The main goal of cervical screening programs is to detect and treat precancer before cancer develops. Human papillomavirus (HPV) testing is more sensitive than cytology for detecting precancer. ...However, reports of rare HPV-negative, cytology-positive cancers are motivating continued use of both tests (cotesting) despite increased testing costs.
We quantified the detection of cervical precancer and cancer by cotesting compared with HPV testing alone at Kaiser Permanente Northern California (KPNC), where 1 208 710 women age 30 years and older have undergone triennial cervical cotesting since 2003. Screening histories preceding cervical cancers (n = 623) and precancers (n = 5369) were examined to assess the relative contribution of the cytology and HPV test components in identifying cases. The performances of HPV testing and cytology were compared using contingency table methods, general estimating equation models, and nonparametric statistics; all statistical tests were two-sided.
HPV testing identified more women subsequently diagnosed with cancer (P < .001) and precancer (P < .001) than cytology. HPV testing was statistically significantly more likely to be positive for cancer at any time point (P < .001), except within 12 months (P = .10). HPV-negative/cytology-positive results preceded only small fractions of cases of precancer (3.5%) and cancer (5.9%); these cancers were more likely to be regional or distant stage with squamous histopathology than other cases. Given the rarity of cancers among screened women, the contribution of cytology to screening translated to earlier detection of at most five cases per million women per year. Two-thirds (67.9%) of women found to have cancer during 10 years of follow-up at KPNC were detected by the first cotest performed.
The added sensitivity of cotesting vs HPV alone for detection of treatable cancer affected extremely few women.
Abstract
Background
The authors investigated the durability of vaccine efficacy (VE) against human papillomavirus (HPV)16 or 18 infections and antibody response among nonrandomly assigned women who ...received a single dose of the bivalent HPV vaccine compared with women who received multiple doses and unvaccinated women.
Methods
HPV infections were compared between HPV16 or 18-vaccinated women aged 18 to 25 years who received one (N = 112), two (N = 62), or three (N = 1365) doses, and age- and geography-matched unvaccinated women (N = 1783) in the long-term follow-up of the Costa Rica HPV Vaccine Trial. Cervical HPV infections were measured at two study visits, approximately 9 and 11 years after initial HPV vaccination, using National Cancer Institute next-generation sequencing TypeSeq1 assay. VE and 95% confidence intervals (CIs) were estimated. HPV16 or 18 antibody levels were measured in all one- and two-dose women, and a subset of three-dose women, using a virus-like particle-based enzyme-linked immunosorbent assay (n = 448).
Results
Median follow-up for the HPV-vaccinated group was 11.3 years (interquartile range = 10.9–11.7 years) and did not vary by dose group. VE against prevalent HPV16 or 18 infection was 80.2% (95% CI = 70.7% to 87.0%) among three-dose, 83.8% (95% CI = 19.5% to 99.2%) among two-dose, and 82.1% (95% CI = 40.2% to 97.0%) among single-dose women. HPV16 or 18 antibody levels did not qualitatively decline between years four and 11 regardless of the number of doses given, although one-dose titers continue to be statistically significantly lower compared with two- and three-dose titers.
Conclusion
More than a decade after HPV vaccination, single-dose VE against HPV16 or 18 infection remained high and HPV16 or 18 antibodies remained stable. A single dose of bivalent HPV vaccine may induce sufficiently durable protection that obviates the need for more doses.
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+).
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.
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.
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.
US National Cancer Institute.
Abstract
Background
The Costa Rica HPV Vaccine Trial has documented cross-protection of the bivalent HPV vaccine against HPV31/33/45 up to 7 years after vaccination, even with one dose of the ...vaccine. However, the durability of such protection remains unknown. Here, we evaluate the efficacy of different schedules of the vaccine against HPV31/33/45 out to 11 years postvaccination, expanding to other nontargeted HPV types.
Methods
We compared the rates of HPV infection in vaccinated women with the rates in a comparable cohort of unvaccinated women. We estimated the average vaccine efficacy (VEavg) against incident infections and tested for a change in VE over time.
Results
Among 3-dose women, we observed statistically significant cross-protection against HPV31/33/45 (VEavg = 64.4%, 95% confidence interval CI = 57.7% to 70.0%). Additionally, we observed borderline, statistically significant cross-protection against HPV35 (VEavg = 23.2%, 95% CI = 0.3% to 40.8%) and HPV58 (VEavg = 21.2%, 95% CI = 4.2% to 35.3%). There was no decrease in VE over time (two-sided Ptrend > .05 for HPV31, -33, -35, -45, and -58). As a benchmark, VEavg against HPV16/18 was 82.0% (95% CI = 77.3% to 85.7%). Among 1-dose women, we observed comparable efficacy against HPV31/33/45 (VEavg = 54.4%, 95% CI = 21.0% to 73.7%). Acquisition of nonprotected HPV types was similar between vaccinated and unvaccinated women, indicating that the difference in HPV infection rates was not attributable to differential genital HPV exposure.
