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1.
Br J Clin Pharmacol ; 87(11): 4432-4438, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-33890312

RESUMO

AIM: People living with HIV (PLWH) have a high burden of comorbidities and concomitant medication use. The aim of this study was to analyse the prevalence, predictors and patterns of polypharmacy (PP) in a large therapeutic drug monitoring (TDM) registry. METHODS: We searched our TDM registry and categorized co-medications into 26 drug classes. We included patients with at least one medication recorded: PP and severe polypharmacy (sPP) were defined as the concomitant use of ≥5 or ≥10 nonantiretroviral/nonantitubercular drugs. Multivariable binary logistic analysis were conducted for identifying PP/sPP predictors. A hierarchical average-linkage cluster analysis was performed among drug classes. RESULTS: We included 2432 participants (1158 PLWH) aged 49.6 years (± 14.4) in the 2016-2020 period. A higher number of concomitant medications (4 vs 3.1, P < .001) and a higher prevalence of PP (26.1% vs 21.8%, P = .015) were recorded in controls. At multivariable binary logistic analysis older age, female gender and HIV-positive serostatus (P = .015) were independent predictors of PP; older age and year of inclusion were independent predictors of sPP. Cluster analysis showed that patients receiving oral drug for type 2 diabetes have a high probability of receiving several other drugs; a cluster of co-medications was observed with opioids, diuretics and central nervous system-affecting drugs. CONCLUSION: We observed a moderately high prevalence of polypharmacy in middle-aged PLWH: advanced age and female gender were associated with the greatest prevalence. The observation of co-medication clusters suggests groups of comorbidities but also identifies groups of patients at risk of similar drug-to-drug interactions.


Assuntos
Diabetes Mellitus Tipo 2 , Infecções por HIV , Idoso , Análise por Conglomerados , Estudos Transversais , Monitoramento de Medicamentos , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Humanos , Pessoa de Meia-Idade , Polimedicação
2.
Artigo em Inglês | MEDLINE | ID: mdl-29760129

RESUMO

Atazanavir-ritonavir concentrations change over time during pregnancy in HIV-positive patients; the impact of genetic variants is unknown. Twenty patients were enrolled in this study; plasma and intracellular concentrations of antiretrovirals were measured, in addition to single-nucleotide polymorphisms in transport-related genes. Linear logistic regression showed that genetic variants in organic-anion-transporter-1B1- and pregnane-X-receptor-encoding genes affected third-trimester atazanavir exposure. In this prospective study, genetic variants partially explained the observed interpatient variability in third-trimester exposure to antiretrovirals.


Assuntos
Sulfato de Atazanavir/farmacocinética , Sulfato de Atazanavir/uso terapêutico , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/uso terapêutico , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Receptor de Pregnano X/genética , Ritonavir/farmacocinética , Ritonavir/uso terapêutico , Adulto , Sulfato de Atazanavir/sangue , Esquema de Medicação , Quimioterapia Combinada , Feminino , Inibidores da Protease de HIV/sangue , Inibidores da Protease de HIV/farmacocinética , Humanos , Polimorfismo de Nucleotídeo Único/genética , Gravidez , Complicações Infecciosas na Gravidez/tratamento farmacológico , Terceiro Trimestre da Gravidez , Estudos Prospectivos , Ritonavir/sangue
3.
J Antimicrob Chemother ; 72(11): 3163-3166, 2017 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-28961777

