Resistencia transmitida de VIH-1 en pacientes sin exposición a tratamiento antirretroviral: Guatemala / Transmitted HIV-1 resistance in patients without exposure to antiretroviral treatment: Guatemala / Resistência transmitida ao HIV-1 em pacientes sem exposição ao tratamento antirretroviral: Guatemala

El objetivo del estudio fue describir los niveles de resistencia transmitida de VIH-1 en adultos atendidos en Unidades de Atención Integral de Guatemala. El estudio incluyó registros de 185 pacientes adultos VIH-1 positivo, de reciente diagnóstico sin antecedente de uso de TAR, de noviembre del 2019 a noviembre del 2020. El análisis se realizó en el software DeepChek® v2.0, para la clasificación de la resistencia se siguió el algoritmo de Stanford HIVdb (v9.4 - 07/12/2022). Se encontró 18.4% (IC 95% 13.1 - 24.7%) de resistencia general a alguna familia de ARVs. Se evidenció 15.1% (IC 95% 10.3 - 21.1%) de resistencia individual a la familia de INNTR afectando principalmente a NVP y EFV; 2.2% (IC 95% 0.6 - 5.4%) de resistencia a INTR, mayormente a FTC/3TC; y 2.7% (IC 95% 0.9 - 6.2%) de resistencia intermedia y baja los IP NFV y LPV/r. Tres casos presentaron resistencia múltiple a los INTR + INNTR. Las mutaciones más frecuentemente encontradas fueron K103N (41.2%), M184V/I (8.8%) y M46I (5.9%). La elevada resistencia transmitida del VIH-1 en pacientes atendidos en distintas Unidades de Atención Integral del VIH, demuestra la importancia de analizar periódicamente la tendencia de la resistencia en personas que no han estado expuestas a ARVs, lo cual a su vez es un marcador indirecto de presencia de resistencia adquirida en el país, datos que evidencian la necesidad de acciones e intervenciones prontas y efectivas dado su impacto en la salud pública.

The objective of this study was to describe the levels of transmitted HIV-1 resistance in patients with a recent HIV diagnosis before starting ART, treated in Comprehensive Care Units in Guatemala during the years 2019 and 2020. The study included records of 185 HIV-positive adult patients, recently diagnosed with HIV without a history of ART use. The analysis was carried out in the DeepChek® v2.0 software, the Stanford HIVdb algorithm (v9.4 - 07/12/2022) was followed to classify resistance. 18.4% (95% CI 13.1 - 24.7%) of general resistance to some family of ARVs was found. There was evidence of 15.1% (95% CI 10.3 - 21.1%) of individual resistance to the NNRTI family, mainly affecting NVP and EFV; 2.2% (95% CI 0.6 - 5.4%) resistance to INTR, mostly to FTC/3TC; and 2.7% (95% CI 0.9 - 6.2%) of intermediate and low resistance IP NFV and LPV/r. Three cases presented multiple resistance to NRTIs + NNRTIs. The most frequently found mutations were K103N (41.2%), M184V/I (8.8%) and M46I (5.9%). The high transmitted resistance of HIV-1 in patients treated in different Comprehensive HIV Care Units demonstrates the importance of periodically analyzing the trend of resistance in people who have not been exposed to ARVs, which in turn is an indirect marker. of the presence of acquired resistance in the country, data that demonstrate the need for prompt and effective actions and interventions given its impact on public health.

O objetivo deste estudo foi descrever os níveis de resistência transmitida ao HIV-1 em adultos tratados em Unidades de Cuidados Integrais na Guatemala. O estudo incluiu prontuários de 185 pacientes adultos HIV-1 positivos, recentemente diagnosticados sem histórico de uso de TARV, no período de novembro de 2019 a novembro de 2020. A análise foi realizada no software DeepChek® v2.0, para classificação da resistência, O algoritmo Stanford HIVdb (v9.4 - 07/12/2022) foi seguido. Foi encontrada 18.4% (IC 95% 13.1 - 24.7%) de resistência geral a alguma família de ARVs. Houve evidência de 15.1% (IC 95% 10.3 - 21.1%) de resistência individual à família de NNRTI, afetando principalmente NVP e EFV; 2.2% (IC 95% 0.6 - 5.4%) resistência ao INTR, principalmente ao FTC/3TC; e 2.7% (IC 95% 0.9 - 6.2%) de resistência intermediária e baixa ao IP NFV e LPV/r. Três casos apresentaram resistência múltipla a NRTIs + NNRTIs. As mutações mais frequentemente encontradas foram K103N (41.2%), M184V/I (8.8%) e M46I (5.9%). A elevada resistência transmitida do HIV-1 em pacientes atendidos em diferentes Unidades de Cuidados Integrados ao HIV demonstra a importância de analisar periodicamente a tendência de resistência em pessoas que não foram expostas aos ARVs, o que por sua vez é um marcador indireto da presença de ARVs adquiridos. resistência no país, dados que demonstram a necessidade de ações e intervenções rápidas e eficazes dado o seu impacto na saúde pública.

