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1.  Effect of Different Human Papillomavirus Serological and DNA Criteria on Vaccine Efficacy Estimates 
Lang Kuhs, Krystle A. | Porras, Carolina | Schiller, John T. | Rodriguez, Ana Cecilia | Schiffman, Mark | Gonzalez, Paula | Wacholder, Sholom | Ghosh, Arpita | Li, Yan | Lowy, Douglas R. | Kreimer, Aimée R. | Poncelet, Sylviane | Schussler, John | Quint, Wim | van Doorn, Leen-Jan | Sherman, Mark E. | Sidawy, Mary | Herrero, Rolando | Hildesheim, Allan | Safaeian, Mahboobeh | Lang Kuhs, Krystle A. | Schiller, John T. | Schiffman, Mark | Wacholder, Sholom | Lowy, Douglas R. | Kreimer, Aimée R. | Sherman, Mark E. | Hildesheim, Allan | Safaeian, Mahboobeh | Porras, Carolina | Rodriguez, Ana Cecilia | Gonzalez, Paula | Herrero, Rolando | Gonzalez, Paula | Herrero, Rolando | Ghosh, Arpita | Li, Yan | Poncelet, Sylviane | Schussler, John | Quint, Wim | van Doorn, Leen-Jan | Sidawy, Mary | Self, Steve | Benavides, Adriana | Calzada, Luis Diego | Karron, Ruth | Nayar, Ritu | Roach, Nancy | Cain, Joanna | Davey, Diane | DeMets, David | Fuster, Francisco | Gershon, Ann | Holly, Elizabeth | Raventós, Henriette | Rida, Wasima | Rosero-Bixby, Luis | Suthers, Kristen | Lara, Silvia | Thomas, Sarah | Alfaro, Mario | Barrantes, Manuel | Concepción Bratti, M. | Cárdenas, Fernando | Cortés, Bernal | Espinoza, Albert | Estrada, Yenory | González, Paula | Guillén, Diego | Herrero, Roland | Jiménez, Silvia E. | Morales, Jorge | Villegas, Luis | Morera, Lidia Ana | Pérez, Elmer | Porras, Carolina | Rodríguez, Ana Cecilia | Rivas, Libia | Freer, Enrique | Bonilla, José | García-Piñeres, Alfanso | Silva, Sandra | Atmella, Ivannia | Ramírez, Margarita | Hildesheim, Allan | Kreimer, Aimée R. | Lowy, Douglas R. | Macklin, Nora | Schiffman, Mark | Schiller, John T. | Sherman, Mark | Solomon, Diane | Wacholder, Sholom | Pinto, Ligia | Kemp, Troy | Eklund, Claire | Hutchinson, Martha | Sidawy, Mary | Quint, Wim | van Doorn, Leen-Jan
American Journal of Epidemiology  2014;180(6):599-607.
Two trials of clinically approved human papillomavirus (HPV) vaccines, Females United to Unilaterally Reduce Endo/Ectocervical Disease (FUTURE I/II) and the Papilloma Trial Against Cancer in Young Adults (PATRICIA), reported a 22% difference in vaccine efficacy (VE) against cervical intraepithelial neoplasia grade 2 or worse in HPV-naïve subcohorts; however, serological testing methods and the HPV DNA criteria used to define HPV-unexposed women differed between the studies. We applied previously described methods to simulate these HPV-naïve subcohorts within the Costa Rica HPV16/18 Vaccine Trial and assessed how these criteria affect the estimation of VE. We applied 2 enzyme-linked immunosorbent assay (ELISA) thresholds for HPV16 and HPV18 seropositivity (8 and 7 ELISA units/mL, respectively, for PATRICIA; 54 and 65 ELISA units/mL, respectively, for FUTURE I/II (to approximate the competitive Luminex immunoassay)) and 2 criteria for HPV DNA positivity (12 oncogenic HPV types, plus HPV66 and 68/73 for PATRICIA; or plus HPV6 and 11 for FUTURE I/II). VE was computed in the 2 naïve subcohorts. Using the FUTURE I/II and PATRICIA criteria, VE estimates against cervical intraepithelial neoplasia grade 2 or worse, regardless of HPV type, were 69.0% (95% confidence interval: 40.3%, 84.9%) and 80.8% (95% confidence interval: 52.6%, 93.5%), respectively (P = 0.1). Although the application of FUTURE I/II criteria to our cohort resulted in the inclusion of more sexually experienced women, methodological differences did not fully explain the VE differences.
PMCID: PMC4157699  PMID: 25139208
human papillomavirus; methodological differences; naïve population; vaccine efficacy
2.  Prevalence of and Risk Factors for Oral Human Papillomavirus Among Young Women in Costa Rica 
The Journal of Infectious Diseases  2013;208(10):1643-1652.
Background. Little is known about the epidemiology of oral human papillomavirus (HPV) in Latin America.
Methods. Women (N = 5838) aged 22–29 in the control and vaccine arms of an HPV-16/18 vaccine trial in Costa Rica had oral, cervical, and anal specimens collected. Samples were tested for alpha mucosal HPV types (SPF10/LiPA25 version 1); a subset of oral samples (n = 500) was tested for cutaneous HPV types in the genera alpha, beta, gamma, mu, and nu.
Results. In the control arm (n = 2926), 1.9% of women had an oral alpha mucosal HPV detected, 1.3% had carcinogenic HPV, and 0.4% had HPV-16; similar patterns for non-16/18 HPV types were observed in the vaccine arm. Independent risk factors for any oral alpha mucosal HPV among women in the control arm included marital status (adjusted odds ratio [AOR], 3.2; 95% confidence interval [CI], 1.8–5.7 for single compared to married/living as married), number of sexual partners (AOR, 2.4; 95% CI, 1.0–6.1 for ≥4 partners compared to 0–1 partners), chronic sinusitis (AOR, 3.1; 95% CI, 1.5–6.7), and cervical HPV infection (AOR, 2.6; 95% CI, 1.4–4.6). Detection of beta HPV was common (18.6%) and not associated with sexual activity.
Conclusions. Unlike cutaneous HPV types, alpha mucosal HPV types were uncommon in the oral region and were predominately associated with sexual behavior.
Clinical Trials Registration. NCT00128661.