RESUMO

BACKGROUND: Atazanavir (300 mg) boosted by ritonavir (100 mg) is the preferred third drug in pregnancy. However, there is still discordance on atazanavir dose increase during the third trimester. OBJECTIVES: To evaluate plasma and intracellular atazanavir and ritonavir concentrations in HIV-infected women during pregnancy and after delivery. METHODS: This was an observational study. HIV-infected pregnant patients treated with atazanavir/ritonavir plus either tenofovir/emtricitabine or abacavir/lamivudine had been prospectively enrolled after having signed a written informed consent form. Plasma and intracellular atazanavir and ritonavir Ctrough (24 ±âŸ3 h after drug intake) were measured at each visit during the first, second and third trimesters and post-partum using validated HPLC-MS and HPLC-photodiode array methods (with direct evaluation of cellular volume). Data are described as median (IQR) and compared through non-parametric tests. RESULTS: Twenty-five patients were enrolled; at baseline, the median age was 32 years (27-35). All patients had plasma HIV RNA <50 copies/mL; the median CD4+ count was 736 cells/mm3 (542-779). Atazanavir plasma concentrations were 441 ng/mL (261-1557), 710 ng/mL (338-1085), 556 ng/mL (334-1022) and 837 ng/mL (608-1757) during the first, second and third trimesters and post-partum, respectively; intracellular concentrations were 743 ng/mL (610-1928), 808 ng/mL (569-1620), 756 ng/mL (384-1074) and 706 ng/mL (467-2688), respectively. Atazanavir intracellular/plasma ratios were 1.32 (0.98-2.77), 1.34 (1.13-1.88), 1.38 (0.61-2.63) and 1.07 (0.56-2.69), respectively. Atazanavir intracellular concentrations and intracellular/plasma ratios showed non-significant changes over time (P > 0.05). CONCLUSIONS: This is the first demonstration that intracellular atazanavir exposure remains unchanged during pregnancy supporting the standard 300/100 mg atazanavir/ritonavir dosing throughout pregnancy.


Assuntos
Sulfato de Atazanavir/administração & dosagem , Sulfato de Atazanavir/farmacocinética , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/administração & dosagem , Inibidores da Protease de HIV/farmacocinética , Complicações Infecciosas na Gravidez/tratamento farmacológico , Adulto , Sulfato de Atazanavir/efeitos adversos , Sulfato de Atazanavir/uso terapêutico , Contagem de Linfócito CD4 , Cromatografia Líquida de Alta Pressão , Quimioterapia Combinada , Emtricitabina/uso terapêutico , Feminino , Infecções por HIV/metabolismo , Infecções por HIV/virologia , Inibidores da Protease de HIV/sangue , Inibidores da Protease de HIV/uso terapêutico , HIV-1/efeitos dos fármacos , Humanos , Recém-Nascido , Leucócitos Mononucleares/química , Gravidez , Complicações Infecciosas na Gravidez/metabolismo , Complicações Infecciosas na Gravidez/virologia , Trimestres da Gravidez/metabolismo , Estudos Prospectivos , RNA Viral/sangue , Ritonavir/administração & dosagem , Ritonavir/uso terapêutico , Tenofovir/uso terapêutico , Carga Viral
4.
J Antimicrob Chemother ; 69(11): 3061-6, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24997317

RESUMO

OBJECTIVES: The rate of accumulation of atazanavir and ritonavir within cells is still debated due to methodological limitations. Our aim was to measure peripheral blood mononuclear cell (PBMC) concentrations of atazanavir and ritonavir and investigate whether single-nucleotide polymorphisms of OATP, ABCB1, CYP3A4 and PXR genes are involved in intracellular drug penetration. METHODS: HIV-positive patients administered 300 mg of atazanavir/100 mg of ritonavir were enrolled. Blood sampling was performed at the end of the dosing interval (Ctrough). PBMC-associated and plasma atazanavir and ritonavir concentrations were measured by validated HPLC coupled with a single mass detector (HPLC-MS) and HPLC-photodiode array (PDA) methods, respectively. Cell count and mean cellular volume were determined using a Coulter counter. Genotyping was conducted using real-time PCR. RESULTS: Thirty-five patients were enrolled. Median atazanavir and ritonavir intracellular concentrations were 1844 and 716 ng/mL, respectively. Median plasma concentrations were 645 ng/mL for atazanavir and 75 ng/mL for ritonavir, while median intracellular/plasma concentration ratios were 2.4 and 9.2, respectively. Median ritonavir intracellular concentrations were higher for OATP1B1 521 T→C TC or CC carriers and for PXR 44477 A→G AG or GG carriers. Atazanavir intracellular/plasma concentration ratios were higher in patients GG for the ABCB1 2677 G→T single-nucleotide polymorphism (SNP) compared with GT and TT groups. CONCLUSIONS: Our study showed a higher intracellular ritonavir accumulation than previously reported. Ritonavir intracellular concentrations were associated with OATP1B1 521 and PXR 44477 SNPs while intracellular atazanavir exposure was associated with the ABCB1 2677 SNP. Further clinical studies are necessary in order to confirm these data.


