Next, the variables age, length for known HIV positivity, and use of HAART were compared between groups (Table 2). To adjust for confounding variables, logistic regression analysis was used. The primary selection of covariables for entering in the model, along with group, was based on univariable analysis in 2 by 2 tables; an exact P value below 0.05 was used. Analyses were done using SPSS 18.0.
A total of 250 males were included in this study, 210 without and 40 with AIN. Patients' characteristics are summarized in Table 1. The median age of all males included was 46.5 years (interquartile range [IQR]: 40.0–53.3). The median length of known HIV positivity was 8.0 years (IQR: 4.0–13.0). Of the cohort, 201 patients (80.4%) were on HAART. The median length of use of HAART was 7.0 years (IQR: 3.0–10.0). The median CD4 cell count was 490.0 × 106 cells/L (IQR: 357.5–640.0), and the median nadir CD4 cell count was 229.0 × 106 cells/L (IQR: 120.0–310.0). Of all patients, 67.1% had HIV RNA below the limit of 50 copies/mL. The median number of copies of those with detectable (>50 copies/mL) HIV RNA was 6285.0 (IQR: 322.5–38125.0).
Of all males, 247 (98.8%) had had sex with men only, in the preceding 6 months. Other patients were bisexual. A majority of 69.6% reported to have had receptive anal sex in the preceding 12 months. In all, 111 patients (44.4%) reported a previous history of anogenital warts. Ninety patients (36.0%) were current smokers.
Males using HAART did not significantly differ from the ones without HAART with regard to circumcision before age of 10 years, age at sexual debut, sexual orientation, number of lifetime sexual partners, (recent) practice of receptive anal intercourse, complaints in the anal area, or smoking habit. Those who used HAART were significantly older (median, 48 vs. 39 years; P < 0.0005) and were longer known as being HIV-positive (median, 10 vs. 4 years; P < 0.0005).
Among all 250 patients, 108 (43.2%) had lesions suspicious for HPV-related intraepithelial lesion. A total of 122 biopsies were taken. Of all these biopsies, 60 (49.2%) were taken from the perianal area and 62 (50.8%) from the intra-anal area. In 14 patients, both perianal and intra-anal biopsies were taken. Histologic analyses showed AIN 1 in 24 patients (22.2%), AIN 2 in 6 patients (5.6%), and AIN 3 in 10 patients (9.3%). AIN 3 was observed equally often at the perianal and intra-anal area. Of 10 males with AIN 3, 4 had clinically bowenoid AIN 3. Bowenoid lesions are characterized by pigmented papules, which are histologically similar to Bowen disease (i.e., severe dysplasia) and may have a less aggressive nature than other AIN 3 in HIV-positive MSM. These males were significantly younger than the patients with non-bowenoid clinical expression of their AIN 3 (median age, 27.0 vs. 50.0 years; P = 0.019). The results of all biopsies taken are summarized in Table 4.
In univariable analysis, age (P = 0.011), length for known HIV positivity (P = 0.040), and use of HAART (P = 0.004) were significantly associated with AIN. Neither CD4 cell count, nadir CD4 cell count nor HIV viral load were associated with the prevalence of AIN. All other characteristics in Table 1 were not related with AIN.
In multivariable analyses, the use of HAART was associated with the absence of AIN (Table 2). This was the case when age, length for known HIV positivity, and use of HAART were used in the analyses.
Intermittent anal itch was reported by 59 (23.6%) patients and pain in the anal region on a regular basis by 34 (13.6%) patients. Sporadic bloody or purulent discharge was reported by 51 (20.4%) patients. None of these complaints were significantly more frequent in those diagnosed with AIN.
HPV types were identified in 224 of 247 samples (90.7%). Data are summarized in Table 3. In only 3 specimens (1.2%), no detection could be performed. A median number of 3 HPV types were detected in positive specimens (IQR: 1–4; maximum number: 13). Of those males with HPV, 171 of 224 (76.3%) had one or more HR-HPV type (). LR-HPV was detected in only 27 of 224 (12.1%) positive specimens. HPV types most often detected were HPV-52 (43.8%; HR-HPV), HPV-39 (24.1%; HR-HPV), HPV-74 (21.9%; unknown risk), HPV-54 (21.0%; LR-HPV), and HPV-51 (18.3%; HR-HPV). Well-known HR-HPV types 16 and 18 were detected in 17.4% and 10.7% of positive specimens, respectively. The LR-HPV types 6 and 11 were detected in 17.4% and 14.3% of positive specimens, respectively.
In MSM with AIN, the HPV types 6 and 16 were detected significantly more often compared with those with no dysplasia (P = 0.009 and 0.009)P in the sentence “In MSM with AIN, the HPV…” are OK as given.--. No differences were found regarding high-risk types, number of types, or multiple infections.
In MSM with HAART, the absence of any HPV infection was found significantly more often compared with those who did not use HAART (11.5% vs. 0%; P = 0.010). Multiple infections were detected more often in those who did not use HAART (80.9% vs. 64.5%; P = 0.037).
