RESUMO
Kaposi sarcoma is a rare angioproliferative disease associated with human herpes virus-8 (HHV-8) infection. Kaposi sarcoma is frequent and aggressive in HIV-infected people, whereas the classic form (CKS) generally has an indolent course. Notably, all conventional therapies against Kaposi sarcoma have only temporary efficacy. We have previously shown that indinavir, a HIV protease-inhibitor with direct antiangiogenic and antitumor activity, is safe and effective in patients with early CKS, whereas effects are less prominent in advanced disease, probably due to the larger tumor mass. Therefore, the clinical response to indinavir was assessed in patients with advanced CKS after debulking chemotherapy. This was a monocentric phase 2 trial in elderly with progressive/advanced CKS treated with debulking chemotherapy and indinavir combined, followed by a maintenance phase with indinavir alone. Secondary endpoints included safety and Kaposi sarcoma biomarker evaluation.All evaluable patients (22) responded to debulking therapy. Out of these, 16 entered the indinavir maintenance phase. The overall response rate at end of maintenance was 75% (estimated median response-duration 43 months). Moreover, most responders showed further clinical improvements (lesion number/nodularity) during maintenance and post-treatment follow-up. Notably, after relapse, progressors did not require systemic Kaposi sarcoma therapy and showed clinical improvements (including disease stabilization) remaining on study. Responders also showed immune status amelioration with a consistent B-cell increase and positive changes of other biomarkers, including anti-HHV-8 natural killer activity. In advanced CKS a strategy combining indinavir and chemotherapy is safe and associated with high and durable response rates and it could be rapidly adopted for the clinical management of these patients. SIGNIFICANCE: This phase-2 trial showed that the HIV protease inhibitor indinavir may boost and extend the duration of the effects of chemotherapy in elderly with advanced progressive classic Kaposi sarcoma, without additional toxicity. Further, the amelioration of the immune status seen in responders suggests a better control of HHV-8 infection and tumor-cell killing. Thus, indinavir combined with chemotherapy may represent an important tool for the clinical management of classic Kaposi sarcoma in elderly patients.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Inibidores da Protease de HIV , Indinavir , Sarcoma de Kaposi , Humanos , Sarcoma de Kaposi/tratamento farmacológico , Indinavir/uso terapêutico , Indinavir/administração & dosagem , Indinavir/efeitos adversos , Masculino , Feminino , Idoso , Inibidores da Protease de HIV/uso terapêutico , Inibidores da Protease de HIV/administração & dosagem , Inibidores da Protease de HIV/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Idoso de 80 Anos ou mais , Resultado do Tratamento , Herpesvirus Humano 8RESUMO
BACKGROUND: Increased pericardial adipose tissue is associated with higher risk of cardiovascular disease. We aimed to determine whether human immunodeficiency virus (HIV) status was independently associated with larger pericardial adipose tissue volume and to explore possible HIV-specific risk factors. METHODS: Persons with HIV (PWH) were recruited from the Copenhagen Comorbidity in HIV Infection (COCOMO) Study and matched 1:1 on age and sex to uninfected controls. Pericardial adipose tissue volume was measured using cardiac computed tomography. RESULTS: A total of 587 PWH and 587 controls were included. Median age was 52 years, and 88% were male. Human immunodeficiency virus status was independently associated with 17 mL (95% confidence interval [CI], 10-23; Pâ <â .001) larger pericardial adipose tissue volume. Larger pericardial adipose tissue volume was associated with low CD4+ nadir and prior use of stavudine, didanosine, and indinavir. Among PWH without thymidine analogue or didanosine exposure, time since initiating combination antiretroviral treatment (per 5-year use) was associated with l6 mL (95% CI, -6 to -25; Pâ =â .002) lower pericardial adipose tissue volume. CONCLUSIONS: Human immunodeficiency virus status was independently associated with larger pericardial adipose tissue volume. Severe immunodeficiency, stavudine, didanosine, and indinavir were associated with larger pericardial adipose tissue volume. Persons with HIV with prior exposure to these drugs may constitute a distinct cardiovascular risk population.
