RESUMO
BACKGROUND: We explored the relationship between virological response in the first year of treatment and long-term outcomes in the BENCHMRK studies. METHODS: Patients failing antiretroviral treatment with 3-class resistant HIV-1 received double-blinded raltegravir (or placebo) with optimized background therapy (OBT) until week 156, followed by open-label raltegravir with OBT up to week 240. In this exploratory analysis of patients randomized to raltegravir, virological response over weeks 16-48 was categorized as continuous suppression (CS; viral RNA [vRNA] always <50 copies/ml), low-level viraemia (LLV; vRNA always <400 copies/ml, >50 copies/ml at least once), or not suppressed (NS; vRNA >400 copies/ml at least once). The association between these first-year vRNA response categories and baseline factors was analysed with univariate and multivariate models. Virological and immunological outcomes for years 2-5 were assessed by first-year vRNA response category (observed failure approach). RESULTS: Baseline vRNA, baseline CD4(+) T-cell count and rapid viral decay (vRNA <50 copies/ml between weeks 2-12) correlated with first-year vRNA response (P<0.001); only rapid viral decay remained significant by multiple regression. Virological response rates were similar in the LLV and CS groups and lowest in the NS group. CD4(+) T-cell count increased through week 240 in the CS and LLV groups. Time to loss of virological response (confirmed vRNA ≥400 copies/ml) through week 240 did not support as strong a difference between the LLV and CS groups (log-rank P=0.11) as previously reported through weeks 156 and 192 (P<0.05). CONCLUSIONS: Treatment-experienced patients on a raltegravir-based regimen with early LLV may have long-term virological and immunological benefit when their therapy is maintained.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/genética , Raltegravir Potássico/uso terapêutico , Fármacos Anti-HIV/farmacologia , Contagem de Linfócito CD4 , Relação CD4-CD8 , Feminino , Genótipo , Infecções por HIV/imunologia , HIV-1/efeitos dos fármacos , Humanos , Masculino , Testes de Sensibilidade Microbiana , Raltegravir Potássico/farmacologia , Fatores de Tempo , Resultado do Tratamento , Carga ViralRESUMO
BACKGROUND: Two randomised, placebo-controlled trials-BENCHMRK-1 and BENCHMRK-2-investigated the efficacy and safety of raltegravir, an HIV-1 integrase strand-transfer inhibitor. We report final results of BENCHMRK-1 and BENCHMRK-2 combined at 3 years (the end of the double-blind phase) and 5 years (the end of the study). METHODS: Integrase-inhibitor-naive patients with HIV resistant to three classes of drug and who were failing antiretroviral therapy were enrolled. Patients were randomly assigned (2:1) to raltegravir 400 mg twice daily or placebo, both with optimised background treatment. Patients and investigators were masked to treatment allocation until week 156, after which all patients were offered open-label raltegravir until week 240. The primary endpoint was previously assessed at 16 weeks. We assessed long-term efficacy with endpoints of the proportion of patients with an HIV viral load of less than 50 copies per mL and less than 400 copies per mL, and mean change in CD4 cell count, at weeks 156 and 240. FINDINGS: 1012 patients were screened for inclusion. 462 were treated with raltegravir and 237 with placebo. At week 156, 51% in the raltegravir group versus 22% in the placebo group (non-completer classed as failure) had viral loads of less than 50 copies per mL, and 54% versus 23% had viral loads of less than 400 copies per mL. Mean CD4 cell count increase (analysed by an observed failure approach) was 164 cells per µL versus 63 cells per µL. After week 156, 251 patients (54%) from the raltegravir group and 47 (20%) from the placebo group entered the open-label raltergravir phase; 221 (47%) versus 44 (19%) completed the entire study. At week 240, viral load was less than 50 copies per mL in 193 (42%) of all patients initially assigned to raltegravir and less than 400 copies per mL in 210 (45%); mean CD4 cell count increased by 183 cells per µL. Virological failure occurred in 166 raltegravir recipients (36%) during the double-blind phase and in 17 of all patients (6%) during the open-label phase. The most common drug-related adverse events at 5 years in both groups were nausea, headache, and diarrhoea, and occurred in similar proportions in each group. Laboratory test results were similar in both treatment groups and showed little change after year 2. INTERPRETATION: Raltegravir has a favourable long-term efficacy and safety profile in integrase-inhibitor-naive patients with triple-class resistant HIV in whom antiretroviral therapy is failing. Raltegravir is an alternative for treatment-experienced patients, particularly those with few treatment options. FUNDING: Merck Sharp & Dohme.
