RESUMO
BACKGROUND: Functional variants of inosine triphosphatase (ITPA) were recently found to protect against ribavirin (RBV)-induced hemolytic anemia. However, no definitive data are yet available on the role of plasma RBV concentrations on hemoglobin (Hb) decrement. Moreover, no data have been published on the possible interplay between these 2 factors. METHODS: A retrospective analysis included 167 patients. The ITPA variants rs7270101 and rs1127354 were genotyped and tested using the χ test for association with Hb reduction at week 4. We also investigated, using multivariate logistic regression, the impact of RBV plasma exposure on Hb concentrations. RESULTS: Both single nucleotide polymorphisms were associated with Hb decrease. The carrier of at least 1 variant allele in the functional ITPA single nucleotide polymorphisms was associated with a lower decrement of Hb (-1.1 g/dL), as compared with patients without a variant allele (-2.75 g/dL; P = 4.09 × 10). RBV concentrations were not influenced by ITPA genotypes. A cut-off of 2.3 µg/mL of RBV was found to be associated with anemia (area-under-receiver operating characteristic = 0.630, sensitivity = 50.0%, and specificity = 69.5%, P = 0.008). In multivariate logistic regression analyses, the carrier of a variant allele (P = 0.005) and plasma RBV concentrations <2.3 µg/mL (P = 0.016) were independently associated with protection against clinically significant anemia at week 4. CONCLUSIONS: Although no direct relationship was found between ITPA polymorphisms and plasma RBV concentrations, both factors were shown to be significantly associated with anemia. A multivariate regression model based on ITPA genetic polymorphisms and RBV trough concentration was developed for predicting the risk of anemia. By relying upon these 2 variables, an individualized management of anemia seems to be feasible in recipients of pegylated interferon-RBV therapy.
Assuntos
Antivirais/farmacocinética , Hepatite C/tratamento farmacológico , Pirofosfatases/genética , Ribavirina/farmacocinética , Adulto , Alelos , Anemia Hemolítica/induzido quimicamente , Antivirais/efeitos adversos , Antivirais/uso terapêutico , Estudos de Viabilidade , Feminino , Genótipo , Hemoglobinas/metabolismo , Humanos , Interferon alfa-2 , Interferon-alfa/administração & dosagem , Interferon-alfa/uso terapêutico , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/uso terapêutico , Polimorfismo de Nucleotídeo Único , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/uso terapêutico , Estudos Retrospectivos , Ribavirina/efeitos adversos , Ribavirina/uso terapêutico , Inosina TrifosfataseRESUMO
OBJECTIVES: The aim of this study was to compare amprenavir pharmacokinetics in HIV/hepatitis C virus (HCV)-co-infected cirrhotic patients receiving non-boosted fosamprenavir 700 mg twice daily with HCV/HIV-co-infected non-cirrhotic subjects and HIV-mono-infected subjects receiving fosamprenavir/ritonavir 700/100 mg twice daily. Liver stiffness at baseline and alanine aminotransferase levels at baseline and during follow-up were measured in order to find a correlation between drug levels and liver fibrosis or hepatotoxicity. METHODS: Amprenavir plasma concentration was determined by HPLC. Liver stiffness was measured by transient elastometry. Liver function tests were determined every 1-3 months during follow-up. RESULTS: Nineteen HIV-infected patients were included. Eight had chronic HCV hepatitis (group NC), five had HCV-related liver cirrhosis (group C) and six were HIV-mono-infected (group M). In group C patients, amprenavir C(trough), AUC(0-12) and half-life were 86%/83%, 64%/55% and 58%/59% lower when compared with controls and co-infected subjects without cirrhosis, respectively; conversely, drug clearance in cirrhotics was 181%/124% higher. In 3/5 cirrhotic patients (60%) and in 2/14 non-cirrhotic patients (14%), C(trough) was below the minimum target concentration of 400 ng/mL; nonetheless, in all these patients, HIV viral load was undetectable. No correlation was found between amprenavir pharmacokinetics and liver stiffness or hepatotoxicity at follow-up. CONCLUSIONS: On the basis of these data, it seems reasonable to boost fosamprenavir with ritonavir even in cirrhotic patients; amprenavir pharmacokinetics could not be predicted by liver stiffness and seem not to predict hepatotoxicity at follow-up.
