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  53rd ICAAC Interscience Conference on
Antimicrobial Agents and Chemotherapy
September 10-13, 2013, Denver CO
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HPV-39 Predicts AIN and Anal Cancer in Spanish Group of Men With HIV
  53rd ICAAC, September 10-13, 2013, Denver
Mark Mascolini
Infection with human papillomavirus (HPV) type 39 emerged as the only independent predictor of grade 2 or 3 anal intraepithelial neoplasia (AIN) or anal cancer in a Spanish group of HIV-positive men who have sex with men (MSM) [1]. A few previous studies hinted at the oncogenic potential of HPV-39 in men with HIV (see below).
HIV-positive and negative MSM run a higher risk of AIN and anal cancer than men in the general population. Much research has evaluated risk factors for AIN and anal cancer in men. Although certain consistent factors have emerged (smoking, low CD4 count), independent predictors vary from study to study. Furthermore, whether and how to screen MSM for anal dysplasia and possible cancer remains controversial.
Researchers at the University Hospital Virgen de las Nieves in Granada conducted this study to assess risk factors and screening strategies for AIN grade 2 or 3 (high-grade AIN, HGAIN) or anal cancer in their population of HIV-positive MSM. This cross-sectional study of a prospective cohort involved 103 M=SM screened for anal lesions from April 2010 to September 2012. Each man gave two anal mucosal samples--one for HPV analysis by PCR and one for cytology. Detection of any anal lesion triggered anoscopy.
High-risk (cancer-causing) HPV types are 16, 18, 26, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 68, 73, and 82. HPV-16 and 18 account for most cases of anal and cervical cancer, but some studies link other high-risk HPV types to AIN or anal cancer. The quadrivalent HPV vaccine protects against HPV-16 and 18, as well as HPV-6 and 11, which can cause anal or genital warts.
The 103 study participants averaged 36.2 years in age, had a median of 1.5 sex partners during the study period, and had average current and nadir CD4 counts of 646 and 387. Current viral load averaged 3.67 log10 copies/mL, or about 4700 copies. Forty-two men (41%) had anal warts. Only 15 men had not started antiretroviral therapy (ART), and ART duration reached a median of 35 months in treated men. Forty-nine men were smokers (a frequent AIN and anal cancer risk factor in other studies).
Anal cytology revealed low- and high-grade squamous intraepithelial lesion (LSIL and HSIL) rates of 53.5% and 5.3%, while 5.3% of samples were rated atypical squamous cells of undetermined significance (ASCUS). Only 32.9% of samples had normal cytology. By anoscopy, 35.9% of men had normal histologic results, 43.6% had AIN grade 1, 9.7% had AIN 2 or 3, and 10.7% had carcinoma in situ. Overall, 21 men (20%) had grade 2 or 3 AIN or anal cancer.
Univariate analysis identified only three factors associated with AIN 2/3 or anal cancer: anal HPV-6 (odds ratio [OR] 4.62, 95% confidence interval [CI] 1.43 to 14.56, P = 0.019), anal HPV-39 (OR 5.1, 95% CI 1.04 to 24.98, P = 0.051), and anal HPV-42 (OR 3.94, 95% CI 1.02 to 15.27, P = 0.052). (HPV-6 is a low-risk genotype, while HPV-39 and 42 are high-risk types.) Number of high-risk and low-risk types and smoking did not affect AIN 2/3 or cancer risk in this analysis.
In the multivariate analysis, only anal HPV-39 remained an independent predictor of AIN 2/3 or anal cancer, raising the odds more than 10 times (OR 10.5, 95% CI 1.12 to 98.7, P = 0.040). Anal HPV-42 detection was marginally associated with AIN 2/3 or cancer (OR 4.35, 95% CI 0.88 to 21.35, P = 0.071).
Most screening strategies had high sensitivity and negative predictive value in diagnosing AIN 2/3 or anal cancer. Sensitivity and negative predictive value were 94% and 97.2% for abnormal anal cytology alone, 90.4% and 95.8% for abnormal anal cytology with anoscopy, 83% and 76.9% for high-risk HPV genotype, 78.9% and 87.5% for abnormal cytology and high-risk HPV type, and 100% and 100% for abnormal cytology and/or high-risk HPV type. But specificity (the ability of a test to correctly identify absence of a condition) was 61% or lower for every approach, and positive predictive value was 39.5% or lower.
On the basis of these findings, the researchers propose the following anal lesion/cancer screening model for HIV-positive MSM:
-- HIV-positive MSM should be systematically tested for dysplastic (abnormal) lesions with anal cytology and PCR for HPV.
-- If cytology is abnormal, irrespective of grade, anoscopy should be used for histologic evaluation.
-- If cytology is normal, HPV genotyping should be done, and HPV genotype is high-risk, anoscopy should be performed.
In published studies in Switzerland [2], France [3], and throughout Europe [4], all three analyses identified lower CD4 count as an anal cancer risk factor. The Swiss study, a case-control comparison, identified three other factors: current smoking, antibodies against HPV-16 protein L1, and antibodies against HPV-16 oncogene E6.
A study of 67 HIV-positive MSM in France found that HPV-39, 42, and 53 were the HPV types associated most often with anal cytological abnormalities (28% with each type), followed by HPV 16 (25%) [5]. In a study of 586 HIV-positive MSM in Madrid, HPV-39 was the third most prevalent high-risk anal HPV type (in 23.7%), following HPV-16 (42%) and HPV-51 (24%) [6]. In women HPV-39 predicted invasive cervical cancer, but with less power than HPV-16 or 18, in a meta-analysis of 27 studies [7].
1. Hidalgo Tenorio C, Rivero Rodriguez M, Gil C, et al. Prevalence of, and risk factors for high-grade intraepithelial neoplasia (HGIN) and anal cancer in an HIV MSM Spanish cohort. 53rd ICAAC. September 10-13, 2013. Denver. Abstract H-1532.
2. Bertisch B, Franceschi S, Lise M, et al. Risk factors for anal cancer in persons infected with HIV: a nested case-control study in the Swiss HIV Cohort Study. Am J Epidemiol. 2013 Jul 30. Epub ahead of print.
3. Guiguet M, Boue F, Cadranel J, et al. Effect of immunodeficiency, HIV viral load, and antiretroviral therapy on the risk of individual malignancies (FHDH-ANRS CO4): a prospective cohort study. Lancet Oncol. 2009;10:1152-1159.
4. Reekie J, Kosa C, Engsig F, et al. Relationship between current level of immunodeficiency and non-acquired immunodeficiency syndrome-defining malignancies. Cancer. 2010;116:5306-5315.
5. Damay A, Fabre J, Costes V, et al. Human papillomavirus (HPV) prevalence and type distribution, and HPV-associated cytological abnormalities in anal specimens from men infected with HIV who have sex with men. J Med Virol. 2010;82:592-596.
6. del Amo J, González C, Geskus RB, et al. What drives the number of high-risk human papillomavirus types in the anal canal in HIV-positive men who have sex with men? J Infect Dis. 2013;207:1235-1241.
7. Bernard E, Pons-Salort M, Favre M, et al. Comparing human papillomavirus prevalences in women with normal cytology or invasive cervical cancer to rank genotypes according to their oncogenic potential: a meta-analysis of observational studies. BMC Infect Dis. 2013;13:373.