Assuntos
Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/efeitos adversos , Infecções por HIV/tratamento farmacológico , Pirrolidinonas/administração & dosagem , Pirrolidinonas/efeitos adversos , Adulto , Contagem de Linfócito CD4 , Método Duplo-Cego , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/isolamento & purificação , Humanos , Masculino , Pessoa de Meia-Idade , Placebos/administração & dosagem , Placebos/efeitos adversos , Raltegravir Potássico , Terapia de Salvação/efeitos adversos , Terapia de Salvação/métodos , Resultado do Tratamento , Carga ViralRESUMO
BACKGROUND: DAS181, a novel host-directed antiviral in development for influenza treatment, was assessed in this phase II clinical trial. METHODS: This study was a double-blind, placebo-controlled phase II clinical trial assessing influenza viral load and patient safety in otherwise healthy influenza-infected participants. Participants were randomized to a single-dose, multiple-dose, or placebo group and were followed for safety and virologic outcomes. RESULTS: A total of 177 laboratory-confirmed influenza-infected participants were enrolled in the trial, which encompassed 3 influenza seasons from 2009-2011 in both the Northern and Southern Hemispheres. Thirty-seven percent of participants had confirmed infection with influenza B, 33% with seasonal H3N2, 29% with pandemic 2009 H1N1, and 1 participant was positive for both influenza B and pandemic 2009 H1N1. Significant effects were observed in regard to decreased change from baseline viral load and viral shedding in the multiple-dose group compared with placebo as measured by quantitative polymerase chain reaction (P < .05). No instances of H274Y were observed among viral isolates from this trial. Overall, the drug was generally well tolerated. CONCLUSIONS: DAS181 significantly reduced viral load in participants infected with influenza, thus warranting future clinical development of this novel host-directed therapy. CLINICAL TRIALS.GOV IDENTIFIER: NCT01037205.
Assuntos
Antivirais/administração & dosagem , Influenza Humana/tratamento farmacológico , Proteínas Recombinantes de Fusão/administração & dosagem , Adulto , Antivirais/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Vírus da Influenza A Subtipo H1N1/isolamento & purificação , Vírus da Influenza A Subtipo H3N2/isolamento & purificação , Masculino , Pessoa de Meia-Idade , Placebos/administração & dosagem , Proteínas Recombinantes de Fusão/efeitos adversos , Resultado do Tratamento , Carga ViralRESUMO
Human immunodeficiency virus (HIV) infection is associated with insulin resistance. HIV type 1 Nef downregulates cell surface protein expression, alters signal transduction, and interacts with the cytoskeleton and proteins involved in actin polymerization. These functions are required for glucose uptake by insulin-stimulated adipocytes. We sought to determine whether Nef alters adipocyte glucose homeostasis. Using radiolabeled glucose, we found that adipocytes exposed to recombinant Nef took in 42% less glucose after insulin stimulation than did control cells. This reduction resulted from a Nef-dependent inhibition of glucose transporter 4 (GLUT4) trafficking, as assessed by means of immunofluorescence microscopy. Immunoblot analysis revealed a decrease in phosphorylation of signal transducing proteins after Nef treatment, and fluorescence microscopy showed a dramatic alteration in cortical actin organization. We conclude that Nef interferes with insulin-stimulated processes in adipocytes. We have identified HIV Nef, which is detectable and antigenic in serum samples from HIV-infected people, as a novel contributor to the development of insulin resistance.
