ABSTRACT
OBJECTIVES: Dolutegravir is a second-generation integrase strand transfer inhibitor (InSTI) that has been recently approved by the FDA to treat antiretroviral therapy-naive as well as treatment-experienced HIV-infected individuals, including those already exposed to the first-generation InSTI. Despite having a different mutational profile, some cross-resistance mutations may influence its susceptibility. The aim of this study was to evaluate the impact of a raltegravir-containing salvage regimen on dolutegravir activity. PATIENTS AND METHODS: Blood samples of 92 HIV-infected individuals with virological failure (two or more viral loads >50 copies/mL after 6 months of treatment) using raltegravir with optimized background therapy were sequenced and evaluated according to the Stanford University HIV Drug Resistance Database algorithm. RESULTS: Among the 92 patients analysed, 32 (35%) showed resistance to dolutegravir, in most cases associated with the combination of Q148H/R/K with G140S/A mutations. At genotyping, patients with resistance to dolutegravir had viral load values closer to the highest previously documented viral load. CONCLUSIONS: Changes in viraemia during virological failure may indicate the evolution of raltegravir resistance and may predict the emergence of secondary mutations that are associated with a decrease in dolutegravir susceptibility. Early discontinuation of raltegravir from failing regimens might favour subsequent salvage with dolutegravir, but further studies are necessary to evaluate this issue.
Subject(s)
Pyrrolidinones/therapeutic use , Humans , HIV Infections/drug therapy , HIV-1/drug effects , HIV-1/genetics , Salvage Therapy/methods , Treatment Failure , Sequence Analysis, DNA , Anti-HIV Agents/therapeutic use , Anti-HIV Agents/pharmacology , Adult , Mutation, Missense , Drug Resistance, Viral , Young Adult , Raltegravir Potassium , Genotype , Heterocyclic Compounds/pharmacology , Middle AgedABSTRACT
The use of new antiretroviral drugs in HIV infection is particularly important in patients with intolerance or resistance to other antiretroviral agents. Raltegravir and maraviroc represent new, important resources in salvage regimens. A reduced grade of liver fibro-steatosis after a combination of raltegravir and maraviroc (second-line) has not been studied and the mechanism by which these new drug classes induced a marked reduction of grade of liver diseases is currently unknown. In the present case report, nested in an ongoing multicentre observational study on the use of new antiretroviral inhibitors in heavy treatment-experienced HIV patients, we evaluated the correlation between a "short therapeutic regimen" raltegravir, maraviroc and fosamprenavir and liver diseases. The aim of this report is to describe the use of a three-drug regimen based on two novel-class antiretroviral agents (raltegravir and maraviroc) plus the protease inhibitor fosamprenavir, in an experienced HIV-infected patient with chronic progressive hepatitis C complicated by liver fibrosis; an overwhelming increased serum creatine kinase level occurred during treatment, and is probably related to integrase inhibitor administration. At present no information is available regarding this correlation.
El uso de nuevos medicamentos antiretrovirales para la infección por VIH es particularmente importante en los pacientes con intolerancia o resistencia a otros agentes antiretrovirales. Raltegravir (RTV) y maraviroc (MRV) representan nuevos e importantes recursos en las terapias de salvamento. Un grado reducido de fibroesteatosis hepática después de una combinación de raltegravir y maraviroc (terapia de segunda línea) no ha sido estudiado, y el mecanismo por el cual estas nuevas clases de droga indujeron una marcada reducción de grado de las enfermedades hepáticas se desconoce hasta el momento. Como parte de la realización en curso de un estudio observacional multicentro acerca del uso de nuevos inhibidores antiretrovirales en pacientes de VIH altamente experimentados en el tratamiento, en el presente reporte de caso se evalúa la correlación entre un "régimen terapéutico corto" (raltegravir, maraviroc y fosamprenavir) y las enfermedades del hígado. El objetivo de este reporte es describir el uso de un régimen de tres medicamentos - basado en dos agentes antiretrovirales de nuevo tipo (raltegravir y maraviroc) además del fosamprenavir inhibidor de la proteasa - en un paciente de VIH experimentado. El paciente también sufre de hepatitis C evolutiva, progresiva, crónica, complicada por fibrosis hepática. Durante el tratamiento, se produjo un aumento extraordinario del nivel de creatina quinasa sérica, el cual probablemente esta relacionado con la administración del inhibidor de la integrasa. Actualmente no hay información disponible con respecto a esta correlación.
