Acceptability and Feasibility of Combination Treatment for Cervical Precancer Among Women Living with HIV in South Africa: Primary Outcomes from the ACT 2 Randomized Trial

This Phase 2b randomized trial conducted in South Africa demonstrates that combining loop electrosurgical excision procedure (LEEP) with adjuvant intravaginal 5-fluorouracil is an acceptable and feasible treatment for cervical precancer in women living with HIV, supporting its advancement to a Phase 3 trial despite a higher incidence of mild inflammatory side effects.

The Gist

The Big Picture: A "Double-Whammy" Strategy

Imagine the cervix (the neck of the uterus) as a garden. In women living with HIV, this garden is more vulnerable to a specific type of weed called CIN2/3 (cervical precancer). If left alone, these weeds can grow into a full-blown, dangerous forest fire (cervical cancer).

Usually, doctors use a "weed whacker" called LEEP (a surgical procedure) to cut the weeds out. But for women with HIV, the weeds often grow back quickly because their immune systems are busy fighting a different battle (HIV).

The Question: What if, after using the weed whacker, we also sprayed a special "weed killer" cream to stop the seeds from sprouting again?

The Study: This paper reports on a trial called ACT 2 in South Africa. Researchers tested if adding a cream called 5-Fluorouracil (5FU) to the standard surgery was a good idea. They wanted to know three things:

1. Would women actually use it? (Acceptability)
2. Could the system handle it? (Feasibility)
3. Was it safe? (Safety)

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The Experiment: A "Blind Taste Test"

Think of this study like a blind taste test for a new recipe.

• The Participants: 180 women living with HIV who had already had the "weed whacker" surgery (LEEP).
• The Groups: They were split into two teams.
  • Team A (The Real Deal): Got the actual 5FU cream.
  • Team B (The Placebo): Got a fake cream that looked and felt exactly the same but did nothing.
• The Rule: Neither the women nor the doctors knew who got which cream (Double-Blind).
• The Routine: Every two weeks for four months, the women applied the cream themselves at home, like putting on lotion.

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The Results: Did It Work?

1. The "Will They Use It?" Test (Acceptability & Adherence)

The Verdict: Yes, overwhelmingly.
Imagine asking 100 people to use a new app. If 94 of them say, "I love it, it's easy," that's a huge win.

• 94% of the women said the cream was easy to use and they were happy with it.
• 91% actually followed the rules and used the cream at least 6 out of 8 times.
• The Analogy: It was like getting a group of people to take a daily vitamin. Even though it was a new routine, almost everyone stuck with it.

2. The "Did They Stay?" Test (Retention)

The Verdict: Mostly yes, but the "Real Deal" team had a few dropouts.

• 99% of the women who got the fake cream stayed until the end.
• 92% of the women who got the real cream stayed until the end.
• Why the drop? The real cream caused some side effects (more on that below), which made a few women decide to quit the study early. However, even with the side effects, the vast majority (92%) stuck it out.

3. The "Is It Safe?" Test (Safety)

The Verdict: It was safe, but it had a "kick."
Think of the 5FU cream like a strong cleaning spray. It works well, but it can irritate your skin if you aren't careful.

• The Placebo Team: Had very few issues (about 27% had mild irritation).
• The Real Cream Team: Had more irritation (about 49% had mild to moderate redness or inflammation).
• The Severity: Most of this was just "sunburn-level" irritation (Grade 1 or 2). It was uncomfortable but not dangerous.
• The One Big Scare: One woman had a severe allergic reaction (Grade 3), which is like a severe rash that needed a doctor. She stopped using the cream but was fine afterward. No one died, and no one had life-threatening issues.

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The Takeaway: Why This Matters

The "So What?"
This study didn't prove the cream cures the cancer yet (that's for the next big study). Instead, it proved that the idea is doable.

• The Good News: Women in a low-resource setting (South Africa) were willing to use this home-applied cream. They didn't need a fancy machine or a doctor to apply it every time. They could do it themselves.
• The Challenge: The cream does cause some irritation. Future studies need to make sure women know about this "kick" so they don't get scared and quit.
• The Future: Because the women liked it and stuck with it, the researchers are now ready to move to a Phase 3 trial. This is the "big league" test to see if this combination (Surgery + Cream) actually stops the cancer from coming back better than surgery alone.

In a Nutshell

Imagine you are trying to fix a leaky roof. You patch the hole (Surgery/LEEP), but you know rain might come back. So, you decide to paint a special sealant over the patch (The Cream).

This study asked: "Can we get people to paint this sealant themselves? Is it too messy? Is it safe?"
The answer was: "Yes, people will do it, it's mostly safe, and it's a bit messy, but it's worth trying to see if it stops the roof from leaking for good."

This gives hope that in the future, women with HIV in Africa might have a simple, affordable way to prevent cervical cancer that doesn't require expensive hospital visits.

Technical Summary

1. Problem Statement

Cervical cancer remains a leading cause of cancer-related mortality among women, particularly in low- and middle-income countries (LMICs). Women living with HIV (WLWH) face a disproportionately high burden of high-risk human papillomavirus (hrHPV) infection and high-grade cervical intraepithelial neoplasia (CIN2/3).