Assuntos
Adipócitos/metabolismo , Glucose/metabolismo , Infecções por HIV/complicações , HIV-1 , Resistência à Insulina/fisiologia , Produtos do Gene nef do Vírus da Imunodeficiência Humana/metabolismo , Células 3T3-L1 , Actinas/metabolismo , Adipócitos/efeitos dos fármacos , Adipócitos/virologia , Animais , Western Blotting , Membrana Celular/metabolismo , Relação Dose-Resposta a Droga , Regulação para Baixo , Proteínas Ativadoras de GTPase/metabolismo , Transportador de Glucose Tipo 4/metabolismo , Humanos , Insulina/farmacologia , Camundongos , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/fisiologia , Produtos do Gene nef do Vírus da Imunodeficiência Humana/sangue , Produtos do Gene nef do Vírus da Imunodeficiência Humana/farmacologiaRESUMO
Influenza, respiratory synctial virus, and parainfluenza are common respiratory infections in immunocompromised transplant recipients, causing significant morbidity and mortality in this patient population. This paper focuses on influenza and parainfluenza virus infections in transplant patients with emphasis on the pandemic 2009 H1N1 influenza infection. Current antiviral treatment recommendations for influenza and parainfluenza in immunocompromised patients as well as novel investigational therapeutic approaches currently being tested in the clinic are discussed. In addition to the morbidity and mortality caused by these viruses, the development of multidrug resistance leading to transmission of resistant viruses is of great public health concern. The development of effective new therapies for influenza and parainfluenza in these high-risk patients is needed with randomized placebo-controlled studies to assess their clinical utility.
RESUMO
The emergence of the 2009 H1N1 pandemic influenza A virus, as well as constant antigenic drift of seasonal influenza, underscores the remarkable versatility of this virus in adapting to the human population. While vaccines are the principal public health defence against influenza, rapid vaccine development can be a daunting task. Antiviral drugs offer the promise of inhibiting influenza regardless of its genetic variations. However, the rapid rise of resistance to several antivirals has highlighted the need for developing novel therapeutics with reduced drug resistance potential. In this review, we will summarize the effects of the currently licensed anti-influenza drugs as well as the candidates in development against the seasonal and the 2009 H1N1 pandemic influenza A virus with an emphasis on drug resistance.
Assuntos
Antivirais/farmacologia , Surtos de Doenças , Farmacorresistência Viral , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Influenza Humana/tratamento farmacológico , Ácidos Carbocíclicos , Ciclopentanos/farmacologia , Guanidinas/farmacologia , Humanos , Vírus da Influenza A Subtipo H1N1/isolamento & purificação , Influenza Humana/epidemiologia , Influenza Humana/virologia , Modelos Biológicos , Oseltamivir/farmacologia , Proteínas Recombinantes de Fusão/farmacologia , Zanamivir/farmacologiaRESUMO
BENCHMRK-1 and -2 are ongoing double-blind phase III studies of raltegravir in patients experiencing failure of antiretroviral therapy with triple-class drug-resistant human immunodeficiency virus infection. At week 96 (combined data), raltegravir (400 mg twice daily) plus optimized background therapy was generally well tolerated, with superior and durable antiretroviral and immunological efficacy, compared with optimized background therapy alone.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Pirrolidinonas/uso terapêutico , Fármacos Anti-HIV/efeitos adversos , Contagem de Linfócito CD4 , Método Duplo-Cego , Farmacorresistência Viral , Quimioterapia Combinada , Feminino , HIV-1/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Pirrolidinonas/efeitos adversos , RNA Viral/sangue , Raltegravir Potássico , Carga ViralRESUMO
Raltegravir, an inhibitor of the HIV-1 integrase enzyme, is the first available agent in a new class of antiretroviral drugs. Raltegravir has been studied extensively in clinical trials, and has been well tolerated and highly effective in both treatment-naïve and -experienced patients. Resistance to raltegravir is unusual given its recent availability, but resistance with identified viral mutation pathways in the integrase gene in patients receiving the drug does occur.
RESUMO
BACKGROUND: Raltegravir, an inhibitor of the HIV-1 integrase enzyme, is now available for the treatment of drug-resistant virus. OBJECTIVE: To establish raltegravir as an effective addition to the existing antiretroviral armamentarium by reviewing pharmacokinetics, efficacy, safety and tolerability. METHODS: Data from pharmacokinetic, Phase II and III clinical trials were reviewed. RESULTS/CONCLUSIONS: Results from clinical trials indicate that raltegravir is safe and highly effective in the treatment of both antiretroviral-naïve and -experienced patients.
