RESUMO
BACKGROUND: Factors that lead human papillomavirus (HPV) infections to persist and progress to cancer are not fully understood. We evaluated co-factors for acquisition, persistence, and progression of non-HPV-16/18 infections among HPV-vaccinated women. METHODS: We analyzed 2153 women aged 18-25 years randomized to the HPV-vaccine arm of the Costa Rica HPV Vaccine Trial. Women were HPV DNA negative for all types at baseline and followed for approximately 11 years. Generalized estimating equation methods were used to account for correlated observations. Time-dependent factors evaluated were age, sexual behavior, marital status, hormonally related factors, number of full-term pregnancies (FTPs), smoking behavior, and baseline body mass index. RESULTS: A total of 1777 incident oncogenic non-HPV-16/18 infections were detected in 12 292 visits (average, 0.14 infections/visit). Age and sexual behavior-related variables were associated with oncogenic non-HPV-16/18 acquisition. Twenty-six percent of incident infections persisted for ≥1 year. None of the factors evaluated were statistically associated with persistence of oncogenic non-HPV-16/18 infections. Risk of progression to Cervical Intraepithelial Neoplasia grade 2 or worst (CIN2+) increased with increasing age (P for trend = .001), injectable contraceptive use (relative risk, 2.61 [95% confidence interval, 1.19-5.73] ever vs never), and increasing FTPs (P for trend = .034). CONCLUSIONS: In a cohort of HPV-16/18-vaccinated women, age and sexual behavior variables are associated with acquisition of oncogenic non-HPV-16/18 infections; no notable factors are associated with persistence of acquired infections; and age, parity, and hormonally related exposures are associated with progression to CIN2+.
Assuntos
Infecções por Papillomavirus , Vacinas contra Papillomavirus , Adolescente , Adulto , Costa Rica/epidemiologia , DNA , Feminino , Papillomavirus Humano 16/imunologia , Papillomavirus Humano 18/imunologia , Humanos , Papillomaviridae , Infecções por Papillomavirus/epidemiologia , Infecções por Papillomavirus/prevenção & controle , Gravidez , Fatores de Risco , Resultado do Tratamento , Neoplasias do Colo do Útero/epidemiologia , Neoplasias do Colo do Útero/prevenção & controle , Adulto Jovem , Displasia do Colo do ÚteroRESUMO
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 international epidemiologic studies. METHODS: TypeSeq was evaluated in 2804 cervical specimens from the Study to Understand Cervical Cancer Endpoints and Early Determinants (SUCCEED) and in 2357 specimens from the Costa Rica Vaccine Trial (CVT). Positive agreement and risks of precancer for individual genotypes were calculated for TypeSeq in comparison to Linear Array (SUCCEED). In CVT, positive agreement and vaccine efficacy were calculated for TypeSeq and SPF10-LiPA. RESULTS: We observed high overall and positive agreement for most genotypes between TypeSeq and Linear Array in SUCCEED and SPF10-LiPA in CVT. There was no significant difference in risk of precancer between TypeSeq and Linear Array in SUCCEED or in estimates of vaccine efficacy between TypeSeq and SPF10-LiPA in CVT. CONCLUSIONS: The agreement of TypeSeq with Linear Array and SPF10-LiPA, 2 well established standards for HPV genotyping, demonstrates its high accuracy. TypeSeq provides high-throughput, affordable HPV genotyping for world-wide studies of cervical precancer risk and of HPV vaccine efficacy.
