Assuntos
Aprovação de Drogas , Anticorpos Monoclonais Humanizados/uso terapêutico , Tratamento Farmacológico/enfermagem , Humanos , Insulina de Ação Prolongada/uso terapêutico , Piperazinas/uso terapêutico , Piperidinas/uso terapêutico , Polímeros/uso terapêutico , Pirrolidinonas/uso terapêutico , Estados Unidos , United States Food and Drug Administration , Ureia/análogos & derivados , Ureia/uso terapêuticoRESUMO
CONTEXTO: Uma epilepsia é definida como uma condição neurológica caracterizada por convulsões epilépticas recorrentes. Uma convulsão epiléptica é a manifestação clínica de uma descarga anormal e excessiva de um conjunto de neurônios no cérebro. A epilepsia deve ser vista como um sintoma de uma doença neurológica subjacente e não como uma entidade isolada. TECNOLOGIA: Levetiracetam. PERGUNTA: Levetiracetam é eficaz e seguro para o tratamento epilepsia? EVIDÊNCIAS: Revisão sistemática com network meta-analyses comparou a tolerabilidade relativa de todos os antiepilépticos em monoterapia para todos os tipos de epilepsia, bem como a sua eficácia na monoterapia da epilepsia focal. Levetiracetam mostrou melhor resultado de eficácia para número de indivíduos livre de convulsão em comparação com fenobarbital e primidona, e para o desfecho descontinuação por ineficácia terapêutica em comparação com pregabalina e gabapentina. Levetiracetam apresentou pior perfil de tolerabilidade quando comparado com clobazam e lamotrigina e melhor perfil de tolerabilidade do que fenobarbital e primidona. Não houve diferenças estatisticamente significativas para eficácia e segurança entre levetiracetam e carbamazepina, fenitoína, valproato, etossuximida, topiramato e vigabrina. CONCLUSÕES: Os medicamentos clobazam e lamotrigina, são medicamentos disponibilizados pelo SUS, que não apresentaram diferenças estatisticamente significantes para eficácia quando comparados com o levetiracetam, mas apresentaram melhor perfil de segurança.
Assuntos
Humanos , Anticonvulsivantes/uso terapêutico , Epilepsia/tratamento farmacológico , Pirrolidinonas/uso terapêutico , Análise Custo-Benefício , Avaliação da Tecnologia Biomédica , Resultado do TratamentoRESUMO
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.
Assuntos
Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Farmacorresistência Viral , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Compostos Heterocíclicos com 3 Anéis/farmacologia , Pirrolidinonas/uso terapêutico , Adulto , Feminino , Genótipo , HIV-1/classificação , HIV-1/genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Oxazinas , Piperazinas , Piridonas , Raltegravir Potássico , Terapia de Salvação/métodos , Análise de Sequência de DNA , Falha de Tratamento , Adulto JovemRESUMO
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.
Assuntos
Pirrolidinonas/uso terapêutico , Humanos , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , HIV-1/genética , Terapia de Salvação/métodos , Falha de Tratamento , Análise de Sequência de DNA , Fármacos Anti-HIV/uso terapêutico , Fármacos Anti-HIV/farmacologia , Adulto , Mutação de Sentido Incorreto , Farmacorresistência Viral , Adulto Jovem , Raltegravir Potássico , Genótipo , Compostos Heterocíclicos/farmacologia , Pessoa de Meia-IdadeRESUMO
Raltegravir (RAL) is the first licensed antiretroviral integrase inhibitor that may be used both for treatment-naïve human immunodeficiency virus type 1 (HIV-1) patients and for salvage therapy. The Brazilian public free access programme limits its use for salvage therapy, with scarce information regarding RAL resistance from patients failing a RAL-containing salvage regimen. This study evaluated RAL resistance mutations detected by population sequencing in 69 HIV-infected patients with advanced disease failing a RAL-containing regimen in a real-world setting. RAL resistance mutations were identified in 47/69 patients (68%). The most common salvage regimen, used by 56/69 patients (81%), included lamivudine, tenofovir, darunavir/ritonavir and RAL. At failure, major RAL resistance mutations included Q148H/R/K (21/47; 45%), N155H (14/47; 30%), Y143R/H/C (3/47; 6%) and E92Q (1/47; 2%). Most samples with Q148H/R/K also showed G140S/A/C (21/47; 45%). RAL resistance was significantly associated with less than two active drugs in the optimised background therapy regimen at failure [39/39 (100%) vs. 9/17 (53%); P<0.001] and with a longer cumulative duration with detectable viraemia (viral load >50 copies/mL) (86 weeks vs. 32 weeks; P=0.001). A high frequency of RAL mutations was observed in this study. In addition, these results reinforce the importance of close monitoring of RAL-containing regimens to reduce the time of failure and consequent resistance accumulation.
