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Anal squamous cell carcinoma is rare, in general, but considerably higher in HIV-infected men who have sex with men. There is no consensus on the screening of at-risk populations.This study aimed to determine the incidence rates of anal squamous cell carcinoma and the efficacy of a screening program.This is a cohort study (SeVIHanal/NCT03713229).This study was conducted at an HIV outpatient clinic in Seville, Spain.From 2004 to 2017, all patients with at least 1 follow-up visit were analyzed (follow-up group), including a subgroup of men who have sex with men who participated in a specialized program for screening and treating anal neoplasia (SCAN group) from 2011 onward.The primary outcome measure was the incidence rate of anal squamous cell carcinoma.Of the 3878 people living with HIV included in the follow-up group, 897 were transferred to the SCAN group; 1584 (41%) were men who have sex with men. Total follow-up was 29,228 person-years with an overall incidence rate for anal squamous cell carcinoma of 68.4/100,000 person-years (95% CI, 46.7-97.4). The changes in the incidence rate/100,000 person-years (95% CI) over time was 20.7 (3.40-80.5) for 2004 to 2006, 37.3 (13.4-87.3) for 2007 to 2010, and 97.8 (63.8-144.9) for 2011 to 2017 (p0.001). The strongest impact on the incidence of anal squamous cell carcinoma was made by the lack of immune restoration (adjusted incidence rate ratio (95% CI): 6.59 (4.24-10); p0.001), the Centers for Disease Control and Prevention category C (adjusted incidence rate ratio (95% CI): 7.49 (5.69-9.85); p0.001), and non-men who have sex with men (adjusted incidence rate ratio (95% CI): 0.07 (0.05-0.10); p0.001) in a Poisson analysis. From 2010 to 2017, incidence rates (95% CI) of anal squamous cell carcinoma within the SCAN group and the men who have sex with men of the follow-up group were 95.7 (39.6-202) and 201 (101-386)/100,000 person-years (adjusted incidence rate ratio (95% CI): 0.30 (0.23-0.39); p0.001). The incidence rate ratio (95% CI) including non-men who have sex with men in the follow-up group was 0.87 (0.69-1.11); p = 0.269.Adherence to the visits could not be quantified.Incidence rates of anal squamous cell carcinoma in people living with HIV increased significantly from 2004 to 2017, especially in men who have sex with men who were not being screened. Participation in the SCAN program significantly reduced the incidence of anal squamous cell carcinoma in men who have sex with men, in whom focus should be placed, especially on those presenting with Centers for Disease Control and Prevention category C and advanced immune suppression. See Video Abstract at http://links.lww.com/DCR/B734.ANTECEDENTES:El carcinoma anal a células escamosas es generalmente raro, pero considerablemente más alto en hombres infectados por el VIH que tienen relaciones sexuales con hombres. No hay consenso sobre el cribado de poblaciones en riesgo.OBJETIVO:Este estudio tuvo como objetivo determinar las tasas de incidencia del carcinoma anal a células escamosas y la eficacia de un programa de detección.DISEÑO:Estudio de cohorte (SeVIHanal / NCT03713229).AJUSTE:Clínica ambulatoria de VIH en Sevilla, España.PACIENTES:De 2004 a 2017, se analizaron todos los pacientes con al menos una visita de seguimiento (grupo F / U), incluido un subgrupo de hombres que tenían relaciones sexuales con hombres que participaron en un programa especializado de cribado y tratamiento de neoplasias anales (SCAN-group) a partir de 2011.PRINCIPALES MEDIDAS DE RESULTADO:Tasas de incidencia del carcinoma anal a células escamosas.RESULTADOS:De las 3878 personas que viven con el VIH incluidas en el grupo F / U, 897 fueron transferidas al grupo SCAN, 1584 (41%) eran hombres que tenían relaciones sexuales con hombres. El seguimiento total fue de 29228 personas-año con una tasa de incidencia general de carcinoma anal a células escamosas de 68,4 / 100000 personas-año [intervalo de confianza del 95%: 46,7-97,4]. El cambio en las tasas de incidencia / 100000 personas-año (intervalo de confianza del 95%) a lo largo del tiempo fue 20,7 (3,40-80,5) para 2004-2006, 37,3 (13,4-87,3) para 2007-2010 y 97,8 (63,8-144,9) para 2011-2017, p0,001. El impacto más fuerte en la incidencia del carcinoma a células escamosas anal fue la falta de restauración inmunológica [índice de tasa de incidencia ajustado (intervalo de confianza del 95%): 6,59 (4,24-10); p0,001], categoría C de los Centros de Control de Enfermedades [índice de tasa de incidencia ajustado (intervalo de confianza del 95%): 7,49 (5,69-9,85); p0,001] y no hombres que tenían relaciones sexuales con hombres [razón de tasa de incidencia ajustada (intervalo de confianza del 95%): 0,07 (0,05-0,10); p0,001] en el análisis de Poisson. Desde 2010-2017, las tasas de incidencia (intervalo de confianza del 95%) de carcinoma anal a células escamosas dentro del grupo SCAN y los hombres que tienen relaciones sexuales con hombres del grupo F / U fueron 95,7 (39,6-202) y 201 (101- 386) / 100000 personas-año [razón de tasa de incidencia ajustada (intervalo de confianza del 95%): 0,30 (0,23-0,39); p0,001]. La razón de la tasa de incidencia (intervalo de confianza del 95%), incluidos los no hombres que tenían relaciones sexuales con hombres en F / U, fue de 0,87 [0,69-1,11); p = 0,269].LIMITACIONES:No se pudo cuantificar la adherencia a las visitas.CONCLUSIÓNES:La tasa de incidencia del carcinoma anal a células escamosas en personas que viven con el VIH aumentó significativamente de 2004 a 2017, especialmente en hombres que tenían relaciones sexuales con hombres que no se someten a pruebas de detección. La participación en el programa SCAN redujo significativamente la incidencia de carcinoma anal a células escamosas en hombres que tenían relaciones sexuales con hombres, en quienes se debe prestar una especial atención, sobre todo en aquellos que se presentan en la categoría C de los Centros de Control de Enfermedades con inmunodeficiencia avanzada. Consulte Video Resumen en http://links.lww.com/DCR/B734.

Plasmacytoid dendritic cells (pDCs) sense microbial products through TLR-7 and -9 and translate this sensing in Interferon-α (IFN-α) production and T-cell polarization. The understanding of the mechanisms involved in pDCs stimulation may contribute to immunotherapeutic strategies aiming to decrease HIV-1 reservoir. Here, we characterize the immunomodulatory effects of TLR agonist stimulations through a pDC/T-cell coculture in different HIV-1 disease progression phenotypes and healthy donors (HD). pDCs were previously stimulated with AT-2-HIV-1, CpGA, CpGC and GS9620. After coculture with autologous CD4 or CD8 T-cells we observed an increase of pDCs activation markers levels, interferon related genes, HIV-1 restriction factors and cytokines levels. This pDCs coordinate activation was prominent with CpGC and GS9620 and induced an increase of HIV-specific T-cell response. These results shed light on the mechanisms associated with TLR-specific pDCs stimulation associated with T cell polarization for eliciting antiviral response which is essential for HIV eradication strategies.