Assuntos
Líquido Intracelular/metabolismo , Oligopeptídeos/sangue , Transportadores de Ânions Orgânicos/genética , Piridinas/sangue , Receptores de Esteroides/genética , Ritonavir/sangue , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Adulto , Sulfato de Atazanavir , Biomarcadores/sangue , Feminino , Humanos , Leucócitos Mononucleares/metabolismo , Transportador 1 de Ânion Orgânico Específico do Fígado , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Receptor de Pregnano X
5.
J Antimicrob Chemother ; 68(4): 907-10, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23221630

RESUMO

OBJECTIVES: Ritonavir, used at low doses as a boosting agent of other protease inhibitors (PIs), is known to be associated with metabolic complications and gastrointestinal disturbances. The rate of accumulation of ritonavir within cells is still debated due to scarce data and methodological limitations. Therefore, our aim was to evaluate intracellular ritonavir penetration when used with different boosted PIs in the clinical setting. METHODS: Patients administered with atazanavir/ritonavir (300/100 mg, once daily), darunavir/ritonavir [600/100 mg, twice daily (darunavir-600) and 800/100 mg, once daily (darunavir-800)], lopinavir/ritonavir (400/100 mg, twice daily) and tipranavir/ritonavir (500/200 mg, twice daily) were considered. Blood sampling at the end of the dosing interval (Ctrough) was performed. Peripheral blood mononuclear cell (PBMC)-associated and plasma ritonavir and PI concentrations were measured by validated HPLC methods. PBMC count and individual mean cell volume (MCV) were measured using a Coulter Counter instrument. RESULTS: One hundred patients were enrolled. Frequencies of ritonavir-boosted PIs were atazanavir, 37%; darunavir-600, 23%; lopinavir, 19%; tipranavir, 13%; and darunavir-800, 8%. The median intracellular and plasma concentrations of ritonavir were 1279 ng/mL (IQR 727-2087) and 170 ng/mL (IQR 82-384), respectively, accounting for a cellular accumulation ratio of 7.69 (5.7-10.9). Significant differences in ritonavir intracellular concentrations emerged among different PIs (P<0.001): specifically between darunavir-600 and atazanavir (P<0.001), between darunavir-600 and tipranavir (P=0.009), between atazanavir and lopinavir (P<0.001) and between lopinavir and tipranavir (P=0.027). CONCLUSIONS: Our study showed a higher rate of ritonavir intracellular accumulation than previously reported, possibly due to the more accurate calculation of intracellular concentrations by MCV. The ratio varied according to concomitantly administered PIs, suggesting their influence on the rate of ritonavir intracellular penetration.


Assuntos
Citosol/química , Inibidores da Protease de HIV/farmacocinética , Leucócitos Mononucleares/química , Plasma/química , Ritonavir/farmacocinética , Adulto , Cromatografia Líquida de Alta Pressão , Quimioterapia Combinada/métodos , Feminino , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Ritonavir/administração & dosagem
7.
J Antimicrob Chemother ; 62(2): 384-7, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18487231

RESUMO

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 Tratamento
8.
Artigo em Inglês | MEDLINE | ID: mdl-17964231