Assuntos
Tecido Adiposo/efeitos dos fármacos , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/uso terapêutico , Doenças Cardiovasculares/induzido quimicamente , Infecções por HIV/tratamento farmacológico , Pericárdio/fisiopatologia , Carga Viral , Tecido Adiposo/fisiopatologia , Adulto , Doenças Cardiovasculares/fisiopatologia , Dinamarca , Didanosina/efeitos adversos , Feminino , Infecções por HIV/fisiopatologia , Inibidores da Protease de HIV/uso terapêutico , Voluntários Saudáveis , Humanos , Indinavir/efeitos adversos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Estavudina/efeitos adversosRESUMO
OBJECTIVE: The study set out to determine if the HIV protease inhibitor, indinavir, alters responsiveness of α7-nicotinic acetylcholine receptors to acetylcholine. DESIGN: Treatment with HAART has dramatically reduced development of HIV-associated dementia and more severe forms of cognitive impairment. However, many individuals continue to experience cognitive decline of uncertain cause. Previous studies have failed to demonstrate significant alterations of functional brain connectivity, structural brain changes, or changes in cerebral blood flow sufficient to explain cognitive decline in virally suppressed individuals. This suggests that the mechanisms underlying development and progression of cognitive problems likely occurs at a micro rather than macro level, such as disruptions in neurotransmitter system signaling. MATERIALS AND METHODS: Indinavir's effects on α7-nicotinic acetylcholine receptor activity was tested using a ScreenPatch IonWorks Barracuda-based assay in a mammalian cell model. RESULTS: At low concentrations (0.0003-10âµmol/l) indinavir acts as a positive allosteric modulator (EC50â=â0.021âµmol/l), whereas at concentrations greater than 10âµmol/l (30-100âµmol/l) indinavir acts as an inhibitor of the α7-nicotinic acetylcholine receptor. CONCLUSION: At concentrations greater than 10âµmol/l indinavir reduces synaptic transmission in the acetylcholine neurotransmitter system, which could possibly contribute to cognitive dysfunction. These results suggest that further experiments should be considered to assess whether patients might benefit from treatment with cholinesterase inhibitors that counteract the effects of indinavir.
Assuntos
Disfunção Cognitiva , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/efeitos adversos , Indinavir/efeitos adversos , Antagonistas Nicotínicos/efeitos adversos , Receptor Nicotínico de Acetilcolina alfa7/efeitos dos fármacos , Animais , Células CHO , Cricetulus , Inibidores da Protease de HIV/administração & dosagem , Indinavir/administração & dosagem , Antagonistas Nicotínicos/administração & dosagem , Técnicas de Patch-ClampRESUMO
Molecular mechanisms behind the defects in insulin production and secretion associated with antihuman immunodeficiency virus (anti-HIV) therapy and the development of HIV-associated lipodystrophy syndrome (HALS) are discussed in this article. Data suggesting insulin resistance on the beta cell and defects in first-phase insulin release of HALS patients are presented. Hepatic extraction of insulin, nonglucose insulin secretagogues and insulin-like growth factor release may exert influence on the demand of circulating insulin and on insulin secretion in HIV-infected patients. Finally, the paucity in understanding the incretin effects in HIV and HIV therapy in relation to insulin secretion is highlighted.
Assuntos
Inibidores da Protease de HIV/efeitos adversos , Síndrome de Lipodistrofia Associada ao HIV/induzido quimicamente , Resistência à Insulina , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Carbamatos/efeitos adversos , Carbamatos/uso terapêutico , Furanos , Inibidores da Protease de HIV/uso terapêutico , Humanos , Indinavir/efeitos adversos , Indinavir/uso terapêutico , Secreção de Insulina , Células Secretoras de Insulina/efeitos dos fármacos , Nelfinavir/efeitos adversos , Nelfinavir/uso terapêutico , Ritonavir/efeitos adversos , Ritonavir/uso terapêutico , Sulfonamidas/efeitos adversos , Sulfonamidas/uso terapêuticoRESUMO
Hyperbilirubinemia may arise due to inadequate clearance of bilirubin from the body. Bilirubin elimination is a multifaceted process consisting of uptake of bilirubin into the hepatocytes facilitated by OATP1B1 and OATP1B3. Once in the hepatocytes, it is extensively glucuronidated by UGT1A1. Eventually, the glucuronide metabolite is excreted into the bile via MRP2. UGT1A1 inhibition has been previously shown to be linked with hyperbilirubinemia. However, because drug transporters also contribute to bilirubin elimination, the purpose of this work was to investigate the in vitro inhibition of OATP1B1, OATP1B3, MRP2, and BSEP of select test drugs known to elicit hyperbilirubinemia. Test drugs investigated in this study were atazanavir and indinavir, which are associated with hyperbilirubinemia and elevations in serum transaminase; ritonavir and nelfinavir, which are not associated with hyperbilirubinemia; and bromfenac, troglitazone, and trovafloxacin, which are associated with severe idiosyncratic hepatotoxicity exhibiting elevations in serum bilirubin and transaminase. Due to limited solubility and poor ionization of bilirubin and its glucuronide, the formation of estradiol 3-glucuronide was used as a surrogate to assess UGT1A1 activity, while the transport of pitavastatin, CDCF, and taurocholate were used as surrogate probe substrates to monitor the function of OATP1B1/OATP1B3, MRP2, and BSEP, respectively. It was assumed that any inhibition of the surrogate probe substrates by test drugs is indicative of the potential impact of test drugs to modulate the function of proteins involved in bilirubin disposition. In vitro inhibition was determined by calculating IC50. Moreover, Cmax and Cmax,free were integrated with IC50 values to calculate R and Rfree, respectively, which represents the ratio of probe drug glucuronidation/transport in the absence and presence of test drugs. Analysis of the data showed that Rfree demonstrated the best correlation to hyperbilirubinemia. Specifically, Rfree was above the 1.1 target threshold against UGT1A1, OATP1B1, and BSEP for atazanavir and indinavir. In contrast, Rfree was below this threshold for ritonavir and nelfinavir as well as for bromfenac, troglitazone, and trovafloxacin. For all test drugs examined, only minor inhibition against OATP1B3 and MRP2 were observed. These data suggest that the proposed surrogate probe substrates to evaluate the in vitro inhibition of UGT1A1, OATP1B1, and BSEP may be suitable to assess bilirubin disposition. For protease inhibitors, inclusion of OATP1B1 and BSEP inhibition may improve the predictability of hyperbilirubinemia.
