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

Comparación entre terapia basada en dolutegravir o efavirenz en población con Virus de Inmunodeficiencia Humana / Comparison between dolutegravir or efavirenz-based therapy in population with Human Inmunodeficiency Virus

En el año 2018 la Organización Mundial de la Salud (OMS) actualizó sus recomendaciones para el tratamiento en infecciones por Virus de Inmunodeficiencia Humana (VIH), estableciendo el régimen basado en dolutegravir como primera línea y el régimen basado en efavirenz como línea alternativa, posteriormente en el año 2019 Honduras introdujo dolutegravir para su uso en hombres y mujeres con métodos de planificación familiar. Objetivo: Comparar la efectividad entre dolutegravir y efavirenz para lograr la supresión viral en población con infección por VIH en el Servicio de Atención Integral del Hospital Mario Catarino Rivas (SAI-HMCR) en el período 2017-2020. Pacientes y métodos: Estudio observacional retrospectivo, que se realizó en el SAI-HMCR en Honduras. Se estudió la población mayor de 18 años con diagnóstico nuevo de VIH que inició tratamiento antirretroviral (TAR) con base en dolutegravir en el período 2019-2020, y se comparó con los que iniciaron TAR con base en efavirenz en el período 2017-2018. Resultados: La mediana (rango intercuartil) de carga viral basal fué de 8,658 copias/ml (1,036-27,710) en el grupo con efavirenz y 44,303 copias/ml (2,040-115,240) en el grupo con dolutegravir; la carga viral a las 24 semanas de terapia fue de 0 copias/ml (0-139) y 40 copias/ml (40-90) respectivamente. Conclusiones: La terapia basada en dolutegravir es superior a la terapia basada en efavirenz para lograr la supresión viral y aumentar el conteo de linfocitos T CD4...(AU)

Perfil lipídico e inhibidores de integrasa: revisión sistemática y metaanálisis / Lipid profile and integrase inhibitors: a systematic review and metaanalysis

Resumen Introducción: en pacientes con virus de inmunodeficiencia humana algunos antirretrovirales afectan el perfil lipídico incrementando el riesgo cardiovascular. Hay evidencia de que los inhibidores de integrasa afectan poco al perfil lipídico. El presente estudio buscó evaluar la mejor evidencia disponible sobre cambios en lípidos de pacientes con virus de inmunodeficiencia humana que cambiaron su terapia antirretroviral a esquemas con inhibidores de integrasa. Métodos: revisión sistemática de la literatura con intención metaanalítica. A partir de la pregunta: "En pacientes mayores de 16 años con virus de inmunodeficiencia humana, los esquemas antirretrovirales que incluyen inhibidores de integrasa comparados con aquellos esquemas antirretrovirales que no los incluyen, ¿presentan cambios en el perfil lipídico?" se extrajeron palabras clave para búsqueda de la evidencia publicada entre 1997 y diciembre 2019. Se incluyeron estudios experimentales y observacionales y su calidad fue evaluada. Se realizó análisis por inhibidor de integrasa y parámetro lipídico buscándose síntesis cuantitativa de la evidencia. Resultados: se identificaron 17 estudios relevantes susceptibles de síntesis de la evidencia con un total de 5 683 pacientes. De estos, 2 878 entraron a síntesis cuantitativa. Acorde a lo encontrado, los inhibidores de integrasa presentan mejor perfil lipídico comparados a otros antirretrovirales. Dolutegravir fue el que mostró mejor perfil lipídico cuando la comparación se hizo con inhibidores de proteasa. Raltegravir tuvo mejor perfil lipídico comparándolo con inhibidores de transcriptasa inversa no análogos de nucleósidos. Conclusiones: el uso de inhibidores de integrasa es un factor relevante en el control del riesgo cardiovascular en pacientes con virus de inmunodeficiencia humana.