Establishment of a rapid identification of adverse drug reaction program in R language implementation based on monitoring data / 浙江大学学报·医学版

OBJECTIVE@#To establish a clinically applicable model of rapid identification of adverse drug reaction program (RiADP) for risk management and decision-making of clinical drug use.@*METHODS@#Based on the theory of disproportion analysis, frequency method and Bayes method, a clinically applicable RiADP model in R language background was established, and the parameters of the model were interpreted by MedDRA coding. Based on the actual monitoring data of FDA, the model was validated by the assessing hepatotoxicity of lopinavir/ritonavir (LPV/r).@*RESULTS@#The established RiADP model included four parameters: standard value of adverse drug reaction signal information, empirical Bayesian geometric mean value, ratio of reporting ratio and number of adverse drug reaction cases. Through the application of R language parameter package "phViD", the model parameters could be output quickly. After being encoded by MedDRA, it was converted into clinical terms to form a clinical interpretation report of adverse drug reactions. In addition, the evaluation results of LPV/r hepatotoxicity by the model were matched with the results reported in latest literature, which also proved the reliability of the model results.@*CONCLUSIONS@#In this study, a rapid identification method of adverse reactions based on post marketing drug monitoring data was established in R language environment, which is capable of sending rapid warning of adverse reactions of target drugs in public health emergencies, and providing intuitive evidence for risk management and decision-making of clinical drugs.

Efectividad y seguridad del cambio a esquema basado en raltegravir en pacientes con infección por VIH dislipidémicos bajo terapia anti-retroviral en Fundación Arriarán / Efectiveness and safety of switching to raltegravir-based regimen in dyslipidemic HIV-infected patients receiving antiretroviral therapy at Arriaran Foundation

Resumen Introducción: El impacto del cambio de terapia antiretroviral (TAR) para tratar la dislipidemia en pacientes infectados por VIH no ha sido reportado en Chile. Objetivo: Evaluar la efectividad y seguridad a 12 meses del cambio de TAR a esquema con raltegravir (RAL) para tratar la dislipidemia. Material y Métodos: Cohorte retrospectiva de pacientes con infección por VIH en TAR, atendidos en Fundación Arriarán, con dislipidemia y que cambiaron a esquema con RAL para tratarla. Resultados: Se incluyó 73 casos, en TAR con inhibidores no nucleosídicos de transcriptasa reversa (INNTR; 50,7%) o inhibidores de proteasa (IP; 49,3%), con dislipidemia mixta (42,5%) o hipertrigliceridemia aislada (57,5%). La mediana de colesterol total (CT) y triglicéridos (TG) basales era 228 mg/dl y 420 mg/dl, respectivamente. El 94,5% tenía carga viral (CV) indetectable. Se modificó TAR de base en 58,4%; 89,1% recibía hipolipemiantes. Las concentraciones plasmáticas de lípidos descendieron significativamente a 12 meses (TG= −43,6%; CT= −19,3%). Ningún paciente presentó fracaso virológico, aunque 10,9% tuvo viremia detectable a 12 meses, mayoritariamente transitoria. Conclusiones: El cambio de TAR a RAL en pacientes dislipidémicos tratados con INNTR o IP reduce significativamente las concentraciones plasmáticas de TG y CT a 12 meses. Es una estrategia segura, pero puede observarse viremia transitoria.

Background: The impact of switching antiretroviral therapy (ART) regimen for dyslipidemia management in HIV-infected (HIV+) patients has not been reported in Chile. Aim: To assess effectiveness and safety at 12 months after switching to raltegravir-based regimen for dyslipidemia management. Methods: Retrospective cohort of HIV+ patients receiving ART at Arriaran Foundation, with dyslipidemia switched to raltegravir-based regimen for lipid management. Results: 73 patients were included, receiving ART based in nonnucleoside reverse transcriptase inhibitor (NNRTI; 50,7%) or protease inhibitor (PI; 49,3%), with mixed dyslipidemia (42,5%) or isolated hypertriglyceridemia (57,5%). At baseline, median total cholesterol (TC) and triglycerides (TG) were 228 mg/dl and 420 mg/dl, respectively; undetectable viral load (VL) was present in 94,5% of patients. Backbone ART was switched in 58,4% and lipid-lowering therapy was used by 89,1% of them. At 12 months, there was a significant decrease in TG (-43,6%) and TC (-19,3%). No cases of virologic failure were observed, although 10,9% of patients had detectable VL at 12 months, mostly transient. Conclusions: Switching ART to raltegravir-based regimen in dyslipidemic patients receiving NNRTI or PI is associated with a significative decrease in TG and TC at 12 months. This strategy is safe, but VL can be increased temporarily.

