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Background:
Human papillomaviruses (HPV) cause over 500 000 cervical cancers each year, most of which occur in low-resource settings. Human papillomavirus genotyping is important to study natural history and vaccine efficacy. We evaluated TypeSeq, a novel, next-generation, sequencing-based assay that detects 51 HPV genotypes, in 2 large internatio...
Contexts in source publication
Context 1
... evaluated the agreement of TypeSeq with LA in SUCCEED and SPF10-LiPA in CVT. Comparing TypeSeq with LA in SUCCEED, 10 of 13 carcinogenic types had at least 80% positive agreement and HPV16 had 94% positive agreement ( Table 2). The 3 types with lower agreement were HPV51, 52, and 56; all showed higher detection with TypeSeq. ...Context 2
... types (HPV31, 33, 35, 52, 56, and 58) showed a significantly higher positivity for TypeSeq among the discrepant results (McNemar, P < .05). There was high agreement for detecting overall HPV positivity, and positive agreement for detecting any HR type reached 95% between TypeSeq and LA (see Supplementary Table 2). ...Citations
... Specifically, primers were used to amplify a fragment from the L1 region of HPV genotypes, after which the DEIA system detected the amplified products. All DEIA-positive SPF10 amplimers were used to identify HPV genotype by reverse hybridization with the LiPA25 HPV line probe assay (Labo Bio-medical Products, Rijswijk, Netherlands 34 . More detailed HPV DNA detection and genotyping methods are presented elsewhere 31,32 . ...
The AS04-adjuvanted human papillomavirus (HPV)16/18 vaccine, an L1-based vaccine, provides strong vaccine efficacy (VE) against vaccine-targeted type infections, and partial cross-protection to phylogenetically-related types, which may be affected by variant-level heterogeneity. We compared VE against incident HPV31, 33, 35, and 45 detections between lineages and SNPs in the L1 region among 2846 HPV-vaccinated and 5465 HPV-unvaccinated women through 11-years of follow-up in the Costa Rica HPV Vaccine Trial. VE was lower against HPV31-lineage-B (VE=60.7%;95%CI = 23.4%,82.8%) compared to HPV31-lineage-A (VE=94.3%;95%CI = 83.7%,100.0%) (VE-ratio = 0.64;95%CI = 0.25,0.90). Differential VE was observed at several lineage-associated HPV31-L1-SNPs, including a nonsynonymous substitution at position 6372 on the FG-loop, an important neutralization domain. For HPV35, the only SNP-level difference was at position 5939 on the DE-loop, with significant VE against nucleotide-G (VE=65.0%;95%CI = 28.0,87.8) but not for more the common nucleotide-A (VE=7.4%;95%CI = −34.1,36.7). Because of the known heterogeneity in precancer/cancer risk across cross-protected HPV genotype variants by race and region, our results of differential variant-level AS04-adjuvanted HPV16/18 vaccine efficacy has global health implications.
... As oncogenic potential is largely associated with HPV type, standardized HPV genotyping is needed to adequately assess the natural history and epidemiology of each type. Different assays are available for HPV genotyping, with many studies assessing their performance utilizing cervical specimens [8][9][10][11][12][13] but fewer have assessed performance with anal samples in the most vulnerable population. ...
Introduction
Young sexual minority men (SMM) bear the greatest burden of anal human papillomavirus (HPV) infections. We assessed anal HPV genotype discordance between the Linear Array (LA) and SPF10 PCR-DEIA-LiPA25 (LiPA25).
Methods
Discordance was assessed between LA and LiPA25 using self-collected anal swabs from 120 SMM aged 18–29 who were recruited in 2014–2016. Multiple-type infection was explored as a potential confounder of testing agreement, along with clinical and behavioral factors such as HIV status, syphilis status, incarceration history, health insurance coverage, having 3 or more sex partners in the past 6 months, and co-infection with HPV-16.
Results
Significant discordance was found for HPV-6, -11, -16, -31, -42, -54, and -59. Exploratory analyses suggest higher prevalence of genotype discordance in those living with HIV, those with 3 or more sex partners, and those who were positive for 4 or more HPV types.
