RESUMO
BACKGROUND: Randomised comparative data on efficacy and safety of second-line antiretroviral therapy (ART) after failure of non-nucleoside reverse transcriptase inhibitors (NNRTIs) across diverse geographical settings are scarce. The aim of this study was to evaluate optimal second-line ART for people with HIV. METHODS: D2EFT is a completed international, randomised, open-label, phase 3b/4 trial evaluating three second-line ART strategies in adults (aged ≥18 years) with HIV-1 for whom first-line NNRTI therapy has failed. The study was done at 28 sites across 14 countries in Asia, Africa, and Latin America. It was originally designed to compare recommended standard of care (ritonavir-boosted darunavir [800 mg darunavir plus 100 mg ritonavir once daily] plus two nucleoside reverse transcriptase inhibitors [NRTIs; dosed once or twice daily]) with a novel nucleoside sparing regimen of dolutegravir (50 mg once daily) with ritonavir-boosted darunavir. The study was adapted during the first year to add a third arm of dolutegravir (50 mg once daily) with fixed tenofovir disoproxil fumarate (300 mg once daily) plus either lamivudine (300 mg once daily) or emtricitabine (200 mg once daily). Participants were randomly assigned with a computer-generated, blocked randomisation scheme (block size of two) stratified by site, previous tenofovir disoproxil fumarate use, and HIV viral load. The trial was designed to evaluate non-inferiority of either interventional arm against standard of care for the primary outcome of virological suppression, as determined by HIV RNA load of less than 50 copies per mL at 48 weeks. The prespecified non-inferiority margin was 12%. Comparisons were made with a modified intention-to-treat population, including all participants randomly assigned but excluding administrative withdrawals. This study is registered with ClinicalTrials.gov, NCT03017872. FINDINGS: 1190 individuals were screened; 828 participants were enrolled between Nov 1, 2017, and Dec 31, 2021. Two participants were unable to receive their assigned regimen for administrative reasons; and 826 participants were included in analyses. Median age was 39 years (IQR 33-46), and 450 (54%) participants were female. Baseline median CD4 count was 206 cells per µL (23-354) and median HIV RNA was 15 400 copies per mL (3600-65 986). The proportion of participants with HIV RNA of less than 50 copies per mL at 48 weeks was 194 (75%) of 257 in the ritonavir-boosted darunavir plus two NRTIs group, 222 (84%) of 264 in the ritonavir-boosted darunavir plus dolutegravir group, and 227 (78%) of 291 in the dolutegravir with tenofovir disoproxil fumarate plus either lamivudine or emtricitabine group. Compared with ritonavir-boosted darunavir plus two NRTIs, the difference in virological suppression was 8·6% (95% CI 1·7 to 15·5; p=0·016) for dolutegravir plus ritonavir-boosted darunavir and 6·7% (-1·2 to 14·4; p=0·093) for dolutegravir with tenofovir disoproxil fumarate plus either lamivudine or emtricitabine. Six deaths occurred, none of which were related to treatment. 19 pregnancies (11 livebirths) occurred with no congenital defects. INTERPRETATION: In individuals experiencing failure of an NNRTI-based first-line ART, a switch to either dolutegravir plus ritonavir-boosted darunavir or dolutegravir with tenofovir disoproxil fumarate plus either lamivudine or emtricitabine, without universal access to genotyping, was non-inferior in achieving viral suppression compared with ritonavir-boosted darunavir plus two NRTIs. These global data support the most recent WHO treatment guidelines. FUNDING: UNITAID; National Institute of Allergy and Infectious Diseases, USA; National Health and Medical Research Council, Australia; ViiV Healthcare; and Janssen.