Avaliação da resistência aos inibidores da protease em pacientes vivendo com HIV em falha terapêutica / Evaluation of resistance to protease inhibitors in patients living with HIV in therapeutic failure

Inibidores de protease (IP) são importantes nos esquemas de resgate para pacientes que não respondem à terapia antirretroviral (TARV). O uso prévio de IP pode limitar o tratamento e a detecção de mutações de resistência a estes medicamentos (IP-DRM) e pode subsidiar a seleção do regime. O objetivo deste estudo consistiu em descrever as mutações principais para os IP em pacientes do Estado de São Paulo, expostos a pelo menos um IP e que estavam falhando à terapia antirretroviral, para avaliar os preditores do surgimento de IPDRM e o possível impacto dos subtipos do HIV-1 na resistência. Foram avaliadas sequências parciais do gene da polimerase do HIV-1 (RNA - Sequenciamento de Sanger) de 1696 pacientes em falha virológica, com genotipagem entre 2014 e 2017. Mutações de resistência aos antirretrovirais (Drug Resistance Mutations - DRM), susceptibilidade aos antirretrovirais (Genotypic Susceptibility Score ­ GSS) e subtipo viral, juntamente com os parâmetros clínicos e laboratoriais, foram avaliados utilizando-se regressões logísticas para acessar os preditores do surgimento de DRM e sua relação com os subtipos do HIV-1 circulantes em São Paulo (B, C e F). No total, 466 sequências apresentaram pelo menos uma IP-DRM (27,5%), mais comumente nos códons M46 (14,7%; 250/1696), V82 (13,8%; 234/1696) e I54 (13,3%; 225/1696). Mutações para as classes dos ITRN e ITRNN estavam presentes em 69,9% (1181) e 59,9% (1016), respectivamente, das 1696 sequências analisadas. De todas as sequências, 1496 (88,2%) tiveram predição de atividade plena ao darunavir (DRV), mas apenas 57,1% das sequências com pelo menos uma IP-DRM tiveram atividade plena ao DRV (266/466). A presença de IP-DRM teve associação (p<0,05) com maior tempo em tratamento, presença de mutações para os ITRN, uso de algum IP e com o subtipo F. Sequências de subtipo C tiveram menor quantidade de IP-DRM (10%; 9/87) em comparação com as de subtipo B (28%; 338/1216) e de subtipo F (35%; 58/168) (p <0,001), mas a análise ajustada sugere que esta associação não foi independente do tempo de tratamento mais curto e de menos esquemas utilizados por pacientes com HIV-1 C (OR: 0,59; IC 95: 0,2 ­ 2,5; p=0,48). HIV-1 F, juntamente com presença de mutações para os ITRN e maior tempo em tratamento estão associados com a presença de IP-DRM, com GSS mais baixo para o DRV e com a presença de mutação no códon I50. Entre pacientes com IP-DRM, a atividade plena ao DRV foi comprometida e esforços para detectar precocemente a falha são necessários, particularmente para o subtipo F do HIV-1, que mostrou associação com o surgimento de resistência e potencial impacto na susceptibilidade aos IP. Além disso, os resultados sugerem que as mutações para os ITRN podem servir como indicativo de um nível minimamente suficiente de adesão terapêutica, que permita o surgimento de IP-DRM. (AU)

Protease inhibitors (PI) are important in the salvage regimens for patients failing antiretroviral therapy (ART). Previous PI use may limit treatment and the detection of PI drug resistance mutations (PI-DRM) may subsidize the regimen selection. The aim of this study was to describe the major PI mutations among patients from São Paulo State, exposed to at least one PI and failing antiretroviral therapy to evaluate the predictors of mutation emergence and the possible impact of HIV-1 subtypes on resistance. Were evaluated HIV-1 partial polymerase sequences (RNA - Sanger sequencing) from 1696 patients on virological failure, genotyped between 2014 and 2017. Drug resistance mutations (DRM), antiretroviral susceptibility (Genotypic Susceptibility Score ­ GSS) and virus subtype, along with clinical and laboratory parameters, were evaluated using logistic regressions to access the predictors of mutations emergence and its relation with the circulating HIV-1 subtypes (B, C and F) in São Paulo State. A total of 466 sequences showed at least one PI-DRM (27.5%), most commonly M46 (14.7%; 250/1696), V82 (13.8%; 234/1696) and I54 (13.3%; 225/1696). Mutations to NRTI and to NNRTI drug classes were present in 69.9% and 59.9%, respectively, of the 1696 analyzed sequences. Full activity to darunavir was predicted for 88% of the patients (1496/1696), but it was only 57% among those with at least one PI-DRM (266/466). Presence of a PI-DRM was associated (p<0.05) to longer total time on treatment, presence of a NRTI mutation, use of any PI and subtype F. Subtype C sequences had less major PI-DRMs (10%, 9/87) compared with B (28%, 338/1216) or F (35%, 58/168) (p <0.001) but adjusted analysis suggested that this association was not independent from a shorter treatment time and fewer regimens (OR 0.59, Confidence Interval 95: 0.2 - 2.5, p=0.48). Subtype F, together with NRTI mutations and longer time on treatment was associated with the presence of PI-DRM, with a lower darunavir GSS and with mutations at codon I50. Among patients with PI-DRM, the full activity to darunavir was compromised in many cases and efforts to detect the failure at earlier time are warranted, particularly for HIV-1 subtype F that showed association with the emergence of resistance, with potential impact in protease inhibitors sequencing. Furthermore, the results suggest that NRTI mutations may serve as an indicative of a minimally sufficient level of therapy adherence to allow PI-DRM emergence. (AU)

