L’infection génitale par le Virus du Papillome Humain (VPH) est l’infection transmissible sexuellement la plus fréquente. Sa prévalence la plus élevée est retrouvée chez les femmes en âge de procréer. Bien que la littérature expérimentale s’accorde sur la plausibilité biologique de l’effet du VPH sur les issues négatives de grossesse, les résultats des études observationnelles sont équivoques. Parmi ces issues négatives figure l’accouchement prématuré qui reste une cause majeure de mortalité périnatale et de morbidité à vie dans le monde. La présente thèse avait alors pour but de faire la lumière sur la qualité de la littérature actuelle sur les issues négatives de grossesse en lien avec le VPH en général et d’approfondir l’association entre le VPH et l’accouchement prématuré en particulier. À cette fin, trois objectifs de recherche étaient visés, à savoir: 1) évaluer systématiquement l’ampleur de l’association entre l’infection VPH et les issues négatives de grossesse dans la littérature et la qualité des évidences sur ces relations, 2) estimer l’association entre l’infection VPH pendant la grossesse et l’accouchement prématuré et 3) identifier les déterminants de la transmission du VPH dans le placenta chez les femmes infectées par le VPH au niveau vaginal. Trois analyses ont été menées pour répondre à chacun des objectifs. D’abord, nous avons effectué une revue systématique et des méta-analyses pour chacune des issues négatives de grossesse suivantes: avortement spontané, rupture prématurée et/ou préterme et des membranes, accouchement prématuré, faible poids de naissance, retard de croissance intra-utérine, troubles hypertensifs gestationnels et mortinaissance. Ensuite, en utilisant les données des femmes éligibles de la cohorte prospective HERITAGE (n=899), nous avons estimé l’association entre l’infection VPH (pendant la grossesse et dans le placenta) et l’accouchement prématuré. Dans un modèle de régression logistique, un ajustement pour la confusion a été assuré par pondération par l’inverse de probabilité de l’infection VPH au premier trimestre en fonction des caractéristiques maternelles. Enfin, l’analyse des déterminants du VPH dans le placenta a été réalisée sur l’échantillon de la cohorte de femmes positives au VPH au premier trimestre de grossesse (n=354) en utilisant un modèle d’équations d’estimation généralisée. La revue systématique et les méta-analyses ont montré que l’infection VPH est associée à plusieurs issues négatives de grossesse dont l’accouchement prématuré. Cependant, ces résultats doivent être interprétés avec prudence, compte tenu des limites dans certaines études en raison d’erreur de mesure de l’exposition au VPH, d’une détection du VPH en dehors de la période de grossesse, et d’un contrôle insuffisant pour la confusion. Les résultats de notre étude de cohorte prospective ont montré que la persistance des VPH16/18 pendant la grossesse et la présence du VPH dans le placenta sont associées à l’accouchement prématuré avec un odds ratio ajusté (aOR) de 3,72 (IC 95% 1,47-9,39) et 2,53 (IC 95% 1,06- 6,03) respectivement. Cet effet est indépendant des antécédents de traitement de dysplasies cervicales. Par ailleurs, la présence du VPH dans le placenta est associée à l’origine ethnique autre que blanc (aOR 1,78; IC 95% 1,08-2,96), aux anomalies cervicales (aOR 1,92; IC 95% 1,14-3,24), à l’infection génitale ou urinaire (aOR 2,32; IC 95% 1,15-4,68), à la coinfection VPH au 1er trimestre (aOR 2,56; IC 95% 1,72-3,83), à la persistance d’un VPH à haut risque autre que les génotypes 16/18 (2,31; IC 95% 1,20-4,45) et à la persistance des VPH-16/18 pendant la grossesse (aOR 4,55; IC 95% 2,40-8,66). Dans l’ensemble, les résultats de cette thèse apportent de nouvelles connaissances sur l’infection VPH vaginale pendant la grossesse et dans le placenta. L’association entre l’accouchement prématuré et la persistance du VPH-16/18 en cours de grossesse ou l’infection VPH dans le placenta indique qu’un certain nombre d’accouchements prématurés, jusque-là inexpliqués, pourraient être en lien avec le VPH. Cet effet direct de l’infection VPH sur l’accouchement prématuré vient s’ajouter à celui, déjà montré, du traitement cervical des lésions dysplasiques. Le VPH placentaire est associé aux marqueurs d’une réponse immunitaire inadéquate contre le VPH vaginal. Nos résultats plaident en faveur de la couverture vaccinale optimale contre le VPH dans le but d’alléger le fardeau des naissances prématurées. / Human Papillomavirus (HPV) genital infection is the most common sexually transmitted infection. Its highest prevalence is found in women of childbearing age. Although experimental studies agree on the biological plausibility of detrimental effect of HPV on pregnancy outcomes, observational studies yielded contradictory findings. Among these negative outcomes there is preterm delivery, which remains a major cause of perinatal mortality and lifelong morbidity worldwide. Therefore, this thesis aimed to shed light on the quality of the current literature on negative outcomes related to HPV in general and specifically to further investigate the association between HPV and preterm birth. We targeted three research objectives: 1) systematic assessment of the association between HPV infection and negative pregnancy outcomes in the literature and the quality of the evidence on these relationships, 2) estimate the association between HPV infection during pregnancy and preterm delivery; and 3) to identify the determinants of HPV transmission in the placenta in women infected with in the first trimester. Three analyzes were carried out to meet each of the objectives. We performed a systematic review and meta-analyzes for each of the following negative pregnancy outcomes: spontaneous abortion, premature and / or preterm rupture and membranes, preterm