Caracterización epidemiológica, clínica y virológica de los nuevos diagnósticos de infección por el VIH-1 (2004-2015): impacto en la respuesta al tratamiento antirretroviral

Programa Oficial de Doutoramento en Ciencias da Saúde. 5007V01[Resumen] La infección por el virus de la inmunodeficiencia humana (VIH) produce un progresivo deterioro del sistema inmunológico que conduce a la aparición de enfermedades definitorias del síndrome de inmunodeficiencia adquirida (SIDA) como consecuencia del descenso paulatino en los niveles de linfocitos T CD4+, principal diana del virus [Barré-Sinuossi et al. 1983; Popovic et al. 1983]. La introducción del tratamiento antirretroviral (TAR) de alta eficacia ha disminuido de manera significativa la morbimortalidad de los pacientes VIH+ convirtiendo a la infección por VIH en una patología crónica. La evolución de la infección en el momento actual y en países con acceso a tratamiento va a estar condicionada por diferentes factores: relacionados con el paciente (e.j. factores epidemiológicos, situación inmunológica, adherencia al tratamiento), con el virus (e.j. carga viral plasmática, presencia de mutaciones de resistencia) o con los fármacos antirretrovirales (e.j. eficacia, tolerabilidad). Por lo tanto, es importante conocer las características epidemiológicas, clínicas y virológicas en nuestra área sanitaria para establecer y optimizar las estrategias de diagnóstico y manejo clínico de los pacientes con infección por VIH. En la presente tesis se desarrollan tres estudios: - Estudio 1. Analizó las características epidemiológicas, clínicas e inmunovirológicas de los nuevos diagnósticos de infección por VIH en el área sanitaria de A Coruña durante el período 2004-2013. La principal vía de transmisión de la infección por VIH fue la sexual, con un aumento de la transmisión entre hombres que tienen sexo con hombres (HSH) en los últimos años. El diagnóstico tardío afecta a la mitad de las nuevas infecciones por VIH, y un tercio de ellas cumplen criterios definitorios de SIDA en el momento del diagnóstico; esta prevalencia ha permanecido estable durante el periodo de estudio. En cambio, la prevalencia de mutaciones de resistencia a los fármacos antirretrovirales ha disminuido significativamente (de un 10.2% a un 2.6%) en general y para cada una de las familias de fármacos antirretrovirales. - Estudio 2. Evaluó las características genéticas de las variantes de VIH circulantes en nuestra área sanitaria y comparó las características epidemiológicas, inmunovirológicas y la respuesta al TAR entre los dos subtipos genéticos más frecuentes en nuestra población, el subtipo B (65.6 %) y el subtipo F (25.8%). El subtipo F es el subtipo no-B más prevalente entre los nuevos diagnósticos de infección por VIH, a diferencia de lo observado en otras regiones de España o Europa y se transmite principalmente entre HSH. La tasa de supresión virológica fue significativamente menor en los pacientes infectados por el subtipo F del VIH en comparación con los pacientes infectados por el subtipo B (51.7% vs. 85.2%, respectivamente, a las 48 semanas de tratamiento). Se identificaron la infección por subtipo F y tener una carga viral del ARN-VIH > 100.000 copias/mL como factores predictores independientes de una peor respuesta al TAR. - Estudio 3. Evaluó la frecuencia y el impacto de la viremia plasmática de bajo nivel en la cohorte de nuevos diagnósticos de infección por VIH que habían alcanzado la supresión virológica con TAR. Aquellos pacientes con viremia persistente por debajo de los límites de cuantificación de los ensayos comerciales actualmente empleados (20 copias/mL), presentaron un mayor riesgo de fracaso virológico en el seguimiento. En resumen, los resultados obtenidos durante el desarrollo de esta tesis han permitido un conocimiento detallado de las características epidemiológicas, clínicas y virológicas de la infección por VIH en nuestra área sanitaria. Entre los principales hallazgos encontrados hay que destacar la alta tasa de diagnósticos tardíos (53.1%), la alta prevalencia del subtipo F (25.8%) y su peor respuesta al TAR en comparación con el subtipo B, y la relevancia de mantener una viremia plasmática por debajo de los límites de cuantificación y detección de los ensayos actuales (20 copias/mL) para optimizar el control de la infección en el paciente VIH+.[Resumo] A infección polo virus da inmunodeficiencia humana provoca un empeoramento progresivo do sistema inmunolóxico, que leva á aparición de enfermidades definitorias da síndrome de inmunodeficiencia adquirida (a sida) como consecuencia da lenta diminución dos niveis de linfocitos T CD4+, a principal diana do virus [Barré-Sinoussi et al. 1983; Popovic et al. 1983]. A introdución do TAR de alta eficacia diminuíu de xeito importante a morbilidade e a mortaldade dos pacientes VIH+ polo que a infección polo VIH se converteu nunha enfermidade crónica. A evolución da infección neste momento en países con acceso ao tratamento vai estar condicionada por diferentes factores ora relacionados co paciente (ex.: factores epidemiolóxicos, situación inmunolóxica, adherencia ao tratamento), ora co virus (ex.: carga viral plasmática, presenza de mutacións de resistencia) ou ora cos antirretrovirais (ex.: eficacia, tolerabilidade). Por tanto, cómpre coñecer as características epidemiolóxicas, clínicas e virolóxicas da infección polo VIH na nosa área sanitaria para establecer e optimizar as estratexias de diagnóstico e manexo clínico dos pacientes con infección polo VIH+. Nesta tese preséntanse tres estudos: - Estudo 1. Analízanse as características epidemiolóxicas, clínicas e inmuno-virolóxicas dos novos diagnósticos de infección polo VIH na área sanitaria da Coruña durante o período 2004-2013. A principal vía de transmisión da infección polo VIH foi a sexual, cun aumento da transmisión entre os homes que