Medical Grand Rounds

Update on infectious disease prevention: Human papillomavirus, hepatitis A

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ABSTRACTKey studies on the prevention of human papillomavirus and hepatitis A published during the past year found that:

  • A quadrivalent vaccine against human papillomavirus prevents cervical intraepithelial neoplasia, vulvar and vaginal intraepithelial neoplasia, and anogenital disease in young women. The vaccine is likely cost-effective when given to girls, but perhaps not when given to boys.

  • Although hepatitis A immune globulin is modestly better than hepatitis A vaccine for postexposure prophylaxis against hepatitis A, both are highly effective. Hepatitis A vaccine is now recommended by the Advisory Committee on Immunization Practices as the preferred agent in healthy individuals between the ages of 2 and 40.



How we prevent human papillomavirus (HPV) infection, and how we prevent hepatitis A following exposure to an index case have changed, based on the results of several key clinical trials published during the past year. The results of these studies should influence the measures we take in our daily practice to prevent these diseases. Here is a brief overview of these “impact” studies.


FUTURE II Study Group. Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med 2007; 356:1915–1927.

Cervical cancer is the second most common type of cancer in women and is the leading cause of cancer-related deaths in developing countries. More than 500,000 new cases of cervical cancer are reported worldwide each year, and about 250,000 women die of it.1

Nearly all cases of cervical cancer are caused by HPVs, and the oncogenic types HPV-16 and HPV-18 together account for about 70%. These two types also cause vulvo-vaginal cancer, which accounts for about 6% of all gynecologic malignancies.2 Two other HPV types, HPV-6 and HPV-11, cause genital warts and, less often, cervical intraepithelial neoplasia and cervical invasive cancers.

Two HPV vaccines have been developed. One, sold as Cervarix, is directed against HPV-16 and HPV-18; it is not yet available in the United States. The other, sold as Gardasil, is directed against four HPV types: 6, 11, 16, and 18, and it is currently available (reviewed by Widdice and Kahn3).

The study. The Females United to Unilaterally Reduce Endo/Ectocervical Cancer (FUTURE) II study4 assessed the ability of the quadrivalent vaccine to prevent high-grade cervical lesions. Between June 2002 and September 2003, more than 12,000 women ages 15 to 26 were enrolled at 90 sites in 13 countries. Eligible women were not pregnant, had no abnormal Papanicolaou (Pap) smear, had had four or fewer lifetime sexual partners, and agreed to use effective contraception throughout the course of the study.

In a randomized, double-blind fashion, patients received vaccine or a placebo injection at day 1 and again 2 and 6 months later. They returned for follow-up 1, 6, 24, 36, and 48 months after the third injection, with Pap smears and colposcopy of cervical lesions.

The primary composite end point was the development of grade 2 or 3 cervical intraepithelial neoplasia, adenocarcinoma in situ, or invasive cervical carcinoma, with detection of HPV-16 or HPV-18 or both in one or more of the adjacent sections of the same lesion.

In all, 6,087 patients received vaccine and 6,080 received placebo; the two groups were well matched. About 23% had serologic evidence of exposure to either HPV-16 or HPV-18 at enrollment.

Findings. In the analysis of the data, the patients were divided into three overlapping subgroups. The first comprised women who had no serologic evidence of HPV-16 or HPV-18 infection at enrollment, who received all three injections, who remained DNA-negative at month 7, and who had no protocol violations. In this “per-protocol susceptible population,” at an average of 3 years of follow-up, lesions associated with HPV-16 or HPV-18 had developed in 42 of 5,260 women who received placebo, compared with only 1 of 5,305 who received the vaccine. The vaccine efficacy was calculated at 98% (95% confidence interval [CI] 86–100).

The second subgroup were women who had no evidence of HPV-16 or HPV-18 infection at baseline, but whose compliance with the protocol was considered imperfect. In this “unrestricted susceptible population,” the vaccine efficacy was 95% (95% CI 85–99).

The third group included all comers, regardless of whether they were already infected at baseline. In this “intention-to-treat population,” the vaccine efficacy was 44% (95% CI 26–58).

The authors concluded that in young women not previously infected with HPV-16 or HPV-18, vaccine recipients had a significantly lower occurrence of high-grade cervical intraepithelial neoplasia related to these two oncogenic HPV types.


Garland SM, Hernandez-Avila M, Wheeler CM, et al; Females United to Unilaterally Reduce Endo/Ectocervical Disease (FUTURE) Investigators. Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. J Engl J Med 2007; 356:1928–1943.

The study. This double-blind, placebo-controlled study5 tested the usefulness of the quadrivalent HPV vaccine to prevent anogenital disease. It included 5,400 women ages 16 to 24 and was conducted over 14 months in 2002 and 2003 at 62 sites in 16 countries. Women received vaccine or placebo at day 1 and again 2 and 6 months later, and then underwent anogenital and gynecologic examinations at intervals for up to 4 years.

The co-primary composite end points were the incidence of genital warts, vulvar or vaginal intraepithelial neoplasia or cancer, cervical intraepithelial neoplasia, cervical adenocarcinoma in situ, or cervical cancer associated with HPV types 6, 11, 16, or 18.

Findings. In all, 2,700 women were assigned to receive vaccine and 2,700 to receive placebo, and they were followed for an average of 3 years. Twenty percent had pre-existing serologic evidence of infection with one of these four HPV types. In the per-protocol population who were seronegative at day 1 and were compliant, the vaccine efficacy was 100%. In the intention-to-treat group, vaccine reduced the rate of vulvar or vaginal perianal lesions regardless of HPV type by 34%, and reduced the rate of cervical lesions regardless of type by 20%.

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