RESUMO
A higher incidence of anemia has been observed during the treatment of hepatitis C virus genotype 1 (HCV-1) infection with pegylated alpha interferon (pegIFN-α), ribavirin, and telaprevir. We assessed the impacts that concomitant administration of telaprevir and changes in the glomerular filtration rate have on ribavirin plasma levels. The minimum concentrations of ribavirin in plasma (ribavirin Cmin) determined during triple therapy including telaprevir were compared with those observed after telaprevir withdrawal and those observed in the same subjects and in a large cohort during a previous course of pegIFN-α plus ribavirin. Intensive pharmacokinetic sampling for ribavirin was performed at steady state during the triple-therapy phase. Ribavirin levels were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Twenty-seven HCV-1/HIV-coinfected patients were enrolled. The median ribavirin Cmin for triple therapy (4.08 µg/ml; range, 2.14 to 5.56 µg/ml) was higher than that observed after telaprevir withdrawal (1.96 µg/ml; range, 0.41 to 3.45 µg/ml) (P < 0.001) and that observed for 125 HCV-1/HIV-coinfected patients treated only with pegIFN-α plus ribavirin (1.65 µg/ml; range, 0.41 to 5.56 µg/ml) (P < 0.001). The estimated glomerular filtration rate (eGFR) decreased >20% from the baseline value in 11 of 27 patients and became normal after telaprevir removal in almost all cases. There was a negative correlation between eGFR and ribavirin clearance (r(2) = 0.257; P = 0.064) but not the ribavirin area under the concentration-time curve from 0 to 12 h (AUC0-12) (r(2) = 0.001; P = 0.455). Thus, there is a significant pharmacokinetic interaction between telaprevir and ribavirin that results in very high ribavirin levels, which explains the excess of toxicity observed with this drug combination. A blockade of the proximal tubular transporters might be implicated in both the increase in plasma creatinine and the high ribavirin levels. (This study has been registered at ClinicalTrials.gov under registration no. NCT01818856.).
Assuntos
Antivirais/farmacocinética , Infecções por HIV/tratamento farmacológico , Hepatite C Crônica/tratamento farmacológico , Interferon-alfa/farmacocinética , Oligopeptídeos/farmacocinética , Ribavirina/farmacocinética , Adulto , Antivirais/uso terapêutico , Coinfecção/sangue , Coinfecção/tratamento farmacológico , Creatinina/sangue , Quimioterapia Combinada , Feminino , Infecções por HIV/sangue , Hepatite C Crônica/sangue , Humanos , Interferon-alfa/uso terapêutico , Masculino , Pessoa de Meia-Idade , Oligopeptídeos/uso terapêutico , Ribavirina/uso terapêutico , Espectrometria de Massas em TandemRESUMO
BACKGROUND: Detrimental bidirectional pharmacokinetic interactions have been observed when telaprevir (TVR) and ritonavir (RTV)-boosted human immunodeficiency virus (HIV) protease inhibitors are coadministered in healthy volunteers. Our aim was to evaluate the role of RTV in the bidirectional TVR and atazanavir (ATV) interactions. METHOD: An open-label, sequential study was carried out in hepatitis C virus (HCV)/HIV-coinfected patients on a RTV-boosted ATV-based (ATVr) antiretroviral regimen (300/100 mg every 24 hours) and triple therapy for chronic C hepatitis genotype 1 (TVR, 1125 mg every 12 hours, pegylated interferon-alpha and ribavirin). Pharmacokinetic profiles were acquired before and after switching from ATVr to unboosted ATV (200 mg every 12 hours). The plasma levels of both drugs were determined by liquid chromatography coupled with mass spectrometry. Pharmacokinetic parameters were calculated by noncompartmental analysis and compared by geometric mean ratios and their 90% confidence intervals. RESULTS: Fourteen white HCV/HIV-coinfected males were enrolled in this study. After RTV was withdrawn, the TVR AUC(0-12) (area under the concentration-time curve), maximum concentration (C(max)), and minimum concentration (C(min)) values increased by 19% (7%-30%), 12% (0.9%-29%), and 18% (2%-34%), respectively, without any changes in the TVR terminal half-life. The ATV AUC(0-12), C(max), and C(min) values were 39% (13%-66%), 19% (8%-59%), and 48% (1%-96%) higher, respectively, with a significantly shorter terminal half-life (22.6 hours vs 10.4 hours). CONCLUSIONS: RTV is responsible for the adverse interactions that occur when TVR and ATVr are administered together, possibly by influencing either the absorption phase or first-pass metabolism of TVR. The boost effect of TVR on ATV exposure is higher than on RTV, despite its shorter terminal half-life. The coadministration of TVR and unboosted ATV results in increased exposure of both drugs compared with their coadministration with RTV. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov: NCT01818856. European Medicines Agency EudraCT no. 2012-002515-25.