• Current Limitations: Standard treatment for CIN2/3 involves surgical excision (Loop Electrosurgical Excision Procedure [LEEP]) or ablation. While effective for immunocompetent women, WLWH experience high rates of persistent or recurrent disease (20–55%) post-surgery.
• The Gap: Repeat surgeries are often required, but follow-up and surgical capacity are frequently limited in LMIC settings. There is an urgent need for adjuvant therapies that can reduce recurrence rates without requiring complex clinical infrastructure.
• Proposed Solution: Intravaginal 5-fluorouracil (5FU) cream, a topical chemotherapeutic agent that inhibits DNA synthesis, has shown promise in previous U.S. trials. However, its acceptability, feasibility, and safety profile had not been evaluated in an African LMIC setting among WLWH.

2. Methodology

Study Design:

• Type: Double-blind, randomized, placebo-controlled Phase 2b feasibility trial (ACT 2).
• Setting: Public-sector teaching hospital in Johannesburg, South Africa.
• Population: 180 WLWH aged ≥18 years with confirmed CIN2/3 (via LEEP histology) and on antiretroviral therapy (ART) for ≥60 days.
• Randomization: 1:1 allocation to either the intervention or placebo arm using a permuted block design.

Intervention:

• Procedure: All participants underwent a standard LEEP.
• Intervention Arm: Self-administered 8 doses of 5% intravaginal 5FU cream (2g) every other week for 24 weeks.
• Control Arm: Self-administered 8 doses of an inert emollient placebo cream (matching appearance/consistency) on the same schedule.
• Blinding: Double-blind (participants and outcome assessors); unblinded pharmacist handled allocation.

Primary Outcomes:
The study focused on acceptability and feasibility rather than efficacy. Key metrics included:

• Acceptability: Measured via a 7-item Likert-scale questionnaire (score ≥80% considered acceptable).
• Adherence: Measured via Ultraviolet Inspection (UVI) of applicators (primary), applicator counts, and self-report. Defined as completing ≥6 of 8 doses.
• Retention: Completion of the 24-week follow-up.
• Safety/Tolerability: Monitoring for adverse events (AEs), specifically Grade 1 genital lesions (blisters, pustules, ulcers) and Grade ≥2 AEs. Dose-limiting toxicities (DLTs) were defined as events requiring dose reduction or discontinuation.

Statistical Analysis:

• Primary analysis used a modified intention-to-treat (mITT) population (all randomized participants who received at least one dose).
• Comparisons between arms were made using probability differences (PD) or risk differences (RD) with 95% confidence intervals (CIs).

3. Key Contributions

• First LMIC Trial: This is the first randomized controlled trial (RCT) to evaluate LEEP combined with adjuvant intravaginal 5FU in an African setting, addressing the region with the highest cervical cancer burden.
• Feasibility Validation: It provides critical data on the practical implementation of a self-administered topical therapy in a resource-limited context, informing the design of future Phase 3 efficacy trials.
• Safety Profile Characterization: It establishes the specific safety and tolerability profile of a lower-potency, every-other-week 5FU regimen in WLWH, distinguishing it from historical high-frequency dosing regimens that caused severe toxicity.
• Methodological Rigor: The study utilized multiple adherence measures (UVI, counts, self-report) and a double-blind placebo control, which is rare for feasibility studies, reducing bias in outcome assessment.

4. Results

Demographics:

• Median age: 41 years; Median CD4+ count: 636 cells/mm³; 98.9% virologically suppressed.
• Baseline characteristics were well-balanced between the 5FU (n=90) and placebo (n=90) arms.

Primary Outcomes:

• Acceptability: High and comparable between arms. At Week 24, 94.0% of the 5FU arm and 94.4% of the placebo arm had an acceptability score ≥80% (PD -0.5%, 95% CI -7.4% to 6.5%).
• Adherence: High adherence was observed. By UVI, 91.1% of the 5FU arm and 95.6% of the placebo arm completed ≥6 doses (PD -4.4%, 95% CI -11.7% to 2.8%). Agreement between adherence measures was high (ICC 0.88).
• Retention: Overall retention was high (>92%), but there was a statistically significant difference at Week 24. The 5FU arm had lower attendance (92.2%) compared to the placebo arm (98.9%) (PD -6.7%, 95% CI -14.4% to -0.5%).
• Safety:
  • Primary safety events (Grade 1 genital lesions or Grade ≥2 AEs) occurred more frequently in the 5FU arm (49.2%) than the placebo arm (26.7%) (RD 22.5%, 95% CI 8.6% to 36.4%).
  • Most events were mild (Grade 1 or 2) cervical inflammation.
  • Severe Events: One Grade 3 adverse event (allergic reaction to 5FU) occurred in the 5FU arm, leading to drug discontinuation. No Grade 4 events or deaths occurred.
• Tolerability: Only one DLT occurred (in the 5FU arm).

5. Significance and Conclusion

The ACT 2 trial demonstrates that LEEP combined with adjuvant intravaginal 5FU is acceptable and feasible for treating cervical precancer in WLWH in South Africa.

• Clinical Implication: Despite a higher burden of mild-to-moderate side effects in the 5FU arm, acceptability and adherence remained high (>90%). This suggests that women can manage the self-administration regimen even with side effects, a crucial finding for the success of future efficacy trials.
• Future Directions: The results support proceeding to a Phase 3 efficacy trial. However, future trial designs must account for the observed differential in retention and safety events between arms. Strategies may include enhanced counseling, monitoring for DPD deficiency (a genetic risk factor for 5FU toxicity), and adjusting sample size calculations for anticipated attrition.
• Public Health Impact: If proven effective in Phase 3, this combination therapy offers a scalable, low-cost, and pragmatic strategy for reducing cervical cancer incidence in LMICs, as it relies on self-administration rather than specialized clinical infrastructure.