Temporal trend of drug-resistance and APOBEC editing in PBMC genotypic resistance tests from HIV-1 infected virologically suppressed individuals.

BACKGROUND: We aimed at evaluating the temporal trend of drug-resistance and APOBEC editing from HIV-DNA genotypic resistance tests (GRT) in virologically suppressed individuals. MATERIAL AND METHODS: Major resistance mutations (MRM), genotypic susceptibility score (GSS) for the current regimen and APOBEC-related mutations (APO-M) were evaluated. Potential changes in trends of MRM and APO-M over-time were assessed and predictors of MRM detection or sub-optimal GSS (GSS<2) at HIV-DNA-GRT were estimated through logistic regression analyses. RESULTS: Among the 1126 individuals included, 396 (35.2%) harboured at least one MRM (23.4% to NRTI, 18.8% to NNRTI, 7.7% to PI and 1.4% to INSTI [N=724]); 132 (12.3%) individuals showed a GSS <2. APO-M and stop codons were found in 229 (20.3%) and 105 (9.3%) individuals, respectively. APO-DRMs were found in 16.8% of individuals and were more likely observed in those individuals with stop codons (40.0%) compared to those without (14.4%, P<0.001). From 2010 to 2021 no significant changes of resistance or APO-M were found. Positive predictors of MRM detection at HIV-DNA GRT were drug abuse, subtype B infection, and a prolonged and complex treatment history. Perinatal infection and having at least 2 stop codons were associated with a current suboptimal regimen. CONCLUSIONS: In virologically suppressed individuals, resistance in HIV-DNA and the extent of APOBEC editing were generally stable in the last decade. A careful evaluation of APOBEC editing might be helpful to improve the reliability of HIV-DNA GRT. Further investigations are required to understand how to apply the estimation of APOBEC editing in refining genotypic evaluation.

HIV MDR is still a relevant issue despite its dramatic drop over the years.

OBJECTIVES: To evaluate the prevalence and therapeutic relevance of drug resistance among isolates from ART-experienced HIV-1-infected patients over the past two decades in Italy. METHODS: Dynamics of resistance to one, two and three or more antiretroviral classes were evaluated from 1999-2018. Virological success (VS) after the latest therapy switch was evaluated according to cumulative class resistance and cumulative genotypic susceptibility score (Stanford HIV_DB algorithm). RESULTS: Among 13 663 isolates (from 6739 patients), resistance to at least one drug class decreased sharply from 1999 to 2010 (≤2001, 84.6%; 2010, 43.6%; P < 0.001), then remained relatively constant at ∼40% during 2010-18, with the proportion of resistance to three or more classes also stable (∼5%). After 2008, integrase inhibitor resistance slightly increased from 5.6% to 9.7% in 2018 and contributed to resistance, particularly in isolates with resistance to three or more classes (one class, 8.4%; two classes, 15.3%; three or more classes, 34.7%, P < 0.001). Among 1827 failing patients with an available follow-up, by 1 year after genotype-guided therapy start the probability of VS was 87.6%. Patients with cumulative resistance to three or more classes and receiving a poorly active regimen showed the lowest probability (62.6%) of VS (P < 0.001) compared with all other patients (≥81.8%). By Cox regression analysis, cumulative MDR and receiving poorly active antiretroviral regimens were associated with a lower hazard of VS compared with those without resistance. CONCLUSIONS: A dramatic drop of HIV-1 drug resistance at failure has been achieved over the last two decades in Italy; resistance to three or more classes is low but present among currently failing patients. Its management still requires a rational and careful diagnostic and therapeutic approach.

Sexto reporte de eventos adversos con tratamientos biológicos en Argentina: Informe del registro BIOBADASAR / Sixth report of adverse events with biological treatments in Argentina: Report of the BIOBADASAR registry

Objetivo: Actualizar los resultados del registro BIOBADASAR sobre seguridad, duración y causas de interrupción del tratamiento luego de 8 años de seguimiento. Métodos: BIOBADASAR es un registro de seguridad de terapias biológicas establecido por la Sociedad Argentina de Reumatología. Se presenta la descripción de BIOBADASAR 3.0, una cohorte compuesta por 53 centros de Argentina seguidos prospectivamente desde agosto de 2010 hasta enero de 2018. Resultados: Se registraron 4656 pacientes, 6234 tratamientos [3765 casos (terapia con biológicos) y 2469 controles (terapia no biológicos)]. Se interrumpió el tratamiento en el 44,6% en los casos vs. 27,9% en los controles. Causa principal de discontinuación fue por ineficacia (40% casos vs. 32% controles). Se presentaron 3154 eventos adversos (2230 en casos vs. 924 en controles), de los cuales el 13,6% fueron graves (9,8% en casos y 3,7% en controles). El evento adverso (EA) más frecuente en ambos grupos fueron las infecciones (43,56% en casos vs. 34,31% en los controles, RR: 3,42; IC 95%: 3,02-3,88), y de ellas las de vías aéreas superiores (14,5%). Las neoplasias se presentaron en 78 casos vs. 45 en controles (RR: 1,98; IC 95%: 1,37-2,86). Conclusiones: En este sexto reporte no se observan tendencias diferentes sobre seguridad, duración y causas de interrupción del tratamiento respecto a informes previos. Las infecciones fueron el principal EA y la ineficacia, seguido por EA y la pérdida de pacientes las principales causas de suspensión del tratamiento. El advenimiento de nuevos agentes biológicos y la necesidad de control en seguridad a largo plazo, fortalece el uso de este tipo de registro.