Transmitted drug resistance in patients with acute/recent HIV infection in Brazil

Abstract Introduction: The widespread use of antiretroviral therapy increased the transmission of antiretroviral resistant HIV strains. Antiretroviral therapy initiation during acute/recent HIV infection limits HIV reservoirs and improves immune response in HIV infected individuals. Transmitted drug resistance may jeopardize the early goals of early antiretroviral treatment among acute/recent HIV infected patients. Methods: Patients with acute/recent HIV infection who underwent resistance test before antiretroviral treatment initiation were included in this analysis. HIV-1 sequences were obtained using an in house protease/reverse transcriptase genotyping assay. Transmitted drug resistance was identified according to the Stanford HIV Database for Transmitted Drug Resistance Mutations, based on WHO 2009 surveillance list, and HIV-1 subtyping according to Rega HIV-1 subtyping tool. Comparison between patients with and without transmitted drug resistance was made using Kruskal-Wallis and Chi-square tests. Results: Forty-three patients were included, 13 with acute HIV infection and 30 with recent HIV infection. The overall transmitted drug resistance prevalence was 16.3% (95% confidence interval [CI]: 8.1-30.0%). The highest prevalence of resistance (11.6%, 95% CI: 8.1-24.5) was against non-nucleoside reverse transcriptase inhibitors, and K103N was the most frequently identified mutation. Conclusions: The high prevalence of nonnucleoside reverse transcriptase inhibitors resistance indicates that efavirenz-based regimen without prior resistance testing is not ideal for acutely/recently HIV-infected individuals in our setting. In this context, the recent proposal of including integrase inhibitors as a first line regimen in Brazil could be an advantage for the treatment of newly HIV infected individuals. However, it also poses a new challenge, since integrase resistance test is not routinely performed for antiretroviral naive individuals. Further studies on transmitted drug resistance among acutely/recently HIV-infected are needed to inform the predictors of transmitted resistance and the antiretroviral therapy outcomes among these population.

Síndrome de Cushing iatrogénico por corticoides inhalados en paciente VIH / Cushing syndrome in a HIV patient using inhaled steroids: report of one case

We report a 41-year-old man with HIV and a chronic obstructive pulmonary disease, treated for seven months with Fluticasone/Salmeterol and antiretroviral therapy (Lamivudine, Tenofovir, Atazanavir and Ritonavir). While using these medications, the patients developed a Cushing syndrome in a period of five months. After performing laboratory and imaging tests, it was concluded that the most probable cause of the syndrome was the interaction of inhaled steroids with Ritonavir. After discontinuing these medications the syndrome reverted in a period of 8 months.

Antiretroviral drugs saquinavir and ritonavir reduce inhibitory concentration values of itraconazole against Histoplasma capsulatum strains in vitro

Abstract Recent studies have shown that some drugs that are not routinely used to treat fungal infections have antifungal activity, such as protease inhibitor antiretroviral drugs. This study investigated the in vitro susceptibility of Histoplasma capsulatum var. capsulatum to saquinavir and ritonavir, and its combination with the antifungal itraconazole. The susceptibility assay was performed according to Clinical and Laboratory Standards Institute guidelines. All strains were inhibited by the protease inhibitor antiretroviral drugs. Saquinavir showed minimum inhibitory concentrations ranging from 0.125 to 1 μg mL−1 for both phases, and ritonavir presented minimum inhibitory concentrations ranging from 0.0312 to 4 μg mL−1and from 0.0625 to 1 μg mL−1 for filamentous and yeast phase, respectively. Concerning the antifungal itraconazole, the minimum inhibitory concentration values ranged from 0.0019 to 0.125 μg mL−1 and from 0.0039 to 0.0312 μg mL−1 for the filamentous and yeast phase, respectively. The combination of saquinavir or ritonavir with itraconazole was synergistic against H. capsulatum, with a significant reduction in the minimum inhibitory concentrations of both drugs against the strains (p < 0.05). These data show an important in vitro synergy between protease inhibitors and itraconazole against the fungus H. capsulatum.