Assuntos
Antivirais/farmacocinética , Interações Medicamentosas , Infecções por HIV/tratamento farmacológico , Hepatite C Crônica/tratamento farmacológico , Oligopeptídeos/farmacocinética , Piridinas/farmacocinética , Ritonavir/farmacocinética , Adulto , Antivirais/uso terapêutico , Sulfato de Atazanavir , Cromatografia Líquida , Quimioterapia Combinada/métodos , Infecções por HIV/complicações , Hepatite C Crônica/complicações , Humanos , Interferon-alfa/uso terapêutico , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Oligopeptídeos/uso terapêutico , Plasma/química , Piridinas/uso terapêutico , Ribavirina/uso terapêutico , Ritonavir/uso terapêuticoRESUMO
There is significant intra- and intersubject variability in lopinavir (LPV) plasma concentrations after standard dosing; thus, this prospective study was conducted to determine whether low plasma LPV concentrations could be associated with virological outcome throughout lopinavir-ritonavir maintenance monotherapy (mtLPVr) in the clinical practice setting. If this hypothesis would be confirmed, LPV drug monitoring could improve the efficacy of mtLPVr regimens. Patients with previous virological failure (VF) on protease inhibitor-based regimens were also included if the genotypic resistance tests showed no major resistance mutation associated with reduced susceptibility to lopinavir-ritonavir. VF was defined as 2 consecutive determinations of HIV RNA levels of >200 copies/ml. Efficacy was analyzed by per-protocol analysis. Plasma LPV trough concentrations were measured by high-performance liquid chromatography using a UV detector. A total of 127 patients were included (22% with previous failure on protease inhibitors). After 96 weeks, the efficacy rate was 82.3% (95% confidence interval [CI(95)], 75.3 to 89.3%). Virological efficacy was independent of LPV plasma concentrations even when LPVr was given once daily. An adherence of <90% (HR, 4.4 [CI(95), 1.78 to 10.8; P = 0.001]) and the presence of blips in the preceding 12 months (HR, 3.06 [CI(95), 1.17 to 8.01; P = 0.022]) were the only variables independently associated with time to VF. These findings suggest that the LPV concentrations achieved with the standard doses of LPVr are sufficient to maintain virological control during monotherapy and that measurement of LPV concentrations is not useful for predicting virological outcome. Tight control of viral replication in the previous months and strict adherence throughout the mtLPVr regimen could improve the virological efficacy of this maintenance regimen.
Assuntos
Infecções por HIV/tratamento farmacológico , HIV-1/patogenicidade , Lopinavir/sangue , Ritonavir/uso terapêutico , Adulto , Idoso , Combinação de Medicamentos , Feminino , Inibidores da Protease de HIV/administração & dosagem , Inibidores da Protease de HIV/uso terapêutico , Humanos , Lopinavir/administração & dosagem , Lopinavir/uso terapêutico , Masculino , Pessoa de Meia-Idade , Cooperação do Paciente , Modelos de Riscos Proporcionais , Estudos Prospectivos , RNA Viral/análise , Ritonavir/administração & dosagem , Falha de Tratamento , Carga ViralRESUMO
OBJECTIVES: To compare intracellular and plasma etravirine concentrations when etravirine was given at 200 mg/12 h versus 400 mg/24 h and to evaluate whether the results would support once-daily dosing. METHODS: This was an open-label sequential study in which eight patients on protease inhibitor (PI)-sparing regimens containing etravirine were included. Full pharmacokinetic profiles were performed while on 200 mg of etravirine/12 h and after switching to 400 mg of etravirine/24 h. Intracellular and plasma levels were determined by liquid chromatography coupled with mass spectrometry. Pharmacokinetic parameters were calculated by non-compartmental analysis and compared by geometric mean ratios (GMRs) using 200 mg of etravirine/12 h as the reference group. TRIAL REGISTRATION: ClinicalTrials.gov NCT01121809. RESULTS: The geometric mean (GM) for etravirine AUC(0-τ) (5602 versus 5076 ng · h/mL, GMR 0.91), C(max) (403 versus 495 ng/mL, GMR 1.23) and C(min) (139 versus 102 ng/mL, GMR 0.74) were similar with both dosing schedules at the intracellular level. In plasma, the GMRs for AUC(0-τ), C(max) and C(min) were 1.31, 1.76 and 0.99, respectively. The mean intracellular penetration, evaluated as intracellular and plasma AUC(0-τ) ratios, was 81% when etravirine was dosed twice daily and 56% with once-daily dosing. CONCLUSIONS: Our results show that intracellular etravirine levels were similar with both dosing regimens in patients with PI-sparing regimens, while etravirine plasma AUC(0-τ) and C(max) were 30% and 76% higher with the once-daily regimen, respectively. Thus, a once-daily dosing regimen is supported not only by plasma etravirine pharmacokinetic profiles but also by intracellular levels.