Objective: Update the results of the BIOBADASAR registry on safety, duration and causes of treatment interruption after 8 years of follow-up. Methods: BIOBADASAR is a safety record of biological therapies established by the Argentine Society of Rheumatology. The description of BIOBADASAR 3.0 is presented, a cohort of 53 centers in Argentina followed prospectively from August 2010 to January 2018. Results: 4656 patients were registered, 6234 treatments [3765 cases (therapy with biologicals) and 2469 controls (non-biological therapy)]. Treatment was interrupted in 44.6% in cases vs. 27.9% in controls. Main cause of discontinuation was due to inefficiency (40% cases vs. 32% controls). There were 3154 adverse events (2230 in cases vs. 924 in controls), of which 13.6% were tombs (9.8% in cases and 3.7% in controls). The most frequent adverse event (AE) in both groups were infections (43.56% in cases vs. 34.31% in controls, RR: 3.42, 95% CI: 3.02-3.88), and the upper airway pathways (14.5%). Neoplasms were published in 78 cases versus 45 controls (RR: 1.98, 95% CI: 1.37-2.86). Conclusions: In this article, there are no different trends regarding safety, duration and causes of interruption of treatment compared to previous reports. Infections were the main causes of treatment discontinuation. The advent of new biological agents and the need for control over long-term security, strengthens the use of this type of registration.

Condiciones inflamatorias no infecciosas en el contexto de la fiebre de origen desconocido: el ejemplo de enfermedad de Still / Noninfectious inflammatory conditions in the context of fever of unknown origin: the example of adult onset Still's disease

La lista de etiologías en la fiebre de origen desconocido (FOD) es extensa, siendo las infecciones una causa significativa. Aunque en la actualidad, la mayoría de los casos se deben a desórdenes inflamatorios no infecciosos. La enfermedad de Still del adulto (ESA) es una entidad poco frecuente que sólo debe considerarse luego de descartar otras etiologías. El diagnóstico es clínico ya que no se disponen de métodos complementarios específicos. El curso clínico se divide en 3 patrones: monofásico, con curso de semanas o meses, intermitente, en brotes y articular crónico. Los fármacos antiinflamatorios no esteroideos y los glucocorticoides son útiles en la enfermedad aguda; dado que las recaídas son comunes, la necesidad de terapia inmunosupresora es frecuente. (AU)

Many conditions may cause fever of unknown origin (FUO). While infections remain a significant cause, most FUOs are caused by noninfectious inflammatory disorders. Adult onset Still's disease (AOSD) is a rare condition that should be considered only after the exclusion of other disorders that can cause FUO. The diagnosis of AOSD remains clinical as other diagnostic markers are not available yet1. The disease may present with three different patterns: monophasic, intermittent with relapses and chronic articular . Typically, AOSD is treated with NSAIDs and glucocorticoids, however, relapses are frequent ensuing the use of immunosuppressive drugs. (AU)

Dynamics and phylogenetic relationships of HIV-1 transmitted drug resistance according to subtype in Italy over the years 2000-14.

Background: Transmitted drug-resistance (TDR) remains a critical aspect for the management of HIV-1-infected individuals. Thus, studying the dynamics of TDR is crucial to optimize HIV care. Methods: In total, 4323 HIV-1 protease/reverse-transcriptase sequences from drug-naive individuals diagnosed in north and central Italy between 2000 and 2014 were analysed. TDR was evaluated over time. Maximum-likelihood and Bayesian phylogenetic trees with bootstrap and Bayesian-probability supports defined transmission clusters. Results: Most individuals were males (80.2%) and Italian (72.1%), with a median (IQR) age of 37 (30-45) years. MSM accounted for 42.2% of cases, followed by heterosexuals (36.4%). Non-B subtype infections accounted for 30.8% of the overall population and increased over time (<2005-14: 19.5%-38.5%, P < 0.0001), particularly among Italians (<2005-14: 6.5%-28.8%, P < 0.0001). TDR prevalence was 8.8% and increased over time in non-B subtypes (<2005-14: 2%-7.1%, P = 0.018). Overall, 467 transmission clusters (involving 1207 individuals; 27.9%) were identified. The prevalence of individuals grouping in transmission clusters increased over time in both B (<2005-14: 12.9%-33.5%, P = 0.001) and non-B subtypes (<2005-14: 18.4%-41.9%, P = 0.006). TDR transmission clusters were 13.3% within the overall cluster observed and dramatically increased in recent years (<2005-14: 14.3%-35.5%, P = 0.005). This recent increase was mainly due to non-B subtype-infected individuals, who were also more frequently involved in large transmission clusters than those infected with a B subtype [median number of individuals in transmission clusters: 7 (IQR 6-19) versus 4 (3-4), P = 0.047]. Conclusions: The epidemiology of HIV transmission changed greatly over time; the increasing number of transmission clusters (sometimes with drug resistance) shows that detection and proper treatment of the multi-transmitters is a major target for controlling HIV spread.