RESUMO

A new method using high performance liquid chromatography coupled with electrospray mass spectrometry (HPLC-MS) was developed and validated, for the quantification of plasma concentration of the new protease inhibitors darunavir (DRV) and other 11 antiretroviral agents (ritonavir, amprenavir, atazanavir, lopinavir, saquinavir, indinavir, nelfinavir and its metabolite M-8, nevirapine, efavirenz and tipranavir). A simple protein precipitation extraction procedure was applied on 50 microl of plasma aliquots and chromatographic separation of drugs and Internal Standard (quinoxaline) was achieved with a gradient (acetonitrile and water with formic acid 0.05%) on an C-18 reverse phase analytical column with 25 min of analytical run. Calibration curves were optimised according to expected ranges of drug concentrations in patients, and correlation coefficient (r2) was higher than 0.998 for all analytes. Mean intra- and inter-day precision (relative standard deviation %) for all compounds were 8.4 and 8.3%, respectively, and mean accuracy (% of deviation from nominal level) was 3.9%. Extraction recovery ranged within 93 and 105% for all drugs analysed. This novel HPLC-MS methodology allows a specific, sensitive and reliable determination of DRV and 11 other antiretrovirals. In our hand, it was used to measure DRV and ritonavir plasma concentration in HIV-positive patients, and it is now successfully applied for routine therapeutic drug monitoring and pharmacokinetics studies.


Assuntos
Antirretrovirais/sangue , Cromatografia Líquida de Alta Pressão/métodos , Infecções por HIV/sangue , Sulfonamidas/sangue , Darunavir , Estabilidade de Medicamentos , Humanos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
9.
J Clin Virol ; 87: 30-36, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27992788

RESUMO

BACKGROUND: Unboosted atazanavir with raltegravir has been investigated at 300mg twice daily showing frequent hyperbilirubinemia and selection of resistance-associated mutations. OBJECTIVES: Atazanavir 200mg twice daily could increase tolerability and plasma exposure. STUDY DESIGN: Patients on atazanavir/raltegravir (200/400 twice daily), with self-reported adherence >95% and no concomitant interacting drugs were retrospectively evaluated. RESULTS: 102 patients [72.5% male, age 46.4 years (42-54), BMI 24kg/m2 (22-26)] were included. CD4+ T lymphocytes were 417 cell/µL (302-704) and 76 patients (74.5%) had HIV-RNA <50 copies/ml. After 123 weeks 18.6% patients showed virological failure and 3.9% discontinued for intolerance. Available genotypes showed selection of major integrase (7/10 patients) and protease resistance-associated mutations (5/13 patients). In patients switching with dyslipidemia (n=67) total, LDL cholesterol and triglycerides significantly decreased. Patients switching with eCRCL<60ml/min (n=27) had no significant changes while patients with eCRCL >60ml/min showed significant decrease (-9.8ml/min, p=0.003) at 96-weeks. Atazanavir and raltegravir trough concentrations were 321ng/mL (147-720) and 412ng/mL (225-695). Self-reported non-adherence (n=4) was significantly associated with virological failure (p=0.02); patients with virological success had borderline longer previous virological control (33 vs. 18 months, p=0.07). DISCUSSION: Switch to atazanavir/raltegravir was safe and well tolerated allowing optimal drugs' plasma exposure. However, a concerning rate (18.6%) failed with newly selected mutations and stopped ATV/RAL because of DDI and intolerance issues or were lost to follow-up. This regimen might be considered in selected patients, without history of protease inhibitors failure or HBV infection, showing optimal adherence and prolonged suppression.


Assuntos
Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/efeitos adversos , Sulfato de Atazanavir/administração & dosagem , Sulfato de Atazanavir/efeitos adversos , Infecções por HIV/tratamento farmacológico , Raltegravir Potássico/administração & dosagem , Raltegravir Potássico/efeitos adversos , Adulto , Fármacos Anti-HIV/farmacocinética , Sulfato de Atazanavir/farmacocinética , Contagem de Linfócito CD4 , Farmacorresistência Viral , Feminino , Infecções por HIV/virologia , HIV-1/genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Plasma/química , Raltegravir Potássico/farmacocinética , Estudos Retrospectivos , Seleção Genética , Resultado do Tratamento , Carga Viral
10.
AIDS ; 30(6): 915-20, 2016 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-26636928