Assuntos
Glucuronosiltransferase/metabolismo , Hiperbilirrubinemia/induzido quimicamente , Hiperbilirrubinemia/metabolismo , Transportadores de Ânions Orgânicos Sódio-Independentes/metabolismo , Transportadores de Ânions Orgânicos/metabolismo , Sulfato de Atazanavir , Bilirrubina/metabolismo , Linhagem Celular , Humanos , Indinavir/efeitos adversos , Transportador 1 de Ânion Orgânico Específico do Fígado , Modelos Biológicos , Oligopeptídeos/efeitos adversos , Piridinas/efeitos adversos , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de SolutoRESUMO
The molecular basis of insulin resistance induced by HIV protease inhibitors (HPIs) remains unclear. In this study, Chinese hamster ovary cells transfected with high levels of human insulin receptor (CHO-IR) and 3T3-L1 adipocytes were used to elucidate the mechanism of this side effect. Indinavir and nelfinavir induced a significant decrease in tyrosine phosphorylation of the insulin receptor ß-subunit. Indinavir caused a significant increase in the phosphorylation of insulin receptor substrate-1 (IRS-1) on serine 307 (S307) in both CHO-IR cells and 3T3-L1 adipocytes. Nelfinavir also inhibited phosphorylation of Map/ERK kinase without affecting insulin-stimulated Akt phosphorylation. Concomitantly, levels of protein tyrosine phosphatase 1B (PTP1B), suppressor of cytokines signaling-1 and -3 (SOCS-1 and -3), Src homology 2B (SH2B) and adapter protein with a pleckstrin homology domain and an SH2 domain (APS) were not altered significantly. When CHO-IR cells were pre-treated with sodium salicylate (NaSal), the effects of indinavir on tyrosine phosphorylation of the IR ß-subunit and phosphorylation of IRS-1 at S307 were abrogated. These data suggest a potential role for the NFκB pathway in insulin resistance induced by HPIs.
Assuntos
Anti-Infecciosos/farmacologia , Inibidores da Protease de HIV/efeitos adversos , Indinavir/efeitos adversos , Resistência à Insulina , Nelfinavir/efeitos adversos , Receptor de Insulina/metabolismo , Ácido Salicílico/farmacologia , Células 3T3-L1 , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Células CHO , Cricetinae , Cricetulus , Inibidores da Protease de HIV/farmacologia , Humanos , Indinavir/farmacologia , Proteínas Substratos do Receptor de Insulina/genética , Proteínas Substratos do Receptor de Insulina/metabolismo , Camundongos , NF-kappa B/genética , NF-kappa B/metabolismo , Nelfinavir/farmacologia , Fosforilação/efeitos dos fármacos , Fosforilação/genética , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor de Insulina/genética , Transdução de SinaisRESUMO
The highly active antiretroviral therapy (HAART) can cause a metabolic syndrome consisting of lipodystropy/lipoatrophy, dyslipidemia, and type 2 diabetes mellitus with an increased cardiovascular risk. The pathogenetic bases of HAART-associated lipodystrophy are poorly known. A genetic screen was used to evaluate proteins that are modulated in HIV-1-infected patients with or without lipodystrophy syndrome, that are routinely treated with HAART regimens. The most significant modulation was represented by FAP48 expression. Stable over-expression of FAP48 was able to alter, in vitro, adipogenesis, acting both on calcineurin and glucocorticoid pathways. Finally, we demonstrated that FAP48 over-expression was able to influence the capacity of some HIV drugs, Saquinavir and Efavirenz, but not Stavudine, Amprenavir, and Indinavir to inhibit adipocyte formation. In conclusion, this molecule could be a potential target for novel therapeutic approaches to the HAART related lipodystrophy in HIV patients.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adipócitos/efeitos dos fármacos , Síndrome de Lipodistrofia Associada ao HIV/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Adipócitos/metabolismo , Adipócitos/patologia , Alcinos , Animais , Terapia Antirretroviral de Alta Atividade/efeitos adversos , Benzoxazinas/efeitos adversos , Benzoxazinas/farmacologia , Calcineurina/genética , Calcineurina/metabolismo , Carbamatos/efeitos adversos , Carbamatos/farmacologia , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Ciclopropanos , Furanos , Expressão Gênica/efeitos dos fármacos , Glucocorticoides/metabolismo , HIV-1/efeitos dos fármacos , HIV-1/fisiologia , Síndrome de Lipodistrofia Associada ao HIV/induzido quimicamente , Humanos , Indinavir/efeitos adversos , Indinavir/farmacologia , Camundongos , Saquinavir/efeitos adversos , Saquinavir/farmacologia , Transdução de Sinais/efeitos dos fármacos , Estavudina/efeitos adversos , Estavudina/farmacologia , Sulfonamidas/efeitos adversos , Sulfonamidas/farmacologia , TransfecçãoRESUMO