Perfil lipídico e inflamación en pacientes con artritis reumatoidea: una contradicción? / Lipid profile and inflammatory state in patients with rheumatoid arthritis

INTRODUCCIÓN: Los pacientes con artritis reumatoidea (AR) presentan una mobimortalidad cardiovascular (CV) 50-60% más alta comparada con la población general. En este grupo poblacional, la carga inflamatoria acumulada, medida por los niveles de VSG y PCR durante un período prolongado, se ha asociado con aterosclerosis subclínica, riesgo cardiovascular y mortalidad. En contrapartida, la presencia de un estado pro-inflamatorio conduciría a una disminución del colesterol total (CT), colesterol HDL y colesterol LDL, por lo que la contribución de los lípidos como factor de riesgo CV es, ciertamente, contradictorio. OBJETIVO Correlacionar los reactantes de fase aguda (VSG-PCR) y los valores de lípidos (CT, HDL, LDL) en una muestra de pacientes con AR. PACIENTES Y METODO: Estudio observacional, retrospectivo, analítico, en el que se incluyeron pacientes con diagnóstico de AR según criterios ACR/EULAR 2010. La relación entre los valores de CT, HDL, LDL con la PCR y VSG se analizó con correlación de Pearson. Dada la distribución no simétrica de los valores de PCR, se obtuvo una transformación logarítmica (logaritmo normal) de la misma. En un segundo modelo, los valores de CT, HDL y LDL se correlacionaron con el logaritmo normal de la PCR realizando distintos cortes de la misma (concentración de PCR ≤5 mg/l, > 5 a 10 mg/l). Finalmente, las correlaciones significativas, se incluyeron en un modelo de regresión lineal multivariado ajustado por edad, género, tiempo de evolución de la enfermedad, uso de hipolipemiantes, medicamentos biológicos y dosis de glucocorticoides. RESULTADOS El análisis de este estudio incluyó 449 mediciones del perfil de lípidos y reactantes de fase aguda (PCR y VSG) correspondientes a 318 pacientes. Los pacientes fueron predominantemente mujeres (79.5%), con una edad media (desviación estándar) de 57.7 (12.3) años. La mediana (rango intercuartilo) del tiempo de evolución de la enfermedad fue de 74.0 (108.0) meses. La mayoría de los pacientes eran seropositivos (67%). La correlación entre PCR y CT (r= 0.16; p= 0.60), así como sus fracciones HDL (0.09; p= 0.30) y LDL (r= 0.09; p= 0.36), fueron débiles. En el sub-análisis de la PCR dividida en tres valores de corte, tanto el CT (r= -0.18 a 0.09) y la fracción LDL (r= -0.34 a 0.11) mostraron correlaciones débiles, independientemente del valor de corte analizado de PCR. Por el contrario, se observó una correlación positiva moderada entre los valores positivos intermedios de PCR y HDL (r= 0.53; p= 0.01). Las correlación entre VSG y CT (r=- 0.03; p= 0.58), así como su fracción LDL (r= 0.10; p= 0.88), fueron débiles. Se observó una correlación negativa débil, pero estadísticamente significativa entre VSG y la fracción HDL (r=-0.14; p= 0.02). En el análisis multivariado de regresión lineal la VSG mantuvo una asociación negativa y significativa con los valores de colesterol HDL (coeficiente ß= -0.179, IC95% -0.28 -0.07; p= 0.001). CONCLUSION: En este estudio pudimos corroborar una relación inversa, aunque débil, entre la VSG y la fracción HDLcolesterol, por el contrario, no pudimos reproducir los hallazgos previamente publicados sobre la relación inversa entre la PCR y los niveles séricos de colesterol y sus fracciones. (AU)

INTRODUCTION: Cardiovascular disease (CVD) is the main cause of premature mortality in patients with rheumatoid arthritis (RA). The risk of CVD mortality is increased by approximately 50% compared to the general population. In patients with RA, the cumulative inflammatory burden, as measured by the levels of the globular sedimentation rate (GSR) and the Creactive protein (CRP), has been associated with sub-clinical atherosclerosis, CV risk and mortality. On the contrary, the presence of a proinflammatory state, as observed in patients with RA, may lead to a decline of the total cholesterol (TC) and HDL fraction. This observation suggests that inflammation may play a confounding role in the association of lipids with CVD. OBJETIVO: To correlate acute phase reactants (GSR and CRP) with the lipid measurements (TC, HDL and LDL) in a sample of patients with RA. PATIENTS Y METHOD: In this observational, retrospective and analytic study, we included 318 patients fulfilling the CR/EULAR 2010 criteria for RA. The relationship between the TC, HDL, LDL and the CRP (normal logarithm) and GSR was analyzed with the Pearson´s correlation. In a second model, the relationship of the TC, HDL and LDL with the normal logarithm of CRP was analyzed using different cutoff values (CRP ≤5 mg/l, > 5 a <10 mg/l y >10 mg/l). Finally, all the significant correlations were included in a multivariate linear regression model adjusting for age, gender, disease duration, use of lipid lowering drugs, biologic disease modifying antirheumatic drugs and glucocorticoid doses. RESULTS: The study included 449 measurements of the lipid profile and acute phase reactants. Patients were predominantly women (79.5%) with mean (SD) age of 57.7 (12.3) years. Median (IQR) disease duration was 74.0 (108.0) months. Most of the patients (67%) were either positive for the rheumatoid factor and/or anti-citrullinated antibodies. The correlation of the CRP and TC (r= 0.16; p= 0.6) and their fractions HDL (0.09; p= 0.30) and LDL (r= 0.09; p= 0.36) were positive and weak. In the sub-analyses using the three cut-off values of the CRP, the correlations of both, TC (r= -0.18 to 0.09) and LDL (r= -0.34 to 0.11) were also weak. On the contrary, the correlation between the intermediate values of CRP and HDL was positive and moderate (r= 0.53; p= 0.01). The correlation of the GSR and TC (r=-0.03; p= 0.58) and LDL (r= 0.10; p= 0.88) were weak. There was, however, a negative and significant, although weak correlation between the GSR and HDL (r=-0.14; p= 0.02). In the multivariate analyses, the GSR had a negative and significant association with the levels of HDL (ß coefficient = -0.179, 95%CI - 0.28 -0.07; p= 0.001). CONCLUSION: In this study we confirmed an inverse, although weak, relationship between the GSR and HDL-cholesterol. On the contrary, we were not able to reproduce previous published data regarding the inverse relationship between the CRP values and the levels of the TC or their fractions. (AU)