Assuntos
Darunavir , Infecções por HIV , HIV-1 , Compostos Heterocíclicos com 3 Anéis , Oxazinas , Piperazinas , Piridonas , Inibidores da Transcriptase Reversa , Ritonavir , Carga Viral , Humanos , Darunavir/uso terapêutico , Darunavir/administração & dosagem , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Feminino , Adulto , Masculino , HIV-1/efeitos dos fármacos , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Carga Viral/efeitos dos fármacos , Pessoa de Meia-Idade , Inibidores da Transcriptase Reversa/uso terapêutico , Inibidores da Transcriptase Reversa/administração & dosagem , Ritonavir/uso terapêutico , Ritonavir/administração & dosagem , Padrão de Cuidado , Fármacos Anti-HIV/uso terapêutico , Fármacos Anti-HIV/administração & dosagem , Quimioterapia Combinada , Emtricitabina/uso terapêutico , Emtricitabina/administração & dosagem , Resultado do Tratamento , Terapia Antirretroviral de Alta Atividade , Tenofovir/uso terapêutico , Tenofovir/administração & dosagem , Contagem de Linfócito CD4 , Falha de Tratamento , Lamivudina/uso terapêutico , Lamivudina/administração & dosagemRESUMO
BACKGROUND: There is increasing interest in utilising two-drug regimens for HIV treatment with the goal of reducing toxicity and improve acceptability. The D3 trial evaluates the efficacy and safety of DTG/3TC in children and adolescents and includes a nested pharmacokinetics(PK) substudy for paediatric drug licensing. METHODS: D3 is an ongoing open-label, phase III, 96-week non-inferiority randomised controlled trial(RCT) conducted in South Africa, Spain, Thailand, Uganda and the United Kingdom. D3 has enrolled 386 children aged 2- < 15 years, virologically suppressed for ≥6 months, with no prior treatment failure. Participants were randomised 1:1 to receive DTG/3TC or DTG plus two nucleoside reverse transcriptase inhibitors(NRTIs), stratified by region, age (2- < 6, 6- < 12, 12- < 15 years) and DTG use at enrolment (participants permitted to start DTG at enrolment). The primary outcome is confirmed HIV-1 RNA viral rebound ≥50 copies/mL by 96-weeks. The trial employs the Smooth Away From Expected(SAFE) non-inferiority frontier, which specifies the non-inferiority margin and significance level based on the observed event risk in the control arm. The nested PK substudy evaluates WHO weight-band-aligned dosing in the DTG/3TC arm. DISCUSSION: D3 is the first comparative trial evaluating DTG/3TC in children and adolescents. Implications of integrating a PK substudy and supplying data for prompt regulatory submission, were carefully considered to ensure the integrity of the ongoing trial. The trial uses an innovative non-inferiority frontier for the primary analysis to allow for a lower-than-expected confirmed viral rebound risk in the control arm, while ensuring interpretability of results and maintaining the planned sample size in an already funded trial. TRIAL REGISTRATION: International Standard Randomised Clinical Trial Number Register: ISRCTN17157458. European Clinical Trials Database: 2020-001426-57. CLINICALTRIALS: gov: NCT04337450.
Assuntos
Infecções por HIV , HIV-1 , Compostos Heterocíclicos com 3 Anéis , Lamivudina , Oxazinas , Piperazinas , Piridonas , Humanos , Adolescente , Infecções por HIV/tratamento farmacológico , Piridonas/administração & dosagem , Piridonas/uso terapêutico , Piridonas/farmacocinética , Criança , Oxazinas/administração & dosagem , Oxazinas/uso terapêutico , Pré-Escolar , Lamivudina/administração & dosagem , Lamivudina/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Piperazinas/administração & dosagem , Masculino , Feminino , HIV-1/efeitos dos fármacos , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/uso terapêutico , Fármacos Anti-HIV/farmacocinética , Carga Viral , Estudos de Equivalência como Asunto , RNA Viral , Quimioterapia Combinada , Combinação de Medicamentos , Inibidores da Transcriptase Reversa/administração & dosagem , Inibidores da Transcriptase Reversa/uso terapêutico , Inibidores da Transcriptase Reversa/farmacocinéticaRESUMO
Background: In this study, the clinical effect of lamivudine combined with leflunomide and methylprednisolone in the treatment of hepatitis B virus-associated glomerulonephritis (HBV-GN) and their influence on renal function indexes was explored. Methods: Patients with HBV-GN were selected for retrospective analysis and divided into the group B and group A, with 41 cases in each group. The group B was given leflunomide and methylprednisolone, whereas the group A was supplemented with lamivudine. The level of 24 h proteinuria (PRO), albumin (ALB), beta2-microglobulin (β2-MG), alanine aminotransferase (ALT), interferon-gamma (IFN-γ) and interleukin-4 (IL-4) in two groups was measured. The clinical efficacy, adverse reactions appetite, spirit, sleep and daily life scores of the two groups were recorded. Results: With the extension of treatment time to end of the treatment, the level of 24 h PRO, ALB and β2-MG in the group A significantly changed compared with that before treatment (p < 0.05). Moreover, the level of ALT, IFN-γ and IL-4 in the two groups significantly decreased compared with that before treatment, and the level of the three indexes in the group A decreased more significantly (p < 0.05). The total effective rate in the group A was higher than that in the group B (p < 0.05). The occurrence of adverse reactions showed no statistically significant difference between the two groups. After treatment, scores of appetite, spirit, sleep and daily living were increased in the two groups, and the increase in the group A was more significant than that in the group B (p < 0.05). Conclusions: Lamivudine combined with methylprednisolone and leflunomide treatment is conducive to clearing Hepatitis B virus (HBV) and improving renal function (AU)