Conclusions
Our results highlight the importance of HPV detection methods which may inform different interpretations of research assessing anal HPV natural history among SMM at highest risk for HPV.
... The design has been published previously. [15][16][17] In brief, women were enrolled between November 2003 and September 2007. They were excluded if they were younger than 18 years of age, pregnant or living with HIV at the time of their visit, previously treated with chemotherapy or radiation for any cancer, or previously had a hysterectomy. ...
The World Health Organization recommends human papillomavirus (HPV) testing for cervical screening. Extended genotyping can identify the highest‐risk HPV‐positive women. An inexpensive, rapid, mobile isothermal amplification assay (ScreenFire HPV RS test) was recently redesigned to yield four channels ordered by cancer risk (ie, hierarchical approach): HPV16, HPV18/45, HPV31/33/35/52/58 and HPV39/51/56/59/68. Stored specimens from 2076 women (mean age 30.9) enrolled in a colposcopy clinic, with high HPV prevalence, were tested with ScreenFire. We calculated hierarchical channel positivity and non‐hierarchical channel and type positivity, according to histologic diagnosis (256 cancer, 350 cervical intraepithelial neoplasia [CIN]3, 409 CIN2, 1020 < CIN2) and known virologic reference results (Linear Array and TypeSeq). Additionally, we analyzed ScreenFire time‐to‐positive up to 60 min by channel and histology. Overall clinical sensitivity for CIN3+ was 94.7% (95% confidence interval 92.6‐96.4), similar to Linear Array (92.3, 89.7‐94.3) and TypeSeq (96.0, 93.9‐97.6). Sensitivity was high for all types and channels. The hierarchical approach was well in line with HPV typing and histologic diagnosis, prioritizing higher risk women having HPV16 and precancer. For HPV16, time‐to‐positive was shorter in women with precancer. ScreenFire showed excellent agreement with research reference typing tests and detection of CIN2+. Risk‐based type results could help guide clinical management of HPV‐positive women. Time‐to‐positive combined with genotyping might be useful. ScreenFire is rapid, mobile, relatively inexpensive and designed for implementation of HPV‐based screening and management, including in lower‐resource settings. Further validation in screening by self‐sampling and practical effectiveness merit evaluation.
... HPV determination was made using two validated methods with similar sensitivity and specificity. 12 In the first method (DDL Diagnostic Laboratory, The Netherlands), the L1 region of HPV was amplified using the SPF10 PCR primer system, followed by detection using DNA enzyme immunoassay. 13 14 The DNA enzyme immunoassay-positive SPF10 amplimers were used to identify 25 HPV genotypes by reverse hybridisation with the HPV line probe assay (LiPA25). ...
... No difference in vaccine efficacy was observed when using either test to define outcomes. 12 TypeSeq was used in years 9 and 11 and in the clinical management visits after year 4. ...
... The strengths of the present study include the large sample size and the use of well-validated HPV detection/ Original research genotyping methods. 12 HPV vaccination has shown to reduce the HPV prevalence and HPV-related diseases, in countries with high vaccine coverage. [22][23][24] Evidence suggests that the bivalent and quadrivalent vaccines induce cross-protection against the not targeted types HPV31/33/45. ...
Introduction
Human papillomavirus (HPV) vaccines protect against incident HPV infections, which cause cervical cancer.
Objectives
We estimated the prevalence and incidence of HPV infections in young adult women to understand the impact of an HPV vaccination programme in this population.
Methods
We collected cervical specimens from 6322 unvaccinated women, aged 18–37 years, who participated in the Costa Rica Vaccine Trial and its long-term follow-up. Women were followed for (median) 4.8 years and had (median) 4.0 study visits. Cervical specimens were tested for the presence/absence of 25 HPV genotypes. For each age band, we estimated the percentage of women with 1+ prevalent or 1+ incident HPV infections using generalised estimating equations. We also estimated the prevalence and incidence of HPV as a function of time since first sexual intercourse (FSI).