Subject(s)
Adult , Humans , Male , Carbamates/adverse effects , Cardiomyopathies/drug therapy , Creatine Kinase/blood , Cyclohexanes/adverse effects , Chemical and Drug Induced Liver Injury/diagnosis , Fatty Liver/chemically induced , HIV Fusion Inhibitors/adverse effects , HIV Infections/drug therapy , HIV Integrase Inhibitors/adverse effects , HIV Protease Inhibitors/adverse effects , Hepatitis C, Chronic/drug therapy , Liver Cirrhosis/chemically induced , Organophosphates/adverse effects , Pyrrolidinones/adverse effects , Sulfonamides/adverse effects , Triazoles/adverse effects , Carbamates/therapeutic use , Cyclohexanes/therapeutic use , Drug Substitution , Drug Therapy, Combination , Fatty Liver/diagnosis , HIV Fusion Inhibitors/therapeutic use , HIV Integrase Inhibitors/therapeutic use , HIV Protease Inhibitors/therapeutic use , Liver Cirrhosis/diagnosis , Organophosphates/therapeutic use , Pyrrolidinones/therapeutic use , Sulfonamides/therapeutic use , Triazoles/therapeutic useABSTRACT
Piracetam, used clinically for cognitive disorders, was found to have significant anti-ulcerogenic activity against immobilization stress- and aspirin-induced gastric ulcers in rats. The anti-ulcer effect of piracetam was exerted by augmentation of mucosal resistance. This was indicated by the significant attenuation of the decrease in total carbohydrate: protein ratio induced by aspirin. It also reversed the marked increase in gastric juice protein and DNA induced by aspirin, indicating that piracetam attenuated the augmented mucosal cell exfoliation induced by the ulcerogen. The drug also increased gastric mucosal serotonin concentrations. Piracetam, thus appears to have a profile of activity associated with cytoprotective agents.
Subject(s)
Animals , Aspirin , Female , Male , Piracetam/therapeutic use , Pyrrolidinones/therapeutic use , Rats , Rats, Inbred F344 , Stomach Ulcer/chemically inducedABSTRACT
One month following carbon monoxide poisoning, a 39 year-old man developed incontinence, memory impairment, disorientation and emotional instability. He was hospitalized 7weeks later, and during hospitalization he exhibited myoclonic movements of the neck and lower limbs. He was given piracetam intravenously for 11 days. The myoclonus was significantly reduced by the third day of treatment and had disappeared by the seventh day. There was no recurrence following cessation of treatment.
Subject(s)
Adult , Humans , Male , Carbon Monoxide Poisoning/complications , Myoclonus/drug therapy , Myoclonus/etiology , Piracetam/therapeutic use , Pyrrolidinones/therapeutic useABSTRACT
Quarenta pacientes, abaixo dos 70 anos de idade, portadores de labirintopatias, foram tratados sob esquema duplo-cego com aniracetan (1 g/dia) ou placebo durante seis semanas. A avaliaçäo final da eficácia mostrou diferença estatisticamente significativa a favor do aniracetam (remissäo dos sintomas ou melhora acentuada em 55% dos pacientes tratados com aniracetam, contra 20% daqueles que receberam placebo). O sintoma que mostrou melhor resposta ao aniracetam foi o "zumbido" durante as crises. A tolerabilidade foi excelente tanto para o aniracetam quanto para o placebo, näo havendo diferença estatística significativa entre os dois grupos