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.

Lesiones costrosas a estudio / Scabby injuries

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Oportunidades perdidas en el diagnóstico de la infección por el virus de inmunodeficiencia humana en la Comunidad de Aragón. Importancia del diagnóstico tardío / Missed opportunities in the diagnosis of human immunodeficiency virus infection in the Region of Aragon. Late diagnosis importance

Introducción: El diagnóstico tardío (DT) de la infección por el virus de la inmunodeficiencia humana (VIH) (linfocitos CD4<350/μl al diagnóstico de la enfermedad) empeora el pronóstico de los afectados y aumenta las probabilidades de transmisión. El objetivo del presente trabajo fue analizar la prevalencia de DT, identificar las oportunidades diagnósticas perdidas (ODP) y averiguar el nivel asistencial donde se produjeron. Métodos: Estudio retrospectivo, observacional, descriptivo de la población diagnosticada de infección por VIH/sida en el periodo 2011-2015 en Aragón. Se identificaron las ODP durante los 3 años previos al diagnóstico de la enfermedad en todos los niveles asistenciales, así como la frecuentación asistencial. Se analizaron las condiciones indicadoras (CI) que generaron más ODP, según las últimas recomendaciones para el diagnóstico precoz del VIH en el medio sanitario. Resultados: Se analizaron 435 nuevos casos de VIH/sida. El 45,1% fueron diagnosticados en Atención Primaria (AP). El 49,4% presentaron criterios de DT y el 61,1% se contagiaron vía heterosexual. La mayor parte de ODP (68,5%) se dieron en AP. Las CI que generaron más ODP fueron la dermatitis seborreica/exantema (19,4%) y la fiebre sin causa aparente (10,3%). Sin embargo, las CI que se asociaron a mayor DT fueron la neumonía adquirida en la comunidad y la pérdida de peso injustificada. Conclusión: En Aragón, la prevalencia de DT es elevada, la principal vía de transmisión es la heterosexual y la mayor parte de las CI pasan desapercibidas en AP. La difusión de las guías actuales para solicitar una prueba de VIH orientada por CI y el screening VIH en todo preoperatorio es una medida eficaz para disminuir el DT

Introduction: Late Diagnosis (LD) of Human Immunodeficiency Virus (HIV) infection (CD4 lymphocytes <350/μl at diagnosis of the disease), deteriorates the condition of those affected and increases the probability of transmission. The objective of the present study was to analyse the prevalence of LD, to identify missed diagnostic opportunities (MDO) and to find out which level of the health care delivery system they took place. Methods: Retrospective, observational and descriptive study of the population diagnosed with infection of HIV/AIDS in the period 2011-2015 in Aragon. MDO were identified during the 3 years prior to diagnosis of the disease in all levels of the health care delivery system as well as frequentation of consultations. The indicator conditions (IC) that generated more MDO were analysed according to the latest recommendations for early diagnosis of HIV in the health care setting. Results: 435 newly diagnosed HIV/AIDS cases were analysed. 45.1% were diagnosed in Primary Healthcare (PH). 49.4% presented criteria of LD and 61.1% were infected through heterosexual contact. The majority of MDO (68.5%) were given in PH. The IC that generated the most MDO were seborrheic dermatitis/exanthema (19.4%) and fever of unknown origin (10.3%). However, the IC that were associated with higher LD were pneumonia acquired in the community and unjustified weight loss. Conclusion: In Aragon, prevalence of LD is high, the main route of infection is heterosexual and most of MDO go unnoticed in PH. The dissemination of current guidelines for requesting IC guided HIV testing and HIV screening across the preoperative period will result in an effective measure to decrease the LD

Missed opportunities in the diagnosis of human immunodeficiency virus infection in the Region of Aragon. Late diagnosis importance. / Oportunidades perdidas en el diagnóstico de la infección por el virus de inmunodeficiencia humana en la Comunidad de Aragón. Importancia del diagnóstico tardío.

