Factores predictivos de respuesta al tratamiento del VHC en pacientes coinfectados VIH

La infección por el virus de la hepatitis C (VHC) es un problema de salud mundial que afecta a más de 170 millones de personas [1]. De ellos, aproximadamente el 20% está coinfectado por el virus de la inmunodeficiencia humana (VIH) [2]. El tratamiento estándar frente al VHC ha cambiado de forma drástica durante los últimos 15 años. En primer lugar la incorporación de ribavirina a la terapia con interferón en monoterapia, posteriormente la sustitución del interferon estándar por interferón pegylado, y por último la incorporación de los nuevos inhibidores de la proteasa NS3 (IPs) para los pacientes infectados por genotipo 1 del VHC, han conseguido que el porcentaje de pacientes que alcanzan respuesta viral sostenida (RVS), gold estándar de curación, pase de un dramático 5% a un esperanzador 70% [3]. No obstante, tanto la terapia con INF-PEG/RBV como la incorporación de los nuevos IPs no están exentas de efectos adversos, teniendo incluso en un porcentaje no despreciable de pacientes en los que es necesario suprimir la terapia [3]. Por ello, en estos pacientes es importante individualizar el tratamiento de la hepatitis C en función de la predicción de tolerancia, el beneficio clínico esperado, de las futuras opciones terapéuticas, pero sobre todo en función de la predicción de la respuesta. En este sentido, en los últimos años se han descrito múltiples factores, tanto medidos en el momento basal del tratamiento como determinados durante la terapia, pronósticos de respuesta al tratamiento que pueden permitir la personalización del tratamiento frente al VHC [4-6]. El objetivo del presente proyecto de tesis doctoral es el estudio de factores predictivos de respuesta al tratamiento del VHC en pacientes coinfectados por el VIH. 2.Contenido de la investigación El presente proyecto de tesis engloba 7 trabajos científicos publicados en revistas de enfermedades infecciosas. En estos trabajos se ha estudiado la influencia en la respuesta al tratamiento frente al VHC con IFN-Peg/RBV de variables del paciente (genéticas y clínicas), del VHC (genotipo y subtipo viral), del VIH (tratamiento antirretroviral), así como del propio tratamiento (dosis de tratamiento, cinética viral durante el tratamiento) frente al VHC en la respuesta al mismo en pacientes co-infectados por el VIH. Los trabajos presentados, de los que el doctorando es el primer firmante, son: Twelve week post-treatment follow-up predicts sustained virological response to pegylated interferon and ribavirin therapy in HIV/hepatitis C virus co-infected patients. Journal of Antimicrobial Chemotherapy. 2011, 66, 1351-3. Association between the IL28B genotype and hepatitis C viral kinetics in the early days of treatment with pegylated interferon plus ribavirin in HIV/HCV co-infected patients with genotypes 1 or 4. Journal of Antimicrobial Chemotherapy. 2012, 67. 202-5. LDLr Genotype Modifies the Impact of IL28B on HCV Viral Kinetics after the First Weeks of Treatment with PEG-IFN/RBV in HIV/HCV Patients. AIDS. 2012. 26. 1009-15. Atazanavir-Based Therapy Is Associated with Higher Hepatitis C Viral Load in HIV Type 1-Infected Subjects with Untreated Hepatitis C. AIDS Res Hum Retroviruses. 2013; 29: 223-25. Baseline risk factors for relapse in HIV/HCV co-infected patients treated with PEG-IFN/RBV. Infection. 2013; 41: 21-6. Differences in HCV Viral Decline between Low and Standard-Dose Pegylated-Interferon-alpha-2a with Ribavirin in HIV/HCV Genotype 3 Patients. PLoS ONE. 2012;7(11):e48959. The IL28B effect on HCV kinetics of among HIV patients after the first weeks of Peg-IFN/RBV treatment varies according to HCV-1 subtype. AIDS. 2013 [In press]. 3.Conclusión Existen factores predictores de respuesta al tratamiento del VHC con IFN-Peg/RBV en pacientes co-infectados por el VIH valorables tanto en el momento basal del tratamiento como durante el mismo. Los resultados de estos estudios permitirían optimizar el tratamiento del VHC en pacientes coinfectados por el VIH en base a la predcción de la respuesta al mismo

Using machine learning methods to determine a typology of patients with HIV-HCV infection to be treated with antivirals

