Laura A. Koutsky

Prophylactic quadrivalent human papillomavirus (types 6, 11, 16, and 18) L1 virus-like particle vaccine in young women: a randomised double-blind placebo-controlled multicentre phase II efficacy trial

BACKGROUND A randomised double-blind placebo-controlled phase II study was done to assess the efficacy of a prophylactic quadrivalent vaccine targeting the human papillomavirus (HPV) types associated with 70% of cervical cancers (types 16 and 18) and with 90% of genital warts (types 6 and 11). METHODS 277 young women (mean age 20.2 years [SD 1.7]) were randomly assigned to quadrivalent HPV (20 microg type 6, 40 microg type 11, 40 microg type 16, and 20 microg type 18) L1 virus-like-particle (VLP) vaccine and 275 (mean age 20.0 years [1.7]) to one of two placebo preparations at day 1, month 2, and month 6. For 36 months, participants underwent regular gynaecological examinations, cervicovaginal sampling for HPV DNA, testing for serum antibodies to HPV, and Pap testing. The primary endpoint was the combined incidence of infection with HPV 6, 11, 16, or 18, or cervical or external genital disease (ie, persistent HPV infection, HPV detection at the last recorded visit, cervical intraepithelial neoplasia, cervical cancer, or external genital lesions caused by the HPV types in the vaccine). Main analyses were done per protocol. FINDINGS Combined incidence of persistent infection or disease with HPV 6, 11, 16, or 18 fell by 90% (95% CI 71-97, p<0.0001) in those assigned vaccine compared with those assigned placebo. INTERPRETATION A vaccine targeting HPV types 6, 11, 16, 18 could substantially reduce the acquisition of infection and clinical disease caused by common HPV types.

Epidemiology of Genital Human Papillomavirus Infection

Although it is difficult to estimate the overall prevalence of genital human papillomavirus (HPV) infection, current figures suggest that visible genital warts are present in approximately 1% of sexually active adults in the United States and that at least 15% have subclinical infection, as detected by HPV DNA assays. Genital HPV infection is thus extremely common. The highest rates of genital HPV infection are found in adults 18-28 years of age. Although risk factors for infection are difficult to assess because of the high frequency of subclinical infection, it is clear that major risk factors for acquiring genital HPV infection involve sexual behavior, particularly multiple sex partners. Other possible risk factors for acquisition of genital HPV infection include oral contraceptive use, pregnancy, and impairment of cell-mediated immunity. Strong epidemiologic and molecular data link HPV infection to cervical and other anogenital cancers. The types of HPV most commonly detected in cancers are HPV-16 and HPV-18. In summary, genital HPV infection is common among sexually active populations and causes both benign and malignant neoplasms of the genital tract.

A cohort study of the risk of cervical intraepithelial neoplasia grade 2 or 3 in relation to papillomavirus infection.

Abstract Background. Human papillomavirus (HPV) has been associated with cervical intraepithelial neoplasia, but the temporal relation between the infection and the neoplasia remains unclear, as does the relative importance of the specific type of HPV, other sexually transmitted diseases, and other risk factors. Methods. We studied prospectively a cohort of 241 women who presented for evaluation of sexually transmitted disease and had negative cervical cytologic tests. The women were followed every four months with cytologic and colposcopic examinations of the uterine cervix and tests for HPV DNA and other sexually transmitted diseases. Results. Cervical intraepithelial neoplasia grade 2 or 3 was confirmed by biopsy in 28 women. On the basis of survival analysis, the cumulative incidence of cervical intraepithelial neoplasia at two years was 28 percent among women with a positive test for HPV and 3 percent among those without detectable HPV DNA. The risk was highest among those with HPV type 16 or 18 infe...

