Age-Specific Prevalence of Anal and Cervical Human Papillomavirus Infection and High-Grade Lesions in 11 177 Women by Human Immunodeficiency Virus Status: A Collaborative Pooled Analysis of 26 Studies.

BACKGROUND: Age-specific data on anal, and corresponding cervical, human papillomavirus (HPV) infection are needed to inform female anal cancer prevention. METHODS: We centrally reanalyzed individual-level data from 26 studies reporting HPV prevalence in paired anal and cervical samples by human immunodeficiency virus (HIV) status and age. For women with HIV (WWH) with anal high-grade squamous intraepithelial lesions or worse (HSIL+), we also investigated concurrent cervical cytopathology. RESULTS: In HIV-negative women, HPV16 prevalence decreased significantly with age, both at anus (4.3% at 15-24 years to 1.0% at ≥55 years; ptrend = 0.0026) and cervix (7.4% to 1.7%; ptrend < 0.0001). In WWH, HPV16 prevalence decreased with age at cervix (18.3% to 7.2%; ptrend = 0.0035) but not anus (11.5% to 13.9%; ptrend = 0.5412). Given anal HPV16 positivity, concurrent cervical HPV16 positivity also decreased with age, both in HIV-negative women (ptrend = 0.0005) and WWH (ptrend = 0.0166). Among 48 WWH with HPV16-positive anal HSIL+, 27 (56%) were cervical high-risk HPV-positive, including 8 with cervical HPV16, and 5 were cervical HSIL+. CONCLUSIONS: Age-specific shifts in HPV16 prevalence from cervix to anus suggest that HPV infections in the anus persist longer, or occur later in life, than in the cervix, particularly in WWH. This is an important consideration when assessing the utility of cervical screening results to stratify anal cancer risk.

Prevalencia y determinantes de la infección por virus de papiloma humano en mujeres jóvenes de Guanacaste y Puntarenas, Costa Rica, 2004-2005.

OBJETIVO: Estimar la prevalencia e identificar determinantes de la infección por el virus del papiloma humano (VPH) en mujeres jóvenes (18-25 años). Material y métodos. Se analizaron datos de 5 871 mujeres sexualmente activas a quienes se les realizó una entrevista y toma de muestras cervicouterinas para detección de VPH y citología durante la visita de reclutamiento del Ensayo de Vacunación contra VPH16/18 en Costa Rica. Se calculó la prevalencia total para cualquier tipo de VPH y tipos oncogénicos, no oncogénicos y específicos, con intervalos de confianza al 95% (IC95%). Se utilizó regresión logística múltiple paso-a-paso para identificar determinantes asociados con la infección. RESULTADOS: La prevalencia total de VPH fue 50.0% (IC95% 48.8,51.3) y por tipos oncogénicos fue 33.8% (IC95% 32.6,35.0). El VPH-16 fue el tipo más prevalente (8.3%, IC95% 7.6,9.0). Los determinantes asociados con un alto riesgo de infección prevalente por VPH oncogénicos fueron no estar casada/unión libre, >1 compañero sexual, infección concomitante por Chlamydia trachomatis, y entre aquéllas con un único compañero sexual en su vida, un compañero con antecedente de múltiples compañeras sexuales. Conclusión. Se confirma la asociación de las infecciones por VPH oncogénicos con el comportamiento sexual de la mujer y se destacan los comportamientos del compañero sexual.

Efficacy of the bivalent HPV vaccine against HPV 16/18-associated precancer: long-term follow-up results from the Costa Rica Vaccine Trial.

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.

Differential long-term bivalent HPV vaccine cross-protection by variants in the Costa Rica HPV vaccine trial.

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.

Cohort profile: evaluation of immune response and household transmission of SARS-CoV-2 in Costa Rica: the RESPIRA study.

PURPOSE: The RESPIRA cohort aims to describe the nature, magnitude, time course and efficacy of the immune response to SARS-CoV-2 infection and vaccination, population prevalence, and household transmission of COVID-19. PARTICIPANTS: From November 2020, we selected age-stratified random samples of COVID-19 cases from Costa Rica confirmed by PCR. For each case, two population-based controls, matched on age, sex and census tract were recruited, supplemented with hospitalised cases and household contacts. Participants were interviewed and blood and saliva collected for antibodies and PCR tests. Participants will be followed for 2 years to assess antibody response and infection incidence. FINDINGS TO DATE: Recruitment included 3860 individuals: 1150 COVID-19 cases, 1999 population controls and 719 household contacts from 304 index cases. The age and regional distribution of cases was as planned, including four age strata, 30% rural and 70% urban. The control cohort had similar sex, age and regional distribution as the cases according to the study design. Among the 1999 controls recruited, 6.8% reported at enrolment having had COVID-19 and an additional 12.5% had antibodies against SARS-CoV-2. Compliance with visits and specimens has been close to 70% during the first 18 months of follow-up. During the study, national vaccination was implemented and nearly 90% of our cohort participants were vaccinated during follow-up. FUTURE PLANS: RESPIRA will enable multiple analyses, including population prevalence of infection, clinical, behavioural, immunological and genetic risk factors for SARS-CoV-2 acquisition and severity, and determinants of household transmission. We are conducting retrospective and prospective assessment of antibody levels, their determinants and their protective efficacy after infection and vaccination, the impact of long-COVID and a series of ancillary studies. Follow-up continues with bimonthly saliva collection for PCR testing and biannual blood collection for immune response analyses. Follow-up will be completed in early 2024. TRIAL REGISTRATION NUMBER: NCT04537338.

Rationale and design of a long term follow-up study of women who did and did not receive HPV 16/18 vaccination in Guanacaste, Costa Rica.

The Costa Rica Vaccine Trial (CVT) was a randomized clinical trial conducted between 2004 and 2010, which randomized 7466 women aged 18 to 25 to receive the bivalent HPV-16/18 vaccine or control Hepatitis-A vaccine. Participants were followed for 4 years with cross-over vaccination at the study end. In 2010 the long term follow-up (LTFU) study was initiated to evaluate the 10-year impact of HPV-16/18 vaccination, determinants of the immune response, and HPV natural history in a vaccinated population. Herein, the rationale, design and methods of the LTFU study are described, which actively follows CVT participants in the HPV-arm 6 additional years at biennial intervals (3 additional study visits for 10 years of total follow-up), or more often if clinically indicated. According to the initial commitment, women in the Hepatitis-A arm were offered HPV vaccination at cross-over; they were followed 2 additional years and exited from the study. 92% of eligible CVT women accepted participation in LTFU. To provide underlying rates of HPV acquisition and cervical disease among unvaccinated women to compare with the HPV-arm during LTFU, a new unvaccinated control group (UCG) of women who are beyond the age generally recommended for routine vaccination was enrolled, and will be followed by cervical cancer screening over 6 years. To form the UCG, 5000 women were selected from a local census, of whom 2836 women (61% of eligible women) agreed to participate. Over 90% of participants complied with an interview, blood and cervical specimen collection. Evaluation of comparability between the original (Hepatitis-A arm of CVT) and new (UCG) control groups showed that women's characteristics, as well as their predicted future risk for cervical HPV acquisition, were similar, thus validating use of the UCG. LTFU is poised to comprehensively address many important questions related to long-term effects of prophylactic HPV vaccines.