Biterapia con atazanavir/ritonavir más raltegravir versus terapia triple en segunda línea: Ensayo ARTE / ATV/r+RAL (DT) after failure with NNRTI

Antecedentes: La terapia dual ha surgido como un nuevo concepto para el tratamiento del VIH. Este estudio tenía como objetivo comparar un régimen dual basado en ATV/r + RAL (TD) frente a estándar de tres drogas con ATV/r + TDF/FTC (TT) luego del fracaso de un primer esquema ba-sado en INNTR.ClinicalTrials.gov, Número: NCT01829802.Método: Estudio piloto abierto, multicéntrico y aleatoriza-do. Resultado primario: proporción de sujetos con ARN del VIH-1 menor a 50 copias/mL en semana 48 (S48). Resulta-dos secundarios: discontinuaciones asociadas a eventos adversos (EA), tiempo transcurrido hasta la supresión viral, desarrollo de mutaciones de resistencia a la integrasa y proteasa, cambio en recuento de CD4. Resultados: De los 57 participantes seleccionados, 34 fue-ron asignados aleatoriamente para recibir: TD (n: 18) o TT (n: 16). En semana 48, 67% (n: 12/18) en TD tuvo respues-ta virológica y 88% (n: 14/16) en rama según el análisis FDA, intención de tratamiento/expuestos (p = NS) y 73% (TD) y 93% (TT) según análisis por protocolo (p = NS). El cambio de CD4 entre basal - S48: +119 y +52 células/µL en DT y TT, respectivamente. Cuatro participantes en TD y uno en TT presentaron fracaso virológico en la semana 48. Un participante desarrolló una mutación de resistencia a integrasa (155H).Conclusión: ATV/r+RAL como terapia dual de segunda línea mostró una tendencia al fracaso virológico más frecuente, en comparación con TT, aunque el estudio piloto no tenía potencia para demostrar esta diferencia. Este estudio está registrado en ClinicalTrials.gov, Número: NCT01829802

Background: Dual therapy has emerged as a novel concept for HIV treatment. This study was aimed at comparing a nucleoside-sparing dual regimen consisting of ATV/r + RAL (DT) vs standard therapy of ATV/r + TDF/FTC (TT) among individuals failing first NNRTI-containing treatment.Methods: Randomized multicenter open-label pilot study. Primary outcome: proportion of subjects with plasma HIV-1 RNA below the limit of detection (<50 copies/mL) at 48 weeks (W48). Secondary outcomes: proportion of discontinuation due to adverse events (AEs), time until viral suppression, time until loss of virological response, development of integrase resistance mutations, and absolute change in CD4 counts. The primary outcome was analyzed using the FDA snapshot analysis.Results: Out of 57 participants screened, 34 were randomized to receive: DT (n: 18) or TT (n: 16). At W48, virological response was achieved in 67% (n: 12/18) of participants receiving DT and 88% (n: 14/16) receiving TT by FDA snapshot analysis (p = NS) and 73% and 93% by per-protocol analysis (p = NS). CD4 cell count median change from baseline to W48 was +119 and + 52 cell/µL in DT and TT, respectively. Four participants receiving DT and one TT presented virological failure at W48, with low pVL. One participant developed an integrase resistance mutation (155H) and suppressed later on TT.Conclusion: ATV/r+RAL as second-line therapy showed a trend to more frequent virological failure, compared to TT, although the study was unpowered to prove this difference. No major differences were seen in tolerance or toxicity.This study is registered with ClinicalTrials.gov, Number: NCT01829802

The protective role of raltegravir in experimental acute lung injury in vitro and in vivo