Efficacy of a quadrivalent prophylactic human papillomavirus (types 6, 11, 16, and 18) L1 virus-like-particle vaccine against high-grade vulval and vaginal lesions: a combined analysis of three randomised clinical trials

BACKGROUND Vulval and vaginal cancers among younger women are often related to infection with human papillomavirus (HPV). These cancers are preceded by high-grade vulval intraepithelial neoplasia (VIN2-3) and vaginal intraepithelial neoplasia (VaIN2-3). Our aim was to do a combined analysis of three randomised clinical trials to assess the effect of a prophylactic quadrivalent HPV vaccine on the incidence of these diseases. METHODS 18 174 women (16-26 years) were enrolled and randomised to receive either quadrivalent HPV6/11/16/18 L1 virus-like-particle vaccine or placebo at day 1, and months 2 and 6. Individuals underwent detailed anogenital examination at day 1, 1 month after dose three, and at 6-12-month intervals for up to 48 months. Suspect genital lesions were biopsied and read by a panel of pathologists and vaccine HPV type-specific DNA testing was done. The primary endpoint was the combined incidence of VIN2-3 or VaIN2-3 associated with HPV16 or HPV18. Primary efficacy analyses were done in a per-protocol population. FINDINGS The mean follow-up time was 3 years. Among women naive to HPV16 or HPV18 through 1 month after dose three (per-protocol population; vaccine n=7811; placebo n=7785), the vaccine was 100% effective (95% CI 72-100) against VIN2-3 or VaIN2-3 associated with HPV16 or HPV18. In the intention-to-treat population (which included 18 174 women who, at day 1, could have been infected with HPV16 or HPV18), vaccine efficacy against VIN2-3 or VaIN2-3 associated with HPV16 or HPV18 was 71% (37-88). The vaccine was 49% (18-69) effective against all VIN2-3 or VaIN2-3, irrespective of whether or not HPV DNA was detected in the lesion. The most common treatment-related adverse event was injection-site pain. INTERPRETATION Prophylactic administration of quadrivalent HPV vaccine was effective in preventing high-grade vulval and vaginal lesions associated with HPV16 or HPV18 infection in women who were naive to these types before vaccination. With time, such vaccination could result in reduced rates of HPV-related vulval and vaginal cancers.

Comparison of Human Papillomavirus Types 16, 18, and 6 Capsid Antibody Responses Following Incident Infection

The relationship between human papillomavirus (HPV) DNA in the genital mucosa and serum IgG to HPV-16, -18, and -6 was studied in a cohort of 588 college women. Among women with incident HPV infections, 59.5%, 54.1%, and 68.8% seroconverted for HPV-16, -18, or -6, respectively, within 18 months of detecting the corresponding HPV DNA. Transient HPV DNA was associated with a failure to seroconvert following incident HPV infection; however, some women with persistent HPV DNA never seroconverted. Antibody responses to each type were heterogeneous, but several type-specific differences were found: seroconversion for HPV-16 occurred most frequently between 6 and 12 months of DNA detection, but seroconversion for HPV-6 coincided with DNA detection. Additionally, antibody responses to HPV-16 and -18 were significantly more likely to persist during follow-up than were antibodies to HPV-6.

Efficacy of Human Papillomavirus-16 Vaccine to Prevent Cervical Intraepithelial Neoplasia A Randomized Controlled Trial