OBJECTIVE: To evaluate the incidence and determinants of diabetes in a cohort of HIV-infected adults initiated with combination antiretroviral treatment (cART) in 1997-1999 and followed up to 2009. DESIGN: Prospective study of 1046 patients at 47 French clinical sites. METHODS: Potential determinants of diabetes occurrence, defined by confirmed increased glycemia and/or initiation of antidiabetic treatment, were assessed by a proportional hazards model, including time-updated metabolic parameters and ART exposure. RESULTS: Among the cohort, representing 7846 person-years of follow-up (PYFU), 54% received indinavir, 75% stavudine and 52% didanosine. Overall, 111 patients developed diabetes, with an incidence of 14.1/1000 PYFU (14.6 in men, 12.6 in women). Incidence peaked in 1999-2000 (23.2/1000 PYFU) and decreased thereafter. The incidence of diabetes was associated [adjusted hazard ratio (aHR), all P<0.02] with older age (hazard ratio = 2.13 when 40-49 years, hazard ratio = 3.63 when ≥50 years), overweight (hazard ratio = 1.91 for a BMI 25-29 kg/m(2), hazard ratio = 2.85 >30 kg/m(2)), waist-to-hip ratio (hazard ratio = 3.87 for ≥0.97 male/0.92 female), time-updated lipoatrophy (hazard ratio = 2.14) and short-term exposure to indinavir (0-1 year: hazard ratio = 2.53), stavudine (0-1 year: hazard ratio = 2.56, 1-2 years: hazard ratio = 2.65) or didanosine (2-3 years: hazard ratio = 3.16). Occurrence of diabetes was not associated with HIV-related markers, hepatitis C, hypertension or family history of diabetes. Insulin resistance was predictive for incident diabetes. CONCLUSIONS: In this nationwide cohort, followed for 10 years after cART initiation, diabetes incidence peaked in 1990-2000, was markedly higher than that reported for European uninfected or other HIV-infected populations (4-6/1000 PYFU) and linked with age and adiposity. Adiposity and glycemic markers should be monitored in aging HIV-infected patients.
Assuntos
Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/efeitos adversos , Diabetes Mellitus/epidemiologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Adiposidade , Adulto , Terapia Antirretroviral de Alta Atividade , Índice de Massa Corporal , Estudos de Coortes , Diabetes Mellitus/induzido quimicamente , Diabetes Mellitus/tratamento farmacológico , Didanosina/administração & dosagem , Didanosina/efeitos adversos , Feminino , Seguimentos , Infecções por HIV/complicações , Humanos , Incidência , Indinavir/administração & dosagem , Indinavir/efeitos adversos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Modelos de Riscos Proporcionais , Estudos Prospectivos , Fatores de Risco , Estavudina/administração & dosagem , Estavudina/efeitos adversos , Relação Cintura-QuadrilRESUMO
Highly active antiretroviral therapy (HAART) has increased the survival of HIV-infected patients. However, adverse effects play a major role in adherence to HAART. Some protease inhibitors (mainly atazanavir and indinavir) act as inhibitors of uridine diphosphate-glucuronosyltransferase (UGT1A1), the enzyme responsible for hepatic conjugation of bilirubin. Variations in the promoter region of the UGT1A1 gene (UGT1A1*28, rs8175347) can influence bilirubin plasma levels, modulating the susceptibility to hyperbilirubinemia. Aiming to analyze the association between UGT1A1*28 allele and hyperbilirubinemia in individuals exposed to HAART, we evaluated 375 HIV-positive individuals on antiretroviral therapy. Individuals carrying the UGT1A1*28 allele had a higher risk of developing severe hyperbilirubinemia [prevalence ratio (PR)=2.43, 95% confidence interval (CI) 1.08-5.45, p=0.032] as well as atazanavir users (PR=7.72, 95% CI=3.14-18.98, p<0.001). This is the first description of such an association in Brazilian HIV patients, which shows that in African-American and Euroamerican HAART users, the UGT1A1*28 allele also predisposes to severe hyperbilirubinemia, especially in those exposed to atazanavir.
