Leen-Jan van Doorn

DDL Diagnostic Laboratory, Rijswijk, South Holland, Netherlands

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Publications (63)319.58 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: 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.
    American journal of epidemiology. 08/2014;
  • The Journal of infectious diseases. 06/2014;
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    ABSTRACT: 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.
    BMC Infectious Diseases 03/2014; 14(1):120. · 3.03 Impact Factor
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    ABSTRACT: The Costa Rica HPV16/18 Vaccine Trial (CVT) showed that four-year vaccine efficacy against 12-month HPV16/18 persistent infection was similarly high among women who received one, two, or the recommended three doses of the bivalent HPV16/18 L1 virus-like particle (VLP) vaccine. Live-attenuated viral vaccines, but not simple-subunit vaccines, usually induce durable lifelong antibody responses after a single dose. It is unclear whether noninfectious VLP vaccines behave more like live-virus or simple-subunit vaccines in this regard. To explore the likelihood that efficacy will persist longer term, we investigated the magnitude and durability of antibodies to this vaccine by measuring HPV16- and HPV18-specific antibodies by VLP-ELISA using serum from enrollment, vaccination, and annual visits through four years in four vaccinated groups; one-dose (n = 78), two-doses separated by one month (n = 140), two doses separated by six months (n = 52), and three scheduled doses (n = 120, randomly selected). We also tested enrollment sera from n = 113 HPV16- or HPV18 L1-seropositive women prevaccination, presumably from natural infection. At four years, 100% of women in all groups remained HPV16/18 seropositive; both HPV16/18 geometric mean titers (GMT) among the extended two-dose group were non-inferior to the three-dose group, and ELISA titers were highly correlated with neutralization titers in all groups. Compared with the natural infection group, HPV16/18 GMTs were, respectively, at least 24 and 14 times higher among the two-dose and 9 and 5 times higher among one-dose vaccinees. Antibody levels following one-dose remained stable from month 6 through month 48. Results raise the possibility that even a single dose of HPV VLPs will induce long-term protection. Cancer Prev Res; 6(11); 1242-50. ©2013 AACR.
    Cancer Prevention Research 11/2013; 6(11):1242-50. · 4.89 Impact Factor
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    ABSTRACT: 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. 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 regression 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.
    American journal of otolaryngology 09/2013; · 0.77 Impact Factor
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    ABSTRACT: 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.
    The Journal of Infectious Diseases 09/2013; · 5.85 Impact Factor
  • PLoS ONE 07/2013; 8(7):68329-. · 3.53 Impact Factor
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    ABSTRACT: 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. Methods: Samples are from 3-dose HPV vaccine recipients from the Costa Rica HPV16/18 vaccine trial. Women with a new HPV31, HPV45, or HPV58 infections over follow-up were compared with randomly selected women - with no new infection with HPV31/45/58 - with respect to HPV16 and HPV18 antibody, HPV31, HPV45, and HPV58 neutralization, and HPV16 avidity. Results: HPV31 cases had lower HPV16 antibody levels than controls (OR 4th quartile compared to 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. 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.
    Human vaccines & immunotherapeutics. 04/2013; 9(7).
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    ABSTRACT: HPV epidemiological and vaccine studies require highly sensitive HPV detection and genotyping systems. To improve HPV detection by PCR, the broad-spectrum L1 based SPF(10) PCR DEIA LiPA system and a novel E6 based multiplex type-specific system (MPTS123) using Luminex xMAP technology were combined into a new testing algorithm. To evaluate this algorithm, cervical swabs (n=860) and cervical biopsies (n=355) were tested with a focus on HPV detected by the MPTS123 assay (HPV-16, -18, -31, -33, -35, -39, -45, -51, -52, -56, -58, -59, -66, -68, -6 and -11). Among the HPV positive samples, identification of individual HPV genotypes was compared. When all MPTS123 targeted genotypes were taken together a good overall agreement was found (κ = 0.801, 95% CI: 0.784-0.818) with identification by SPF(10) LiPA, but significantly more genotypes (P<0.0001) were identified by the MPTS123 PCR Luminex assay, especially for HPV-16, -35, -39, -45, -58, and -59. An alternative type-specific assay was evaluated, based on detection of a limited number of HPV genotypes by type-specific PCR and a reverse hybridization assay (MPTS12 RHA). This assay showed similar results as 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 offers a highly accurate method for the analysis of HPV infections and diminishes the rate of false-negative results, which may be particularly useful for epidemiological and vaccine studies.