Results
The model estimated HPV incident infections peaked at 28.0% (95% CI 25.3% to 30.9%) at age 20 years then steadily declined to 11.8% (95% CI 7.6% to 17.8%) at age 37 years. Incident oncogenic HPV infections (HPV16/18/31/33/35/39/45/51/52/56/58/59) peaked and then declined from 20.3% (95% CI 17.9% to 22.9%) to 7.7% (95% CI 4.4% to 13.1%); HPV16/18 declined from 6.4% (95% CI 5.1% to 8.1%) to 1.1% (95% CI 0.33% to 3.6%) and HPV31/33/45/52/58 declined from 11.0% (95% CI 9.3% to 13.1%) to 4.5% (95% CI 2.2% to 8.9%) over the same ages. The percentage of women with 1+ incident HPV of any, oncogenic, non-oncogenic and vaccine-preventable (HPV16/18, HPV31/33/45, HPV31/33/45/52/58, and HPV6/11) types peaked <1 year after FSI and steadily declined with increasing time since FSI (p for trends <0.001). We observed similar patterns for model estimated HPV prevalences.
Conclusion
Young adult women may benefit from HPV vaccination if newly acquired vaccine-preventable oncogenic infections lead to cervical precancer and cancer. HPV vaccination targeting this population may provide additional opportunities for primary prevention.
Trial registration number
NCT00128661 .
... 24,25 A subset was tested by TypeSeq in parallel. 26 A validation study showed that major cervical HPV DNA screening and typing tests had similar analytic sensitivity for the HPV genotypes they distinguished. ...
Necessary stages of cervical carcinogenesis include acquisition of a carcinogenic human papillomavirus (HPV) type, persistence associated with the development of precancerous lesions, and invasion. Using prospective data from immunocompetent women in the Guanacaste HPV Natural History Study (NHS), the ASCUS‐LSIL Triage Study (ALTS) and the Costa Rica HPV Vaccine Trial (CVT), we compared the early natural history of HPV types to inform transition probabilities for health decision models. We excluded women with evidence of high‐grade cervical abnormalities at any point during follow‐up and restricted the analysis to incident infections in all women and prevalent infections in young women (aged <30 years). We used survival approaches accounting for interval‐censoring to estimate the time to clearance distribution for 20 529 HPV infections (64% were incident and 51% were carcinogenic). Time to clearance was similar across HPV types and risk classes (HPV16, HPV18/45, HPV31/33/35/52/58, HPV 39/51/56/59 and noncarcinogenic HPV types); and by age group (18‐29, 30‐44 and 45‐54 years), among carcinogenic and noncarcinogenic infections. Similar time to clearance across HPV types suggests that relative prevalence can predict relative incidence. We confirmed that there was a uniform linear association between incident and prevalent infections for all HPV types within each study cohort. In the absence of progression to precancer, we observed similar time to clearance for incident infections across HPV types and risk classes. A singular clearance function for incident HPV infections has important implications for the refinement of microsimulation models used to evaluate the cost‐effectiveness of novel prevention technologies.
... HC2 also detects high viral loads of genetically related types (25). At year 11, this test was replaced by Aptima HPV (Hologic, CA, USA), which detects HPV E6/E7 mRNA from 13 (27). TypeSeq is a nextgeneration sequencing-based assay using TypeSeq 3-PCR stage workflow and a custom Torrent Suite plugin. ...
Background
We investigated the impact of HPV vaccination on the performance of cytology-based and HPV-based screening for detection of cervical precancer among women vaccinated as young adults and reaching screening age.
Methods
A total of 4632 women aged 25–36 years from the Costa Rica HPV Vaccine Trial were included (2418 HPV-vaccinated as young adults and 2214 unvaccinated). We assessed the performance of cytology- and HPV-based cervical screening modalities in vaccinated and unvaccinated women to detect high-grade cervical precancers diagnosed over four years, and the absolute risk of cumulative cervical precancers by screening results at entry.