OBJECTIVE: Human papillomavirus (HPV) virus-like particle (VLP) vaccines have demonstrated effectiveness in preventing persistent HPV infections. Whether protection lasts longer than 18 months and, thus, impacts rates of cervical intraepithelial neoplasia (CIN) 2–3 has not yet been established. We present results from an HPV16 L1 VLP vaccine trial through 48 months. METHODS: A total of 2,391 women, aged 16–23 years, participated in a randomized, double-blind, placebo-controlled trial. Either 40 &mgr;g HPV16 L1 VLP vaccine or placebo was given intramuscularly at day 1, month 2, and month 6. Genital samples for HPV16 DNA and Pap tests were obtained at day 1, month 7, and then 6-monthly through month 48. Colposcopy and cervical biopsies were performed if clinically indicated and at study exit. Serum HPV16 antibody titer was measured by radioimmunoassay. RESULTS: Among 750 placebo recipients in the per protocol population, 12 women developed HPV16-related CIN2–3 (6 CIN2 and 6 CIN3). Among 755 vaccine recipients, there were no cases (vaccine efficacy 100%, 95% confidence interval [CI] 65–100%). There were 111 cases of persistent HPV16 infection in placebo recipients and 7 cases in vaccine recipients (vaccine efficacy 94%, 95% CI 88–98%). After immunization, HPV16 serum antibody geometric mean titers peaked at month 7 (1,519 milli-Merck units [mMU]/mL), declined through month 18 (202 mMU/mL), and remained relatively stable between month 30 and month 48 (128–150 mMU/mL). CONCLUSION: The vaccine HPV16 L1 VLP provides high-level protection against persistent HPV16 infection and HPV16-related CIN2–3 for at least 3.5 years after immunization. Administration of L1 VLP vaccines targeting HPV16 is likely to reduce risk for cervical cancer. LEVEL OF EVIDENCE: I

Factors That Are Associated With Parental Acceptance of Human Papillomavirus Vaccines: A Randomized Intervention Study of Written Information About HPV

OBJECTIVES. Prophylactic vaccines against human papillomavirus (HPV) are expected to be available for public use by 2007 and likely will be targeted to preadolescent children. Parental acceptance of these vaccines will be critical for their success. The objectives of this study were (1) to determine the overall acceptance of HPV vaccines for preadolescent children by parents, (2) to evaluate the influence of written educational information about HPV on parental acceptability of HPV vaccines, and (3) to identify independent predictors associated with HPV vaccine acceptability by parents. METHODS. A randomized intervention study within a cross-sectional survey was conducted. Parental HPV vaccine acceptability was measured under 3 different hypothetical scenarios. A self-administered survey on the knowledge, attitudes, and beliefs about HPV and HPV vaccines was sent to 1600 parents of 8- to 12-year-old children. In addition to a baseline paragraph about HPV that was received by all study participants, a random half of the study participants received a detailed “HPV Information Sheet” outlining the epidemiology and potential clinical sequelae of HPV infection. Independent predictors of parental HPV vaccine acceptability were determined using multivariate linear regression models. RESULTS. Parents who received the HPV information sheet had higher mean scores on the HPV knowledge assessment tool than the control group. However, despite this apparent improvement in knowledge, there was not a statistically significant difference in HPV vaccine acceptability between the 2 groups. CONCLUSIONS. Providing parents with an HPV information sheet did seem to improve knowledge about HPV, but this increased knowledge had little effect on the acceptability of these vaccines by parents for their children. Instead, attitudes and life experiences seemed to be more important factors influencing HPV vaccine acceptability among parents.

Development and Duration of Human Papillomavirus Lesions, after Initial Infection

BACKGROUND To determine the potential value of human papillomavirus (HPV) vaccines, information concerning the incidence and duration of clinically important lesions is needed. METHODS A total of 603 female university students were followed for a mean duration of 38.8 months. Triannual gynecologic examinations included cervical and vulvovaginal specimen collection for Pap and HPV DNA testing. Women with cytologic evidence of a high-grade squamous intraepithelial lesion (SIL) were referred for colposcopically directed biopsy. RESULTS Among women with incident HPV infection, the 36-month cumulative incidence of cervical SILs found by cytologic testing (47.2%; 95% confidence interval [CI], 38.9%-56.4%) was higher than that of vaginal SILs (28.8%; 95% CI, 21.3%-38.2%). The median time to clearance of cervical and vaginal SILs was 5.5 and 4.7 months, respectively. Among women with incident HPV-16 or HPV-18 infection, the 36-month cumulative incidence of cervical intraepithelial neoplasia (CIN) grade 2 was 20.0% (95% CI, 10.8%-35.1%), and that of CIN grade 3 was 6.7% (95% CI, 2.5%-17.0%). The 36-month cumulative incidence of clinically ascertained genital warts among women with incident HPV-6 or HPV-11 infection was 64.2% (95% CI, 50.7%-77.4%). CONCLUSIONS Intraepithelial lesions are common early events among women with incident HPV infection, and the interval between incident HPV-16 or HPV-18 infection and biopsy-confirmed CIN grade 2-3 appears to be relatively short.

