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Combining anal cytology with high-risk human papillomavirus (HPV) testing was more effective in detecting anal cancers and precancers in people with HIV than either test alone, and reduced referrals for high-resolution anoscopy, according to a new study.

Of five approaches to anal cancer screening, high-risk HPV along with cytology triage had an acceptable sensitivity (85%), the highest specificity (48%), the highest positive-predictive value (54%), and the lowest percentage of referrals for high-risk anoscopy (66%), Michael Gaisa, MD, PhD, of the Icahn School of Medicine at Mount Sinai in New York City, reported at the International AIDS Conference in Munich.

Performance was similar for anal cancer screening that used anal cytology with high-risk HPV triage or cytology and high-risk HPV co-testing.

"The combined approach of anal cytology and high-risk HPV testing, whether used as triage or co-testing, optimizes test performance," Gaisa told attendees. "It does so by improving specificity with limited impact on sensitivity compared to cytology or high-risk HPV testing alone."

In 2024, the International Anal Neoplasia Society (IANS) published new that outlined five effective screening strategies:

• Anal cytology alone
• Anal cytology plus high-risk HPV testing as triage for atypical squamous cells of undetermined significance
• High-risk HPV testing alone
• High-risk HPV testing plus anal cytology as triage when high-risk HPV testing is positive
• Cytology and high-risk HPV co-testing

Gaisa and colleagues wanted to determine which of these screening strategies was most effective in a real-world cohort of people with HIV. In their analysis, all screening strategies showed relatively high sensitivities in detecting anal cancers or precancers, ranging from 85% to 96%. However, individual tests had far lower specificities -- just 30% for cytology alone and 27% for high-risk HPV testing alone.

High-risk HPV testing alone had the highest sensitivity (96%) and negative predictive value (92%), but this strategy also led to the highest numbers of referrals for high-resolution anoscopy, with 83% being referred. Cytology alone resulted in 77% being referred.

"Even in high-resource settings, the infrastructure for anal cancer screening is limited with a finite capacity to screen even the highest risk individuals," Gaisa emphasized. Without compromising sensitivity, "screening strategies with higher specificity, like the ones combining anal cytology with high-risk HPV testing, may be more efficient because they curtail the use of diagnostic resources, specifically the use of high-resolution anoscopy," he explained.

"We don't see enough presentations on anal cancer prevention in people with HIV at this conference and it's great to see," Andrew Grulich, MBBS, PhD, of the University of New South Wales in Sydney, commented in a Q&A session. "In regard to getting a more specific screening test, I think a lot of clinicians who are trying to set up anal cancer screening programs for their populations are struggling with the high positivity rate, given the limited resources for treatment." Grulich was not associated with the study.

Persons with HIV have a very high risk of HPV-associated anal cancer, and that risk increases with age. The in men who have sex with men or transgender women ages 30 to 44 is greater than 70 per 100,000 person-years, rising to greater than 100 per 100,000 person years in those ages 45 and older. In comparison, the risk in the general population is 1.7 cases per 100,000 person-years.

Grulich also asked how using screening tests for further triaging could free up resources for management and treatment in places that have few clinicians who perform high-resolution anoscopy, but thousands of patients who may need evaluation.

"I do think we need better screening strategies and potentially additional biomarkers to identify people who are at the highest risk, because the infrastructure is just so dire," Gaisa replied. "It's already dire in the U.S., and if you look at middle-income or low-income countries, it will be much more challenging."

"In terms of treatment, that's a tough one because you know, in order to identify an individual who needs treatment, you're going to have to do the [high-resolution anoscopy] first," Gaisa pointed out. "So I'm not sure if tweaking the diagnostic test will have a downstream effect on reducing the number of folks that need treatment."

"I do believe we need to risk stratify and characterize further the histologic [high-grade squamous intraepithelial lesions] that we find ... because we know not every anal precancerous lesion ends up progressing to cancer," Gaisa added.

Gaisa and colleagues used cohort data from a large clinical database of persons with HIV who underwent primary anal cancer screening at Mount Sinai Health System in New York City. Researchers included 1,620 persons with HIV in the analysis who had anal cytology, high-risk HPV testing, and high-resolution anoscopy-guided biopsy results available between 2012 and 2019. The median age was 45, with a range of 34 to 54 years. The vast majority (90%) were men who have sex with men. The histological anal precancer rate was 42%.

Using biopsy-proven high-grade squamous intraepithelial lesion (i.e., the precancerous stage of anal cancer) as an endpoint, researchers calculated sensitivity, specificity, positive and negative predictive values, and the number of high-resolution anoscopies or referrals that would be triggered by each screening strategy.

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