via Medscape, by Nick Mulcahy

In young men who have sex with men (MSM), the human papillomavirus (HPV) quadrivalent vaccine (Gardasil, Merck) reduced the rates of anal intraepithelial neoplasia (AIN), compared with placebo, according to an international team of investigators.

The study on the vaccine was published in the October 27 issue of the New England Journal of Medicine.
“Our study suggests that [the quadrivalent] HPV vaccination could be a tool for preventing anal HPV-related disease, potentially even cancer,” write the investigators, led by Joel M. Palefsky, MD, professor of medicine at the University of California at San Francisco.

Dr. Palefsky and his colleagues are referring to the fact that an estimated 80% to 90% of anal cancers in American men are related to HPV.

The results of this study were first presented at a European conference and at the federal Advisory Committee on Immunization Practices (ACIP) in 2010, as previously reported by Medscape Medical News.

At that time, a critic said that the study neither proves that anal cancers can be prevented by the vaccine nor robustly proves that the type of AINs that are of the most concern as precancers are prevented.

That critic, Diane M. Harper, MD, professor of medicine in the Departments of Community and Family Medicine, Obstetrics/Gynecology, and Informatic Medicine and Personalized Health at the University of Missouri–Kansas City School of Medicine, has been involved in clinical trials of HPV vaccines in women.

But, in a 2010 interview, Dr. Palefsky told Medscape Medical News that study’s data are “strongly suggestive” of cancer prevention and that Gardasil has proven effectiveness against warts, which is a protection that is highly meaningful to MSM.

“Gardasil will prevent both external genital warts and anal warts, and all indications are that it will prevent cancer with the 2 most important cancer-causing types: HPV 16 and 18,” he said. The “indications” that Dr. Palefsky refers to are the efficacy data in the study related to both biopsy-proven lesions and swab-detected persistent infections.

The published study also indicates that Gardasil reduced the incidence of anal condyloma, “a substantial added benefit of vaccination,” according to the authors.
In their paper, the authors acknowledge that Gardasil has not been proven to prevent anal cancer and that the study was not expected to show that result. At the same time, they say that “vaccination may be the best long-term approach to reducing the risks of both anal cancer and anal condyloma.”

The vaccine was well tolerated. “The proportion of participants who reported serious adverse events or who discontinued the study owing to an adverse event was relatively low and was similar in the 2 groups,” write the authors. About 58% of men in both the placebo and vaccine groups had injection-site reactions, and 18% had some sort of systemic reaction in both groups.

Efficacy Details

The new data on Gardasil in MSM come from a trial known as protocol 020, which involves 4065 young men, including 602 MSM (aged 16 to 26 years), and tests the ability of the vaccine to prevent the abovementioned external genital lesions.

However, in the paper, which is a substudy, the primary efficacy objective was the prevention of AIN or anal cancer related to infection with HPV 6, 11, 16, or 18.

The authors report on 2 populations of MSM in the study — the intention-to-treat population (n = 551) and the per-protocol efficacy population (n = 402).

In the per-protocol efficacy population, 5 men in the vaccine group and 24 men in the placebo group developed an AIN related to HPV 6, 11, 16, or 18.

In the intention-to-treat population, 38 men in the vaccine group and 77 men in the placebo group developed an AIN related to HPV 6, 11, 16, or 18.

These figures translate into an efficacy of the vaccine against AINs associated with HPV 6, 11, 16, or 18 of 77.5% (95% confidence interval [CI], 39.6 to 93.3) in the per-protocol population and 50.3% (95% CI, 25.7 to 67.2) in the intention-to-treat population, report the authors.

Focus on AIN Grade 2/3 Caused by HPV 16 or 18

Dr. Harper suggested that the study’s end point in MSM — the combined incidence of AIN related to HPV 6, 11, 16, and 18 — is a case of mixing apples and oranges.

AINs caused by HPV 6 or 11 is not considered precancerous or carcinogenic, whereas grade 2 and 3 AINs caused by HPV 16 or 18 are precancerous, she explained.

“AIN caused by HPV 6 or 11 is immaterial, as this is never carcinogenic,” said Dr. Harper in an earlier interview.

The study authors touch on this subject too, but with a different emphasis. HPV 6 or 11 “alone are rarely causal,” they write.

Dr. Harper continued her criticism by saying that the study’s primary end point is “a composite end point that hides the true efficacy.”

Dr. Harper focused her comments on the data from the per-protocol population. To have been included in the per-protocol analysis, the young men in the study had to have been free of HPV infections from the time of enrollment until a month after the last vaccine dose. The men in this population were followed for a mean of 2.2 years after month 7, the time of last dose.

Dr. Harper noted that, of the 5 cases of AIN in the vaccinated men, 3 infections were related to HPV 6, and 2 were related to HPV 16. Only by combining the noncancerous and precancerous anal lesions did the investigators achieve statistical significance, compared with placebo, with this efficacy finding, she explained.

Dr. Harper also said that more data are needed to strongly prove that Gardasil is effective against high-grade precancerous anal lesions (AIN grade 2 or 3) caused by the 2 most common cancer-causing HPV types — 16 and 18.

She explained that Merck, at ACIP, revealed data that indicated that the point estimate of efficacy of Gardasil against AIN grade 2/3 caused by HPV 16 or 18 was 86.6% (95% CI, 0.013% to 100.000%). Dr. Harper described this as “evidence, but rather weak evidence,” of the effectiveness of Gardasil against these lesions.

[If an item is not written by an IRMA member, it should not be construed that IRMA has taken a position on the article’s content, whether in support or in opposition.]