ANCHOR

Incomplete

J.M. Palefsky et al.. "Treatment of Anal High-Grade Squamous Intraepithelial Lesions to Prevent Anal Cancer". NEJM. 2022. 386(24):2273‑2282.
PubMed • Full text • PDF

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Clinical Question

Among persons with HIV, does treatment of high-grade squamous intraepithelial lesion (HSIL) reduce progression to anal cancer compared with active monitoring?

Bottom Line

Treatment of anal HSIL reduces the risk of progression to anal cancer compared with active monitoring in people living with HIV.

Major Points

This phase 3 randomized controlled trial included 4459 HIV positive participants assigned to either protocoled HSIL treatment or active monitoring. The primary outcome was progression to anal cancer, with the trial powered at 90% to detect a 75% reduction in cancer incidence with treatment compared to surveillance.

With a median follow-up of 25.8 months, anal cancer incidence was 173 vs. 402 per 100,000 person-years in the treatment and monitoring arms, respectively (HR 0.43, 95% CI 0.20–0.92; P = 0.03)Palefsky JM et al. Treatment of Anal High-Grade Squamous Intraepithelial Lesions to Prevent Anal Cancer. N Engl J Med 2022. 386:2273-2282.. This provides the first high-quality evidence that treating anal HSIL in patients with HIV effectively prevents progression to anal cancer.

Guidelines

• Office-based hyfrecation (i.e. electrocautery) is a reasonable first-line approach to treatment of anal HSIL among persons living with HIV.
• Biopsy-confirmed anal HSIL should undergo treatment to reduce the cancer risk in persons living with HIV (Grade A, Level I evidence)

U.S. Department of Health and Human Services (DHHS); Centers for Disease Control and Prevention (CDC); Infectious Diseases Society of America (IDSA); HIV Medicine Association (HIVMA); Panel on Opportunistic Infections in Adults and Adolescents with HIV. Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV. ClinicalInfo.HIV.gov. 2024. Available at: https://clinicalinfo.hiv.gov/sites/default/files/guidelines/documents/adult-adolescent-oi/guidelines-adult-adolescent-oi.pdf. Accessed June 22, 2025.

“International Anal Neoplasia Society (IANS) – 2024 Consensus Guidelines”

• Treating anal HSIL reduces the progression to anal cancer
• Routine anal screening for high risk groups
  • Age 35 in HIV-positive MSM/transgender women,
  • Age 45 in other people with HIV or high-risk HIV-negative MSM,
  • Within 1 year after diagnosis for women with vulvar/vaginal neoplasia
• Recommended screening Anal cytology ± HPV testing, reflex HRA for abnormal screens reflects ANCHOR’s approach of early HSIL detection

“Infectious Diseases Societies (HIV Primary Care Guidance) – IDSA/HIVMA 2024”

• Annual DRE in HIV patients with anal Pap tests in at-risk individuals
  • HIV+ transgender women ≥35 who have sex with men
  • HIV+ cisgender men ≥35 who have sex with men
  • All other HIV+ persons ≥45, provided referrals for HRA and treatment are available

HIV Medicine Association (HIVMA); Infectious Diseases Society of America (IDSA). Primary Care Guidance for Persons with HIV. 2024. Available at: https://www.idsociety.org/practice-guideline/primary-care-hiv/. Accessed June 22, 2025.

Design

• Setting: 25 U.S. sites
• Phase: 3 randomized controlled trial
• Enrollment: 10,723 participants assessed for eligibility, with 4459 randomized after excluding 6264 for ineligibility, baseline cancer, refusal, or other reasons.
• Treatment: Randomized to HSIL treatment (ablative, excisional, or topical therapy) vs active monitoring with high-resolution anoscopy every 6 months and biopsy as indicated.
• Randomization: 1:1 HSIL treatment vs monitoring, stratified by site, nadir CD4 (≤200 vs >200 cells/mm³), lesion size (≤50% vs >50% of anal canal/perianal region)
• Primary endpoint: Progression to anal cancer, measured as incidence per 100,000 person-years.
• Secondary endpoints: Safety outcomes associated with the interventions, adverse events
• Analysis: Intention-to-treat. Sensitivity analysis performed to account for non-adherence.
• Power: 90% to detect 75% reduction in anal cancer incidence; target 31 cancer cases

Population

Inclusion Criteria

• Age ≥35 years, living with HIV
• Biopsy‑confirmed anal HSIL (AIN3 or p16‑positive and AIN2)

Exclusion Criteria

• Personal history or findings of anal cancer at screening

Baseline Characteristics

“Data shown for treatment group”