RESUMO

OBJECTIVE: To assess if tenofovir (TFV) clearance is associated with urinary retinal-binding protein (RBP) in HIV-positive patients with normal estimated filtration rate. DESIGN: A cross-sectional diagnostic study. METHODS: HIV-positive patients with estimated creatinine clearance above 60 ml/min, on tenofovir disoproxil fumarate (TDF)-containing combination since at least 6 months, taking TDF at night, and without significant comorbidities (diabetes, untreated hypertension, known renal malformations, recurrent nephrolithiasis) and nephrotoxic drugs were included. TFV plasma and urinary concentrations were measured 12 h after drug intake (C12). RBP was measured through enzyme immunoassay kit on spot urines and corrected per urinary creatinine (uRBP/uCr); normality ranges were below 130 µg/g (in patients aged <50 years) and below 172 µg/g (in patients aged ≥50 years). RESULTS: Two hundred and eighty-nine patients were included (median age of 45.8 years, 71.6% male and 85.4% whites); patients were concomitantly treated with nonnucleoside reverse transcriptase inhibitors (155, 53.6%), protease inhibitors (118, 40.8%), or integrase inhibitors (16, 5.5%)-containing regimens. Estimated creatinine clearance was 89.4 ml/min (78.6-105.9). Urinary RBP (uRBP) and uRBP/uCr were 204.6 ng/ml (92-380) and 169.7 µg/g (85.8-318.3), respectively; abnormally high uRBP/uCr was observed in 157 patients (54.3%). A multivariate binary logistic regression confirmed that both ethnicity (P = 0.004, ß 2.93, 95% confidence interval 1.41-6.10) and TFV urinary C12 less than 21 mg/ml (P = 0.006, ß 2.04, 95% confidence interval 1.12-3.41) were significantly associated with abnormal uRBP/uCr. CONCLUSION: HIV-positive TDF-treated patients showed a high prevalence of proximal tubular impairment: ethnicity (whites) and low urinary TFV concentrations were significantly associated with elevated uRBP. SDC VIDEO:: http://links.lww.com/QAD/A852.


Assuntos
Fármacos Anti-HIV/farmacocinética , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Insuficiência Renal/patologia , Tenofovir/farmacocinética , Adulto , Fármacos Anti-HIV/administração & dosagem , Doenças Assintomáticas , Estudos Transversais , Feminino , Humanos , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Plasma/química , Tenofovir/administração & dosagem , Urina/química
11.
Curr HIV Res ; 14(1): 54-60, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26415700

RESUMO

BACKGROUND: Tolerability, long-term toxicities and selection of resistant variants limit the use and efficacy of antiretroviral drugs in HIV-positive patients. Novel combinations are needed for mantaining long-term control of HIV replication; nevertheless scarse data are available on protease inhibitor-free dual antiretroviral therapies. METHODS: A multi-centric retrospective study was conducted including HIV-1-positive patients on raltegravir/nevirapine dual regimens. Plasma concentrations were measured as therapeutic drug monitoring while a subset of patients underwent intensive 12-hour pharmacokinetic evaluation. RESULTS: A total of 77 patients switching from successful regimens (76.6% male, median age 52 years) was included; 10 patients on raltegravir plus nevirapine once-daily while 67 subjects on twice-daily schedule. After a median follow-up of 32 months 69 patients (89.6%) were still successfully on treatment. Three patients discontinued for side effects (skin rash or hepatoxicity). Virological failure was observed in five patients (6.5%, 3 on once-daily schedule): in 4 patients (80%) resistance-associated mutations were observed (4 reverse transcriptase, 2 integrase). Triglycerides decreased in patients switching with lipid abnormalities (n=52) and estimated creatinine clearance increased in those with less than 60 ml/min (n=13). Median trough raltegravir and nevirapine concentrations were 83 ng/ml (32-227) and 5460 ng/ml (4037-7221); intensive 12-hours pharmacokinetic parameters (n=7) were similar to published data. CONCLUSION: Dual therapy with raltegravir/nevirapine in selected patients was highly effective over a 32-month follow up: virological failure was infrequent (6.5%), most common with once-daily schedule (60%) and often associated with the selection of resistance-associated mutations (80%). Twice-daily raltegravir plus nevirapine deserves further clinical evaluation as an NRTI- and PI-sparing strategy in selected patients.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/uso terapêutico , Quimioterapia de Manutenção/métodos , Nevirapina/uso terapêutico , Raltegravir Potássico/uso terapêutico , Adulto , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/farmacocinética , Esquema de Medicação , Farmacorresistência Viral Múltipla/efeitos dos fármacos , Quimioterapia Combinada , Feminino , Infecções por HIV/metabolismo , Inibidores de Integrase de HIV/efeitos adversos , Inibidores de Integrase de HIV/farmacocinética , Humanos , Masculino , Pessoa de Meia-Idade , Nevirapina/efeitos adversos , Nevirapina/farmacocinética , Raltegravir Potássico/efeitos adversos , Raltegravir Potássico/farmacocinética , Estudos Retrospectivos , Carga Viral
12.
AIDS Res Hum Retroviruses ; 31(10): 999-1008, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26165150