Assuntos
Humanos , Masculino , Feminino , Adulto , Inibidores da Transcriptase Reversa/administração & dosagem , Lamivudina/administração & dosagem , Leflunomida/administração & dosagem , Metilprednisolona/administração & dosagem , Hepatite B/tratamento farmacológico , Glomerulonefrite/tratamento farmacológico , Quimioterapia Combinada , Testes de Função Renal , Estudos RetrospectivosAssuntos
Humanos , Masculino , Feminino , Adolescente , Adulto , Pessoa de Meia-Idade , Adulto Jovem , Pirimidinas/administração & dosagem , Infecções por HIV/prevenção & controle , HIV-1 , Inibidores da Transcriptase Reversa/administração & dosagem , Pirimidinas/efeitos adversos , Vagina , Infecções por HIV/epidemiologia , Método Duplo-Cego , Estudos Multicêntricos como Assunto , Fatores Etários , Cooperação do Paciente , Ensaios Clínicos Fase III como Assunto , Inibidores da Transcriptase Reversa/efeitos adversos , África Austral/epidemiologia , Farmacorresistência Viral , Ensaios Clínicos Controlados não Aleatórios como AssuntoRESUMO
INTRODUCCIÓN: El objetivo del estudio Perfil-es era conocer, en la práctica clínica, la proporción de TARV de inicio basado en ITINAN o IP/r e identificar los factores implicados en la decisión terapéutica. Métodos Estudio observacional, retrospectivo en 65 hospitales. Resultados Se iniciaron 1.687 TARV: un 53% basado en ITINAN y un 42% en IP/r. Se analizaron 642 pacientes. El 72% presentaba un recuento de CD4 < 350 células/μl. Conclusión En España el TARV de inicio sigue siendo tardío. Los ITINAN son la elección más frecuente aunque los IP/r desempeñan un importante papel
INTRODUCTION: The purpose of Perfil-es study was to identify the proportion of patients starting ARV treatment based on NNRTIs or PI/r, and to identify the variables involved in the therapeutic decision-makingin standard clinical practice. METHODS: An observational restrospective study performed in 65 Spanish hospitals. RESULTS: Was a total of 1,687 starts: 53% with NNRTI-based regimen and 42% with PI/r, and of the642 patients analyzed, 72% had a CD4 count < 350 cells/l. CONCLUSION: The initiation of ARV treatment is still late in Spain. NNRTIs are the more frequent choice, although PI/r plays an important role
Assuntos
Humanos , Infecções por HIV/tratamento farmacológico , Terapia Antirretroviral de Alta Atividade/métodos , Antirretrovirais/administração & dosagem , Complexo Relacionado com a AIDS/tratamento farmacológico , Estudos Retrospectivos , Inibidores da Transcriptase Reversa/administração & dosagem , Ritonavir/administração & dosagem , Inibidores da Protease de HIV/administração & dosagem , Padrões de Prática MédicaRESUMO
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
Assuntos
Humanos , Fármacos Anti-HIV/farmacocinética , Citocromo P-450 CYP3A/metabolismo , Indutores do Citocromo P-450 CYP3A/farmacocinética , Nitrilas/farmacocinética , Pirimidinas/farmacocinética , Inibidores da Transcriptase Reversa/farmacocinética , Fármacos Anti-HIV/uso terapêutico , Anti-Infecciosos , Anticonvulsivantes/farmacocinética , Inibidores do Citocromo P-450 CYP3A/farmacocinética , Anticoncepcionais Orais/farmacocinética , Fármacos Gastrointestinais/farmacocinética , Nitrilas/uso terapêutico , Bombas de Próton/farmacocinética , Pirimidinas/uso terapêutico , Inibidores da Transcriptase Reversa/administração & dosagemRESUMO
De los 25 anti-retrovirales disponibles en el mercado, sólo 16 están autorizados en la edad pediátrica. Los antiretrovirales, pertenecientes a las tres primeras familias, usados desde hace dos décadas, continúan vigentes y son parte importante de la terapia anti-retroviral en niños naïve. Se describen las dosis, presentaciones y asociaciones actuales de estos fármacos en la edad pediátrica y además se comentan las nuevas co-formulaciones que permitirán disminuir el número de dosis, mejorar la tolerancia y por lo tanto conseguir mejor adherencia de los pacientes pediátricos.
Of the 25 antiretroviral drugs available in the market, only 16 are allowed for prescription in the pediatric patients. The antiretroviral, pertaining to the first three families, used for two decades, remain valid and are important components of antiretroviral therapy in naive children. We describe doses, presentations and current associations for these drugs in children, and also discuss new co-formulations that will reduce the number of doses, improve tolerance and therefore achieve better adherence of pediatric patients.