PMCID: PMC3805238  PMID: 24014882
human papillomavirus vaccine; HPV; oropharynx cancer; Costa Rica; Guanacaste; oral HPV DNA
3.  Reduced Prevalence of Vulvar HPV16/18 Infection Among Women Who Received the HPV16/18 Bivalent Vaccine: A Nested Analysis Within the Costa Rica Vaccine Trial 
The Journal of Infectious Diseases  2014;210(12):1890-1899.
Vaccine efficacy (VE) against vulvar human papillomavirus (HPV) infection has not been reported and data regarding its epidemiology are sparse.
Women (n = 5404) age 22–29 present at the 4-year study visit of the Costa Rica Vaccine Trial provided vulvar and cervical samples. A subset (n = 1044) was tested for HPV DNA (SPF10/LiPA25 version 1). VE against 1-time detection of vulvar HPV16/18 among HPV vaccinated versus unvaccinated women was calculated and compared to the cervix. Prevalence of and risk factors for HPV were evaluated in the control arm (n = 536).
Vulvar HPV16/18 VE (54.1%; 95% confidence interval [CI], 4.9%–79.1%) was comparable to cervix (45.8%; 95% CI, 6.4%–69.4%). Vulvar and cervical HPV16 prevalence within the control arm was 3.0% and 4.7%, respectively. Independent risk factors for vulvar HPV were similar to cervix and included: age (adjusted odds ratio [aOR] 0.5 [95% CI, .3–.9] ≥28 vs 22–23]); marital status (aOR 2.3 [95% CI, 1.5–3.5] single vs married/living-as-married); and number of sexual partners (aOR 3.6 [95% CI, 1.9–7.0] ≥6 vs 1).
In this intention-to-treat analysis, VE against vulvar and cervical HPV16/18 were comparable 4 years following vaccination. Risk factors for HPV were similar by anatomic site.
Clinical Trials Registration
PMCID: PMC4271025  PMID: 24958910
Costa Rica; HPV; HPV vaccine; vulvar human papillomavirus vaccine
4.  Detection of HPV DNA in paraffin-embedded cervical samples: a comparison of four genotyping methods 
BMC Infectious Diseases  2015;15:544.
Identification of human papillomavirus (HPV) DNA in cervical tissue is important for understanding cervical carcinogenesis and for evaluating cervical cancer prevention approaches. However, HPV genotyping using formalin-fixed, paraffin-embedded (FFPE) tissues is technically challenging. We evaluated the performance of four commonly used genotyping methods on FFPE cervical specimens conducted in different laboratories and compared to genotyping results from cytological samples.
We included 60 pairs of exfoliated-cell and FFPE specimens from women with histologically confirmed cervical intraepithelial lesions grade 2 or 3. Cytology specimens were genotyped using the Linear Array assay. Four expert laboratories processed tissue specimens using different preparation methods and then genotyped the resultant sample preparations using four different HPV genotyping methods: SPF10-PCR DEIA LiPA25 (version 1), Inno-LiPA, Linear Array and the Onclarity assay. Percentage agreement, kappa statistics and McNemar’s chi-square were calculated for each comparison of different methods and specimen types.
Overall agreement with respect to carcinogenic HPV status for FFPE samples between different methods was: 81.7, 86.7 and 91.7 % for Onclarity versus Inno-LiPA, Linear Array and SPF-LiPA25, respectively; 81.7 and 85.0 % for Linear Array versus Inno-LiPA and SPF-LiPA25, respectively; and 86.7 % for SPF-LiPA25 versus Inno-LiPA. Type-specific agreement was >88.3 % for all pair-wise comparisons. Comparisons with cytology specimens resulted in overall agreements from 80 to 95 % depending on the method and type-specific agreement was >90 % for most comparisons.
Our data demonstrate that the four genotyping methods run by expert laboratories reliably detect HPV DNA in FFPE specimens with some variation in genotype-specific detection.
Electronic supplementary material
The online version of this article (doi:10.1186/s12879-015-1281-5) contains supplementary material, which is available to authorized users.
PMCID: PMC4660657  PMID: 26607224
Genotyping; Formalin-fixed paraffin-embedded tissues; Cervical intraepithelial lesions; Exfoliated-cell
5.  In Vitro Antiviral Activity and Preclinical and Clinical Resistance Profile of Miravirsen, a Novel Anti-Hepatitis C Virus Therapeutic Targeting the Human Factor miR-122 
Miravirsen is a β-d-oxy-locked nucleic acid-modified phosphorothioate antisense oligonucleotide targeting the liver-specific microRNA-122 (miR-122). Miravirsen demonstrated antiviral activity against hepatitis C virus (HCV) genotype 1b replicons with a mean 50% effective concentration (EC50) of 0.67 μM. No cytotoxicity was observed up to the highest concentration tested (>320 μM) in different cell culture models, yielding a therapeutic index of ≥297. Combination studies of miravirsen with interferon α2b, ribavirin, and nonnucleoside (VX-222) and nucleoside (2′-methylcytidine) inhibitors of NS5B, NS5A (BMS-790052), or NS3 (telaprevir) indicated additive interactions. Miravirsen demonstrated broad antiviral activity when tested against HCV replicons resistant to NS3, NS5A, and NS5B inhibitors with less than 2-fold reductions in susceptibility. In serial passage studies, an A4C nucleotide change was observed in the HCV 5′ untranslated region (UTR) from cells passaged in the presence of up to 20 μM (40-fold the miravirsen EC50 concentration) at day 72 of passage but not at earlier time points (up to 39 days of passage). Likewise, a C3U nucleotide change was observed in the HCV 5′UTR from subjects with viral rebound after the completion of therapy in a miravirsen phase 2 clinical trial. An HCV variant constructed to contain the A4C change was fully susceptible to miravirsen. A C3U HCV variant demonstrated overall reductions in susceptibility to miravirsen but was fully susceptible to all other anti-HCV agents tested. In summary, miravirsen has demonstrated broad antiviral activity and a relatively high genetic barrier to resistance. The identification of nucleotide changes associated with miravirsen resistance should help further elucidate the biology of miR-122 interactions with HCV. (The clinical trial study has been registered at under registration no. NCT01200420).
PMCID: PMC4291405  PMID: 25385103
6.  Racial Disparities in Human Papillomavirus (HPV) associated Head and Neck Cancer 
Poorer survival from head and neck squamous cell carcinoma (HNSCC) in African Americans (AA) may be due to disparity in the prevalence of Human Papillomavirus (HPV) but earlier studies often failed to control other etiological factors. We aimed to elucidate whether racial disparities in HPV prevalence and overall survival were due to confounding from smoking or alcohol use.