Nephrotoxicity during tenofovir treatment: a three-year follow-up study in a Brazilian reference clinic

Abstract In this study, 275 patients in use of tenofovir were retrospectively followed-up for three years to evaluate risk factors involved in impaired renal function. Analysis of variance (ANOVA) and Tukey's test were used to verify any differences in creatinine levels and estimated clearance at 0, 6, 12, 24 and 36 months, adjusting for the co-variables sex, skin color, age >50 years, arterial hypertension, diabetes and the use of the ritonavir-boosted protease inhibitors (PI/r) lopinavir/r or atazanavir/r. The software package STATISTICA 10® was used for statistical analysis. The patients’ mean age was 43.2 ± 10.7 years. Systemic arterial hypertension (SAH) and diabetes were found in 20.4% and 8.7% of the patients, respectively. Overall, 96.7% were on tenofovir associated with lamivudine (TDF + 3TC), 39.3% on lopinavir/r, 29.8% on efavirenz, and 17.6% on atazanavir/r. There was a statistically significant difference in estimated creatinine clearance at 24 months, when the co-variables male (F = 3.95; p = 0.048), SAH (F = 6.964; p = 0.009), and age over 50 years (F = 45.81; p < 0.001) were taken into consideration. Analysis of the co-variable use of atazanavir/r showed a tendency toward an increased risk over time (F = 2.437; p = 0.063); however, no significant time interaction was seen. At 36-month, a statistically significant difference was found for age over 50 years, (F = 32.02; p < 0.05) and there was a significant time-by-sex interaction (F = 3.117; p = 0.0149). TDF was discontinued in 12 patients, one because of a femoral neck fracture (0.7%) and 11 due to nephrotoxicity (4%). Of these latter cases, 9/11 patients were also using protease inhibitors. These data strongly alert that tenofovir use should be individualized with careful attention to renal function especially in male patients, over 50 years, with SAH, and probably those on ATV/r.

Seroconversión frente a primovacunación reforzada contra hepatitis B en niños con cáncer / Seroconversion in response to a reinforced primary hepatitis B vaccination in children with cancer

Introducción: La respuesta inmune a los antígenos de las vacunas está disminuida en los niños con cáncer. El objetivo de este estudio fue evaluar la seroconversión frente a vacuna ADN recombinante contra hepatitis B al momento del inicio de la quimioterapia y/o remisión en niños con cáncer. Pacientes y método: Estudio prospectivo, bicéntrico, controlado, no aleatorizado de niños con diagnóstico reciente de cáncer pareados con niños sanos. Los casos fueron vacunados a tiempo 0, 1 y 6 meses, a dosis de 20 y 40 μg si eran < ó > 10 años, respectivamente, con vacuna ADN recombinante contra hepatitis B, en el momento del diagnóstico en el caso de los tumores sólidos y luego de la remisión en el caso de los tumores hematológicos. El grupo control recibió el mismo esquema, con dosis de 10 o 20 μg respectivamente. Se midieron anticuerpos séricos anti-HBs a los 2, 8 y 12 meses posvacunación. Seroconversión se definió como títulos anti-HBs > 10 mUI/ml al octavo mes. Resultados: Un total de 78 niños con cáncer y 25 controles fueron evaluados con títulos anti-HBs al octavo mes. La tasa de seroconversión fue de 26,9%, en niños con cáncer, sin diferencia por edad, género ni tipo de tumor (p = 0,13; 0,29; y 0,44, respectivamente), y de 100% en el grupo control (p < 0,0001, comparado con los niños con cáncer). En el seguimiento a los 12 meses solo el 31,9% de los niños con cáncer presentaba títulos anti-HBs > 10 mUI/ml. Conclusiones: La vacunación contra hepatitis B con vacuna ADN recombinante, con esquema reforzado de 3 dosis, en el momento del inicio de la quimioterapia y/o remisión provee una respuesta inmune insuficiente en la mayoría de los niños con cáncer. En esta población debieran evaluarse vacunas de tercera generación, con adyuvantes más inmunogénicos, esquemas reforzados a los 0, 1, 2 y 6 meses, medición de títulos de anticuerpos al octavo y duodécimo mes, eventual uso de refuerzos y reevaluación de inmunogenicidad si correspondiese.