Comparación de ortesis para el tratamiento de la artrosis de la base del pulgar / Compare splint for patients with thumb osteoarthritis (OA)

INTRODUCCIÓN: El tratamiento de la osteoartritis (OA) tiene como primer objetivo reducir el dolor y mejorar la función de la articulación afectada. La primera indicación para el tratamiento conservador de la rizartrosis es la inmovilización. La intención de inmovilizar es proveer soporte a la articulación carpometacarpiana (CMC) del pulgar mientras se permiten movimientos funcionales de la mano. Hay una variedad de ortesis para el pulgar disponibles, tanto prefabricadas como hechas a medida, y en diferentes tipos de material. Lamentablemente no hay lineamientos específicos del tipo de ortesis adecuada para la OA de la articulación CMC. El abordaje del Terapista Ocupacional incluye la consideración de la utilización de ortesis. Además el Terapista Ocupacional confecciona ortesis termoconformadas hechas a medida. OBJETIVO: Evaluar la efectividad de las ortesis termoconformadas inmovilizadoras de las articulaciones CMC y Metacarpofalangica (MCF) del pulgar vs. las ortesis termoconformadas inmovilizadoras de la articulación CMC. PACIENTES Y MÉTODO: Ensayo clínico no farmacológico de tecnología médica de riesgo no significativo, usando un diseño cruzado de nueve semanas de duración con dos períodos de tratamiento de cuatro semanas cada uno y una semana intermedia de washout (sin ortesis). En el primer período de tratamiento al paciente se le asignó aleatoriamente una ortesis corta o la larga que utilizó durante cuatro semanas y luego de una semana de washout cambió a la otra durante otras cuatro semanas. El estudio se realizó con pacientes derivados consecutivamente asignados al azar a fin de un tratamiento diferente. El dolor se evaluó con la Escala Visual Analógica. (EVA). La capacidad funcional manual se evaluó con la Sub Escala Funcional del Australian Canadian Osteoarthritis Hand Index versión (AUSCAN; Queensland, Australia), validada al español. RESULTADOS: Se incluyeron 18 pacientes, 13 (72%) eran de sexo femenino y tenían una mediana (p25-75) edad de 59.00 (55.00-66.50) años. En cuanto al estadio radiológico 1 (5.6%) paciente tenía estadío radiológico Eaton I, 10 (55.6 %) Eaton II, y 7 (38.9%) Eaton III. Siete pacientes (38.9%) comenzaron la intervención con la ortesis corta y 11 (61.1%) con la ortesis larga. El dolor disminuyó significativamente en el primer período: al día 0 la mediana de dolor fue 7.5 (5.00-9.00), en comparación con el día 28 donde la mediana fue de 3.00 (2-6.25) (p=000.1). La función mejoró significativamente en el primer período; la mediana de función manual al día 0 fue 0.54 (00.47-00.68), en comparación con el día 28 que fue de 0.76 (0.51-0.86) (p=0.028). No se observaron cambios significativos en dolor y función en el segundo período. No hubo diferencia en el tipo de ortesis asignada de acuerdo a mano dominante, mano tratada, uso de analgésicos y estadio de Eaton, pero hubo una mayor tendencia de utilizar la ortesis corta en ocupaciones de carga media, de 12.00 pacientes (66%), 7.00 (58,3%) ortesis cortas, versus 5.00 (41,7%) ortesis larga (p=0.017). Para pacientes con ocupaciones de carga liviana de 6.00 pacientes (33,3%), 6.00 (100%) tuvieron una tendencia de utilizar ortesis largas (p=0.017). CONCLUSIONES: Independiente del modelo de ortesis que se utilice, en este estudio se observó una mejoría clínica de los pacientes tanto en intensidad de dolor como en la función al primer mes de tratamiento. Estos hallazgos indicarían que este tipo de intervención terapéutica es positiva en rizartrosis. (AU)