Several European countries have established criteria for prioritising initiation of treatment in patients infected with the hepatitis C virus (HCV) by grouping patients according to clinical characteristics. Based on neural network techniques, our objective was to identify those factors for HIV/HCV co-infected patients (to which clinicians have given careful consideration before treatment uptake) that have not being included among the prioritisation criteria. This study was based on the Spanish HERACLES cohort (NCT02511496) (April-September 2015, 2940 patients) and involved application of different neural network models with different basis functions (product-unit, sigmoid unit and radial basis function neural networks) for automatic classification of patients for treatment. An evolutionary algorithm was used to determine the architecture and estimate the coefficients of the model. This machine learning methodology found that radial basis neural networks provided a very simple model in terms of the number of patient characteristics to be considered by the classifier (in this case, six), returning a good overall classification accuracy of 0.767 and a minimum sensitivity (for the classification of the minority class, untreated patients) of 0.550. Finally, the area under the ROC curve was 0.802, which proved to be exceptional. The parsimony of the model makes it especially attractive, using just eight connections. The independent variable "recent PWID" is compulsory due to its importance. The simplicity of the model means that it is possible to analyse the relationship between patient characteristics and the probability of belonging to the treated group

Epidemiological survey and risk factors associated with hepatitis E virus in small ruminants in southern Spain

Autochthonous cases of hepatitis E (HE) associated with zoonotic genotypes HEV-3 and HEV-4 have significantly increased in industrialized countries over the last decade. Suidae are generally recognized as the main reservoirs of these genotypes. Susceptibility to HE virus (HEV) infection and zoonotic potential have also been confirmed in other species, including sheep and goat. However, the information about their role in the epidemiology of HEV remains very scarce. The objective of this study was to assess the prevalence, spatial distribution and risk factors associated with HEV exposure in sheep and goats in southern Spain, the country with the highest census of small domestic ruminants in the European Union. Blood samples from 240 sheep and 240 goats were collected between 2015 and 2017. Sera were analysed in parallel using a commercial double-antigen ELISA and real-time PCR. A total of 38 (7.9%; 95%CI: 5.5–10.3) out of 480 sampled animals showed anti-HEV antibodies. By species, the seroprevalences found in sheep and goats were 2.1% (5/240; 95%CI: 0.3–3.9) and 13.8% (33/240; 95%CI: 9.4–18.1) respectively. Anti-HEV antibodies were found on 19 (59.4%; 95%CI: 42.4–76.4) of the 32 sampled farms. The GEE model showed that species (goat) and number of small ruminants in the farm (≤348 animals and ≥538 animals) were risk factors potentially associated with HEV exposure in small ruminants in the study area. HEV RNA was not detected in any of the 480 (0.0%; 95%CI: 0.0–0.8) tested animals. Our results confirm that sheep and goats are naturally, but not equally exposed to HEV and indicate the widespread spatial distribution of HEV among small ruminant populations in southern Spain. Further studies are required to elucidate the role of sheep and goat in the epidemiology of HEV and their potential implications for public health

From abundance to gastronomic delights: An ethnography of the new opportunities for attracting tourism in Las Hurdes (Cáceres)

Las Hurdes ha sido el símbolo en España durante mucho tiempo del hambre más atroz y la pobreza más extrema. Diferentes estudios han evidenciado cómo aquella dramática existencia sigue condicionando algunos hábitos hoy en día. A partir de un estudio cualitativo de naturaleza etnográfica, nos hemos aproximado a la manera en que ese pasado sigue influyendo en los usos y costumbres alimentarias y gastronómicas. Un material empírico que nos ha permitido delimitar diferentes categorías como abundancia, tradición, sostenibilidad y exquisitez que evidencian un importante giro en la restauración de la zona. Se abre de esta manera una nueva vía de atracción turística que bien podría ayudar a un desarrollo turístico que aún resulta insuficiente en la comarca. Se exhorta, en las conclusiones, a las administraciones públicas a apostar con firmeza por ello, superando las dificultadas tradicionales de colaboración entre el sector público y el privado tradicionalmente subrayadas.Las Hurdes has long been the symbol in Spain for the most atrocious hunger and extreme poverty. Different studies have shown how that dramatic association continues to condition many habits still in the present. Based on a qualitative ethnographic study, we have approached the way in which this past contin‐ ues influencing food and gastronomic habits and customs. This empirical material has allowed us to delimit different categories such as abundance, tradition, sustainability and exquisiteness that show an important change in the catering business in the area. This opens up a new avenue of tourist attractions that could well help tourism development, still largely insufficient in the region. In the conclusions, the public admin‐ istrations are urged to make a firm commitment to changing associations and to overcome the traditional difficulties of collaboration between public and private sectors