teñen sexo con outros homes nos últimos anos. O diagnóstico tardío abrangue a metade das novas infeccións polo VIH, e unha terceira parte delas teñen criterios definitorios de sida no momento do diagnóstico; esta prevalencia mantívose estable durante o período de estudo. Pola contra, a prevalencia das mutacións de resistencia ás drogas antirretrovirais reduciuse de xeito significativo (dende o 10.2% ao 2.6%) en xeral e para cada unha das familias de drogas antirretrovirais. - Estudo 2. Avalíanse as características xenéticas das variantes do VIH circulantes na nosa área sanitaria e compáranse as características epidemiolóxicas, inmunovirolóxicas e a resposta á terapia antirretroviral entre os dous subtipos xenéticos máis comúns na nosa poboación, o subtipo B (65.6%) e mais o subtipo F (25.8%). O subtipo F é o subtipo non-B máis prevalente entre os novos diagnósticos de infección polo VIH, a diferenza do observado noutras rexións de España ou Europa, e transmítese principalmente entre os homes que teñen sexo con outros homes. A taxa de supresión virolóxica foi significativamente menor nos enfermos infectados polo VIH e subtipo F en comparación cos pacientes con subtipo B (51.7% vs. 85.2%, respectivamente, ás 48 semanas de tratamento). Identificouse a infección polo subtipo F e unha carga viral do ARN-VIH > 100000 copias/mL como factores preditores independentes dunha peor resposta ao TAR. - Estudo 3. Avalíase a frecuencia e o impacto da viremia plasmática de baixo nivel na cohorte de persoas recentemente infectadas polo VIH que acadaran a supresión virolóxica con TAR. Aqueles pacientes con viremia persistente por baixo dos límites de cuantificación dos ensaios comerciais empregados (20 copias/mL), tiveron un maior risco de fallo virolóxico no seguimento. En resumo, os resultados obtidos durante o desenvolvemento desta tese permitiron un coñecemento preciso das características epidemiolóxicas, clínicas e virolóxicas da infección polo VIH na nosa área sanitaria. Entre os principais resultados atopados hai que salientar a alta taxa de diagnósticos tardíos (53.1%), a alta prevalencia do subtipo F (25.8%) e a súa peor resposta ao tratamento en comparación co subtipo B, e a importancia de manter a viremia plasmática por debaixo dos límites de cuantificación e detección dos ensaios actuais (20 copias/mL) para optimizar o control da infección no paciente VIH+.[Abstract] Human immunodeficiency virus (HIV) infection causes progressive deterioration of immune system leading to the presence of acquired immunodeficiency syndrome defining-diseases (AIDS) as consequence of a gradual decline of lymphocytes CD4+, main target of the virus [Barré-Sinoussi et al. 1983; Popovic et al. 1983]. High efficacy antiretroviral treatment (ART) introduction has significantly decreased the morbidity and mortality of HIV+ patients making HIV infection a chronic disease. Nowadays, the course of the infection in countries with access to treatment will be influenced by several factors: related to the patient (i.e. epidemiological factors, immunological status, adherence to treatment), to the virus (i.e. plasma viral load, presence of drug resistance mutations) or to antiretroviral therapy (i.e. efficacy, tolerability). Therefore, it is important to know epidemiological, clinical and immunovirological characteristics in our medical area to establish and optimize diagnostic strategies and the clinical management of patients with HIV infection. In this thesis, three studies have been developed: - Study 1. Epidemiological, clinical and immuno-virological characteristics of newly diagnosed HIV patients in the medical area of A Coruña during the period 2004-2013 were analysed. Main route of transmission of HIV infection was sexual route, with an increase between men who have sex with men in the last years. Late diagnosis affects half of newly-HIV infections and a third of these new infections met AIDS-defining criteria at diagnosis time; of note, these prevalences had been stable along the study period. However, the prevalence of drug resistance mutations have significantly reduced (from 10.2% to 2.6%), globally and for each of the antiretroviral-drug families. - Study 2. Epidemiological and immunovirological characteristics, as well as response to ART, between the two most common genetic subtypes in our population, subtype B (65.6%) and subtype F (25.8%) were compared. Subtype F is the most common non-B subtype between newly-HIV infections that it differs from the prevalence of this subtype observed in other Spanish or European regions. Subtype F is mainly transmitted between men who have sex with men. The rate of virological suppression was significantly lower in HIV-infected patients with subtype F compared to subtype B (51.7% vs. 85.2%, respectively, at 48 weeks of ART). Subtype F and viral load of HIV-RNA > 100.000 copies/mL were identified as independent predictor factors of a poor virological response. - Study 3. Presence and impact of low-level plasma viremia in the cohort of newly diagnosed HIV patients who had achieved virological suppression on ART were assessed. Those HIV patients with persistent viremia below limits of quantification (20 copies/mL) are associated with an increased risk for virological failure during follow-up. In summary, the results obtained during the developing of this thesis have allowed a detailed knowledge of epidemiological, clinical and immunovirological characteristics of HIV infection in our medical area. Among the major findings should be noted the high rate of late diagnosis (53.1%), high prevalence of subtype F (25.8%) and their worse response to treatment compared to subtype B, and the relevance of maintain plasma viremia below the limits of quantification and detection of current test (20 copies/mL) to optimize the control of infection in HIV-infected patients