Assuntos
Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/uso terapêutico , Pirrolidinonas/uso terapêutico , Ensaios Clínicos como Assunto , Farmacorresistência Viral , Inibidores de Integrase de HIV/efeitos adversos , Inibidores de Integrase de HIV/farmacocinética , Humanos , Pirrolidinonas/efeitos adversos , Pirrolidinonas/farmacocinética , Raltegravir PotássicoRESUMO
BACKGROUND: We evaluated the efficacy of raltegravir and the development of viral resistance in two identical trials involving patients who were infected with human immunodeficiency virus type 1 (HIV-1) with triple-class drug resistance and in whom antiretroviral therapy had failed. METHODS: We conducted subgroup analyses of the data from week 48 in both studies according to baseline prognostic factors. Genotyping of the integrase gene was performed in raltegravir recipients who had virologic failure. RESULTS: Virologic responses to raltegravir were consistently superior to responses to placebo, regardless of the baseline values of HIV-1 RNA level; CD4 cell count; genotypic or phenotypic sensitivity score; use or nonuse of darunavir, enfuvirtide, or both in optimized background therapy; or demographic characteristics. Among patients in the two studies combined who were using both enfuvirtide and darunavir for the first time, HIV-1 RNA levels of less than 50 copies per milliliter were achieved in 89% of raltegravir recipients and 68% of placebo recipients. HIV-1 RNA levels of less than 50 copies per milliliter were achieved in 69% and 80% of the raltegravir recipients and in 47% and 57% of the placebo recipients using either darunavir or enfuvirtide for the first time, respectively. At 48 weeks, 105 of the 462 raltegravir recipients (23%) had virologic failure. Genotyping was performed in 94 raltegravir recipients with virologic failure. Integrase mutations known to be associated with phenotypic resistance to raltegravir arose during treatment in 64 patients (68%). Forty-eight of these 64 patients (75%) had two or more resistance-associated mutations. CONCLUSIONS: When combined with an optimized background regimen in both studies, a consistently favorable treatment effect of raltegravir over placebo was shown in clinically relevant subgroups of patients, including those with baseline characteristics that typically predict a poor response to antiretroviral therapy: a high HIV-1 RNA level, low CD4 cell count, and low genotypic or phenotypic sensitivity score. (ClinicalTrials.gov numbers, NCT00293267 and NCT00293254.)
Assuntos
Farmacorresistência Viral/genética , Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/uso terapêutico , Integrase de HIV/genética , HIV-1 , Compostos Orgânicos/uso terapêutico , Adolescente , Adulto , Idoso , Contagem de Linfócito CD4 , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Genótipo , Inibidores de Integrase de HIV/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Compostos Orgânicos/efeitos adversos , Fenótipo , Pirrolidinonas , RNA Viral/sangue , Raltegravir Potássico , Resultado do Tratamento , Carga ViralRESUMO
BACKGROUND: Raltegravir (MK-0518) is an inhibitor of human immunodeficiency virus type 1 (HIV-1) integrase active against HIV-1 susceptible or resistant to older antiretroviral drugs. METHODS: We conducted two identical trials in different geographic regions to evaluate the safety and efficacy of raltegravir, as compared with placebo, in combination with optimized background therapy, in patients infected with HIV-1 that has triple-class drug resistance in whom antiretroviral therapy had failed. Patients were randomly assigned to raltegravir or placebo in a 2:1 ratio. RESULTS: In the combined studies, 699 of 703 randomized patients (462 and 237 in the raltegravir and placebo groups, respectively) received the study drug. Seventeen of the 699 patients (2.4%) discontinued the study before week 16. Discontinuation was related to the study treatment in 13 of these 17 patients: 7 of the 462 raltegravir recipients (1.5%) and 6 of the 237 placebo recipients (2.5%). The results of the two studies were consistent. At week 16, counting noncompletion as treatment failure, 355 of 458 raltegravir recipients (77.5%) had HIV-1 RNA levels below 400 copies per milliliter, as compared with 99 of 236 placebo recipients (41.9%, P<0.001). Suppression of HIV-1 RNA to a level below 50 copies per milliliter was achieved at week 16 in 61.8% of the raltegravir recipients, as compared with 34.7% of placebo recipients, and at week 48 in 62.1% as compared with 32.9% (P<0.001 for both comparisons). Without adjustment for the length of follow-up, cancers were detected in 3.5% of raltegravir recipients and in 1.7% of placebo recipients. The overall frequencies of drug-related adverse events were similar in the raltegravir and placebo groups. CONCLUSIONS: In HIV-infected patients with limited treatment options, raltegravir plus optimized background therapy provided better viral suppression than optimized background therapy alone for at least 48 weeks. (ClinicalTrials.gov numbers, NCT00293267 and NCT00293254.)
