Asociación de los alelos de HLA con la persistencia, depuración y reinfección de tipos de Virus del Papiloma Humano de alto riesgo

Este trabajo tuvo como objetivo identificar los alelos y haplotipos HLA-DRB1 y DQB1 relacionados con la persistencia, depuración y redetección de 6 tipos de VPH de alto riesgo (VPH-AR) (-16, -18, -31, -33, -45 y -58) en una cohorte de mujeres colombianas. A partir de muestras de cérvix de 276 mujeres, se realizó la tipificación de los loci DRB1 y DQB1 mediante el sistema MiSeq-Illumina. Se estimó la probabilidad de depuración y redetección en función del tiempo para cada uno de los 6 tipos de VPH-AR, con el método de Kaplan Meier. Se ajustaron modelos de supervivencia para identificar los alelos y haplotipos relacionados con la depuración y redetección teniendo en cuenta otras covariables. Se encontraron, para DRB1, 47 asociaciones (20 alelos), para DQB1, 6 asociaciones (3 alelos) y para los haplotipos, 87 asociaciones (34 haplotipos) con la depuración/persistencia de VPH. Con respecto a la redetección, 45 asociaciones de alelos DRB1 (23 alelos), 6 asociaciones para DQB1 (3 alelos) y 64 asociaciones, de 36 haplotipos, fueron identificadas. Se encontraron asociaciones tanto a favor como en contra de los eventos analizados, siendo algunas consistentes entre los tipos de VPH infectantes y otras diferentes. El efecto de los alelos y haplotipos de HLA sobre el curso clínico de las infecciones de VPH (depuración, persistencia y redetección viral) es dependiente del tipo de VPH responsable de la infección. El efecto independiente de algunos alelos fue consistente al configurar los haplotipos, mientras que para otros se observó una modificación del efecto.Abstract: The objective of this work was to identify HLA-DRB1 and DQB1 alleles and haplotypes related to the persistence, clearance and redetection of 6 high-risk HPV types (HR-HPV) (- 16, -18, -31, -33, - 45 and -58) in a cohort of Colombian women. From cervical samples of 276 women, DRB1 and DQB1 typing was performed using the MiSeq-Illumina system. The likelihood of clearance and redetection was estimated as a function of time for each of the 6 HR-HPV types with the Kaplan Meier method. Survival models were adjusted to identify alleles and haplotypes related to clearance and redetection, taking into account other covariates. We found, for DRB1, 47 associations (20 alleles), for DQB1, 6 associations (3 alleles) and for haplotypes, 87 associations (34 haplotypes) with clearance/persistence of HPV. With regard to redetection, 45 associations for DRB1 (23 alleles), 6 associations for DQB1 (3 alleles) and 64 associations for 36 haplotypes, were identified. Associations were found both in favor and against the events analyzed, with some being consistent between the infecting HPV types and others different. The effect of HLA alleles and haplotypes on the clinical course of HPV infections (clearance, persistence and viral redetection) is dependent on the HPV type responsible for the infection. The independent effect of some alleles was consistent when configuring the haplotypes, while for others a modification of the effect was observed.Maestrí

The DNA load of six high-risk human papillomavirus types and its association with cervical lesions

Background: Analysing human papillomavirus (HPV) viral load is important in determining the risk of developing cervical cancer (CC); most knowledge to date regarding HPV viral load and cervical lesions has been related to HPV-16. This study evaluated the association between the viral load of the six most prevalent high-risk viral types in Colombia and cervical intraepithelial neoplasia (CIN) frequency. Methods: 114 women without CIN and 59 women having CIN confirmed by colposcopy, all of them positive by conventional PCR for HPV infection in the initial screening, were included in the study. Samples were tested for six high-risk HPV types to determine viral copy number by real-time PCR. Crude and adjusted odds ratios (ORa) were estimated for evaluating the association between each viral type's DNA load and the risk of cervical lesions occurring. Results: The highest viral loads were identified for HPV-33 in CIN patients and for HPV-31 in patients without lesions (9.33 HPV copies, 2.95 interquartile range (IQR); 9.41 HPV copies, 2.58 IQR). Lesions were more frequent in HPV-16 patients having a low viral load (3.53 ORa, 1.16-10.74 95%CI) compared to those having high HPV-16 load (2.62 ORa, 1.08-6.35 95%CI). High viral load in HPV-31 patients was associated with lower CIN frequency (0.34 ORa, 0.15-0.78 95%CI). Conclusions: An association between HPV DNA load and CIN frequency was seen to be type-specific and may have depended on the duration of infection. This analysis has provided information for understanding the effect of HPV DNA load on cervical lesion development.This project was supported by the Basque Development Cooperation Agency, the Spanish International Development Cooperation Agency (AECID) (Project 10-CAP1-0197) and the Colombian Science, Technology and Innovation Department (COLCIENCIAS) (contract # 0709-2013)