birth, low birth weight, intra-uterine growth retardation, pregnancy induced hypertensive disorders and stillbirth. Using data from eligible women in the HERITAGE prospective cohort (n = 899), we assessed the association between HPV infection (during pregnancy and in the placenta) and preterm birth. In a logistic regression model, we adjusted for confounding by inverse propensity treatment weighting of HPV infection in the first trimester based on maternal characteristics. Finally, the analysis of the determinants of HPV in the placenta was performed on the sample of the cohort of HPV positive women in the first trimester of pregnancy (n = 354) using a generalized estimation equations model. The systematic review and meta-analyzes showed that HPV infection is associated with several negative pregnancy outcomes including preterm birth. However, these results should be interpreted with caution, given the limitations in some studies regarding misclassification of HPV exposure, inappropriate HPV time-point detection, and insufficient control for confusion. Our prospective cohort study showed that the persistence of HPV16/18 during pregnancy and the presence of any HPV in the placenta are associated with preterm birth with an adjusted odds ratio (aOR) of 3.72 (CI 95 % 1.47-9.39) and 2.53 (95% CI 1.06-6.03) respectively. These findings are independent of the history of cervical dysplasia treatment. In addition, the presence of any HPV in the placenta is associated with ethnic origin other than white (aOR 1.78; 95% CI 1.08-2.96), cervical abnormalities (aOR 1.92; 95% CI 1.14-3.24), genital or urinary infection (aOR 2.32; 95% CI 1.15-4.68), HPV coinfection in the 1st trimester (aOR 2.56; 95% CI 1.72-3.83), persistence of high-risk HPV other than genotypes 16/18 (2.31; 95% CI 1.20-4.45) and persistence of HPV-16/18 during pregnancy (aOR 4.55; 95% CI 2.40-8.66). Overall, our findings provide new evidence on vaginal HPV infection during pregnancy and in the placenta. The association between preterm birth and persistence of HPV-16/18 during pregnancy or any HPV infection in the placenta indicates that a number of unexplained preterm deliveries may be related to HPV. This direct effect of HPV infection on preterm birth is in addition to that already shown of cervical treatment of dysplastic lesions. Placental HPV is associated with markers of an inadequate immune response against vaginal HPV. Our results argue in favor of an increase in vaccine coverage against HPV in order to reduce the burden of preterm births.

Indiana University-Purdue University Indianapolis (IUPUI) / In this study we compared the distribution of HPV types in cervical cancer specimens from women living in either Indiana or Botswana. Paraffin-embedded blocks of formalin-fixed cervical cancer specimens were identified from women living in Indiana (n=51) or Botswana (n=171)

L’accouchement prématuré a été récemment associé à la persistance du virus du papillome humain de type 16 (VPH-16) en grossesse. Il demeure toutefois difficile de savoir si cette association est causale et d’en expliquer les mécanismes biologiques potentiels. Afin de mieux caractériser cette association, nous avons étudié l'association entre la charge virale du VPH-16 en grossesse et l’accouchement prématuré. Les données de 48 femmes enceintes qui étaient positives pour le VPH-16 dans la cohorte HERITAGE ont été analysées avec un modèle de régression logistique, où la confusion a été ajustée avec scores de propension et pondération par l’inverse de probabilité de traitement. La charge virale du VPH, mesurée avec test PCR en nombre de copies/cellule au 1er et 3ième trimestre de grossesse, a été analysée en continue et dichotomisée à l’aide de différents seuils (0,5, 1,0 et 2,0). La charge virale (en continue) au 1er trimestre de grossesse a été associée à l’accouchement prématuré avec un OR ajusté (aOR) de 1,13 [IC 95% 1,03-1,25]. Le aOR pour la charge virale catégorisée avec seuil de 1,0 copie/cellule au 1er trimestre était de 15,03 [IC 95 % 1,75- 129,26]. Les analyses avec des seuils différents et au 3ième trimestre de grossesse ont données des résultats similaires quoique les ORs n’étaient pas toujours statistiquement significatifs. Nos résultats suggèrent une forte association entre la charge virale du VPH-16 et l’accouchement prématuré. Cette étude contribue à une meilleure compréhension des mécanismes tout en supportant la causalité. / Preterm birth has recently been associated with the persistence of human papillomavirus 16 (HPV-16) during pregnancy. However, it remains difficult to determine whether this association is causal and to explain its potential biological mechanisms. To better characterize this association, we investigated the association between HPV-16 viral load during pregnancy and preterm birth. Data from 48 pregnant women positive with HPV-16 infection from the HERITAGE cohort were analyzed using a logistic regression model, where confounders were adjusted with propensity scores and inverse probability treatment weighting. HPV viral load, measured with a PCR test as copy numbers/cell during the 1st and 3rd trimester of pregnancy was analyzed continuously, and categorized using different cutoffs (0.5, 1.0 and 2.0). Continuous viral load at 1st trimester of pregnancy was associated with preterm birth with an adjusted OR (aOR) of 1.13 [95% CI: 1.03-1.25]. The aOR viral load categorized with cutoff 1 copy/cell at 1st trimester was 15.03 [1.75-129.26]. Analyses with different cutoffs in 3rd trimester of pregnancy gave similar results although the ORs were not always statistically significant. Our results suggest a strong association between HPV-16 viral load and preterm birth. This study contributes to a better understanding of the mechanisms and provides an additional argument on causality.