Plasmacytoid dendritic cells (pDCs) sense viral and bacterial products through Toll-like receptor (TLR)-7 and -9 and translate this sensing in Interferon-α (IFN-α) production and T cell polarization. These cells are considered a link between innate and adaptive immunity, inducing and maintaining antigen-specific T cell responses and contributing to the control and eventually to the chronic immune activation and disease progression in HIV-1 infection scenario. The understanding of the mechanisms involved in pDCs stimulation may contribute to immunotherapeutic strategies aiming to decrease HIV-1 reservoir. The objective of the present study was to characterize the immunomodulatory effects of TLR agonist stimulations through a pDC/T cell coculture in different HIV-1 disease progression phenotypes and healthy donors (HD). pDCs were previously stimulated with AT-2-HIV-1, CpGA, CpGC and GS9620. After coculture with autologous CD4 or CD8 T cells we observed an increase of pDCs activation markers levels, interferon related genes, HIV-1 restriction factors and cytokines levels. This pDCs coordinate activation was prominent with CpG-C and GS9620 and induced an increase of HIV-specific T cell response. This pDCs dependent HIV-1 specific T-cell response was associated with the upregulation of HIV-1 restriction factors and IFN-α production. Interestingly, pDCs activation in people on ART was similar to that found in people that spontaneously control the virus. These results shed light on the mechanisms associated with TLR-specific pDCs stimulation associated with T cell polarization for eliciting antiviral response which is essential for HIV eradication strategies.

GEHEP-004 Study Group: María Dolores Ocete, Miguel Ángel Simón, Pilar Rincón, Sergi Reus, Alberto De la Iglesia, Isabel García-Arata, Miguel Jiménez, Fernando Jiménez, José Hernández-Quero, Carlos Galera, Mohamed Omar Balghata, Joaquín Primo, Mar Masiá, Nuria Espinosa, Marcial Delgado, Miguel Ángel von-Wichmann, Antonio Collado, Jesús Santos, Carlos Mínguez, Felícitas Díaz-Flores, Elisa Fernández, Enrique Bernal, José De Juan, José Joaquín Antón, Mónica Vélez, Antonio Aguilera, Daniel Navarro, Juan Ignacio Arenas, Clotilde Fernández, María Dolores Espinosa, María José Ríos, Roberto Alonso, Carmen Hidalgo, Rosario Hernández, María Jesús Téllez, Francisco Javier Rodríguez, Pedro Antequera, Cristina Delgado, Patricia Martín, Javier Crespo, Berta Becerril, Óscar Pérez, Antonio García-Herola, José Montero, Carolina Freyre, Concepción Grau., [Background & Aims] Most hepatitis C virus (HCV)-infected patients failing NS5A inhibitors develop resistance-associated substitutions (RASs). Here we report the use of resistance-guided retreatment of patients who failed prior NS5A inhibitor-containing regimens in the GEHEP-004 cohort. This is the largest direct-acting antiviral (DAA)-resistance cohort study conducted in Spain. We aim to provide indications on how to use resistance information in settings where sofosbuvir/velpatasvir/voxilaprevir may not be available., [Methods] GEHEP-004 is a prospective multicenter cohort enrolling HCV-infected patients treated with interferon (IFN)-free DAA regimens. Prior to retreatment, population-based sequencing of HCV NS3, NS5A and NS5B genes was performed. After receiving a comprehensive resistance interpretation report, the retreatment regimen was chosen and the sustained virological response (SVR) at 12 weeks after treatment completion (SVR12) was recorded., [Results] A total of 342 patients experiencing virological failure after treatment with sofosbuvir/ledipasvir±ribavirin (54%), sofosbuvir/daclatasvir±ribavirin (23%), or paritaprevir-ritonavir/ombitasvir±dasabuvir±ribavirin (20%) were studied. After a resistance report, 186 patients were retreated. An SVR12 was achieved for 88.1% of the patients who failed after sofosbuvir/ledipasvir±ribavirin, 83.3% of the patients who failed after sofosbuvir/daclatasvir±ribavirin, 93.7% of the patients who failed after paritaprevir-ritonavir+ombitasvir±dasabuvir±ribavirin., [Conclusions] In our study, we show how resistance-guided retreatment in conjunction with an interpreted report allows patients to achieve SVR rates close to 90%. We hypothesize that SVR rates may even be improved if resistance data are discussed between experienced virologists and treating clinicians. We believe that our data may be relevant for countries where the access to new DAA combination regimens is limited., [Lay summary] Hepatitis C infection can be cured with currently available antiviral agents. Only a small proportion of patients experience treatment failure, however, in absolute numbers, a high number of patients may require retreatment. Highly effective combinations of antivirals are also available for retreatment. However, these antivirals might not be available in resource-limited settings. Herein, we show how, by analyzing the cause of resistance, retreatment efficacy with old drugs can get very close to the efficacy of new drug combinations., This work was supported in part by grants from Fondo de Investigación Sanitaria (www.isciii.es) (PI15/00713), Plan Nacional de I+D+I and Fondo Europeo de Desarrollo Regional-FEDER (www.redes/redes/inicio) (RD16/0025/0040), Fundación Progreso y Salud, Junta de Andalucia (http://www.juntadeandalucia.es/fundacionprogresoysalud/es) (PI-0411-2014), and GEHEP-SEIMC (GEHEP-004).

Introduction Standard therapy for HIV treatment has consisted of two nucleoside analogue reverse transcriptase inhibitors (NRTI) paired with a third agent. Use of two-drug regimens (2DR) has been considered for selected patients in part to avoid toxicities associated with the use of NRTIs. This study aimed to compare the real-world outcomes of integrase inhibitor (INSTI)-based three-drug regimens (3DR) versus 2DR of dolutegravir (DTG) + rilpivirine (RPV) or DTG + lamivudine (3TC). Methods All patients in the Spanish VACH cohort switching to INSTI-based 3DR or a 2DR consisting of DTG + RPV or DTG + 3TC between May 2, 2016 and May 15, 2019 were included. Kaplan-Meier curves and Cox proportional hazard models were used to assess time to/risk of discontinuation due to treatment failure (TF) (defined as virologic failure [VF], immunologic failure, or disease progression) and adverse events (AEs). Three secondary analyses were performed: (1) in restricting the analysis to patients who were virologically suppressed (HIV RNA < 50 copies/mL) at switch; (2) matched analysis (2:1, matched by age, sex, number of previous VFs, and line of regimen), and (3) using VF as the primary endpoint in all patients. Results Overall, 5047 3DR and 617 2DR patients were analyzed. Baseline characteristics differed between groups; 2DR patients were older, more treatment experienced, and more likely to be virologically suppressed at switch. Time to discontinuation due to TF was significantly shorter for 2DR (P = 0.002). The hazard ratio (HR) for discontinuation due to TF on 2DR vs 3DR was 2.33 (P = 0.003). No difference was observed for time to discontinuation (P = 0.908) or risk of discontinuation due to AEs (HR = 0.80; P = 0.488). Results were qualitatively similar in virologically suppressed patients, matched analysis, and for VF. Conclusion In the real world, the risks of discontinuation due to TF and VF were more than two times higher in patients switching to DTG-based 2DR than INSTI-based 3DR, with no difference in discontinuation due to AEs. Plain Language Summary People living with HIV (PLHIV) need lifelong treatment to prevent progression to AIDS. Standard HIV treatments use three different drugs in combination, but these can potentially cause unwanted side effects. Treatments using just two drugs have been developed. These aim to reduce side effects and treat HIV effectively. This study included 5664 participants in Spain who were split into two groups: 5047 participants switched from their old treatment to a three-drug regimen (3DR), and 617 participants switched to a two-drug regimen (2DR). The researchers measured how long it took for the participants to stop taking their treatment because it was not working, or it caused too many side effects. At the end of the study, more than 70% of participants in either group were still taking the same treatment. Of the 30% of participants who stopped treatment because it stopped working, those taking a 2DR stopped sooner than those taking a 3DR. This difference started to appear at about 18 months and got bigger until the study ended, which was 3 years after starting treatment. Participants taking a 2DR were twice as likely to stop treatment because it was not working than those taking a 3DR. There was no difference between the groups for how long it took for participants to stop their treatment because of side effects. These results show that for some PLHIV, the 2DR stopped working sooner than 3DR, without the benefit of fewer side effects.