Persistence, clearance and reinfection regarding six high risk human papillomavirus types in Colombian women: a follow-up study

Background: The design of new healthcare schemes which involve using molecular HPV screening means that both persistence and clearance data regarding the most prevalent types of HR-HPV occurring in cities in Colombia must be ascertained. Methods: This study involved 219 HPV positive women in all of whom 6 types of HR-HPV had been molecularly identified and quantified; they were followed-up for 2 years. The Kaplan-Meier survival function was used for calculating the time taken for the clearance of each type of HPV. The role of a group of independent variables concerning the time taken until clearance was evaluated using a Cox proportional-hazards regression model or parametric (log-logistic) methods when necessary. Regarding viral load, the Wilcoxon rank-sum test was used for measuring the difference of medians for viral load for each type, according to the state of infection (cleared or persistent). The Kruskal-Wallis test was used for evaluating the change in the women's colposcopy findings at the start of follow-up and at the end of it (whether due to clearance or the end of the follow-up period). Results: It was found that HPV-18 and HPV-31 types had the lowest probability of becoming cleared (1.76 and 2.75 per 100 patients/month rate, respectively). Women from Colombian cities other than Bogota had a greater probability of being cleared if they had HPV-16 (HR 2.58: 1.51-4.4 95% CI) or HPV-58 (1.79 time ratio: 1.33-2.39 95% CI) infection. Regarding viral load, HPV-45-infected women having 1 x 10(6) to 9.99 x 10(9) viral copies had better clearance compared to those having greater viral loads (1.61 time ratio: 1.01-2.57 95% CI). Lower HPV-31 viral load values were associated with this type's persistence and changes in colposcopy findings for HPV-16 gave the worst prognosis in women having low absolute load values. Conclusions: HPV infection clearance in this study was related to factors such as infection type, viral load and the characteristics of the cities from which the women came. Low viral load values would indicate viral persistence and a worse prognosis regarding a change in colposcopy findings

Persistence, clearance and reinfection regarding six high risk human papillomavirus types in Colombian women : A follow-up study

Background: The design of new healthcare schemes which involve using molecular HPV screening means that both persistence and clearance data regarding the most prevalent types of HR-HPV occurring in cities in Colombia must be ascertained.Methods: This study involved 219 HPV positive women in all of whom 6 types of HR-HPV had been molecularly identified and quantified; they were followed-up for 2 years. The Kaplan-Meier survival function was used for calculating the time taken for the clearance of each type of HPV. The role of a group of independent variables concerning the time taken until clearance was evaluated using a Cox proportional-hazards regression model or parametric (log-logistic) methods when necessary. Regarding viral load, the Wilcoxon rank-sum test was used for measuring the difference of medians for viral load for each type, according to the state of infection (cleared or persistent). The Kruskal-Wallis test was used for evaluating the change in the women's colposcopy findings at the start of follow-up and at the end of it (whether due to clearance or the end of the follow-up period).Results: It was found that HPV-18 and HPV-31 types had the lowest probability of becoming cleared (1.76 and 2.75 per 100 patients/month rate, respectively). Women from Colombian cities other than Bogotá had a greater probability of being cleared if they had HPV-16 (HR 2.58: 1.51-4.4 95% CI) or HPV-58 (1.79 time ratio: 1.33-2.39 95% CI) infection. Regarding viral load, HPV-45-infected women having 1 × 106 to 9.99 × 109 viral copies had better clearance compared to those having greater viral loads (1.61 time ratio: 1.01-2.57 95% CI). Lower HPV-31 viral load values were associated with this type's persistence and changes in colposcopy findings for HPV-16 gave the worst prognosis in women having low absolute load values.Conclusions: HPV infection clearance in this study was related to factors such as infection type, viral load and the characteristics of the cities from which the women came. Low viral load values would indicate viral persistence and a worse prognosis regarding a change in colposcopy findings. © 2014 Soto-De León et al.; licensee BioMed Central Ltd

Carga viral de seis tipos de Virus del Papiloma Humano de alto riesgo y su asociacion con lesiones cervicales