Introduction: Immune response against vaccine antigens may be impaired in children with cancer. The aim of this study was to evaluate the seroconversion response against hepatitis B vaccination (HBV) at the time of chemotherapy onset and/or remission in children with cancer. Patients and method: Prospective, two-centre, controlled, non-randomised study conducted on children recently diagnosed with cancer, paired with healthy subjects. Cases received HBV at time 0, 1 and 6 months with DNA recombinant HBV at a dose of 20 and 40 μg if < or > than 10 years of age, respectively, at the time of diagnosis for solids tumours and after the remission in case of haematological tumours. Controls received the same schedule, but at of 10 and 20 μg doses, respectively. HBs antibodies were measured in serum samples obtained at 2, 8 and 12 months post-vaccination. Protective titres were defined as > 10 mIU/ml at 8th month of follow up. Results: A total of 78 children with cancer and 25 healthy controls were analysed at month 8th of follow up. Seroconversion rates in the cancer group reached 26.9%, with no differences by age, gender or type of tumour (P = .13, .29, and .44, respectively). Control group seroconversion was 100% at the 8th month, with P < .0001 compared with the cancer group. At month 12 of follow up, just 31.9% of children with cancer achieved anti-HBs antibodies > 10 mIU/ml. Conclusions: Vaccination against hepatitis B with three doses of DNA recombinant vaccine at an increased concentration, administrated at the time of onset of chemotherapy and/or remission provided an insufficient immune response in a majority of children with cancer. More immunogenic vaccines should be evaluated in this special population, such as a third generation, with more immunogenic adjuvants, enhanced schedules at 0, 1, 2, 6 month, evaluation of antibody titres at month 8 and 12 h to evaluate the need for further booster doses.

Impacto del tratamiento antirretroviral en la función sexual de mujeres con VIH / Impact of antiretroviral treatment on sexual function of HIV-infected women

Objetivo. Describir la función sexual de un grupo de mujeres con VIH bajo tratamiento antirretroviral. Evaluar si existe diferencia entre las tratadas con un esquema que contiene Inhibidores No Nucleósidos de la Transcriptasa Inversa (INNTI) y aquéllas que reciben Inhibidores de la Proteasa (IP). Material y métodos. Estudio descriptivo, transversal. Muestra: 92 pacientes mujeres con VIH bajo tratamiento antirretroviral, que son asistidas en el Instituto Centralizado de Asistencia e Investigación Clínica Integral (CAICI). Instrumento: Se les realizó una encuesta que consta de características demográficas, preguntas referidas al VIH y al The Female Sexual Function Index (FSFI). Análisis estadístico: se utilizó ANOVA, Kruskall-Wallis, Chi cuadrado, regresión logística y alpha de Cronbach. Resultados. Edad media: 42±10 años; 65% tenían pareja estable, siendo el 73% de estas sero-discordantes. La mayoría (45,7%) estaban en tratamiento antirretroviral por más de dos años, con una media de CD4 mayor a 500 cél/ml y el 90% con carga viral plasmática indetectable. El 64,1% presentaba otra enfermedad asociada, por lo que el 55,4% tomaba medicación concomitante. El 27,2% continuó con su actividad sexual luego del diagnóstico de VIH, pero el 26,1% nunca la retomó. La puntuación total alcanzada por medio del FSFI fue de 20,4±10,1 para las tratadas con IP y 20±10,6 para las tratadas con INNTI (p <0,005). Conclusiones. La muestra analizada presentó un puntaje compatible con disfunción sexual. No hubo diferencia estadísticamente significativa en la función sexual de las mujeres tratadas con IP y las tratadas con INNTI

Summary Objective: To describe the sexual function in a group of women with HIV on antiretroviral treatment. To assess whether there is a difference between those treated with Non-nucleoside Inhibitors of he Reverse Transcriptase (NNRTI) and those receiving protease inhibitors (PIs). Material and methods: Descriptive, transversal study. Study sample: 92 women with HIV on antiretroviral therapy who are assisted in the Central Institute of Integral Assistance and Clinical Research (CAICI). Instrument: They completed a survey consisting of questions about demographic characteristics, HIV, and The Female Sexual Function Index (FSFI). Statistical analysis: ANOVA, Kruskal-Wallis, Chi-square, logistic regression and Cronbach’s alpha. Results: Average age was 42±10 years; 65% had a steady partner, of which 73% were sero-discordant. Most patients (45.7%) had been on antiretroviral treatment for more than two years, with a mean CD4 greater than 500 cells/ml and 90% with undetectable plasma viral load. Other illnesses were present in 64.1%, and 55.4% were taking concomitant medication. Sexual activity after HIV diagnosis was continued by 27.2%, while 26.1% never resumed it. The total score achieved by the FSFI was 20.4±10.1 among those treated with IP and 20.0±10.6 among those treated with NNRTI(p<0.005). Conclusions: The score in the present sample supports the existence of sexual dysfunction. There was no statistically significant difference in the sexual function of women treated with either PI or NNRTI