Assuntos
Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade/métodos , Pirrolidinonas/uso terapêutico , Terapia de Salvação/métodos , Síndrome da Imunodeficiência Adquirida/epidemiologia , Adulto , Brasil/epidemiologia , Farmacorresistência Viral , Feminino , HIV/efeitos dos fármacos , HIV/genética , HIV/isolamento & purificação , Humanos , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Prevalência , Raltegravir Potássico , Análise de Sequência de DNA , Falha de Tratamento , Adulto JovemRESUMO
The effectiveness of switching from enfuvirtide to raltegravir in HIV-1-infected patients on a suppressive antiretroviral regimen has been poorly studied in the clinical practice of developing countries. We conducted a multicenter retrospective cohort study in HIV-1-infected, multidrug-experienced adults (≥18 years old) with plasma HIV-1-RNA <400 copies/ml for at least 4 months on an enfuvirtide-containing therapy between 2005 and 2010, in whom the attending physician switched from enfuvirtide to raltegravir. Effectiveness endpoints were measured at week 48 after switch. Analyses were conducted on an intent-to-treat basis and two strategies for handling missing outcome data were used (hereafter, strategies 1 and 2). Overall, 87 patients were eligible for analysis. At baseline, the median CD4(+) T cell count was 400 cells/µl and 91.9% of patients had <50 HIV-1-RNA copies/ml. At week 48, the proportions of patients with plasma HIV-1-RNA <50 and <400 copies/ml were, respectively, 86.2% (95% CI=77.1; 92.7%) and 88.5% (95% CI=79.9; 94.3%) (strategies 1 and 2) and 89.7% (95% CI=81.3; 95.2%) and 90.8% (95% CI=82.7; 95.9%) (strategies 1 and 2). This was a -10.3% (95% CI=-2.8; -17.9%) and -9.2% (95% CI=-2; -16.4%) difference from baseline in the proportion of patients with plasma HIV-1-RNA <400 copies/ml. The median increase in CD4(+) T cell counts was 41 and 64 cells/µl (p<0.001) (strategies 1 and 2). No patient withdrew raltegravir or developed opportunistic infections, but one was diagnosed with HIV-related dementia. In conclusion, switching from enfuvirtide to raltegravir in patients on a virologically suppressive regimen is an effective strategy even in a Brazilian clinical setting.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Farmacorresistência Viral , Proteína gp41 do Envelope de HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , Fragmentos de Peptídeos/uso terapêutico , Pirrolidinonas/uso terapêutico , Adolescente , Adulto , Brasil , Contagem de Linfócito CD4 , Estudos de Coortes , Enfuvirtida , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , RNA Viral/sangue , Raltegravir Potássico , Resultado do Tratamento , Carga Viral , Adulto JovemRESUMO
The risk of HIV-1 mother-to-child transmission (MTCT) is clearly correlated with the maternal HIV cell-free viral load (VL) at delivery. Preventing MTCT in late-presenting (after 28 weeks) HIV-infected pregnant women remains a clinical challenge, and ensuring a rapid decrease of maternal VL is an important preventive strategy. Raltegravir (RGV) has a higher first and second phase viral decay rate, has a high placental transfer, with a potential preloading effect for neonate, and demonstrates effective accumulation in cervicovaginal secretions. We report 14 cases in which RGV was used late in pregnancy for HIV-1 MTCT prophylaxis. All women were RGV naive and the prophylaxis regimens included RGV plus at least two other antiretroviral agents. At RGV initiation, the median gestational age was 36 weeks (range 34-38) and the median maternal plasma HIV-1 RNA viral load was 35,364 copies/ml (range 636-391,535). At delivery, the median gestational age was 38 weeks (range 37-40). The median exposure time to RGV was 17 days (range 7-32), with a mean maternal VL decay of 2.6 log. At delivery, seven women had undetectable (<50 copies/ml) VL, four had between 64 and 457 copies/ml, and in three VL was not available. All but one infant's HIV-RNA tests were negative at 1 and 3 months (one case of in utero MTCT). Raltegravir-containing antiretroviral regimens induced a rapid HIV-RNA decline in maternal VL at delivery, and were safe and effective in preventing MTCT for late-presenting, HIV-infected women.