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Human papillomavirus (HPV) vaccination is recommended for children and younger adults but not older adults or those with prior HPV exposure, leaving a large portion of the population at risk for HPV-mediated disease. Emerging data suggest a possible role for vaccination as an adjuvant treatment for individuals with HPV-related clinical disease.To systematically review the literature regarding HPV vaccination for secondary disease prevention after treatment of active clinical disease across disease sites to serve as a platform for the management of HPV-related disease of the head and neck.A systematic search from August 3 to 21, 2015, of the PubMed, MEDLINE, EMBASE, CINAHL, Cochrane Library, Web of Science, Biosis Citation Index, Current Contents Connect, Scientific Library Online, and Global Health databases used PRISMA guidelines to identify 326 relevant articles related to adjuvant use of HPV vaccination. Primary search terms were (HPV vaccine OR human papillomavirus vaccine OR papillomarvirus vaccines OR alphapapillomavirus vaccine) AND (HPV OR human papillomavirus OR alphapapillomavirus OR papillomaviridae OR virus warts OR wart virus) AND (recurrence OR relapse OR reoccurrence OR recurrences OR relapses OR relapsing). Forty-five full texts in English were reviewed, with 19 articles included in the final review. In some studies, subpopulations of individuals with HPV DNA positivity and/or seropositivity were extracted for inclusion. Included studies were assessed for bias and separated based on the presence of active clinical disease or HPV DNA positivity or seropositivity.Nineteen studies with 22 474 unique patients were included in the review. When HPV vaccination was used as an adjuvant treatment for active clinical disease, 9 of 12 studies reported decreased disease recurrence, decreased disease burden, or increased intersurgical interval. In contrast, none of the 7 studies of vaccination in individuals with HPV DNA positivity and/or seropositivity without clinical disease reported improved outcomes.Differences between adjuvant vaccination in HPV-mediated clinical disease and vaccination in HPV DNA–positive and/or HPV-seropositive populations posit underlying differences in disease and immune processes. These data suggest that additional evaluation of adjuvant HPV vaccination in individuals with active clinical disease is warranted.