Assuntos
Criança , Humanos , Antirretrovirais/administração & dosagem , Infecções por HIV/tratamento farmacológico , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Fármacos Anti-HIV/administração & dosagem , Esquema de Medicação , Inibidores da Protease de HIV/administração & dosagem , Transcriptase Reversa do HIV/antagonistas & inibidores , Inibidores da Transcriptase Reversa/administração & dosagemRESUMO
Etravirina (ETR) se ha mostrado eficaz en pacientes multitratados con fallos virológicos previos y mutaciones de resistencia a varias familias de fármacos antirretrovirales. La mayor evidencia surge de los estudios DUET. Éstos son 2 ensayos clínicos multicéntricos idénticos, aleatorizados y doble ciego, que incluyeron alrededor de 1.200 pacientes, donde se observó una respuesta virológica e inmunológica superior a placebo y que se tradujo en una reducción en la incidencia de ingresos hospitalarios y de progresión a sida/muerte. Además, ETR fue muy bien tolerado en estos pacientes. El efecto adverso más frecuente fue el exantema que, generalmente, fue leve o moderado y únicamente obligó a suspender el tratamiento en el 2% de los pacientes. No hubo diferencias en cuanto a toxicidades gastrointestinales, hepáticas o lipídicas, comparado con la rama placebo. El desarrollo reciente de nuevos fármacos permite disponer hoy de pautas activas eficaces para pacientes multitratados. El estudio TRIO ha evaluado la eficacia y tolerabilidad de una de las pautas más utilizadas actualmente en la práctica habitual: ETR/raltegravir/darunavir/r, con excelentes resultados de respuesta virológica e inmunológica (el 86% de carga viral < 50 copias y CD4 +108 a las 48 semanas) y, al mismo tiempo, una muy buena tolerabilidad. ETR es eficaz y bien tolerada y es el primer inhibidor de la transcriptasa inversa no análogo de nucleósidos (ITINAN) que permite el uso secuencial de fármacos de esta familia, gracias a su elevada barrera genética comparando con los ITINAN de primera generación. Además, su larga vida media permite su administración una vez al día en caso de que los pacientes necesitaran una pauta qd
Etravirine (ETR) has demonstrated efficacy in patients with multiple prior treatments with prior virological failure and resistance mutations to various families of antiretroviral drugs. Most of the evidence concerning this drug has been drawn from the DUET studies, consisting of two multicenter, randomized, double-blind clinical trials with identical designs that included 1,200 patients. These trials showed that ETR obtained a superior virological and immunological response to placebo, reducing the incidence of hospital admissions and progression to AIDS/death. The most frequent adverse effect was rash, which was generally mild to moderate and required treatment discontinuation in only 2%. There were no differences in gastrointestinal, liver or lipid toxicities compared with the placebo arm. Because of the recent development of new drugs, effective regimens are now available for multi-treated patients. The TRIO study evaluated the efficacy and tolerability of one of the regimens most widely used today (ETR/raltegravir/darunavir/r) with excellent virological and immunological response (86% of viral load < 50 copies and CD4 +108 at 48 weeks) and excellent tolerance. ETR is effective and well tolerated and is the first non-nucleoside reverse transcriptase inhibitor (NNRTI) that allows the sequential use of drugs in this family, due to its high genetic barrier compared with firstgeneration NNRTI. Moreover, its long half-life allows once daily administration in patients requiring a QD régimen
Assuntos
Humanos , Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Inibidores da Transcriptase Reversa/uso terapêutico , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1 , Piridazinas/uso terapêutico , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/farmacocinética , Terapia Antirretroviral de Alta Atividade , Inibidores da Transcriptase Reversa/administração & dosagem , Inibidores da Transcriptase Reversa/farmacologia , Inibidores da Transcriptase Reversa/farmacocinética , HIV-1/genéticaRESUMO
Etravirina (ETR) es un nuevo fármaco antirretroviral que pertenece a la familia de los inhibidores de la transcriptasa inversa no análogos de los nucleósidos (ITINAN) y que ha sido recientemente autorizado por las agencias reguladoras para el tratamiento de pacientes con experiencia previa a antirretrovirales, con evidencia de replicación viral activa y que albergan cepas de virus de la inmunodeficiencia humana 1 multirresistentes. En este contexto, en Europa se ha autorizado su uso en combinación con inhibidores de proteasa potenciados e inhibidores de la transcriptasa inversa análogos de nucleósidos. Dicha indicación se ha establecido basándose en los resultados de los estudios DUET, estudios aleatorizados y doble ciego, en los que los pacientes que se aleatorizaron a ETR evidenciaron una respuesta estadísticamente superior en cuanto a eficacia virológica, recuperación inmunológica y calidad de vida relacionada con la salud. Desde el punto de vista de la seguridad, ETR mostró en dichos estudios ser tan bien tolerada como el placebo, con una única excepción, la aparición de exantema. Éste fue más frecuente que en el grupo placebo, generalmente leve a moderado, y obligó a interrumpir el tratamiento con ETR sólo en un 2% de los pacientes. Sin embargo, las características de ETR, es decir, su potencia virológica, su excelente perfil de seguridad, su perfi l de resistencias, sus propiedades farmacocinéticas y su perfil de interacciones farmacológicas permiten entrever que su utilidad no se halla restringida al perfil de pacientes aprobado por las agencias reguladoras. No obstante, en la mayoría de estos supuestos no hay evidencias