Chemical constituents from culture of Streptomyces sp. CPCC 202950 / 中国中药杂志

Eleven compounds were isolated from the culture of Streptomyces sp. CPCC 202950 by a combination of various chromatographic techniques including column chromatography over macroporous resin HP-20, MCI, and reversed-phase HPLC. Their structures were identified as 1H-pyrrole-2-carboxamide(1),5'-deoxy-5'-methylthioinosine(2), vanillamide(3), trans-3-methylthioacrylamide(4), 1,2,3,4-Tetraydro-1H-pyrido[3,4-b]indole-3-carboxylic acid(5), cyclo(L-pro-L-tyr) (6), N-[2-(4-hydroxyphenyl)]ethylacetamide(7), benzamide (8), cyclo ('L-leucyl-trans-4-hydroxy-L-proline)(9), cyclo-(Phe-Gly) (10), and tryptophan (11). Among them, compounds 1 and 2 were new natural products. In the preliminary assays, none of the compounds exhibited obvious inhibition of HIV-1 protease activity (IC50 > 10 micromol x L(-1)).

¿Es posible que se genere resistencia al dolutegravir cuando se utiliza este agente en el tratamiento de primera línea? / Is resistance to Dolutegravirpossible when this drug is used in first-line therapy?

Dolutegravir (DTG) es un inhibidor de la integrasa del VIH aprobado recientemente como tratamiento por la FDA (Food and Drug Administration) en los Estados Unidos. Utilizado como parte de un tratamiento de primera línea, DTG es el único tratamiento antirretroviral frente al cual no se ha seleccionado resistencia en la clínica. Nuestra teoría es que esto se debe al prolongado tiempo de unión del DTG a la enzima integrasa así como a una capacidad de replicación muy disminuida por parte de los virus que podrían volverse resistentes al DTG. Además, conjeturamos que DTG podría ser utilizado en estrategias que apunten a la erradicación del VIH...

Dolutegravir (DTG) is an HIV integrase inhibitor that was recently approved for therapy by the Food and Drug Administration in the United States. When used as part of First-line therapy, DTG is the only HIV drug that has not selected for resistance mutations in the clinic. We believe that this is due to the long binding time of DTG to the integrase enzyme as well as greatly diminished replication capacity on the parte of viruses that might become resistant to DTG. We further speculatethat DTG might be able to be used in strategies aimed at HIV eradication...

In vivo assessment of antiretroviral therapy-associated side effects

Antiretroviral therapy has been associated with side effects, either from the drug itself or in conjunction with the effects of human immunodeficiency virus infection. Here, we evaluated the side effects of the protease inhibitor (PI) indinavir in hamsters consuming a normal or high-fat diet. Indinavir treatment increased the hamster death rate and resulted in an increase in triglyceride, cholesterol and glucose serum levels and a reduction in anti-oxLDL auto-antibodies. The treatment led to histopathological alterations of the kidney and the heart. These results suggest that hamsters are an interesting model for the study of the side effects of antiretroviral drugs, such as PIs.

Effect and mechanism of endoplasmic reticulum stress on cisplatin resistance in ovarian carcinoma / 中华肿瘤杂志

<p><b>OBJECTIVE</b>The study intended to investigate the effect and mechanism of endoplasmic reticulum stress on cisplatin resistance in ovarian carcinoma.</p><p><b>METHODS</b>RT-PCR and Western blot were used to test the expression of mTOR and Beclin1 mRNA and protein in ovarian cancer SKOV3 cells after saquinavir induction. MTT assay was used to analyze the influence of saquinavir on cisplatin sensitivity in SKOV3 cells.</p><p><b>RESULTS</b>The IC50 of SKOV3 cells was (5.490 ± 1.148) µg/ml. After induced by Saquinavair 10 µmol/L and 20 µmol/L, the IC50 of SKOV3 cells was increased to (11.199 ± 0.984) µg/ml and (14.906 ± 2.015) µg/ml, respectively. It suggested that the sensitivity of ovarian cancer cells to cisplatin was decreased significantly (P = 0.001). The expression of mTOR and Beclin1 mRNA and protein was significantly different among the five groups: the (Saquinavair+DDP) group of, Saquinavair group, LY294002 group, DDP group and control group (P < 0.001) . The expressions of mTOR and Beclin1 mRNA were highest in the (Saquinavair+DDP) group, 0.684 ± 0.072 and 0.647 ± 0.047, respectively; Secondly, the Saquinavair group, 0.577 ± 0.016 and 0.565 ± 0.037, respectively. The expressions of mTOR and Beclin1 proteins were also highest in the (Saquinavair+DDP) group, 0.624 ± 0.058 and 0.924 ± 0.033, respectively, followed by the Saquinavair group, 0.544 ± 0.019 and 0.712 ± 0.024. 3-MA inhibited the autophagy and restored cisplatin sensitivity in the SKOV3 cells after Saquinavir induced ER stress (P < 0.001).</p><p><b>CONCLUSIONS</b>Saquinavir can effectively induce endoplasmic reticulum stress in SKOV3 cells. Endoplasmic reticulum stress can decrease the sensitivity to cisplatin in SKOV3 cells. The mechanism of the decrease of sensitivity to cisplatin in SKOV3 cells may be that ERS regulates cell autophagy through the mTOR and Beclin1 pathways. ERS of tumor cells and autophagy may become a new target to improve the therapeutic effect of chemotherapy and to reverse the drug resistance in tumor treatment.</p>