Assuntos
Genótipo , Técnicas de Genotipagem/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Papillomaviridae/classificação , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/diagnóstico , Neoplasias do Colo do Útero/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Costa Rica , Custos e Análise de Custo , Estudos Transversais , Feminino , Técnicas de Genotipagem/economia , Sequenciamento de Nucleotídeos em Larga Escala/economia , Humanos , Pessoa de Meia-Idade , Papillomaviridae/genética , Infecções por Papillomavirus/prevenção & controle , Infecções por Papillomavirus/virologia , Vacinas contra Papillomavirus/imunologia , Neoplasias do Colo do Útero/prevenção & controle , Neoplasias do Colo do Útero/virologia , Adulto JovemRESUMO
Human papillomavirus (HPV), an etiological agent of cervical cancer (CC), has infected humans since ancient times. Amerindians are the furthest migrants out of Africa, and they reached the Americas more than 14,000 years ago. Some groups still remain isolated, and some migrate to towns, forming a gradient spanning urbanization. We hypothesized that, by virtue of their history, lifestyle, and isolation from the global society, remote Amerindian women have lower HPV diversity than do urban women (Amerindian or mestizo). Here we determined the diversity of the 25 most relevant cervical HPV types in 82 Amerindians spanning urbanization (low, medium, and high, consistent with the exposure to urban lifestyles of the town of Puerto Ayacucho in the Venezuelan Amazonas State), and in 29 urban mestizos from the town. Cervical, anal, oral, and introitus samples were taken, and HPVs were typed using reverse DNA hybridization. A total of 23 HPV types were detected, including 11 oncogenic or high-risk types, most associated with CC. Cervical HPV prevalence was 75%, with no differences by group, but Amerindians from low and medium urbanization level had significantly lower HPV diversity than mestizos did. In Amerindians, but not in mestizos, infections by only high-risk HPVs were higher than coinfections or by exclusively low-risk HPVs. Cervical abnormalities only were observed in Amerindians (9/82), consistent with their high HPV infection. The lower cervical HPV diversity in more isolated Amerindians is consistent with their lower exposure to the global pool, and transculturation to urban lifestyles could have implications on HPV ecology, infection, and virulence.IMPORTANCE The role of HPV type distribution on the disparity of cervical cancer (CC) incidence between human populations remains unknown. The incidence of CC in the Amazonas State of Venezuela is higher than the national average. In this study, we determined the diversity of known HPV types (the viral agent of CC) in Amerindian and mestizo women living in the Venezuelan Amazonas State. Understanding the ecological diversity of HPV in populations undergoing lifestyle transformations has important implication on public health measures for CC prevention.
Assuntos
Variação Genética , Genótipo , Papillomaviridae/classificação , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/epidemiologia , Infecções por Papillomavirus/virologia , Adolescente , Adulto , Indígena Americano ou Nativo do Alasca , Coinfecção/epidemiologia , Coinfecção/virologia , Feminino , Técnicas de Genotipagem , Humanos , Pessoa de Meia-Idade , Hibridização de Ácido Nucleico , Papillomaviridae/genética , Prevalência , Venezuela/epidemiologia , Adulto JovemRESUMO
BACKGROUND: Vaccine efficacy (VE) against vulvar human papillomavirus (HPV) infection has not been reported and data regarding its epidemiology are sparse. METHODS: Women (n = 5404) age 22-29 present at the 4-year study visit of the Costa Rica Vaccine Trial provided vulvar and cervical samples. A subset (n = 1044) was tested for HPV DNA (SPF10/LiPA25 version 1). VE against 1-time detection of vulvar HPV16/18 among HPV vaccinated versus unvaccinated women was calculated and compared to the cervix. Prevalence of and risk factors for HPV were evaluated in the control arm (n = 536). RESULTS: Vulvar HPV16/18 VE (54.1%; 95% confidence interval [CI], 4.9%-79.1%) was comparable to cervix (45.8%; 95% CI, 6.4%-69.4%). Vulvar and cervical HPV16 prevalence within the control arm was 3.0% and 4.7%, respectively. Independent risk factors for vulvar HPV were similar to cervix and included: age (adjusted odds ratio [aOR] 0.5 [95% CI, .3-.9] ≥28 vs 22-23]); marital status (aOR 2.3 [95% CI, 1.5-3.5] single vs married/living-as-married); and number of sexual partners (aOR 3.6 [95% CI, 1.9-7.0] ≥6 vs 1). CONCLUSIONS: In this intention-to-treat analysis, VE against vulvar and cervical HPV16/18 were comparable 4 years following vaccination. Risk factors for HPV were similar by anatomic site. CLINICAL TRIALS REGISTRATION: NCT00128661.