This thesis focuses on the effects of the human papillomavirus (HPV) in tonsillar cancer, mobile tongue cancer, and recurrent respiratory papillomatosis (RRP). The purpose was to characterize patients with RRP in northern Sweden in order to identify more care-intensive RRP patients and to describe the voice and quality of life aspects that follow RRP. Further aims were to confirm the expected increase of HPV-positive tonsillar cancer cases in northern Sweden, and to study the correlation between HPV, its surrogate marker p16 and HPV receptor syndecan-1 in both tonsillar cancer and mobile tongue cancer. A total of 27 consecutive patients with RRP were evaluated at 3 months postoperatively using the voice handicap index (VHI) and SF-36 questionnaires to assess the impact on life and voice in a RRP population. The values were compared to normative data. This report was further extended by examining consecutive data from 21 new patients in order to characterize RRP patients in northern Sweden. In order to study HPV DNA in tonsillar (n= 65) and mobile tongue cancer (n=109), HPV DNA was extracted from paraffin-embedded biopsies and detected by polymerase chain reaction using general primers Gp5+/6+ and CpI/IIG. Expression of HPV surrogate marker p16 and the HPV receptor syndecan-1 was analysed by immunohistochemistry. Patients that underwent more than one RRP surgery per year were younger than those treated less frequently and they had significantly impaired voice quality as compared to normal subjects. Females, patients with frequent surgical treatment sessions, and patients with the high-risk HPV subtypes scored significantly lower in several domains of the quality of life assessment as compared with normal subjects. Forty-eight RRP patients had a median age of 44.5 years; 71% were men and 29% females, preferentially infected with HPV6. Patients with high surgical treatment frequency/year showed more widespread RRP in the larynx compared to the patients treated less frequently. A total of 214 tonsillar cancer cases were identified. The vast majority were men. They had a median age of 58 years at diagnosis and expressed HPV as well as p16. The incidence of tonsillar cancer revealed a 2,7-fold increase in men between the years 1990 and 2013. The study demonstrates a strong association between p16 and HPV infection in tonsillar malignancies. These findings are in contrast to the mobile tongue cancer cases, where no evidence of HPV DNA could be detected although one-third showed p16 staining. This demonstrated a poor correlation between HPV and p16 in mobile tongue cancer. There was no difference in the expression of the primary HPV receptor, syndecan-1, between tonsillar and mobile tongue cancer. In conclusion, the frequency of RRP operations, age at onset, gender and subtype of the HPV may be used as factors to predict voice disability. RRP patients with high surgical treatment frequency were significantly younger and had a more widespread laryngeal disease compared to the low-frequency treated group. This study confirms the existence of a clinical RRP group, not primarily related to HPV subtype, but to a more care-intensive RRP population. Our findings identify a 2,7-fold increase in the incidence of tonsillar cancer, HPV and p16 in men between 1990-2013. We can use p16 to detect HPV in tonsillar cancer but not in tongue cancer. The introduction of vaccination against HPV may have a role in the prevention of specific HPV-subtype positive head and neck malignancies and recurrent respiratory papillomatosis since the current vaccine protects against HPV6, 11, 16, 18, 31, 33, 45, 52 and 58. Males will definitely benefit indirectly from vaccination of females, though males will still remain at risk of cancers associated with HPV. This highlights the need for sex-neutral vaccination strategy. Our intention is that this thesis will provide scientific data to support a gender-neutral vaccination and to develop simple tools to detect HPV in tonsillar cancer. / Syftet med avhandlingen är att beskriva effekterna av humant papillomvirus (HPV) vid cancer i halsmandlarna, cancer i tungan och vid luftvägspapillom. Totalt 27 patienter med luftvägspapillom (RRP) under åren 2004-2012 utvärderades 3 månader efter operationen med röst handikapp index (VHI) och livskvalitetformuläret SF-36. Resultaten jämfördes med normal data. Studiematerialet utökades med 21 patienter till totalt 48 RRP patienter i syfte att karakterisera patientgruppen i norra Sverige. För att studera HPV-DNA i tonsillcancer (n = 65) och i cancer i mobil del av tungan (n = 109) extraherades HPV-DNA från paraffininbäddade provbitar som sedan analyserades med PCR teknik och GP5 + / 6 + och CPI/IIG primer. Uttryck av surrogatmarkör p16 och HPV-receptorn syndekan -1 analyserades med immunhistokemi. RRP patienter hade en medianålder på 44,5 år; 71% var män och 29% kvinnor, företrädesvis infekterade med HPV6. Patienter som opererades mer än en gång per år var yngre än de som behandlats mindre ofta och hade en statistiskt sämre röstkvalitet än friska kontroller. Kvinnor, patienter med täta kirurgiska behandlingsintervall och högrisk-HPV hade signifikant sämre livskvalitet jämfört med friska kontroller. Patienter med hög kirurgisk behandlingsfrekvens per år var signifikant yngre och hade mer utbredd RRP sjukdom i luftstrupen, jämfört med gruppen med låg behandlingsfrekvens. Sammanlagt, 214 fall av halsmandelscancer identifierades i norra Sverige under åren 1990-2013; majoriteten var män, med en medianålder på 58 år och positiva för både HPV och p16. Andelen halsmandelscancer fall ökade med 2,7 gånger bland männen på 23 år. Vi fann ett starkt samband mellan uttryck av p16 och HPV infektion i halsmandelscancer men inte i HPV-negativ, delvis p16-positiv (33%) mobil tungcancer. Det fanns ingen skillnad i uttrycket av den primära HPV-receptorn, syndekan -1, jämförande tung-, och halsmandelscancer. Antalet RRP operationer, ålder vid insjuknandet, kön och genetisk variant av HPV kan användas som indikatorer för att förutsäga grad av röststörning. RRP patienter med hög kirurgisk behandlingsfrekvens var signifikant yngre och hade en mer utbredd luftvägssjukdom jämfört med RRP patienter som behandlas mindre ofta. Vi har identifierat en undergrupp av RRP patienter som inte primärt karakteriseras efter HPV virusets genetik utan av ett mer vårdintensivt förlopp. Den aktuella avhandlingen har identifierat en 2,7-faldig ökning av antalet halsmandelscancer hos män och ett starkt samband mellan p16 och HPV infektion i halsmandlar men inte i HPV-negativ tungcancer som inte korrelerar till p16 uttryck. Vi kan använda p16 för att påvisa HPV i tonsillcancer men inte i cancer i mobil tunga. Idag ingår HPV vaccination i det allmänna vaccinationsprogrammet för flickor. Vi förväntar oss en tydlig profylaktisk effekt avseende insjuknande i HPV-relaterad huvud- och hals cancer samt luftvägspapillom eftersom vaccinet skyddar mot HPV bl.a. 6, 11, 16 och 18. Män kommer definitivt att gynnas indirekt genom vaccination av kvinnor men kommer att ha fortsatt högre risk än kvinnor att insjukna i HPV relaterad cancer vilket understryker behovet av könsneutral vaccination. Vår avsikt med avhandlingen är att ge vetenskapligt stöd för könsneutralt vaccination och enkla metoder att påvisa halsmandelscancer.