Introducción: La infección por un tipo de Virus del Papiloma Humano de alto riesgo (VPH-AR), es el factor principal en el desarrollo de Cáncer de Cérvix (CC). La carga viral puede modular esta asociación, por lo que resulta importante su cuantificación y el establecimiento de su relación con lesiones precursoras de CC.\ud Metodología: 60 mujeres con lesiones escamosas intraepiteliales (LEI) y 120 mujeres sin LEI, confirmadas por colposcopia, fueron incluidas en el estudio. Se determinó la carga viral de 6 tipos de VPH-AR, mediante PCR en tiempo real. Se estimaron OR crudos y ajustados para evaluar la asociación entre la carga viral de cada tipo y las lesiones cervicales. \ud Resultados: 93.22% de mujeres con LEI y 91.23% de mujeres negativas, fueron positivas para al menos un tipo de VPH. VPH-18 y VPH-16 fueron los tipos más prevalentes, junto con VPH-31 en mujeres sin LEI. No se encontraron diferencias estadísticamente significativas de las cargas virales entre éstos dos grupos, aunque se observó un mayor carga viral en lesiones para algunos tipos virales. Una mayor frecuencia de lesiones se asoció a infecciones con carga baja de VPH-16 (ORa: 3.53; IC95%: 1.16 – 10.74), en comparación a mujeres con carga alta de VPH-16, (ORa: 2.63; IC95%: 1.09 – 6.36). En infecciones por VPH-31, la presencia de carga viral alta, se asoció con una menor frecuencia de lesiones (ORa: 0.34; IC95%: 0.15 – 0.78).\ud Conclusiones: La prevalencia tipo-específica de VPH se corresponde con las reportadas a nivel mundial. La asociación entre la carga viral del VPH y la frecuencia de LEI es tipo específica y podría depender de la duración de la infección, altas cargas relacionadas con infecciones transitorias, y bajas cargas con persistentes. Este trabajo contribuye al entendimiento del efecto de la carga viral en la historia natural del CC; sin embargo, estudios prospectivos son necesarios para confirmar estos resultados.Background: Infection with high risk of human papillomavirus (HR-HPV) is the main factor in the development of Cervical Cancer (CC). Viral load can modulate this relationship, so it is important to quantify and establish its association with CC precursor lesions.\ud \ud Methods: 60 women having cervical intraepithelial neoplasia (CIN) and 120 women without CIN and confirmed by colposcopy, were included in the study. Samples were tested for six high-risk HPV types to determine viral copy number by real-time PCR. Crude and adjusted odds ratios (ORa) were estimated for evaluating the association between each viral type’s DNA load and the risk of cervical lesions occurring.\ud \ud Results: 93.22% of women with CIN and 91.23% negative women were positive for at least one type of HPV. HPV-18 and HPV-16 were the most prevalent types, with HPV-31 in women without CIN. No statistically significant differences in viral load between these two groups were identified, although a higher viral load was observed in CIN regarding some viral types. Lesions were more frequent in HPV-16 patients having a low viral load (3.53 ORa, 1.16-10.74 95%CI) compared to those having high HPV-16 load (2.62 ORa, 1.08-6.35 95%CI). High viral load in HPV-31 patients was associated with lower CIN frequency (0.34 ORa, 0.15-0.78 95%CI).\ud \ud Conclusions: The type-specific prevalence of HPV is consistent with the reported worldwide. An association between HPV DNA load and CIN frequency was seen to be type-specific and may have depended on the duration of infection, high viral loads related to transient infections and low viral loads with persistent infections. This analysis has provided information for understanding the effect of HPV DNA load on cervical lesion development. However prospective studies are needed

Identification of congenital defects temporal clusters in the surveillance and monitoring programs of Bogotá and Cali between 2011 and 2018