Assuntos
Papillomavirus Humano 16/isolamento & purificação , Papillomavirus Humano 18/isolamento & purificação , Infecções por Papillomavirus/epidemiologia , Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus/imunologia , Doenças da Vulva/epidemiologia , Doenças da Vulva/prevenção & controle , Adolescente , Adulto , Colo do Útero/virologia , Costa Rica/epidemiologia , DNA Viral/genética , DNA Viral/isolamento & purificação , Feminino , Humanos , Vacinas contra Papillomavirus/administração & dosagem , Prevalência , Fatores de Risco , Vulva/virologia , Adulto JovemRESUMO
BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.
Assuntos
Anticorpos Antivirais/sangue , Glutationa Transferase/sangue , Infecções por Papillomavirus/diagnóstico , Adolescente , Adulto , Anticorpos Neutralizantes/sangue , Costa Rica , DNA Viral/análise , Ensaio de Imunoadsorção Enzimática , Estudos Epidemiológicos , Feminino , Papillomavirus Humano 16 , Papillomavirus Humano 18 , Humanos , Razão de Chances , Infecções por Papillomavirus/sangue , Vacinas contra Papillomavirus/uso terapêutico , Estudos Soroepidemiológicos , Adulto JovemRESUMO
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.
Assuntos
Anticorpos Antivirais/sangue , Papillomaviridae/imunologia , Infecções por Papillomavirus/imunologia , Vacinas contra Papillomavirus/uso terapêutico , Vacinas de Partículas Semelhantes a Vírus/uso terapêutico , Anticorpos Antivirais/imunologia , Formação de Anticorpos , Costa Rica , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Infecções por Papillomavirus/prevenção & controle , Infecções por Papillomavirus/virologiaRESUMO
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.
Assuntos
Papillomaviridae , Infecções por Papillomavirus/epidemiologia , Estomatite/epidemiologia , Adulto , Costa Rica/epidemiologia , Feminino , Papillomavirus Humano 16/genética , Papillomavirus Humano 16/imunologia , Papillomavirus Humano 18/genética , Papillomavirus Humano 18/imunologia , Humanos , Papillomaviridae/classificação , Papillomaviridae/genética , Papillomaviridae/imunologia , Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus/imunologia , Prevalência , Fatores de Risco , Estomatite/prevenção & controle , Adulto JovemRESUMO
BACKGROUND: Human papillomavirus (HPV) infection, particularly with type 16, causes a growing fraction of oropharyngeal cancers, whose incidence is increasing, mainly in developed countries. In a double-blind controlled trial conducted to investigate vaccine efficacy (VE) of the bivalent HPV 16/18 vaccine against cervical infections and lesions, we estimated VE against prevalent oral HPV infections 4 years after vaccination. METHODS AND FINDINGS: A total of 7,466 women 18-25 years old were randomized (1â¶1) to receive the HPV16/18 vaccine or hepatitis A vaccine as control. At the final blinded 4-year study visit, 5,840 participants provided oral specimens (91·9% of eligible women) to evaluate VE against oral infections. Our primary analysis evaluated prevalent oral HPV infection among all vaccinated women with oral and cervical HPV results. Corresponding VE against prevalent cervical HPV16/18 infection was calculated for comparison. Oral prevalence of identifiable mucosal HPV was relatively low (1·7%). Approximately four years after vaccination, there were 15 prevalent HPV16/18 infections in the control group and one in the vaccine group, for an estimated VE of 93·3% (95% CIâ=â63% to 100%). Corresponding efficacy against prevalent cervical HPV16/18 infection for the same cohort at the same visit was 72·0% (95% CIâ=â63% to 79%) (p versus oral VEâ=â0·04). There was no statistically significant protection against other oral HPV infections, though power was limited for these analyses. CONCLUSIONS: HPV prevalence four years after vaccination with the ASO4-adjuvanted HPV16/18 vaccine was much lower among women in the vaccine arm compared to the control arm, suggesting that the vaccine affords strong protection against oral HPV16/18 infection, with potentially important implications for prevention of increasingly common HPV-associated oropharyngeal cancer. ClinicalTrials.gov, Registry number NCT00128661.