Disruption of pulmonary endothelial permeability and associated barrier integrity increase the severity of acute respiratory distress syndrome (ARDS). This study investigated the potential ability of the human immunodeficiency virus-1 (HIV-1) integrase inhibitor raltegravir to protect against acute lung injury (ALI) and the underlying mechanisms. Accordingly, the impact of raltegravir treatment on an in vitro lipopolysaccharide (LPS)-stimulated human pulmonary microvascular endothelial cell (HPMEC) model of ALI and an in vivo LPS-induced two-hit ALI rat model was examined. In the rat model system, raltegravir treatment alleviated ALI-associated histopathological changes, reduced microvascular permeability, decreased Evans blue dye extravasation, suppressed the expression of inflammatory proteins including HMGB1, TLR4, p-NF-κB, NLRP3, and MPO, and promoted the upregulation of protective proteins including claudin 18.1, VE-cadherin, and aquaporin 5 as measured via western blotting. Immunohistochemical staining further confirmed the ability of raltegravir treatment to reverse LPS-induced pulmonary changes in NLRP3, claudin 18.1, and aquaporin 5 expression. Furthermore, in vitro analyses of HPMECs reaffirmed the ability of raltegravir to attenuate LPS-induced declines in VE-cadherin and claudin 18.1 expression while simultaneously inhibiting NLRP3 activation and reducing the expression of HMGB1, TLR4, and NF-kB, thus decreasing overall vascular permeability. Overall, our findings suggested that raltegravir may represent a viable approach to treating experimental ALI that functions by maintaining pulmonary microvascular integrity.

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.

Cambios electrocardiográficos en pacientes con VIH con y sin inhibidores de proteasa vs NNRTI / Differences in electrocardiographic changes in HIV patients with and without treatment with protease inhibitors vs NNRTI

Resumen ANTECEDENTES La infección por el virus de inmunodeficiencia humana (VIH) incrementa la prevalencia de prolongación del intervalo QT corregido (QTc), lo que es un factor independiente de eventos de enfermedad cardiovascular en esta población. En la bibliografía mundial se asocia este cambio con la administración de los antirretrovirales inhibidores de proteasa y efavirenz. Sin embargo, no se conocen datos de estos cambios en la población mexicana. MATERIAL Y MÉTODO Estudio prospectivo observacional en el que se seleccionaron expedientes de marzo de 2015 a mayo de 2016 de la consulta externa del Instituto Nacional de Enfermedades Respiratorias (INER); se dividieron en dos grupos: sin tratamiento, por reciente diagnóstico, y con tratamiento antirretroviral. Se registraron datos clínicos, tratamiento farmacológico, electrocardiograma y química sanguínea. RESULTADOS No se encontraron diferencias entre ambos grupos respecto a edad ni electrólitos séricos. Tampoco se encontró relación entre la prolongación del QTc con efavirenz o los inhibidores de proteasa. Raltegravir disminuyó la duración del QTc (p = 0.001) mientras que la coinfección por molusco contagioso se asoció con prolongación del QTc (p = 0.02). CONCLUSIÓN En nuestro estudio no logramos demostrar en población mexicana relación de la prolongación del QTc con los antirretrovirales de primera ni segunda línea. Se requieren más estudios para determinar la importancia clínica del efecto de raltegravir y molusco contagioso en el QTc.

Abstract BACKGROUND Human immunodeficiency virus (HIV) infection increases the prevalence of QTc prolongation (QTc), which is an independent factor of cardiovascular disease events in this population. In the world literature this change is associated with the use of the protease inhibitors and efavirenz antiretrovirals. However, no data are available on these changes in the Mexican population. MATERIAL AND METHOD A prospective observational study was done selecting records from March 2015 to May 2016 of the external consultation of the National Institute of Respiratory Diseases (INER), Mexico City; they were divided into two groups, those without treatment, because recent diagnosis, and with antiretroviral treatment. We recorded clinical data, pharmacological treatment, electrocardiogram and blood chemistry. RESULTS We found no differences between the two groups regarding age or serum electrolytes. We found no association between QTc prolongation and efavirenz or protease inhibitors. Raltegravir decreased QTc duration (p = 0.001) while molluscum contagiosum coinfection was associated with QTc prolongation (p = 0.02). CONCLUSION In our study, we failed to demonstrate in Mexican population association of QTc prolongation with first- and second-line antiretrovirals. More studies are needed to determine the clinical significance of the effect of raltegravir and molluscum contagiosum on QTc.