formales de su uso, aunque algunos de ellos están en fase de ensayo clínico. Así pues, hay en marcha un estudio en pacientes naïve (SENSE) con administración en toma única diaria con el objetivo de demostrar mejor tolerabilidad sobre el sistema nervioso central que efavirenz. En otros supuestos, su perfil de tolerabilidad hepática, neuropsiquiátrica, e incluso cutánea sugieren que ETR puede constituir una buena alternativa cuando haya toxicidad, o peligro de la misma, causada por los ITINAN de primera generación. Cuando hay fracaso virológico a un régimen de inicio con ITINAN de primera generación, el perfil diferencial de resistencias de ETR puede permitir construir una combinación de rescate basada en ETR. Su ausencia de teratogenicidad la hace potencialmente útil en pacientes embarazadas o en mujeres que hayan expresado deseo gestacional. Finalmente, su benigno perfil de interacciones medicamentosas debe permitir una mejor utilización en pacientes que se hallen sometidos a comedicación, y ello puede ser especialmente importante en áreas con elevada prevalencia de tratamiento con metadona puesto que no hay interacción significativa entre ambos fármacos. ETR se halla aprobada para uso en rescate avanzado. Sin embargo, sus características permiten suponer que hay una serie de indicaciones potenciales basadas en su potencia antiviral, perfil diferencial de resistencias, seguridad y tolerabilidad y perfil de interacciones medicamentosas
Etravirine (ETR) is a new antiretroviral drug of the non-nucleoside reverse transcriptase inhibitor (NNRTI) family that has recently been approved by the regulatory agencies for the treatment of patients with prior experience with antiretrovirals, evidence of active viral replication, and who harbor multidrug resistant HIV-1 strains. In this context, in Europe, the use of this drug has been authorized combined with boosted protease inhibitors and nucleoside reverse transcriptase inhibitors. This approval was based on the results of the randomized double-blind DUET studies, in which the ETR arm was statistically superior to the placebo arms in terms of virological efficacy, immunological recovery, clinical progression and health related quality of life. These studies showed that ETR was as well-tolerated as placebo, except for the appearance of rash, which was more common in the ETR arm. However, rash was usually mild or moderate and caused discontinuation of ETR in only 2% of the patients. The characteristics of ETR, i.e., potency, benign safety profile, resistance profile, pharmacokinetic characteristics, and drug interactions suggest that the use of this drug may go beyond its currently approved indications. Nevertheless, the evidence supporting these alternative uses is still scarce, although a randomized, double-blind, placebo controlled trial (SENSE) is under way in treatment-naïve patients. In this trial ETR will be administered once daily and the principal objective is to show that ETR has better tolerability in the central nervous system (CNS) than efavirenz. Moreover, the tolerability profile in the CNS, liver, and even skin suggest that ETR may be a good option when there are toxicity problems, or a risk of toxicity, with first-generation NNRTIs. When there is virological failure with an initial first-generation NNRTI-based regimen, the differential resistance profile of ETR may allow this drug to be used to construct a rescue combination. ETR is not teratogenic and can therefore be safely used in pregnant or fertile women. Finally, ETR has an excellent drug-drug interaction profile, which may be useful in patients administered other medications. This interaction profile may be especially important in areas with a high prevalence of methadone treatment, as both drugs can be coadministered safely. ETR has received approval as advanced rescue therapy. However, the characteristics of this drug suggest that it may be useful in a series of potential indications, due to its antiviral potency, differential resistance profile, safety, tolerability and drug-drug interaction profile
Assuntos
Humanos , Masculino , Feminino , Fármacos Anti-HIV/administração & dosagem , Infecções por HIV/tratamento farmacológico , Inibidores da Transcriptase Reversa/administração & dosagem , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1 , Piridazinas/administração & dosagem , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade , Inibidores da Transcriptase Reversa/efeitos adversos , Inibidores da Transcriptase Reversa/uso terapêutico , Piridazinas/efeitos adversos , Piridazinas/farmacologia , Dislipidemias/induzido quimicamenteRESUMO
La impresionante mejora en el arsenal terapéutico hahecho real la posibilidad de convivir crónicamente con elvirus de la inmunodeficiencia humana. Nuestrospacientes, como nosotros, están envejeciendo y suesperanza de vida se aproxima a la de la población dereferencia. Por ello se necesitan fármacos seguros, fácilesde tomar, con interacciones controlables y con el menorimpacto posible sobre comorbilidades de granprevalencia, como la aterosclerosis o la coinfección porvirus hepatotropos.Fármacos que se adapten al estilo de vida del paciente sinafectarle en su calidad y libres, sobre todo, de efectosestigmatizantes como la lipoatrofia, que supone hoy unagran preocupación para la mayoría de los pacientes dereciente diagnóstico.La elección de la pareja análogos de nucleósidosinhibidoresde la transcriptasa inversa (ANITI) al inicio deltratamiento antirretroviral (TAR) debe sustentarse en laevaluación cuidadosa de los ya muchos datosacumulados acerca de todos estos determinantes que yaestán configurando una nueva era en el control de lainfección.Así, en este escenario, los análogos timidínicos han sidorelegados a un uso alternativo. Las combinaciones a dosisfijas de tenofovir (TDF) y emtricitabina (FTC) o abacavir(ABC) y lamivudina (3TC) son el ®backbone» electivo aliniciar el TAR.Los datos comparativos directos aún son escasos, peroapuntan a una eficacia virológica similar, con algún datode desventaja, muy preliminar del ABC/3TC. Aunque, trasexcluir a los pacientes con riesgo de hipersensibilidad aABC, ambos ®combos» son muy bien tolerados, elTDF/FTC se asocia a un mejor perfil lipídico. Los recientesdatos del DAD que muestran una inesperada asociacióndel ABC con el incremento del riesgo cardiovascularprecisan estudios en profundidad(AU)