Assuntos
Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Terapia Antirretroviral de Alta Atividade/efeitos adversos , Bilirrubina/sangue , Glucuronosiltransferase/efeitos dos fármacos , Glucuronosiltransferase/genética , Inibidores da Protease de HIV/efeitos adversos , Hiperbilirrubinemia/induzido quimicamente , Indinavir/efeitos adversos , Oligopeptídeos/efeitos adversos , Piridinas/efeitos adversos , Síndrome da Imunodeficiência Adquirida/sangue , Síndrome da Imunodeficiência Adquirida/genética , Adulto , Alelos , Terapia Antirretroviral de Alta Atividade/métodos , Sulfato de Atazanavir , Bilirrubina/genética , Brasil , Estudos Transversais , Feminino , Genótipo , Humanos , Hiperbilirrubinemia/sangue , Hiperbilirrubinemia/genética , Masculino , Valor Preditivo dos Testes , Fatores de Risco , Índice de Gravidade de DoençaRESUMO
The HIV protease inhibitor indinavir presents a wide inter-individual variability related to an intense hepatic metabolism. Published studies were analyzed to establish whether there is evidence that therapeutic drug monitoring of indinavir could improve patient care. It was reported that indinavir virological efficacy in HIV-infected patients with wild-type virus was significantly associated with trough concentrations > 100-150 ng/mL. Concerning the exposure-toxicity relationship, the risk of occurrence of nephrotoxicity was more frequently associated with trough concentrations > 500-1 000 ng/mL. Studies with concentration-controlled indinavir therapy suggest that therapeutic drug monitoring allows to achieve safe and effective concentrations, therefore, the level of evidence of the interest of indinavir therapeutic drug monitoring is highly recommended when indinavir is not associated with ritonavir and recommended when ritonavir is combined with ritonavir.
Assuntos
Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/uso terapêutico , Indinavir/uso terapêutico , Relação Dose-Resposta a Droga , Interações Medicamentosas , Monitoramento de Medicamentos , Medicina Baseada em Evidências , Inibidores da Protease de HIV/efeitos adversos , Inibidores da Protease de HIV/economia , Inibidores da Protease de HIV/farmacocinética , Humanos , Indinavir/efeitos adversos , Indinavir/economia , Indinavir/farmacocinética , Nefropatias/induzido quimicamenteRESUMO
AIM: Assess possible adverse effects of the chronic use of indinavir during pregnancy in a rat model. METHODS: 40 pregnant EOM-1 albino rats were randomly allocated into four groups of 10 animals each: a control (Ctr) group (without any handling) and three experimental groups (Exp 1, Exp 2 e Exp 3) which received indinavir 9, 27 e 81 mg/kg, respectively). Rats were treated by gavage once daily. The treatment period extended from day 0 until the 20th day of pregnancy. Body weights were recorded on days 0, 7, 14 and 20. At term, the rats were sacrificed, and the implantation sites, number of live and dead fetuses and placentas, resorptions, fetal and placental weights were recorded. The fetuses were evaluated for external abnormalities under a stereomicroscope. RESULTS: Weight gain during pregnancy did not differ significantly between the groups. Average weight gains between the 7th and 20th day were 7.95-42.70 g; 7.22-45.27 g; 7.12-46.26 g and 8.05-42.29 g in groups Ctr, Exp 1, Exp 2 and Exp 3, respectively. All other parameters assessed did not differ significantly between groups. CONCLUSIONS: Chronic use of various dosages of indinavir during pregnancy was not associated significant adverse outcomes.
Assuntos
Inibidores da Protease de HIV/efeitos adversos , Indinavir/efeitos adversos , Anormalidades Induzidas por Medicamentos/embriologia , Animais , Relação Dose-Resposta a Droga , Feminino , Desenvolvimento Fetal/efeitos dos fármacos , Inibidores da Protease de HIV/administração & dosagem , Indinavir/administração & dosagem , Placentação/efeitos dos fármacos , Gravidez , Distribuição Aleatória , Ratos , Ratos WistarRESUMO
Indinavir boosted with ritonavir (IDV/r) dosing with 400/100 mg, twice daily, is preferred in Thai adults, but this dose can lead to concentrations close to the boundaries of its therapeutic window. The objectives of this analysis were to validate a population pharmacokinetic model to describe IDV/r concentrations in HIV-infected Thai patients and to investigate the impact of patient characteristics on achieving adequate IDV concentrations. IDV/r concentration data from 513 plasma samples were available. Population means and variances of pharmacokinetic parameters were estimated using a nonlinear mixed effects regression model (NONMEM Version VI). Monte Carlo simulations were performed to estimate the probability of achieving IDV concentrations within its therapeutic window. IDV/r pharmacokinetics were best described by a one-compartment model coupled with a single transit compartment absorption model. Body weight influenced indinavir apparent oral clearance and volume of distribution and allometric scaling significantly reduced the interindividual variability. Final population estimates (interindividual variability in percentage) of indinavir apparent oral clearance and volume of distribution were 21.3 L/h/70 kg (30%) and 90.7 L/70 kg (22%), respectively. Based on model simulations, the probability of achieving an IDV trough concentration greater than 0.1 mg/L was greater than 99% for 600/100 mg and greater than 98% for 400/100 mg, twice daily, in patients weighing 40 to 80 kg. However, the probability of achieving IDV concentrations associated with an increased risk of drug toxicity (greater than 10.0 mg/L) increased from 1% to 10% with 600/100 mg compared with less than 1% with 400/100 mg when body weight decreased from 80 to 40 kg. The validated model developed predicts that 400/100 mg of IDV/r, twice daily, provides indinavir concentrations within the recommended therapeutic window for the majority of patients. The risk of toxic drug concentrations increases rapidly with IDV/r dose of 600/100 mg for patients less than 50 kg and therapeutic drug monitoring of IDV concentrations would help to reduce the risk of IDV-induced nephrotoxicity.
