Reports based on a press release in October suggested it, but now the full data tell the story: Early monitoring and treatment of anal high-grade squamous intraepithelial lesions (HSIL) cut risk for anal cancer by 57% in people living with HIV.
"We now show, for the first time, that treatment of anal HSIL is effective in reducing the incidence of anal cancer," said Joel Palefsky, MD, lead investigator of the Anal Cancer/HSIL Outcomes Research (ANCHOR) study and founder/director of the University of California, San Francisco's, Anal Neoplasia Clinic. "These data should be included in an overall assessment for inclusion of screening for and treating HSIL as standard of care in people living with HIV."
Palefsky presented the full results in a special session at the Conference on Retroviruses and Opportunistic Infections (CROI) 2022 Annual Meeting, which drew excitement, gratitude, and relief from both researchers and clinicians, who flocked to the session.
But it's not just people with HIV who will benefit from this research. Palefsky suggested that the findings should also be considered as guides for other people at high-risk for anal cancer, such as people who are immunocompromised for other reasons, including those with lupus, ulcerative colitis, Crohn's disease, or cisgender women who have had vulvar or cervical cancer or precancer.
"If we can show efficacy in the most challenging group of all, which are people living with HIV, we think the results can be as good, if not even better, in the other groups at high risk of anal cancer," Palefsky said.
But to serve anyone — whether living with HIV or not — infrastructure, algorithms, and workforce training are going be needed to meet the currently unserved people through use of high-resolution anoscopy (HRA) and other screening technology, he said.
Palefsy and colleagues screened 10,723 people living with HIV being served at 15 clinics nationwide. More than half, 52.2%, had anal HSIL — 53.3% of the cisgender men living with HIV in the trial, 45.8% of the cis women living with HIV, and a full 62.5% of transgender participants.
Those 4446 participants were split evenly between the treatment arm and the control arm. Those in the treatment arm received treatment for HSIL on their first study visit via one of five options: hyfrecation, office-based electrocautery ablation, infrared coagulation, topical 5-fluorouracil cream, or topical imiquimod. Then, every 6 months after that, they came in for HRA, blood tests, anal Pap smears, and biopsies to check for any lingering or new HSIL. If clinicians found such cells, they received treatment again. If biopsies still showed HSIL and clinician and participant were worried about cancer, they could come in as frequently as every 3 months and receive treatment each time.
The active-monitoring control group still received an anal Pap smear, blood tests, biopsy, and HRA every 6 months — a level of care that is currently not mandated anywhere for people living with HIV, Palefsky told Medscape Medical News. They were also able to come in for more frequent monitoring (every 3 months) if clinicians were worried about cancer.
"Those in both arms would have been getting more attention than if they had not participated in the study," he said.
In addition, during screening, researchers found that cancer was already present in 17 other people, who skipped the study to go right to treatment.
Participants reflected the demographics of the HIV epidemic in the US. They were older (median age, 51 years), mostly gay (78%) and cisgender male (80%). Close to half, 42%, were Black, and 16% were Latino. In addition, cisgender women made up 16% of the participants and transgender people, and nonbinary individuals accounted for more than 3% of the participants. In addition, 1 in 3 smoked.
The vast majority of participants had well-controlled HIV and healthy immune systems, though half in each arm had a history of AIDS, defined as lowest-ever CD4 immune cell counts below 200. Today, more than 80% of participants had undetectable viral loads, defined as a viral load less than 50 copies/mL, and another 7% had HIV viral loads below 200. In total, 9.3% in the treatment arm and 10.9% in the control arm had HIV viral loads higher than that. At time of enrollment, CD4 counts were above 600 in each group, indicating healthy immune systems.
Although all participants were there because they had anal HSIL, more than 1 in 10 — 13% — had abnormal cells so extensive that they covered more than half of the anal canal or the perianal region.
Once everyone was enrolled, researchers began monitoring and treatment, looking specifically for 31 cases of cancer — a number the team had determined that they'd need in order to draw any conclusions. Palefsky didn't have to wait long. They were still trying to enroll the last 1000 participants to have the power necessary to reach that number when the cancer diagnoses came in.
Palefsky told Medscape Medical News that the reason for that is unclear. It could be that some of those cases would have resolved on their own, and so the swiftness with which they reached the required number of cancer cases belies their seriousness. It could also be that the particular people who enrolled in this trial were engaging in behaviors that put them at even higher risk for anal cancer than the population of people living with HIV in the US.
Or it could be that symptom-based screening is missing a lot of cancers that currently go untreated.