Abstract Introduction: some antiretrovirals affect the lipid profile in human immunodeficiency virus patients increasing their cardiovascular risk. Integrase inhibitors generate little lipid alteration. The present study evaluated the best available evidence about changes in the lipid profile in human immunodeficiency virus patients who had switch from different antiretroviral therapies to schemes with integrase inhibitors. Methods: a systematic review with meta-analytic intention was carried out. From the question "How does antiretroviral schemes with integrase inhibitors impact in lipid profile in human immunodeficiency virus patients compared to antiretroviral schemes without integrase inhibitors?" an evidence search was done. Articles from experimental and observational studies were included and the quality was evaluated. An analysis by integrase inhibitor and lipid parameters was performed. Results: 17 relevant studies were identified and 2 878 patients were included in the quantitative synthesis. According to evidence, integrase inhibitors had a better lipid profile compared to other antiretrovirals. Dolutegravir had a better metabolic profile when it was compared with protease inhibitors. Raltegravir had a better lipid profile when it was compared to non-nucleoside analog reverse transcriptase inhibitors. Conclusions: integrase inhibitors are a relevant factor for cardiovascular risk control in patients with human immunodeficiency virus.

Efectos adversos neuropsiquiátricos de dolutegravir en la práctica clínica real / Neuropsychiatric adverse effects of dolutegravir in real-life clinical practice

Introducción: Los inhibidores de la integrasa, y especialmente dolutegravir (DTG), son el tratamiento de primera línea antirretroviral por su eficacia y seguridad. Aunque en los ensayos pivotales la tasa de efectos adversos (EA) era baja (2-3%), en los estudios de vida real parece ser mayor, especialmente los EA neuropsiquiátricos. El objetivo fue determinar el porcentaje de EA e interrupción de DTG en nuestro centro y la relación con los antecedentes psiquiátricos. Métodos: Estudio descriptivo retrospectivo de pacientes que iniciaron DTG entre 2015-2017. Se registraron: interrupción del tratamiento, EA y enfermedad psiquiátrica. Se realizó seguimiento desde el inicio del del tratamiento con DTG y se registraron las hospitalizaciones y las visitas a urgencias y atención primaria. Fue autorizado por el Comité Ético de Investigación Clínica de Aragón. Resultados: Se incluyeron 283 pacientes, entre 11-87 años, 70% varones. El 21% naive. Interrumpieron el tratamiento con DTG el 24%, un 10% por EA. Se detectó un 5% de EA neuropsiquiátricos. Este grupo tenía más antecedentes psiquiátricos (62 vs. 41%; p=0,002) que el de pacientes que continuaron el tratamiento, y precisaron más visitas en atención primaria (18,8 vs. 8,4%; p=0,016) y urgencias (8,7 vs. 3,3%; p=0,061). Conclusión: Los pacientes que interrumpieron el tratamiento con DTG tenían más antecedentes psiquiátricos. Por ello, aunque se precisan más estudios, sería necesario valorar este antecedente previamente al tratamiento con inhibidores de la integrasa. Síntomas como ansiedad, insomnio o depresión pueden ser EA de DTG con una frecuencia mayor de la esperada. Ser identificados por los médicos de atención primaria y urgencias podría evitar una cascada de prescripción innecesaria.(AU)

Introduction: Integrase inhibitors and especially dolutegravir (DTG) are placed as a first-line antiretroviral treatment for their efficacy and safety. Although in the pivotal trials the rate of adverse effects (AEs) was low (2-3%), in real-life studies it appears to be higher, especially neuropsychiatric AEs. The objective is to determine the percentage of AEs and discontinuation of DTG in our site and the relationship with the psychiatric background. Methods: Retrospective descriptive study of patients starting DTG from 2015 to 2017. Discontinuation of treatment, AEs and previous psychiatric pathology were recorded. Follow-up is carried out since the beginning of the treatment, and hospitalizations and emergency room and primary care visits were registered. The study was authorized by the Ethics Committee for Clinical Research of Aragon. Results: Two hundred and eighty-three patients were included, between 11 and 87 years old, 70% male. 21% were naive. 24% of the patients discontinued treatment with DTG, 10% due to AEs. Neuropsychiatric AEs were detected in 5%. This group of patients had a more frequent previous psychiatric history (62 vs. 41%; P=.002) than the ongoing treatment group and they needed more visits to primary care (18.8 vs. 8.4%; P=.016) and emergency room (8,7 vs. 3.3%; P=.061). Conclusion: Patients who discontinued treatment with DTG had more psychiatric history. Although more studies are required, it is necessary to assess this background before starting treatment with integrase inhibitors. Symptoms such as anxiety, insomnia or depression can be DTG AEs more frequently than expected. Being identified by primary care and emergency physicians could avoid the unnecessary prescription of other medications.(AU)

Neuropsychiatric adverse effects of dolutegravir in real-life clinical practice. / Efectos adversos neuropsiquiátricos de dolutegravir en la práctica clínica real.