Assuntos
Alphapapillomavirus/imunologia , Boca/virologia , Vacinas contra Papillomavirus/uso terapêutico , Adolescente , Adulto , Alphapapillomavirus/isolamento & purificação , Costa Rica/epidemiologia , Feminino , Vacina Quadrivalente Recombinante contra HPV tipos 6, 11, 16, 18 , Humanos , Infecções por Papillomavirus/prevenção & controle , Prevalência , Adulto JovemRESUMO
BACKGROUND: We investigated the role of antibody responses as potential mechanism for the cross-protective vaccine-efficacies (VE) observed from randomized clinical trials of the HPV16/18 bivalent vaccine. Results HPV31 cases had lower HPV16 antibody levels than controls (OR 4th quartile compared with 1st quartile = 0.63; 95%CI: 0.36-1.08; p-trend = 0.03). HPV31 cases were also less likely to have detectable HPV31 neutralization, and HPV16 avidity than controls. No statistically significant differences by HPV18 antibody or HPV45 neutralization were observed among HPV45 cases and controls. Protection against HPV58 was not associated with any of the markers, confirming the specificity of our findings. METHODS: Samples are from three-dose HPV vaccine recipients from the Costa Rica HPV16/18 vaccine trial. Women with a new HPV31, HPV45, or HPV58 infections over four years of follow-up were compared with randomly selected control women--with no new infection with HPV31/45/58--with respect to HPV16 and HPV18 antibody, HPV31, HPV45, and HPV58 neutralization, and HPV16 avidity. CONCLUSIONS: High HPV16 levels and avidity, and the ability to neutralize HPV31 were associated with protection against newly detected HPV31 infections, suggesting that the partial VE demonstrated for HPV31 is likely to be mediated at least in part through antibodies induced by HPV16/18 vaccination.
Assuntos
Papillomavirus Humano 16/imunologia , Papillomavirus Humano 18/imunologia , Papillomavirus Humano 31/imunologia , Infecções por Papillomavirus/imunologia , Vacinas contra Papillomavirus/imunologia , Adolescente , Adulto , Anticorpos Antivirais/sangue , Formação de Anticorpos/imunologia , Estudos de Casos e Controles , Costa Rica , Proteção Cruzada/imunologia , Feminino , Humanos , Imunidade Humoral , Infecções por Papillomavirus/prevenção & controle , Infecções por Papillomavirus/virologia , Vacinas contra Papillomavirus/uso terapêutico , Adulto JovemRESUMO
In a large Phase III trial conducted in 10 Latin American countries, the safety and efficacy of the live attenuated monovalent rotavirus vaccine RIX4414 was evaluated in 15,183 healthy infants followed up during the first two years of life. Belém was the only site in Brazil included in this multicentre trial. The study in Belém included a subset of 653 infants who were followed up until 24 months of age for protection against severe rotavirus gastroenteritis. These subjects were randomly assigned in a 1:1 ratio to receive two doses of vaccine (n = 328) or two doses of placebo (n = 325) at approximately two and four months of age. Of the 653 enrolled infants, 23 dropped out during the study period. For the combined two-year period, the efficacy of RIX4414 was 72.3% [95% confidence interval (CI) 37.5-89.1%] against severe rotavirus-related gastroenteritis, reaching a protection rate of 81.8% (95% CI 36.4-96.6%) against circulating wild-type G9 rotavirus strains. It is concluded that two doses of RIX4414 are highly efficacious against severe rotavirus gastroenteritis in Belém during the first two years of life and provide high protection against the worldwide emergence and spread of G9P[8] strains.
Assuntos
Anticorpos Antivirais/imunologia , Gastroenterite/prevenção & controle , Infecções por Rotavirus/prevenção & controle , Vacinas contra Rotavirus/administração & dosagem , Administração Oral , Anticorpos Antivirais/genética , Pré-Escolar , Método Duplo-Cego , Feminino , Gastroenterite/virologia , Genótipo , Humanos , Lactente , Masculino , Infecções por Rotavirus/virologia , Vacinas contra Rotavirus/efeitos adversos , Vacinas contra Rotavirus/imunologia , Índice de Gravidade de Doença , Vacinas Atenuadas/administração & dosagem , Vacinas Atenuadas/efeitos adversos , Vacinas Atenuadas/imunologiaRESUMO
In a large Phase III trial conducted in 10 Latin American countries, the safety and efficacy of the live attenuated monovalent rotavirus vaccine RIX4414 was evaluated in 15,183 healthy infants followed up during the first two years of life. Belém was the only site in Brazil included in this multicentre trial. The study in Belém included a subset of 653 infants who were followed up until 24 months of age for protection against severe rotavirus gastroenteritis. These subjects were randomly assigned in a 1:1 ratio to receive two doses of vaccine (n = 328) or two doses of placebo (n = 325) at approximately two and four months of age. Of the 653 enrolled infants, 23 dropped out during the study period. For the combined two-year period, the efficacy of RIX4414 was 72.3% [95% confidence interval (CI) 37.5-89.1%] against severe rotavirus-related gastroenteritis, reaching a protection rate of 81.8% (95% CI 36.4-96.6%) against circulating wild-type G9 rotavirus strains. It is concluded that two doses of RIX4414 are highly efficacious against severe rotavirus gastroenteritis in Belém during the first two years of life and provide high protection against the worldwide emergence and spread of G9P[8] strains.