Materials and Methods
385 patients with SCC of the mouth, pharynx, nose, or larynx who had surgical resection at Wayne State University affiliated hospitals were identified through a population-based cancer registry. Formalin fixed paraffin embedded tissue blocks were used to determine the presence of HPV DNA and its genotype using a sensitive broad-spectrum PCR technique. Patients’ demographics, tumor characteristics and vital status were obtained through record linkage with the registry data and smoking and alcohol information was abstracted from medical record. Cox’s proportional hazard model and unconditional logistic models were employed to analyze the overall survival and tumor HPV-positivity, respectively.
HPV positivity in oropharyngeal cancer was substantially lower in AA than in other racial groups (odds ratio 0.14, 95% confidence interval (CI) 0.05–0.37) and adjustment for smoking or alcohol did not change this association. However, a significantly increased hazard ratio of death in AA oropharyngeal cancer patients (univariable hazard ratio (HR) 2.55, 95% CI 1.42–4.59) decreased to almost unity (HR 1.49, 95% CI 0.75–2.93) after adjustment for HPV and smoking.
Lower HPV prevalence in AA largely accounts for their poorer survival from oropharyngeal cancer, but not other HNSSC.
PMCID: PMC3947473  PMID: 24209992
7.  Gastroenteritis attributable to rotavirus in hospitalized Saudi Arabian children in the period 2007–2008 
Clinical Epidemiology  2015;7:129-137.
Rotavirus (RV) is a leading cause of severe gastroenteritis (GE) in children across the world. As there is a lack of epidemiological data for RV gastroenteritis (RVGE) in Saudi Arabia, this hospital-based study was designed to estimate the disease burden of RVGE and assess the prevalent RV types in Saudi children younger than 5 years of age.
Patients and methods
Children hospitalized for acute GE were enrolled at four pediatric referral hospitals in Saudi Arabia. The study was conducted from February 2007 to March 2008 and used the World Health Organization’s generic protocol for RVGE surveillance. The Vesikari severity scale was used to assess the severity of RVGE. Stool samples were tested for RV using an enzyme-linked immunosorbent assay. Samples were further typed by reverse transcriptase–polymerase chain reaction and hybridization assay for determining the G and P types.
A total of 1,007 children were enrolled; the final analysis included 970 children, of whom 395 were RV positive, 568 were RV negative, and seven had unknown RV status. The proportion of RVGE among GE hospitalizations was 40.7% (95% confidence interval: 37.6–43.9). The highest percentage of RVGE hospitalizations (83.1%) was seen in children younger than 2 years of age. The highest proportion of RV among GE hospitalizations was in June 2007 with 57.1%. The most common RV types detected were G1P[8] (49.3%), G1G9P[8] (13.2%), and G9P[8] (9.6%). Before hospitalization, severe GE episodes occurred in 88.1% RV-positive and 79.6% RV-negative children. Overall, 94% children had recovered by the time they were discharged. Two children (one RV positive and one RV negative) died due to GE complications.
RVGE is responsible for a high proportion of hospitalizations in Saudi children younger than 5 years of age. Routine RV vaccination has therefore been introduced into the national immunization program and may help reduce the morbidity, mortality, and disease burden associated with RVGE in Saudi Arabia.
PMCID: PMC4334312  PMID: 25709500
disease burden; Saudi Arabia; rotavirus; RVGE; epidemiology
8.  Post Hoc Analysis of the PATRICIA Randomized Trial of the Efficacy of Human Papillomavirus Type 16 (HPV-16)/HPV-18 AS04-Adjuvanted Vaccine against Incident and Persistent Infection with Nonvaccine Oncogenic HPV Types Using an Alternative Multiplex Type-Specific PCR Assay for HPV DNA 
The efficacy of the human papillomavirus type 16 (HPV-16)/HPV-18 AS04-adjuvanted vaccine against cervical infections with HPV in the Papilloma Trial against Cancer in Young Adults (PATRICIA) was evaluated using a combination of the broad-spectrum L1-based SPF10 PCR-DNA enzyme immunoassay (DEIA)/line probe assay (LiPA25) system with type-specific PCRs for HPV-16 and -18. Broad-spectrum PCR assays may underestimate the presence of HPV genotypes present at relatively low concentrations in multiple infections, due to competition between genotypes. Therefore, samples were retrospectively reanalyzed using a testing algorithm incorporating the SPF10 PCR-DEIA/LiPA25 plus a novel E6-based multiplex type-specific PCR and reverse hybridization assay (MPTS12 RHA), which permits detection of a panel of nine oncogenic HPV genotypes (types 16, 18, 31, 33, 35, 45, 52, 58, and 59). For the vaccine against HPV types 16 and 18, there was no major impact on estimates of vaccine efficacy (VE) for incident or 6-month or 12-month persistent infections when the MPTS12 RHA was included in the testing algorithm versus estimates with the protocol-specified algorithm. However, the alternative testing algorithm showed greater sensitivity than the protocol-specified algorithm for detection of some nonvaccine oncogenic HPV types. More cases were gained in the control group than in the vaccine group, leading to higher point estimates of VE for 6-month and 12-month persistent infections for the nonvaccine oncogenic types included in the MPTS12 RHA assay (types 31, 33, 35, 45, 52, 58, and 59). This post hoc analysis indicates that the per-protocol testing algorithm used in PATRICIA underestimated the VE against some nonvaccine oncogenic HPV types and that the choice of the HPV DNA testing methodology is important for the evaluation of VE in clinical trials. (This study has been registered at under registration no. NCT00122681.)
PMCID: PMC4308870  PMID: 25540273
9.  Risk of advanced gastric precancerous lesions in Helicobacter pylori infected subjects is influenced by ABO blood group and cagA status 
A higher incidence of stomach cancer in ABO blood type A individuals than in those with blood type O has been known for a long time. We studied this association in relation to Helicobacter pylori (Hp) of different cagA status.
For this study we used baseline gastric histopathology data and DNAs from frozen gastric biopsies of 2077 subjects enrolled in a chemoprevention trial for gastric precancerous lesions in Venezuela. We analyzed 6 single nucleotide polymorphisms in the ABO gene and we assessed the presence of the Hp cagA gene. Odds ratios for risk of advanced precancerous gastric lesions were calculated using individuals with normal gastric epithelium or non-atrophic gastritis as a reference.