Cervical cancer is a major cause of death in women and is strongly associated with infection by human papillomavirus (HPV). Integration of HPV is thought to form a key step in the formation of cancer, and is thought to involve the upregulation of HPV E6 and E7 due to the loss of E2 transcriptional control. Leptomycin B (LMB), a nuclear export inhibitor, has previously been shown to induce apoptosis in HPV-containing cancer cell lines and HPV 16 E7 or E6/E7 transduced primary keratinocytes, but not in normal cells. This thesis shows that LMB can induce apoptosis and a reduction in the colony survival of derivatives of the W12 cell line that contain HPV 16 in either episomal or integrated form. The HPV genome status, including variations in viral integration type, appears to influence the cumulative and temporal pattern of LMB-induced apoptosis. The effects of LMB were also apparent in cells grown in organotypic raft culture, with differences in behaviour again apparent between cells containing episomal and integrated HPV. As previously noted, treatment with LMB was associated with increased expression of the cell regulators p53 and p21; however, the induction of apoptosis was not dependent upon transcriptionally active p53. It is therefore likely that induction and mediation of LMB-induced apoptosis occurs via alternative, currently unidentified, pathways. These findings suggest that LMB can induce apoptosis in keratinocytes containing HPV 16 in either episomal or integrated form, with genome status and potentially lesion grade likely to influence the response of HPV-associated anogenital lesions to LMB treatment.

Introdução. O Papilomavírus humano (HPV), particularmente o tipo 16, têm sido associado com risco e prognóstico de tumores de cabeça e pescoço. Contudo, o papel do DNA do HPV e resposta sorológica na sobrevida neste grupo de pacientes ainda não está claro. Objetivos. Avaliar o efeito do HPV (resposta sorológica e detecção do DNA no tecido tumoral) na sobrevida de pacientes com carcinoma epidermóide de cabeça e pescoço, considerando-se as distintas localizações anatômicas (cavidade oral, orofaringe, hipofaringe e laringe). Material e métodos. Coorte de 1.475 pacientes com carcinoma epidermóide de cabeça e pescoço, oriundos de dois estudos multicêntricos, diagnosticados entre novembro de 1998 e dezembro de 2008 e acompanhados até 30 de junho de 2009. Detecção de DNA do HPV no tecido tumoral foi feita pela técnica de PCR (Polymerase Chain Reaction) em tecido fresco e material parafinado. Resposta sorológica às proteínas do HPV foi determinada pela técnica Multiplex Luminex. Sobrevida global e específica pela doença foram calculadas pelo método atuarial (tábuas de vida). Curvas de sobrevida de Kaplan-Meier e teste Log-rank para comparação de curvas de sobrevida foram calculados. Hazard ratio (HR) do efeito da infecção pelo HPV nos tumores de cabeça e pescoço e respectivo intervalo com 95 por cento de confiança (IC95 por cento ) foram calculados via modelo de regressão de Cox ajustado pelas variáveis: estudo de origem dos casos, sexo, idade, educação, consumo de tabaco e de álcool, estadiamento do tumor e tratamento, assim como hábitos sexuais para a subcoorte com esta informação. Resultados. Prevalência de DNA do HPV 16 no tecido tumoral foi de 6,7 por cento nos casos recentes (2003-2008) comparado com 1 por cento nos casos iniciais (1998-2002) para a subcoorte de São Paulo. Aumento da soropositividade para HPV 16 E7 nos casos do estudo mais recente (2003-2008) comparado com os casos do estudo inicial (1998-2002) resultou estatisticamente significante. Foi observada pobre concordância entre os resultados de sorologia e DNA do HPV. Pacientes mais jovens (50 anos), que não fumavam e com tumores de orofaringe apresentaram risco aumentado na resposta sorológica à proteína E6 do HPV 16. Prática de sexo oral associou-se com resposta sorológica conjunta às proteínas E6 e E7 do HPV 16. Pacientes soropositivos para HPV 16 E6 apresentaram maior sobrevida global (HR=0,62; IC95 por cento =0,44-0,87), adicionalmente observou-se que a resposta sorológica conjunta às proteínas E6 e E7 do HPV incrementou a sobrevida dos pacientes com tumores de cabeça e pescoço (HR=0,34; IC95 por cento 0,17-0,70) e de orofaringe (HR=0,17; IC95 por cento 0,05-0,59). Conclusões. A prevalência da infecção pelo HPV entre pacientes com tumores de cabeça e pescoço aumentou no período estudado. O estudo sugere que resposta sorológica conjunta às proteínas E6 e E7 do HPV 16 pode estar associada com maior sobrevida global nos tumores de cabeça e pescoço, especificamente nos pacientes com tumores de orofaringe / Introduction. Human papillomavirus (HPV), especially type 16, had been associated with risk and prognostic of head and neck cancer. However, the role of HPV DNA and serological response in survival of patients with head and neck cancer is not yet clear. Objectives. Evaluate the effect of HPV (serological response and HPV DNA tumor status) in survival of patients with squamous cell carcinoma of head and neck (SCCHN), according to anatomical sites (oral cavity, oropharynx, hypopharynx and larynx). Material and methods. Cohort of 1,475 patients with SCCHN, from two multicentre studies diagnosed between November 1998 and December 2008 and followed-up until 30 of June 2009. HPV DNA detection was evaluated by PCR (Polymerase Chain Reaction) in fresh tissue and paraffin blocks. Antibodies to HPV in the serum were determinated by Multiplex Luminex technique. Overall and disease specific survival were calculated by actuarial method. Kaplan-Meier survival curves and Log-rank test in order to compare survival curves were calculated. Hazard ratio (HR) and 95 per cent of interval confidence (95 per cent IC) for Cox model regression were used to evaluate the effect of HPV infection in SCCHN, adjusted