INTRODUCTION: Late Diagnosis (LD) of Human Immunodeficiency Virus (HIV) infection (CD4 lymphocytes <350/µl at diagnosis of the disease), deteriorates the condition of those affected and increases the probability of transmission. The objective of the present study was to analyse the prevalence of LD, to identify missed diagnostic opportunities (MDO) and to find out which level of the health care delivery system they took place. METHODS: Retrospective, observational and descriptive study of the population diagnosed with infection of HIV/AIDS in the period 2011-2015 in Aragon. MDO were identified during the 3 years prior to diagnosis of the disease in all levels of the health care delivery system as well as frequentation of consultations. The indicator conditions (IC) that generated more MDO were analysed according to the latest recommendations for early diagnosis of HIV in the health care setting. RESULTS: 435 newly diagnosed HIV/AIDS cases were analysed. 45.1% were diagnosed in Primary Healthcare (PH). 49.4% presented criteria of LD and 61.1% were infected through heterosexual contact. The majority of MDO (68.5%) were given in PH. The IC that generated the most MDO were seborrheic dermatitis/exanthema (19.4%) and fever of unknown origin (10.3%). However, the IC that were associated with higher LD were pneumonia acquired in the community and unjustified weight loss. CONCLUSION: In Aragon, prevalence of LD is high, the main route of infection is heterosexual and most of MDO go unnoticed in PH. The dissemination of current guidelines for requesting IC guided HIV testing and HIV screening across the preoperative period will result in an effective measure to decrease the LD.

Effectiveness and security of chronic hepatitis C treatment in coinfected patients in real-world.

Background HIV-HCV coinfection produces high morbi-mortality. Direct-acting antivirals (DAAs) have shown high efficacy, although special attention should be paid to the risk of drug interactions. However, due to the lack of representativeness of coinfected patients in clinical trials, it is important to know real-world results. Objective To evaluate DAA treatment effectiveness in coinfected patients. We also analyse safety profile of DAA treatment and drug interactions between HCV and HIV therapy. Setting Descriptive study carried in a tertiary hospital of Spain Method HIV-HCV coinfected patients treated with DAAs between November 2014 and June 2016 were included. Main outcome measure Efficacy was measured in terms of sustained virologic response at week 12 after the end of therapy. Adverse events that led to treatment discontinuation were registered to evaluate the safety profile, and also drug interactions between DAAs and antiretroviral treatment were evaluated. Results Main HCV genotypes were 1a (34.9%) and 4 (24.5%). 51.9% were HCV previously treated, 54.7% had grade 4 liver fibrosis. SVR12 was reported in 90.6%. HCV treatment was well tolerated and there were no discontinuations because of adverse events. 30.2% of HIV treatments had to be modified before DAA treatment was started due to interactions, HIV suppression was not compromised. Conclusion DAA treatment in coinfected patients seems to be highly effective and secure. Evaluation of drug interactions must be a priority in order to maximize effectiveness and avoid toxicity.

[Pharmacokinetic interactions]. / Interacciones farmacocinéticas.

Rilpivirine (RPV) is a nonnucleoside reverse transcriptase inhibitor (NNRTI) that has been approved for use in treatment-naïve patients and which has potent antiviral activity. Its adverse effects profile differs from that of first-generation NNRTs. The pharmacological interactions produced by RPV are due to its effects on the CYP450 system; RPV is a substrate and mild inducer of CYP3A4. Moreover, in vitro, RPV inhibits glycoprotein-P. RPV has clinically significant pharmacological interactions, especially with protease inhibitors (except boosted darunavir and lopinavir) and the NNRTIs efavirenz and nevirapine. Coadministration of RPV with drugs that increase gastric pH, such as omeprazole, or those inducing CYP3A4, such as rifampicin, can significantly reduce RPV concentrations and is contraindicated. The concomitant use of RPV with a CYP3A4 inhibitor (such as clarithromycin) can increase RPV concentrations. Administration of PRV with food is recommended to obtain better absorption and adequate plasma values.

Interacciones farmacocinéticas / Pharmacokinetic interactions

Rilpivirina (RPV) es un fármaco perteneciente a la familia de los inhibidores no nucleósidos de la transcriptasa inversa (INNTI), con potente actividad antiviral, aprobado para pacientes naïve, con perfil de efectos secundarios diferente a los INNTI de primera generación. Las interacciones farmacológicas producidas por RPV se deben a su efecto sobre el sistema CYP450, es sustrato de CYP3A4 y ligeramente inductor. Además, in vitro es inhibidor de la glucoproteína-P. RPV presenta interacciones farmacológicas clínicamente significativas, entre las que destacan los inhibidores de la proteasa, a excepción de darunavir y lopinavir potenciados, y los INNTI efavirenz y nevirapina. La toma de RPV junto con fármacos que aumentan el pH gástrico, como omeprazol, o los que inducen el CYP3A4, como rifampicina, puede causar reducciones significativas en las concentraciones de RPV y está contraindicada. El uso concomitante de RPV con un inhibidor del CYP3A4, por ejemplo claritromicina, puede provocar aumento de las concentraciones de RPV. Se recomienda la administración de RPV con alimentos para obtener mejor absorción y valores plasmáticos adecuados