Among individuals carrying a cagA negative Hp infection or no Hp infection, those with blood type A had a lower risk of intestinal metaplasia and dysplasia than those with blood type O (OR=0.60; 95% CI 0.38-0.94). In carriers of cagA positive Hp strains, individuals with blood type A had a higher risk of intestinal metaplasia or dysplasia than those with blood type O (OR=1.42, 95% CI 1.09-1.86) and a higher risk if compared with subjects carrying cagA− strain and non-A blood group (OR=3.82, 95%CI=2.80-5.20). The interaction between Hp cagA status and blood type was statistically significant (P=0.0006).
We showed that SNPs in the ABO gene, predictive of ABO blood groups, are associated with risk of advanced precancerous gastric lesions in individuals infected with Hp, but the assessment of the risk is strictly dependent on cagA status.
PMCID: PMC3656130  PMID: 23319424
Helicobacter pylori; ABO blood groups; risk of preneoplastic gastric lesions
10.  Cross-protective vaccine efficacy of the bivalent HPV vaccine against HPV31 is associated with humoral immune responses 
Human Vaccines & Immunotherapeutics  2013;9(7):1399-1406.
Background: We investigated the role of antibody responses as potential mechanism for the cross-protective vaccine-efficacies (VE) observed from randomized clinical trials of the HPV16/18 bivalent vaccine.
Results: HPV31 cases had lower HPV16 antibody levels than controls (OR4th quartile compared with 1st quartile = 0.63; 95%CI: 0.36–1.08; p-trend = 0.03). HPV31 cases were also less likely to have detectable HPV31 neutralization, and HPV16 avidity than controls. No statistically significant differences by HPV18 antibody or HPV45 neutralization were observed among HPV45 cases and controls. Protection against HPV58 was not associated with any of the markers, confirming the specificity of our findings.
Methods: Samples are from three-dose HPV vaccine recipients from the Costa Rica HPV16/18 vaccine trial. Women with a new HPV31, HPV45, or HPV58 infections over four years of follow-up were compared with randomly selected control women—with no new infection with HPV31/45/58—with respect to HPV16 and HPV18 antibody, HPV31, HPV45, and HPV58 neutralization, and HPV16 avidity.
Conclusions: High HPV16 levels and avidity, and the ability to neutralize HPV31 were associated with protection against newly detected HPV31 infections, suggesting that the partial VE demonstrated for HPV31 is likely to be mediated at least in part through antibodies induced by HPV16/18 vaccination.
PMCID: PMC3974884  PMID: 23571174
HPV vaccine; humoral; immune response; cross-protection; mechanisms for protection
11.  Glutathione S-transferase L1 multiplex serology as a measure of cumulative infection with human papillomavirus 
BMC Infectious Diseases  2014;14:120.
Several assays are used to measure type-specific serological responses to human papillomavirus (HPV), including the bead-based glutathione S-transferase (GST)-L1 multiplex serology assay and virus-like particle (VLP)-based ELISA. We evaluated the high-throughput GST-L1, which is increasingly used in epidemiologic research, as a measure of cumulative HPV infection and future immune protection among HPV-unvaccinated women.
We tested enrollment sera from participants in the control arm of the Costa Rica Vaccine Trial (n = 488) for HPV16 and HPV18 using GST-L1, VLP-ELISA, and two assays that measure neutralizing antibodies (cLIA and SEAP-NA). With statistical adjustment for sampling, we compared GST-L1 serostatus to established HPV seropositivity correlates and incident cervical HPV infection using odds ratios. We further compared GST-L1 to VLP-ELISA using pair-wise agreement statistics and by defining alternate assay cutoffs.
Odds of HPV16 GST-L1 seropositivity increased with enrollment age (OR = 1.20 per year, 95%CI 1.03-1.40) and lifetime number of sexual partners (OR = 2.06 per partner, 95%CI 1.49-2.83), with similar results for HPV18. GST-L1 seropositivity did not indicate protection from incident infection over 4 years of follow-up (HPV16 adjusted OR = 1.72, 95%CI 0.95-3.13; HPV18 adjusted OR = 0.38, 95%CI 0.12-1.23). Seroprevalence by GST-L1 (HPV16 and HPV18, respectively) was 5.0% and 5.2%, compared to 19.4% and 23.8% by VLP-ELISA, giving positive agreement of 39.2% and 20.8%. Lowering GST-L1 seropositivity cutoffs improved GST-L1/VLP-ELISA positive agreement to 68.6% (HPV16) and 61.5% (HPV18).
Our data support GST-L1 as a marker of cumulative HPV infection, but not immune protection. At lower seropositivity cutoffs, GST-L1 better approximates VLP-ELISA.
PMCID: PMC3973893  PMID: 24588945
12.  Long-Term Follow-Up of HPV16-Positive Women: Persistence of the Same Genetic Variant and Low Prevalence of Variant Co-Infections 
PLoS ONE  2013;8(11):e80382.
HPV16 variants correlate with geographic origin and ethnicity. The association between infection with a specific variant and the cervical disease risk remains unclear. We studied the prevalence, persistence and association with cervical intraepithelial neoplasia (CIN) of different HPV16 variants, using cervical swabs and whole tissue sections (WTS) of biopsies from 548 women in the placebo group of a HPV16/18 vaccine trial. In HPV16-positive samples, HPV16 variants were identified by a reverse hybridization assay (RHA). Laser-capture micro-dissection (LCM) was performed for localized detection of HPV. HPV16 variants were determined in 47 women. Frequency of mixed HPV16 variant infections was lower (8.5%) than for multiple HPV genotypes (39.1%). Among 35 women having consecutive HPV16 variant-positive swabs, 32 (91.4%) had the same variant while in three (8.6%) women a change in variant(s) was observed. HPV16-positive WTS were obtained from 12 women having consecutive HPV16 variant-positive swabs. The same variant was present in WTS of 10 women, while two were negative. WTS of five women were histologically normal. A single HPV16 variant was detected in four women having CIN1-3, while additional HPV genotypes were found in three other women having CIN2 and CIN3. In the WTS of one woman with mixed genotypes, the HPV16 variant was assigned to a CIN2 lesion by LCM. HPV16 variant infections can be effectively studied in cervical swabs and tissue specimens by the HPV16 variant RHA. Multiple HPV16 variants in one woman are rare. The HPV16 genotype consistently detected in follow-up samples usually involves a persistent infection with the same variant.
PMCID: PMC3823622  PMID: 24244682
13.  Prevalence of and Risk Factors for Anal Human Papillomavirus Infection Among Young Healthy Women in Costa Rica 
The Journal of Infectious Diseases  2012;206(7):1103-1110.