Teleconsultation for the pharmaceutical care of HIV outpatients in receipt of home antiretrovirals delivery: clinical, economic, and patient-perceived quality analysis

Observational study[Abstract] Background/Introduction: Pharmacist teleconsultations, combined with home drug delivery or mail-order pharmacy (MOP), can help hospital outpatients with difficulties accessing treatment. The objectives of this study are to describe a teleconsultation protocol and to evaluate clinical, economic, and patient-perceived quality results. Materials and Methods: A cohort observational study was carried out for 3 years on HIV outpatients. Clinical variables were adherence, plasma HIV-RNA, and CD4+ levels. A pharmacoeconomic analysis was carried out through a cost-minimization study. Patient-perceived quality was assessed through a satisfaction survey. Simple random sampling was performed for 95% safety, accuracy ±1%, and losses ±20%. Results: The 38 participants (sample size) consisted of 82% male patients, aged 44.7 ± 8.4 years. There were 854 teleconsultations and 100% treatment adherence. All HIV outpatients kept virally suppressed (p = 1.00) and maintained a controlled immunological level (p = 0.87). The economic evaluation revealed 137 ± 23 € patient/year costs-saved and 18.5 ± 7.2 h/patient/year working time gained. Patient-perceived quality average score was >9.4 out of 10 in all items; the most valued factors were the saving of direct costs and reconciliation with work commitments (45%) and the least valued attributes were making the payment for the shipment and having to adjust to a telephone appointment (41%). Discussion/Conclusions: A teleconsultation protocol associated with home antiretrovirals delivery or MOP obtains a high degree of satisfaction from the HIV hospital outpatients receiving treatment, without repercussions on the therapeutic objectives and with the saving of important direct costs for the patient and indirect costs in relation to labor productivity