Rilpivirine (RPV) is a nonnucleoside reverse transcriptase inhibitor (NNRTI) that has been approved for use in treatment-naïve patients and which has potent antiviral activity. Its adverse effects profile differs from that of first-generation NNRTs. The pharmacological interactions produced by RPV are due to its effects on the CYP450 system; RPV is a substrate and mild inducer of CYP3A4. Moreover, in vitro, RPV inhibits glycoprotein-P. RPV has clinically significant pharmacological interactions, especially with protease inhibitors (except boosted darunavir and lopinavir) and the NNRTIs efavirenz and nevirapine. Coadministration of RPV with drugs that increase gastric pH, such as omeprazole, or those inducing CYP3A4, such as rifampicin, can significantly reduce RPV concentrations and is contraindicated. The concomitant use of RPV with a CYP3A4 inhibitor (such as clarithromycin) can increase RPV concentrations. Administration of PRV with food is recommended to obtain better absorption and adequate plasma values

Etravirina en primeras líneas de tratamiento / Etravirine in first-line therapy

Etravirina (ETR) es un inhibidor de la transcriptasa inversa no análogo de nucleósidos (ITINAN), con potente y amplia actividad in vitro frente al virus de la inmunodeficiencia humana 1 y a virus con resistencias a ITINAN, lo que permite el uso secuencial de esta familia. La potencia, eficacia y seguridad están demostradas en pacientes multitratados, pero se dispone de pocos datos en primeras líneas de tratamiento antirretroviral (TAR), sin estar definido su papel en fases iniciales. La presencia de resistencias a ITINAN primarias y adquiridas durante la primera línea de tratamiento es cada vez más frecuente. Gracias a su barrera genética y eficacia, ETR puede formar parte de un segundo régimen de TAR en pacientes que han fallado en un primer régimen. En fases iniciales, los efectos adversos siguen siendo el motivo principal por el que se modifica el TAR. ETR se ha mostrado segura y con buena tolerabilidad. No presenta efectos adversos en el sistema nervioso central y tiene un buen perfil hepático, lipídico y gastrointestinal. El efecto adverso más frecuente es el exantema, efecto adverso común al resto de ITINAN. Su buen perfil de tolerabilidad lo convierte en un fármaco que se debe considerar en la configuración de un nuevo tratamiento en cambios por tolerabilidad. Las características de ETR, posibilidad de administración 1 vez al día, posibilidad de administrar disuelta en agua y no interacción con metadona, hacen que sea un fármaco especialmente atractivo en primeras líneas de tratamiento y en pacientes a los que se les ha atribuido mala adherencia, como son los usuarios de drogas por vía parenteral en tratamiento con metadona

Etravirine (ETR) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) with a potent and broad in vitro spectrum of activity against HIV-1 and viruses with NNRTI resistances, allowing sequential use of drugs of this family. The potency, efficacy and safety of etravirine have been demonstrated in multi-treated patients, but few data are available on first-line antiretroviral therapy (ART) and the role of this drug in initial treatment phases has not been defined. The presence of primary NNRTI resistances and those acquired during first-line therapy is increasingly frequent. Due to its genetic barrier and efficacy, ETR can form part of a second-line ART regimen in patients with failure to a first-line regimen. In the initial phases, adverse effects continue to be the main reason for modifying ART. ETR has demonstrated safety and tolerability, with no central nervous system adverse effects and a good liver, lipid and gastrointestinal safety profile. As with the other NNRTIs, the most common adverse effect is rash. Because of ETR good tolerability profile, this drug can be considered when a new treatment is required due to adverse effects. Because of the characteristics of ETR the possibility of once-daily administration and dissolution in water, as well as the absence of drug-drug interactions with methadone this drug is especially attractive as a firstline therapy and in patients with poor adherence, such as intravenous drug users receiving methadone treatment