Ergotismo y HIV / Ergotism and HIV

El ergotismo es una complicación de la intoxicación aguda y/o el abuso crónico de los derivados del ergot. Se manifiesta por síndrome vasomotor con enfermedad vascular periférica que frecuentemente compromete extremidades. Presentamos cuatro casos de pacientes infectados con el virus de la inmunodeficiencia humana 1 (HIV-1), en tratamiento con antirretrovirales que incluyen inhibidores de la proteasa reforzados con ritonavir, y que habían recibido ergotamina como automedicación. Ellos desarrollaron síntomas de enfermedad vascular periférica y al examen físico sus pulsos estaban disminuidos o ausentes. El Doppler arterial confirmó signos de espasmo arterial difuso en dos de ellos. Se hizo diagnóstico de ergotismo secundario a la asociación de ergotamina-inhibidores de la proteasa. Los pacientes fueron tratados con la discontinuación de las drogas involucradas (inhibidores de la proteasa y ergotamina), bloqueantes cálcicos, profilaxis antitrombótica con enoxaparina, antiagregación con ácido acetil salicílico y uno ellos recibió pentoxifilina e infusión de prostaglandinas vasodilatadoras con mejoría de los síntomas. Discutimos la presentación clínica de esta interacción medicamentosa, difícil de diagnosticar correctamente sin una fuerte sospecha de su existencia.

Ergotism is a complication of acute intoxication and/or chronic abuse of ergot derivatives. It expresses itself through a vasomotor syndrome with peripheral vascular disease which frequently involves extremities. We report four cases of HIV-1 infected patients treated with antiretroviral drugs including boosted-protease inhibitors who had self-treated themselves with ergotamine. They developed peripheral vascular disease symptoms and their pulses where diminished or absent in the physical examination. Arterial Doppler confirmed diffused arterial spasm in two of them. Ergotism following ergotamine-protease inhibitors association was diagnosed. Patients were treated through the discontinuity of involved drugs (protease inhibitors and ergotamine), calcium blockers; antithrombotic prophylaxis with enoxaparine, antiaggregant therapy with acetylsalicylic acid, and one of them received pentoxifylline and vasodilator prostaglandins infusion, with amelioration of the symptoms. We discuss the clinical presentation of this drug interaction, difficult to diagnose properly without a strong suspicion of its existence.

Desenvolvimento de métodos analíticos qualitativos para a análise de darunavir comprimidos / Development of qualitative analytical methods for monitoring darunavir tablets

O darunavir é um inibidor de protease utilizado para o tratamento da infecção pelo HIV. Trata-se de um dos pilares da terapia de coquetel para pacientes portadores do vírus. O controle de qualidade na indústria farmacêutica, para identificação do teor de substância ativa e estudo das características físico-químicas do fármaco, é de fundamental importância para garantir a qualidade do produto final. O darunavir, até então, não possui métodos de análise padronizados em compêndios oficiais. Este fato justifica novas pesquisas nesta área para o desenvolvimento e validação de métodos analíticos, bem como a análise químico-farmacêutica para este fármaco tanto na matéria-prima como no produto acabado. Dessa forma, neste trabalho foram realizados (a) peso médio; (b) determinação do ponto de fusão; (c) cromatografia em camada delgada; (d) análise na região do ultravioleta; (e) análise na região do infravermelho e (f) cromatografia líquida de alta eficiência. Através do desenvolvimento das técnicas propostas é possível avaliar qualitativamente a qualidade de darunavir em comprimidos.

Darunavir is a protease inhibitor used in the treatment of HIV infection. It is a pillar of the drug cocktail for patients diagnosed with the virus. Quality control in the pharmaceutical industry, to verify the content of active substance and study the physicochemical characteristics of the drug, is essential to ensure final product quality. Until now, standardized methods for the analysis of darunavir have not been available in official compendia. This justifies new research, to develop and validate analytical methods, as well as physicochemical and pharmaceutical analysis for this drug, both as a raw material and a finished product. Thus, in this study, (a) the average weight of darunavir tablets and (b) the melting point of the pure drug were determined, and the following analytical techniques were performed: (c) thin-layer chromatography, (d) ultraviolet spectroscopy, (e) infrared spectroscopy and (f) high performance liquid chromatography. By developing the above techniques, it is possible to make a qualitative assessment of the quality of darunavir tablets.