Assuntos
Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Anticorpos Antivirais/imunologia , Gastroenterite/prevenção & controle , Infecções por Rotavirus/prevenção & controle , Vacinas contra Rotavirus/administração & dosagem , Administração Oral , Anticorpos Antivirais/genética , Método Duplo-Cego , Genótipo , Gastroenterite/virologia , Infecções por Rotavirus/virologia , Vacinas contra Rotavirus/efeitos adversos , Vacinas contra Rotavirus/imunologia , Índice de Gravidade de Doença , Vacinas Atenuadas/administração & dosagem , Vacinas Atenuadas/efeitos adversos , Vacinas Atenuadas/imunologiaRESUMO
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.
Assuntos
Neoplasias do Ânus/epidemiologia , Infecções por Papillomavirus/epidemiologia , Adulto , Neoplasias do Ânus/virologia , Costa Rica/epidemiologia , Feminino , Papillomavirus Humano 16/genética , Papillomavirus Humano 18/genética , Humanos , Modelos Logísticos , Análise Multivariada , Infecções por Papillomavirus/virologia , Prevalência , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Adulto JovemRESUMO
BACKGROUND: 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. METHODS: 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). RESULTS: 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). CONCLUSIONS: 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.
Assuntos
Anticorpos Antivirais/sangue , Ensaio de Imunoadsorção Enzimática/normas , Papillomaviridae/imunologia , Infecções por Papillomavirus/imunologia , Biomarcadores , Intervalos de Confiança , Costa Rica , DNA Viral/isolamento & purificação , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Papillomavirus Humano 16/classificação , Papillomavirus Humano 16/genética , Papillomavirus Humano 16/imunologia , Papillomavirus Humano 18/classificação , Papillomavirus Humano 18/genética , Papillomavirus Humano 18/imunologia , Humanos , Análise Multivariada , Papillomaviridae/classificação , Papillomaviridae/genética , Infecções por Papillomavirus/diagnóstico , Infecções por Papillomavirus/virologia , Vacinas contra Papillomavirus , Reação em Cadeia da Polimerase , Sensibilidade e Especificidade , Adulto JovemRESUMO
BACKGROUND: 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). METHODS: 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. FINDINGS: 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. INTERPRETATION: The AS04-adjuvanted vaccine affords strong protection against anal HPV infection, particularly among women more likely to be HPV naive at enrolment. FUNDING: National Cancer Institute with contributions from the National Institutes of Health Office of Research on Women's Health. Vaccine was provided by GlaxoSmithKline Biologicals.
Assuntos
Neoplasias do Ânus/prevenção & controle , Papillomavirus Humano 16/imunologia , Papillomavirus Humano 18/imunologia , Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus/administração & dosagem , Lesões Pré-Cancerosas/prevenção & controle , Neoplasias do Colo do Útero/prevenção & controle , Adjuvantes Imunológicos/administração & dosagem , Adolescente , Adulto , Hidróxido de Alumínio/administração & dosagem , Neoplasias do Ânus/epidemiologia , Neoplasias do Ânus/virologia , Distribuição de Qui-Quadrado , Costa Rica/epidemiologia , Método Duplo-Cego , Feminino , Humanos , Esquemas de Imunização , Lipídeo A/administração & dosagem , Lipídeo A/análogos & derivados , Infecções por Papillomavirus/epidemiologia , Infecções por Papillomavirus/virologia , Lesões Pré-Cancerosas/epidemiologia , Lesões Pré-Cancerosas/virologia , Prevalência , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Neoplasias do Colo do Útero/epidemiologia , Neoplasias do Colo do Útero/virologia , Adulto JovemRESUMO
BACKGROUND: 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. OBJECTIVE: To validate the performance of a novel assay for identification of HPV16 variants. STUDY DESIGN: 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. RESULTS: 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. CONCLUSIONS: 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.