Darunavir en pacientes avanzados con multirresistencias. Estudios POWER, DUET y BENCHMRK / Darunavir in patients with advanced HIV and multiresistance. The POWER, DUET and BENCHMRK studies

Darunavir (DRV) es un nuevo inhibidor de proteasa (IP)muy activo frente a cepas del virus de la inmunodeficienciahumana (VIH) salvajes y multirresistentes, que se unefirmemente a la proteasa del VIH-1, presenta una potenteafinidad por la proteasa, y potenciado con una dosissubterapéutica de ritonavir tiene un perfil de resistenciasfavorable y no coincidente con los IP actuales.En los ensayos clínicos en fase IIb (estudios POWER 1 y 2),tras determinar la dosis óptima, se observó su graneficacia virológica e inmunológica muy superior a la de losIP con los que se comparó. Los resultados del estudio enfase III (POWER 3) ratifican de nuevo la eficacia y seguridadde DRV, y los 3 estudios POWER demuestran su elevadabarrera genética frente a las mutaciones que confierenresistencias a otros IP, aunque la sensibilidad basal de DRVy las mutaciones específicas a este IP influyen en surespuesta virológica.Se ha demostrado que cuando hay 2 o másantirretrovirales activos frente al VIH conmultirresistencias se obtienen mejores respuestasterapéuticas. En los estudios en fase III (DUET 1 y DUET 2)en los que se administra junto con un nuevo inhibidor de latranscriptasa inversa, la etravirina, se observa que si seadministran estos 2 fármacos en pacientes con altaexperiencia en el tratamiento antirretroviral puedeconseguirse, en una elevada proporción de casos, lasupresión de la viremia plasmática y la recuperacióninmunológica. Estos datos se ratifican con los resultadosde los estudios BENCHMRK, en los que el DRV estabaincluido en el tratamiento optimizado en un importantenúmero de pacientes. En estos ensayos se observó quecuando se administraba con el inhibidor de la integrasa, elraltegravir, la indetectabilidad tanto en la rama delraltegravir como en la del control mejoraba de formaimportante respecto a los resultados globales de la rama control(AU)

Darunavir is a new protease inhibitor. This drug is highlyactive against wild-type and multiresistant HIV strains, bindsstrongly to the HIV-1 protease, has extremely high affinityfor the protease and, when enhanced by subtherapeuticdoses of ritonavir, has a favorable resistance profile differingfrom that of current protease inhibitors (PIs).After determining the optimal dose, phase IIb clinical trials(POWER studies 1 and 2) observed much higher virologicaland immunological efficacy with darunavir than with thecomparator PIs. The results of a phase III clinical trial(POWER 3) provide further support for the safety andefficacy of darunavir, and the three POWER studiesdemonstrate the high genetic barrier of this drug againstmutations conferring resistance to other PIs, although thebaseline sensitivity of darunavir and the specific mutationsto this PI influence the virological response.Better therapeutic responses have been obtained whenthere are two or more antiretroviral drugs active againstmultiresistant HIV strains. The phase III trials (DUET 1 and2), in which darunavir was administered with the new nonnucleosidereverse transcriptase inhibitor, etravirine, foundthat if these two drugs were administered in highlytreatment-experienced patients, a large percentageshowed suppression of plasma viremia and immunologicalrecovery. These data have been supported by the resultsof the BENCHMARK studies, in which darunavir wasincluded in an optimized regimen in a substantial numberof patients. In these trials, when darunavir wasadministered with the integrase inhibitor, raltegravir,undetectable viral loads both in the raltegravir arm and inthe control group were substantially improved withrespect to the overall results obtained in the control group(AU)

Darunavir en pacientes avanzados con multirresistencias. Estudios POWER, DUET y BENCHMRK / Darunavir in patients with advanced HIV and multiresistance. The POWER, DUET and BENCHMRK studies