Assuntos
Fármacos Anti-HIV/farmacocinética , Carbamatos/farmacocinética , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Hepatite C/complicações , Cirrose Hepática , Organofosfatos/farmacocinética , Sulfonamidas/farmacocinética , Adulto , Alanina Transaminase/sangue , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/uso terapêutico , Carbamatos/administração & dosagem , Carbamatos/uso terapêutico , Cromatografia Líquida de Alta Pressão , Técnicas de Imagem por Elasticidade , Feminino , Furanos , HIV/isolamento & purificação , Humanos , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Organofosfatos/administração & dosagem , Organofosfatos/uso terapêutico , Plasma/química , Sulfonamidas/administração & dosagem , Sulfonamidas/uso terapêutico , Carga ViralRESUMO
BACKGROUND: Early virological response (VR) to enfuvirtide-based salvage regimens at week 12 has been described as a predictor of long-term therapeutic success. The relationship between enfuvirtide plasma exposure and VR has not yet been investigated in the clinical setting. Our aim was to investigate the role of enfuvirtide plasma exposure as a determinant of early VR in the clinical setting. METHODS: Forty-two multidrug-experienced patients starting a salvage enfuvirtide-based regimen were prospectively evaluated over a 12 week period. HIV-RNA levels and enfuvirtide C(trough) were regularly measured. VR was considered as achievement of viral load (VL) undetectability and/or a decrease of more than 1 log at week 12. RESULTS: Optimized background score (OBS) and enfuvirtide C(trough) concentrations were associated with VL decrease at week 12. An OBS > or =2 and enfuvirtide C(trough) >2100 ng/mL were associated with VR. The pharmacokinetic/pharmacodynamic (PK/PD) analysis confirmed this exposure-response relationship both in the total population and in different groups according to OBS <2 or > or =2. Higher estimates of IC(50) were calculated for the OBS <2 group when compared with the OBS > or =2 group (7551 versus 2330 ng/mL, respectively), without a marked difference in I(0) (0.31 versus 0.21 log) and I(max) (-2.64 versus -3.33 log). CONCLUSIONS: Enfuvirtide plasma exposure and OBS were found to significantly influence the magnitude and rate of early VR. The PK/PD modelling of enfuvirtide concentrations was different in our clinical setting, compared with previous data obtained under trial conditions. Therefore, optimization of enfuvirtide plasma exposure could deserve further evaluation as a determinant of therapeutic response in HIV-positive patients.
Assuntos
Proteína gp41 do Envelope de HIV/farmacocinética , Proteína gp41 do Envelope de HIV/uso terapêutico , Inibidores da Fusão de HIV/farmacocinética , Inibidores da Fusão de HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Fragmentos de Peptídeos/farmacocinética , Fragmentos de Peptídeos/uso terapêutico , Carga Viral , Enfuvirtida , Feminino , Proteína gp41 do Envelope de HIV/farmacologia , Inibidores da Fusão de HIV/farmacologia , Humanos , Concentração Inibidora 50 , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Fragmentos de Peptídeos/farmacologia , Plasma/química , Plasma/virologia , Estudos Prospectivos , Terapia de Salvação , Resultado do TratamentoRESUMO
BACKGROUND: Chronic iatrogenic scleroderma is a possible obstacle to the absorption of subcutaneously administered drugs. This study correlated the clinical and histopathological pattern of injection-site reactions (ISRs) to the pharmacokinetics of enfuvirtide in patients with HIV. METHODS: Fourteen patients treated with an enfuvirtide-based antiretroviral regimen for a median of 45 weeks were enrolled and their ISRs were evaluated. Twelve patients with evidence of ISRs underwent cutaneous biopsies using a 4-mm punch. The maximum plasma enfuvirtide concentration (Cmax) and the area under the enfuvirtide concentration-time curve (AUC) were assessed using blood sampling. RESULTS: Four different macroscopic patterns of ISR were identified: A--no evidence of cutaneous lesions; B--transient infiltrative lesions that auto-resolved within 24 hours; C--transient nodular lesions that auto-resolved within 7-15 days; and D--stable lesions after more than 30 days. Histological examination showed three morphological patterns: (1) acute urticaria/vasculitis-like pattern, (2) subacute pattern and (3) chronic scleroderma-like pattern. No differences among patients with the various patterns of ISRs were observed, except for a higher Cmax and AUC in patients with pattern 1. CONCLUSIONS: These results confirm that although iatrogenic scleroderma is not related to impaired enfuvirtide absorption, higher Cmax and AUC values are observed in patients with urticaria/vasculitis-like patterns.