INTRODUCTION: Integrase inhibitors and especially dolutegravir (DTG) are placed as a first-line antiretroviral treatment for their efficacy and safety. Although in the pivotal trials the rate of adverse effects (AEs) was low (2-3%), in real-life studies it appears to be higher, especially neuropsychiatric AEs. The objective is to determine the percentage of AEs and discontinuation of DTG in our site and the relationship with the psychiatric background. METHODS: Retrospective descriptive study of patients starting DTG from 2015 to 2017. Discontinuation of treatment, AEs and previous psychiatric pathology were recorded. Follow-up is carried out since the beginning of the treatment, and hospitalizations and emergency room and primary care visits were registered. The study was authorized by the Ethics Committee for Clinical Research of Aragon. RESULTS: Two hundred and eighty-three patients were included, between 11 and 87 years old, 70% male. 21% were naive. 24% of the patients discontinued treatment with DTG, 10% due to AEs. Neuropsychiatric AEs were detected in 5%. This group of patients had a more frequent previous psychiatric history (62 vs. 41%; P=.002) than the ongoing treatment group and they needed more visits to primary care (18.8 vs. 8.4%; P=.016) and emergency room (8,7 vs. 3.3%; P=.061). CONCLUSION: Patients who discontinued treatment with DTG had more psychiatric history. Although more studies are required, it is necessary to assess this background before starting treatment with integrase inhibitors. Symptoms such as anxiety, insomnia or depression can be DTG AEs more frequently than expected. Being identified by primary care and emergency physicians could avoid the unnecessary prescription of other medications.

Effectiveness and safety of integrase inhibitors in HIV-infected pregnant women followed up in the Madrid Cohort. / Efectividad y seguridad de inhibidores de integrasa en la gestante con infección VIH en la Cohorte de embarazadas de la Comunidad de Madrid.

INTRODUCTION: The risk of HIV-1 mother-to-child transmission (MTCT) is associated mainly with gestational age at which antiretroviral therapy begins and the HIV-1 RNA plasma viral load at delivery. Regimens with integrase inhibitors (INI) are increasing in high-risk pregnant women. The objective was to review the experience with INI in a Madrid Cohort of mother-infant pairs. PATIENTS AND METHODS: Retrospective, multicentric, observational study, of HIV-infected pregnant women exposed to INI. Patients of 9 hospitals were included (2000-2017). RESULTS: Sixty-seven pregnant women exposed to INI (cohort: 1,423) and 68 children (17.6% premature babies, 34.3% with combined postexposure prophylaxis). There were no cases of MTCT. Of 24 women with no previous antiretroviral therapy, 20 were diagnosed in current pregnancy. Of 43 women with antiretroviral therapy before pregnancy, 65% received INI before conception. Raltegravir was the most used (80.5%). There was a statistically significant increase (p = 0,02) of mothers with undetectable viral load at delivery. INI were well tolerated. In 11.7% of exposed children minor congenital anomalies were detected. CONCLUSIONS: INI seem safe and effective in the prevention of MTCT. Our findings support their use as intensification regimens in pregnant women with high risk of MTCT.

Identificación de mutaciones asociadas con resistencia a inhibidores de la transferencia de cadena de integrasa en pacientes VIH-1 positivos naive para tratamiento antirretroviral en Medellín, Colombia / Identification of mutations associated with resistance to Integrase Strand Transfer Inhibitors (INSTI) in ART-naïve HIV- 1 patients in Medellin, Colombia

Objetivo: Estimar las frecuencias de mutaciones y de polimorfismos adicionales asociados con resistencia a los fármacos inhibidores de la integrasa del virus de inmunodeficiencia humana tipo 1 (VIH-1). Metodología: Estudio descriptivo, de corte transversal, en individuos VIH-1 positivos de la ciudad de Medellín, quienes no habían recibido tratamiento antirretroviral. En ellos se determinó, a través del método de 2-dideoxinucleótidos y el sistema ABI3730XL, la secuencia del gen de la integrasa del VIH-1 a partir del ARN viral circulante, la cual fue analizada en la base de datos de resistencia a medicamentos antirretrovirales de la Universidad de Stanford y según reportes de literatura científica. Resultados: Se encontraron las siguientes mutaciones (con sus respectivas frecuencias): una mutación mayor, E138K (1/46), tres mutaciones accesorias G163E (3/46), L74I (3/50) y E157Q (2/48), una mutación no polimórfica A128T (1/49) y otras dos mutaciones potencialmente asociadas con resistencia a inhibidores de integrasa S230N (9/39) y S119P/R/T (4/47, 2/47 y 14/47, respectivamente). Conclusiones: En las secuencias analizadas, llama la atención la presencia de al menos una mutación asociada a resistencia a inhibidores de integrasa en el 14% de los individuos estudiados, sugiriendo una pobre presión selectiva de este tipo de fármacos en la población viral circulante en la zona.