Darunavir (DRV) es un nuevo inhibidor de proteasa (IP)muy activo frente a cepas del virus de la inmunodeficiencia humana (VIH) salvajes y multirre-sistentes, que se une firmemente a la proteasa del VIH-1, presenta una potente afinidad por la proteasa, y potenciado con una dosis subterapéutica de ritonavir tiene un perfil de resistencias favorable y no coincidente con los IP actuales. En los ensayos clínicos en fase IIb (estudios POWER 1 y 2), tras determinar la dosis óptima, se observó su gran eficacia virológica e inmunológica muy superior a la de los IP con los que se comparó. Los resultados del estudio en fase III (POWER 3) ratifican de nuevo la eficacia y seguridadde DRV, y los 3 estudios POWER demuestran su elevadabarrera genética frente a las mutaciones que confierenresistencias a otros IP, aunque la sensibilidad basal de DRV y las mutaciones específicas a este IP influyen en surespuesta virológica.Se ha demostrado que cuando hay 2 o másantirretrovirales activos frente al VIH conmultirresistencias se obtienen mejores respuestasterapéuticas. En los estudios en fase III (DUET 1 y DUET 2) en los que se administra junto con un nuevo inhibidor de la transcriptasa inversa, la etravirina, se observa que si se administran estos 2 fármacos en pacientes con alta experiencia en el tratamiento antirretroviral puedeconseguirse, en una elevada proporción de casos, lasupresión de la viremia plasmática y la recuperacióninmunológica. Estos datos se ratifican con los resultadosde los estudios BENCHMRK, en los que el DRV estabaincluido en el tratamiento optimizado en un importantenúmero de pacientes. En estos ensayos se observó quecuando se administraba con el inhibidor de la integrasa, el raltegravir, la indetectabilidad tanto en la rama delraltegravir como en la del control mejoraba de formaimportante respecto a los resultados globales de la ramacontrol

Darunavir is a new protease inhibitor. This drug is highly active against wild-type and multiresistant HIV strains, binds strongly to the HIV-1 protease, has extremely high affinity for the protease and, when enhanced by subtherapeutic doses of ritonavir, has a favorable resistance profile differing from that of current protease inhibitors (PIs). After determining the optimal dose, phase IIb clinical trials (POWER studies 1 and 2) observed much higher virological and immunological efficacy with darunavir than with thecomparator PIs. The results of a phase III clinical trial (POWER 3) provide further support for the safety and efficacy of darunavir, and the three POWER studiesdemonstrate the high genetic barrier of this drug againstmutations conferring resistance to other PIs, although the baseline sensitivity of darunavir and the specific mutations to this PI influence the virological response.Better therapeutic responses have been obtained whenthere are two or more antiretroviral drugs active againstmultiresistant HIV strains. The phase III trials (DUET 1 and 2), in which darunavir was administered with the new nonnucleoside reverse transcriptase inhibitor, etravirine, found that if these two drugs were administered in highly treatment-experienced patients, a large percentage showed suppression of plasma viremia and immunological recovery. These data have been supported by the results of the BENCHMARK studies, in which darunavir was included in an optimized regimen in a substantial number of patients. In these trials, when darunavir was administered with the integrase inhibitor, raltegravir, undetectable viral loads both in the raltegravir arm and in the control group were substantially improved with respect to the overall results obtained in the control group

[Darunavir in patients with advanced HIV and multiresistance. The POWER, DUET and BENCHMRK studies]. / Darunavir en pacientes avanzados con multirresistencias. Estudios POWER, DUET y BENCHMRK.

Darunavir is a new protease inhibitor. This drug is highly active against wild-type and multiresistant HIV strains, binds strongly to the HIV-1 protease, has extremely high affinity for the protease and, when enhanced by subtherapeutic doses of ritonavir, has a favorable resistance profile differing from that of current protease inhibitors (PIs). After determining the optimal dose, phase IIb clinical trials (POWER studies 1 and 2) observed much higher virological and immunological efficacy with darunavir than with the comparator PIs. The results of a phase III clinical trial (POWER 3) provide further support for the safety and efficacy of darunavir, and the three POWER studies demonstrate the high genetic barrier of this drug against mutations conferring resistance to other PIs, although the baseline sensitivity of darunavir and the specific mutations to this PI influence the virological response. Better therapeutic responses have been obtained when there are two or more antiretroviral drugs active against multiresistant HIV strains. The phase III trials (DUET 1 and 2), in which darunavir was administered with the new nonnucleoside reverse transcriptase inhibitor, etravirine, found that if these two drugs were administered in highly treatment-experienced patients, a large percentage showed suppression of plasma viremia and immunological recovery. These data have been supported by the results of the BENCHMARK studies, in which darunavir was included in an optimized regimen in a substantial number of patients. In these trials, when darunavir was administered with the integrase inhibitor, raltegravir, undetectable viral loads both in the raltegravir arm and in the control group were substantially improved with respect to the overall results obtained in the control group.