Conclusions
Substantial cross-protection afforded by the bivalent vaccine against HPV31/33/45, and to a lesser extent, HPV35 and HPV58, was sustained and remained stable after 11 years postvaccination, reinforcing the notion that the bivalent vaccine is an effective option for protection against HPV-associated cancers.
Human Papillomavirus (HPV) type variants have been classified into lineages and sublineages based upon their whole genome sequence. Here we have examined the specificity of antibodies generated ...following natural infection with lineage variants of oncogenic types (HPV16, 18, 31, 33, 45, 52 and 58) by testing serum samples assembled from existing archives from women residing in Africa, The Americas, Asia or Europe against representative lineage-specific pseudoviruses for each genotype. We have subjected the resulting neutralizing antibody data to antigenic clustering methods and created relational antigenic profiles for each genotype to inform the delineation of lineage-specific serotypes. For most genotypes, there was evidence of differential recognition of lineage-specific antigens and in some cases of a sufficient magnitude to suggest that some lineages should be considered antigenically distinct within their respective genotypes. These data provide compelling evidence for a degree of lineage specificity within the humoral immune response following natural infection with oncogenic HPV.
Abstract
Background
The AS04-adjuvanted HPV16/18 (AS04-HPV16/18) vaccine provides excellent protection against targeted human papillomavirus (HPV) types and a variable degree of cross-protection ...against others, including types 6/11/31/33/45. High efficacy against any cervical intraepithelial neoplasia grade 3 or greater (CIN3+; >90%) suggests that lower levels of protection may exist for a wide range of oncogenic HPV types, which is difficult to quantify in individual trials. Pooling individual-level data from two randomized controlled trials, we aimed to evaluate AS04-HPV16/18 vaccine efficacy against incident HPV infections and cervical abnormalities .
Methods
Data were available from the Costa Rica Vaccine Trial (NCT00128661) and Papilloma Trial Against Cancer in Young Adults trial (NCT00122681), two large-scale, double-blind randomized controlled trials of the AS04-HPV16/18 vaccine. Primary analyses focused on disease-free women with no detectable cervicovaginal HPV at baseline.
Results
A total of 12 550 women were included in our primary analyses (HPV arm = 6271, control arm = 6279). Incidence of 6-month persistent oncogenic and nononcogenic infections, excluding known and accepted protected types 6/11/16/18/31/33/45 (focusing on 34/35/39/40/42/43/44/51/52/53/54/56/58/59/66/68/73/70/74), was statistically significantly lower in the HPV arm than in the control arm (efficacy = 9.9%, 95% confidence interval CI = 1.7% to 17.4%). Statistically significant efficacy (P < .05) was observed for individual oncogenic types 16/18/31/33/45/52 and nononcogenic types 6/11/53/74. Efficacy against cervical abnormalities (all types) increased with severity, ranging from 27.7% (95% CI = 21.7% to 33.3%) to 58.7% (95% CI = 34.1% to 74.7%) for cytologic outcomes (low-grade squamous intraepithelial neoplasia lesion or greater, and high-grade squamous intraepithelial neoplasia lesion or greater, respectively) and 66.0% (95% CI = 54.4% to 74.9%) to 87.8% (95% CI = 71.1% to 95.7%) for histologic outcomes (CIN2+ and CIN3+, respectively). Comparing Costa Rica Vaccine Trial and Papilloma Trial Against Cancer in Young Adults results, there was no evidence of heterogeneity, except for type 51 (efficacy = −28.6% and 20.7%, respectively; two-sided P = .03).
Conclusions
The AS04-HPV16/18 vaccine provides some additional cross-protection beyond established protected types, which partially explains the high efficacy against CIN3+.