Late HIV Diagnosis but Earlier Antiretroviral Treatment Initiation in Northwest Spain: Impact of Current Treatment Guidelines.

BACKGROUND: Current HIV treatment guidelines recommend antiretroviral treatment (ART) initiation for all HIV-infected individuals regardless of CD4 count. This study evaluates the immunological and virological status and the clinical characteristics of patients who have started ART in the last 8 years in the Northwest of Spain. METHODS: All HIV-infected patients who have started ART between January 2009 and December 2016 at a reference hospital in the Northwest of Spain were included in this retrospective observational study. Epidemiological, clinical, and immunovirological features and antiretroviral drugs used for initiation were recorded. A statistical analysis was performed using SPSS version 19 software. Categorical and continuous variables were compared by the specific statistical tests, and a logistic regression model was used to identify time associated with Center for Disease Control and Prevention (CDC) categories change. RESULTS: A high proportion of HIV-infected patients (66.7%) had initiated ART with CD4 counts <350 cells/mm(3) in the last 8 years. From these, most of them (68.3%) had <350 CD4 counts at first contact with HIV specialist medical team, 12.2% had no indications for ART initiation in the last clinic visit before ART initiation according to the national guidelines at that moment, 11.0% were lost to follow-up because of lack of compliance with scheduled visits and 8.5% of patients refused treatment. A logistic regression model showed that a delay of one month since the first contact with HIV specialist medical team to ART initiation involves a risk of worsening in the CDC clinical category (odds ratio: 1.02 [95% confidence interval: 1.012-1.029]; P < .001). A trend towards an earlier start of ART was observed during 2015 and 2016, likely influenced by the last treatment guidelines recommendations. CONCLUSION: High proportion of HIV-infected patients (66.7%) had initiated ART with CD4 counts <350 cells/mm(3) in the last 8 years. The main reasons for this problem were analyzed and an important rate of late diagnosis was identified. However, a trend towards an earlier start of ART was observed during 2015 and 2016, likely influenced by the last treatment guidelines recommendations. These findings highlight the need to promote and facilitate HIV testing to reduce the late diagnosis as well as counseling on HIV prevention, treatment, and linkage care

Spatiotemporal Characteristics of the Largest HIV-1 CRF02_AG Outbreak in Spain: Evidence for Onward Transmissions

Background and Aim: The circulating recombinant form 02_AG (CRF02_AG) is the predominant clade among the human immunodeficiency virus type-1 (HIV-1) non-Bs with a prevalence of 5.97% (95% Confidence Interval-CI: 5.41–6.57%) across Spain. Our aim was to estimate the levels of regional clustering for CRF02_AG and the spatiotemporal characteristics of the largest CRF02_AG subepidemic in Spain.Methods: We studied 396 CRF02_AG sequences obtained from HIV-1 diagnosed patients during 2000–2014 from 10 autonomous communities of Spain. Phylogenetic analysis was performed on the 391 CRF02_AG sequences along with all globally sampled CRF02_AG sequences (N = 3,302) as references. Phylodynamic and phylogeographic analysis was performed to the largest CRF02_AG monophyletic cluster by a Bayesian method in BEAST v1.8.0 and by reconstructing ancestral states using the criterion of parsimony in Mesquite v3.4, respectively.Results: The HIV-1 CRF02_AG prevalence differed across Spanish autonomous communities we sampled from (p &lt; 0.001). Phylogenetic analysis revealed that 52.7% of the CRF02_AG sequences formed 56 monophyletic clusters, with a range of 2–79 sequences. The CRF02_AG regional dispersal differed across Spain (p = 0.003), as suggested by monophyletic clustering. For the largest monophyletic cluster (subepidemic) (N = 79), 49.4% of the clustered sequences originated from Madrid, while most sequences (51.9%) had been obtained from men having sex with men (MSM). Molecular clock analysis suggested that the origin (tMRCA) of the CRF02_AG subepidemic was in 2002 (median estimate; 95% Highest Posterior Density-HPD interval: 1999–2004). Additionally, we found significant clustering within the CRF02_AG subepidemic according to the ethnic origin.Conclusion: CRF02_AG has been introduced as a result of multiple introductions in Spain, following regional dispersal in several cases. We showed that CRF02_AG transmissions were mostly due to regional dispersal in Spain. The hot-spot for the largest CRF02_AG regional subepidemic in Spain was in Madrid associated with MSM transmission risk group. The existence of subepidemics suggest that several spillovers occurred from Madrid to other areas. CRF02_AG sequences from Hispanics were clustered in a separate subclade suggesting no linkage between the local and Hispanic subepidemics