by variables: study group, sociodemographics, tobacco and alcohol consumption, tumor clinical stage and treatment, and also sexual habits in the subcohort with available information. Results. HPV DNA 16 tumoral status prevalence was 6.7 per cent in recent cases (2003-2008) compared to 1 per cent in old cases (1998-2002), only for subcohort of São Paulo. Seropositivity to HPV 16 E7 increased in the late cases (2003-2008) compared to old cases (1998-2002) and was statistically significant. Poor concordance was showed between DNA HPV and serological response to HPV. Younger patients (50 years old), no smokers and with oropharyngeal tumors showed increased risk to HPV 16 E6 serological response. Oral sex was associated with HPV 16 E6 and E7 simultaneously. Seropositivity to HPV 16 E6 had longer overall survival (HR=0.62; 95 per cent CI=0.440.87), additionally HPV 16 E6 and E7 serological response increased the survival of head and neck cancers (HR=0.34; 95 per cent CI 0.17-0.70) and oropharyngeal cancer (HR=0.17; 95 per cent CI 0.05-0.59) Conclusions. Prevalence of HPV infection in patients with SCCHN had increased in the study period. The study suggests that HPV 16 E6 serological response could be associated with increased overall survival in patients with SCCHN tumors and specifically with oropharyngeal cancer

Made available in DSpace on 2016-08-10T10:29:48Z (GMT). No. of bitstreams: 1 JOSE ANTONIO VIANA DE MORAIS.pdf: 5002285 bytes, checksum: e2868ed24afede10446be19dffff5108 (MD5) Previous issue date: 2010-05-28 / Human papillomavirus (HPV) is one of the infections through sexual intercourse more often disseminated throughout the world. In Brazil it is estimated that there are around 3 to 6 million cases of HPV. There are few studies about HPV in men. This study examined the therapeutic response of patients men infected with HPV and treated topic with a solution of 90% trichloroacetic acid (ATA 90%). Were treated between January 2007 and December 2008, at the Hospital for Tropical Diseases in Araguaina (TO) 1056 patients undergoing clinical analysis by means of physical examination and penioscopia. The records of these patients were analyzed and found that 589 (55.8%) were diagnosed with HPV. Of these, 529 were selected for study as these met the following inclusion criteria: patients with macroscopic and penioscópico of HPV, which did not undergo any treatment before consultation, which were treated only with ATA 90% before and monitored for any recurrence, at least twelve months. After collecting data it was found that only 68 (12,8%) patients treated with ATA 90% had recurrence of lesions. The age of initial and final of HPV ranged from 18 to 73 years. The average age of patients with recurrence was 34.9 years, coinciding with the peak of sexual activity and the presence of multiple parters. About 80% of cases of recurrence occurred in the first six months. The association with other sexual diseases was recorded and the most prevalent pathologies: balanoposthistis (31,3%), genital herpes (9,2%), gonococal urethritis (2,8%) and no-gonococcal urethritis (0,9%). We found that the presence of other STDs contributes to treatment failure, whereas 75% of cases had tumor recurrence ATA 90% occurred in patients with an STD associated with HPV. Regarding the location of the lesions, it was found that 61.1% occurred at the distal end of the male phallus. The number of lesions detected per patient ranged from 1 to 9, with the majority (82.3%) patients had 2-5 lesions. In this study, we identified that the prevalence of HPV infection in men, STD clinic with urological monitoring was high. The therapeutic efficacy of ATA 90% was higher than the values commonly found in the literature and the recurrence rate of patients was low. We suggest that monitoring of patients with HPV after treatment with ATA is 90% done with routine queries for up to twenty-four months and quarterly consultations with the cases of recurrence. We emphasize the need for a focus on serving the man aiming to prevent controllable diseases evolve into malignancies. / O papilomavírus humano (HPV) é uma das infecções por via sexual mais frequentemente disseminadas em todo o mundo. No Brasil estima-se que existam em torno de 3 a 6 milhões de casos de HPV. Há poucos estudos sobre o HPV em homens. Este trabalho analisou a resposta terapêutica de pacientes do sexo masculino infectados HPV e tratados topicamente com solução de ácido tricloroacético à 90% (ATA 90%). Foram atendidos entre janeiro de 2007 e dezembro de 2008, no ambulatório do Hospital de Doenças Tropicais de Araguaína (TO), 1056 pacientes submetidos a analise clínica por meio do exame físico minucioso e penioscopia. Os prontuários desses pacientes foram analisados e verificou-se que 589 (55,8%) apresentaram diagnóstico de HPV. Destes, 529 foram selecionados para o estudo por atenderem aos seguintes critérios de inclusão: pacientes com diagnóstico macroscópico e penioscópico de HPV, que não realizaram qualquer tratamento antes da consulta, que foram tratados exclusivamente com ATA 90% antes de qualquer recidiva e monitorados por, no mínimo, doze meses. Após coleta de dados verificou-se que apenas 68 (12,8%) pacientes que realizaram tratamento com ATA 90% apresentaram recidiva das lesões. A faixa etária de acometimento do HPV variou de 18 a 73 anos. A idade média dos pacientes com recidiva foi de 34,9 anos, coincidente com o pico de atividade sexual e a presença de múltiplos parceiros. Cerca de 80% dos casos de recidiva ocorreram nos seis primeiros meses. A associação com outras DSTs foi observada, sendo as patologias mais prevalentes: a balanopostite (31,3%), o herpes genital (9,2%), a uretrite gonocócica (2,8%) e a uretrite não gonocócica (0,9%). Verificamos que a presença de outra DST contribui para o insucesso terapêutico, visto que 75% dos