Assuntos
Peso Corporal , Monitoramento de Medicamentos , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/farmacocinética , Indinavir/farmacocinética , Ritonavir/farmacocinética , Adulto , Quimioterapia Combinada , Feminino , Infecções por HIV/sangue , Inibidores da Protease de HIV/efeitos adversos , Inibidores da Protease de HIV/sangue , Inibidores da Protease de HIV/uso terapêutico , Humanos , Indinavir/efeitos adversos , Indinavir/sangue , Indinavir/uso terapêutico , Masculino , Pessoa de Meia-Idade , Método de Monte Carlo , Ritonavir/efeitos adversos , Ritonavir/sangue , Ritonavir/uso terapêutico , Tailândia , Adulto JovemRESUMO
The introduction of potent combination antiretroviral therapy (ART) in the treatment of HIV infection has permitted reliable control of disease progression and has markedly improved survival among people with HIV. As a result, health care providers and patients have shifted clinical priorities; whereas once delaying opportunistic illness was a primary focus, increasing emphasis is now placed on preventative health, management of comorbid chronic disease and avoiding long-term toxicities of ART. Although renal disease is common in people with HIV, renal disease specifically due to ART remains relatively rare. Still, as the use of ART continues to increase, health care providers are likely to encounter this potentially serious complication with increasing frequency. Distinguishing ART-related nephrotoxicity from the myriad of other potential causes of renal disease in people with HIV is important in order to avoid unnecessary discontinuation of an appropriate ART regimen. This review focuses on the early recognition of renal disease associated with ART and suggests strategies for management and prevention.
Assuntos
Antirretrovirais/efeitos adversos , Infecções por HIV/tratamento farmacológico , Nefropatias/induzido quimicamente , Adenina/efeitos adversos , Adenina/análogos & derivados , Sulfato de Atazanavir , Humanos , Indinavir/efeitos adversos , Nefropatias/diagnóstico , Oligopeptídeos/efeitos adversos , Organofosfonatos/efeitos adversos , Piridinas/efeitos adversos , TenofovirRESUMO
The era of highly active antiretroviral therapy (HAART) has controlled AIDS and its related disorders considerably; however, the prevalence of HIV-1-associated neurocognitive disorders has been on the rise in the post-HAART era. In view of these developments, we investigated whether a HAART drug combination of 3'-azido-2',3'-deoxythymidine (AZT) and indinavir (IDV) can alter the functionality of the blood-brain barrier (BBB) endothelial cells, thereby exacerbating this condition. The viability of hCMEC/D3 cells (in vitro model of BBB) that were exposed to these drugs was significantly reduced after 72h treatment, in a dose-dependent manner. Reactive oxygen species were highly elevated after the exposure, indicating that mechanisms that induce oxidative stress were involved. Measures of oxidative stress parameters, such as glutathione and malondialdehyde, were altered in the treated groups. Loss of mitochondrial membrane potential, as assessed by fluorescence microscopy and decreased levels of ATP, indicated that cytotoxicity was mediated through mitochondrial dysfunction. Furthermore, AZT+IDV treatment caused apoptosis in endothelial cells, as assessed by the expression of cytochrome c and procaspase-3 proteins. Pretreatment with the thiol antioxidant N-acetylcysteine amide reversed some of the pro-oxidant effects of AZT+IDV. Results from our in vitro studies indicate that the AZT+IDV combination may affect the BBB in HIV-infected individuals treated with HAART drugs.
Assuntos
Terapia Antirretroviral de Alta Atividade/efeitos adversos , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Acetilcisteína/análogos & derivados , Acetilcisteína/farmacologia , Acetilcisteína/uso terapêutico , Trifosfato de Adenosina/análise , Apoptose/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Caspase 3/análise , Caspase 3/biossíntese , Linhagem Celular Transformada , Citocromos c/análise , Citocromos c/biossíntese , Células Endoteliais/citologia , Glutationa/análise , Infecções por HIV/tratamento farmacológico , Infecções por HIV/metabolismo , Inibidores da Protease de HIV/efeitos adversos , Inibidores da Protease de HIV/farmacologia , HIV-1/metabolismo , Humanos , Indinavir/efeitos adversos , Indinavir/farmacologia , Malondialdeído/análise , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Zidovudina/efeitos adversos , Zidovudina/farmacologiaRESUMO
Nephrolithiasis is a known side effect of indinavir sulfate, a protease inhibitor used in the treatment of human immunodeficiency virus (HIV). The duration of its side effects, however, has not been well defined. We present a case where a patient presented with symptomatic indinavir-induced nephrolithiasis 3.5 years after discontinuing indinavir. We use this case to illustrate the pathophysiology of indinavir stones and hypothesize how they can occur years after discontinuation by discussing the pharmacokinetics of the drug.