Assuntos
Papillomavirus Humano 16/classificação , Papillomavirus Humano 16/isolamento & purificação , Técnicas de Diagnóstico Molecular/métodos , Hibridização de Ácido Nucleico/métodos , Infecções por Papillomavirus/diagnóstico , Reação em Cadeia da Polimerase/métodos , Virologia/métodos , Colo do Útero/virologia , Primers do DNA/genética , Feminino , Genótipo , Papillomavirus Humano 16/genética , Humanos , Proteínas Oncogênicas Virais/genética , Infecções por Papillomavirus/virologia , Proteínas Repressoras/genéticaRESUMO
OBJECTIVE: We investigated coinfection patterns for 25 human papillomavirus (HPV) types and assessed the risk conferred by multiple HPV types toward cervical disease. METHODS: Sexually active women (n=5,871) in the NCI-sponsored Costa Rica HPV Vaccine Trial's prevaccination enrollment visit were analyzed. Genotyping for 25 HPVs was performed using 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. RESULTS: Of the 2478 HPV-positive women, 1070 (43.2%) were infected with multiple types. Multiple infections occurred significantly more frequently than predicted by chance. However, this affinity to be involved in a coinfection (pooled OR for 300 type-type combinations=2.2; 95% confidence interval [CI]=2.1-2.4) was not different across HPV type-type combinations. Compared with single infections, coinfection with multiple α9 species was associated with significantly increased risk of CIN2+(OR=2.2; 95% CI=1.1-4.6) and HSIL+(OR=1.6; 95% CI=1.1-2.4). However, disease risk was similar to the sum of estimated risk from individual types, with little evidence for synergistic interactions. CONCLUSIONS: Coinfecting HPV genotypes occur at random and lead to cervical disease independently.
Assuntos
Colo do Útero/virologia , Papillomaviridae/classificação , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/epidemiologia , Infecções por Papillomavirus/virologia , Neoplasias do Colo do Útero/epidemiologia , Adolescente , Adulto , Costa Rica/epidemiologia , DNA Viral/genética , Feminino , Genótipo , Humanos , Incidência , Papillomaviridae/genética , Infecções por Papillomavirus/complicações , Medição de Risco , Neoplasias do Colo do Útero/virologia , Adulto JovemRESUMO
BACKGROUND: The efficacy of a rotavirus vaccine against severe rotavirus gastroenteritis when coadministered with routine Expanded Program on Immunization (EPI) vaccines including oral polio vaccine (OPV) was evaluated in this study. METHODS: Double-blind, randomized (2:1), placebo-controlled study conducted across 6 Latin American countries. Healthy infants (N = 6568) 6 to 12 weeks of age received 2 doses of RIX4414 vaccine or placebo following a 0, 1- to 2-month schedule. Routine vaccines including OPV were coadministered according to local EPI schedule. Vaccine efficacy (VE) against severe rotavirus gastroenteritis caused by circulating wild-type rotavirus from 2 weeks post-Dose 2 until 1 year of age was calculated with 95% confidence interval [CI]. Safety was assessed during the entire study period. Immunogenicity of RIX4414 and OPV was also assessed. RESULTS: During the efficacy follow-up period (mean duration = 7.4 months), 7 and 19 cases of severe rotavirus gastroenteritis were reported in the vaccine and placebo groups, respectively, with a VE of 81.6% (95% CI: 54.4-93.5). VE against severe rotavirus gastroenteritis caused by G1 type was 100% (95% CI: <0-100) and 80.6% (95% CI: 51.4-93.2) against the pooled non-G1 rotavirus types, respectively. There was no difference (P = 0.514) in the incidence of serious adverse events reported in the 2 groups. Antirotavirus IgA seropositivity rate at 1 to 2 months post-Dose 2 was 61.4% (95% CI: 53.7-68.6) in the RIX4414 group; similar seroprotection rates (≥96.0%) against the 3 antipoliovirus types was observed 1 month post-Dose 3 of OPV in both groups. CONCLUSION: RIX4414 was highly efficacious against severe rotavirus gastroenteritis caused by the circulating wild-type rotavirus (G1 and non-G1) when coadministered with routine EPI vaccines including OPV.