Aim: To estimate the frequencies of major and accessory mutations, as well as additional polymorphisms associated with resistance to human immunodeficiency virus type 1 (VIH-1) integrase strand transfer inhibitors. Materials and methods: Descriptive cross-sectional study, focused on HIV-1 positive individuals from Medellín, recruited between 2013 and 2015, and that had not received antiretroviral therapy. In these patients, the sequence from HIV-1 integrase was determined from circulating viral RNA through Sanger chain termination method with the ABI3730XL system, and the sequences were analyzed using the HIV Drug Resistance Database from the University of Stanford, together with previous literature reports. Results: The following mutations associated with resistance to integrase strand transfer inhibitors, along with its respective frequencies, were found: one major mutation, E138K (1/46), three accessory mutations, G163E (3/46), L74I (3/50) and E157Q (2/48); one non-polymorphic mutation, A128T (1/49); and two mutations potentially associated with resistance to integrase strand transfer inhibitors, S230N (9/39) and S119P/R/T (4/47, 2/47 and 14/47, respectively). Conclusions: In the sequences analyzed, it is noteworthy the presence of at least one mutation related with resistance to integrase inhibitors in 14% of the studied patients, suggesting a poor selective pressure of this kind of drugs in the circulating viral population in our region.

Inhibidores de Transferencia de la Cadena de Integrasa: Bases para su uso en la práctica clínica / Integrase Strand Transfer Inhibitors: Bases for its use in the clinical practice

Los inhibidores de transferencia de la cadena de integrasa (INSTI) son medicamentos cuyo mecanismo de acción consiste en bloquear el proceso de integración del ADN proviral al ADN del hospedero mediante la unión al sitio catalítico de la integrasa viral y de esta manera evitar su replicación. Actualmente se cuenta con la aprobación INSTI de primera y segunda generación, presentan similitud en su mecanismo de acción, cambios en su estructura que modifican su barrera genética, pero mantienen su perfil de seguridad y efectividad. Desde su aprobación en el año 2007, se han llevado a cabo múltiples estudios clínicos cuyos resultados han permitido avanzar en el conocimiento de su efectividad en diferentes escenarios clínicos; (pacientes naive, experimentados, esquemas de simplificación y profilaxis, así, como en el conocimiento de su perfil de mutaciones de resistencia). En el presente artículo se hizo una revisión de los miembros de esta familia de antirretrovirales (ARV).

Integrase strand transfer inhibitors (INSTI) are drugs whose mechanism of action consists of blocking the integration process of the proviral DNA to the host DNA by binding to the catalytic site of the viral integration and thus preventing its replication. Currently it has the approval of INSTI of first generation, two of second generation and in process of approval of a third of second generation. The two generations has similitude in its mechanisms of action, changes in its structures that modify its genetic barrier, but keeping his security and effectiveness profile. Since the approval of INSTI´s in 2007 to date, multiple clinical studies have been carried out, whose results have allowed us to advance in the knowledge of their effectiveness in different clinical scenarios; (naive patients, experienced patients, simplification and prophylaxis schemes, as well as in the knowledge of their profile of resistance mutations). In the present article, we made a review of the members of this family of antiretrovirals (ARV).