Do condoms prevent genital HPV infection external genital warts or cervical neoplasia? A meta-analysis.

Background Although condoms most likely prevent HIV infection, evidence of their effectiveness against other sexually transmitted diseases is mixed. Goal The goal of the study was to determine whether condom use prevents genital human papillomavirus (HPV) infection and HPV-related conditions. Study Design We conducted a literature review and meta-analysis of the effect of condom use on the prevention of genital warts, subclinical HPV infection, cervical intraepithelial neoplasia (CIN), and invasive cervical cancer (ICC). Results Among 27 estimates from 20 studies, there was no consistent evidence that condom use reduces the risk of becoming HPV DNA–positive. However, risk for genital warts, CIN of grade II or III (CIN II or III), and ICC was somewhat reduced. Conclusions Available data are too inconsistent to provide precise estimates. However, they suggest that while condoms may not prevent HPV infection, they may protect against genital warts, CIN II or III, and ICC.

Four year efficacy of prophylactic human papillomavirus quadrivalent vaccine against low grade cervical, vulvar, and vaginal intraepithelial neoplasia and anogenital warts: randomised controlled trial.

Objectives To evaluate the prophylactic efficacy of the human papillomavirus (HPV) quadrivalent vaccine in preventing low grade cervical, vulvar, and vaginal intraepithelial neoplasias and anogenital warts (condyloma acuminata). Design Data from two international, double blind, placebo controlled, randomised efficacy trials of quadrivalent HPV vaccine (protocol 013 (FUTURE I) and protocol 015 (FUTURE II)). The trials were to be 4 years in length, and the results reported are from final study data of 42 months’ follow-up. Setting Primary care centres and university or hospital associated health centres in 24 countries and territories around the world. Participants 17 622 women aged 16-26 years enrolled between December 2001 and May 2003. Major exclusion criteria were lifetime number of sexual partners (>4), history of abnormal cervical smear test results, and pregnancy. Intervention Three doses of quadrivalent HPV vaccine (for serotypes 6, 11, 16, and 18) or placebo at day 1, month 2, and month 6. Main outcome measures Vaccine efficacy against cervical, vulvar, and vaginal intraepithelial neoplasia grade I and condyloma in a per protocol susceptible population that included subjects who received all three vaccine doses, tested negative for the relevant vaccine HPV types at day 1 and remained negative through month 7, and had no major protocol violations. Intention to treat, generally HPV naive, and unrestricted susceptible populations were also studied. Results In the per protocol susceptible population, vaccine efficacy against lesions related to the HPV types in the vaccine was 96% for cervical intraepithelial neoplasia grade I (95% confidence interval 91% to 98%), 100% for both vulvar and vaginal intraepithelial neoplasia grade I (95% CIs 74% to 100%, 64% to 100% respectively), and 99% for condyloma (96% to 100%). Vaccine efficacy against any lesion (regardless of HPV type) in the generally naive population was 30% (17% to 41%), 75% (22% to 94%), and 48% (10% to 71%) for cervical, vulvar, and vaginal intraepithelial neoplasia grade I, respectively, and 83% (74% to 89%) for condyloma. Conclusions Quadrivalent HPV vaccine provided sustained protection against low grade lesions attributable to vaccine HPV types (6, 11, 16, and 18) and a substantial reduction in the burden of these diseases through 42 months of follow-up. Trial registrations NCT00092521 and NCT00092534.