• Median age (IQR): 51 years (44–57)
• Median time since HIV diagnosis (IQR): 17 years (10–24)
• Median follow-up (IQR): 25.3 months (11.7–42.0)
• Gender identity
  • Male: 1793 (80.5%)
  • Female: 346 (15.5%)
  • Transgender: 85 (3.8%)
  • Nonbinary: 2 (0.1%)
  • Declined to answer: 1 (<0.1%)
• Race or ethnic group
  • Black: 935 (42.0%)
  • Non-Hispanic White: 695 (31.2%)
  • Non-Black Hispanic: 381 (17.1%)
  • Asian or Pacific Islander: 27 (1.2%)
  • Other or unknown: 189 (8.5%)
• CDC criterion for risk of HIV infection
  • Male-to-male sexual contact: 1716 (77.1%)
  • Heterosexual: 532 (23.9%)
  • Injection-drug use: 152 (6.8%)
  • Transfusion: 53 (2.4%)
  • Hemophilia: 2 (0.1%)
  • Other: 34 (1.5%)
• Smoking history
  • Current smoker: 710 (31.9%)
  • Smoked >100 cigarettes over lifetime: 1268 (56.9%)
• History of HSIL treatment ≥6 months before randomization: 228 (10.2%)
• Plasma HIV-1 RNA copies/ml
  • <50: 1853/2213 (83.7%)
  • 51–199: 155/2213 (7.0%)
  • 200–1000: 83/2213 (3.8%)
  • >1000: 122/2213 (5.5%)
• Median CD4 count (IQR): 602 cells/mm³ (393–827)
• Nadir CD4 count
  • ≤200 cells/mm³: 1130 (50.7%)
  • >200 cells/mm³: 1097 (49.3%)
• HSIL size at screening
  • >50% of anal canal or perianal region: 285 (12.8%)
  • ≤50% of anal canal or perianal region: 1942 (87.2%)

Interventions

• Treatment arm: Initial therapy to remove HSIL using ablative, excisional, or topical methods, followed by high-resolution anoscopy every 6 months with repeat treatment for persistent or recurrent HSIL to maintain disease clearance.
  • 81% ablative therapy, 4% excision under anesthesia, 4% topical therapy, and 11% combination
• Monitoring arm: high-resolution anoscopy every 6 months and biopsy annually or as needed; no HSIL treatment unless cancer suspected

Outcomes

Comparisons are Treatment vs Monitoring’’

Primary Outcome

Progression to Anal Cancer

9/2227 (0.4%; 173 per 100,000 person-years) vs. 21/2232 (0.9%; 402 per 100,000 person-years) (HR 0.43, 95% CI 0.20–0.92; P = 0.03)

Secondary Outcomes

• Multivariable Cox regression Analysis of Variables that Influence Progression of HSIL to Anal Cancer

Lesion size >50% of anal canal or perianal region

HR 5.26, 95% CI 2.54–10.87

Nadir CD4 count ≤200 cells/mm³

HR 1.93, 95% CI 0.88–4.23

Smoking history (>100 lifetime cigarettes)

HR 0.74, 95% CI 0.35–1.56

Prior HSIL treatment ≥6 months before randomization

HR 1.06, 95% CI 0.36–3.10

Adverse Events

Adverse events

683/2227 (30.7%) vs. 635/2219 (28.6%)

Serious adverse events

586/2227 (26.3%) vs. 568/2219 (25.6%)

Trial-related adverse events

43/2227 (1.9%) vs. 4/2219 (0.2%)

Trial-related serious adverse events

7/2227 (0.3%) vs. 1/2219 (<0.1%)

Skin ulceration due to fluorouracil

1/2227 (<0.1%) vs. 0/2219 (0%)

Anal abscess due to electrocautery

1/2227 (<0.1%) vs. 0/2219 (0%)

Pain due to electrocautery

1/2227 (<0.1%) vs. 0/2219 (0%)

Pain due to treatment under anesthesia

1/2227 (<0.1%) vs. 0/2219 (0%)

Pain due to infrared coagulation

1/2227 (<0.1%) vs. 0/2219 (0%)

Infection or abscess due to anal biopsy

2/2227 (<0.1%) vs. 1/2219 (<0.1%)

Criticisms

• Median follow‑up of ~26 months may be insufficient for long-term cancer prevention assessment
• Variation in treatment modalities
• Results are specific to PLWH and may not apply to HIV-negative populations
• Unclear extrapolation to p16 negative AIN2

Funding

• Funded by National Cancer Institute
• No commercial support