ABSTRACT
INTRODUCCIÓN La tuberculosis (TB) sigue siendo la principal causa de muerte de personas infectadas por el VIH en todo el mundo. VIH. La infección aumenta el riesgo de progresión a la enfermedad de TB activa, incluso entre los que están bien controlados con la terapia antirretroviral (TAR) contra el VIH. No obstante, el TAR reduce la morbimortalidad y está indicado para todos los pacientes coinfectados por TB/VIH. Dolutegravir (DTG) es un inhibidor de transferencia de cadena de integrasa de segunda generación recientemente recomendado por la Organización Mundial de la Salud (OMS) como régimen preferido de primera línea para el tratamiento de pacientes infectados por el VIH nuevos y experimentados con TAR (1). Sin embargo, los primeros estudios indican que las interacciones farmacológicas entre DTG y Rifampicina pueden resultar en una disminución concentraciones de DTG, lo que plantea preocupaciones sobre la seguridad y el desarrollo potencial de resistencia del VIH en el contexto de niveles subterapéuticos de DTG. OBJETIVO: El objetivo de esta revisión es identificar y sistematizar la evidencia disponible sobre la eficacia y seguridad de la doble dosis de dolutegravir (100 mg) en comparación con la dosis habitual (50 mg) en pacientes con infección por VIH y tuberculosis que se encuentran recibiendo el esquema estándar de tratamiento para tuberculosis. METODOLOGÍA: Se realizó una revisión rápida basada en la comparación con el esquema estándar. Para ello, se elaboró una búsqueda sistemática en las bases de datos MEDLINE/PubMed, LILACS (BVS), la Biblioteca Cochrane, además de una búsqueda manual. Luego de eliminar duplicados, fueron seleccionaron los artículos que cumplieran con la pregunta de investigación. RESULTADOS: La búsqueda sistemática identificó 139 registros, de ellos 120 fueron tamizados por títulos y resúmenes, solo dos artículos pasaron a lectura de texto completo. Finalmente, no se incluyó ningún estudio con evidencia tanto para el desenlace de eficacia y seguridad. CONCLUSIONES: No se identificaron ensayos clínicos para evaluar la eficacia y seguridad de la dosis de 100mg de dolutegravir vs la dosis de 50 mg en pacientes coinfección por TB/VIH. Actualmente, se encuentra em desarrollo el ensayo clínico fase 2 RADIANT-TB que compara la doble dosis dolutegravir (100 mg) vs la dosis habitual de 50 mg en pacientes con coinfección por TB/VIH (ID: NCT03851588).
Subject(s)
Humans , Tuberculosis, Pulmonary/drug therapy , HIV Infections/drug therapy , Integrase Inhibitors/pharmacokinetics , Efficacy , Cost-Benefit Analysis , Biomarkers, PharmacologicalABSTRACT
BACKGROUND: As a simplification strategy for treatment-experienced HIV-infected patients who have achieved virologic suppression on a multi-drug, multi-class antiretroviral regimen, the aim of this study was to evaluate the safety, efficacy, and pharmacokinetics of once-daily elvitegravir/cobicistat/emtricitabine/tenofovir disproxil fumarate (E/C/F/TDF) with darunavir. METHODS: A single arm, open-label 48-week study was conducted of regimen simplification to E/C/F/TDF plus darunavir 800 mg daily from stable therapy including two nucleoside/nucleotide reverse transcriptase inhibitors, a ritonavir-boosted protease inhibitor, and an integrase inhibitor. Participants had plasma HIV viral load consistently < 200 copies/mL for ≥ 6 months, estimated glomerular filtration rate (eGFR) ≥ 60 mL/min, and no genotypic resistance to major components of the study regimen. Plasma viral load was measured at weeks 2 and 4, then every 4 weeks throughout the study. Safety laboratory assessments were conducted at baseline and at weeks 12, 24, 36, and 48. Antiretroviral drug concentrations were measured at baseline and once ≥ 2 weeks after the regimen change. RESULTS: Ten HIV-infected adults (8 male and 2 female; median age 50.5 years) were enrolled. All maintained virologic suppression on the new regimen for 48 weeks. One subject experienced a decrease in eGFR from 62 mL/min at baseline to 52 mL/min at week 12; study medications were continued and his eGFR remained stable (50-59 mL/min) thereafter. No subjects discontinued study medications for renal function changes or other adverse events. Darunavir trough concentration were lower on the new regimen than on darunavir/ritonavir 800/100 mg (n = 5; p < 0.05). CONCLUSIONS: Despite low darunavir trough concentrations, treatment simplification to a two-pill, once-daily regimen of E/C/F/TDF plus darunavir was safe and effective for 48 weeks among 10 selected treatment-experienced HIV-infected patients. Trial registration The study protocol was registered with ClinicalTrials.gov (NCT02199613) on July 22, 2014.
