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Precancer Anal Lesion Arises in 10% of Australian MSM--But Clearance Common
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17th European AIDS Conference, November 6-9, 2019, Basel
Mark Mascolini
High-grade squamous intraepithelial lesions (HSIL), an anal cancer precursor, arose in about 10% of Australian men who have sex with men (MSM) enrolled in a 3-year natural history study [1]. HSIL clearance without treatment was high, at about 20% per year.
Researchers at Sydney's Kirby Institute noted that anal cancer poses a particular threat to distinct populations: women with previous anogenital human papillomavirus (HPV) disease (relative risk [RR] 5-20 compared with general population), organ transplant recipients (RR 5-10), HIV-negative MSM (RR 5-20), HIV-positive people (RR 10+), and HIV-positive MSM (RR 50). In Australia anal cancer incidence (the new-diagnosis rate) has risen steeply among HIV-positive MSM in the last 2 decades [2].
Whether people at high risk for anal cancer should be screened for HSIL--and treated if HSIL is detected--remains a fraught and controversial question. To address these issues, Australian researchers organized the Study of Prevention of Anal Cancer (SPANC), a 3-year undertaking that recruited 617 MSM between September 2010 and May 2018 [3]. Enrollees had to be gay or bisexual men at least 35 years old; they could be HIV-positive or negative. Most detected HSIL cases were closely monitored, not treated. At the initial study visit, then at 6, 12, 24, and 36 months, men had a behavioral interview, an anal swab for cytology and HPV testing, and high-resolution anoscopy and biopsy.
Of the 617 men enrolled, 220 had HIV and 397 did not. The groups were similar in age, averaging 50 years, and in proportions having 2 or more male sex partners in the last 6 months (69.5% and 73.6%). But the HIV-positive group differed from the negative group in proportion of current smokers (19.6% versus 11.1%), proportion with 200 or more lifetime male sex partners (63.4% versus 46.6%), and proportion with 50 or more lifetime episodes of receptive condom-free anal sex (37.3% versus 8.3%).
Men with HIV had been infected for an average 15.3 years, 44.9% had a nadir CD4 count below 200, 93.6% currently took antiretroviral therapy, 12% had a latest CD4 count below 350, and 89.6% had an undetectable viral load the last time tested. A significantly higher proportion of men with versus without HIV had composite HSIL (HSIL on cytology and/or histology): 47.3% versus 32.3% (P < 0.001).
Incidence of composite HSIL proved significantly higher in men who had cleared HSIL than in those who never had detected HSIL (23.4 versus 10.4 per 100 person-years, P < 0.001). Univariate Cox regression analysis identified several predictors of composite HSIL: age 44 or older versus younger lowered the risk by about 40% (hazard ratio [HR] 0.61, 95% confidence interval [CI] 0.41 to 0.90, P = 0.012), and having HIV nonsignificantly raised the risk about 40% (HR 1.43, 95% CI 0.99 to 2.06, P = 0.054). Past or current smoking did not significantly affect the risk of HSIL.
Compared with a negative HSIL result, greater composite HSIL severity at a visit before newly detected composite HSIL raised chances of composite HSIL: composite low-grade squamous intraepithelial lesion (HR 2.40, 95% CI 1.58 to 3.65) and composite ASC-H (HR 4.59, 95% CI 2.76 to 7.62) (P < 0.001). (ASC-H indicates atypical squamous cells-cannot exclude HSIL).
Compared with men who were positive for high-risk HPV-16 at both their last and current visit, those positive at the last visit and negative at the current visit had a 65% lower risk of composite HSIL (HR 0.35, 95% CI 0.14 to 0.87) and those negative for HPV-16 at both the last and current visit had a 72% lower risk (HR 0.28, 95% CI 0.19 to 0.41, P < 0.001). The same associations held for men negative for HPV-16 but positive or negative for other high-risk HPV types.
Overall spontaneous clearance of composite HSIL came to 22.0 cases per 100 person-years, meaning 22% of men spontaneously cleared HSIL every year without treatment (P < 0.001). Clearance after prevalent composite HSIL was 24.7 per 100 person-years, and clearance after incident (newly detected) composite HSIL was even higher, 44.5 per 100 person-years.
Factors that predicted a lower chance of HSIL clearance in univariate Cox regression analysis were age 44 or older versus younger (HR 0.66, 95% CI 0.46 to 0.93, P = 0.018), composite AIN3 (anal intraepithelial neoplasia) versus AIN2 (HR 0.56, 95% CI 0.40 to 0.78, P = 0.001) and multi-octant HSIL versus cytological HSIL/single octant (HR 0.62, 95% CI 0.42 to 0.90, P = 0.012). One factor predicted a higher chance of HSIL clearance--being negative for HPV-16 at the last and current visit (HR 1.74, 95% CI 1.22 to 2.48, P = 0.004).
Overall rate of progression of HSIL to anal cancer was low: 0.224 cases per 100 person-years. (Only 1 of 617 men had progression to anal cancer.) The progression rate was higher in HIV-negative men (0.414 cases per 100 person-years) and undetectable in HIV-positive men (0 cases per 100 person-years). The researchers noted that limited statistical power affected estimates of HSIL progression to anal cancer.
The SPANC investigators believe their findings "strongly suggest that not all anal HSIL detected in screening requires treatment." In this study men with persistent HPV-16 had a lower chance of spontaneously clearing HSIL and stood the greatest chance of benefitting from treatment. The researchers suggested that active monitoring of HSIL may be most appropriate for (1) younger, HIV-negative men, (2) men with new HSIL lesions, HSIL-AIN2, and a smaller HSIL burden, and (3) men without persistent high-risk HPV, especially HPV-16.
References
1. Templeton DJ, Poynten IM, Jin F, et al. The natural history of anal high grade squamous intraepithelial lesions in HIV positive and HIV negative gay and bisexual men. 17th European AIDS Conference, November 6-9, 2019, Basel. Abstract PS6/1.
2. Jin F, Vajdic CM, Law M, et al. Incidence and time trends of anal cancer among people living with HIV in Australia. AIDS. 2019;33:1361-1368.
3. Machalek DA, Grulich AE, Hillman RJ, et al. The Study of the Prevention of Anal Cancer (SPANC): design and methods of a three-year prospective cohort study. BMC Public Health. 2013; 13: 946.
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