Evolving understanding of cardiovascular, cerebrovascular and peripheral arterial disease in people living with HIV and role of novel biomarkers. A study of the Spanish CoRIS cohort, 2004-2015

OBJECTIVES: To analyze the incidence rates (IR) and spectrum of vascular events in people living with HIV (PLWH) in Spain from 2004 to 2015. Serial measurements of different plasma cardiovascular biomarkers were assessed in relation to disease development. METHODS: Longitudinal study in a nationwide contemporary multicenter cohort of PLWH. A nested case-control study was performed to evaluate the predictive value of cardiovascular biomarkers. Additive generalized and Cox mixed models were used for the analyses. RESULTS: 9,712 PLWH and 48,341 person-years of follow-up were analysed. During 2004-2015, 147 persons developed 154 vascular events; 80 (54.42%) coronary-related; 65 (44.22%) cerebrovascular-related, and 9 (6.12%) peripheral arterial disease. The 2004-2015 IR (95% confidence interval) of vascular events was 3.17 (2.69-3.71) x1,000 person-years; 1.64 (1.30-2.05) for coronary events; 1.34 (1.03-1.70) for cerebrovascular events; and 0.19 (0.09-0.35) for peripheral arterial disease (p65 years) and vascular event (1.81 [1.12-2.94]) were associated with total mortality. Adjusted levels of intercellular-adhesion-molecule (sICAM), pro-b-type-natriuretic-peptide (pro-BNP) and marginally sCD14, were higher among patients who subsequently developed vascular events. CONCLUSION: Vascular events in PLWH do preferentially occur in the older age-strata, they are associated with increased mortality and, compared to the general population, the excess risk occurs at younger ages. Peripheral arterial disease is unusual. Vascular events are preceded by increased levels of sICAM, pro-BNP and, marginally, sCD14

¿Sirve la escala ABCD2 del AIT para predecir y prevenir Ictus?

