Associated variables for HSIL vs. no SIL in univariable logistic regression analyses were age, duration of cART use, having had an STD in the preceding 6 months, HIV plasma viral load, and number of years living with viral suppression. Nadir and current CD4+ cell count were not associated with HSIL. Univariable associations between risk factors and outcome were largely similar between the four outcome measures (Suppl. Table 1, http://links.lww.com/QAD/B156).
In multivariable logistic regression analysis, nested within clinic and comparing HSIL vs. no SIL, increasing age [adjusted odds ratio (aOR) 0.82, 95% confidence interval (CI) 0.70–0.94; P = 0.006], and years living with suppressed viral load were significantly protective for HSIL [1–5 years viral suppression aOR 0.52 (95% CI 0.34–0.80), 5.01–10 years viral suppression aOR 0.47 (95% CI 0.29–0.74), >10 years viral suppression aOR 0.54 (0.34–0.87), all compared to less than 1 year viral suppression, P = 0.009]. Outcome measures HSIL-AIN2 vs. no SIL, HSIL-AIN3 vs. no SIL, and HSIL vs. no HSIL yielded similar results (Table 2).
Additionally, we assessed risk factors for intra- and perianal HSIL vs. no SIL separately. Intra-anal HSIL showed results comparable to the overall model. Only being a current smoker was found to be a significant risk factor of perianal HSIL in multilevel multivariable logistic regression analyses [previously smoked aOR 2.41 (95% CI 0.77–7.57), current smoker aOR 4.90 (95% CI 1.80–13.35), compared to participants who never smoked, P = 0.006; Supplementary Table 3, http://links.lww.com/QAD/B156].
In contrast to our results, several smaller studies, with less than 400 patients each, reported various demographic and HIV-related risk factors that significantly increased the risk for anal hHSIL: the number of specific HPV types and current use of cART , increasing age and CD4+ cell counts less than 50/μl before starting cART , and smoking [23,24]. We found smoking to be a risk factor, but for perianal HSIL only. We also confirmed that duration of cART use showed a reduced risk for hHSIL [12,25]. Living more than 1 year with viral suppression might reduce the risk for hHSIL as it could be a proxy for immune restoration over time. We have no good explanation how older age could be protective for anal HSIL.
A limitation of our study is that no data were collected on anal HPV infections, but given that 95% of all HIV-positive MSM have anal HPV present, the value of this risk factor is debatable [13,26]. More specifically, HPV16 testing might be considered to have more discriminatory power, but given that HPV16 was the causative HPV type in only 60% of anal carcinomas in HIV-positive MSM in another study by our group , 40% of potential anal carcinomas would be missed. Also, patient populations differed significantly between clinics, which may be explained by differences in calendar year of starting with HRA screening and by the large study populations, easily leading to statistically significant but not clinically important differences. Furthermore, multiple anoscopists performed the HRAs, and given the long learning curve for HRA, some HSIL lesions may have been missed [28,29]. Also, in clinic B p16 staining was not always used to confirm AIN2 graded biopsies. Finally, social desirability bias might have occurred for self-reported STDs and sexual behavior.
We thank Michiel Nieuwenhuis and Djurre Bismijer for data collection and the Stichting HIV Monitoring (SHM) for sharing data on HIV-related parameters.
M.S.V.D.L. reports grants from Merck, Sanofi Pasteur MSD, and Janssen outside the submitted work. H.J.C.D.V. reports a grant from Medicine outside the submitted work.
The abstract of this manuscript has been presented at the International Anal Neoplasia Society Scientific Meeting in San Francisco, California, USA, 11–13 November 2016.
There are no conflicts of interest.
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* Matthijs L. Siegenbeek van Heukelom and Elske Marra equally contributed to this article.