Selección de variantes de HIV-1 resistentes a los inhibidores de integrasa en la población pediátrica / Selection of HIV-1 variants resistant to integrase inhibitors in the pediatric population

INTRODUCCIÓN Las mutaciones que confieren resistencia a los antirretrovirales son la principal causa de fallo terapéutico al tratamiento antirretroviral. Los Inhibidores de Integrasa poseen buena tolerabilidad y alta potencia, reservados para casos especiales, por el costo y para evitar el surgimiento de mutaciones de resistencia que pongan en riesgo su eficacia. El estudio de la resistencia viral y los subtipos de HIV-1 circulantes en nuestra población podría contribuir a mejorar la elección de los esquemas, en base a evidencia científica y así optimizar el uso de nuevos fármacos. MATERIALES Y MÉTODOS En un total de 33 pacientes HIV-1 positivos (14 adolescentes y 19 adultos) en tratamiento con raltegravir, se realizó secuenciación del gen de integrasa del HIV-1. Se utilizó Stanford HIVdb para identificar mutaciones asociadas de resistencia, y su nivel de susceptibilidad. Se utilizó el análisis de recombinación y reconstrucción filogenética con el método de Neighbor-Joining para el análisis de subtipo. Las comparaciones estadísticas entre grupos se realizaron con el test Exacto de Fisher. RESULTADOS Las secuencias genómicas de la integrasa se caracterizaron como; subtipo F (16, 49%), subtipo B (8, 24%) o recombinantes BF (9, 27%). En 26 casos (78%) se encontró al menos una mutación de resistencia. Los genomas de la integrasa del subtipo B seleccionaron la mutación Q148H/R+G140S y E138K/A, mientras que el subtipo F fue asociada con la N155H y con la falta de mutaciones. Los perfiles mutacionales predijeron un mayor nivel de resistencia cruzada a Dolutegravir en los genomas del subtipo B frente al F. DISCUSIÓN Se reconoció una amplia diversidad sobre el genoma de la Integrasa para los recombinantes BF. La caracterización del subtipo de HIV-1 en la secuencia genómica de Integrasa podría ser útil para guiar el uso de Raltegravir y preservar las opciones terapéuticas de segunda generación como el Dolutegravir y el Cabotegravir en nuestra población

[Mechanisms of action, pharmacology and interactions of dolutegravir]. / Mecanismo de acción, farmacología e interacciones de dolutegravir.

Dolutegravir is a second-generation integrase strand transfer inhibitor (INSTI), whose potential and binding half-life in the integrase are far superior to those of raltegravir and elvitegravir, conferring it with unique characteristics in terms of its genetic barrier to resistance and activity against viruses with one or more mutations in the integrase. The pharmacokinetic properties of dolutegravir allow once-daily dosing (50 mg), with or without food, maintaining concentrations far above those effective against wild-type viruses. If integrase resistance mutations are present, the recommended dosing regimen is 50 mg/12 h. The distribution of dolutegravir in cerebrospinal fluid is good and effective concentrations are also reached in the male and female genital tracts. Dolutegravir is metabolized by UGT1A1 and, to a lesser extent, by CYP3A4, without being an inducer or inhibitor of the usual metabolic systems. It has a very low potential for drug interactions and can be administered in routine doses with most drugs. Dose adjustment is not required, even in patients with renal insufficiency or mild or moderate liver failure. Increasing the dose of dolutegravir (50 mg/12 h) is only recommended when administered with efavirenz, nevirapine, fosamprenavir/r, tipranavir/r, rifampicin, carbamazepine, phenytoin and phenobarbital. Coadministration of dolutegravir with etravirine is not recommended without a protease inhibitor or with Hypericum perforatum. Dolutegravir should be administered 2 h before or 6 h after antacids or products with polyvalent cations. Dolutegravir can reduce renal tubule secretion of substances excreted via OCT2, with a slight initial increase in creatinine, with no risk of renal toxicity. The drug can also increase metformin concentrations and consequently monitoring is recommended in case dose adjustment is required. In summary, dolutegravir has excellent pharmacokinetic and drug interaction profiles.

[Safety profile of dolutegravir]. / Perfil de seguridad de dolutegravir.