ABSTRACT Background and objectives: Independent validations of the ABCD2 score used to predict stroke development have reported conflicting results, yet expert opinion as to proper diagnostic approach and best treatment differs widely. A model predictive power can be modified by the concomitant use of effective diagnostic and pharmacological treatments. We aimed to determine the predictive power of the ABCD2 score while simultaneously providing patients with current urgent recommended treatments and recording their early and long term health outcomes. Methods: Data was retrospectively collected from all the patients presenting with a TIA for a whole year and were followed for another whole year. Physicians completed data forms with the ABCD2 score when patients arrived at the emergency department (ED).We calculated sensitivity, specificity for predicting stroke at 7 and 30 days after visiting the ED using the high-risk cutpoint of an ABCD2 score &#8805; 4.Univariate Cox proportional hazards regression modelling was performed for ABCD2 score to estimate the hazard ratios relative to the low-risk category and to assess the effect of the individual components of the ABCD2 score and other potential risk factors to predict stroke development. Results: We enrolled 172 patients (mean age 71 yr, 51 % women) with a new incident diagnosis of TIA. The mean (SD) ABCD2 score was 4.2 (1.4). There were 12 new TIA, 21 non fatal strokes and 3 fatal strokes. Intrahospital mortality was 1.7% and 12% during the 1 year follow up. An ABCD2 score of &#8805; 4 had a sensitivity of 88% and 82 % for a stroke at 7 and 30 days respectively, with a poor specificity of 30%. Negative predictive value at 7 days was 98%. ABCD2 score &#8805; 4 had no significant predictive value for stroke within 7 days (hazard ratio [HR], 3.49; 95%CI, 0.42 to 27.93) and 30 days (HR, 1.97; 95%CI, 0.43 to 9.13) of the event. Only diabetes predicted an increased likelihood of stroke over the first week (HR, 5.47; 95%IC 1.43 to 20.95) and over the first month (HR, 3.60; 95%IC 1.08 to 12). Conclusions: The accuracy of the ABCD2 score fails to help us make treatment decisions except for its negative predictive value (98%). It was only being diabetic that was significantly related to the probability of stroke development. TIA probably justifies early accurate identification of the underlying TIA etiology for nearly all presentations. We recommend adding a systematic Brain CT, carotid ultrasound and ECG within 24 hours while concomitantly starting urgent treatment. RESUMEN Introducción y objetivo: Las validaciones de la escala ABCD2 para predecir un Ictus después de un AIT han sido contradictorias y la opinión de los expertos sobre cual es mejor método de diagnostico y tratamiento son muy variables. Ademas los el poder predictivo de las escalas puede variar mucho si al mismo tiempo se usan procesos diagnósticos y terapéuticos efectivos en variar el curso de la enfermedad. Nuestro objetivo es evaluar el poder predictivo real de la escala ABCD2 cuando al mismo tiempo a los pacientes se les somete a métodos diagnósticos adecuados y tratamientos efectivos urgentes. Metodología: Se recogieron de manera retrospectiva todos los pacientes que acudieron a un hospital terciario durante un año y fueron seguidos prospectivamente durante 1 año. Los datos de la escala ABCD2 fueron los que presentaban al momento de llegada a urgencias. Calculamos cual era la sensibilidad, especificidad y poder discriminatorio de una puntuación &#8805; 4 para predecir la aparición de un Ictus a los 7 y 30 días. Se aplicó un modelo de regresión univariante de Cox a la escala ABCD2 para estimar el cociente de riesgo correspondiente a la categoría de bajo riesgo y valorar la capacidad predictiva de ictus de sus componentes individuales y de otros potenciales predictores de riesgo. Resultados: Incluimos 172 pacientes ( edad media 71 años, 51% mujeres) con un nuevo diagnostico de AIT. La puntuación media de la escala ABCD2 fue de 4.2 ± 1.4. Se produjeron 12 nuevos AIT, 21 Ictus no fatales y 3 ictus fatales durante el seguimiento. La mortalidad intrahospitalaria fue del 1.7% y la total durante el seguimiento de 1 año del 12 %. Una puntuación en la escala de ABCD2 de &#8805; 4 tenia una sensibilidad del 88% y del 82% para predecir un ictus a los 7 y 30 días respectivamente, con una pobre especificidad del 30%.El valor predictivo negativo a 7 dias fue del 98%. Una puntuación ABCD2 &#8805; 4 no tuvo valor predictivo significativo de ictus a los 7 días (hazard ratio [HR], 3.49; 95%CI, 0.42 to 27.93) ni a 30 días (HR, 1.97; 95%CI, 0.43 to 9.13). Como componente individual, solo la diabetes predijo la probabilidad de desarrollar un ictus en la primera semana (HR, 5.47; 95%IC 1.43 to 20.95) y durante el primer mes (HR, 3.60; 95%IC 1.08 to 12). Conclusiones: El poder discriminativo de la escala ABCD2 no ayuda a tomar decisiones de tratamiento salvo por su valor predictivo negativo del 98%. Solo la variable diabetes de la escala se asocio con una probabilidad relevante de tener un ictus.Probablemente cualquier tipo de presentación de AIT justifica la búsqueda rápida de la etiologia subyacente. Consideramos que en el AIT, independientemente de la escala ABCD2 , se debe realizar en menos de 24 horas un TAC cerebral, ECG, e imagen de carótida, mientras al mismo tiempo se inicia tratamiento preventivo urgente