casos de recidiva pós ATA 90% ocorreram em pacientes portadores de alguma DST associada ao HPV. Em relação à localização das lesões, verificou-se que 61,1% ocorreram na extremidade distal do falo masculino. O número de lesões encontradas por paciente variou de 1 a 9, sendo que a maioria (82,3%) dos pacientes apresentou de 2 a 5 lesões. Neste estudo, identificamos que a prevalência da infecção por HPV em homens, em ambulatório de DST com acompanhamento urológico foi elevada. A eficácia terapêutica do ATA 90% mostrou-se maior que os valores comumente encontrados na literatura e o índice de recidiva dos pacientes foi baixo. Sugerimos que o acompanhamento dos pacientes com HPV após o tratamento com ATA 90% seja realizado com consultas rotineiras por até vinte e quatro meses e com consultas trimestrais para os casos de recidiva. Reforçamos a necessidade de um enfoque no atendimento do homem com intuito de evitar que doenças controláveis evoluam para doenças oncológicas.

Made available in DSpace on 2016-08-10T10:39:25Z (GMT). No. of bitstreams: 1 LARISSA FERNANDES DE CARVALHO.pdf: 2794684 bytes, checksum: a117224e860c989d8636ee7805cfc679 (MD5) Previous issue date: 2010-05-31 / Cancer has been a major public health problem both in developed and developing countries . Each year, cancer is responsible for more than six million deaths, imposing a population burden that claims about 12% of all causes of that worldwide. Under a genetic perspective, there are two major classes of gene that hold an important role on cancer development: the proto-oncogenes and the tumor suppress genes. Mutations in these genes are the underlying cause of uncontrolled cell proliferation. Under the spectrum of male urological tumors, penile carcinoma is the one that most resembles cervical carcinoma in women. Epidemiological studies have frequently implicated HPV genome as a potential initiator factor for carcinomas of different anatomical sites. HPV role in cancer induction is well documented for cervical carcinomas and a significant association has been found in up to 99,7% of all cases worldwide. The occurrence of HPV in both male and female genital areas has increased the scientific interest around the potential association of HPV genome and penile carcinomas. The HPV genome is mode of one copy of the double-stranded circular DNA molecule, organized in three distinct regions: a Long Control Region (LCR), an Early (E) and a Late (L) protein coding regions. Following viral insertion in a cell genome, the viral LCR becomes the target of an intracellular regulatory mechanism. When infected cells lose this control mechanism, tumor progression towards malignancy and increased viral gene expression occur. Penile cancer is a rare disease, however by far the most common type is the squamous cell carcinoma which is found in about 95% of the penile malignancies. As any other Sexually Transmitted Disease, men are the major link in the chain of infection of HPV. The Polimerase Chain Reactions is the most sensitive procedure to detect and genotype HPV DNA in human biological samples. The current study is a meta-analysis which comprised the result of several studies that using PCR detected and genotyped HPV genome in association with penile cancers. Herein we report on the results of 39 research articles published from 1989 to 2009. We found the published data had large heterogeneity, tending to significance when combined within the 95% confidence interval. The DermonSaimonian-Laird analysis indicated significance between HPV infection and penile cancer development. / O HPV atua como uma importante causa de câncer cervical, em cerca de 99,7% dos casos em todo mundo. Como ocorre em toda infecção de transmissão sexual, o homem é o principal elo na cadeia epidemiológica do HPV e tem sido bastante discutido a associação deste vírus aos carcinomas penianos. O câncer de pênis é uma doença rara, sendo o carcinoma de células escamosas responsável por 95% dos casos. Assim, a infecção por HPV em homens, promove modificações bioquímicas e moleculares, alterando significativamente a população de células, através da interação do genoma viral com o genoma da célula hospedeira ou de proteínas virais com proteínas celulares necessárias ao controle do ciclo celular, como as proteínas supressoras de tumor pRb e p53, podendo desencadear a progressão para o processo maligno. Dentre as técnicas moleculares para detecção de DNA do HPV, a PCR é a mais sensível, pois é capaz de identificar o tipo do HPV. Neste contexto, o presente estudo teve como objetivo, investigar a associação entre o HPV e os pacientes com câncer de pênis através de uma meta-análise. Um procedimento destinado a examinar, de modo simultâneo, os resultados de várias investigações sobre um mesmo tópico, de forma a gerar conclusões com maior segurança e confiabilidade. De um total de quarenta e quatro (44) artigos encontrados, foram incluídos na meta-análise, trinta e nove (39) artigos e duas (2) dissertações entre os anos de 1989 a 2009 que estabeleciam a co-relação e utilizavam as mesmas técnicas e primers para detecção e genotipagem do HPV. Na presente meta-análise, observou-se que os artigos analisados apresentaram heterogeneidade quando avaliados os tipos de HPV 16 e 18, em conjunto. O HPV do tipo 18 isolado não apresentou significância, enquanto o HPV 16 demonstrou estar significativamente relacionado ao carcinoma espinocelular de pênis. Pelo teste de DerSimonian-Laird os resultados dos estudos combinados demonstram que os mesmos são significativos e heterogêneos em relação a IC 95%. Assim, pode-se concluir que a associação entre câncer de pênis e HPV se confirma por meta-análise, demonstrando assim a importância da força estatística da meta-análise diante dos estudos isolados na tentativa de desenvolvimento de novas estratégias de prevenção do HPV.