Resumen Objetivo Determinar la proporcion de personas con infeccion por VIH o sida que se encontraban en seguimiento en la cohorte VACH en 2012 y que resultaron perdidas del mismo en 2013 y 2014, asi como establecer las caracteristicas sociodemograficas relacionadas con dicha perdida. Metodos Consideramos perdidos del seguimiento a los sujetos con menos de un registro de consulta por ano analizado. Construimos modelos de regresion logistica para la estimacion de las razones de ventajas (odds ratio [OR]) y sus intervalos de confianza del 95% (IC del 95%) de las variables relacionadas con la perdida de seguimiento. Resultados El porcentaje global de perdidas en seguimiento fue del 15,5% (IC del 95%: 14,9-16,1). Las variables asociadas con la perdida de seguimiento fueron no recibir tratamiento antirretroviral (TAR) (OR: 1,948; IC del 95: 1,651-2,298), ser inmigrante (OR: 1,746; IC del 95: 1,494-2,040), el consumo de farmacos por via intravenosa como mecanismo de transmision del VIH (OR: 1,498; IC del 95: 1,312-1,711), encontrarse en situacion de desempleo (OR: 1,331; IC del 95: 1,179-1,503), no tener pareja (OR: 1,948, IC del 95: 1,651-1,298), pertenecer a un estrato socioeconomico bajo (OR: 1,279; IC del 95: 1,143-1,431) y ser atendido en un hospital con menos de 1.000 pacientes en seguimiento (OR: 1,257; IC del 95%: 1,121-1,457), ademas de menor edad y menos tiempo de seguimiento en la cohorte. Conclusiones El 15,5% de los pacientes fueron perdidos del seguimiento en un periodo de 2 anos en la cohorte VACH. Ello se asocio a una serie de variables sociodemograficas y epidemiologicas, cuya identificacion puede ser util para disenar iniciativas focalizadas sobre las poblaciones mas susceptibles de abandonar los circuitos asistenciales y a orientar estrategias disenadas a la consecucion del objetivo 90-90-90.

Teràpia antiretroviral; Diagnòstic i gestió del VIH; Teràpia amb inhibidors de la proteasa Terapia antirretroviral; Diagnóstico y gestión del VIH; Terapia con inhibidores de la proteasa Antiretroviral therapy; HIV diagnosis and management; Protease inhibitor therapy Background Since 1996, the standard of care (SOC) therapy for HIV treatment has consisted of a backbone of two nucleoside analogue reverse transcriptase inhibitors (NRTI) paired with a third agent. Use of two-drug combinations (2DC) has been considered for selected patients to avoid toxicities associated with the use of NRTIs. This study aimed to compare the real-world outcomes of integrase strand transfer inhibitor (INSTI)-containing triple therapy (TT) to dolutegravir- (DTG) and/or boosted protease inhibitor (bPI)-based 2DC in a large Spanish cohort of HIV patients. Methods A retrospective analysis was performed using data from the VACH cohort, a prospective multicentre Spanish cohort of adult HIV patients. All treatment experienced patients initiating a TT of an INSTI combined with two NRTIs or a 2DC-containing DTG and/or a bPI between 01/01/2012 and 01/06/2017 were included. The unit of analysis was patient-regimens. The overall sample analysis was complemented with two sub-analyses. The first sub-analysis focused on patients treated with a backbone plus DTG compared to those treated with DTG+ one other antiretroviral. The second sub-analysis focused on patients with HIV RNA

REIPI-SEIMC COVID-19 group and COVID@HULP group., [Background] The clinical presentation of COVID-19 in patients admitted to hospital is heterogeneous. We aimed to determine whether clinical phenotypes of patients with COVID-19 can be derived from clinical data, to assess the reproducibility of these phenotypes and correlation with prognosis, and to derive and validate a simplified probabilistic model for phenotype assignment. Phenotype identification was not primarily intended as a predictive tool for mortality., [Methods] In this study, we used data from two cohorts: the COVID-19@Spain cohort, a retrospective cohort including 4035 consecutive adult patients admitted to 127 hospitals in Spain with COVID-19 between Feb 2 and March 17, 2020, and the COVID-19@HULP cohort, including 2226 consecutive adult patients admitted to a teaching hospital in Madrid between Feb 25 and April 19, 2020. The COVID-19@Spain cohort was divided into a derivation cohort, comprising 2667 randomly selected patients, and an internal validation cohort, comprising the remaining 1368 patients. The COVID-19@HULP cohort was used as an external validation cohort. A probabilistic model for phenotype assignment was derived in the derivation cohort using multinomial logistic regression and validated in the internal validation cohort. The model was also applied to the external validation cohort. 30-day mortality and other prognostic variables were assessed in the derived phenotypes and in the phenotypes assigned by the probabilistic model., [Findings] Three distinct phenotypes were derived in the derivation cohort (n=2667)—phenotype A (516 [19%] patients), phenotype B (1955 [73%]) and phenotype C (196 [7%])—and reproduced in the internal validation cohort (n=1368)—phenotype A (233 [17%] patients), phenotype B (1019 [74%]), and phenotype C (116 [8%]). Patients with phenotype A were younger, were less frequently male, had mild viral symptoms, and had normal inflammatory parameters. Patients with phenotype B included more patients with obesity, lymphocytopenia, and moderately elevated inflammatory parameters. Patients with phenotype C included older patients with more comorbidities and even higher inflammatory parameters than phenotype B. We developed a simplified probabilistic model (validated in the internal validation cohort) for phenotype assignment, including 16 variables. In the derivation cohort, 30-day mortality rates were 2·5% (95% CI 1·4–4·3) for patients with phenotype A, 30·5% (28·5–32·6) for patients with phenotype B, and 60·7% (53·7–67·2) for patients with phenotype C (log-rank test p, [Interpretation] Patients admitted to hospital with COVID-19 can be classified into three phenotypes that correlate with mortality. We developed and validated a simplified tool for the probabilistic assignment of patients into phenotypes. These results might help to better classify patients for clinical management, but the pathophysiological mechanisms of the phenotypes must be investigated., [Funding] Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation, and Fundación SEIMC/GeSIDA., Funding: Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation, and Fundación SEIMC/GeSIDA.

The activation phenotypes and functional changes in monocyte subsets during hepatitis C virus (HCV) elimination in HIV/HCV-coinfected patients were evaluated. Twenty-two HIV/HCV-coinfected patients on suppressive combination antiretroviral treatment (cART) achieving HCV elimination after direct-acting antiviral (DAA) therapy and 10 HIV-monoinfected patients were included. The activation phenotype (10 markers) and polyfunctionality (intracellular interleukin-1α [IL-1α], IL-1β, IL-6, IL-8, tumor necrosis factor alpha [TNF-α], and IL-10 production) in three monocyte subsets (classical, intermediate, and nonclassical) were evaluated by flow cytometry before and at the end of treatment. Cell-associated HIV DNA levels were assayed by droplet digital PCR. After HCV clearance, there was a significant increase in classical monocyte and decreases in intermediate and nonclassical monocyte levels. The levels of the activation markers CD49d, CD40, and CX3CR1 were decreased after treatment in the monocyte subsets, reaching the levels in HIV-monoinfected patients. After lipopolysaccharide (LPS) stimulation, although polyfunctionality significantly decreased in intermediate and nonclassical monocytes, some combinations, such as the IL-1α− (IL-1α-negative) IL-1β− IL-6+ (IL-6-producing) IL-8− TNF-α− IL-10− combination, were remarkably increased at the end of treatment compared to the control group. Cell-associated HIV DNA levels correlated with activation markers before but not after treatment. HCV clearance after DAA treatment in patients on cART exerts an anti-inflammatory profile on monocyte subsets, activation phenotypes, and polyfunctionality. However, there is not a complete normalization compared with HIV-monoinfected patients., This work was supported by the Instituto de Salud Carlos III (research contracts CPII014/00025 to E.R.-M., CP19/00159 to A.G.-V., FI17/00186 to M.R.J.-L., and FI14/00431 to L.T.-D. and research projects PI16/00684 and PI19/01127 to E.R.-M.) and the Red Temática de Investigación Cooperativa en SIDA (RD16/0025/0020 and RD16/0025/0019), which is included in the Acción Estratégica en Salud, Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica, 2008 to 2011 and 2013 to 2016, Instituto de Salud Carlos III, Fondos FEDER. E.R.-M. was supported by the Consejería de Salud y Bienestar Social of the Junta de Andalucía through the Nicolás Monardes program (C-0032/17).