Results
We detected 95 CIN3 + (52 in unvaccinated and 43 in vaccinated women). HPV16/18/31/33/45 was predominant (69%) among unvaccinated participants, and HPV35/52/58/39/51/56/59/66/68 predominated (65%) among vaccinated participants. Sensitivity and specificity of cervical screening approaches were comparable between women vaccinated as young adults and unvaccinated women. Colposcopy referral rates were lower in the vaccinated group for HPV-based screening modalities, but the positive predictive value (PPV) was comparable between the two groups.
Conclusions
Among women approaching screening ages, vaccinated as young adults and with a history of intensive screening, the expected reduction in the PPV of HPV testing, associated with dropping prevalence of HPV-associated lesions, was not observed. This is likely due to the presence of high-grade lesions associated with non-vaccine HPV types, which may be less likely to progress to cancer.
... Specimens that were not sent for clinical HPV testing were sent to the National Cancer Institute's Cancer Genomics Research Laboratory for testing with TypeSeq. 18,19 TypeSeq detects 51 HPV types (HPV3, 6, 11, 13, 16, 18, 26, Specimens not meeting minimum human and/or HPV read thresholds were reported as "failed to amplify." To generate results compatible with cobas, we classified the same 14 types as high-risk and also separately analyzed types 16 and 18 versus other HR12. ...
... However, TypeSeq has shown high agreement with commercial HPV assays, and we did not observe meaningful differences in the patterns by race and age by assay. 18,19 We were not able to evaluate individual genotypes in our study; however, extended genotyping of all specimens in the larger STRIDES cohort is ongoing, allowing to evaluate genotype-specific results in the future. ...
Background
Mississippi (MS) has among the highest rates of cervical cancer incidence and mortality in the United States, with disproportionately higher rates among Blacks compared to Whites. Here, we evaluate the prevalence of high-risk human papillomavirus (HPV) and abnormal cytology in a representative baseline sample from a diverse statewide cohort of individuals attending cervical screening in MS from the STRIDES Study (STudying Risk to Improve DisparitiES in cervical cancer).
Methods
We included individuals aged 21–65 years undergoing screening at the University of Mississippi Medical Center (UMMC) and the Mississippi State Department of Health (MSDH) from May to November 2018. We calculated age-specific HPV prevalence, overall and by partial HPV16/18 genotyping, and abnormal cytology by race.
Results
A total of 6871 individuals (mean age 35.7 years) were included. HPV prevalence was 25.6% and higher in Blacks (28.0%) compared to Whites (22.4%). HPV prevalence was significantly higher in Blacks aged 21–24 years (50.2%) and 30–34 years (30.2%) compared to Whites in the same age groups (32.1% and 20.7%; p < 0.0001, respectively). The prevalence of high-grade cytologic abnormalities, a cytologic sign of cervical precancer, peaked earlier in Blacks (ages 25–29) compared to Whites (35–39). For comparison, we also analyzed HPV prevalence data from the National Health and Nutrition Examination Survey (NHANES, 2013–2016) and observed similar racial differences in HPV prevalence among women aged 21–24 years.
Conclusions
Our findings suggest that Blacks undergoing cervical cancer screening in MS have higher prevalence of other high-risk 12 HPV types at younger ages and experience an earlier peak of high-grade cytologic abnormalities compared to Whites.
... Currently, the importance of the non-LA LR types may be debatable but a few of these types (HPV30, 44, 68a, 87, 90, 114) were detected in at least 5-8 samples by PCR-15. TypeSeq also detected a few of these non-LA LR types (HPV30, 43, 74, 87, 90, 91, 114) in the SUCCEED study that tested 2804 specimens [29]. These results suggest that these non-LA LR types could be useful in the evaluation of HPV-negative cervical lesions [30] and in epidemiologic studies of HPV in geographical regions that may have uncommon types in circulation [31]. ...