Made available in DSpace on 2016-08-10T10:54:58Z (GMT). No. of bitstreams: 1 LUANA CARVALHO DA SILVA.pdf: 1919863 bytes, checksum: 43845eab7ebc38ce4258c581e7475ae9 (MD5) Previous issue date: 2015-05-29 / Cervical cancer is considered an important public health problem, since it affects and kills a large number of women throughout the world. The main risk factor for cervical cancer is the infection by the Human Papillomavirus (HPV), considered to be the most common sexually transmitted disease, in the present days. Despite the high incidence, cervical cancer prevention programs have been implemented worldwide, through the Pap smear and HPV vaccine. Objective: To evaluate the perception and knowledge of nursing students about HPV infection, HPV associated diseases and HPV vaccine, in a private education institution, in Goiânia-GO. METHODS: It comprises a descriptive study with a quantitative approach, carried out through a questionnaire with objective questions that allowed to quantify the knowledge of the participants with regard to HPV infection, diseases associated with the virus and HPV vaccine, ensuring the analysis and interpretation of the results. The research was applied to 361 scholars from both genders. RESULTS: Correct answers related to the knowledge about HPV infection ranged from 40.3% to 99.2%, with an average of 73.8%; about the diseases associated with viruses, the indexes of correct answers ranged from 24.8% to 82.8%, with an average of 61.8%; regarding the HPV vaccine, the indexes of correct answers ranged from 40.8% to 93.0%, averaging 74.6%. CONCLUSION: The results allowed to conclude that academic nursing knowledge was reasonable in relation to HPV infection and HPV vaccine. However, insufficient results were obtained with respect to the knowledge about cancer of the uterine cervix. Thus, we highlight the need for continuing education about the subject, during and after graduation of these professionals, since nursing presents an important role in health teams and in the process of health education of the population. / O câncer do colo do útero é considerado um importante problema de saúde pública, pois ainda acomete e mata um grande número de mulheres em todo mundo. O principal fator de risco para o câncer do colo do útero é a infecção pelo Papilomavírus humano (HPV), considerada a doença sexualmente transmissível mais comum, nos dias atuais. Apesar da alta incidência, o câncer do colo do útero apresenta programa de prevenção, por meio do exame de Papanicolaou e da vacina anti-HPV. OBJETIVO: Avaliar a percepção e o conhecimento dos acadêmicos de enfermagem de uma instituição de ensino superior privada de Goiânia-GO, sobre a infecção pelo HPV, o câncer do colo do útero e a vacina anti-HPV. MÉTODOS: Estudo descritivo com abordagem quantitativa, realizado por meio de questionário com perguntas objetivas que permitiu quantificar o conhecimento dos participantes com relação à infecção pelo HPV, as doenças associadas ao vírus e a vacina anti-HPV, garantindo a análise e interpretação dos resultados. A pesquisa foi aplicada a 361 acadêmicos de ambos os gêneros. RESULTADOS: Os níveis de acertos observados para as questões relacionadas ao conhecimento sobre a infecção pelo HPV variaram de 40,3% a 99,2%, com média de 73,8%; sobre o câncer do colo do útero, os índices de acertos variaram de 24,8% a 82,8%, com média de 61,8%; com relação à vacina anti-HPV, os índices de acertos variaram de 40,8% a 93,0%, com média de 74,6%. CONLUSÃO: Os resultados desse estudo permitiram concluir que o conhecimento dos acadêmicos de enfermagem foi razoável em relação à infecção pelo HPV e à vacina anti-HPV. Entretanto, resultados insuficientes foram obtidos com relação ao conhecimento sobre o câncer do colo do útero. Assim, destacase a necessidade da educação continuada durante e após a graduação desses profissionais, pois a enfermagem apresenta um importante papel em equipes de saúde e no processo de educação em saúde da população.