Assuntos
Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/farmacocinética , Proteína gp41 do Envelope de HIV/efeitos adversos , Proteína gp41 do Envelope de HIV/farmacocinética , Fragmentos de Peptídeos/efeitos adversos , Fragmentos de Peptídeos/farmacocinética , Esclerodermia Localizada/induzido quimicamente , Esclerodermia Localizada/metabolismo , Adulto , Área Sob a Curva , Enfuvirtida , Feminino , Humanos , Doença Iatrogênica , Injeções Intravenosas/efeitos adversos , Masculino , Pessoa de Meia-Idade , Pele/patologia , Urticária/patologia , Vasculite/patologiaRESUMO
A simple method for the quantification of tipranavir, the first non-peptidic HIV protease inhibitor, was developed and validated. Quinoxaline, as internal standard, was added to 50 microl of plasma before a liquid-liquid extraction by 600 microl of protein precipitation solution. The extracts were diluted before being injected in the chromatographic system. Chromatographic separation was made on a C18 column using potassium phosphate buffer (pH 3.2) and acetonitrile with gradient. Detection was performed by an UV detector at 260 nm. Relative error at three control quality concentrations ranged from -1.81 to 1.72%. Intra-day (CV%) and inter-day (CV%) precision ranged from 0.94 to 2.55% and from 3.07 to 4.24%, respectively. LOQ and LOD were 0.090 microg/ml and 0.035 microg/ml, respectively. Mean recovery was 87.1%+/-2.4%. Calibration curve was linear up to 180 microg/ml. Concentration range when optimized (0.703-180 microg/ml) proved to be adequate to measure tipranavir concentration in HIV-1-positive patients, therefore this method could be suitable for therapeutic drug monitoring of this drug.
Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Piridinas/sangue , Pironas/sangue , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/sangue , Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/sangue , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/administração & dosagem , Inibidores da Protease de HIV/sangue , Inibidores da Protease de HIV/uso terapêutico , Humanos , Piridinas/administração & dosagem , Piridinas/uso terapêutico , Pironas/administração & dosagem , Pironas/uso terapêutico , Reprodutibilidade dos Testes , Espectrofotometria Ultravioleta/métodos , SulfonamidasRESUMO
Measurement of ribavirin plasma levels in HCV-positive patients have been shown to be useful in order to optimise individual ribavirin exposure. Efficacy and toxicity of this drug are shown to be concentration-dependant. A simple HPLC-UV method was developed and validated, which has an easy liquid/liquid extraction, sensitive limit of detection, without any interference peaks, reproducible and linear over the range of clinical relevant concentrations. The assay warrants further evaluation as a tool for ribavirin therapeutic drug monitoring in HCV-positive patients.
Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Ribavirina/sangue , Fracionamento Químico/métodos , Monitoramento de Medicamentos/métodos , Hepatite C Crônica/sangue , Humanos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Raios UltravioletaRESUMO
Liver enzyme elevations are frequently seen in patients treated with nevirapine (NVP). Both elevated NVP plasma levels and hepatitis C virus (HCV) infection seem to favor the development of NVP-related liver toxicity. We have examined variation on NVP C(trough) over time, as well as the impact of NVP C(trough) concentrations and the role of chronic hepatitis C on the incidence of liver enzyme elevations over a 48-week study period in HIV-infected patients on NVP therapy. Thirty-seven patients who initiated a triple regimen of NVP (200 mg bid) plus two nucleoside reverse transcriptase inhibitors (NRTI) were analyzed. A significant increase in serum transaminase levels occurred progressively over time. However, no significant variations in NVP plasma C(trough) were noticed in 48 weeks. In total population, maximum fold increase (MFI) in serum AST, ALT, and GGT was correlated with 24 week NVP C(trough). In HCV+ subjects, 12-week NVP C(trough) was closely correlated with maximum transaminase elevations, whereas in HCV- patients, 24-week concentrations were correlated with maximum transaminase increase. However, no differences in either NVP plasma C(trough) or in MFI in transaminase levels could be determined when comparing patients with and without hepatitis C at any time point.
Assuntos
Fármacos Anti-HIV/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas , Infecções por HIV/tratamento farmacológico , Hepatite C Crônica/complicações , Nevirapina/efeitos adversos , Inibidores da Transcriptase Reversa/efeitos adversos , Adulto , Alanina Transaminase/sangue , Fármacos Anti-HIV/sangue , Aspartato Aminotransferases/sangue , Quimioterapia Combinada , Feminino , Infecções por HIV/complicações , Infecções por HIV/virologia , Humanos , Fígado/enzimologia , Hepatopatias/sangue , Masculino , Nevirapina/sangue , Inibidores da Transcriptase Reversa/sangueRESUMO
BACKGROUND: Patients on two nucleoside analogs plus nevirapine (NVP) who show low-level plasma HIV RNA might have insufficient NVP plasma levels and therefore might benefit from an increase in NVP dosing. METHOD: The dose of NVP was increased from 400 mg/day to 600 mg/day in 25 participants taking NVP-containing triple combinations for at least 3 months and experiencing a first virological failure (>50 HIV RNA copies/mL). The levels of NVP were measured in plasma samples taken prior to and 3 months after the intervention. HIV genotyping was performed at the time of dose increase. A control group of 25 participants who showed early virological failure with NVP continued with standard doses of the drug for 3 months. RESULTS: The median HIV RNA and CD4 cell counts were 100 copies/mL and 635 cells/mm(3), respectively. Similar figures were recorded in the control arm. Mean NVP plasma levels that were reached with a dose of 600 mg/day were significantly higher than those with 400 mg/day (7.4 microg/mL [95% CI, 6.4-8.4] vs. 3.4 microg/mL [95% CI, 2.9-3.9]; p <.0001). Thirteen (52%) participants reached <50 HIV RNA copies/mL after the intervention. The greater levels of NVP were relatively well tolerated, with no development of rashes and only mild elevations in transaminase levels. NVP-associated mutations were recognized in 9 of 10 participants who did not respond but only in 3 of 9 responders (p =.019). More frequent mutations appeared at positions 181, 103, 106, and 190. The levels of NVP did not change significantly in participants who were included in the control arm, and only one reached complete virological suppression after continuing treatment for 3 additional months. CONCLUSION: An increase of one pill of NVP per day led to a significant rise in NVP plasma levels. A greater virologic response was noticed among participants with higher NVP plasma levels. Major resistance mutations that conferred resistance to NVP were recognized in all participants who failed to regain virological suppression after increasing NVP dose.