Background. Anal cancer is caused by human papillomavirus (HPV), yet little is known about anal HPV infection among healthy young women.
Methods. A total of 2017 sexually active women in the control arm of an HPV-16/18 vaccine trial had a single anal specimen collected by a clinician at the 4-year study visit. Samples were tested for HPV by SPF10 PCR/DEIA/LiPA25, version 1.
Results. A total of 4% of women had HPV-16, 22% had oncogenic HPV, and 31% had any HPV detected in an anal specimen. The prevalence of anal HPV was higher among women who reported anal intercourse, compared with those who did not (43.4% vs 28.4%; P < .001). Among women who reported anal intercourse, cervical HPV (adjusted odds ratio [aOR], 5.3 [95% confidence interval {CI}, 3.4–8.2]), number of sex partners (aOR, 2.2 [95% CI, 1.1–4.6] for ≥4 partners), and number of anal intercourse partners (aOR, 1.9 [95% CI, 1.1–3.3] for ≥2 partners) were independent risk factors for anal HPV detection. Among women who reported no anal intercourse, cervical HPV (aOR, 4.7 [95% CI, 3.7–5.9]), number of sex partners (aOR, 2.4 [95% CI, 1.7–3.4] for ≥4 partners), and report of anal fissures (aOR, 2.3 [95% CI, 1.1–4.8]) were associated with an increased odds of anal HPV detection.
Conclusion. Anal HPV is common among young women, even those who report no anal sex, and was associated with cervical HPV infection. Anal fissures in women who report never having had anal intercourse may facilitate HPV exposure.
Clinical Trials Registration. NCT00128661.
PMCID: PMC3499109  PMID: 22850119
14.  A Human Papilloma Virus Testing Algorithm Comprising a Combination of the L1 Broad-Spectrum SPF10 PCR Assay and a Novel E6 High-Risk Multiplex Type-Specific Genotyping PCR Assay 
Journal of Clinical Microbiology  2013;51(4):1171-1178.
Human papillomavirus (HPV) epidemiological and vaccine studies require highly sensitive HPV detection and genotyping systems. To improve HPV detection by PCR, the broad-spectrum L1-based SPF10 PCR DNA enzyme immunoassay (DEIA) LiPA system and a novel E6-based multiplex type-specific system (MPTS123) that uses Luminex xMAP technology were combined into a new testing algorithm. To evaluate this algorithm, cervical swabs (n = 860) and cervical biopsy specimens (n = 355) were tested, with a focus on HPV types detected by the MPTS123 assay (types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68, 6, and 11). Among the HPV-positive samples, identifications of individual HPV genotypes were compared. When all MPTS123 targeted genotypes were considered together, good overall agreement was found (κ = 0.801, 95% confidence interval [CI], 0.784 to 0.818) with identification by SPF10 LiPA, but significantly more genotypes (P < 0.0001) were identified by the MPTS123 PCR Luminex assay, especially for HPV types 16, 35, 39, 45, 58, and 59. An alternative type-specific assay was evaluated that is based on detection of a limited number of HPV genotypes by type-specific PCR and a reverse hybridization assay (MPTS12 RHA). This assay showed results similar to those of the expanded MPTS123 Luminex assay. These results confirm the fact that broad-spectrum PCRs are hampered by type competition when multiple HPV genotypes are present in the same sample. Therefore, a testing algorithm combining the broad-spectrum PCR and a range of type-specific PCRs can offer a highly accurate method for the analysis of HPV infections and diminish the rate of false-negative results and may be particularly useful for epidemiological and vaccine studies.
PMCID: PMC3666791  PMID: 23363835
15.  Characteristics and survival of head and neck cancer by HPV status: a cancer registry-based study 
Elucidation of the role of human papillomavirus (HPV) in the etiology and prognosis of squamous carcinomas of the head and neck (HNSCC) is essential to optimize prevention and treatment strategies for this disease. We analyzed 385 HNSCC tissue blocks identified through a population-based cancer registry in Metropolitan Detroit for HPV DNA using a broad-spectrum PCR technique (SPF10-LiPA25) to correlate with patient and tumor characteristics and overall survival. Overall, HPV DNA (any type) was detected in 29.4% of all HNSCC, but it was significantly more prevalent (50.6%) in oropharyngeal sites (N=81), where 90% of HPV were type 16, than in other sites. HPV prevalence (any type) in oropharyngeal sites was highest in patients with a negative smoking indicator, Caucasians, and in regional tumor stage. Likewise, only in oropharyngeal sites did patients overall positive to HPV show significantly better survival compared with HPV-negative patients, notably among those who had been irradiated. The best and the worst survival from cancer in oropharyngeal sites were found, respectively, among HPV-positive patients with negative smoking indicator and among HPV-negative patients with positive smoking indicator. The results of the present study revealed that the presence of HPV DNA was associated with patients’ specific characteristics and better overall survival exclusively in oropharyngeal sites. To define the fraction of HNSCC preventable by HPV vaccination or amenable to less aggressive treatment, however, tobacco exposure and HPV markers other than DNA presence need to be taken into account.
PMCID: PMC3319485  PMID: 22020866
Human papillomavirus (HPV); PCR; Surveillance, Epidemiology and End Results; Head and neck cancer; Survival
16.  Reduced Prevalence of Oral Human Papillomavirus (HPV) 4 Years after Bivalent HPV Vaccination in a Randomized Clinical Trial in Costa Rica 
PLoS ONE  2013;8(7):e68329.
Human papillomavirus (HPV) infection, particularly with type 16, causes a growing fraction of oropharyngeal cancers, whose incidence is increasing, mainly in developed countries. In a double-blind controlled trial conducted to investigate vaccine efficacy (VE) of the bivalent HPV 16/18 vaccine against cervical infections and lesions, we estimated VE against prevalent oral HPV infections 4 years after vaccination.
Methods and Findings
A total of 7,466 women 18–25 years old were randomized (1∶1) to receive the HPV16/18 vaccine or hepatitis A vaccine as control. At the final blinded 4-year study visit, 5,840 participants provided oral specimens (91·9% of eligible women) to evaluate VE against oral infections. Our primary analysis evaluated prevalent oral HPV infection among all vaccinated women with oral and cervical HPV results. Corresponding VE against prevalent cervical HPV16/18 infection was calculated for comparison. Oral prevalence of identifiable mucosal HPV was relatively low (1·7%). Approximately four years after vaccination, there were 15 prevalent HPV16/18 infections in the control group and one in the vaccine group, for an estimated VE of 93·3% (95% CI = 63% to 100%). Corresponding efficacy against prevalent cervical HPV16/18 infection for the same cohort at the same visit was 72·0% (95% CI = 63% to 79%) (p versus oral VE = 0·04). There was no statistically significant protection against other oral HPV infections, though power was limited for these analyses.