"So perhaps we will be seeing an increase in anal cancer reported in the future compared the currently reported rates," he said. "We don't really know."
Regardless of the reason for the speed to cases of cancer, the results were definitive: Nine participants were diagnosed with invasive anal cancer in the treatment arm, while 21 were diagnosed with invasive anal cancer in the control arm. That's a 57% reduction in cancer occurrence between the arms. Or, to put it another way, the rate of anal cancer among people in the treatment arm was 173 per 100,000 people-years. In the active monitoring arm, it was 402 per 100,000 person-years. For context, the overall rate of anal cancer among people living with HIV is 50 per 100,000 person-years. The rate in the general US population is 8 per 100,000 people-years.
The experimental treatment was such a definitive success that investigators stopped the trial and shifted all participants in the control arm to treatment.
"We Have to Build"
Before Palefsky was even done presenting the data, clinicians, people living with HIV, and experts at the session were already brainstorming as to how to get these results into practice.
"These data are what we have LONG needed to fuel some action on this important problem, including medical cost reimbursement through insurance and increasing the number of persons trained and capable in anal cancer screening," John Brooks, MD, head of the epidemiology research team at the Centers for Disease Control and Prevention's Division of HIV/AIDS Prevention, wrote in the virtual chat.
Jeff Taylor, a member of the ANCHOR advisory board and a person living with HIV who participated in one of the first AZT trials in the late 1980s, responded quickly.
"What kind of advocacy from researchers, HIV clinicians and [people living with HIV] is needed to get this on treatment guidelines, HRA providers trained and certified, and payors to cover this so [people living with HIV] actually have access to lifesaving screening and [treatment]?" Taylor asked.
It's a serious challenge. David Malebranche, MD, commented in an interview with Medscape. He's an Atlanta-based internal medicine physician who specializes in sexual health and HIV. When he saw the initial press release last year on the ANCHOR findings, his first reaction was, "Thank god. We finally have some data to show what we've been trying to get people to do" all along.
But then he wondered, who is going to perform these tests? It's a fair question. Currently, the wait for an HRA is 6 to 12 months in many parts of the country. And Malebranche can't imagine this being added to his already full plate as a primary care provider.
"If you tell a primary care provider now that they have to do a rectal Pap smear, that's going to be a problem while you're also asking them to screen each patient for depression, anxiety, domestic abuse, intimate partner violence, all the healthcare maintenance and all the other screening tests — and then you deal with not only the urgent complaint but then all the complex medical issues on top of that — in a 15-minute or 10-minute visit," he said.
Now that we have these data, he said, "we have to build."
Palefsky agreed. Very few centers have enough people skilled at performing HRAs to meet the current demand, and it's not realistic to expect clinicians to perform an HRA every 6 months like the study team did, he said. There need to be algorithms put in place to help practitioners figure out who among their patients living with HIV could benefit from this increased screening, as well as biomarkers to identify HSIL progression and regression without the use of HRA, Palefsky told attendees. And more clinicians need to be recruited and trained to read HRAs, which can be difficult for the untrained eye to decipher.
Malebranche added another, more fundamental thing that needs to be built. Malebranche has worked in HIV clinics where the majority of his patients qualify for insurance under the Ryan White Program and get their medications through the AIDS Drug Assistance Program. While Ryan White programs can provide critical wraparound care, Malebranche has had to refer out for something like an HRA or cancer treatment. But the people who only access care through such programs may not have coverage with the clinics that perform HRA or that treat cancer. And that's if they can even find someone to see them.
"If I live in a state like Georgia, which doesn't have Medicaid expansion and we have people who are uninsured, where do you send them?" Malebranche asked Medscape Medical News. "This isn't theoretical. I ran into this problem when I was working at the AIDS Healthcare Foundation last year.... This is a call for infrastructure."
The study was funded by the National Cancer Institute at the National Institutes of Health. Brooks reports no relevant financial relationships. Palefsky has received consultant fees from Merck and Co, Vir Biotechnology, Virion Therapeutics, and Antiva Bioscience, as well as speaker fees from Merck and Co. Malebranche has received consulting and advising fees from ViiV Healthcare.
Conference on Retroviruses and Opportunistic Infections (CROI) 2022 Annual Meeting: Abstract 98. Presented February 15, 2022.
Heather Boerner is a science journalist based in Pittsburgh, Pennsylvania. Her book, Positively Negative: Love, Pregnancy, and Science's Surprising Victory Over HIV, was published in 2014.
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Cite this: Full Results of Anal Cancer Study Point to Barriers to Care - Medscape - Feb 18, 2022.