    Journal of clinical microbiology 01/2013; · 4.16 Impact Factor
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    ABSTRACT: 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. 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.
    PLoS ONE 01/2013; 8(1):e53067. · 3.53 Impact Factor
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    ABSTRACT: 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.
    PLoS ONE 01/2013; 8(11):e80382. · 3.53 Impact Factor
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    ABSTRACT: 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 SPF(10) PCR/DEIA/LiPA(25), 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.
    The Journal of Infectious Diseases 07/2012; 206(7):1103-1110. · 5.85 Impact Factor
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    ABSTRACT: Two HPV serological assays, the competitive Luminex immunoassay (cLIA), and an enzyme-linked immunoassay (ELISA) against HPV16 have been used to define HPV-naïve subcohorts within large HPV vaccination trials. Some of the variation in estimated vaccine efficacies may be due to the differences in these assays used to define the HPV-naïve subgroups. To guide the interpretation of published results, we compared these assays. Replicate enrollment sera from a stratified sample of 388 unvaccinated women from the control arm of the Costa Rica HPV 16/18 Vaccine Trial were measured for antibodies against HPV16 using cLIA and ELISA. Agreement between the assays was estimated using standard and alternative assay cutoffs. Using laboratory-determined seropositivity cutoffs, sampling-adjusted HPV16 seropositivity was 24.8% by ELISA and 7.2% by cLIA. Comparing cLIA and ELISA antibody levels based on the standard cutoffs, overall agreement was 53% (positive-agreement = 49%). The poor agreement was mainly driven by the higher sensitivity of the ELISA than cLIA, resulting in 30% of the ELISA-positive sample that were cLIA-negative (none of the ELISA-negatives were cLIA-positive). Increasing ELISA cutoff to 54 ELISA units (EU)/mL (the level which maximized agreement with cLIA; ELISA standard cutoff is 8 EU/mL) resulted in higher agreement (overall agreement = 91%; positive agreement = 78%). ELISA and cLIA are different from each other based on the laboratory-determined cutoff. Increasing ELISA cutoff increased agreement with cLIA, which could facilitate comparisons among studies that use different assays. Impact: Keeping cLIA at the laboratory-determined cutoff but altering ELISA cutoff for seropositivity might facilitate vaccine efficacy comparisons in the naïve cohorts defined by cLIA. Cancer Epidemiol Biomarkers Prev; 21(9); 1547-54. ©2012 AACR.
    Cancer Epidemiology Biomarkers &amp Prevention 07/2012; 21(9):1547-54. · 4.56 Impact Factor
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    ABSTRACT: 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 this 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.
    International Journal of Cancer 10/2011; 131(5):1179-86. · 6.20 Impact Factor
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    ABSTRACT: Seropositivity to human papillomavirus (HPV)16 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 enzyme-linked immunosorbent assay (ELISA) HPV16 and 18 serological assays as a measure of HPV exposure. Biologic (e.g., HPV infection at the cervix) and behavioral characteristics (e.g., 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). Prevaccination serum was measured for antibodies against HPV16 and 18 by ELISA; cervical samples were tested for HPV DNA using PCR SPF10/LiPA25. ELISA results were analyzed using receiver-operator characteristic curves; performance was evaluated at the manufacturer set cut point (HPV16 = 8, HPV18 = 7) and at cut points chosen to optimize sensitivity and specificity (HPV16 = 34, HPV18 = 60). Defining cases as type-specific HPV DNA positive with high-grade abnormal cytology (i.e., combined molecular and microscopic markers of infection), HPV16-ELISA gave sensitivity that was lower at the optimal cut point than the manufacturer cut point (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 cut point than the manufacturer cut point (34.5 compared with 51.7, respectively; P = 0.40), with higher specificities (94.9 compared with 72.6, respectively; P < 0.0001). Modifying cut points did not improve the low sensitivity. The low sensitivity of this assay does not support its use for risk stratification or clinical settings.