This study describes the incidence and severity of COVID-19 among 77 590 HIV-positive patients receiving antiretroviral therapy (ART). These findings warrant further investigation of HIV ART in HIV preexposure prophylaxis studies and randomized trials among persons without HIV., Visual Abstract. Incidence and Severity of COVID-19 in HIV-Positive Persons Receiving ART This study describes the incidence and severity of COVID-19 among 77 590 HIV-positive patients receiving antiretroviral therapy (ART). These findings warrant further investigation of HIV ART in HIV preexposure prophylaxis studies and randomized trials among persons without HIV. Visual Abstract. Incidence and Severity of COVID-19 in HIV-Positive Persons Receiving ART This study describes the incidence and severity of COVID-19 among 77 590 HIV-positive patients receiving antiretroviral therapy (ART). These findings warrant further investigation of HIV ART in HIV preexposure prophylaxis studies and randomized trials among persons without HIV., Background: The incidence and severity of coronavirus disease 2019 (COVID-19) among HIV-positive persons receiving antiretroviral therapy (ART) have not been characterized in large populations. Objective: To describe the incidence and severity of COVID-19 by nucleos(t)ide reverse transcriptase inhibitor (NRTI) use among HIV-positive persons receiving ART. Design: Cohort study. Setting: HIV clinics in 60 Spanish hospitals between 1 February and 15 April 2020. Participants: 77 590 HIV-positive persons receiving ART. Measurements: Estimated risks (cumulative incidences) per 10 000 persons and 95% CIs for polymerase chain reaction–confirmed COVID-19 diagnosis, hospitalization, intensive care unit (ICU) admission, and death. Risk and 95% CIs for COVID-19 diagnosis and hospital admission by use of the NRTIs tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC), tenofovir alafenamide (TAF)/FTC, abacavir (ABC)/lamivudine (3TC), and others were estimated through Poisson regression models. Results: Of 77 590 HIV-positive persons receiving ART, 236 were diagnosed with COVID-19, 151 were hospitalized, 15 were admitted to the ICU, and 20 died. The risks for COVID-19 diagnosis and hospitalization were greater in men and persons older than 70 years. The risk for COVID-19 hospitalization was 20.3 (95% CI, 15.2 to 26.7) among patients receiving TAF/FTC, 10.5 (CI, 5.6 to 17.9) among those receiving TDF/FTC, 23.4 (CI, 17.2 to 31.1) among those receiving ABC/3TC, and 20.0 (CI, 14.2 to 27.3) for those receiving other regimens. The corresponding risks for COVID-19 diagnosis were 39.1 (CI, 31.8 to 47.6), 16.9 (CI, 10.5 to 25.9), 28.3 (CI, 21.5 to 36.7), and 29.7 (CI, 22.6 to 38.4), respectively. No patient receiving TDF/FTC was admitted to the ICU or died. Limitation: Residual confounding by comorbid conditions cannot be completely excluded. Conclusion: HIV-positive patients receiving TDF/FTC have a lower risk for COVID-19 and related hospitalization than those receiving other therapies. These findings warrant further investigation in HIV preexposure prophylaxis studies and randomized trials in persons without HIV. Primary Funding Source: Instituto de Salud Carlos III and National Institutes of Health.

ObjectivesWe compared 48 week effectiveness and safety of first-line antiretroviral regimens.MethodsWe analysed HIV treatment-naive adults from the Cohort of the Spanish HIV/AIDS Research Network (CoRIS) starting the most commonly used antiretroviral regimens from 2014 to 2018. We used multivariable regression models to assess the impact of initial regimen on: (i) viral suppression (VS) (viral load 0.4 and >1); (iv) CD4 percentage normalization (>29%); (v) multiple T-cell marker recovery (MTMR: CD4 > 500 cells/mm3 plus CD4 percentage >29% plus CD4/CD8 > 1); (vi) lipid, creatinine and transaminase changes; and (vii) discontinuations due to adverse events (AE).ResultsAmong 3945 individuals analysed, the most frequently prescribed regimens were ABC/3TC/DTG (34.0%), TAF/FTC/EVG/CBT (17.2%), TDF/FTC + DTG (11.9%), TDF/FTC/EVG/CBT (11.7%), TDF/FTC/RPV (11.5%), TDF/FTC + bDRV (8.3%) and TDF/FTC + RAL (5.3%). At 48 weeks, 89.7% of individuals achieved VS with no significant differences by initial regimen. CD4 mean increase was 257.8 (249.3; 266.2) cells/mm3, and it was lower with TAF/FTC/EVG/CBT and TDF/FTC/RPV compared with ABC/3TC/DTG. CD4 percentage normalization was less likely with TAF/FTC/EVG/CBT, and MTMR was less likely with TAF/FTC/EVG/CBT and TDF/FTC + RAL. The proportion of discontinuations due to AE was higher with TDF/FTC + bDRV (9.7%), followed by TDF/FTC/EVG/CBT (9.5%) and TDF/FTC + DTG (7.9%). Compared with ABC/3TC/DTG, cholesterol and LDL mean increases were higher with TAF/FTC/EVG/CBT and lower with TDF/FTC + DTG, TDF/FTC/RPV and TDF/FTC + RAL. Higher mean increases in triglycerides were significantly associated with TAF/FTC/EVG/CBT. Regimens containing DTG showed higher creatinine increases.ConclusionsThe significantly greater immunological response and safety of some combinations may be useful for making decisions when initiating treatment.

© The Author(s) 2020., [Background]: The aim of this study was to investigate the effectiveness and tolerability of the combination elvitegravir/cobicistat/tenofovir/emtricitabine plus darunavir (EVG/COB/TFV/FTC + DRV) in treatment-experienced patients from the cohort of the Spanish HIV/AIDS Research Network (CoRIS)., [Methods]: Treatment-experienced patients starting treatment with EVG/COB/TFV/FTC + DRV during the years 2014–2018 and with more than 24 weeks of follow-up were included. TFV could be administered either as tenofovir disoproxil fumarate or tenofovir alafenamide. We evaluated virological response, defined as viral load (VL), [Results]: We included 39 patients (12.8% women). At baseline, 10 (25.6%) patients had VL, [Conclusions]: EVG/COB/TFV/FTC + DRV was well tolerated and effective in treatment-experienced patients with undetectable viral load as a simplification strategy, allowing once-daily, two-pill regimen with three antiretroviral drug classes. Effectiveness was low in patients with detectable viral loads., The RIS cohort (CoRIS) is supported by the Instituto de Salud Carlos III through the Red Temática de Investigación Cooperativa en Sida (RD06/006, RD12/0017/0018 and RD16/0002/0006) as part of the Plan Nacional I+D+i and cofnanced by ISCIII-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER)”.

[Objectives] To analyse whether integrase inhibitor (InSTI)-based regimens achieve better immunological recovery than NNRTI- or boosted PI (bPI)-based regimens as initial ART., [Methods] In a retrospective analysis, we selected patients who initiated ART with two NRTIs plus an InSTI, an NNRTI or a bPI and maintained both the same ‘third drug’ and an HIV-RNA, [Results] Of the 836 patients included, 208, 481 and 147 initiated with InSTI, NNRTI and bPI, respectively. For CD4+, %CD4+ and CD4+/CD8+ two main slopes were identified: from month 0 to month 6, with the highest increments; and from month 6 to month 24, with smaller increases every semester. Although the patients on InSTI achieved undetectable viral load faster, for CD4+ and %CD4+ there were no differences in the slopes of change according to the third drug either for the first phase (P=0.137 and P=0.393, respectively) or from month 6 onwards (P=0.834 and P=0.159, respectively). The increase in CD4+/CD8+ was slightly higher for bPI compared with InSTI (difference of 0.0119, 95% CI 0.0020–0.0205; P=0.018), but clinically negligible. From month 6 onwards, no differences were found between treatment groups (P=0.176)., [Conclusions] Immune restoration measured as CD4+ count, %CD4+ and CD4+/CD8+ increases was independent of the third antiretroviral drug class used when given with two NRTIs., This work was supported by Red de Investigación en SIDA (RD16/0025/0020-ISCIII-FEDER) and Instituto de Salud Carlos III and Proyectos de investigación en salud (AES 2018) (exp. PI18/01298).