INTRODUCTION: The treatment of osteoarthritis (OA) has as its primary objective to reduce pain and improve function of the affected joint. The first indication for conservative treatment is immobilization. The intention is to provide support to immobilize the carpometacarpal (CMC) of the thumb while functional hand movements are allowed. There are a variety of thumb splints available, both prefabricated and custommade, and different types of material. Unfortunately there are no specific guidelines on the type of correct splint for OA of the CMC joint. The Occupational Therapist approach includes consideration of the use of orthotics. OBJECTIVE: Analyze the effect of two different splints: thermoformed orthotics immobilizing the CMC and metacarpophalangeal (MCP) joints of the thumb vs. the thermoformed orthotics immobilizing the CMC joint, on hand function and pain in individuals with CMC OA. PATIENTS AND METHODS: Non-pharmacological medical technology clinical trial no significant risk, using a two period crossover design, the two four-week treatment periods were separated by oneweek washout period (without splint). A table of random symbols was used to determine treatment order assignments. Pain was evaluated by the Visual Analogue Scale (VAS); and hand functional by the Functional Sub Scale of Canadian Osteoarthritis Hand Index Australian version (AUSCAN, Queensland, Australia), validated in Spanish. RESULTS: Eighteen patients were included, 13 (72%) were female and they were middle-aged (p 25-75) of 59.00 (55.00-66.50) years. As for the radiological stage 1 (5.6%) patient had Radiological stage Eaton I, 10 (55.6 %) Eaton II, y 7 (38.9%) Eaton III. Seven patients (38.9%) started the intervention with the short orthosis and 11 (61.1%) with the long orthosis. The pain decreased significantly in the first period: at day 0 the median pain was 7.5 (5.00-9.00), compared to day 28 where the median was 3.00 (2- 6.25) (p = 000.1). The function improved significantly in the first period; the median manual function at day 0 was 0.54 (00.47- 00.68), compared to day 28 which was 0.76 (0.51-0.86) (p = 0.028). There were no significant changes in pain and function in the second period. There was no difference in the type of splint assigned according to dominant hand, hand treated, analgesic use and Eaton stage, but there was a greater tendency to use short orthotics in medium load occupations of 12.00 patients (66%), 7.00 (58.3%) short orthoses, versus 5.00 (41.7%) long orthoses (p = 0.017). For patients with light load occupations of 6.00 patients (33.3%), 6.00 (100%) had a tendency to use long orthoses (p = 0.017). CONCLUSIONS: Regardless of the orthotic model used, in this study clinical improvement was observed in both pain intensity and function at the first month of treatment. These findings would indicate that this type of therapeutic intervention is positive in thumb osteoarthritis. (AU)

Pre-existent NRTI and NNRTI resistance impacts on maintenance of virological suppression in HIV-1-infected patients who switch to a tenofovir/emtricitabine/rilpivirine single-tablet regimen.

Objectives: To evaluate the maintenance of virological suppression (VS) in antiretroviral-treated HIV-1-suppressed patients switching to a tenofovir/emtricitabine/rilpivirine (TDF/FTC/RPV) single-tablet regimen, by considering pre-existent resistance (pRes). Methods: pRes was evaluated according to resistance on all previous plasma genotypic resistance tests. Probability and predictors of virological rebound (VR) were evaluated. Results: Three hundred and nine patients were analysed; 5.8% of them showed resistance to both NRTIs and NNRTIs, while 12.6% showed resistance to only one of these drug classes. By 72 weeks, the probability of VR was 11.3%. A higher probability of VR was found in the following groups: (i) patients with NRTI + NNRTI pRes compared with those harbouring NRTI or NNRTI pRes and with those without reverse transcriptase inhibitor pRes (39.2% versus 11.5% versus 9.4%, P < 0.0001); (ii) patients with a virus with full/intermediate resistance to both tenofovir/emtricitabine and rilpivirine compared with those having a virus with full/intermediate resistance to tenofovir/emtricitabine or rilpivirine and those having a virus fully susceptible to TDF/FTC/RPV (36.4% versus 17.8% versus 9.7%, P < 0.001); and (iii) patients with pre-therapy viraemia >500 000 copies/mL compared with those with lower viraemia levels (>500 000: 16.0%; 100 000-500 000: 9.3%; <100 000 copies/mL: 4.8%, P = 0.009). pRes and pre-therapy viraemia >500 000 copies/mL were independent predictors of VR by multivariable Cox regression. Conclusions: TDF/FTC/RPV as a treatment simplification strategy shows a very high rate of VS maintenance. The presence of pRes to both NRTIs and NNRTIs and a pre-therapy viraemia >500 000 copies/mL are associated with an increased risk of VR, highlighting the need for an accurate selection of patients before simplification.

Virological response and resistance profile in HIV-1-infected patients starting darunavir-containing regimens.

OBJECTIVES: We evaluated the virological response in patients starting a regimen based on darunavir/ritonavir (DRV/r), which is currently the most widely used ritonavir-boosted protease inhibitor. METHODS: Data from 206 drug-naïve and 327 PI-experienced patients starting DRV/r 600/100 mg twice daily (DRV600) or 800/100 mg once daily (DRV800) were examined. The probabilities of virological success (VS) and virological rebound (VR) were evaluated in survival analyses. Baseline DRV/r resistance and its evolution at failure were also examined. RESULTS: DRV600 was preferentially administered in patients with complex requirements (older age, higher viraemia, lower CD4 cell count and DRV/PI resistance) compared with DRV800. By 12 months, the probability of achieving VS was 93.2% and 84.3% in drug-naïve and PI-experienced patients, respectively. The higher the baseline viraemia, the longer was the time required to achieve VS, both in drug-naïve patients [>500 000 HIV-1 RNA copies/mL: median [interquartile range (IQR)] 6.1 (5.1-10.3) months; 100 000-500 000 copies/mL: median (IQR) 4.9 (3.8-6.1) months; <100 000 copies/mL: median (IQR) 3.9 (3.5-4.8) months; P < 0.001] and in PI-experienced patients [≥100 000 copies/mL: median (IQR) 7.2 (5.7-11.6) months; <100 000 copies/mL: median (IQR) 2.8 (2.4-3.3) months; P < 0.001]. In PI-experienced patients, the probability of VR was higher for higher viraemia levels (22.3% for ≥100 000 copies/ml vs. 9.7% for <100 000 copies/mL; P = 0.007). Baseline resistance did not affect the virological response. At failure, a high percentage of patients maintained virus susceptible to all PIs (drug-naïve: 95%; PI-experienced: 80%). Despite being used more often in patients with more complex requirements, DRV600 performed as well as DRV800. CONCLUSIONS: In clinical practice, use of DRV/r (with its flexible dosage) results in high rates of virological response. These data support the use of PI/r in patients whose characteristics require potent drugs with a high genetic barrier.