Subject(s)
Anti-HIV Agents/therapeutic use , Cobicistat/pharmacokinetics , Darunavir/pharmacokinetics , Emtricitabine/pharmacokinetics , HIV Infections/drug therapy , Integrase Inhibitors/therapeutic use , Protease Inhibitors/therapeutic use , Quinolones/pharmacokinetics , Reverse Transcriptase Inhibitors/therapeutic use , Ritonavir/pharmacokinetics , Tenofovir/pharmacokinetics , Adult , Aged , Anti-HIV Agents/adverse effects , Anti-HIV Agents/pharmacokinetics , Cobicistat/adverse effects , Cobicistat/therapeutic use , Darunavir/adverse effects , Darunavir/therapeutic use , Drug Therapy, Combination , Emtricitabine/adverse effects , Emtricitabine/therapeutic use , Female , HIV-1/drug effects , Humans , Integrase Inhibitors/adverse effects , Integrase Inhibitors/pharmacokinetics , Male , Middle Aged , Protease Inhibitors/adverse effects , Protease Inhibitors/pharmacokinetics , Quinolones/adverse effects , Quinolones/therapeutic use , Reverse Transcriptase Inhibitors/adverse effects , Reverse Transcriptase Inhibitors/pharmacokinetics , Ritonavir/adverse effects , Ritonavir/therapeutic use , Tenofovir/adverse effects , Tenofovir/therapeutic use , Viral Load/drug effectsABSTRACT
Long-acting GSK1265744 (GSK744 LA) is a strand transfer inhibitor of the HIV/SIV (simian immunodeficiency virus) integrase and was shown to be an effective preexposure prophylaxis (PrEP) agent in a low-dose intrarectal SHIV (simian-human immunodeficiency virus) rhesus macaque challenge model. We examined the pharmacokinetics and efficacy of GSK744 LA as PrEP against repeat high-dose intravaginal SHIV challenge in female rhesus macaques treated with Depo-Provera (depot medroxyprogesterone acetate), which promotes viral transmission vaginally. When Depo-Provera-treated female rhesus macaques were dosed with GSK744 LA (50 mg/kg) monthly, systemic and tissue drug concentrations were lower than previously observed in male rhesus macaques. GSK744 concentrations were fivefold lower on average in cervical tissues than in rectal tissues. Eight female rhesus macaques were treated with GSK744 LA at week 0, and four female rhesus macaques served as controls. All animals received a high-dose challenge of SHIV162P3 at week 1. No infection was detected in GSK744 LA-treated rhesus macaques, whereas viremia was detected 1 to 2 weeks after SHIV challenge in all control animals. The GSK744 LA-treated rhesus macaques were given a second administration of drug at week 4 and further challenged at weeks 5 and 7. GSK744 LA treatment protected six of eight female rhesus macaques against three high-dose SHIV challenges, whereas all control animals became infected after the first challenge (P = 0.0003, log-rank test). These results support further clinical development of GSK744 LA for PrEP.
Subject(s)
Anti-Retroviral Agents/therapeutic use , Integrase Inhibitors/therapeutic use , Simian Acquired Immunodeficiency Syndrome/prevention & control , Simian Immunodeficiency Virus/drug effects , Administration, Intravaginal , Animals , Anti-Retroviral Agents/pharmacokinetics , Female , Genome, Viral , Integrase Inhibitors/pharmacokinetics , Likelihood Functions , Macaca , Medroxyprogesterone Acetate/chemistry , Molecular Sequence Data , Mutation , Pyridones/chemistry , Simian Acquired Immunodeficiency Syndrome/virology , Vagina/virology , Viral LoadABSTRACT
Integrase inhibitors are a promising new group of antiretroviral drugs that suppress the integrase yielded by human immunodeficiency viruses (HIV) via inhibiting the ,,integration" of the viral deoxyribonucleic acid (DNA) into the hosts' DNA genome. In 2007, raltegravir was the first integrase inhibitor that has been approved for the treatment of HIV-1 infections in antiretroviral-pretreated (-experienced) and antiretroviral-naive patients. Recently, elvitegravir, as a fixed coformulation with cobicistat, tenofovir und emtricitabine, has been approved for the treatment of HIV-1-infected antiretroviral-naive patients. InAugust of 2013, dolutegravir, a third integrase inhibitor, has been approved by the US Food and Drug Adiministation (FDA) for the treatment of HIV-1 infections in adults and children aged 12 years and older. Raltegravir has to be applied twice daily without a boosting agent. Elvitegravir and dolutegravir are applied once daily in the presence of a booster (elvitegravir) or unboosted (dolutegravir). In contrast to raltegravir and elvitegravir, dolutegravir shows a high genetic barrier to resistance, and is also applicable for the treatment of several HIV-1 infections with raltegravir and elvitegravir-resistant HIV variants. During the last years, raltegravir, elvitegravir and dolutegravir have been proven and established in the antiretroviral treatment of HIV-1 infections as effective, safe and well-tolerated agents. However, reliable statement forecasts of long-term toxicity of these substances can not yet be made.
Subject(s)
HIV Infections/drug therapy , HIV-1/drug effects , Integrase Inhibitors/pharmacology , Integrase Inhibitors/therapeutic use , Anti-HIV Agents/pharmacology , Contraindications , Drug Resistance, Viral , Heterocyclic Compounds, 3-Ring/pharmacology , Heterocyclic Compounds, 3-Ring/therapeutic use , Humans , Integrase Inhibitors/pharmacokinetics , Oxazines , Piperazines , Pyridones , Pyrrolidinones/pharmacology , Pyrrolidinones/therapeutic use , Raltegravir Potassium , United StatesABSTRACT
Our group has focused on expanding the scope of a two-metal binding pharmacophore concept to explore HIV-1 integrase inhibitors through medicinal chemistry efforts to design novel scaffolds which allow for improvement of pharmacokinetic (PK) and resistance profiles. A novel chelating scaffold was rationally designed to effectively coordinate two magnesium cofactors and to extend an aromatic group into an optimal hydrophobic pharmacophore space. The new chemotype, consisting of a carbamoyl pyridone core unit, shows high inhibitory potency in both enzymatic and antiviral assay formats with low nM IC50 and encouraging potency shift effects in the presence of relevant serum proteins. The new inhibitor design displayed a remarkable PK profile suggestive of once daily dosing without the need for a PK booster as demonstrated by robust drug concentrations at 24 h after oral dosing in rats, dogs, and cynomolgus monkeys.