ObjectivesTo assess the attitudes and opinions about generic antiretroviral drugs (ARVs) and single-tablet regimen (STR) de-simplification among physicians prescribing HIV treatment in the cohort of the Spanish HIV/AIDS Research Network (CoRIS).MethodsAn online questionnaire with 27 structured questions was sent to all physicians (n = 199) who prescribed ARVs among the 45 centres participating in the cohort.ResultsA total of 169 (84.9%) physicians answered the questionnaire. Only 4.1% of the physicians would never prescribe generic ARVs, but 53.3% would not prescribe them if the number of pills per day increased and 89.3% would not prescribe them if the number of doses per day increased. However, 84.0% of the physicians agreed to prescribe generic ARVs if doing so would decrease costs for the public healthcare system. The percentages of physicians stating that generic ARVs (compared with branded ones) would be associated with worse adherence, more adverse effects or more probability of virological failure, provided that the number of pills and doses per day would not change, were low: 0.6%, 7.7% and 3.6%, respectively. However, these percentages were much higher if the generic ARV entailed breaking an STR: 63.9%, 18.9% and 42.0%, respectively. Most physicians stated that they needed more information about the effectiveness and safety of generic ARVs and the price difference compared with their branded equivalents.ConclusionsAlthough most physicians were confident about prescribing generic ARVs, the majority had strong concerns about de-simplifying STR, and they also needed more information about generic drugs.

BIRDi study group., The use of two potent, well-tolerated, drugs could permit the maintenance of virologic suppression even in heavily pretreated people living with HIV. In this retrospective, multicenter, simplification study (NCT03348449), we included those patients with virologic suppression who switched to raltegravir (RAL) plus boosted darunavir (b/DRV). Overall, 345 patients (75 females, 25%) were included. Patients were largely pretreated (mean, 9.4 regimens), suppressed for a median of 41.1 months. Fifty patients had ≥1 mutation against DRV. At 96 weeks, the efficacy by intention-to-treat analysis (snapshot) was 73% (95%CI, 68.4–77.8%), but 97.1% (95%CI, 95.4–98.9) excluding changes due to non-virologic reasons, and virologic failure was rare (0.9%; 95%CI, 0.1–1.2%). Median CD4/CD8 ratio increased from 0.59 to 0.62 (p

[Background]: Little is known about the impact of baseline resistance-associated mutations (RAMs) on the outcomes of alternative therapeutic strategies such as dual regimens. We assessed the efficacy of boosted darunavir plus raltegravir (DRV + RAL) dual regimen as a simplification strategy in virologically suppressed patients with protease inhibitors RAMs., [Methods]: Retrospective, multicentre study on the evolution of 228 heavily pretreated patients who switched to boosted DRV + RAL according to genotypic sensitivity score (GSS). Patients were classified as full susceptible (GSS = 2; n = 177), or with reduced darunavir susceptibility (GSS < 2; n = 51)., [Results]: Median (range) number of prior antiretroviral regimens was 9 (6–14), with a median (range) of 2 (1–3), 4 (3–6), and 5 (2–9) major mutations to non-nucleoside reverse transcriptase inhibitors, nucleoside reverse transcriptase inhibitors, and protease inhibitors, respectively. The median time of virological suppression before simplification was 49 months (IQR 39.8–63.5). Patients with reduced darunavir GSS showed a higher number of protease inhibitors-RAMs (9.3 vs 4.5, p, [Conclusions]: Treatment simplification to a dual regimen of boosted DRV + RAL after long-term virological suppression was not associated with a high risk of treatment failure, even in patients harbouring protease inhibitors-resistant HIV infection., This study was supported by the MSD Investigator-Initiated Studies Program (MISP) under grant number 57180.

[Objectives]: The aim of this study was to evaluate adherence to the recommendations of the Spanish guidelines for the initial assessment of patients with HIV infection in the multicentre Cohort of the Spanish HIV/AIDS Network (CoRIS) during the years 2004–2017., [Methods]: We calculated the percentage of patients who had each of 11 clinical and analytical recommended examinations performed in their initial evaluation. We evaluated the factors associated with not performing each examination with multivariable logistic regression models., [Results]: We included 13 612 patients in the study. In the initial assessment, CD4 count and viral load were determined in more than 98.0% of the patients. Serologies for hepatitis A, B and C and syphilis were determined in 55.8%, 66.4%, 89.8% and 81.7% of the patients, respectively. Total cholesterol and creatinine were determined in 78.7% and 78.9% of the patients, respectively. The lowest proportions of examinations were observed for blood pressure, smoking status and latent tuberculosis screening, which were performed in 43.2%, 50.6% and 53.9% of the patients, respectively. Injecting drug users and heterosexual patients (compared to men who have sex with men) and patients with a lower educational level had a higher risk of having an incomplete initial assessment for a substantial number of examinations. Latent tuberculosis screening was less likely in patients with CD4 counts < 200 cells/µL., [Conclusions]: The initial assessment of HIV‐infected patients is suboptimal for the evaluation of cardiovascular risk, smoking status, screening of syphilis and viral hepatitis, and diagnosis of latent tuberculosis: adherence to the guidelines was low for these examinations., The RIS cohort (CoRIS) is supported by the Instituto de Salud Carlos III through the Red Temática de Investigación Cooperativa en Sida (RD06/006, RD12/ 0017/0018 and RD16/0002/0006) as part of the Plan Nacional I+D+i and cofinanced by ISCIII-Subdireccion General de Evaluacion and the Fondo Europeo de Desarrollo Regional (FEDER).

[Background] HIV-infected patients are at risk of hepatitis B virus (HBV) coinfection, however, respond worse to HBV vaccination (HBV-V) than immunocompetent adults. This study aimed to determine the response to reinforced HBV-V in HIV-infected subjects under real-life conditions., [Methods] HIV-infected patients followed at a Spanish University Hospital who were seronegative for HBV and who received three double-doses (40 µL) of HBV-V at 0, 1 and 2 months were included. Response to HBV-V was defined as HBV surface antibody concentration of ≥10 IU/L 1–12 months after the last HBV-V dose., [Results] Of 332 patients included in the study, 256 (77.1%) showed response to HBV-V. Median (interquartile range) CD4+/CD8+ ratio among the responders was 0.75 (0.52–1.01) versus 0.61 (0.38–0.84) among the non-responders (p = 0.002). Independent predictors for HBV-V response were: female gender [adjusted odds ratio (AOR): 6.240; 95% confidence interval (95%CI): 1.954–19.925; p = 0.002]; non-smoking [AOR: 2.151; 95%CI: 1.243–3.721; p = 0.006]; a CD4+/CD8+ ratio ≥0.67 [AOR: 2.580; 95%CI: 1.209–5.505; p = 0.014] and baseline HIV-RNA ≤50 copies/mL [AOR: 2.049; 95%CI: 1.098–3.824; p = 0.024]., [Conclusion] Accelerated administration of three double-doses results in considerable high, however still suboptimal, response rates to HBV-V in HIV-infected patients in the clinical practice. A fourth dose should be considered., This work was partially funded by the Plan Nacional R+D+I and Red de Investigación en SIDA [grant number RD16/0025/0020-ISCIII-FEDER]. K.N. is the recipient of a Miguel Servet research grant [grant number CPII18/00033] from the Instituto de Salud Carlos III.

