Level 1: Likely reliable evidence

The Females United to Unilaterally Reduce Endo/Ectocervical Disease (FUTURE) I and II trials evaluated efficacy of the quadrivalent human papillomavirus (HPV) recombinant Gardasil. In the FUTURE II trial, 12,167 nonpregnant women aged 15-26 years were randomized to Gardasil or placebo (N Engl J Med. 2007;356: 1915-1927). All women were asked to use an effective contraception method for the first seven months. The primary per-protocol analysis included 10,565 women (87%) with no virologic evidence of HPV-16 or HPV-18 infection at seven months (one month after the third dose), receipt of all three doses, and no protocol violations (4.5% vaccine and 5.2% placebo group had protocol violations). The primary composite end point of high-grade cervical lesion included cervical intraepithelial neoplasia (CIN) grade 2 or 3, adenocarcinoma in situ, or cervical cancer related to HPV-16 or HPV-18. Mean follow-up was three years after the first dose of vaccine.

In an intention-to-treat (ITT) analysis for lesions of any HPV type, the vaccine was associated with lower rates of high-grade cervical lesion (3.6% vs. 4.4%) and CIN 2 (2.5% vs. 3.2%). There were no significant differences in rates of CIN 3 or adenocarcinoma in situ.


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For lesions specific to HPV-16 or HPV-18 type, vaccination was associated with lower rates of high-grade cervical lesion (1.4% vs. 2.4%). Rates of CIN 2 and CIN 3 were each reduced in both ITT and per-protocol analyses.

In an analysis of 911 patients who completed vaccination report cards for 15 days after each vaccination, 83% vaccine vs. 75.8% placebo patients reported injection-site pain. There were no significant differences in rates of systemic events and no large differences in pregnancy outcomes in 3,225 pregnancies of 2,832 women who got pregnant after receiving either vaccine or placebo. In the FUTURE I trial, 5,455 nonpregnant women aged 16-24 years with no history of genital warts were randomized to Gardasil vs. placebo (N Engl J Med. 2007;356:1928-1943). All women were required to use an effective contraception method for the first seven months. The primary per-protocol analysis included 4,540 women (83%) with no virologic evidence of HPV-16 or HPV-18 infection at seven months (one month after the third dose), receipt of all three doses, and no protocol violations (7.3% vaccine and 6.8% placebo group had protocol violations). The primary end point was a composite of genital warts, vulvar or vaginal intraepithelial neoplasia, or cancer. Mean follow-up was three years after the first dose of vaccine.

Comparing vaccine vs. placebo in ITT analysis for lesions of any HPV type, the rate of a high-grade cervical lesion was 10% vs. 13.3% (NNT 30). There were no significant differences in rates of CIN 2, CIN 3, or adenocarcinoma in situ. For lesions of vaccine-type HPV (HPV-6, HPV-11, HPV-16, HPV-18), the vaccine was associated with lower rates of external anogenital or vaginal lesions, any cervical lesion, and high-grade cervical lesion. The vaccine was also associated with lower rates of CIN 2, CIN 3, and adenocarcinoma in situ; differences were statistically significant in the primary per-protocol analysis but not significant in ITT analysis.

Rates of adverse events were also higher with placebo: 86.8% vs. 77.4% injection-site events (erythema, pain, pruritus, or swelling) and 13.3% vs. 10.3% fever. In patients seropositive for at least one vaccine HPV type at baseline, 85.4% vs. 76.5% had an injection-site event and 17.4% vs. 10.3% had fever.