Synthetic process improvement of raltegravir / 国际药学研究杂志

Objective To improve the synthetic procedure of the HIV integrase inhibitor raltegravir. Methods With 2-ami-no-2-methyl-propionitrile hydrochloride as starting material,the target compound raltegravir was synthesized through amino protection by benzyl chloroformate ,amidoxime formation,cyclization induced by michael addition&Claisen rearrangement,N-methylation,N-acylation,hydroxyl protection by trimethylacetyl chloride,hydrogenolysis by the system of Pd/C and formic acid,amidation with the 5-methyl-1,3,4-oxadiazol-formyl chloride,and immediate hydrolysis without more purification. Results The chemical structure of raltegravir and the intermediates were characterized by 1H NMR,13C NMR and MS. The overall yield was about 19.45%. Conclusion Compared with the preceding process,the developed route is easy to operate,safe and suitable for industrialized production in accor-dance with the quality standard of active pharmaceutical ingredient(API).

Tratamiento anti-retroviral conteniendo raltegravir en mujeres gestantes con infección por VIH: revisión sistemática / Antiretroviral therapy containing raltegravir in HIV-infected pregnant women: systematic review

Introduction: The risk of mother to child transmission (MTCT) of HIV increases in pregnant women diagnosed late in pregnancy. Some experts suggest that the use of raltegravir (RAL), as part of the antiretroviral treatment in these pregnant women, could reduce the risk of MTCT, since RAL can quickly decrease the viral load. Objective: To evaluate the available scientific information on the efficacy and safety of RAL, during the third trimester of pregnancy, in reducing MTCT of HIV. Methods: We conducted a systematic review of the literature. The following databases were consulted: MEDLINE, Tripdatabase, Cochrane, Lilacs and Web of Science. We included systematic reviews, clinical trials, observational studies or case reports. The search was not filtered by language. Results: Fourteen studies met the inclusion criteria. Selected studies were case reports or case series. We included, in total, 44 pregnancies (with 45 live births). A case of TMI of HIV was reported. Eight studies reported adverse events, of which four cases can be attributed to the use of RAL. Conclusion: There is insufficient evidence on the efficacy and safety of RAL to decrease the risk of MTCT in HIV pregnant women who present in the last trimester of pregnancy.

Introducción: El riesgo de transmisión materno-infantil (TMI) del VIH incrementa en mujeres gestantes diagnosticadas tardíamente en el embarazo. Algunos expertos sugieren que el uso de raltegravir (RAL), como parte del esquema de tratamiento anti-retroviral en estas pacientes, puede reducir el riesgo de TMI al disminuir rápidamente la carga viral. Objetivo: Evaluar la información científica existente sobre la eficacia y seguridad de RAL durante el tercer trimestre de gestación en la reducción de la TMI del VIH. Materiales y Métodos: Revisión sistemática de la literatura. Las bases de datos consultadas fueron: MED-LINE, Tripdatabase, Cochrane, Lilacs y Web of Science. En la búsqueda se incluyeron revisiones sistemáticas, ensayos clínicos, estudios observacionales o reportes de caso. La búsqueda no se filtró por idioma. Resultados: Catorce estudios cumplieron los criterios de inclusión. Los estudios seleccionados fueron reportes o series de caso. Se incluyeron 44 embarazos (con 45 nacidos vivos), se reportó un caso de TMI del VIH y ocho estudios reportaron eventos adversos, cuatro de ellos atribuibles al uso de RAL. Conclusión: No se encontró evidencia suficiente sobre la eficacia y seguridad RAL en mujeres gestantes con infección por VIH que se presentan en el último trimestre del embarazo, para disminuir el riesgo de TMI.

Selective and rapid determination of raltegravir in human plasma by liquid chromatography-tandem mass spectrometry in the negative ionization mode / 药物分析学报

A selective and rapid high-performance liquid chromatography–tandem mass spectrometry method was developed and validated for the quantification of raltegravir using raltegravir-d3 as an internal standard (IS). The analyte and IS were extracted with methylene chloride and n-hexane solvent mixture from 100 mL human plasma. The chromatographic separation was achieved on a Chromolith RP-18e endcapped C18 (100 mm ? 4.6 mm) column in a run time of 2.0 min. Quantitation was performed in the negative ionization mode using the transitions of m/z 443.1-316.1 for raltegravir and m/z 446.1-319.0 for IS. The linearity of the method was established in the concentration range of 2.0–6000 ng/mL. The mean extraction recovery for raltegravir and IS was 92.6% and 91.8%, respectively, and the IS-normalized matrix factors for raltegravir ranged from 0.992 to 0.999. The application of this method was demonstrated by a bioequivalence study on 18 healthy subjects.