Los defectos congénitos o anomalías congénitas son alteraciones estructurales o funcionales que se producen durante la vida intrauterina y que pueden ser evidentes antes del nacimiento, en el nacimiento o más tarde en la vida. Se estima una prevalencia de defectos congénitos a nivel mundial entre un 2% y un 3%. En Colombia, para el año 2018, se reportó una prevalencia de 1,1%. Se ha reportado, a nivel mundial, que cada año, aproximadamente 303.000 recién nacidos fallecen. En Colombia, se cuenta con el Sistema Nacional de Vigilancia en Salud Pública -SIVIGILA que desarrolla el programa de vigilancia pasivo para defectos congénitos de aplicación nacional. De manera adicional, en Bogotá y en Cali, se cuenta con un programa de vigilancia activo vinculado al Estudio Colaborativo Latinoamericano de Malformaciones Congénitas (ECLAMC). Dentro de estos programas, también se debe asegurar la identificación de agregaciones inusuales reales o percibidas de defectos congénitos, es decir de clústeres. Estos clústeres pueden ser agregaciones en un grupo de personas en un área geográfica en particular por un periodo de tiempo definido o una combinación de estos dos. En Colombia, hasta el momento, se ha identificado un clúster de sirenomelia en la ciudad de Cali, que surgió a partir de una preocupación generada en la comunidad de profesionales de salud (investigación reactiva). Sin embargo, no se cuenta con información acerca de clústeres temporales considerando todos los defectos congénitos. Se planteó un estudio observacional descriptivo, en el cual se identificaron clústeres temporales ocurridos entre 2011 y 2018. Una vez identificados, se realizó el análisis contemplando el desarrollo de las 3 fases siguientes a la identificación: evaluación e investigación, manejo y comunicación. El análisis de los clústeres permitirá que se puedan iniciar y completar la evaluación de los mismos y así evaluar el comportamiento de los defectos congénitos en Colombia como un evento de importancia en salud pública que permitan a futuro generar un impacto en la prevención de defectos congénitos.Congenital defects or congenital anomalies are structural or functional alterations that occur during intrauterine life and that may be evident before birth, at birth, or later in life. A worldwide prevalence of congenital defects is estimated between 2% and 3%. In Colombia a prevalence of 1.1% was reported in 2018. It has been reported, worldwide, that each year, approximately 303,000 newborns die. In Colombia, there is the Sistema Nacional de Vigilancia en Salud -SIVIGILA that develops the passive surveillance program for congenital defects of national application. Additionally, in Bogotá and Cali, there is an active surveillance program linked to the Latin American Collaborative Study of Congenital Malformations (ECLAMC-Estudio Colaborativo Latinoamericano de Malformaciones Congénitas). Within these programs, the identification of real or perceived unusual aggregations of congenital defects, ie clusters, must also be ensured. These clusters can be aggregations in a group of people in a particular geographic area for a defined period of time or a combination of these two. In Colombia, to date, a cluster of sirenomelia has been identified in the city of Cali, which arose from a concern generated in the community of health professionals (reactive research). However, there is no information about temporal clusters considering all congenital defects. A descriptive observational study was proposed, in which temporal clusters occurred between 2011 and 2018 were identified. Once identified, the analysis was carried out considering the development of the 3 phases following the identification: evaluation and research, management and communication. The analysis of the clusters may be able to start and complete their evaluation and thus evaluate the behavior of congenital defects in Colombia as an important event in public health that in the future generate an impact on the prevention of congenital defects

The prevalence of high-risk HPV types and factors determining infection in female colombian adolescents

This study reports six HR-HPV types' infection prevalence discriminated by species and multiple infection in unvaccinated Colombian female adolescents, as well as some factors modulating the risk of infection. HPV DNA for six high-risk viral types was identified in cervical samples taken from 2,134 12-19 year-old females using conventional generic and typespecific PCR. Binomial logistical regression analysis was used for modelling HR-HPV infection and multiple infection risk. The interaction between variables in a stepwise model was also included in such analysis. Viral DNA was detected in 48.97% of the females; 28.52% of them had multiple infections, HPV-16 being the most frequently occurring type (37.44%). Cytological abnormality prevalence was 15.61%. Being over 16 years-old (1.66: 1.01-2.71 95%CI), white ethnicity (4.40: 1.16-16.73 95%CI), having had 3 or more sexual partners (1.77: 1.11-2.81 95%CI) and prior sexually-transmitted infections (STI) (1.65: 1.17-2.32 95%CI) were associated with a greater risk of HPV infection. Having given birth was related to a higher risk of infection by A7 species and antecedent of abortion to less risk of coinfection. Where the females in this study came from also influenced the risk of infection by A7 species as female adolescents from the Andean region had a lower risk of infection (0.42: 0.18-0.99 95%CI). The presence of factors related to risky sexual behaviour in the study population indicated that public health services should pay special attention to female adolescents to modify the risk of infection by high-risk HPV types and decrease their impact on this age group. © 2016 Del Río-Ospina et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

The prevalence of high-risk HPV types and factors determining infection in female colombian adolescents