A genome-wide association study on liver stiffness changes during hepatitis c virus infection cure

Liver stiffness (LS) at sustained virological response (SVR) after direct-acting antivirals (DAA)-based therapy is a predictor of liver events in hepatitis C virus (HCV)-infected patients. The study aim was to identify genetic factors associated with LS changes from the moment of starting anti-HCV therapy to SVR. This prospective study included HCV-infected patients from the GEHEP 011 cohort who achieved SVR with DAA-based therapy, with LS pre-treatment ≥9.5 kPa and LS measurement available at SVR. Plink and Magma software were used to carry out genome-wide single-nucleotide polymorphism (SNP)-based and gene-based association analyses, respectively. The ShinyGO application was used for exploring enrichment in Gene Ontology (GO) categories for biological processes. Overall, 242 patients were included. Median (quartile 1, quartile 3) LS values at pre-treatment and at SVR were 16.8 (12, 28) kPa and 12.0 (8.5, 19.3) kPa, respectively. Thirty-five SNPs and three genes reached suggestive association with LS changes from the moment of starting anti HCV therapy to SVR. GO categories related to DNA packaging complex, DNA conformation change, chromosome organization and chromatin organization were significantly enriched. Our study reports possible genetic factors associated with LS changes during HCV-infection cure. In addition, our results suggest that processes related to DNA conformation are also involved in these changes

Seroreversion of IgG anti-HEV in HIV cirrhotic patients: A long-term multi-sampling longitudinal study

The aim of our study was to evaluate HEV antibody kinetics in HIV/HCV-coinfected patients with cirrhosis. A longitudinal retrospective study was designed. Patients were followed up every 6 months; anti-HEV IgG and IgM antibodies levels and HEV-RNA by qPCR were analysed. The prevalence and incidence of every HEV infection marker were calculated. The kinetics of anti-HEV IgG and IgM during the follow-up were evaluated. Seventy-five patients comprised the study population. The seroprevalence observed was 17.3%. None showed IgM antibodies or HEV-RNA at baseline. None showed detectable HEV viral load during the study period. After a median follow-up of 5.1 years, two of 62 seronegative patients (3.2%) seroconverted to IgG antibody. The incidence for IgM was 2.7%. Of the 13 patients with IgG seropositivity at baseline, five (38.5%) seroreverted. Meanwhile, of the two patients who exhibited IgM positivity during the study, one (50%) showed intermittent positivity. We found that HEV seropositivity is common in HIV/HCV-coinfected cirrhotic patients. A remarkable rate of IgG seroreversions and IgM intermittence was found, limiting the use of antibodies for the diagnosis of HEV infection in this population

Serological and molecular survey of hepatitis E virus in cats and dogs in Spain

Hepatitis E virus (HEV) is an emerging zoonotic pathogen that is currently recognized as one of themajor causes of acute human hepatitis worldwide. In Europe, the increasing number of hepatitis E cases is mainly associated with the consumption of animal food products or contact with infected animals. Dogs and cats have been suggested as a zoonotic source of HEV infection. The aim of this study was to assess Orthohepevirus circulation, including HEV-A, HEV-B and HEV-C species, in sympatric urban cats and dogs in southern Spain. Between 2017 and 2020, blood samples were collected from 144 stray cats and 152 dogs, both strays and pets. The presence of antibodies againstHEV were tested using a double-antigen sandwich ELISA and seropositive simples were further analysed bywestern blot.ART-PCR was performed to detect RNAof Orthohepevirus species (HEV-A,HEV-B andHEV-C).Atotal of 19 (6.4%; 95%CI: 3.6-9.2) of the 296 animals tested showed anti-HEV antibodies by ELISA. Seropositivity was significantly higher in dogs (9.9%; 15/152; 95%CI: 5.1-14.6) than in cats (2.8%; 4/144; 95%CI: 0.1-5.5). Ten of the 18 ELISA-positive animals that could be further analysed by western blot, reacted against HEV-3 and/or HEV-C1 antigens, which suggest circulation of both genotypes in urban cats and dogs in the study area. However, HEV-A, HEV-B and HEV-C RNA were not detected in any of the tested sera. This is the first study to assess HEV circulation in both stray cats and dogs in Europe. Our results provide evidence of HEV exposure in sympatric urban cat and dog populations in southern Spain. Further studies are needed to determine the role of these species in the epidemiology of HEV