Assuntos
Inibidores da Protease de HIV/efeitos adversos , Indinavir/efeitos adversos , Nefrolitíase/induzido quimicamente , Inibidores da Protease de HIV/administração & dosagem , Humanos , Indinavir/administração & dosagem , Masculino , Pessoa de Meia-Idade , Fatores de TempoRESUMO
OBJECTIVES: Chronic kidney disease (CKD) in HIV-positive persons might be caused by both HIV and traditional or non-HIV-related factors. Our objective was to investigate long-term exposure to specific antiretroviral drugs and CKD. DESIGN: A cohort study including 6843 HIV-positive persons with at least three serum creatinine measurements and corresponding body weight measurements from 2004 onwards. METHODS: CKD was defined as either confirmed (two measurements >or=3 months apart) estimated glomerular filtration rate (eGFR) of 60 ml/min per 1.73 m or below for persons with baseline eGFR of above 60 ml/min per 1.73 m or confirmed 25% decline in eGFR for persons with baseline eGFR of 60 ml/min per 1.73 m or less, using the Cockcroft-Gault formula. Poisson regression was used to determine factors associated with CKD. RESULTS: Two hundred and twenty-five (3.3%) persons progressed to CKD during 21 482 person-years follow-up, an incidence of 1.05 per 100 person-years follow-up [95% confidence interval (CI) 0.91-1.18]; median follow-up was 3.7 years (interquartile range 2.8-5.7). After adjustment for traditional factors associated with CKD and other confounding variables, increasing cumulative exposure to tenofovir [incidence rate ratio (IRR) per year 1.16, 95% CI 1.06-1.25, P < 0.0001), indinavir (IRR 1.12, 95% CI 1.06-1.18, P < 0.0001), atazanavir (IRR 1.21, 95% CI 1.09-1.34, P = 0.0003) and lopinavir/r (IRR 1.08, 95% CI 1.01-1.16, P = 0.030) were associated with a significantly increased rate of CKD. Consistent results were observed in wide-ranging sensitivity analyses, although of marginal statistical significance for lopinavir/r. No other antiretroviral drugs were associated with increased incidence of CKD. CONCLUSION: In this nonrandomized large cohort, increasing exposure to tenofovir was associated with a higher incidence of CKD, as was true for indinavir and atazanavir, whereas the results for lopinavir/r were less clear.
Assuntos
Fármacos Anti-HIV/efeitos adversos , Soropositividade para HIV/tratamento farmacológico , HIV-1 , Falência Renal Crônica/induzido quimicamente , Adenina/efeitos adversos , Adenina/análogos & derivados , Adulto , Sulfato de Atazanavir , Progressão da Doença , Métodos Epidemiológicos , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Soropositividade para HIV/epidemiologia , Soropositividade para HIV/fisiopatologia , Humanos , Indinavir/efeitos adversos , Falência Renal Crônica/epidemiologia , Falência Renal Crônica/fisiopatologia , Masculino , Pessoa de Meia-Idade , Oligopeptídeos/efeitos adversos , Organofosfonatos/efeitos adversos , Piridinas/efeitos adversos , Inibidores da Transcriptase Reversa/efeitos adversos , TenofovirRESUMO
OBJECTIVE: To investigate the potential for a pharmacokinetic interaction between darunavir (DRV, TMC114, Prezista), indinavir (IDV, Crixivan) and low-dose ritonavir (RTV, Norvir). METHODS: In three 7-day sessions, 17 HIV-negative healthy volunteers received treatment A (DRV/r 400/100 mg b.i.d.), treatment B (IDV/r 800/100 mg b.i.d.) and treatment C (DRV/r 400/100 mg b.i.d. + IDV 800 mg b.i.d.). On day 7, full pharmacokinetic profiles of DRV, IDV and RTV were determined. Safety and tolerability were also assessed. RESULTS: Based on the least-squares means ratios, the steady-state exposure (area under the curve, AUC(12h)) and plasma concentrations (C(min) and C(max)) of IDV were increased by 23, 125 and 8%, respectively, when DRV was co-administered. The co-administration of IDV with DRV/r resulted in increases of 24, 44 and 11% for, respectively, DRV AUC(12h), C(min) and C(max), compared with administration of DRV/r alone. Eight volunteers discontinued due to an adverse event. Overall, adverse events and laboratory abnormalities were more commonly reported during treatments including IDV. CONCLUSIONS: When used in combination with DRV/r, dose adjustment of IDV from 800 mg b.i.d. to 600 mg b.i.d. may be warranted in cases of intolerance.