HPV prevalence four years after vaccination with the ASO4-adjuvanted HPV16/18 vaccine was much lower among women in the vaccine arm compared to the control arm, suggesting that the vaccine affords strong protection against oral HPV16/18 infection, with potentially important implications for prevention of increasingly common HPV-associated oropharyngeal cancer., Registry number NCT00128661
PMCID: PMC3714284  PMID: 23873171
17.  HPV16 Seropositivity and Subsequent HPV16 Infection Risk in a Naturally Infected Population: Comparison of Serological Assays 
PLoS ONE  2013;8(1):e53067.
Several serological assays have been developed to detect antibodies elicited against infections with oncogenic human papillomavirus (HPV) type 16. The association between antibody levels measured by various assays and subsequent HPV infection risk may differ. We compared HPV16-specific antibody levels previously measured by a virus-like particle (VLP)-based direct enzyme-linked immunoassay (ELISA) with levels measured by additional assays and evaluated the protection against HPV16 infection conferred at different levels of the assays.
Methodology/Principal Findings
Replicate enrollment serum aliquots from 388 unvaccinated women in the control arm of the Costa Rica HPV vaccine trial were measured for HPV16 seropositivity using three serological assays: a VLP-based direct ELISA; a VLP-based competitive Luminex immunoassay (cLIA); and a secreted alkaline phosphatase protein neutralization assay (SEAP-NA). We assessed the association of assay seropositivity and risk of subsequent HPV16 infection over four years of follow-up by calculating sampling-adjusted odds ratios (OR) and HPV16 seropositivity based on standard cutoff from the cLIA was significantly associated with protection from subsequent HPV16 infection (OR = 0.48, CI = 0.27–0.86, compared with seronegatives). Compared with seronegatives, the highest seropositive tertile antibody levels from the direct ELISA (OR = 0.53, CI = 0.28–0.90) as well as the SEAP-NA (OR = 0.20, CI = 0.06, 0.64) were also significantly associated with protection from HPV16 infection.
Enrollment HPV16 seropositivity by any of the three serological assays evaluated was associated with protection from subsequent infection, although cutoffs for immune protection were different. We defined the assays and seropositivity levels after natural infection that better measure and translate to protective immunity.
PMCID: PMC3534652  PMID: 23301022
18.  Evaluation of the polyclonal ELISA HPV serology assay as a biomarker for HPV exposure 
Sexually transmitted diseases  2011;38(10):976-982.
Seropositivity to HPV16 and 18 antibodies is used as a measure of cumulative HPV exposure and as a stratifier of HPV exposure for vaccine efficacy analyses. Overall performance of these assays, as a measure of HPV exposure, has not been evaluated.
Using data from the enrollment phase of the HPV16/18 vaccine trial in Costa Rica, we evaluated the performance of the polyclonal ELISA HPV16 and 18 serological assays as a measure of HPV exposure. Biological (for eg. HPV infection at the cervix) and behavioral characteristics (for eg. lifetime number of sexual partners) with known associations with current and past HPV infection were used to define cases and controls (HPV exposed vs. not exposed). Pre-vaccination serum was measured for antibodies against HPV16 and HPV18 by ELISA; cervical samples were tested for HPV DNA using PCR SPF10/LiPA25. ELISA results were analyzed using receiver-operator-characteristic curves (ROC); performance was evaluated at the manufacturer set cutpoint (HPV16 =8, HPV18 =7) and at cutpoints chosen to optimize sensitivity and specificity (HPV16 =34, HPV18 =60).
Defining cases as type-specific HPV DNA positive with high-grade abnormal cytolzogy (i.e. combined molecular and microscopic markers of infection), HPV16-ELISA gave sensitivity that was lower at the optimal cutpoint than the manufacturer cutpoint (62.2 compared with 75.7, respectively; p=0.44). However, specificity was higher (85.3 compared with 70.4, respectively; p<0.0001). Similarly, HPV18-ELISA gave sensitivity that was lower at the optimal cutpoint than the manufacturer cutpoint (34.5 compared with 51.7, respectively; p=0.40), with higher specificities (94.9 compared with 72.6, respectively; p<0.0001).
Modifying cutpoints did not improve the low sensitivity. The low sensitivity of this assay does not support its use for risk stratification or clinical settings.
PMCID: PMC3178897  PMID: 21934576
Human Papillomavirus; serology; polyclonal ELISA
19.  Human rotavirus vaccine Rotarix™ provides protection against diverse circulating rotavirus strains in African infants: a randomized controlled trial 
BMC Infectious Diseases  2012;12:213.
Rotaviruses are the most important cause of severe acute gastroenteritis worldwide in children <5 years of age. The human, G1P[8] rotavirus vaccine Rotarix™ significantly reduced severe rotavirus gastroenteritis episodes in a Phase III clinical trial conducted in infants in South Africa and Malawi. This paper examines rotavirus vaccine efficacy in preventing severe rotavirus gastroenteritis, during infancy, caused by the various G and P rotavirus types encountered during the first rotavirus-season.
Healthy infants aged 5–10 weeks were enrolled and randomized into three groups to receive either two (10 and 14 weeks) or three doses of Rotarix™ (together forming the pooled Rotarix™ group) or three doses of placebo at a 6,10,14-week schedule. Weekly home visits were conducted to identify gastroenteritis episodes. Rotaviruses were detected by ELISA and genotyped by RT-PCR and nucleotide sequencing. The percentage of infants with severe rotavirus gastroenteritis caused by the circulating G and P types from 2 weeks post-last dose until one year of age and the corresponding vaccine efficacy was calculated with 95% CI.