Is entheses ultrasound reliable? A reading Latin American exercise.

The objective of this study is to evaluate inter-reader entheses ultrasound (US) reliability and the influence of the type of image or degree of sonographer experience on US reliability in patients with spondyloarthritis (SpA). Eighteen Latin American ultrasonographers with different experience took part in an US reading exercise evaluating 60 entheseal images (50 % static images and 50 % videos) from healthy controls and SpA patients. The following sonographic lesions were assessed: structure, thickness, bone proliferation/tendon calcification, erosions, bursitis, and Doppler signal. Another group of three experts with significant experience in entheses US read all images too. Inter-reader reliability among participants and experts was calculated by the Cohen's kappa coefficient. Thresholds for kappa values were <0.2 poor, 0.21-0.4 fair, 0.41-0.6 moderate, 0.61-0.8 good, and 0.81-1 excellent. Furthermore, the results for the expert group were stratified based on the type of image. Kappa correlation coefficients among participants, showed variability depending on the type of lesion, being fair for structure and thickness, moderate for calcifications, erosions, and bursitis, and excellent for Doppler signal. Inter-reader reliability among experts was higher, being moderate for structure and thickness, good for calcifications and bursitis, and excellent for erosions and Doppler. Inter-reader reliability for assessing calcification and structure using static images was significantly higher than for videos. Overall inter-reader reliability for assessing entheses by US in SpA is moderate to excellent for most of the lesions. However, special training seems fundamental to achieve better inter-reader reliability. Moreover, the type of image influenced these results, where evaluation of entheses by videos was more difficult than by static images.

HCV NS3 sequencing as a reliable and clinically useful tool for the assessment of genotype and resistance mutations for clinical samples with different HCV-RNA levels.

OBJECTIVES: This study aims to evaluate the reliability and clinical utility of NS3 sequencing in hepatitis C virus (HCV) 1-infected patients who were candidates to start a PI-containing regimen. METHODS: NS3 protease sequencing was performed by in-house-developed HCV-1 subtype-specific protocols. Phylogenetic analysis was used to test sequencing reliability and concordance with previous genotype/subtype assignment by commercial genotyping assays. RESULTS: Five hundred and sixty-seven HCV plasma samples with quantifiable HCV-RNA from 326 HCV-infected patients were collected between 2011 and 2014. Overall, the success rate of NS3 sequencing was 88.9%. The success rate between the two subtype protocols (HCV-1a/HCV-1b) was similarly high for samples with HCV-RNA >3 log IU/mL (>92% success rate), while it was slightly lower for HCV-1a samples with HCV-RNA ≤3 log IU/mL compared with HCV-1b samples. Phylogenetic analysis confirmed the genotype/subtype given by commercial genotyping assays in 92.9% (303/326) of cases analysed. In the remaining 23 cases (7.1%), 1 was HCV-1g (previously defined as subtype 1a), 1 was HCV-4d (previously defined as genotype 1b) and 1 was HCV-1b (previously defined as genotype 2a/2c). In the other cases, NS3 sequencing precisely resolved the either previous undetermined/discordant subtype 1 or double genotype/subtype assignment by commercial genotyping assays. Resistance-associated variants (RAVs) to PI were detected in 31.0% of samples. This prevalence changed according to PI experience (17.1% in PI-naive patients versus 79.2% in boceprevir/telaprevir/simeprevir-failing patients). Among 96 patients with available virological outcome following boceprevir/telaprevir treatment, a trend of association between baseline NS3 RAVs and virological failure was observed (particularly for HCV-1a-infected patients: 3/21 failing patients versus 0/22 achieving sustained virological response; P = 0.11). CONCLUSIONS: HCV-NS3 sequencing provides reliable results and at the same time gives two clinically relevant pieces of information: a correct subtype/genotype assignment and the detection of variants that may interfere with the efficacy of PI.

Características de los tratamientos biológicos en enfermedades reumáticas en Argentina: quinto informe del registro BIOBADASAR / Features of rheumatic diseases biological treatments in Argentina: BIOBADASAR fifth report

Introducción: El proyecto BIOBADASAR (Registro argentino deeventos adversos con tratamientos biológicos en reumatología)comenzó en agosto de 2010, para recabar información a largo plazosobre los eventos adversos en tratamientos biológicos en pacientescon enfermedades reumáticas en la práctica clínica cotidiana enArgentina.Pacientes y método: Se registraron datos de cada paciente,tratamientos y acontecimientos adversos relevantes o importantes.Los pacientes debían tener enfermedad diagnosticada y tratadacon un agente biológico. Cada caso se comparó con un control:un paciente con tratamiento no biológico con característicasdemográficas similares. Se analizaron los datos con análisis de lavarianza, con test de t de Student, Mann Whitney, test chi2, o testexacto de Fisher. El análisis de supervivencia de los tratamientoshasta su discontinuación o interrupción se realizó con el método deKaplan-Meier y test log-rank...

