Anal Human Papillomavirus Infection Among Thai Men Who Have Sex With Men With and Without HIV Infection

BackgroundHIV-positive men who have sex with men (MSM) have a higher prevalence of anal human papillomavirus (HPV) infection and anal cancer incidence than HIV-negative MSM. High-risk HPV persistence is an important risk factor for the development of anal cancer.MethodsA total of 123 HIV-positive and 123 HIV-negative MSM were enrolled from the Thai Red Cross AIDS Research Centre in Bangkok, Thailand, and followed for 12 months. Anal sample collection for HPV genotyping was performed at every visit. HPV prevalence, incidence, clearance, and persistence were calculated. A logistic regression model was used to study factors associated with high-risk HPV persistence.ResultsThe prevalence of any anal HPV infection was 85% in HIV-positive and 58.5% in HIV-negative MSM (P < 0.0001). The prevalence of high-risk HPV infection was 57.5% in HIV-positive and 36.6% in HIV-negative MSM (P = 0.001). HPV 16 was the most common high-risk HPV type. HIV-positive MSM had a higher prevalence (22.5% vs. 9.8%, P = 0.008) and persistence (16.7% vs. 1.3%, P < 0.001) of HPV 16 than HIV-negative MSM and a trend for higher incidence (16.1 vs. 6.1 episodes/1000 person-months, incidence rate ratio 2.6, P = 0.058). HIV infection (odds ratio: 4.45, 95% confidence interval: 2.11 to 9.4, P < 0.001) and smoking in HIV-positive MSM (odds ratio: 2.3, 95% confidence interval: 1.17 to 4.5, P = 0.015) were independently associated with high-risk HPV persistence in multivariate models.ConclusionsIn addition to targeting HIV-positive MSM who are at higher risk for anal, high-risk HPV persistence, anal cancer prevention programs should also integrate behavioral interventions such as smoking cessation to modify risk for high-risk HPV persistence

Use of human papillomavirus DNA, E6/E7 mRNA, and p16 immunocytochemistry to detect and predict anal high-grade squamous intraepithelial lesions in HIV-positive and HIV-negative men who have sex with men.

Men who have sex with men (MSM) are at high risk of having anal cancer. Anal high-grade squamous intraepithelial lesion (HSIL) is the precursor of anal cancer. We explored the use of different biomarkers associated with human papillomavirus (HPV) infection and HPV-mediated cell transformation to detect and predict HSIL among HIV-positive and HIV-negative MSM.A total of 123 HIV-positive and 123 HIV-negative MSM were enrolled and followed for 12 months. High-resolution anoscopy (HRA) with biopsies were performed at every visit along with anal sample collection for cytology, high-risk HPV DNA genotyping, HPV E6/E7 mRNA, and p16 immunocytochemistry. Performance characteristics and area under the receiver operator characteristics curve were calculated for these biomarkers at baseline, and Cox regression compared the usefulness of these biomarkers in predicting incident HSIL. High-risk HPV DNA, E6/E7 mRNA, and p16 immunocytochemistry each identified 43-46% of MSM whose baseline test positivity would trigger HRA referral. E6/E7 mRNA had the highest sensitivity (64.7%) and correctly classified the highest number of prevalent HSIL cases. With the exception of p16 immunochemistry, most tests showed significant increases in sensitivity but decreases specificity versus anal cytology, while the overall number of correctly classified cases was not significantly different. Baseline or persistent type 16 and/or 18 HPV DNA was the only test significantly predicting incident histologic HSIL within 12 months in models adjusted for HIV status and low-grade squamous intraepithelial lesions at baseline.Countries with a high HIV prevalence among MSM and limited HRA resources may consider using biomarkers to identify individuals at high risk of HSIL. E6/E7 mRNA had the highest sensitivity for prevalent HSIL detection regardless of HIV status, whereas type 16 and/or 18 HPV DNA performed best in predicting development of incident HSIL within 12 months

Baseline positivity of anal cytology and biomarkers by histologic anal diagnosis.

<p>P values correspond to a comparison of the proportion of subjects with no SIL or LSIL versus those with HSIL, who were identified by each biomarker.</p><p>SIL, squamous intraepithelial lesion; LSIL, low-grade squamous intraepithelial lesion; HSIL, high-grade squamous intraepithelial lesion; HPV, human papillomavirus.</p><p>LSIL group included MSM with anal intraepithelial neoplasia (AIN) 1 on histology. HSIL group included MSM with AIN 2 or AIN 3 on histology. No SIL group included MSM without LSIL or HSIL.</p

Baseline positive and persistent positive biomarkers predicting incident anal histologic HSIL at subsequent visits among those who were free of disease at baseline.

<p>HSIL, high-grade squamous intraepithelial lesion; HPV, human papillomavirus; CI, confidence interval.</p><p>HSIL included anal intraepithelial neoplasia (AIN) 2 or AIN 3 on histology.</p>a<p>High-risk HPV DNA included HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68.</p>b<p>E6/E7 mRNA positivity was defined as greater than or equal to 2% of cells which had E6/E7 mRNA over-expression in the sample.</p>c<p>p16 immunocytochemistry was considered positive if there was a presence of cells with cytoplasmic and/or nuclear staining.</p>d<p>Multivariate model adjusted for HIV status and low-grade squamous intraepithelial lesion at baseline.</p

Performance characteristics of anal cytology, high-risk HPV DNA, HPV E6/E7 mRNA, and p16 immunocytochemistry to detect anal histologic HSIL at baseline, by HIV status.

<p>HSIL, high-grade squamous intraepithelial lesion; CI, confidence interval; PPV, positive predictive value; NPV, negative predictive value; AROC, area under the receiver operator characteristics curve; HPV, human papillomavirus.</p><p>HSIL included anal intraepithelial neoplasia (AIN) 2 or AIN 3 on histology.</p>a<p>High-risk HPV DNA included HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68.</p>b<p>E6/E7 mRNA positivity was defined as greater than or equal to 2% of cells which had E6/E7 mRNA over-expression in the sample.</p>c<p>p16 immunocytochemistry was considered positive if there was a presence of cells with cytoplasmic and/or nuclear staining.</p>d<p>*P≤0.05 and ‡ P≤0.001 in pairwise comparisons against anal cytology, in subjects with HSIL for sensitivity and subjects without HSIL for specificity.</p>e<p>P values for pairwise comparisons of the AROC relative to anal cytology as a reference group.</p

Receiver operator characteristics plots of biomarker performances to detect anal histologic HSIL.

<p>(A) Performance characteristics of anal cytology, high-risk HPV DNA, HPV 16 and/or 18, E6/E7 mRNA, and p16 immunocytochemistry, when each test was used alone to detect HSIL. (B) Performance characteristics when tests were used in combination to detect HSIL. HSIL, high-grade squamous intraepithelial lesion. HSIL included anal intraepithelial neoplasia (AIN) 2 or AIN 3 on histology.</p