Assuntos
Fármacos Anti-HIV/farmacocinética , Indinavir/farmacocinética , Ritonavir/farmacocinética , Sulfonamidas/farmacocinética , Adulto , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/efeitos adversos , Darunavir , Interações Medicamentosas , Feminino , Voluntários Saudáveis , Humanos , Indinavir/administração & dosagem , Indinavir/efeitos adversos , Masculino , Plasma/química , Ritonavir/administração & dosagem , Ritonavir/efeitos adversos , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Adulto JovemRESUMO
The widespread introduction of highly active antiretroviral therapy (HAART) in the mid-1990s dramatically altered the course of human immunodeficiency virus (HIV) infection, with improvements in survival and reductions in the incidence of AIDS-defining illnesses. Although antiretroviral therapy has been shown to reduce the incidence of both AIDS-defining and non-AIDS conditions, long-term exposure to HAART may also be associated with significant toxicity. This article reviews the potential nephrotoxicity of specific antiretroviral agents and the impact of antiretroviral therapy on related metabolic disorders. The antiretroviral agents most strongly associated with direct nephrotoxicity include the nucleotide reverse transcriptase inhibitor, tenofovir, and the protease inhibitor indinavir, although other agents have been implicated less frequently. Tenofovir and related nucleotide analogs have primarily been associated with proximal tubular dysfunction and acute kidney injury, whereas indinavir is known to cause nephrolithiasis, obstructive nephropathy, and interstitial nephritis. Kidney damage related to antiretroviral therapy is typically reversible with early recognition and timely discontinuation of the offending agent, and nephrologists should be familiar with the potential toxicity of these agents to avoid delays in diagnosis.
Assuntos
Nefropatia Associada a AIDS/tratamento farmacológico , Adenina/análogos & derivados , Fármacos Anti-HIV/efeitos adversos , Terapia Antirretroviral de Alta Atividade , Indinavir/efeitos adversos , Rim/efeitos dos fármacos , Organofosfonatos/efeitos adversos , Adenina/efeitos adversos , Humanos , TenofovirRESUMO
Misspecification of the covariance structure for repeated measurements in longitudinal analysis may lead to biased estimates of the regression parameters and under or overestimation of the corresponding standard errors in the presence of missing data. The so-called sandwich estimator can 'correct' the variance, but it does not reduce the bias in point estimates. Removing all assumptions from the covariance structure (i.e. using an unstructured (UN) covariance) will remove such biases. However, an excessive amount of missing data may cause convergence problems for iterative algorithms, such as the default Newton-Raphson algorithm in the popular SAS PROC MIXED. This article examines, both through theory and simulations, the existence and the magnitude of these biases. We recommend the use of UN covariance as the default strategy for analyzing longitudinal data from randomized clinical trials with moderate to large number of subjects and small to moderate number of time points. We also present an algorithm to assist in the convergence when the UN covariance is used.
Assuntos
Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Viés , Contagem de Linfócito CD4/estatística & dados numéricos , Simulação por Computador , Humanos , Indinavir/administração & dosagem , Indinavir/efeitos adversos , Indinavir/uso terapêutico , Lamivudina/administração & dosagem , Lamivudina/efeitos adversos , Lamivudina/uso terapêutico , Estudos Longitudinais , Modelos Estatísticos , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , Zidovudina/administração & dosagem , Zidovudina/efeitos adversos , Zidovudina/uso terapêuticoRESUMO
OBJECTIVES: The aims of the present study were to estimate the prevalence of renal impairment (RI) among HIV-infected adult patients and to investigate the associated factors. METHODS: A cross-sectional survey was conducted in a French hospital-based cohort. Clearance of creatinine (CC) was calculated using the Cockcroft-Gault formula. Four stages of RI were defined: mild (60-90 mL/min), moderate (30-60), severe (15-30) and end stage (<15). Logistic regression models were used to investigate factors associated with RI. RESULTS: The male/female ratio of the 2588 patients enrolled was 3:1 and the median age was 42 years. At the time of assessment of CC, the median CD4 count was 430 cells/microL and HIV plasma viral load (VL) was<50 copies/mL in 60%. The overall prevalence of RI was 39.0%: 34.2% mild, 4.4% moderate, 0.3% severe and 0.2% end-stage. Mild RI was associated with female gender [odds ratio (OR)=3.3: 95% CI 2.6-4.3)], age >50 years (OR=9.8: 7.4-13.0) and 40-50 years (OR=1.9: 1.5-2.4), body mass index (BMI) <22 kg/m(2) (OR=3.3: 2.7-4.3) and tenofovir exposure (OR=1.4: 1.0-1.9 for <1 year and OR=1.5: 1.2-2.0 for >1 year). Advanced RI (CC <60 mL/min) was associated with age >50 years (OR=5.6: 2.9-10.9) and 40-50 years (OR=2.2: 1.1-1.4), BMI <22 kg/m(2) (OR=1.5: 1.0-2.4), hypertension (OR=2.5: 1.4-2.5) and indinavir (IDV) exposure >1 year (OR=2.3: 1.5-3.6). CONCLUSION: This survey confirms the high prevalence of RI in HIV-infected patients and indicates the importance of the investigation of renal function especially in women, older patients, those with a low BMI or treated with tenofovir or IDV.