Background
The incidence of anal squamous cell carcinoma is significantly increased in people with HIV (PWH). Early detection of high-grade squamous intraepithelial lesions (HSIL) through high-resolution anoscopy (HRA) in individuals with abnormal anal cytology can prevent over half of these cases. However, the poor specificity of anal cytology leads to a high number of unnecessary HRAs. This poses significant challenges to anal cancer screening, considering the scarce availability of HRA. Overexpression of adenosine deaminase acting on RNA 1 (ADAR1) has been reported in several cancers, including cervical cancer. This study aimed to determine whether quantifying ADAR1 mRNA levels could improve the selection of candidates for HRA.
Methods
A prospective cohort study was conducted between 2022 and 2023, involving consecutive HIV-positive adults with abnormal anal cytology (atypical squamous cells of undetermined significance or worse). All patients underwent HRA to collect anal swabs and biopsies. ADAR1 mRNA expression levels were quantified using RT-qPCR in anal swabs. The diagnostic performance of ADAR1 mRNA to discriminate HSIL from low-grade squamous cell intraepithelial lesions (LSIL)/normal biopsies was analyzed using receiver operating characteristic (ROC) curves.
Results
HSIL was confirmed by anal biopsy in 40/171 participants (23.4%) with abnormal anal cytology. Participants with HSIL had a higher median [IQR] number of HPV genotypes compared to those without HSIL (5 [4-8] vs 3 [1-5], p<0.001). ADAR1 mRNA levels were significantly higher in the HSIL group compared to the non-HSIL group (49.4 vs 4.1, p<0.001). The ROC curve for ADAR1 mRNA showed an area under the curve of 0.83 (95% CI: 0.75-0.92). Using a threshold of ≥24.8 relative units to endogenous control, the test achieved 73% sensitivity, 92% specificity, 74% positive predictive value and 92% negative predictive value. This threshold would reduce the need for HRA to 22.8% of participants with abnormal anal cytology. Among the 132 (73%) participants with ADAR1 levels <24.8, incorporating HPV genotype quantification with a threshold of >4 improved HSIL detection rates to 95%, though it would require 40 (23%) additional HRAs.
Conclusions
ADAR1 mRNA quantification helps mitigate the limited availability of HRA by more accurately identifying PWH who need the procedure. By increasing specificity and reducing unnecessary HRAs, ADAR1 mRNA presents a more efficient, targeted and less invasive strategy for detecting HSIL.
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