Background: BIOBADASAR (Argentine Registry of Adverse Eventsin Biological Treatments in Rheumatology) was started in August2010 to obtain long-term information of patients with rheumatic diseases,treatments and adverse events in everyday clinical practice.Patients and methods: Data on patients’ demographics,treatments and adverse events were collected. Patients had a diagnosisof a rheumatic disease and were treated with biological agent.To compare information, a control group was included, consisting ofpatients treated with similar demographic characteristics but treatedwith a non-biological agent. Data were analysed with Anova,Student´s t, Mann Whitney, chi2, Fisher´s exact tests, as appropriate.Survival analysis of treatments was performed with Kaplan-Meiercurves and log-rank test...

HIV-1 integrase genotyping is reliable and reproducible for routine clinical detection of integrase resistance mutations even in patients with low-level viraemia.

OBJECTIVES: Integrase drug resistance monitoring deserves attention because of the increasing number of patients being treated with integrase strand-transfer inhibitors. Therefore, we evaluated the integrase genotyping success rate at low-level viraemia (LLV, 51-1000 copies/mL) and resistance in raltegravir-failing patients. METHODS: An integrase genotypic resistance test (GRT) was performed on 1734 HIV-1 samples collected during 2006-13. Genotyping success rate was determined according to the following viraemia levels: 51-500, 501-1000, 1001-10 000, 10 001-100 000 and >100 000 copies/mL. The reproducibility of integrase GRT was evaluated in 41 plasma samples processed in duplicate in two reference centres. The relationship between LLV and resistance prevalence was evaluated in a subset of 120 raltegravir-failing patients. RESULTS: Overall, the integrase genotyping success rate was 95.7%. For viraemia levels 51-500 and 501-1000 copies/mL, the rate of success was 82.1% and 94.0%, respectively. GRT was reproducible, producing sequences with a high similarity and an equal resistance profile regardless of the sequencing centre or viraemia level. Resistance was detected both at LLV and at viraemia >1000 copies/mL (51-500 copies/mL = 18.2%; 501-1000 = 37.5%; 1001-10 000 = 53.7%; 10 001-100 000 = 30.0%; and >100 000 = 30.8%). At viraemia ≤500 copies/mL, Q148H/K/R and N155H had the same prevalence (9.1%), while the Y143C/H/R was completely absent. At early genotyping (within 3 months of raltegravir treatment), Q148H/K/R and N155H mutations were detected regardless of the viraemia level, while Y143C/H/R was observed only in samples with viraemia >1000 copies/mL. CONCLUSIONS: Our findings prove the reliability of HIV-1 integrase genotyping and reinforce the concept that this assay may be useful in the management of failures even at LLV.

Genotypic testing on HIV-1 DNA as a tool to assess HIV-1 co-receptor usage in clinical practice: results from the DIVA study group.

PURPOSE: We have developed a sequencing assay for determining the usage of the genotypic HIV-1 co-receptor using peripheral blood mononuclear cell (PBMC) DNA in virologically suppressed HIV-1 infected patients. Our specific aims were to (1) evaluate the efficiency of V3 sequences in B versus non-B subtypes, (2) compare the efficiency of V3 sequences and tropism prediction using whole blood and PBMCs for DNA extraction, (3) compare the efficiency of V3 sequences and tropism prediction using a single versus a triplicate round of amplification. RESULTS: The overall rate of successful V3 sequences ranged from 100 % in samples with >3,000 copies HIV-1 DNA/10(6) PBMCs to 60 % in samples with <100 copies total HIV-1 DNA /10(6) PBMCs. Analysis of 143 paired PBMCs and whole-blood samples showed successful V3 sequences rates of 77.6 % for PBMCs and 83.9 % for whole blood. These rates are in agreement with the tropism prediction obtained using the geno2pheno co-receptor algorithm, namely, 92.1 % with a false-positive rate (FPR) of 10 or 20 % and of 96.5 % with an FPR of 5.75 %. The agreement between tropism prediction values using single versus triplicate amplification was 98.2 % (56/57) of patients using an FPR of 20 % and 92.9 % (53/57) using an FPR of 10 or 5.75 %. For 63.0 % (36/57) of patients, the FPR obtained via the single amplification procedure was superimposable to all three FPRs obtained by triplicate amplification. CONCLUSIONS: Our results show the feasibility and consistency of genotypic testing on HIV-1 DNA tropism, supporting its possible use for selecting patients with suppressed plasma HIV-1 RNA as candidates for CCR5-antagonist treatment. The high agreement between tropism prediction by single and triple amplification does not support the use of triplicate amplification in clinical practice.

Aroma characterisation and UV elicitation of purple basil from different plant tissue cultures.