RESUMO

The aim of this study was to evaluate the impact of HIV-1 very low-level viremia (<50 copies/ml) on the 2-year risk of virological failure. A retrospective analysis including HIV-positive patients presenting two consecutive HIV RNA below 50 copies/ml (outpatient clinic in Italy, first semester of 2010) was performed. HIV RNA was measured through real time polymerase chain reaction (PCR) assay CAP/CTM HIV-1 version 2.0 (detection limit: 20 copies/ml) and stratified as undetectable RNA ("Target Not Detected", TND), <20 copies/ml, 20-50 copies/ml. After 96 weeks virological failure was defined as two consecutive viral loads above 50 copies/ml. Log-rank tests and a multivariate Cox proportional hazard model were used for univariate and multivariate analysis. A total of 1,055 patients (71.4% male, 87.4% white, aged 46.7 years) were included: nadir and current CD4 cell counts were 203 cells/mm(3) (106-292) and 554 cells/mm(3) (413-713.5). HIV RNA was undetectable in 781 patients (74%), <20 copies/ml in 190 patients (18%) and 20-50 copies/ml in 84 patients (8%). Virological failure was observed in 81 patients (7.7%); at multivariate analysis detectable RNA at baseline (p=0.017), HCV infection (p=0.020), more than three pills in the regimen (p=0.003), and duration of HIV RNA <50 copies/ml below 2 years (p<0.001) were independently associated with virological failure. In 14 patients newly selected resistance-associated mutations were observed. Undetectable HIV RNA by real-time PCR is significantly associated with a lower 2-year risk of virological failure along with Ab HCV negativity, longer viral control, and lower pill burden. Studies investigating the management of residual viremia under antiretroviral treatment are warranted.


Assuntos
Antirretrovirais/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/isolamento & purificação , Carga Viral , Viremia , Adulto , Bioestatística , Feminino , Humanos , Itália , Masculino , Pessoa de Meia-Idade , RNA Viral/sangue , Reação em Cadeia da Polimerase em Tempo Real , Estudos Retrospectivos , Falha de Tratamento
14.
Antivir Ther ; 16(4): 499-504, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21685537

RESUMO

BACKGROUND: Use of unboosted atazanavir (ATV) with tenofovir disoproxil fumarate (TDF), although attractive from a clinical view point, has not been tested in trials and is not currently recommended because of the risk of suboptimal ATV pharmacokinetics (PK). In order to improve ATV exposure, plasma and intracellular (IC) PK of ATV in patients administered with ATV 400 mg once daily and TDF/emtricitabine (FTC) and switched to ATV 200 mg twice daily were studied. METHODS: On day 0, 10 subjects on ATV 400 mg plus TDF/FTC once daily underwent intensive plasma and IC PK evaluation and bilirubin measurement. Patients were subsequently switched to ATV 200 mg twice daily for 10 days. On day 11, they once again underwent intensive PK and bilirubin evaluation. RESULTS: Switch to 200 mg twice daily led (in plasma) to a significant increase of the observed concentration at the end of dosing interval (C(trough); ratio twice daily/once daily 2.20; P=0.005), with a decrease from 60% to 20% of suboptimal values, a significant decrease of the maximum concentration (C(max); ratio twice daily/once daily 0.47; P=0.022), whereas no differences of other PK parameters or bilirubin were observed. IC ATV concentrations at 400 once daily showed higher C(trough) (ratio peripheral blood mononuclear cells [PBMCs]/plasma 2.86; P=0.005) and longer half-life (ratio PBMCs/plasma 1.44; P=0.007) as compared with plasma. After the switch, IC ATV accumulation showed changes similar to plasma. CONCLUSIONS: Switch to 200 mg twice daily appeared to optimize plasma and IC ATV PK, by increasing the determinant of efficacy (C(trough)) and decreasing C(max), without significant effect on total ATV plasma exposure and bilirubin. Dosage of 200 mg might provide an option to patients showing suboptimal ATV exposure with standard unboosted dosing.