Background] Various recent outbreaks of hepatitis A virus (HAV) have been described in men who have sex with men despite the availability of an effective vaccine. This study aimed to determine the current rates of seroconversion after receiving HAV vaccine (HAV-V) in HIV-infected patients under real-life conditions. Setting: Patients were selected from a Southern Spanish multicentric cohort of HIV-infected subjects. Methods: Retrospective analysis of all patients who received 2 doses (standard scheme) from April 2008 to May 2016 or from June 2016 to February 2018 facing an HAV outbreak with shortage of HAV-V, 1 single dose of HAV-V. Response to HAV-V was defined as positive anti-HAV IgG between 1 and 12 months after the last vaccination dose. Results: A total of 522 patients were included, mainly men who have sex with men (86.2%). In the standard-dose group, 303/343 [88.3%; 95% confidence interval (CI): 84.5 to 91.5] patients showed seroconversion as compared with 149/179 (83.2%; 95% CI: 76.9 to 88.4) of the single-dose group (P = 0.107). Undetectable baseline HIV-RNA (adjusted odds ratio: 4.86; 95% CI: 1.86 to 12.75; P = 0.001) and a CD4+ T-cell count ≥350/μL (adjusted odds ratio, 3.96; 95% CI: 1.26 to 12.49; P = 0.019) were independently associated with response to both regimens. A higher CD4/CD8+ ratio was also associated with response after a single dose. Conclusions: HIV-infected patients should be encouraged to undergo HAV-V with 2 standard doses 6 months apart; a single dose achieves a high rate of seroconversion in those patients with favorable response factors and may be enough to limit future outbreaks in case of HAV-V shortage until supply is reestablished., [Setting] Patients were selected from a Southern Spanish multicentric cohort of HIV-infected subjects., [Methods] Retrospective analysis of all patients who received 2 doses (standard scheme) from April 2008 to May 2016 or from June 2016 to February 2018 facing an HAV outbreak with shortage of HAV-V, 1 single dose of HAV-V. Response to HAV-V was defined as positive anti-HAV IgG between 1 and 12 months after the last vaccination dose., [Results] A total of 522 patients were included, mainly men who have sex with men (86.2%). In the standard-dose group, 303/343 [88.3%; 95% confidence interval (CI): 84.5 to 91.5] patients showed seroconversion as compared with 149/179 (83.2%; 95% CI: 76.9 to 88.4) of the single-dose group (P = 0.107). Undetectable baseline HIV-RNA (adjusted odds ratio: 4.86; 95% CI: 1.86 to 12.75; P = 0.001) and a CD4+ T-cell count ≥350/μL (adjusted odds ratio, 3.96; 95% CI: 1.26 to 12.49; P = 0.019) were independently associated with response to both regimens. A higher CD4/CD8+ ratio was also associated with response after a single dose., [Conclusions] HIV-infected patients should be encouraged to undergo HAV-V with 2 standard doses 6 months apart; a single dose achieves a high rate of seroconversion in those patients with favorable response factors and may be enough to limit future outbreaks in case of HAV-V shortage until supply is reestablished.

Purpose: Optimisation strategies for volumetric modulated arc therapy (VMAT) in most treatment planning systems for breast cancer do not account for patient positioning, breathing, or anatomical changes. To overcome this limitation, a pseudo-skin flash strategy using a virtual bolus has been proposed. Using this strategy, we determined optimal thickness and value of Hounsfield units (HU) assigned to the virtual bolus to ensure adequate CTV irradiation. Materials and methods: We modified the original computed tomography data (CT0) by adding combinations of thicknesses and densities of a virtual bolus on PTVs (CT') of seven bilateral breast cancer patients. Using a single optimization objective template, we obtained a VMAT plan on CT' and recalculated this on the CT0. Optimal CT' parameters were defined as those that minimized dose differences between CT' and CT0 plans regarding PTV and OAR dose-volume parameters. We studied bolus parameters regarding robustness by shifting the isocenter 5 and 10 mm in the breathing direction for each CT0 plan. Results: The minimal dosimetric impact was between - 400 and - 600 HU depending on bolus thickness. OARs doses were not significantly affected. Best robustness was found for - 500 HU and 15 mm bolus thickness against shifts of up to 10 mm in the breathing direction. Conclusion: Our results support a bolus thickness equal to the CTV-PTV margin plus 5 mm and a virtual bolus HU value around - 500 and - 400 depending on the bolus thickness chosen. These findings could play a useful role in maximising robustness and minimising the need for plan renormalization.

[Background]: Screening methods for anal squamous intraepithelial lesions (SILs) are suboptimal. We aimed to determine the diagnostic performance of a composite endpoint comprising anal liquid-based cytology (aLBC) and high-risk human papillomavirus (HR-HPV) testing to predict histological high-grade SILs (hHSILs). [Methods]: From the SeVIHanal cohort, human immunodeficiency virus (HIV)-infected men who have sex with men (MSM) who had an aLBC with concomitant HR-HPV testing were included. hHSILs were determined by high-resolution anoscopy (HRA)-guided biopsy. [Results]: A total of 705 visits obtained from 426 patients were included. The prevalence of HR-HPV among aLBC results were 51.9% (133/215) normal, 87.9% (20/232) low-grade SILs (LSILs), and 90.9% (149/164) high-grade SILs; P (linear association) normal/noHR-HPV> (10%) and >LSIL/noHR-HPV> (4%). The prognostic values (95% confidence interval) for HR-HPV to predict hHSILs in normal cytology were positive predictive value (PPV), 29.3% (25.6%-33.3%); negative predictive value (NPV), 90.2% (82.8%-94.7%); sensitivity, 83% (69.2%-92.4%); and specificity, 44.1% (36.4%-51.9%). Corresponding figures for cytologic LSILs were PPV, 39.2% (37.4%-41.1%); NPV, 96.4% (78.9%-99.5%); sensitivity, 98.8% (93.3%-99.9%); and specificity, 17.9% (12.1%-24.9%). A positive interaction and a synergistic effect for the composite endpoint were observed (relative excess risk = 1.50, attributable proportion of histological results to interaction = 0.17, synergy index = 1.24). [Conclusions]: HRA should not be indicated in the setting of LSILs/noHR-HPV following aLBC-based screening. In contrast, HIV-infected MSM with normal aLBC/HR-HPV infection should be considered for HRA. Clinical Trials Registration: NCT03713229., This work was supported by the Plan Nacional R+D+I and the Red de Investigación en SIDA (grant RD16/0025/0020-ISCIII-FEDER). K. N. is the recipient of a Miguel Servet II contract by the Instituto de Salud Carlos III (number CPII18/00033).

Background: Integrase strand-transfer inhibitors (INSTIs) constitute at present one of the pillars of first-line ART. Objectives: To study the prevalence of and the trend in transmitted drug resistance (TDR) to INSTIs in ART-naive patients in Spain. Methods: During the period 2012-17, 1109 patients from CoRIS were analysed. The Stanford algorithm v8.7 was used to evaluate TDR and transmission of clinically relevant resistance. To describe individual mutations/polymorphisms, the most recent IAS list (for INSTIs) and the 2009 WHO list update (for the backbone NRTIs used in combination with INSTIs in first-line treatment) were used. Results: Clinically relevant resistance to the INSTI class was 0.2%: T66I, 0.1%, resistance to elvitegravir and intermediate resistance to raltegravir; and G163K, 0.1%, intermediate resistance to raltegravir and elvitegravir. No clinical resistance to dolutegravir or bictegravir was observed. The prevalence of INSTI TDR following the IAS-USA INSTI mutation list was 2.6%, with no trend towards changes in the prevalence throughout the study period. The overall prevalence of NRTI WHO mutations was 4.3%, whereas clinically relevant resistance to tenofovir, abacavir and emtricitabine/ lamivudine was 1.7%, 1.9% and 0.7%, respectively. Conclusions: Given the low prevalence of clinically relevant resistance to INSTIs and first-line NRTIs in Spain, it is very unlikely that a newly diagnosed patient will present with clinical resistance to a first-line INSTI-based regimen. These patients may not benefit from INSTI and NRTI baseline resistance testing.