    Sexually transmitted diseases 10/2011; 38(10):976-82. · 2.58 Impact Factor
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    ABSTRACT: Anal cancer remains rare (incidence of about 1·5 per 100,000 women yearly), but rates are increasing in many countries. Human papillomavirus (HPV) 16 and 18 infections cause most cases of anal cancer. We assessed efficacy of an AS04-adjuvanted HPV 16 and HPV 18 vaccine against anal infection with HPV 16, HPV 18, or both (HPV 16/18). Women from Costa Rica were registered between June 28, 2004, and Dec 21, 2005, in a randomised double-blind controlled trial that was designed to assess vaccine efficacy against persistent cervical HPV 16/18 infections and associated precancerous lesions. Eligible women were residents of Guanacaste and selected areas of Puntarenas, Costa Rica, age 18-25 years, in good general health, willing to provide informed consent, and were not pregnant or breastfeeding. Participants were randomly assigned (1:1) to receive an HPV vaccine (Cervarix, GlaxoSmithKline, Rixensart, Belgium) or a control hepatitis A vaccine (modified preparation of Havrix, GlaxoSmithKline, Rixensart, Belgium). Vaccines were administered in three 0·5 mL doses at enrolment, 1 month, and 6 months. Women, selected at the final blinded study visit 4 years after vaccination, provided anal specimens for assessment of vaccine efficacy against anal HPV 16/18 infection. Prevalence of anal HPV 16/18 infections, reported as vaccine efficacy, was the primary endpoint of the study described here. Vaccine efficacy against cervical HPV 16/18 infection in the same women at the 4-year visit was used as a comparator. Analyses were done in a restricted cohort of women who were negative for both cervical HPV 16 and HPV 18 DNA and who were HPV 16 and HPV 18 seronegative before enrolment (HPV naive), and also in the full cohort of women who provided an anal specimen. Investigators were masked to group assignment. This study is registered at ClinicalTrials.gov, number NCT00128661. All women who attended the final blinded study visit and consented to anal specimen collection were included in the analysis (4210 of 6352 eligible women). In the full cohort, vaccine efficacy against prevalent HPV 16/18 infection measured one-time, 4 years post vaccination was lower at the anus (62·0%, 95% CI 47·1-73·1) compared with the cervix (76·4%, 67·0-83·5; p for interaction by anatomical site 0·031). In the restricted cohort, vaccine efficacy against anal HPV 16/18 infection was 83·6% (66·7-92·8), which was similar to vaccine efficacy against cervical HPV 16/18 infection (87·9%, 77·4-94·0). Safety issues were not addressed in the current analysis. Additional safety data will be published later in a separate article. The AS04-adjuvanted vaccine affords strong protection against anal HPV infection, particularly among women more likely to be HPV naive at enrolment. National Cancer Institute with contributions from the National Institutes of Health Office of Research on Women's Health. Vaccine was provided by GlaxoSmithKline Biologicals.
    The Lancet Oncology 08/2011; 12(9):862-70. · 25.12 Impact Factor
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    ABSTRACT: Isolates of HPV16 comprise six variants: European (Eu), Asian (As), Asian-American (AA), North American (NA), African-1 (AF1), and African-2 (AF2) with different carcinogenic potentials. Highly reliable automatable techniques for HPV variant genotyping would be helpful to confirm the role of variants in cervical cancer in large epidemiological studies. To validate the performance of a novel assay for identification of HPV16 variants. The test is a multiplex PCR amplifying four small fragments from the E6 open reading frame (ORF). Variants are identified in a reverse hybridization assay with variant specific probes. The novel assay was compared to sequence analysis of the E6 ORF in 68 clinical samples. In addition, HPV16 variant distribution was studied in 218 cervical samples from women with normal cytology, squamous cell carcinoma (SCC) and adenocarcinoma of countries in Africa, Asia and South-America. There was 95.6% agreement between the test and sequencing. Analysis of the clinical panel including 218 positive samples revealed worldwide distribution patterns of HPV16 variants. Finally, a threefold increased risk for SCC with grouped Eu and As variants in South-American countries as compared to controls was found, although the association was not statistically significant. The novel assay is a reliable and simple technique, distribution patterns of HPV16 variants in different world regions and disease associations could be established and it may be useful in further epidemiological studies investigating the role of HPV16 variants in cervical carcinogenesis.