The huge improvement in the therapeutic arsenal for HIVinfection has led to HIV becoming a chronic disease. Likeus, our patients are aging and their life expectancy isclose to that of the general population. Consequently, weneed safe, easily administered drugs with interactionsthat can be controlled and the least possible impact onhighly prevalent comorbidities such as atherosclerosis orcoinfection with hepatotropic viruses. Drugs should fitthe patients lifestyle without affecting quality of life and,above all, be free of effects leading to stigma, such aslipoatrophy, a major concern for most recently diagnosedpatients. The choice of the two nucleoside analoguereverse transcriptase inhibitors used at the start ofantiretroviral therapy should be based on carefulevaluation of the abundant data accumulated on all thesedetermining factors which are heralding a new era in thecontrol of HIV infection. Thus, in this scenario, thymidineanalogues have been relegated to alternative use. Fixeddosecombinations of tenofovir and emtricitabine(TDF/FTC) or abacavir and lamivudine (ABC/3TC) are thebackbone of choice when initiating antiretroviral therapy.Direct comparative data are still scarce but suggestsimilar virological efficacy, with highly preliminary datasuggesting some disadvantages associated with the useof ABC/3TC. After excluding patients at risk ofhypersensitivity to ABC, both combinations are welltolerated, but TDF/FTC is associated with a better lipidprofile. Recent data from the Data Collection on AdverseEvents of Anti-HIV drugs (DAD) study show anunexpected association of ABC with increasedcardiovascular risk and thus more detailed studies arerequired(AU)
Assuntos
Humanos , Terapia Antirretroviral de Alta Atividade/métodos , Timidina/análogos & derivados , Infecções por HIV/tratamento farmacológico , Antirretrovirais/administração & dosagem , Combinação de Medicamentos , /prevenção & controle , Nucleosídeos/administração & dosagem , Inibidores da Transcriptase Reversa/administração & dosagem , Síndrome de Lipodistrofia Associada ao HIV/prevenção & controleAssuntos
Humanos , Adenina/análogos & derivados , Fármacos Anti-HIV/administração & dosagem , Didanosina/administração & dosagem , Infecções por HIV/tratamento farmacológico , Ácidos Fosforosos , Inibidores da Transcriptase Reversa/administração & dosagem , Adenina/administração & dosagem , Adenina , Fármacos Anti-HIV , Quimioterapia Combinada , Didanosina , Infecções por HIV/virologia , Ácidos Fosforosos , Inibidores da Transcriptase Reversa , Falha de Tratamento , Carga ViralRESUMO
There are few long-term data on which to base decisions of drug management of HIV infection in pregnancy. The determination of safe medications must take into consideration the need for certain drugs and the possibility of inadvertent fetal exposure because of unplanned pregnancies. The aim of this study was to evaluate the effects of foscarnet on the entire period of rat pregnancy. Female pregnant rats were randomly assigned to four treatment groups (n = 10): one control (C) treated with the drug vehicle (bidestilled water) and three experimental groups (E1, E2 and E3) treated with 180, 360 or 720 mg/Kg of foscarnet, respectively. Rats were treated by gavage once daily. The treatment period extended from the first until the 20th day of pregnancy. Body weights were recorded weekly along this period. At term, the rats were sacrificed, the implantation sites and the number of fetuses and resorptions were recorded. The fetuses were evaluated for externally visible abnormalities under a stereomicroscope. No differences in body weights among the groups were observed; however, foscarnet-treated rats showed reduced fetal and placental weights. The incidence 137of resorptions and major malformations (shortening of limbs) in the E3 group was significantly raised. Foscarnet treatment during the entire period of rat pregnancy can produce definite toxic effects, mainly on the placental and fetal compartments.
Foscarnet es un inhibidor de la transcriptasis reversa del HIV que actúa en la síntesis del DNA. En este trabajo evaluamos los efectos crónicos del foscarnet durante la preñez de la rata albina. Ratas preñadas fueron distribuidas aleatoriamente en cuatro grupos (n = 10 para cada grupo): uno control (C), tratadas con agua bidestilada, y tres experimentales (E1, E2 y E3), tratadas con 180, 360 o 720 mg/Kg al día de foscarnet. El fármaco y el vehículo (siempre 1 ml) fueron administrados una vez al día desde el día 0 hasta el día 20 de la gestación. Las ratas fueron pesadas semanalmente y sacrificadas al término de la preñez. No se observaron alteraciones significativas en cuanto al incremento de peso corporal entre los grupos. Sin embargo, las ratas tratadas con foscarnet (especialmente las de los grupos E2 y E3) presentaron reducciones del peso promedio de los fetos y de las respectivas placentas. La incidencia de reabsorciones y malformaciones (acortamiento de miembros) fue significativa en el grupo E3. Se concluye que la administración de foscarnet durante toda la preñez de la rata puede producir efectos tóxicos definidos, especialmente en los compartimientos placentario y fetal.