High-throughput HPV typing assays with increased automation, faster turnaround and type-specific digital readout would facilitate studies monitoring the impact of HPV vaccination. We evaluated the NanoString nCounter® platform for detection and digital readout of 48 HPV types in a single reaction. NanoString (NS) used proprietary software to design CodeSets: type-specific probe pairs targeting 48 HPV types and the globin gene. We tested residual DNA extracts from epidemiologic specimens and defined samples (HPV plasmids at 10 to 104 copies/reaction) directly (No-PCR) as well as after L1 consensus PCR of 45 (PCR-45) or 15 cycles (PCR-15). Assay and interpretation followed NS recommendations. We evaluated analytic performance by comparing NanoString results for types included in prior assays: Roche Linear Array (LA) or HPV TypeSeq assay. No-PCR results on 40 samples showed good type-specific agreement with LA (k = 0.621) but sensitivity was 65% with lower limit of detection (LOD) at 104 plasmid copies. PCR-45 results showed almost perfect type-specific agreement with LA (k = 0.862), 82% sensitivity and LOD at 10 copies. PCR-15 results on 75 samples showed substantial type-specific agreement with LA (k = 0.796, 92% sensitivity) and TypeSeq (k = 0.777, 87% sensitivity), and LOD at 10 copies of plasmids. This proof-of-principle study demonstrates the efficacy of the NS platform with HPV CodeSet for type-specific detection using a low number of PCR cycles (PCR-15). Studies are in progress to evaluate assay reproducibility and analytic validation with a larger number of samples.
... TypeSeq detects viral DNA for 51 HPV genotypes [11]. SPF10-LiPA25 and TypeSeq results had a 93.1% positive agreement for detecting any oncogenic HPV type, the agreement for non-HPV16/18 oncogenic types ranged from 71.4% (HPV59) to 100% (HPV58), and no difference in vaccine efficacy was observed when using either test to define outcomes [12]. HPV determination was based on SPF10-LiPA25 for the initial 4 years of the study and on SPF10-LiPA25 or TypeSeq results thereafter. ...
Background
Factors that lead human papillomavirus (HPV) infections to persist and progress to cancer are not fully understood, especially among vaccinated women. We evaluated co-factors for acquisition, persistence and progression of non-HPV16/18 infections in a cohort of HPV-vaccinated women.
Methods
We analyzed 2,153 18-25-year-old women randomized to the HPV-vaccine arm of CVT. Women were HPV-DNA-negative for all types at baseline and followed for ~11 years. Acquisition was a type-specific cervical infection not present/detected at the previously scheduled visit. Persistence was a type-specific incident infection that persisted for ≥1-year with no intervening negatives. Progression of persistent incident infections to CIN2+ was based on histological findings by expert pathologists. GEE methods were used to account for correlated observations. Time-dependent factors evaluated were age, sexual behavior, marital status, hormonal-related factors, number of full-term pregnancies (FTP), smoking behavior, and baseline-BMI.
Results
1,777 incident oncogenic non-HPV16/18 infections were detected in 12,292 visits (average 0.14 infections per visit). Age and sexual behavior-related variables were associated with oncogenic non-HPV16/18 acquisition. 26% of incident infections persisted for ≥1-year. None of the factors evaluated were statistically associated with persistence of oncogenic non-HPV16/18 infections. Risk of progression to CIN2+ increased with increasing age (p-trend=0.001), injectable contraceptives use [relative risk 2.61 (95%CI 1.19–5.73) ever vs. never] and increasing FTP (p-trend=0.034).
Conclusion
In a cohort of HPV16/18-vaccinated women, age and sexual behavior variables are associated with acquisition of oncogenic non-HPV16/18 infections, no notable factors are associated with persistence of acquired oncogenic non-HPV16/18 infections, and age, parity and hormonally-related exposures are associated with progression to CIN2+.
... Safe and effective vaccines against HPV are available since 2006, and the World Health Organization (WHO) recommends countries to vaccinate adolescent girls. 3 Three vaccines are WHO pre-qualified: bivalent against HPV 16 and 18, quadrivalent against HPV 6,11,16, and 18 and nonavalent (HPV 6,11,16,18,31,33,45,52, and 58). ...
... Overall and positive agreement was high and no difference in vaccine efficacy was observed when using either test to define outcomes. 18 SPF10 HPV DNA enzyme immunoassay (DEIA) system followed by HPV typing using the line probe assay (LiPA) 25 version 1-line detection system were performed as described previously. [14] Extracted DNA from cervical specimens was used for amplification with SPF10 primers followed by DEIA detection of amplimers. ...