This study reports six HR-HPV types' infection prevalence discriminated by species and multiple infection in unvaccinated Colombian female adolescents, as well as some factors modulating the risk of infection. HPV DNA for six high-risk viral types was identified in cervical samples taken from 2,134 12-19 year-old females using conventional generic and typespecific PCR. Binomial logistical regression analysis was used for modelling HR-HPV infection and multiple infection risk. The interaction between variables in a stepwise model was also included in such analysis. Viral DNA was detected in 48.97% of the females; 28.52% of them had multiple infections, HPV-16 being the most frequently occurring type (37.44%). Cytological abnormality prevalence was 15.61%. Being over 16 years-old (1.66: 1.01-2.71 95%CI), white ethnicity (4.40: 1.16-16.73 95%CI), having had 3 or more sexual partners (1.77: 1.11-2.81 95%CI) and prior sexually-transmitted infections (STI) (1.65: 1.17-2.32 95%CI) were associated with a greater risk of HPV infection. Having given birth was related to a higher risk of infection by A7 species and antecedent of abortion to less risk of coinfection. Where the females in this study came from also influenced the risk of infection by A7 species as female adolescents from the Andean region had a lower risk of infection (0.42: 0.18-0.99 95%CI). The presence of factors related to risky sexual behaviour in the study population indicated that public health services should pay special attention to female adolescents to modify the risk of infection by high-risk HPV types and decrease their impact on this age group. © 2016 Del Río-Ospina et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

The prevalence of high-risk HPV types and factors determining infection in female colombian adolescents

This study reports six HR-HPV types' infection prevalence discriminated by species and multiple infection in unvaccinated Colombian female adolescents, as well as some factors modulating the risk of infection. HPV DNA for six high-risk viral types was identified in cervical samples taken from 2,134 12-19 year-old females using conventional generic and typespecific PCR. Binomial logistical regression analysis was used for modelling HR-HPV infection and multiple infection risk. The interaction between variables in a stepwise model was also included in such analysis. Viral DNA was detected in 48.97% of the females; 28.52% of them had multiple infections, HPV-16 being the most frequently occurring type (37.44%). Cytological abnormality prevalence was 15.61%. Being over 16 years-old (1.66: 1.01-2.71 95%CI), white ethnicity (4.40: 1.16-16.73 95%CI), having had 3 or more sexual partners (1.77: 1.11-2.81 95%CI) and prior sexually-transmitted infections (STI) (1.65: 1.17-2.32 95%CI) were associated with a greater risk of HPV infection. Having given birth was related to a higher risk of infection by A7 species and antecedent of abortion to less risk of coinfection. Where the females in this study came from also influenced the risk of infection by A7 species as female adolescents from the Andean region had a lower risk of infection (0.42: 0.18-0.99 95%CI). The presence of factors related to risky sexual behaviour in the study population indicated that public health services should pay special attention to female adolescents to modify the risk of infection by high-risk HPV types and decrease their impact on this age group. © 2016 Del Río-Ospina et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Identifying the HLA DRB1-DQB1 molecules and predicting epitopes associated with high-risk HPV infection clearance and redetection

Several determining factors are involved in HPV infection outcomes; human leukocyte antigen (HLA) polymorphisms have been described as related factors. This study has ascertained the effect of genetic variation on HLA-DRB1 and DQB1 genes on HPV-16/-18/-31/-33/-45 and -58 clearance and redetection in Colombian women. PCR and qPCR were used for viral identification and the Illumina MiSeq system was used for HLA-typing of cervical samples (n=276). Survival models were adjusted for identifying alleles/haplotypes related to HPV clearance/redetection; L1/L2 protein-epitope binding to MHC-II molecules was also predicted. Significant associations suggested effects favouring or hampering clearance/redetection events depending on the viral type involved in infection, e.g. just DRB1*12:01:01G favoured HPV-16 (coeff: 4.8) and HPV-45 clearance (coeff: 12.65) whilst HPV-18 (coeff: 2E-15), HPV-31 (coeff: 8E-17) and HPV-58 hindered elimination (coeff: 1E-14). An effect was only observed for some alelles when configured as haplotypes, e.g. DRB1*04:07:01G (having the greatest frequency in the target population) was associated with DQB1*02:01:1G or *03:02:03. Epitope prediction identified 23 clearance-related peptides and 29 were redetection-related; eight might have been related to HPV-16/-18 and -58 persistence and one to HPV-18 elimination. HLA allele/haplotype relationship with the course of HPV infection (clearance/redetection) depended on the infecting HPV type, in line with the specific viral epitopes displayed