In this large cross-sectional study in a group of 250 HIV-positive MSM, the prevalence of AIN was 16.0%, which is in line with data from German and French studies.7 – 9 Our study supports the data of the longitudinal cohort study by De Pokomandy et al29 that usage of HAART may lower the risk on AIN.
Data on the impact of HAART on the prevalence of AIN are scarce. Earlier studies did not report this association. This maybe due to small numbers of patients18,22 or due to recent introduction of HAART.21 In a more recent longitudinal study in a cohort of 357 HIV seropositive gay men in San Francisco, Palefsky et al did not assess the effect of antiretroviral therapy possibly because some of the patients in his study were still not using a full HAART regimen.23 A single longitudinal cohort study on the effect of HAART on CIN showed that women on HAART were 40% more likely to demonstrate regression and less likely to demonstrate progression.19 Another group confirmed a higher regression rate of CIN in HAART-treated women in a prospective longitudinal study.30 In contrast, in a recent longitudinal cohort study in women with HIV and at-risk women without HIV by Paramsothy et al, HAART was associated with enhanced cervical HPV clearance, but not with Pap test regression.24 In this study, only 20% of the women on HAART had HIV RNA <500 copies/mL due to low adherence, which may have underestimated the effects associated with HAART.
Data of the longitudinal cohort study by De Pokomandy et al29 suggest that receiving HAART for more than 4 years may contribute to some benefit against AIN 2 or 3.
The prevalence of AIN in this study was not associated with duration of known HIV infection, (nadir) CD4 counts, HIV viral load, or the previous occurrence of AIDS-defining events. This may be explained by the high percentage of patients successfully using HAART, with normal median recent CD4 cell counts in both groups.
HPV infection, the etiologic agent of AIN, was detected significantly more often in treatment-naïve patients compared with those who used HAART (100% vs. 88.5%; P < 0.010). Differences regarding prevalence of HPV infections in both groups are in agreement with data from several previous studies.1,20,31,32 Although this difference in our study is significant, a percentage of 88.5%, it is still a high rate of (probably persistent) HPV infections.
Despite potent anti-HIV therapy, with suppression of HIV replication and an increase of CD4 cell counts, this may not be sufficient to reduce HPV persistence but it may be helpful to induce regression of newly acquired acute HPV infection. Our cross-sectional study cannot answer that question. Longitudinal studies on the effect of HAART on HPV persistence in women indeed do report significantly enhanced clearance of HPV after starting HAART.24,33 One may hypothesize that longer duration of successful HAART could eventually diminish the risk of AIN.
In this study, the prevalence of AIN was significantly related with the prevalence of both HPV types 16 and 6. HPV type 16 has been linked to different types of anogenital cancers. There was no association between prevalence of AIN and other HR-HPV types or the number of high-risk types. This can be explained by the high prevalence (90.7%) of HPV in this group of patients, of which 76.3% had at least one high-risk type. The prevalence of at least one high-risk type was detected equally often in those with and without AIN.
In contrast to other studies, we did not find an association with nadir CD4 cell count. The nadir CD4 counts in our study were relatively high. This may explain the lower prevalence of AIN 2 or 3 in this study. In contrast to the study by De Pokomandy et al,29 duration of HAART regimen was not related with the prevalence of AIN.
The strength of this study is the combination of the assessment of AIN and HPV in a group of patients with a high rate of successful HAART, with detailed clinical and laboratory parameters, such as the previous occurrence of AIDS-defining events, recent and nadir CD4 counts, and HIV viral load. Furthermore, the same physician evaluated all patients.
This study was limited by the cross-sectional design. No anal cytology has been used as screening method for the detection of AIN. This limitation might explain the lower percentage of AIN found in this group of HIV-positive MSM compared with other groups where both histology and cytology were used. Due to these small numbers of AIN, it was not possible to separately examine data of AIN 1 versus AIN 2/3. Finally, HPV samples in this study were done on exfoliated anal cells and not from the biopsies taken. Although these superficial specimens are extremely sensitive, this might have influenced the outcomes of HPV infections.
In conclusion, in this cross-sectional study in 250 HIV-positive MSM, the use of HAART was associated with a significantly reduced prevalence of AIN (OR = 2.28; P = 0.045) and a significantly lower prevalence of HPV (P = 0.010). AIN was associated with HPV types 6 and 16. This association between the prevalence of AIN and the absence of HAART may contribute to the current debate on when to start HAART in HIV-infected individuals. Current European guidelines advice initiation of HAART in case of CD4 cell counts between 350 and 500 × 106 cells/L. In patients coinfected with hepatitis B or C, HAART should be initiated even when CD4 cell counts are 500 × 106 cells/L or above. Because HPV infection can be considered coinfection, earlier introduction in these patients may be useful, as it may influence its clinical course and related burden.
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