Overall, 4939 infants were vaccinated and 4417 (pooled Rotarix™ = 2974; placebo = 1443) were included in the per protocol efficacy cohort. G1 wild-type was detected in 23 (1.6%) severe rotavirus gastroenteritis episodes from the placebo group. This was followed in order of detection by G12 (15 [1%] in placebo) and G8 types (15 [1%] in placebo). Vaccine efficacy against G1 wild-type, G12 and G8 types were 64.1% (95% CI: 29.9%; 82%), 51.5% (95% CI:-6.5%; 77.9%) and 64.4% (95% CI: 17.1%; 85.2%), respectively. Genotype P[8] was the predominant circulating P type and was detected in 38 (2.6%) severe rotavirus gastroenteritis cases in placebo group. The remaining circulating P types comprised of P[4] (20 [1.4%] in placebo) and P[6] (13 [0.9%] in placebo). Vaccine efficacy against P[8] was 59.1% (95% CI: 32.8%; 75.3%), P[4] was 70.9% (95% CI: 37.5%; 87.0%) and P[6] was 55.2% (95% CI: -6.5%; 81.3%)
Rotarix™ vaccine demonstrated efficacy against severe gastroenteritis caused by diverse circulating rotavirus types. These data add to a growing body of evidence supporting heterotypic protection provided by Rotarix™.
Trial registration number
PMCID: PMC3462149  PMID: 22974466
20.  Efficacy of a bivalent HPV 16/18 vaccine against anal HPV16/18 infection among young women: a nested analysis within the Costa Rica Vaccine Trial 
The lancet oncology  2011;12(9):862-870.
Anal cancer remains rare (incidence of ∼1.5 per 100,000 women annually) but rates are increasing in many countries. Human papillomavirus-16 (HPV16) infection causes most cases. We evaluated vaccine efficacy (VE) of an ASO4-adjuvanted HPV16/18 vaccine against anal HPV16/18 infection.
In a randomized double-blind controlled trial designed to evaluate VE against persistent cervical HPV16/18 infections and associated precancerous lesions in Costa Rica, 4210 healthy women underwent anal specimen collection (4224 of 5968= 70.8% of eligible women) at the final blinded study visit 4 years after vaccination to evaluate anal HPV16/18 VE. Cervical HPV16/18 VE among the same women at the same visit was calculated as a comparator. For this ancillary work, analyses were conducted in a restricted cohort of women both cervical HPV16/18 DNA negative and HPV 16/18 seronegative prior at enrollment (N=1989), and in the full cohort (all women with an anal specimen).
In the restricted cohort, VE against prevalent HPV16/18 anal infection measured one-time, four-years post-vaccination was 83.6% (95%CI 66.7% to 92.8%), which was comparable to cervical HPV16/18 VE (87.9%, 95%CI 77.4% to 94.0%). In the full cohort, HPV16/18 VE was statistically lower at the anus (62.0%, 95%CI 47.1% to 73.1%) compared to the cervix (76.4%, 95%CI 67.0% to 83.5%) (p for anatomic-site interaction =0.03). Significant and comparable VE estimates against a composite endpoint of HPV31/33/45 (i.e.: cross-protection) was observed at the anus and cervix.
The ASO4-adjuvanted vaccine affords strong protection against anal HPV, particularly among women more likely to be HPV naïve at vaccination. Funding. The Costa Rica HPV Vaccine Trial is sponsored and funded by the NCI (contract N01-CP-11005), with funding support from the National Institutes of Health Office of Research on Women's Health, and conducted with support from the Ministry of Health of Costa Rica. Vaccine was provided for our trial by GlaxoSmithKline Biologicals (GSK), under a Clinical Trials Agreement with the NCI.
PMCID: PMC3172992  PMID: 21865087
Human papillomavirus vaccine; HPV; anal cancer
21.  Human Papillomavirus Infection with Multiple Types: Pattern of Coinfection and Risk of Cervical Disease 
The Journal of Infectious Diseases  2011;203(7):910-920.
Objective. We investigated coinfection patterns for 25 human papillomavirus (HPV) types and assessed the risk conferred by multiple HPV types toward cervical disease.
Methods. Sexually active women (n=5,871) in the NCI-sponsored Costa Rica HPV Vaccine Trial's prevaccination enrollment visit were analyzed. Genotyping for 25 HPVs was performed using SPF10/LiPA25. We calculated odds ratios (ORs) to assess coinfection patterns for each genotype with 24 other genotypes. These ORs were pooled and compared with pair-specific ORs to identify genotype combinations that deviated from the pooled OR. We compared risk of CIN2+/HSIL+between multiple and single infections and assessed additive statistical interactions.
Results. Of the 2478 HPV-positive women, 1070 (43.2%) were infected with multiple types. Multiple infections occurred significantly more frequently than predicted by chance. However, this affinity to be involved in a coinfection (pooled OR for 300 type-type combinations=2.2; 95% confidence interval [CI]=2.1-2.4) was not different across HPV type-type combinations. Compared with single infections, coinfection with multiple α9 species was associated with significantly increased risk of CIN2+(OR=2.2; 95% CI=1.1–4.6) and HSIL+(OR=1.6; 95% CI=1.1–2.4). However, disease risk was similar to the sum of estimated risk from individual types, with little evidence for synergistic interactions.
Conclusions. Coinfecting HPV genotypes occur at random and lead to cervical disease independently.
PMCID: PMC3068034  PMID: 21402543
22.  Epidemiological Study of Anti-HPV16/18 Seropositivity and Subsequent Risk of HPV16 and -18 Infections 
Infection with human papillomavirus (HPV) 16 or HPV18 elicits an antibody response, but whether the elicited antibodies protect women against subsequent infection by a homologous HPV type compared with seronegative women is unknown.
Study participants were women aged 18–25 years at enrollment in the control group of the ongoing National Cancer Institute–sponsored, community-based, randomized HPV16/18 Costa Rica Vaccine Trial. At enrollment, 2813 participants were negative for cervical HPV16 DNA and 2950 for HPV18 DNA. Women were interviewed regarding sociodemographic data and medical and health history. Medical and pelvic examinations were conducted for all consenting sexually experienced women. Serum samples taken at enrollment were tested for total HPV16/18 antibodies with a polyclonal enzyme-linked immunosorbent assay, and cervical specimens were tested for type-specific HPV DNA over 4 years of follow-up. Using Poisson regression, we compared rate ratios of newly detected cervical HPV16 or HPV18 infection among homologous HPV-seropositive and HPV-seronegative women, adjusting for age, education, marital status, lifetime number of sexual partners, and smoking.
