Reference: JAMA Dermatol. 2025 Mar 6:e250531
Practice Point: The HPV vaccine series appears to reduce the burden and progression of actinic keratoses (AKs), at least in older adults with ≥ 15 lesions.
EBM Pearl: When checking to ensure prognostic equivalence in trials, the first step should be to look for any clinically important baseline differences, almost always found in “Table 1.”
At a time when vaccine safety is once again being questioned, we have some good news: A new randomized trial shows that the HPV vaccine seems to help clear AKs in those with a high burden. These potentially precancerous skin lesions affect 14% of people worldwide, racking up $1 billion in treatment costs each year. People with multiple AKs are at the highest risk of progression to squamous cell carcinoma (SCC), with progression rates up to 29% at 5 years. We know that HPV plays some role in AK formation and has been implicated in the development of SCC, especially in immunosuppressed individuals, so this potential “side effect” of the HPV vaccine could actually be a big deal.
Investigators randomized 70 immunocompetent adults (median age 76 years) living in Denmark who had 15 or more AKs to receive either 3 doses of the HPV vaccine or sham vaccine at months 0, 2, and 6. The trial was triple-blinded, and patients were followed up at 12 months for the primary outcome of total AK burden compared to baseline. Due to ethical concerns about untreated AKs, lesions that progressed past a certain point (Olsen grade II or III on a scale of I to III) were treated with cryotherapy.
Results of an intention-to-treat analysis demonstrated a significant reduction in AK burden in the HPV-vaccinated group at all time points from months 2 to 12, on the order of a 20% greater reduction at 12 months in the HPV-vaccinated group. The number of total AKs and thickness were also reduced in the HPV-vaccinated group. Interestingly, the number of new AK lesions was not different between groups.
We’d like to applaud the authors for making it crystal clear that allocation was concealed by writing, “The allocation sequence was generated by computer-based block randomization …”. We wish more authors would do that rather than being vague and leaving us searching for clues. The authors go on to describe that allocation was carried out by a third party using unique computer-generated sequences and was placed in sealed opaque envelopes and stored in a separate facility. Allocation concealment is a critical step in preventing selection bias. In trials, most people believe that the intervention is going to be beneficial and that it’s better to be assigned to the treatment group rather than the control group, so knowing to which group a patient would be assigned may bias the decision to enroll a patient in a study. For example, let’s say we were studying a medication for heart failure. If the treating physician knew a sick patient would be assigned to the sham group, they may not enroll them out of concern for undertreatment, which would lead to healthier people being enrolled into the control group and sicker patients enrolled into the treatment group. The two groups would therefore have dissimilar baseline characteristics, and treatment effects would be skewed. Allocation concealment protects prognostic equivalence, meaning that participants in each group have, on average, the same likelihood of experiencing the outcome of interest based on their baseline characteristics.
Having said that, when allocation is concealed and randomization is well-executed, patients are expected to have similar baseline characteristics. In this case, the sham group ended up with far fewer patients (26% vs. 51%) with the highest-risk skin type (Fitzpatrick type I, fair skin that always burns). As previously described, allocation concealment seems to have been robust, nay, ironclad, in this study. This suggests that perhaps the study size was too small and by random chance more people with fair skin ended up in the treatment group, or, that something went wrong with the randomization process itself. Any time there are clinically important baseline differences between treatment groups, no matter the reason, we must interpret the results cautiously.
One more important thing to note is that the study population consisted of adults attending regular outpatient visits at a dermatology office. Presumably, this means that these patients had a high burden of AKs or were judged to be at high enough risk that a GP (it was Denmark) referred them out. (FYI, PCPs can one million percent treat AKs in the office.) You know what else PCPs can do? Order HPV vaccines. All in all, it seems that even though future studies are certainly indicated, we may not be too far off from considering the HPV vaccine a potential treatment option for clearing AKs.
DynaMed EBM Focus Editorial Team
This EBM Focus was written by Katharine DeGeorge, MD, MS, Senior Deputy Editor at DynaMed and Associate Professor of Family Medicine at the University of Virginia. Edited by Alan Ehrlich, MD, FAAFP, Executive Editor at DynaMed and Associate Professor in Family Medicine at the University of Massachusetts Medical School; Dan Randall, MD, MPH, FACP, Senior Deputy Editor at DynaMed; McKenzie Ferguson, PharmD, BCPS, Senior Clinical Writer at DynaMed; Rich Lamkin, MPH, MPAS, PA-C, Clinical Writer at DynaMed; Matthew Lavoie, BA, Senior Medical Copyeditor at DynaMed; Hannah Ekeh, MA, Senior Associate Editor II at DynaMed; and Jennifer Wallace, BA, Senior Associate Editor at DynaMed.