Effect and Safety of Raltegravir in the Treatment of AIDs / 中国药师

Referred to the latest literatures on raltegravir from home and abroad, the effect and safety of raltegravir in the treat-ment of AIDs were reviewed. The results showed that raltegravir was a necessary component for the initial treatment and repeated treat-ment of AIDs. Up till now, there was no report on its serious adverse reactions and drug interactions.

Simple Spectrophotometric Method for Estimation of Raltegravir Potassium in Bulk and Pharmaceutical Formulations.

A simple, rapid, precise, and economical spectrophotometric method has been developed for quantitative analysis of Raltegravir Potassium (RALP) in tablet formulations. The stock solution of RALP was prepared in water. The standard solution of RALP in water showed absorption maxima at 331.6 nm. The drug obeyed Beer–Lambert’s law in the concentration range of 1–100 μg/mL with coefficient of correlation (R2) was 0.9999. It showed coefficient of variation below 2 % in intra-run and inter-run precision. The recovery was obtained with values close to the 100 % of theoretical at three different concentrations. The results of analysis have been validated as per ICH guidelines. The method can be adopted in routine analysis of RALP in bulk and tablet dosage form and it involves water as a solvent and no complex extraction techniques.

Sustained increase of serum creatine phosphokinase levels and progressive muscle abnormalities associated with raltegravir use during a 32-week follow-up in an HIV-1 experienced patient on simplified HAART regimen, intolerant to protease inhibitors and abacavir: a case report / Aumento sostenido de los niveles de creatina fosfoquinasa sérica y las anormalidades musculares progresivas asociadas con el uso de raltegravir durante un seguimiento de 32 semanas en un paciente de VIH-1 experimentado en régimen de terapia TAAA simplificada, con intolerancia a los inhibidores de proteasa y abacavir: un reporte de caso

Sustained increase of serum creatine phosphokinase (CPK) concentrations and muscle abnormalities have been reported in patients taking raltegravir (RAL). In this report, we describe a case of sustained and asymptomatic increase of serum CPK concentrations associated with raltegravir, zidovudine, and lamivudine in an HIV-1 experienced patient with intolerance to protease inhibitor, abacavir and pencillin during 32 weeks of continuous drug monitoring.

Un aumento sostenido de las concentraciones de creatina fosfoquinasa sérica (CPK) y las anormalidades musculares ha sido reportado en relación con pacientes que toman raltegravir (RAL). En este reporte, describimos un caso de aumento sostenido y asintomático de concentraciones séricas de CPK asociadas con raltegravir, zidovudina y lamivudina en un paciente experimentado de VIH-1 con intolerancia al inhibidor de la proteasa, al abacavir y la penicilina durante 32 semanas de monitoreo farmacológico continuo.

A reduced grade of liver fibros-steatosis after raltegravir, maraviroc and fosamprenavir in an HIV/HCV co-infected patient with chronic hepatitis, cardiomyopathy, intolerance to nelfinavir and a marked increase of serum creatine phosphokinase levels probably related to integrase inhibitor use / Grado reducido de fibroesteatosis tras la administración de raltegravir, maraviroc y fosamprenavir en un paciente co-infectado de VIH/VHC con hepatitis crónica, cardiomiopatía, intolerancia al nelfinavir y un aumento pronunciado de los niveles de creatina fosfoquinasa sérica probablemente debido al uso del inhibidor de la integrasa

The use of new antiretroviral drugs in HIV infection is particularly important in patients with intolerance or resistance to other antiretroviral agents. Raltegravir and maraviroc represent new, important resources in salvage regimens. A reduced grade of liver fibro-steatosis after a combination of raltegravir and maraviroc (second-line) has not been studied and the mechanism by which these new drug classes induced a marked reduction of grade of liver diseases is currently unknown. In the present case report, nested in an ongoing multicentre observational study on the use of new antiretroviral inhibitors in heavy treatment-experienced HIV patients, we evaluated the correlation between a "short therapeutic regimen" raltegravir, maraviroc and fosamprenavir and liver diseases. The aim of this report is to describe the use of a three-drug regimen based on two novel-class antiretroviral agents (raltegravir and maraviroc) plus the protease inhibitor fosamprenavir, in an experienced HIV-infected patient with chronic progressive hepatitis C complicated by liver fibrosis; an overwhelming increased serum creatine kinase level occurred during treatment, and is probably related to integrase inhibitor administration. At present no information is available regarding this correlation.