[Objectives]: Our objective was to identify patient factors associated with being untreated for hepatitis C virus (HCV) infection in HIV-coinfected patients., [Methods]: A prospective longitudinal study was carried out. HIV-infected patients with active chronic HCV infection included in the HERACLES cohort (NCT02511496) constituted the study population. The main study outcome was receipt of HCV direct-acting antiviral (DAA) treatment from 1 May 2015 to 1 May 2017. The population was divided into patients who were receiving HCV treatment during follow-up and those who were not., [Results]: Of the 15 556 HIV-infected patients in care, 3075 (19.7%) presented with chronic HCV infection and constituted the study population. At the end of the follow-up, 1957 patients initiated HCV therapy (63.6%). Age < 50 years, absence of or minimal liver fibrosis, being treatment-naïve, HCV genotype 3 infection, being in the category of people who inject drugs using opioid substitutive therapy (OST-PWID), and being in the category of recent PWID were identified as significant independent risk factors associated with low odds of DAA implementation. When a multivariate analysis was performed including only the PWID population, both OST-PWID [odds ratio (OR) 0.552; 95% confidence interval (CI) 0.409–0.746) and recent PWID (OR 0.019; 95% CI 0.004–0.087) were identified as independent factors associated with low odds of treatment implementation., [Conclusions]: We identified factors, which did not include prioritization of a DAA uptake strategy, that limited access to HCV therapy. The low treatment uptake in several populations seriously jeopardizes the elimination of HCV infection in the coming years., This work was supported by the Ministerio de Sanidad (RD12/0017/0012) integrated in the Plan Nacional de I+D+I, and cofinanced by the ISCIII‐Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER), the Fundación para la Investigación en Salud (FIS) del Instituto Carlos III (PI15/01017), and the Red de Investigación en SIDA de España ISCIII‐RETIC (grant number: RD16/0025/0034).

Introduction: The use of systemic corticosteroids in severely ill patients with coronavirus disease 2019 (COVID-19) is controversial. We aimed to evaluate the efficacy and safety of corticosteroid pulses in patients with COVID-19 pneumonia. Methods: A quasi-experimental study, before and after, was performed in a tertiary referral hospital, including admitted patients showing COVID-19-associated pneumonia. The standard treatment protocol included targeted COVID-19 antiviral therapy from 23rd March 2020, and additionally pulses of methylprednisolone from 30th March 2020. The primary outcome was a composite endpoint combining oro-tracheal intubation (OTI) and death within 7 days. Results: A total of 24 patients were included. Standard of care (SOC) (before intervention) was prescribed in 14 patients, while 10 received SOC plus pulses of methylprednisolone (after intervention). The median age of patients was 64.5 years and 83.3% of the patients were men. The primary composite endpoint occurred in 13 patients (92.9%) who received SOC vs. 2 patients (20%) that received pulses of methylprednisolone (odds ratio, 0.02; 95% confidence interval, 0.001 to 0.25; p = 0.019). Length of hospitalization in survivors was shorter in the corticosteroids group (median, 14.5 [8.5–21.8] days vs. 29 [23–31] days, p = 0.003). There were no differences in the development of infections between both groups. There were 3 deaths, none of them in the corticosteroids group. Conclusions: In patients with severe pneumonia due to COVID-19, the administration of methylprednisolone pulses was associated with a lower rate of OTI and/or death and a shorter hospitalization episode. Resumen: Introducción: El uso de corticosteroides sistémicos en pacientes gravemente enfermos por enfermedad coronavírica de 2019 (covid-19) es controvertido. Nuestro objetivo fue evaluar la eficacia y la seguridad de los pulsos de corticoesteroides en los pacientes con neumonía por covid-19. Métodos: Se realizó un ensayo cuasiexperimental, tipo antes y después, en un hospital terciario de referencia que incluyó a pacientes ingresados por neumonía asociada a covid-19. El protocolo de tratamiento estándar incluía un tratamiento antiviral dirigido contra el virus de la covid-19 desde el 23 de marzo de 2020 y añadió pulsos de metilprednisolona desde el 30 de marzo de 2020. El resultado primario fue un criterio combinado compuesto por la intubación orotraqueal y el fallecimiento durante los siguientes siete días. Resultados: Se incluyó un total de 24 pacientes. El protocolo de tratamiento (antes de la intervención) se prescribió en 14 pacientes, mientras que 10 recibieron el protocolo de tratamiento además de los pulsos de metilprednisolona (después de la intervención). La edad media de los pacientes fue de 64,5 años y el 83,3% de los pacientes eran hombres. El resultado combinado primario tuvo lugar en 13 pacientes (92,9%) que recibieron el protocolo de tratamiento frente a 2 pacientes (20%) que recibieron los pulsos de metilprednisolona (odds ratio = 0,02; intervalo de confianza del 95% = 0,001-0,25; p = 0,019). La duración de la hospitalización en los supervivientes fue más corta en el grupo que recibió corticoesteroides (media = 14,5 [8,5-21,8] días frente a 29 [23-31] días, p = 0,003). No hubo diferencias en el desarrollo de infecciones entre ambos grupos. Hubo tres fallecimientos, ninguno de ellos en el grupo que recibió corticoesteroides. Conclusiones: En los pacientes con neumonía grave por covid-19, la administración de pulsos de metilprednisolona se asoció a unas tasas menores de intubación orotraqueal y/o muerte y a episodios de hospitalización más cortos.

Objectives Chronic oxidative stress (OS) may play a role in cardiovascular disease in HIV-infected patients, and increased bilirubin levels may have a beneficial role in counteracting OS. Atazanavir (ATV) inhibits UDP-glucuronosyl-transferase 1A1 (UGT1A1), thus increasing unconjugated bilirubin levels. We aimed to compare changes in OS markers in patients on ATV/ritonavir (ATV/r)- vs. efavirenz (EFV)-based first-line antiretroviral therapy (ART). Methods A multicentre, prospective cohort study of HIV-infected patients who started first-line ART with either ATV/r or EFV was conducted. Lipoprotein-associated phospholipase A2 (Lp-PLA2), myeloperoxidase (MPO) and oxidized low-density lipoprotein (oxLDL) were measured for 145 patients in samples obtained at baseline and after at least 9 months of ART during which the initial regimen was maintained and the patient was virologically suppressed. The change in OS markers was modelled using multiple linear regressions adjusting for baseline values and confounders. Results After adjustment for baseline variables, patients on ATV/r had a significantly greater decrease in Lp-PLA2 [estimated difference -16.3; 95% confidence interval (CI) -31.4, -1.25; P = 0.03] and a significantly smaller increase in OxLDL (estimated difference -21.8; 95% CI -38.0, -5.6; P < 0.01) relative to those on EFV, whereas changes in MPO were not significantly different (estimated difference 1.2; 95% CI -14.3, 16.7; P = 0.88). Adjusted changes in bilirubin were significantly greater for the ATV/r group than for the EFV group (estimated difference 1.33 mg/dL; 95% CI 1.03, 1.52 mg/dL; P < 0.01). Changes in bilirubin and changes in OS markers were significantly correlated. Conclusions When compared with EFV, ATV/r-based therapy was associated with lower levels of oxidative stress biomarkers, which was in part attributable to increased bilirubin levels.