Assuntos
Infecções por HIV/tratamento farmacológico , Nevirapina/administração & dosagem , Nevirapina/farmacocinética , Adulto , Terapia Antirretroviral de Alta Atividade , Contagem de Linfócito CD4 , Esquema de Medicação , Farmacorresistência Viral , Feminino , Infecções por HIV/sangue , Infecções por HIV/virologia , HIV-1/genética , Humanos , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/sangue , Resultado do Tratamento , Carga ViralAssuntos
Infecções por HIV/metabolismo , Inibidores da Protease de HIV/farmacocinética , HIV-1/genética , Indinavir/farmacocinética , Saquinavir/farmacocinética , Contagem de Linfócito CD4 , Esquema de Medicação , Resistência Microbiana a Medicamentos , Genótipo , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Inibidores da Protease de HIV/uso terapêutico , HIV-1/efeitos dos fármacos , Humanos , Indinavir/uso terapêutico , Masculino , Estudos Multicêntricos como Assunto , Mutação , Plasma , Estudos Prospectivos , RNA Viral/sangue , Saquinavir/uso terapêuticoRESUMO
The virological response (VR) to a tipranavir-ritonavir (TPV-RTV)-based regimen had been shown to be associated with a number of mutations in the protease gene, the use of enfuvirtide (T20), and the TPV phenotypic inhibitory quotient (IQ). The role of the TPV genotypic IQ (gIQ) has not yet been fully investigated. The aim of our study was to evaluate the relationship between the TPV gIQ and the VR at 48 weeks to TPV-based salvage regimens. Patients placed on regimens containing two nucleoside reverse transcriptase inhibitors plus TPV-RTV 500/200 mg twice a day with or without T20 were prospectively studied. Regular follow-up was performed over the study period. VR, considered a viral load (VL) decrease of >or=1 log unit and/or the achievement of <50 copies/ml with no VL rebound of >0.5 log unit compared to the maximal VL decrease at week 48, was assessed. Thirty-eight patients who had received multiple drugs were included. At week 48 the VL decrease was -1.48 (interquartile range [IQR], -2.88 to -0.48), 15 patients (39.5%) had VLs of <50 copies/ml, and the CD4+ cell count increase was 37 cells/mm3 (IQR, -30 to +175). Twenty subjects (52.6%) achieved VRs. The TPV gIQ and optimized background score (OBS) were independently associated with higher VL decreases. The TPV gIQ and OBS were also independent predictors of a VR at week 48. TPV gIQ and OBS cutoff values of 14,500 and 2, respectively, were associated with a higher rate of VR. The TPV gIQ was shown to be able to predict the VR at 48 weeks to TPV-containing salvage regimens better than the TPV trough concentration or TPV-associated mutations alone. A possible TPV gIQ cutoff value of 14,500 for reaching a VR at week 48 was suggested. Further studies are needed in order to evaluate the calculation of TPV gIQ as a new tool for the optimization of TPV-based salvage therapy.
Assuntos
Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Inibidores da Protease de HIV/farmacocinética , Protease de HIV/genética , HIV-1/efeitos dos fármacos , Piridinas , Pironas , Terapia de Salvação , Adulto , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Farmacorresistência Viral/genética , Quimioterapia Combinada , Feminino , Genótipo , Inibidores da Protease de HIV/farmacologia , Inibidores da Protease de HIV/uso terapêutico , HIV-1/enzimologia , HIV-1/genética , Humanos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Piridinas/farmacocinética , Piridinas/farmacologia , Piridinas/uso terapêutico , Pironas/farmacocinética , Pironas/farmacologia , Pironas/uso terapêutico , Inibidores da Transcriptase Reversa/uso terapêutico , Ritonavir/farmacologia , Ritonavir/uso terapêutico , Sulfonamidas , Resultado do TratamentoRESUMO
An improved HPLC fluorimetric method for the quantification of enfuvirtide in plasma of HIV-infected subjects was described and validated. The use of an internal standard improved the reproducibility and precision of the analysis. Our method showed lower limits of detection and quantification (LOD = 32 ng/mL, LOQ = 78 ng/mL), lower intraday (RSD% 1.25-2.95) and interday (RSD% 1.75-4.69) coefficients of variation, greater recovery (>100%), lower duration (16 minutes) and lower cost than previously described fluorimetric methods. Therefore, this method can be used as a reliable tool for pharmacokinetic studies of enfuvirtide.