INTRODUÇÃO: Co-infecção HPV / HIV altera história natural das infecções por HPV, aumentando o risco de verrugas e neoplasias malignas do trato ano-genital. Há, no entanto, escassez de estudos de coorte envolvendo HPV no pênis dessa população. MÉTODOS: Estudo longitudinal, não probabilístico, com 144 homens de 18 e 70 anos de idade, sendo 72 HIV positivos e 72 HIV soronegativos, parceiros de mulheres com patologia associada a infecção pelo HPV. O estudo foi conduzido numa clínica pública de doenças de transmissão sexual em São Paulo (CRT-DST/AIDS), entre fevereiro de 2004 a março de 2005. Os participantes do estudo foram acompanhados por 180 dias para avaliar a persistência, a aquisição e a eliminação do DNA de HPV nos esfregaços penianos por meio da PCR. Este estudo também visou: Correlacionar os aspectos clínicos das lesões genitais com a histologia e a presença de DNA HPV; Comparar a aquisição, persistência, eliminação e ausência da infecção pelo HPV com a carga viral plasmática do HIV, contagem de células T CD4 e uso de terapia anti-retroviral (HAART). RESULTADOS: Não houve associação estatisticamente significativa nos dois grupos em relação a persistência, eliminação, aquisição ou mesmo ausência de HPV durante o seguimento. O grupo HIV positivo apresentou uma maior freqüência dos tipos oncogênicos de HPV em relação ao grupo HIV negativo (P = 0,041), além de uma maior freqüência de múltiplos tipos de HPV durante o seguimento de 180 dias (P = 0,049). As maiores taxas de aquisição e persistência de HPV foram observadas entre portadores de alta carga de HIV, baixo número de células T CD4, e não usuários de HAART. Aqueles em terapia anti-retroviral, com menos cópias de HIV e alto nível de T CD4 apresentaram maiores taxas de eliminação e ausência de HPV. CONCLUSÕES: Homens de ambos grupos podem ser considerados de alto risco, não tendo sido observada diferença na persistência, aquisição e a eliminação de DNA de HPV. Os homens HIV positivos apresentaram uma maior freqüência de infecção múltipla de HPV bem como os tipos mais freqüentes foram os oncogênicos em relação aos HIV negativos durante o seguimento. Os tipos de HPV 16, 6 e 84 foram os mais freqüentes nos homens soropositivos ao HIV, enquanto naqueles HIV negativos, predominaram os tipos de HPV 6, 51 e 84. As lesões clínicas e aceto-brancas observadas nos 2 grupos apresentaram as mesmas características histológicas, sendo coilocitose e papilomatose as mais significativas nas lesões clínicas quando comparada às lesões aceto-brancas. Nas lesões verrucosas, apenas um tipo de HPV foi observado, predominando o tipo 6 ou 11. Em torno de 23% das lesões aceto-brancas eram HPV negativas, sendo que nas positivas predominou o HPV 6. Homens soropositivos ao HIV que estavam usando HAART, com carga viral do HIV alta e contagem de células T CD4 baixa apresentaram maiores taxas de aquisição e persistência da infecção pelo HPV. Entretanto, os que não xvi estavam em terapia anti-retroviral, com carga baixa de HIV e contagem de células T CD4 alta apresentaram maiores taxas de eliminação e ausência de infecção pelo HPV. / BACKGROUND: Co-infection with HPV and HIV modifies its natural history and increases the risk of warts and neoplasia development in the anogenital tract. Cohort studies to address HPV infection in the penis are scarce, mainly in HIV infected individuals. METHODS: A longitudinal study, non-probabilistic, was conducted with 144 men of 18 to 70 years old including 72 HIV-positive and 72 HIV-negative, partners of women with HPV-associated disease. The study was conducted between February 2004 and March 2005 at a large sexually transmitted clinic in São Paulo (CRT-DST/Aids). Men were followed for 180 days to determine persistence, acquisition and clearance of HPV DNA in penile swabs using PCR. In addition, we aimed to correlate the clinical features of genital lesions with histology and the presence of HPV DNA, compare the acquisition, persistence, clearance and absence of HPV infection with plasma HIV viral load, CD4 T-cell count and use of HAART. RESULTS: Both groups showed no significant differences regarding persistence, clearance, acquisition and/or absence of HPV during follow-up. Penile smears of HIV-positive men showed a higher frequency of oncogenic types in relation to the HIV-negative (P = 0.041), as well as a higher frequency of multiple HPV types (P = 0.049). Significantly higher HPV DNA acquisition and persistence rates were observed among HIV-positive men not submitted to HAART, with higher HIV loads and lower CD4+ cells count. Among those men using anti-retroviral therapy, lower viral loads and higher T cell counts, higher rates of clearance and HPV DNA absence were observed. CONCLUSIONS: This male population altogether is considered to be at high risk of HPV DNA infection, which may be the reason why no differences in HPV acquisition, persistence and clearance were observed. HIV-positive men had a higher frequency of multiple HPV infection and the most frequent were oncogenic types. HPV types 16, 6 and 84 were the most frequently found in HIV-positive men, while in HIV-negative men, HPV types 6, 51 and 84 prevailed. Clinical and aceto-white lesions presented the same histological features in both HIV seropositive and -negative men. Koilocytosis and papillomatosis were the most significant histological features found in clinical lesions when compared to the aceto-white lesions. In condylomas, only one type of HPV was present, often HPV 6 or 11. About 23% of aceto-white lesions had no HPV DNA; in HPV-positive lesions, the predominant type was HPV 6. Higher rates of acquisition and persistence of HPV infection occurred in men who were using HAART, with high HIV viral load and low count of CD4. In contrast, those not under anti-retroviral therapy, had low HIV load and high CD4 T cells levels showed higher rates of clearance of HPV infection.