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/prevenção & controle , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , Complicações Infecciosas na Gravidez/tratamento farmacológico , Pirrolidinonas/uso terapêutico , Adolescente , Adulto , Fármacos Anti-HIV/efeitos adversos , Terapia Antirretroviral de Alta Atividade/efeitos adversos , Terapia Antirretroviral de Alta Atividade/métodos , Feminino , HIV-1/isolamento & purificação , Humanos , Gravidez , Pirrolidinonas/efeitos adversos , RNA Viral/sangue , Raltegravir Potássico , Estudos Retrospectivos , Resultado do Tratamento , Carga Viral , Adulto JovemRESUMO
Maraviroc is a first-in-class chemokine coreceptor type-5 (CCR5) antagonist with demonstrated immunovirologic activity in treatment-experienced (TE) patients with CCR5 (R5)-tropic HIV-1; however, experience in regimens containing newer antiretroviral agents is limited. The primary objective of this 96-week open-label, noncomparative, multicenter Phase 3b study (NCT00478231) was to assess the safety of maraviroc in combination with optimized background therapy (OBT), which could include recently introduced agents such as darunavir and raltegravir in TE patients in Brazil with R5 HIV-1 and limited therapeutic options. Immunovirologic activity was a secondary endpoint. Of 638 patients screened, 206 were treated and 125 completed the study. Approximately 70% were male; the mean age was 43.2 years. Most patients (65.0%) received an OBT combination of protease inhibitor plus nucleoside reverse transcriptase inhibitor. Adverse event (AE) and treatment-related AE incidence was 91.3% and 36.9%, respectively. The most common AEs were diarrhea, nasopharyngitis, and headache. Serious AEs and treatment-related serious AEs occurred in 16.5% and 4.4% of patients. Only eight patients (3.9%) discontinued due to AEs. Few AIDS-defining events were observed (4.9%). The proportion of patients with viral load <400 copies/ml increased from 2.4% at baseline to 43.9% at week 8, remaining >40% until week 48. At the end of treatment, 26.7% of patients had a viral load <400 copies/ml. Median CD4(+) cell count increased throughout the study; the mean change from baseline to end of treatment was 174.1 cells/µl. In conclusion, maraviroc, combined with different agents from multiple classes, was well tolerated in highly TE patients. Maraviroc plus OBT was associated with an immunovirologic response in this population.
Assuntos
Antagonistas dos Receptores CCR5 , Cicloexanos/efeitos adversos , Cicloexanos/uso terapêutico , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Triazóis/efeitos adversos , Triazóis/uso terapêutico , Adulto , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/uso terapêutico , Brasil , Contagem de Linfócito CD4 , Darunavir , Quimioterapia Combinada , Feminino , Inibidores da Fusão de HIV/efeitos adversos , Inibidores da Fusão de HIV/uso terapêutico , Inibidores da Protease de HIV/efeitos adversos , Inibidores da Protease de HIV/uso terapêutico , Humanos , Masculino , Maraviroc , Pessoa de Meia-Idade , Inibidores de Proteases/efeitos adversos , Inibidores de Proteases/uso terapêutico , Pirrolidinonas/efeitos adversos , Pirrolidinonas/uso terapêutico , Raltegravir Potássico , Inibidores da Transcriptase Reversa/efeitos adversos , Inibidores da Transcriptase Reversa/uso terapêutico , Sulfonamidas/efeitos adversos , Sulfonamidas/uso terapêutico , Falha de Tratamento , Carga Viral/efeitos dos fármacos , Adulto JovemRESUMO
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.