Integrase inhibitors are the latest drug family to be added to the therapeutic arsenal against human immunodeficiency virus infection. Drugs in this family that do not require pharmacological boosting are characterized by a very good safety profile. The latest integrase inhibitor to be approved for use is dolutegravir. In clinical trials, dolutegravir has shown an excellent tolerability profile, both in antiretroviral-naïve and previously treated patients. Discontinuation rates due to adverse effects were 2% and 3%, respectively. The most frequent adverse effects were nausea, headache, diarrhea and sleep disturbance. A severe hypersensitivity reaction has been reported in only one patient. In patients coinfected with hepatropic viruses, the safety profile is similar to that in patients without coinfection. The lipid profile of dolutegravir is similar to that of raltegravir and superior to those of Atripla® and darunavir/ritonavir. Dolutegravir induces an early, predictable and non-progressive increase in serum creatinine of around 10% of baseline values in treatment-naïve patients and of 14% in treatment-experienced patients. This increase is due to inhibition of tubular creatinine secretion through the OCT2 receptor and does not lead to a real decrease in estimated glomerular filtration rate with algorithms that include serum creatinine. The effect of the combination of dolutegravir plus Kivexa(®) on biomarkers of bone remodeling is lower than that of Atripla(®). Dolutegravir has an excellent tolerability profile with no current evidence of long-term adverse effects. Its use is accompanied by an early and non-progressive increase in serum creatinine due to OCT2 receptor inhibition. In combination with abacavir/lamivudine, dolutegravir has a lower impact than enofovir/emtricitabine/efavirenz on bone remodelling markers.

[Efficacy of dolutegravir in treatment-naïve patients. The SPRING-1, SPRING-2, SINGLE and FLAMINGO trials]. / Eficacia de dolutegravir en pacientes naïve. Estudios SPRING-1, SPRING-2, SINGLE y FLAMINGO.

The efficacy of dolutegravir (DTG) in treatment-naïve patients has been analyzed in the SPRING 1 and 2, SINGLE and FLAMINGO trials, which compared dolutegravir with the agents currently recommended as the drugs of choice in clinical practice guidelines in treatment-naïve patients: efavirenz, raltegravir and darunavir/ritonavir. These trials confirmed the superiority (SINGLE and FLAMINGO) or the non-inferiority (SPRING-2) of dolutegravir. More than 2,000 patients were included in these 4 studies, lending value to their results and reinforcing the view of dolutegravir as the drug of choice in treatment-naïve patients, accompanied either by abacavir/lamivudine (Kivexa(®)) or tenofovir/emtricitabine (Truvada®).

[Efficacy of dolutegravir in treatment-experienced patients: the SAILING and VIKING trials]. / Eficacia de dolutegravir en pacientes experimentados: estudios SAILING y VIKING.

Dolutegravir is an HIV integrase inhibitor with a high genetic barrier to resistance and is active against raltegravir- and/or elvitegravir-resistant strains. The clinical development of dolutegravir for HIV infection rescue therapy is based on 3 clinical trials. In the SAILING trial, dolutegravir (5 mg once daily) in combination with 2 other antiretroviral agents was well tolerated and showed greater virological effect than raltegravir (400 mg twice daily) in the treatment of integrase inhibitor-naïve adults with virological failure infected with HIV strains with at least two-class drug resistance. The VIKING studies were designed to evaluate the efficacy of dolutegravir as rescue therapy in treatment-experienced patients infected with HIV strains with resistance mutations to raltegravir and/or elvitegravir. VIKING-1-2 was a dose-ranging phase IIb trial. VIKING-3 was a phase III trial in which dolutegravir (50 mg twice daily) formed part of an optimized regimen and proved safe and effective in this difficult-to-treat group of patients. Dolutegravir is the integrase inhibitor of choice for rescue therapy in multiresistant HIV infection, both in integrase inhibitor-naïve patients and in those previously treated with raltegravir or elvitegravir.

[Resistance profile and genetic barrier of dolutegravir]. / Perfil de resistencias y barrera genética de dolutegravir.

The resistance profile of dolutegravir differs significantly from those of earlier integrase inhibitors (INI). Dolutegravir displays in vitro activity against mutant HIV-1 harboring any isolated resistance mutations selected during failures to raltegravir or elvitegravir (Y143C/H/, N155H, Q148H/K/R, E92G/Q, T66A/I/K, T97A, E138A/K, G140A/S). Its activity is only compromised by Q148X mutations combined with other mutations, particularly > 1 mutation. The drug has pharmacokinetic/pharmacodynamic properties (plasmatic t1/2 15.3 h, inhibitory quotient 19, dissociative t1/2 from the IN-DNA complex 71 h) that favor a high genetic barrier to resistance. In vitro the selection of HIV-1 resistance to dolutegravir is extremely difficult to achieve. The mutations eventually selected (R263K, H51Y and E138K) do not confer significant resistance, and induce a fitness cost that prevents HIV-1 from evading drug pressure. Suprisingly, HIV-1 is not able to compensate, leading the virus to a previously unnoticed evolutionary pathway with very low chances of developing resistance to INI or the backbone. No treatment-naïve patients starting dolutegravir therapy (+TDF/FTC o ABC/3TC) have selected resistance in IN or against the backbone. No INI- naïve patients with prior virologic failure selected phenotypic dolutegravir resistance. Only 4 out of 354 patients selected resistance mutations in IN, and rates of selection of mutations in IN or against the backbone were significantly lower than with raltegravir. In multitreated patients with widespread resistance including IN resistance, the high efficacy of dolutegravir was confirmed, irrespective of the previous pattern of IN mutations, provided that Q148X associated with other mutations was absent.