Assuntos
Farmacorresistência Viral , Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/uso terapêutico , HIV-1 , Compostos Orgânicos/uso terapêutico , Adolescente , Adulto , Idoso , Contagem de Linfócito CD4 , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Seguimentos , Inibidores de Integrase de HIV/efeitos adversos , HIV-1/genética , HIV-1/isolamento & purificação , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Neoplasias/etiologia , Compostos Orgânicos/efeitos adversos , Pirrolidinonas , RNA Viral/sangue , Raltegravir Potássico , Resultado do Tratamento , Carga ViralRESUMO
In RESIST, enfuvirtide co-administered with ritonavir-boosted tipranavir was associated with higher plasma tipranavir concentrations, which seldom rose above those associated with an increased risk of grade 3/4 transaminase elevations. Transaminase elevation rates (6.5%) and clinical hepatic event rates (5.9 events/100 person exposure years) were lower in the tipranavir/ritonavir with enfuvirtide group than in the tipranavir/ritonavir without enfuvirtide group. Observed increases in plasma tipranavir concentrations thus had no apparent effect on the risk of hepatotoxicity.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Doença Hepática Induzida por Substâncias e Drogas , Proteína gp41 do Envelope de HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , HIV-1 , Fragmentos de Peptídeos/uso terapêutico , Piridinas/uso terapêutico , Pironas/uso terapêutico , Alanina Transaminase/sangue , Quimioterapia Combinada , Enfuvirtida , Inibidores da Fusão de HIV/uso terapêutico , Infecções por HIV/sangue , Infecções por HIV/enzimologia , Inibidores da Protease de HIV/uso terapêutico , Humanos , Hepatopatias/enzimologia , Lopinavir , Piridinas/sangue , Pirimidinonas/uso terapêutico , Pironas/sangue , Ensaios Clínicos Controlados Aleatórios como Assunto , Ritonavir/uso terapêutico , Saquinavir/uso terapêutico , Sulfonamidas , Resultado do Tratamento , Carga ViralRESUMO
BACKGROUND: MK-0518 is a novel HIV-1 integrase strand transfer inhibitor with potent in vitro activity against HIV-1 (95% inhibitory concentration [IC95] = 33 nM in 50% human serum) and good bioavailability in uninfected subjects. This study explored the antiretroviral activity and safety of MK-0518 versus placebo for 10 days as monotherapy in antiretroviral therapy-naive HIV-1-infected patients with plasma HIV-1 RNA levels of at least 5000 copies/mL and CD4 T-cell counts of at least 100 cells/mm. METHODS: This was a multicenter, double-blind, randomized, placebo-controlled 2-part study, with the first part using MK-0518 in 1 of 4 doses (100, 200, 400, and 600 mg) versus placebo (randomized 1:1:1:1:1) given twice daily for 10 days of monotherapy. Patients were monitored for safety, pharmacokinetic parameters, and antiretroviral effect. RESULTS: Thirty-five patients were enrolled (6-8 patients per treatment group) and completed 10 days of therapy; the mean baseline log10 HIV RNA level ranged from 4.5 to 5.0 copies/mL in each group. On day 10, the mean decrease from baseline in the log10 HIV RNA level was -0.2 copies/mL for the placebo group and -1.9, -2.0, -1.7 and -2.2 log10 copies/mL for the MK-0518 100-, 200-, 400-, and 600-mg treatment groups, respectively. All dose groups had superior antiretroviral activity compared with placebo (P < 0.001 for comparison of each dose with placebo). At least 50% of patients in each MK-0518 dose group achieved an HIV RNA level <400 copies/mL by day 10. Mean trough MK-0518 concentrations at each dose exceeded the IC95 of 33 nM. Study therapy was generally well tolerated. The most common adverse experiences were headache and dizziness; these were similar between active and control groups. There were no discontinuations because of adverse experiences and no serious adverse experiences. CONCLUSIONS: MK-0518 showed potent antiretroviral activity as short-term monotherapy and was generally well tolerated at all doses. Based on these results, part 2 of the study, a dose-ranging 48-week trial of MK-0518 versus efavirenz in a combination regimen, has been initiated.