Assuntos
Adenina/análogos & derivados , Fármacos Anti-HIV/farmacocinética , Soropositividade para HIV/tratamento farmacológico , HIV-1 , Oligopeptídeos , Organofosfonatos , Piridinas , Inibidores da Transcriptase Reversa , Adenina/administração & dosagem , Adenina/farmacocinética , Adulto , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/uso terapêutico , Sulfato de Atazanavir , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacocinética , Esquema de Medicação , Quimioterapia Combinada , Emtricitabina , HIV-1/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Oligopeptídeos/administração & dosagem , Oligopeptídeos/farmacocinética , Organofosfonatos/administração & dosagem , Organofosfonatos/farmacocinética , Piridinas/administração & dosagem , Piridinas/farmacocinética , Inibidores da Transcriptase Reversa/administração & dosagem , Inibidores da Transcriptase Reversa/farmacocinética , Tenofovir , Resultado do Tratamento
15.
Antimicrob Agents Chemother ; 52(3): 1066-71, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18160524

RESUMO

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 Tratamento
16.
Emerg Infect Dis ; 11(7): 1118-20, 2005 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16022794

RESUMO

Blackwater fever is characterized by acute intravascular hemolysis with hemoglobinuria in patients with Plasmodium falciparum malaria. Its pathogenesis and management are still debated. Nine cases of this syndrome occurred in 2003 at Kiremba Hospital in Burundi in children receiving multiple quinine treatments.


Assuntos
Antimaláricos/efeitos adversos , Febre Hemoglobinúrica/epidemiologia , Quinina/efeitos adversos , Adolescente , Corticosteroides/administração & dosagem , Antimaláricos/administração & dosagem , Artemeter , Artemisininas/administração & dosagem , Febre Hemoglobinúrica/tratamento farmacológico , Burundi/epidemiologia , Criança , Humanos , Lactente , Masculino , Quinina/administração & dosagem , Sesquiterpenos/administração & dosagem
17.
J Antimicrob Chemother ; 50(6): 1081-4, 2002 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-12461038

RESUMO

The present study evaluated the effect of cimetidine, a histamine H(2) receptor antagonist able to inhibit cytochrome P450 metabolism, on the steady-state pharmacokinetics of saquinavir soft gel. Twelve healthy volunteers (eight males and four females) participated in an open-label, double-phase pharmacokinetic study. Volunteers took saquinavir soft gel 1200 mg three times a day for 13 days and then saquinavir soft gel 1200 mg twice a day with cimetidine 400 mg twice a day from day 14 to 26. The pharmacokinetics of saquinavir on days 13 and 26 were compared. All 12 volunteers completed the study. The association of cimetidine with saquinavir soft gel 1200 mg twice a day resulted in a significant increase in saquinavir AUC(0-24) (120%; P = 0.023) and C(max) (179%; P = 0.019), whereas C(trough) did not differ significantly (32% increase; P = 0.272). Increased exposure to saquinavir was observed in healthy volunteers after co-administration with cimetidine. The most significant increase involved C(max). Further pharmacokinetic studies in HIV-infected subjects are warranted to confirm the boosting effect of cimetidine and to investigate any impact that the increase in saquinavir C(max) may have on intracellular accumulation of the drug.


Assuntos
Cimetidina/farmacocinética , Saquinavir/farmacocinética , Adulto , Cimetidina/administração & dosagem , Cimetidina/sangue , Interações Medicamentosas , Quimioterapia Combinada , Feminino , Humanos , Masculino , Saquinavir/administração & dosagem , Saquinavir/sangue , Estatísticas não Paramétricas
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