[Severe or life-threatening interactions between antiretrovirals and non-HIV drugs]. / Interacciones graves o potencialmente letales entre antirretrovirales y otros medicamentos.

Highly active antiretroviral therapy has helped to improved control of the HIV infection, and has led to a progressively older population with the infection having a life expectancy quite similar to that of the general population. On the other hand, it is also known that HIV infection, even in patients with undetectable viral loads and good immunity, carries an increased cardiovascular risk, as well as an increased incidence of certain cancers. Therefore, the majority of HIV-infected patients receive several drugs (either prescribed by the physician or self-administered) combined with antiretrovirals. This article reviews the interactions between antiretrovirals and other drugs that can cause significant damage to patients, or even be life-threatening and of whom clinicians, especially those not directly treating HIV-infected patients, should be aware. A review is also presented on the implications of interactions between antiretrovirals and other drugs in special situations, such as the co-administration with cytostatics, immunesuppressants used in solid organ transplantation, or patients receiving new treatments for hepatitisC. Generally, combinations with two nucleos(t)ide reverse transcriptase inhibitors and raltegravir (or in the near future, dolutegravir) are those with less potential for clinically significant interactions.

¿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 antirre-troviral 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 resisten-tes 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 part of viruses that might become resistant to DTG.We further speculatethat DTG might be able to be used in strategies aimed at HIV eradication

¿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...

Influence of Mg2+ ions on the interaction between 3,5-dicaffeoylquinic acid and HTLV-I integrase / Influencia de los iones Mg+2 sobre la interacción entre el ácido 3,5- dicafeoilquínico y la integrasa del HTLV-I / Influência dos íons Mg2+ sobre a interação entre o ácido 3,5-dicafeoilquínico e a integrase do HTLV-I

Objective. Using molecular simulation, we studied the influence of Mg2+ ions on the binding mode of HTLV-I Integrase (IN) catalytic domain (modeled by homology) with the 3,5- Dicaffeoylquinic Acid (DCQA). HTLV-I Integrase homology model was built using template-like crystallographic data of the IN catalytic domain solved for Avian Sarcoma Virus (VSA, pdb: 1VSD). Materials and methods. In order to analyze the role of Mg2+ in the interaction or coupling between 3,5-DCQA and Integrase, three models were created: i) in the absence of Mg2+ ions, ii) with a Mg2+ ion coordinated at Asp15 and Asp72 and iii) model with two Mg2+ ions coordinated at Asp15-Asp72 and Asp72-Glu108. Coupling force and binding free energy between 3,5-DCQA and HTLV-I IN were assessed in the three models. Results. The lowest docking score and free energy binding were obtained for the second model. Mg2+ ion strongly affected the coupling of the inhibitor 3,5-DCQA with HTLV-I catalytic domain of Integrase, thus revealing a strong interaction in the ligand-protein complex regardless of the ligand-catalytic interaction sites for all three models. Conclusion. Altogether, these results strengthen the hypothesis that the presence of one Mg2+ ion could enhance the interaction in the complex by decreasing free energy, therefore increasing the affinity. Moreover, we propose 3,5-DCQA as an important pharmacophore in the rational design of new antiretroviral drugs.

