining 61 treated women were free of warts at the next visit (34/56 or 61% among HIV seropositive women and 5/5 or 100% among seronegative women, P = 0.15). Among the 39 women whose lesions had cleared by the first post-treatment visit, treatment effects were durable in 100% among HIV seronegative women but waned with time among 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 2 excluded for missing result.
Women with HIV were more likely to have vulvar lesions biopsied: the vulvar biopsy rate was 0.79 (95% C.I. 0.66–0.94)/100 person-years for HIV seropositive women with HIV and 0.17 (0.08–0.32) for seronegative women (P < 0.0001). In multivariable analysis, risk factors for biopsy included HIV serostatus and CD4 lymphocyte count (compared to HIV seronegative women, H.R. 2.3, 95% C.I. 1.1, 4.9 for women with HIV and CD4 counts >500/cmm, H.R. 4.0, 95% C.I. 2.0, 8.0 for those with CD4 counts 200–500/cmm, H.R. 10.0, 95% C.I. 5.0, 20.0 for those with CD4 counts <200/cmm, P for trend < 0.0001) and vulvar treatment within six months (H.R. 9.38, 95% C.I. 1.3, 67.8, P = 0.03).
The higher vulvar biopsy rate among women with HIV appeared to be due to a truly higher risk for lesions rather than to a lower threshold for biopsy, as the distribution of the histologic severity of biopsies did not differ by HIV status. shows the results of the highest grade biopsy for each woman.
Highest grade of vulvar intraepithelial neoplasia (VIN) found in 213 women undergoing biopsy. For the comparison of HIV seropositive and seronegative women, P = 0.44 by Fisher’s exact test. N (column percent).
shows the demographic and medical characteristics at the time of diagnosis for 116 women (111 with and 5 without HIV) found to have VIN or cancer; HIV seropositive women had fewer sexual partners than seronegative women.
Incident VIN of any grade occurred more frequently among HIV seropositive than seronegative women: 0.42 (0.33 – 0.53) vs 0.07 (0.02 – 0.18)/100 person-years (P < 0.0001). In multivariable analysis, only HIV serostatus/CD4 lymphocyte count was correlated with incident VIN (compared to HIV seronegative women, H.R. 3.7, 95% C.I. 1.2, 11.4 for women with HIV and CD4 counts >500/cmm, H.R. 5.4, 95% C.I. 1.9, 15.7 for those with CD4 counts 200–500/cmm, H.R. 16.3, 95% C.I. 5.6, 47 for those with CD4 counts <200/cmm, P for trend < 0.0001).
VIN2+ was found in 58 women (55 with and 3 without HIV, P < 0.001). Demographic factors from the time of diagnosis are presented in ; no significant differences in VIN2+ were evident between HIV seropositive and seronegative women, though the small number of seronegative women may have been limiting.
Incident VIN2+ was much less common than VIN of any grade but was more frequent among HIV seropositive than seronegative women. The incidence of VIN2+ was 0.18/100 person-years (95% C.I. 0.12–0.26) for women with HIV and 0.03/100 person-years (95% C.I. 0.004–0.12) for HIV seronegative women (P = 0.01).
In multivariable analysis, being HIV seropositive and having lower CD4 lymphocyte count was associated with VIN2+ (compared to HIV seronegative women, H.R. 0.6, 95% C.I. 0.1, 6.3, P = 0.64 for women with HIV and CD4 counts >500/cmm, H.R. 5.5, 95% C.I. 1.2, 25.2, P = 0.03 for those with CD4 counts 200–500/cmm, H.R. 16.3, 95% C.I. 3.6, 73.4, P = 0.0003 for those with CD4 counts <200/cmm). In a separate multivariable model, age, ethnicity, smoking, and the number of sexual partners in the six months before diagnosis did not distinguish women with VIN2+ from those with genital warts and those with VIN1 (not shown). In an additional multivariable model including only women with HIV, risk for VIN2+ was higher among women with a clinical diagnosis of genital warts when CD4 counts were lower (compared to women with CD4 >500/cmm, O.R. for VIN2+ vs warts was 6.3, 95% C.I. 1.5, 27.1, P = 0.01 when CD4 = 200–500/cmm and 5.6, 95% C.I. 1.3, 23.8, P = 0.02 when CD4 <200/cmm). Similarly, the likelihood that biopsies were diagnosed as VIN2+ rather than VIN1 was higher among HIV-infected women with lower CD4 counts (compared to women with CD4 >500/cmm, OR for VIN2+ vs VIN1 was 21.5, 95% C.I. 2.5, 185.5, P = 0.01 when CD4 = 200–500/cmm and 21.8, 95% C.I. 2.4, 195.1, P = 0.01 when CD4 < 200/cmm).
Of 114 women with VIN, 41 (38 HIV seropositive, 3 seronegative), had 54 vulvar treatments. Therapies included ablation (24, 44%), excision (21, 39%), topical therapies (7, 13%), and both excision and ablation (2, 4%). Since 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 following year showed VIN3 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.