Impact of HIV infection on sustained virological response to treatment against hepatitis C virus with pegylated interferon plus ribavirin

[Abstract] It is commonly accepted that human immunodeficiency (HIV) coinfection negatively impacts on the rates of sustained virological response (SVR) to therapy with pegylated interferon plus ribavirin (PR). However, this hypothesis is derived from comparing different studies. The aim of this study was to determine the impact of HIV coinfection on SVR to PR in one single population. In a multicentric, prospective study conducted between 2000 and 2013, all previously naïve hepatitis C virus (HCV)-infected patients who started PR in five Spanish hospitals were analyzed. SVR was evaluated 24 weeks after the scheduled end of therapy. Of the 1046 patients included in this study, 413 (39 %) were coinfected with HIV. Three hundred and forty-one (54 %) HCV-monoinfected versus 174 (42 %) HIV/HCV-coinfected patients achieved SVR (p < 0.001). The corresponding figures for undetectable HCV RNA at treatment week 4 were 86/181 (47 %) versus 59/197 (30 %), p < 0.001. SVR was observed in 149 (69 %) HCV genotype 2/3-monoinfected subjects versus 91 (68 %) HIV/HCV genotype 2/3-coinfected subjects (p = 0.785). In the HCV genotype 1/4-infected population, 188 (46 %) monoinfected patients versus 82 (30 %) with HIV coinfection (p < 0.001) achieved SVR. In this subgroup, absence of HIV coinfection was independently associated with higher SVR [adjusted odds ratio (95 % confidence interval): 2.127 (1.135–3.988); p = 0.019] in a multivariate analysis adjusted for age, sex, baseline HCV RNA load, IL28B genotype, fibrosis stage, and type of pegylated interferon. HIV coinfection impacts on the rates of SVR to PR only in HCV genotype 1/4-infected patients, while it has no effect on SVR in the HCV genotype 2/3-infected subpopulation.Instituto de Salud Carlos III; ISCIII-RETIC RD06/006Instituto de Salud Carlos III; ISCIII-RETIC RD12/0017Andalucía. Junta; PI-0492/2012Andalucía. Junta; AC-0095-201

Monitoring of Schmallenberg virus in Spanish wild artiodactyls, 2006-2015

Schmallenberg disease is an emerging disease that affects domestic and wild ruminants in Europe. An epidemiological survey was carried out to assess exposure to Schmallenberg virus (SBV) in wild artiodactyls in Spain between 2006 and 2015. A total of 1751 sera from wild artiodactyls, including 1066 red deer, 304 fallow deer, 192 mouflon, 109 wild boar, 49 roe deer and 31 Spanish ibex were tested for antibodies against SBV by ELISA and confirmed by virus neutralization test. SBV was not detected between the 2006/2007 and the 2010/2011 hunting seasons. Overall seroprevalence (including samples collected between the 2011/2012 and 2014/2015 hunting seasons) was 14.6% (160/1099; 95%CI: 12.7-16.6). Mean SBV seroprevalence was 13.3±2.6% in red deer, 23.9±4.2% in fallow deer, 16.4±6.1% in mouflon and 2.8±3.1% in wild boar. No antibodies against SBV were found in roe deer or Spanish ibex. The presence of SBV RNA was confirmed in three of 255 (1.2%) spleen samples from wild ruminants analysed by rRT-PCR. In a multivariate mixed-effects logistic regression model, the main risk factors associated with SBV seroprevalence were: species (fallow deer, red deer and mouflon), age (adults) and interactions between hunting areas of more than 1000 hectares and hunting season (2012/2013, 2013/2014 and 2014/2015). The hypothesis of endemic circulation of SBV in the last few years is supported by the detection of SBV RNA in animals sampled in 2011 and 2015, as well as antibodies detected at low level in juveniles in 2012, 2013 and 2014. The results indicate that SBV circulated in wild ruminant populations in Spain during the same period when the virus was first reported in northern Europe, and at least five months before the first case was officially reported in livestock in Spain