Persistent infections with carcinogenic human papillomaviruses (HPV) cause virtually all cervical cancers. Cervical HPV types (
n > 40) also represent the most common sexually transmitted agents, and ...most infections clear in 1–2 years. The risks of persistence and neoplastic progression to cancer and its histologic precursor, cervical intraepithelial neoplasia grade 3 (CIN3), differ markedly by HPV type. To study type-specific HPV natural history, we conducted a 10,000-woman, population-based prospective study of HPV infections and CIN3/cancer in Guanacaste, Costa Rica. By studying large numbers of women, we wished to separate viral persistence from neoplastic progression. We observed a strong concordance of newly-revised HPV evolutionary groupings with the separate risks of persistence and progression to CIN3/cancer. HPV16 was uniquely likely both to persist and to cause neoplastic progression when it persisted, making it a remarkably powerful human carcinogen that merits separate clinical consideration. Specifically, 19.9% of HPV16-infected women were diagnosed with CIN3/cancer at enrollment or during the five-year follow-up. Other carcinogenic types, many related to HPV16, were not particularly persistent but could cause neoplastic progression, at lower rates than HPV16, if they did persist. Some low-risk types were persistent but, nevertheless, virtually never caused CIN3. Therefore, carcinogenicity is not strictly a function of persistence. Separately, we noted that the carcinogenic HPV types code for an E5 protein, whereas most low-risk types either lack a definable homologous E5 ORF and/or a translation start codon for E5. These results present several clear clues and research directions in our ongoing efforts to understand HPV carcinogenesis.
Target groups for human papillomavirus (HPV) vaccination are controversial. We evaluated vaccine efficacy (VE) against 1-year persistent infection, stratified by age and sexual behavior, among young ...women in Costa Rica. We randomized 7,466 healthy women 18 to 25 years of age to HPV16/18 or hepatitis A vaccine (follow-up, 50.4 months). According-to-protocol (ATP) cohorts included compliant HPV-negative women; intention-to-treat (ITT) included all randomized women. ATP VE was 90.9% (95% CI, 82.0-95.9) against HPV16/18 infections, 44.5% against HPV31/33/45 (95% CI, 17.5-63.1), and 12.4% (95% CI, -3.2 to 25.6) against any oncogenic infection. Overall ITT VE against HPV16/18 infections was 49.0%, but ATP and ITT VE almost reached 100% in year 4 of follow-up. ATP efficacy against HPV16/18 was similar by age, but ITT VE was greatest among youngest women (68.9% among those 18-19 years of age; 21.8% among those 24-25 years of age) and 79.8% among virgins. Among previously unexposed women, vaccination is highly efficacious against HPV16/18 and partially against HPV31/33/45. Vaccination is most effective in women and girls before they initiate sexual activity, with programmatic and individual decision implications.
Current HPV vaccines do not protect against all oncogenic HPV types. Following vaccination, type replacement may occur, especially if different HPV types competitively interact during natural ...infection. Because of their common route of transmission, it is difficult to assess type interactions in observational studies. Our aim was to evaluate type replacement in the setting of HPV vaccine randomized controlled trials (RCTs).
Data were pooled from the Costa Rica Vaccine Trial (CVT; NCT00128661) and PATRICIA trial (NCT001226810)-two large-scale, double-blind RCTs of the HPV-16/18 AS04-adjuvanted vaccine-to compare cumulative incidence of nonprotected HPV infections across trial arms after four years. Negative rate difference estimates (rate in control minus vaccine arm) were interpreted as evidence of replacement if the associated 95% confidence interval excluded zero. All statistical tests were two-sided.
After applying relevant exclusion criteria, 21 596 women were included in our analysis (HPV arm = 10 750; control arm = 10 846). Incidence rates (per 1000 infection-years) were lower in the HPV arm than in the control arm for grouped nonprotected oncogenic types (rate difference = 1.6, 95% confidence interval CI = 0.9 to 2.3) and oncogenic/nononcogenic types (rate difference = 0.2, 95% CI = -0.3 to 0.7). Focusing on individual HPV types separately, no deleterious effect was observed. In contrast, a statistically significant protective effect (positive rate difference and 95% CI excluded zero) was observed against oncogenic HPV types 35, 52, 58, and 68/73, as well as nononcogenic types 6 and 70.
HPV type replacement does not occur among vaccinated individuals within four years and is unlikely to occur in vaccinated populations.
Carcinogenic human papillomaviruses (HPV) are thought to be necessary for development of cervical cancer. We assessed whether higher viral loads of such viruses predicted future risk of CIN3 or ...cancer (CIN3+) in a cohort of 20 810 women followed up for 10 years with cytological screening. We measured the viral load for 13 types of carcinogenic HPV (relative light units normalised to 1 pg/mL HPV 16 positive controls RLU/PC) using Hybrid Capture 2 testing of cervicovaginal lavages obtained at enrolment. Results were stratified into four groups (RLU/PC 1 to <10, 10 to <100, 100 to <1000, ⩾1000). Although presence of HPV strongly increased risk of CIN3+, high viral load did not further predict risk of CIN3+.
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