The Role of HPV E6 Oncoprotein as a Biomarker in Anal Cancer Screening in Persons Living with HIV

Abstract

Early detection and prevention of anal cancer in high-risk groups such as persons living with HIV (PLWH) is of utmost importance. Most cases of anal cancer are caused by human papillomavirus (HPV), especially by HPV subtypes 16 and 18. Expression of E6 oncoprotein, particularly in HPV 16/18+ cases, plays a significant role in anal cancer oncogenesis. We evaluated the performance of HPV 16/18 E6 oncoprotein for detecting anal high-grade squamous intraepithelial lesions (HSIL). We analyzed clinical data collected over 125 visits from 82 PLWH (mean age 50.1 years; standard deviation 11.1 years) undergoing screening, high-resolution anoscopy (HRA) or treatment in Seattle, Washington, during 2015-2016. Demographic and clinical data, along with anal cancer screening, diagnosis, and treatment results, were collected through chart abstraction and electronic medical records review. Anal brush specimens were tested for type-specific high-risk HPV (hrHPV) DNA. Samples positive for HPV 16/18 were further tested for E6 oncoprotein. We described prevalence and performance statistics of HPV16/18 E6 oncoprotein, HPV16/18 DNA and any hrHPV DNA as biomarkers. We calculated prevalence ratios (PR) for associations between these biomarkers and HSIL using a generalized linear model with a Poisson family and robust variance adjusted for CD4 count, HIV viral load and age. HPV 16/18 E6 was more specific but less sensitive than HPV16/18 DNA and any hrHPV DNA. HPV 16/18 E6+ showed 100% specificity, 100% positive predictive value and a statistically significant elevated adjusted PR of 6.23 (95% confidence interval: 1.12, 34.50) for HSIL compared to hrHPV negative samples; but demonstrated a low sensitivity (6.1%) and moderate negative predictive value (62.3%). Furthermore, we evaluated the HSIL disease extent data from HRA impression and found that 50% of four HSILs with >75% disease extent had E6+ samples, whereas none of the 30 HSILs with <25% disease extent had E6+ samples. Our study demonstrates that HPV 16/18 E6 oncoprotein is highly specific for identifying HSIL, but with low sensitivity, and may have utility for prioritizing lesions that might be at the highest risk for progression to cancer. Further investigation may establish E6 oncoprotein's role in early detection and prevention of anal cancer, either on its own or in combination with other biomarkers.