El uso de nuevos medicamentos antiretrovirales para la infección por VIH es particularmente importante en los pacientes con intolerancia o resistencia a otros agentes antiretrovirales. Raltegravir (RTV) y maraviroc (MRV) representan nuevos e importantes recursos en las terapias de salvamento. Un grado reducido de fibroesteatosis hepática después de una combinación de raltegravir y maraviroc (terapia de segunda línea) no ha sido estudiado, y el mecanismo por el cual estas nuevas clases de droga indujeron una marcada reducción de grado de las enfermedades hepáticas se desconoce hasta el momento. Como parte de la realización en curso de un estudio observacional multicentro acerca del uso de nuevos inhibidores antiretrovirales en pacientes de VIH altamente experimentados en el tratamiento, en el presente reporte de caso se evalúa la correlación entre un "régimen terapéutico corto" (raltegravir, maraviroc y fosamprenavir) y las enfermedades del hígado. El objetivo de este reporte es describir el uso de un régimen de tres medicamentos - basado en dos agentes antiretrovirales de nuevo tipo (raltegravir y maraviroc) además del fosamprenavir inhibidor de la proteasa - en un paciente de VIH experimentado. El paciente también sufre de hepatitis C evolutiva, progresiva, crónica, complicada por fibrosis hepática. Durante el tratamiento, se produjo un aumento extraordinario del nivel de creatina quinasa sérica, el cual probablemente esta relacionado con la administración del inhibidor de la integrasa. Actualmente no hay información disponible con respecto a esta correlación.

Resistencia a los inhibidores de la integración del Virus de la Inmunodeficiencia Humana Tipo I: [revisión] / Resistance to inhibitors of the Human Immunodeficiency Virus Type I integration: [review]

En esta revisión, se resume el rol de la integrasa en la infección por VIH-1, el mecanismo de los inhibidores de la integrasa y la resistencia, con énfasis en el Raltegravir (RAL), el primer inhibidor de la integrasa autorizado para tratar la infección por VIH-1.

This review will summarize the role of integrase in HIV-1 infection, the mechanism of integrase inhibitors and resistance with an emphasis on Raltegravir (RAL), the first integrase inhibitor licensed to treat HIV-1 infection.

Resistance to inhibitors of the human immunodeficiency virus type 1 integration

This review will summarize the role of integrase in HIV-1 infection, the mechanism of integrase inhibitors and resistance with an emphasis on raltegravir (RAL), the first integrase inhibitor licensed to treat HIV-1 infection.

New antiretroviral therapy and its role in HIV treatment in Asia

Non-nucleoside analog reverse transcriptase inhibitor (NNRTI)-based therapy including fixed-dose combinations (tenofovir/emtracitabine/efavirenz in the developed world, or stavudine or zidovudine/lamivudine/nevirapine in the developing world) has been used widely as preferred first line therapy. However, NNRTIs have a low genetic barrier to resistance which increases the chance of treatment failure in poorly adherent patients. Newer antiretroviral drugs, including etraverine, darunavir, maraviroc, and raltegavir, have demonstrated efficacy and safety in patients who have experienced at least two classes of antiretrovirals. With appropriate use of these new drugs, in combination with other active antiretroviral agents, the goal of suppression of viral load below 50 copies can be achieved.This article is a review of currently available and future new antiretroviral drugs for second line and salvage therapies in resource-limited settings.

Improved synthesis of raltegravir / 中国药科大学学报

Aim: To develop a practical synthetic route of raltegravir, a drug for HIV treatment. Methods: Raltegravir was synthesized through an eight-step process including aminonitrile formation, protection with benzyloxy-carbonyl group, conversion of the nitrile to the amidoxime, cyclization to form hydroxypyrimidinone, N-methyla-tion, amidation with microwave-assistance, deprotection, amidation with acyl chloride. Results: The overall yield of the eight-step synthesis is about 12. 0% and the structure of the target compound was confirmed by ~1H NMR, ~(13)C NMR, LR-MS and HR-MS. Conclusion: The reported synthetic process of raltegravir highlights the advantages in terms of readily available starting materials, convenient operation and low cost.