Assuntos
Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/efeitos adversos , Inibidores de Integrase de HIV/uso terapêutico , Integrase de HIV/metabolismo , Compostos Orgânicos/efeitos adversos , Compostos Orgânicos/uso terapêutico , Adulto , Área Sob a Curva , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Feminino , Inibidores de Integrase de HIV/administração & dosagem , Inibidores de Integrase de HIV/farmacocinética , HIV-1/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Compostos Orgânicos/administração & dosagem , Compostos Orgânicos/farmacocinética , Pirrolidinonas , RNA Viral , Raltegravir Potássico , Carga ViralRESUMO
A double-blind, randomized study of zidovudine-experienced, PI- and lamivudine-naive adults with baseline CD4 cell counts of < or =50 cells/mm3 had demonstrated that the HIV suppression achieved with zidovudine, lamivudine, and indinavir therapy was superior to that achieved with dual-nucleoside or indinavir-only regimens after 24 weeks of therapy. In a 192-week extension of the study, 371 participants received open-label indinavir with or without other antiretroviral drugs. One hundred and eight subjects were originally randomized to receive triple therapy. After 216 weeks, the proportion of subjects with HIV RNA levels of <500 copies/mL were 34%, according to a general estimating equation analysis, 92%, according to an observed data analysis, and 24%, according to an intention-to-treat analysis counting noncompleters as failures; the proportions of subjects with HIV RNA levels of <50 copies/mL were 31%, 85%, and 22%, respectively. Hyperbilirubinemia (experienced by 31% of subjects), nausea (17%), abdominal pain (14%), and nephrolithiasis (13%) were the most common drug-related adverse events during the extension.
Assuntos
Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/uso terapêutico , Zidovudina/uso terapêutico , Adulto , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/uso terapêutico , Contagem de Linfócito CD4 , Diarreia/etiologia , Método Duplo-Cego , Quimioterapia Combinada , Fadiga/etiologia , Feminino , Inibidores da Protease de HIV/efeitos adversos , HIV-1/efeitos dos fármacos , Humanos , Indinavir/efeitos adversos , Indinavir/uso terapêutico , Lamivudina/efeitos adversos , Lamivudina/uso terapêutico , Masculino , Pessoa de Meia-Idade , RNA Viral/metabolismo , Zidovudina/efeitos adversosRESUMO
The insulin-sensitizing drugs thiazolidinediones (TZDs), such as rosiglitazone, improve insulin sensitivity and also promote adipocyte differentiation in vitro. The authors hypothesized that TZDs might be beneficial to patients with HIV disease to improve insulin sensitivity and the distribution of body fat by increasing peripheral fat. The ability of rosiglitazone (8 mg/d) to improve insulin sensitivity (from hyperinsulinemic-euglycemic clamp) and to improve body fat distribution (determined from computed tomography measurements of visceral adipose tissue [VAT] and subcutaneous adipose tissue [SAT]) was determined in 8 HIV-positive patients. Before treatment, the insulin sensitivity of the patients was reduced to approximately 34% of that in control subjects. The rate of glucose disposal during a hyperinsulinemic-euglycemic clamp (Rd) was 3.8 +/-.4 (SEM) mg glucose/kg lean body mass/min compared with 11.08 +/- 1.1 (p<.001) in healthy age- and body mass index (BMI)-matched control subjects. After rosiglitazone treatment of 6 to 12 weeks, Rd increased to 5.99 +/-.9 (p=.02), an improvement of 59 +/- 22%. SAT increased by 23 +/- 10% (p=.05), and, surprisingly, VAT was decreased by 21 +/- 8% (p=.04) with a trend for increased SAT/VAT that failed to reach statistical significance. There were no significant changes in blood counts, viral loads, or CD4 counts with rosiglitazone treatment. The study demonstrates that rosiglitazone therapy improves insulin resistance and body fat distribution in some patients with HIV disease.