There were 231 newly detected HPV16 infections during 5886 person-years among HPV16-seronegative women compared with 12 newly detected HPV16 infections during 581 person-years among HPV16-seropositive women with the highest HPV16 sero-levels. There were 136 newly detected HPV18 infections during 6352 person-years among HPV18-seronegative women compared with six new infections detected during 675 person-years among HPV18 seropositives with the highest sero-levels. After controlling for risk factors associated with newly detected HPV infection, having high HPV16 antibody titer at enrollment was associated with a reduced risk of subsequent HPV16 infection (women in the highest tertile of HPV16 antibody titers, adjusted rate ratio = 0.50, 95% confidence interval = 0.26 to 0.86 vs HPV16-seronegative women). Similarly, having high HPV18 antibody titer at enrollment was associated with a reduced risk of subsequent HPV18 infection (women in the highest tertile of HPV18 antibody titers, adjusted rate ratio = 0.36, 95% confidence interval = 0.14 to 0.76 vs HPV18-seronegative women).
In this study population, having high antibody levels against HPV16 and HPV18 following natural infection was associated with reduced risk of subsequent HPV16 and HPV18 infections.
PMCID: PMC2970577  PMID: 20944077
23.  Assessment of Human Papillomavirus in Lung Tumor Tissue 
Lung cancer kills more than 1 million people worldwide each year. Whereas several human papillomavirus (HPV)–associated cancers have been identified, the role of HPV in lung carcinogenesis remains controversial.
We selected 450 lung cancer patients from an Italian population–based case–control study, the Environment and Genetics in Lung Cancer Etiology. These patients were selected from those with an adequate number of unstained tissue sections and included all those who had never smoked and a random sample of the remaining patients. We used real-time polymerase chain reaction (PCR) to test specimens from these patients for HPV DNA, specifically for E6 gene sequences from HPV16 and E7 gene sequences from HPV18. We also tested a subset of 92 specimens from all never-smokers and a random selection of smokers for additional HPV types by a PCR-based test for at least 54 mucosal HPV genotypes. DNA was extracted from ethanol- or formalin-fixed paraffin-embedded tumor tissue under strict PCR clean conditions. The prevalence of HPV in tumor tissue was investigated.
Specimens from 399 of 450 patients had adequate DNA for analysis. Most patients were current (220 patients or 48.9%) smokers, and 92 patients (20.4%) were women. When HPV16 and HPV18 type–specific primers were used, two specimens were positive for HPV16 at low copy number but were negative on additional type-specific HPV16 testing. Neither these specimens nor the others examined for a broad range of HPV types were positive for any HPV type.
When DNA contamination was avoided and state-of-the-art highly sensitive HPV DNA detection assays were used, we found no evidence that HPV was associated with lung cancer in a representative Western population. Our results provide the strongest evidence to date to rule out a role for HPV in lung carcinogenesis in Western populations.
PMCID: PMC3057981  PMID: 21293027
24.  Comparison of human papillomavirus detection between freshly frozen tissue and paraffin embedded tissue of invasive cervical cancer 
Human Papillomavirus (HPV) detection results comparing paraffin embedded cervical tissue and other cervical specimens have been done with varying degrees of agreement. However, studies comparing freshly frozen specimens and paraffin embedded specimens of invasive cervical carcinomas are lacking. The aim of the study was to compare HPV detection using SPF10 broad-spectrum primers PCR followed by DEIA and genotyping by LiPA25 (version 1) between freshly frozen cervical tissue samples and paraffin embedded blocks of cervical tissue from the same patient. There were 171 pairs of paraffin embedded and freshly frozen samples analyzed from cervical carcinoma cases from Kampala, Uganda.
88.9% (95% CI: 83.2%-93.2%) of paraffin embedded samples were HPV positive compared with 90.1% (95% CI: 84.6%-94.1%) of freshly frozen samples, giving an overall agreement in HPV detection between fresh tissue and paraffin embedded tissue at 86.0% (95% CI: 79.8%-90.8%). Although the proportion of HPV positive cases in freshly frozen tissue was higher than those in paraffin blocks, the difference was not statistically significant (p > 0.05). In both types of tissues, single HPV infections were predominant, with HPV16 accounting for 47% of positive cases. Comparison in the overall agreement, taking into accounts not only positivity in general, but also HPV types, showed a 65% agreement (complete agreement of 59.7%, partial agreement of 5.3%) and complete disagreement of 35.0%. HPV detection in squamous cell carcinomas (SCC) and adenocarcinomas (ADC) was similar in fresh tissue or paraffin blocks (p ≥ 0.05).
p16 immunostaining in samples that had at least one HPV negative results showed that 24 out of 25 cases had an over-expressed pattern.
HPV DNA detection was lower among ADC as compared to SCC. However, such differences were minimized when additional p16 testing was added, suggesting that the technical issues may largely explain the HPV negative cases.
PMCID: PMC2954863  PMID: 20846370
25.  Determinants of seropositivity among HPV-16/18 DNA positive young women 
BMC Infectious Diseases  2010;10:238.
Not all women infected with HPV-16/18 have detectable levels of HPV-16/18 antibodies, those who seroconvert develop low antibody levels, and seroconversion occurs typically several months post-infection. We evaluated determinants of seropositivity among 646 women infected with HPV-16 and/or HPV-18.
Data are from the enrollment visit of the NCI-sponsored Costa Rica HPV Vaccine Trial. Sera were tested for HPV-16/18 antibodies by ELISA; cervical specimens were tested for HPV DNA using HC2 and SPF10/LiPA25. Odds ratios (OR) and 95% confidence intervals (CI) were computed.
Among HPV-16/18 DNA positives, seropositivity was 63.0% and 57.5%, respectively. Among HPV-16 DNA positives, seropositivity increased with lifetime number of sexual partners (p-trend = 0.01). Women with abnormal cytology and/or high viral load had a 1.63-2.79-fold increase in the detection of antibodies compared to women with normal cytology/low viral load. Current users of oral contraceptives had a 1.88-fold (95%CI, 1.14-3.09) increased detection of antibodies and current users of injectables had a 3.38-fold (95%CI, 1.39-8.23) increased detection compared to never users. Among HPV-18 DNA positive women, seropositivity was associated with current oral contraceptive use (OR 2.47; 95%CI 1.08-5.65).
Factors associated with sustained HPV exposure (abnormal cytology, elevated HPV viral load, increasing lifetime partners) were predictive of HPV-16 seropositivity. Hormonal contraceptive use was associated with seropositivity suggesting an effect of hormones on immune responses to HPV. Patterns were less consistent for HPV-18. Follow up of incident HPV infections to evaluate seroconversion and their determinants is needed.
PMCID: PMC2931509  PMID: 20698998

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