Assuntos
Gastroenterite/prevenção & controle , Esquemas de Imunização , Imunização/métodos , Infecções por Rotavirus/prevenção & controle , Vacinas contra Rotavirus/administração & dosagem , Vacinas contra Rotavirus/imunologia , Método Duplo-Cego , Feminino , Humanos , Imunização/efeitos adversos , Lactente , América Latina , Masculino , Placebos/administração & dosagem , Vacina Antipólio Oral/administração & dosagem , Vacinas contra Rotavirus/efeitos adversos , Vacinas Atenuadas/administração & dosagem , Vacinas Atenuadas/efeitos adversos , Vacinas Atenuadas/imunologiaRESUMO
BACKGROUND: Infection with human papillomavirus (HPV) 16 or HPV18 elicits an antibody response, but whether the elicited antibodies protect women against subsequent infection by a homologous HPV type compared with seronegative women is unknown. METHODS: Study participants were women aged 18-25 years at enrollment in the control group of the ongoing National Cancer Institute-sponsored, community-based, randomized HPV16/18 Costa Rica Vaccine Trial. At enrollment, 2813 participants were negative for cervical HPV16 DNA and 2950 for HPV18 DNA. Women were interviewed regarding sociodemographic data and medical and health history. Medical and pelvic examinations were conducted for all consenting sexually experienced women. Serum samples taken at enrollment were tested for total HPV16/18 antibodies with a polyclonal enzyme-linked immunosorbent assay, and cervical specimens were tested for type-specific HPV DNA over 4 years of follow-up. Using Poisson regression, we compared rate ratios of newly detected cervical HPV16 or HPV18 infection among homologous HPV-seropositive and HPV-seronegative women, adjusting for age, education, marital status, lifetime number of sexual partners, and smoking. RESULTS: There were 231 newly detected HPV16 infections during 5886 person-years among HPV16-seronegative women compared with 12 newly detected HPV16 infections during 581 person-years among HPV16-seropositive women with the highest HPV16 sero-levels. There were 136 newly detected HPV18 infections during 6352 person-years among HPV18-seronegative women compared with six new infections detected during 675 person-years among HPV18 seropositives with the highest sero-levels. After controlling for risk factors associated with newly detected HPV infection, having high HPV16 antibody titer at enrollment was associated with a reduced risk of subsequent HPV16 infection (women in the highest tertile of HPV16 antibody titers, adjusted rate ratio = 0.50, 95% confidence interval = 0.26 to 0.86 vs HPV16-seronegative women). Similarly, having high HPV18 antibody titer at enrollment was associated with a reduced risk of subsequent HPV18 infection (women in the highest tertile of HPV18 antibody titers, adjusted rate ratio = 0.36, 95% confidence interval = 0.14 to 0.76 vs HPV18-seronegative women). CONCLUSION: In this study population, having high antibody levels against HPV16 and HPV18 following natural infection was associated with reduced risk of subsequent HPV16 and HPV18 infections.