Assuntos
Animais , Feminino , Gravidez , Ratos , Prenhez/efeitos dos fármacos , Foscarnet/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Peso Corporal , Resultado da Gravidez , Ratos Wistar , Foscarnet/administração & dosagem , Inibidores da Transcriptase Reversa/administração & dosagemRESUMO
BACKGROUND/AIMS: Anti-viral therapy using hepatitis B immune globulin and lamivudine could not prevent HBV recurrence after liver transplantation (LT) completely. Adefovir dipivoxil is a acyclic nucleotide phosphate analogue and known to have potent anti-HBV effect. In this study, we analyzed the therapeutic effect of adefovir for recurrent or de novo HBV infection after LT. METHODS: From December 2002 to October 2004, adefovir was administered in 12 post-LT patients of HBV infection (11 recurrent and 1 de novo infection). In these patients, lamivudine and other combined therapies were used before the introduction of adefovir. Thereafter, adefovir combined with lamivudine was administered to all patients. RESULTS: The duration of adefovir administration was 5.5-18 (median, 15.5) months. The median values of serum AST and ALT levels were significantly reduced from 86+/-80 IU/L and 140+/-103 IU/L, respectively before the adefovir administration to 42+/-19 IU/L and 38+/-33 IU/L after 2 months of administration. This trend of improved liver function persisted throughout the follow-up period. HBeAg seroconversion was achieved in 4 of 10 patients (40%) and HBsAg seroconversion was observed in 1 of 10 patients (10%). HBV DNA levels have decreased to undetectable levels by hybridization assay in 6 of 7 patients within the first 2 months of therapy. Nephrotoxicity and hypophosphatemia were not found in all of these patients. CONCLUSIONS: Based on this preliminary result, adefovir dipivoxil seems to be an effective and safe antiviral agent leading to viral inhibition and clinical improvement in post-LT patients with recurrent or de novo HBV infection.
Assuntos
Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adenina/administração & dosagem , Antivirais/administração & dosagem , Quimioterapia Combinada , Resumo em Inglês , Hepatite B Crônica/tratamento farmacológico , Lamivudina/administração & dosagem , Transplante de Fígado , Ácidos Fosforosos/administração & dosagem , Recidiva , Inibidores da Transcriptase Reversa/administração & dosagemRESUMO
Con la introducción de las terapias antirretrovirales potentes, se ha conseguido disminuir la mortalidad, alargar la supervivencia y mejorar la calidad de vida de los adultos y niños infectados por el VIH. Las potentes combinaciones utilizadas actualmente ofrecen, sin embargo, una eficacia limitada en el tiempo y con frecuencia deben ser modificadas. Las causas que justifican un cambio de tratamiento antirretroviral en niños incluyen la presencia de toxicidad o intolerancia al régimen administrado, la existencia de datos contrastados que demuestren que un nuevo fármaco o régimen es superior al que se está utilizando y la progresión de la enfermedad en alguna de sus facetas: virológica, inmunológica o clínica. El término 'terapia de rescate' lleva implícito un fracaso terapéutico que está produciendo una progresión de la enfermedad, constituyendo éste el motivo que justifica el cambio de tratamiento. Además, para cambiar un tratamiento también es muy importante el cumplimiento terapéutico, la detección de resistencias a antirretrovirales y la evolución de marcadores inmunológicos y virológicos utilizados habitualmente en la clínica. En este estudio, se presenta una completa revisión sobre estos aspectos (AU)
Assuntos
Feminino , Pré-Escolar , Lactente , Masculino , Criança , Humanos , Infecções por HIV/tratamento farmacológico , Terapia de Salvação/métodos , Fármacos Anti-HIV/administração & dosagem , Resultado do Tratamento , RNA Viral/sangue , Carga Viral , Protocolos Clínicos , Inibidores da Protease de HIV/administração & dosagem , Inibidores da Transcriptase Reversa/administração & dosagemRESUMO
En el presente trabajo se analizan los beneficios y limitaciones de la terapia antirretroviral de alta eficacia (HAART). Los objetivos de esta terapia son reducir la carga viral plasmática lo máximo posible y durante el mayor tiempo posible. Esto implica alcanzar niveles de carga viral no detectables con técnicas ultrasensibles. Se evalúan los resultados obtenidos con los principales esquemas de tratamiento asi como sus indicaciones y efectos adversos.