    Journal of clinical virology: the official publication of the Pan American Society for Clinical Virology 07/2011; 51(3):165-9. · 3.12 Impact Factor
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    ABSTRACT: We investigated coinfection patterns for 25 human papillomavirus (HPV) types and assessed the risk conferred by multiple HPV types toward cervical disease. 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 SPF(10)/LiPA(25). 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. 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. Coinfecting HPV genotypes occur at random and lead to cervical disease independently.
    The Journal of Infectious Diseases 04/2011; 203(7):910-20. · 5.85 Impact Factor
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    ABSTRACT: A novel Chlamydia trachomatis (Ct) microsphere suspension (MS) assay was evaluated for identification of the different serovars, using the same PCR primer set established for the Ct Detection and genoTyping assay. Both assays can detect and identify all 14 major serovars (A, B/Ba, C, D/Da, E, F, G/Ga, H, I/Ia, J, K, L1, L2/L2a, and L3) and one genovariant of serovar J. The probe specificity for the Ct-MS assay was determined using 14 Ct reference strains and 1 clinical isolate from a genovariant of serovar J. Also, the Ct-MS assay and the Ct detection and genoTyping assay were compared in 712 Ct-positive clinical samples. The Ct-MS assay showed a highly specific reaction for all probes with the amplicons of the reference strains, giving a very low background median fluorescence intensity signal (median fluorescence intensity ≤ 10). An excellent overall agreement in the Ct detection (kappa = 0.947, 95% confidence interval, 0.89 to 0.999; McNemar's test, P = 1.000) and the Ct genotyping (kappa = 0.993, 95% confidence interval, 0.977 to 1.000; McNemar's test, P = 0.053) was observed between the Ct detection and genoTyping (DT) assay and the Ct-MS assay. In conclusion, the novel Ct-MS assay permits simultaneous detection and genotyping of Ct serovars, making the Ct-MS assay an excellent high throughput method.
    The Journal of molecular diagnostics: JMD 03/2011; 13(2):152-9. · 3.48 Impact Factor
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    ABSTRACT: 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.
    CancerSpectrum Knowledge Environment 02/2011; 103(6):501-7. · 14.07 Impact Factor

Publication Stats

2k Citations
319.58 Total Impact Points

Institutions

  • 2005–2014
    • DDL Diagnostic Laboratory
      Rijswijk, South Holland, Netherlands
    • Slotervaartziekenhuis
      Amsterdamo, North Holland, Netherlands
  • 2011–2013
    • Wayne State University
      • Department of Pathology
      Detroit, Michigan, United States
    • University of Antioquia
      Santa Fe de Antioquia, Antioquia, Colombia
  • 2008–2013
    • National Cancer Institute (USA)
      • • Division of Cancer Epidemiology and Genetics
      • • Infections and Immunoepidemiology
      Bethesda, MD, United States
    • German Cancer Research Center
      Heidelburg, Baden-Württemberg, Germany
    • Makerere University
      Kampala, Central Region, Uganda
    • Johns Hopkins University
      Baltimore, Maryland, United States
  • 2010–2011
    • National Institutes of Health
      • • Branch of Infections and Immunoepidemiology
      • • Division of Cancer Epidemiology and Genetics
      Bethesda, MD, United States
    • Karolinska Institutet
      • Institutionen för medicinsk epidemiologi och biostatistik
      Solna, Stockholm, Sweden
  • 2007
    • International Agency for Research on Cancer
      Lyons, Rhône-Alpes, France
  • 2006–2007
    • Karmanos Cancer Institute
      Detroit, Michigan, United States
    • Leiden University Medical Centre
      • Department of Medical Microbiology
      Leyden, South Holland, Netherlands
  • 2004
    • Reinier de Graaf Groep
      Delft, South Holland, Netherlands
  • 2003
    • Stanford Medicine
      • Department of Medicine
      Stanford, California, United States
  • 2002
    • University of São Paulo
      • Faculty of Medicine (FM)
      São Paulo, Estado de Sao Paulo, Brazil