Objetivo: Usando simulación molecular, estudiamos la influencia de los iones Mg2+ en la interacción del dominio catalítico de la integrasa HTLV-I (IN) (modelado por homología) con el ácido 3,5-Dicafeoilquínico (DCQA). Materiales y métodos. El modelo por homología de la HTLV-I IN fue construido usando como molde la estructura cristalina de la IN del virus del sarcoma aviar (VSA, pdb: 1VSD). Para analizar el rol de los iones Mg2+ en la interacción con el DCQA y la integrasa, tres modelos fueron creados: i) en ausencia de iones Mg2+, ii) con un ion Mg2+ coordinado con Asp15 y Asp72 y iii) con dos iones Mg2+ coordinados con Asp15-Asp72 y Asp72-Glu108. Las fuerzas de interacción y la energía libre de unión entre el DCQA y la HTLV-I IN fueron calculadas en los tres modelos. Resultados. El puntaje más bajo en el docking y la menor energía libre fueron obtenidos para el modelo con un solo ion de Mg2+. El Mg2+ afecta fuertemente el acoplamiento del inhibidor DCQA con el dominio catalítico de la HTLV-I IN, revelando una fuerte interacción entre el complejo ligando-proteína que es independiente del sitio catalítico de los tres modelos usados. Conclusión. Los resultados sugieren que la presencia de un ion de Mg² + podría incrementar la interacción en el complejo debido a la disminución de la energía libre, intensificando así la afinidad. Por lo que, proponemos al DCQA como farmacóforo para el diseño de drogas antiretrovirales.

Objetivo. Usando simulação molecular, estudamos a influência dos íons Mg2+ na interação do domínio catalítico da integrase HTLV-I (IN) (modelado por homologia) com o ácido 3,5-dicafeoilquínico (3,5-diCQA). Materiais e métodos. O modelo de homologia da HTLV-I IN foi construído utilizando como fôrma a estrutura cristalina da IN de vírus do sarcoma aviário (VSA, pdb: 1VSD). Para analisar o papel dos íons Mg2+ na interação com o 3,5-diCQA e a integrase, três modelos foram criados: i) na ausência de íons Mg2+, ii) com um íon Mg2+ coordenado com Asp15 e Asp72 e, iii) com dois íons Mg2+ coordenados com Asp15-Asp72 e Asp72-Glu108. As forças de interação e a energia livre de ligação entre o 3,5-diCQA e a HTLV-I IN foram calculadas nos três modelos. Resultados. A pontuação mais baixa no docking e a menor energia livre foram obtidas para o modelo com um único íon de Mg2+. O Mg2+ afeta fortemente o acoplamento do inibidor 3,5-diCQA com o domínio catalítico da HTLV-I IN, revelando uma forte interação entre o complexo ligando-proteína que é independente do sítio catalítico dos três modelos utilizados. Conclusão. Os resultados sugerem que a presença de um íon Mg2+ poderia aumentar a interação no complexo devido à diminuição da energia livre, aumentando assim a afinidade. Assim, propomos ao 3,5-diCQA como farmacóforo para a fabricação de medicamentos antirretrovirais.

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.

Inhibidores de la integrasa y raltegravir en el manejo de la infección por vírus de la inmunodeficiencia humana en la era de la resistencia a múltiples medicamentos: [revisión] / Integrase Inhibitors and raltegravir use in the management of HIV infection in the era of multidrug resistance: [review]

La infección por el virus de la inmunodeficiencia humana ha generado un impacto mundial que ha sobrepasado los cálculos iniciales previstos para esta enfermedad. En la actualidad, se hace necesaria la búsqueda de nuevos medicamentos antirretrovirales dentro de las familias de medicamentos conocidas, pero, aún más importante, es la búsqueda de nuevos blancos terapéuticos sobre los cuales incidan los fármacos a los que no ha estado expuesto el virus y, asimismo, ante los cuales no presentan resistencia natural. Los inhibidores de la integrasa constituyen la familia de medicamentos antirretrovirales más recientemente aprobada para uso clínico. El raltegravir es un medicamento nuevo, con atributos importantes que lo hacen una herramienta que se debe tener en cuenta en esquemas de rescate, terapia de cambio y acorde con la consideración de paciente naive, es decir, sin tratamiento previo con este fármaco.

Immunodeficiency virus infection in humans (HIV) has generated a worldwide impact exceeding initial estimates for this disease. At present, it is necessary to search for new antiretroviral drugs within the families of known medication, but the search for new therapeutic objectives under the effect of medication which has not been exposed to the virus and, therefore without natural resistance to it, is even more important. Integrase inhibitors are the family of antiretroviral medication most recently approved for clinical use; raltegravir is a new drug with important attributes that make it a tool to be considered in rescue regimens, change therapies, and naïve patient particular cases.