Risk of HPV-16/18 Infections and Associated Cervical Abnormalities in Women Seropositive for Naturally Acquired Antibodies: Pooled Analysis Based on Control Arms of Two Large Clinical Trials

Abstract

Background: Studies on the role of antibodies produced after infection with human papillomavirus 18 (HPV-18) and subsequent protection from HPV-18 infection have been conflicting, mainly due to inadequate sample size.

Methods: We pooled data from the control arms of the Costa Rica Vaccine Trial and the PATRICIA trial. Using Poisson regression we compared the risk of newly detected 1-time HPV-18 infection, HPV-18 1-year persistent infection (12MPI), and HPV-18-associated atypical squamous cells of undetermined significance or greater (ASC-US+) lesions between HPV-18 seropositive and seronegative women.

Results: High HPV-18 antibodies at enrollment was associated with reduced subsequent HPV-18 detection (P trend = 0.001; relative rate [RR] = 0.69; 95% confidence interval [CI], 0.47-1.01 for the third quartile; RR = 0.63; 95% CI, 0.43-0.94 for the fourth quartile, compared to seronegative). The risk of 12MPI showed a decreasing trend with increasing antibodies (P trend = 0.06; RR = 0.72; 95% CI, 0.29-1.77; RR = 0.42; 95% CI, 0.13-1.32 for the third and fourth quartiles, respectively). Lastly, we observed a significant decreased risk of HPV-18 ASC-US+ with increasing antibody (P trend = 0.01; RR = 0.46; 95% CI, 0.21-0.97 for the fourth quartile). We also observed a significant decreased risk of HPV-16 infection, 12MPI, and ASC-US+ with increasing HPV-16 antibody level.

Conclusions: High HPV-18 naturally acquired antibodies were associated with partial protection from future HPV-18 infections and associated lesions.

Clinical trials registration: NCT00128661 and NCT001226810.

Trial registration: ClinicalTrials.gov NCT00128661 NCT01226810.

Figures

Figure 1.

Consort diagram of the study population. Abbreviations: AGC, atypical glandular cells; ASC-H, atypical squamous cells-cannot exclude HSIL; CVT, Costa Rica vaccine trial; HPV, human papillomavirus; HSIL, high-grade squamous intraepithelial lesion; N, number of subjects; PATRICIA, Papilloma Trial Against Cancer in Young Adults; Sero+, seropositive; Sero−, seronegative; TVC-E, total vaccinated cohort for efficacy.

Figure 2.

Quantitative Poisson regression model showing relationship between initial HPV-18 antibody level and incident HPV-18 infection (A) and HPV-18–associated ASC-US+ (B). TVC-E control arm: 15–25 years old, who reported ever having had sexual intercourse. Infection: the adjusted model-predicted HPV-18 antibody titers associated with a 90% risk reduction of incident infection were 622 EU/mL (95% CI, 334–3838). ASU-CS+: the adjusted model-predicted HPV-18 antibody titers associated with a 90% risk reduction of ASC-US+ were 480 EU/mL (95% CI, 217–not determined). The dot size is proportional to the number of subjects; gray/white dot represents all seronegative subjects, and red/blue dots represent approximately 5-percentile classes of seropositive subjects. The solid blue line corresponds to the Poisson regression model (the dotted lines are 95% confidence limits). Abbreviations: ASC-US+, atypical squamous cells of undetermined significance or greater; CI, confidence interval; CVT, Costa Rica Vaccine Trial; HPV, human papillomavirus; n, number of subjects in a given category; PATRICIA, The PApilloma TRIal against Cancer In young Adults; TVC-E, total vaccinated cohort for efficacy.

Figure 3.

Quantitative Poisson regression model showing relationship between initial HPV-16 antibody level and incident HPV-16 infection (A) and ASC-US+ (B). TVC-E control arm: 15–25 years old, who reported ever having had sexual intercourse. Infection: the adjusted model-predicted HPV-16 antibody titers associated with a 90% risk reduction of incident infection were 371 EU/mL (95% CI, 268–606). ASC-US+: the adjusted model-predicted HPV-16 antibody titers associated with a 90% risk reduction of ASC-US+ were 384 EU/mL (95% CI, 245–886). The dot size is proportional to the number of subjects; the gray/white dot represents all seronegative subjects, and red/blue dots represent approximately 5-percentile classes of seropositive subjects. The solid blue line corresponds to the Poisson regression model (the dotted lines are 95% confidence limits). Abbreviations: ASC-US+, atypical squamous cells of undetermined significance or greater; CI, confidence interval; CVT, Costa Rica Vaccine Trial; HPV, human papillomavirus; n, number of subjects in a given category; PATRICIA, The PApilloma TRIal against Cancer In young Adults; TVC-E, total vaccinated cohort for efficacy.