Assuntos
Anticorpos Antivirais/sangue , Papillomavirus Humano 16/imunologia , Papillomavirus Humano 18/imunologia , Infecções por Papillomavirus/epidemiologia , Infecções por Papillomavirus/imunologia , Vacinas contra Papillomavirus/administração & dosagem , Adolescente , Adulto , Análise de Variância , Anticorpos Antivirais/isolamento & purificação , Costa Rica/epidemiologia , Ensaio de Imunoadsorção Enzimática , Estudos Epidemiológicos , Feminino , Humanos , Incidência , Infecções por Papillomavirus/diagnóstico , Infecções por Papillomavirus/prevenção & controle , Infecções por Papillomavirus/virologia , Distribuição de Poisson , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Adulto JovemRESUMO
BACKGROUND: Not all women infected with HPV-16/18 have detectable levels of HPV-16/18 antibodies, those who seroconvert develop low antibody levels, and seroconversion occurs typically several months post-infection. We evaluated determinants of seropositivity among 646 women infected with HPV-16 and/or HPV-18. METHODS: Data are from the enrollment visit of the NCI-sponsored Costa Rica HPV Vaccine Trial. Sera were tested for HPV-16/18 antibodies by ELISA; cervical specimens were tested for HPV DNA using HC2 and SPF10/LiPA25. Odds ratios (OR) and 95% confidence intervals (CI) were computed. RESULTS: Among HPV-16/18 DNA positives, seropositivity was 63.0% and 57.5%, respectively. Among HPV-16 DNA positives, seropositivity increased with lifetime number of sexual partners (p-trend = 0.01). Women with abnormal cytology and/or high viral load had a 1.63-2.79-fold increase in the detection of antibodies compared to women with normal cytology/low viral load. Current users of oral contraceptives had a 1.88-fold (95%CI, 1.14-3.09) increased detection of antibodies and current users of injectables had a 3.38-fold (95%CI, 1.39-8.23) increased detection compared to never users. Among HPV-18 DNA positive women, seropositivity was associated with current oral contraceptive use (OR 2.47; 95%CI 1.08-5.65). CONCLUSIONS: Factors associated with sustained HPV exposure (abnormal cytology, elevated HPV viral load, increasing lifetime partners) were predictive of HPV-16 seropositivity. Hormonal contraceptive use was associated with seropositivity suggesting an effect of hormones on immune responses to HPV. Patterns were less consistent for HPV-18. Follow up of incident HPV infections to evaluate seroconversion and their determinants is needed.
Assuntos
Anticorpos Antivirais/sangue , DNA Viral/isolamento & purificação , Papillomavirus Humano 16/isolamento & purificação , Papillomavirus Humano 18/isolamento & purificação , Infecções por Papillomavirus/epidemiologia , Adolescente , Adulto , Colo do Útero/virologia , Costa Rica/epidemiologia , Ensaio de Imunoadsorção Enzimática , Feminino , Papillomavirus Humano 16/genética , Papillomavirus Humano 16/imunologia , Papillomavirus Humano 18/genética , Papillomavirus Humano 18/imunologia , Humanos , Infecções por Papillomavirus/imunologia , Infecções por Papillomavirus/virologia , Fatores de Risco , Estudos Soroepidemiológicos , Adulto JovemRESUMO
BACKGROUND: Serological indicators of human papillomavirus (HPV) infection are being used to differentiate HPV-naïve from previously infected women in vaccine and epidemiologic/clinical studies. We investigated HPV16 and 18 seroepidemiology among young, unvaccinated women aged between 18 and 25. MATERIALS AND METHODS: We conducted a cross-sectional evaluation of the enrollment visit in the ongoing community-based HPV16/18 Costa Rica Vaccine Trial. Prevaccination serum immunoglobulin G (IgG) antibodies were measured against HPV16 and HPV18 by enzyme-linked immunosorbent assay; cervical samples were tested for HPV DNA using Hybrid Capture 2 and SPF10/LiPA25. Seroprevalence and its correlates were evaluated using unconditional logistic regression. RESULTS: Among 5871 nonvirginal women, HPV16 and 18 seroprevalences were 30.8% and 28.1%, HPV16 and HPV18 DNA prevalences were 8.3% and 3.2%, respectively. About 37% of HPV16 DNA-positives and 42% of HPV18 DNA-positives were seronegative. Seroprevalence increased with time since sexual debut, whereas DNA prevalence did not. The correlates of HPV16 and/or 18 seropositivity were related to sexual behaviors, particularly higher number of lifetime sexual partners. There was no evidence of assay cross-reactivity as HPV16 seroprevalence was similar (approximately 34%) among women singly infected with genetically and nongenetically related species (α9 and non-α9); likewise, seropositivity to HPV18 was similar (approximately 30%) among women singly infected with α7 and non-α7 species. CONCLUSIONS: The increasing seroprevalence observed with time since first sex suggests that HPV serology is a cumulative marker of HPV exposure. However, many DNA infected women were seronegative; thus, serology is an imperfect measure of past exposure to cervical HPV, at best. Additionally, we found no evidence of assay cross-reactivity.