Should individuals with HIV be screened for high-risk HPV infection and anal high-grade squamous intraepithelial lesions?
Cancer is now the most important cause of mortality among HIV-infected individuals in the United States, and anal cancer is the most common potentially preventable cancer in this population. Like cervical cancer, anal cancer is caused by HPV and is preceded by a precursor lesion, high-grade squamous intraepithelial lesion (HSIL).
Screening for and treating cervical HSIL dramatically reduces cervical cancer incidence. We and others use techniques for anal screening adapted from the cervix, including anal cytology, high-resolution anoscopy (HRA)-guided biopsy of lesions, and treatment of biopsy-proven anal HSIL. These procedures are not standard of care because a study has not yet been done to show that they effectively prevent progression to anal cancer.
We are performing an NCI/OAR-supported randomized clinical trial, the Anal Cancer/HSIL Outcomes Research (ANCHOR) study. The study is designed to prospectively compare anal cancer incidence among those treated for anal HSIL with those who are actively monitored. The results are still several years away, so should we screen for/treat HSIL until we have the data?
The answer is no if follow-up care of an abnormal cytology is not available. The answer is yes for those who have access to HRA and office-based ablative treatment, unless and until ANCHOR says that we should not. The incidence of anal cancer is too high to ignore. Cervical cancer screening works. Anal HSIL treatment is safe and can be performed in the office. If we knew someone had HSIL at any other anatomic site, we would want to treat it. Why should anal HSIL be different? All HIV-infected individuals, regardless of HRA and treatment availability, should have an annual digital anorectal exam because palpation of a hard mass may indicate anal cancer.
What about anal HPV testing in screening? Because most HIV-infected individuals have oncogenic HPV infection, testing for the usual mixture of oncogenic HPV types adds little value for determining who needs HRA. However, testing specifically for the most aggressive HPV types — HPV16/18 — may add positive predictive value to cytology, and a negative HPV test may have high negative predictive value. More research definitely is needed on this topic.
Joel Palefsky, MD, FRCP(C), is professor of medicine and laboratory medicine at University of California, San Francisco. He can be reached at firstname.lastname@example.org. Disclosure: Palefsky reports advisory board roles with Antiva Biosciences, Merck, Novan and Vir Biotechnology; honorarium from Janssen; research grant support from Antiva Biosciences, Merck and Vir Biotechnology; and stock options with Vir Biotechnology.
Anal cancer is a major health issue for people living with HIV. Among gay and bisexual men with HIV, anal cancer occurs at annual rates of up to 100 per 100,000, and it has become the most common non-AIDS-defining malignancy. Anal cancer also is much more common among women and heterosexual men living with HIV than the general population.
Based on the cervical cancer paradigm of cytology-based screening with referral for colposcopy, a proposed anal cancer screening algorithm would refer any cytological abnormality for the diagnostic test, HRA. Although this leads to test sensitivity similar to that of cytology screening for cervical cancer, it also leads to the referral of more than 50% of people with HIV for HRA.
At HRA, the prevalence of detected HSIL is 30% to 40%. HRA is a time-consuming, invasive procedure. It is technically much more demanding than cervical colposcopy, and accurate diagnosis requires a well-trained practitioner. Although cervical screening is moving toward primary HPV screening, HPV screening has been little studied as a screening test for anal cancer. Anal HPV prevalence is extremely high among people with HIV. Anal HPV natural history studies are required so pathogenesis-guided approaches to HPV screening can be developed.
A major limitation of introducing a screening program now is that treatment of screen-detected HSIL, usually by locally destructive therapies, has not been shown to be effective. Recurrence rates after treatment are very high, at around 50%. Based on limited natural history data, this may be no different than what would happen without treatment. A large NIH-funded trial, the ANCHOR study, is investigating whether destructive HSIL therapy leads to lower anal cancer rates than follow-up with close observation.
For all of these reasons, no national organization recommends anal cancer screening using cytology or HPV testing. Until the ANCHOR study reports its findings, screening programs for anal cancer precursors using HPV or cytology should not be introduced. Some HIV guidelines recommend digital anorectal examination to detect palpable early anal cancer so it can be diagnosed and treated early, with lower morbidity and mortality than would occur with more advanced diagnosis.
Andrew Grulich, PhD, MBBS, MSc, is head of the HIV epidemiology and prevention program at Kirby Institute at University of New South Wales in Sydney, Australia. He can be reached at email@example.com. Disclosure: Grulich reports no relevant financial disclosures.