Background
Oncogenic human papillomavirus (HPV) infections cause most cases of cervical cancer. Here, we report long-term follow-up results for the Costa Rica Vaccine Trial (publicly funded and initiated before licensure of the HPV vaccines), with the aim of assessing the efficacy of the bivalent HPV vaccine for preventing HPV 16/18-associated cervical intraepithelial neoplasia grade 2 or worse (CIN2+).
Methods
Women aged 18–25 years were enrolled in a randomised, double-blind, controlled trial in Costa Rica, between June 28, 2004, and Dec 21, 2005, designed to assess the efficacy of a bivalent vaccine for the prevention of infection with HPV 16/18 and associated precancerous lesions at the cervix. Participants were randomly assigned (1:1) to receive an HPV 16/18 AS04-adjuvanted vaccine or control hepatitis A vaccine. Vaccines were administered intramuscularly in three 0·5 mL doses at 0, 1, and 6 months and participants were followed up annually for 4 years. After the blinded phase, women in the HPV vaccine group were invited to enrol in the long-term follow-up study, which extended follow-up for 7 additional years. The control group received HPV vaccine and was replaced with a new unvaccinated control group. Women were followed up every 2 years until year 11. Investigators and patients were aware of treatment allocation for the follow-up phase. At each visit, clinicians collected cervical cells from sexually active women for cytology and HPV testing. Women with abnormal cytology were referred to colposcopy, biopsy, and treatment as needed. Women with negative results at the last screening visit (year 11) exited the long-term follow-up study. The analytical cohort for vaccine efficacy included women who were HPV 16/18 DNA-negative at vaccination. The primary outcome of this analysis was defined as histopathologically confirmed CIN2+ or cervical intraepithelial neoplasia grade 3 or worse associated with HPV 16/18 cervical infection detected at colposcopy referral. We calculated vaccine efficacy by year and cumulatively. This long-term follow-up study is registered with ClinicalTrials.gov, NCT00867464.
Findings
7466 women were enrolled in the Costa Rica Vaccine Trial; 3727 received the HPV vaccine and 3739 received the control vaccine. Between March 30, 2009, and July 5, 2012, 2635 women in the HPV vaccine group and 2836 women in the new unvaccinated control group were enrolled in the long-term follow-up study. 2635 women in the HPV vaccine group and 2677 women in the control group were included in the analysis cohort for years 0–4, and 2073 women from the HPV vaccine group and 2530 women from the new unvaccinated control group were included in the analysis cohort for years 7–11. Median follow-up time for the HPV group was 11·1 years (IQR 9·1–11·7), 4·6 years (4·3–5·3) for the original control group, and 6·2 years (5·5–6·9) for the new unvaccinated control group. At year 11, vaccine efficacy against incident HPV 16/18-associated CIN2+ was 100% (95% CI 89·2–100·0); 34 (1·5%) of 2233 unvaccinated women had a CIN2+ outcome compared with none of 1913 women in the HPV group. Cumulative vaccine efficacy against HPV 16/18-associated CIN2+ over the 11-year period was 97·4% (95% CI 88·0–99·6). Similar protection was observed against HPV 16/18-associated CIN3—specifically at year 11, vaccine efficacy was 100% (95% CI 78·8–100·0) and cumulative vaccine efficacy was 94·9% (73·7–99·4). During the long-term follow-up, no serious adverse events occurred that were deemed related to the HPV vaccine. The most common grade 3 or worse serious adverse events were pregnancy, puerperium, and perinatal conditions (in 255 [10%] of 2530 women in the unvaccinated control group and 201 [10%] of 2073 women in the HPV vaccine group). Four women in the unvaccinated control group and three in the HPV vaccine group died; no deaths were deemed to be related to the HPV vaccine.
Interpretation
The bivalent HPV vaccine has high efficacy against HPV 16/18-associated precancer for more than a decade after initial vaccination, supporting the notion that invasive cervical cancer is preventable.
Funding
US National Cancer Institute.