Assuntos
Humanos , Quimioterapia Combinada , Infecções por HIV/terapia , Nucleosídeos/administração & dosagem , Nucleosídeos/uso terapêutico , Inibidores de Proteases/administração & dosagem , Inibidores de Proteases/efeitos adversos , Inibidores de Proteases/uso terapêutico , Retroviridae , Inibidores da Transcriptase Reversa/administração & dosagem , Inibidores da Transcriptase Reversa/efeitos adversos , Inibidores da Transcriptase Reversa/uso terapêutico , Carga Viral , Contagem de Linfócito CD4/efeitos dos fármacos , Interações Medicamentosas , Lipodistrofia/etiologia , Lipodistrofia/fisiopatologiaRESUMO
En el presente trabajo se analizan los beneficios y limitaciones de la terapia antirretroviral de alta eficacia (HAART). Los objetivos de esta terapia son reducir la carga viral plasmática lo máximo posible y durante el mayor tiempo posible. Esto implica alcanzar niveles de carga viral no detectables con técnicas ultrasensibles. Se evalúan los resultados obtenidos con los principales esquemas de tratamiento asi como sus indicaciones y efectos adversos. (AU)
Assuntos
Humanos , Carga Viral , Retroviridae , Infecções por HIV/terapia , Quimioterapia Combinada , Inibidores da Transcriptase Reversa/administração & dosagem , Inibidores da Transcriptase Reversa/uso terapêutico , Inibidores da Transcriptase Reversa/efeitos adversos , Inibidores de Proteases/administração & dosagem , Inibidores de Proteases/efeitos adversos , Inibidores de Proteases/uso terapêutico , Nucleosídeos/administração & dosagem , Nucleosídeos/uso terapêutico , Contagem de Linfócito CD4/efeitos dos fármacos , Lipodistrofia/etiologia , Lipodistrofia/fisiopatologia , Interações MedicamentosasRESUMO
Nucleoside reverse transcriptase inhibitors (NRTIs) plasma concentrations do not correlate with clinical efficacy or toxicity. These agents need to be phosphorylated to become active against HIV-infection. Thus, the characterization of the NRTIs intracellular metabolite pharmacological parameters will provide a better understanding that could lead to the development of more rational dose regimens in the HIV-infected population. Furthermore, intracellular measurements of NRTIs may provide a better marker with respect to clinical efficacy and toxicity than plasma concentrations. Thus, in this article we review the latest information regarding the intracellular pharmacological parameters of zidovudine (ZDV) and lamivudine (3TC) active metabolites in HIV infected patients including the results from our recent clinical studies. We will start the discussion with ZDV and 3TC clinical efficacy, followed by systemic pharmacokinetics studies. We will then discuss the in vitro and in vivo intracellular studies with particular emphasis in the method development to measure these metabolites and we will conclude with the most current data from our clinical trials.
Assuntos
Humanos , Masculino , Feminino , Criança , Adulto , Pessoa de Meia-Idade , Fármacos Anti-HIV/farmacocinética , Antimetabólitos/farmacocinética , Lamivudina/farmacocinética , Leucócitos Mononucleares/metabolismo , Inibidores da Transcriptase Reversa/farmacocinética , Zidovudina/farmacocinética , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/sangue , Antimetabólitos/administração & dosagem , Antimetabólitos/sangue , Células Cultivadas , Cromatografia Líquida de Alta Pressão , Ensaios Clínicos como Assunto , Infecções por HIV/tratamento farmacológico , Lamivudina/administração & dosagem , Lamivudina/sangue , Fosfatos/metabolismo , Fosforilação , Polifosfatos/metabolismo , Radioimunoensaio , Inibidores da Transcriptase Reversa/administração & dosagem , Inibidores da Transcriptase Reversa/sangue , Fatores de Tempo , Zidovudina/administração & dosagem , Zidovudina/sangueRESUMO
Se describe por primera vez una polirradiculopatía lumbosacra producida por el virus herpes simple (VHS) sin coinfección por el citomegalovirus (CMV) en un paciente con infección por VIH. La polirradiculomielitis aguda lumbosacra (PAL) en pacientes con SIDA es una entidad nosológica bien definida y clásicamente asociada a infección por el CMV. No obstante, esta patología puede ser debida a otras etiologías como la toxoplasmosis, sífilis, linfoma, tuberculosis, criptococosis, virus varicela-zoster (VVZ), virus Epstein-Barr (VEB) y VHS asociado a CMV. El caso aportado fue documentado con los hallazgos del líquido cefalorraquídeo, imagen de resonancia magnética y se confirmó con el aislamiento del DNA del VHS mediante técnica de reacción en cadena de la polimerasa. Por el contrario, no se aisló DNA del CMV y no se presentaron hallazgos clínicos de enfermedad por CMV. Este caso respondió adecuadamente al tratamiento con foscarnet. Este fármaco, sin ganciclovir asociado, se ha empleado raramente en el tratamiento de la PAL. Creemos que el foscarnet puede ser un tratamiento alternativo válido para los casos de PAL en los que se sospeche infección por VHS resistente al aciclovir (AU)