Human Papillomavirus Disease and Vaccines

David J. Hutchinson; Kristin C. Klein

Disclosures

Am J Health Syst Pharm. 2008;65(22):2105-2112. 

In This Article

Bivalent Vaccine

Phase II Study

The efficacy of the bivalent vaccine was assessed in a Phase II clinical trial involving an initial phase and an extended follow-up period.[28] This double-blind, multicenter, randomized, placebo-controlled trial assessed the efficacy of the vaccine in the prevention of incident and persistent infection with HPV-16 or HPV-18 for up to 27 months (n=1113 women). A total of 776 women were also eligible for enrollment into the follow-up study (mean duration, 47.7 months) based on the following criteria: participation in the initial efficacy study, administration of all three doses of vaccine or placebo, and maintenance of double blinding of study groups.[29] Researchers defined incident cervical infection as the first positive PCR detection of HPV-16, HPV-18, or other important high-risk types (HPV types 31, 33, 45, 52, and 58). Persistent infection was defined as the presence of HPV-16 or HPV-18 during the extended follow-up study and was evaluated at 6- and 12-month intervals. A 6-month persistent infection required the presence of the same HPV type in two consecutive assessments over a minimum of 5 months, with no negative samples detected in the interim. A 12-month infection required the same criteria as above but was evaluated over a minimum of 10 months. Vaccine efficacy was also assessed for prevention of cytologically confirmed low- and high-grade cervical lesions as secondary objectives.

Women were eligible for study enrollment if they had no more than six sexual partners, had no history of an abnormal Pap test or previous treatment of the cervix, and were not currently receiving treatment for genital warts. Subjects also had to demonstrate that they were seronegative for HPV-16 and HPV-18 antibodies by enzyme-linked immunosorbent assay and HPV DNA negative by PCR for 14 high-risk HPV types within 90 days before study enrollment. Cervical samples were obtained by health care workers prior to vaccination and at months 6, 12, and 18. In addition, cervicovaginal samples were self-obtained by subjects at months 0 and 6 and every three months thereafter.

The efficacy of the vaccine was evaluated using both a per-protocol and intent-to-treat population. Subjects were excluded from the per-protocol population if they were seropositive for HPV type 16 or 18 or other high-risk HPV genotypes on enrollment, had abnormal cervical cytology, violated study protocol, were seropositive for HPV-16 or HPV-18 within six months, had missing HPV DNA or serology results at screening, or dropped out of the study before month 18.

Results obtained from a combined analysis of the initial and follow-up phases indicated that the vaccine was 94.7% (3 cases in the vaccinated group versus 51 in the placebo group) and 88.5% (9 cases in the vaccinated group versus 51 cases in the placebo group) effective against incident infections in the per- protocol population, respectively (95% CIs, 83.5-98.9% and 77-95%, respectively).[28,29] The vaccine was also highly efficacious in the prevention of 6- and 12-month persistent infections in both the follow-up study and the combined analysis. Vaccine efficacy against HPV-16 and HPV-18 at 6 months in the combined analysis was 96% and 100% at 12 months (1 case in the vaccinated group versus 23 cases in the placebo group; 95% CI, 75.2-99.9%; and 0 cases in the vaccinated group versus 9 cases in the placebo group; 95% CI, 52.2-100%, respectively).[28,29] A high level of efficacy was also noted in the intent-to-treat population at 6 months (94.4%; 2 cases in the vaccinated group versus 34 cases in the placebo group; 95% CI, 78.2-99.4%) and 12 months (94%; 1 case in the vaccinated group versus 16 cases in the placebo group; 95% CI, 61.1-99.9%).

Phase III Study

Paavonen et al.[30] conducted a large, randomized trial (Papilloma Trial Against Cancer In Young Adults [PATRICIA]) involving 18,644 women to assess the efficacy of the bivalent vaccine against CIN grade 2 associated with HPV-16 or HPV-18. Secondary objectives of the study included vaccine efficacy against CIN grades 1 and 2 and persistent infection associated with HPV type 16 or 18 or other oncogenic HPV types. All women enrolled (age 15-25 years) were randomly assigned to receive either bivalent vaccine (n=9,319) or hepatitis A vaccine control (n=9,325) at zero, one, and six months.

The primary objective of the study was assessed in women who were seronegative and DNA negative for HPV-16 and HPV-18 on enrollment in the study. However, the study also included women with prevalent oncogenic HPV infections and low-grade cytologic abnormalities. Following are data from an interim analysis that was conducted when at least 23 cases of CIN grade 2 associated with HPV-16 or HPV-18 were reported in the total vaccinated cohort. All results of the interim analysis were obtained on a modified intent-to-treat analysis basis. Of the 23 cases of CIN grade 2 reported, 2 occurred in the HPV vaccine group and 21 were reported in the hepatitis A control group. Based on these results, vaccine efficacy against CIN grade 2 associated with HPV-16 or HPV-18 was estimated to be 90.4% in an interim analysis (2 cases in the vaccinated group versus 21 cases in the placebo group; 95% CI, 53.4-99.3%; p<0.0001). Efficacy against CIN grade 1-associated HPV-16 or HPV-18 was 89.2% (3 cases in the vaccinated group versus 28 cases in the placebo group; 95% CI, 59.4-98.5%; p<0.0001). Researchers also noted a modest cross-protection against other HPV types commonly associated with cervical cancer at six months postvaccination, including HPV-45 (59.9%; 10 cases in the vaccinated group versus 25 cases in the placebo group; 97.9% CI, 2.6-85.2%), HPV-31 (36.1%; 47 cases in the vaccinated group versus 74 cases in the placebo group; 97.9% CI, 0.5-59.5%), and HPV-52 (31.6%; 79 cases in the vaccinated group versus 116 cases in the placebo group; 97.9% CI, 3.5-51.9%).

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