Exposure to stressful environmental conditions can induce severe metabolic variations in basil (Ocimum basilicum) aroma. The aromatic profiles of Dark Opal and Red Rubim varieties (in vivo plants, in vitro shoots, callus, and suspension cultures) were investigated for the first time. The established calli represented the most interesting miniaturised aromatic plant systems, as they were able to emit many typical basil volatiles with very low amounts of phenylpropanoids (1-2%). The hydrocarbon monoterpenes and oxygenated volatiles emitted from calli of both varieties were greatly and conversely affected by UV-C and UV-B, in comparison with the non-irradiated samples. As calli of both varieties still maintained very low levels of phenylpropanoids even after UV elicitation, they might be regarded not only as efficient in vitro plant models to study volatile compounds under UV stress conditions, but also as safe aromatic biomass in comparison with in vivo basil plants.

Spanish LupusPRO: cross-cultural validation study for lupus.

PURPOSE: LupusPRO is a disease-targeted, patient-reported, outcome measure that was developed and validated among US patients with systemic lupus erythematosus (SLE). To expand the availability and use of the tool, we undertook a cross-cultural adaptation and validation study of the Spanish-translated version of the LupusPRO. METHOD: Forward and back translations of the 43-item English LupusPRO were undertaken and pretested in five individuals. The finalized Spanish version was administered to 211 SLE patients of Hispanic ancestry from the US and Latin America. Short Form-36 (Spanish) and Spanish LupusPRO were also administered. Disease activity was ascertained using the systemic lupus erythematosus disease activity index. A Spanish LupusPRO questionnaire that could be completed within 2-3 days was mailed to SLE patients of Hispanic ancestry and they mailed it back. Internal consistency reliability, test-retest reliability, criterion validity (against disease activity or health status) and convergent validity were tested. All reported p values are two-tailed. RESULTS: A total of 211 Spanish-speaking SLE patients (90% women) participated. Test-retest reliability of LupusPRO domains ranged from 0.80-0.95, while internal consistency reliability of the domains ranged from 0.71-0.96. Convergent validity with corresponding domains of the SF-36 was present. All health-related quality of life domains of the LupusPRO (except procreation) performed well against disease activity measures, establishing its criterion validity. Confirmatory factor analysis showed a good fit. CONCLUSION: The Spanish LupusPRO has fair psychometric properties and is now available to be included in clinical trials and in longitudinal studies for testing of responsiveness to change.

Tercer reporte de eventos adversos con tratamientos biológicos en Argentina. Informe de registro biobadasar / Thrid report of adverse events with biologics in Argentina. Report from biobadasar registry

Introducción: BIOBADASAR (Registro Argentino de Eventos Adversos con Tratamientos Biológicos en Reumatología) comenzó en agosto de 2010. La importancia de este registro es mostrar datos locales que, probablemente, puedan diferir de otros registros. El objetivo es comunicar los resultados del tercer reporte de BIOBADASAR. Métodos: Todos los pacientes con enfermedades reumáticas que requirieron tratamiento con agentes biológicos y pacientes controles sin estos tratamientos fueron incluidos en la base de datos provenientes de 32 centros participando a lo largo de la Argentina. Tres áreas de datos son analizados: características de los pacientes, tratamientos y eventos adversos...

Introduction: BIOBADASAR (Argentine Registry of Adverse Events with Biological Treatments in Rheumatology) began in August 2010. The importance of this registry is to show local data that may probably differ from other registries. The objective is to communicate the results of the third BIOBADASAR report. Methods: All patients with rheumatic diseases who required treatment with biological agents and control patients without these treatments were included in the database from 32 participating centers throughout Argentina. Three areas of data are analyzed: patient characteristics, treatments and adverse events...

The lowest X4 Geno2Pheno false-positive rate is associated with greater CD4 depletion in HIV-1 infected patients.

Through this study we evaluated whether the HIV-1 tropism determined by genotypic analysis correlates with HIV-1 markers, such as CD4 cell count and plasma HIV-RNA. The analysis was performed on 1221 HIV-1 B-subtype infected patients with an available V3 sequence (all maraviroc naive). Of them, 532 were antiretroviral therapy (ART) naive and 689 ART experienced. Tropism determination was performed by using the geno2pheno (co-receptor) algorithm set at a false-positive rate (FPR) of 10% and 2%. Potential associations of FPR with CD4 cell count and viraemia were evaluated. Association of V3 mutations with genotypic-determined tropism was also evaluated according to different FPR ranges. About 26% of patients (either ART naive or ART experienced) were infected by X4-tropic viruses (using the classical 10% FPR cut-off). However, a significantly lower proportion of ART-naive patients had FPR ≤ 2% in comparison with ART-experienced patients (4.9% vs. 12.6%, respectively, p <0.001). The risk of advanced HIV-1 infection (with CD4 cell count ≤ 200 cells/mm(3)) was significantly greater in X4-infected patients, either ART-naive (OR (95% CI)), 4.2 (1.8-9.2); p 0.0006) or ART-experienced (2.3 (1.4-3.6); p 0.0003), with FPR set at 2% (but not at 10%). This finding was confirmed by multivariable logistic analysis. No relationship was found between viraemia and FPR ≤2%. Some X4-related mutations were significantly associated with FPR ≤2% (ART-naive patients, S11R, Y21V, G24K and G24R, p ≤0.001; ART-experienced patients, Y7K, S11R, H13Y, p ≤0.002). In conclusion, these findings show that within the context of genotypically-assessed CXCR4 tropism, FPR ≤2% defines (far better than 10%-FPR) a viral population associated with low CD4 rank, with potentially greater cytopathic effect, and with more advanced disease.