Despite high response rates associated to hepatitis C virus (HCV) treatment, no protective immunity is acquired, allowing for reinfection and continued infectiousness. Distinguishing between relapse and reinfection is crucial for patient counselling and to choose the most appropriate retreatment. Here, refined phylogenetic analysis using multiple genes served to assess genotype and reinfection for 53 patients for whom the virus was sampled before start of therapy and at time of sustained virological response evaluation at week 12. At baseline, genotypes were determined as HCV1a (41.5%), HCV1b (24.5%), HCV4 (18.9%) and HCV3a (15.1%), while six cases revealed to be discordantly assigned by phylogeny and commercial assays. Overall, 60.4% was co-infected with HIV. The large majority was classified as people who inject drugs (78.6%), often co-infected with HIV. Transmission was sexual in seven cases, of which five in HIV-positive men-who-have-sex-with-men. Overall, relapse was defined for 44 patients, while no conclusion was drawn for four patients. Five patients were reinfected with a different HCV strain, of which three with a different genotype, showing that phylogeny is needed not only to determine the genotype, but also to distinguish between relapse and intra-subtype reinfection. Of note, phylogenies are more reliable when longer fragments of the viral genome are being sequenced. ispartof: PLOS ONE vol:13 issue:7 ispartof: location:United States status: published

Introduction When darunavir (DRV) 800 mg is boosted with 150 mg cobicistat (DRV cobi), DRV trough concentration (Ctrough) is about 30% lower as compared to 100 mg ritonavir (DRV rtv). DRV cobi shows similar virological efficacy as DRV rtv when combined with two nucleos(t)ide analogue reverse‐transcriptase inhibitors, but it is unknown whether a lower DRV Ctrough would undermine the effectiveness of DRV cobi when given as monotherapy (mtDRV cobi). Methods Prospective observational study on virologically suppressed HIV‐infected subjects who switched to mtDRV cobi. Virological failure was defined as two consecutive HIV‐RNA >200 copies/mL. Efficacy was evaluated by intention‐to‐treat (ITT) and on‐treatment (OT) analyses, and compared with data from a previous cohort of subjects on mtDRV rtv conducted at our centre. Plasma DRV Ctrough was measured using LC–MS/MS. Results A total of 234 subjects were enrolled. At week 96, the efficacy rates were 67.8% (CI 95, 61.8 to 73.7) by ITT and 86.9% (CI 95, 78.0 to 87.7) by OT analyses. The corresponding rates in our historical DRV rtv controls were 67.6% (CI 95, 60.0 to 75.2) and 83.6% (CI 95: 77.2 to 90.0). A total of 135 DRV determinations were performed in 83 subjects throughout the follow‐up period, with a median plasma DRV Ctrough of 1305 ng/mL (range, 150 to 5895) compared with 1710 ng/mL (range, 200 to 3838) in subjects on monotherapy with DRV rtv (p = 0.05). Conclusions DRV Ctrough was lower in HIV‐infected subjects receiving DRV cobi than with DRV rtv. However, this did not appear to influence the efficacy of DRV cobi, when administered as monotherapy.

[Objectives] To evaluate if there are significant drug–drug interactions between cobicistat-boosted elvitegravir and 800 mg darunavir once daily taken simultaneously, as has been suggested previously., [Methods] The study population consisted of three groups of unselected volunteers taking a regimen of elvitegravir, cobicistat, emtricitabine and tenofovir disoproxil fumarate (150, 150, 200 and 300 mg, respectively) co-formulated in a single tablet plus 800 mg darunavir (group A); only co-formulated elvitegravir, cobicistat, emtricitabine and tenofovir disoproxil fumarate (group B); and cobicistat-boosted darunavir (800 mg darunavir + 150 mg cobicistat) plus two nucleos(t)ide analogues (group C). Elvitegravir, cobicistat and darunavir concentrations at the end of the dosing interval (C24) were quantified using a validated LC with tandem MS method., [Results] A total of 170 samples were obtained from 24, 32 and 32 patients in groups A, B and C, respectively. In group A, the elvitegravir C24 were similar to those in group B (233.67 versus 250.39 ng/mL) (P = 0.406) and the darunavir C24 were similar to those in group C (1293.54 versus 1319.34 ng/mL) (P = 0.908). The cobicistat C24 were comparable in groups A and B (20.2 versus 20.9 ng/mL) and slightly higher in group C (27.7 ng/mL) (P = 0.059)., [Conclusions] The results provide evidence of similar elvitegravir and darunavir C24 concentrations when these drugs are co-administered as co-formulated elvitegravir, cobicistat, emtricitabine and tenofovir disoproxil fumarate plus 800 mg darunavir or dosed separately., This work was supported by Fundación Pública Andaluza para la Gestión de la Investigación en Salud de Sevilla

Objectives: To present clinical experience with a regimen including abacavir/lamivudine+darunavir/ritonavir in a cohort of HIV-1-infected patients. Methods: A retrospective, multicentre cohort study, including all consecutive adult HIV-1-infected patients who started abacavir/lamivudine+darunavir/ritonavir from April 2008 to December 2010 and had at least one followup visit. The primary endpoint was HIV-1 viral load (VL) ,40 copies/mL at week 48. Results: One hundred and eighty-three patients (42 naive and 141 experienced) from 19 hospitals in Spain were studied. The median follow-up was 26.7 (0.5–58.6) months, 79.8% were men, the median age was 47.1 (21.4– 80.5) years, 26.2% had AIDS and 38.8% were positive for hepatitis C virus. At baseline, the median CD4 count was 246 cells/mm3 in naive patients and 393 cells/mm3 in experienced patients and the median VL was 4.80 and ,1.59 log copies/mL, respectively. Atweek 48, 81.8% of naive patients and 84.2% of experienced patients receiving the regimen reached a VL ,40 copies/mL, whereas at 96 weeks this occurred in 90.5% and 92.8%, respectively. CD4 cell count increases at 48 and 96 weeks were +176.5 and +283.5 cells/mm3 in naive patients and +74.9 and +93 cells/mm3 in experienced patients, respectively. Overall, 86 (47%) patients discontinued the study regimen, in many cases possibly related to non-medical reasons, such as drug switches to reduce cost or changes in address due to economic constraints. Three patients died of causes unrelated to therapy and 19 (10.4%) discontinued the regimen due to adverse events. Conclusions: In our cohort, abacavir/lamivudine+darunavir/ritonavir was safe, well tolerated and achieved high rates of virological suppression. In a proportion of patients, discontinuation of this effective regimen was possibly due to non-medical reasons.

Background There are several regimens for starting antiretroviral treatment, but it remains unknown whether either of them is more advantageous regarding the time course and magnitude of human immunodeficiency virus (HIV) RNA decay in semen. Objective To evaluate the differential effect of different antiretroviral drug families on viral kinetics in seminal plasma (SP) of treatment-naive HIV-infected patients. Methods Phase II, randomized, open-label study in which participants were randomized 1:1:1 to receive tenofovir-disoproxil fumarate (DF) plus emtricitabine, and either cobicistat-boosted elvitegravir (EVGcobi), rilpivirine (RPV), or ritonavir-boosted darunavir (DRVrtv). The primary endpoint was the proportion of participants with undetectable HIV-RNA in SP at week 12. HIV type 1 (HIV-1) RNA was measured in paired SP and blood plasma (BP) at baseline and after 1, 2, 4, 6, 8, 12, 18, and 24 weeks. Elvitegravir (EVG), RPV, and darunavir (DRV) concentrations were quantified by the liquid chromatography-tandem mass spectrometry method. Results In SP, the HIV-RNA decay rate with RPV was as fast as with EVGcobi; by week 12, all participants in the RPV and the EVGcobi groups reached an undetectable viral load but only 58.3% in the DRVrtv arm (P = .003). The highest SP/BP drug concentration ratio was for EVG (0.43), followed-up by RPV (0.19), and DRV (0.10). For both EVG and RPV, the SP concentrations exceeded >2-fold the protein binding-adjusted EC90 for wild-type HIV-1; for DRV, only 33.7% of the SP showed concentrations above the protein binding-adjusted EC90. Conclusions In SP, both RPV and EVGcobi, associated to tenofovir-DF and emtricitabine, behave similarly and achieve an undetectable viral load much faster than DRVrtv. Registration European Medical Agency (No. EudraCT: 2014-001348-39).