Assuntos
Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/farmacocinética , Células Sanguíneas/química , Infecções por HIV/tratamento farmacológico , Plasma/química , Piridazinas/administração & dosagem , Piridazinas/farmacocinética , Adulto , Cromatografia Líquida , Feminino , Humanos , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Nitrilas , PirimidinasRESUMO
BACKGROUND: Ritonavir-boosted saquinavir (SQVr) is nowadays regarded as an alternative antiretroviral drug probably due to several drawbacks, such as its high pill burden, twice daily dosing and the requirement of 200 mg ritonavir when given at the current standard 1000/100 mg bid dosing. Several once-daily SQVr dosing schemes have been studied with the 200 mg SQV old formulations, trying to overcome some of these disadvantages. SQV 500 mg strength tablets became available at the end of 2005, thus facilitating a once-daily regimen with fewer pills, although there is very limited experience with this formulation yet. METHODS: Prospective, multicentre study in which efficacy, safety and pharmacokinetics of a regimen of once-daily SQVr 1500/100 mg plus 2 NRTIs were evaluated under routine clinical care conditions in either antiretroviral-naïve patients or in those with no previous history of antiretroviral treatments and/or genotypic resistance tests suggesting SQV resistance. Plasma SQV trough levels were measured by HPLV-UV. RESULTS: Five hundred and fourteen caucasian patients were included (47.2% coinfected with hepatitis C and/or B virus; 7.8% with cirrhosis). Efficacy at 52 weeks (plasma RNA-HIV <50 copies/ml) was 67.7% (CI95: 63.6 - 71.7%) by intention-to-treat, and 92.2% (CI95: 89.8 - 94.6%) by on-treatment analysis. The reasons for failure were: dropout or loss to follow-up (18.4%), virological failure (7.8%), adverse events (3.1%), and other reasons (4.6%). The high rate of dropout may be explained by an enrollment and follow-up under routine clinical care condition, and a population with a significant number of drug users. The median SQV Cmin (n = 49) was 295 ng/ml (range, 53-2172). The only variable associated with virological failure in the multivariate analysis was adherence (OR: 3.36; CI95, 1.51-7.46, p = 0.003). CONCLUSIONS: Our results suggests that SQVr (1500/100 mg) once-daily plus 2 NRTIs is an effective regimen, without severe clinical adverse events or hepatotoxicity, scarce lipid changes, and no interactions with methadone. All these factors and its once-daily administration suggest this regimen as an appropriate option in patients with no SQV resistance-associated mutations.
RESUMO
BACKGROUND: More than 50% of patients who start efavirenz treatment develop limiting neuropsychiatric adverse events (NPAEs). OBJECTIVE: To assess whether stepwise dosing of efavirenz decreases the incidence and severity of NPAEs while maintaining virologic efficacy. DESIGN: Randomized, double-blind, controlled trial. SETTING: 7 HIV clinics in Spain. PATIENTS: 114 HIV-infected patients eligible for efavirenz treatment plus 2 nucleoside or nucleotide reverse transcriptase inhibitors. INTERVENTION: Random assignment (by computer-generated sequence) to receive efavirenz, 200 mg/d on days 1 through 6, 400 mg/d on days 7 through 13, and 600 mg/d on day 14 and after, or efavirenz, 600 mg/d, from day 1. Both groups received 2 nucleoside or nucleotide reverse transcriptase inhibitors chosen by the patient's physician. MEASUREMENTS: Neuropsychiatric symptoms and sleep quality were assessed by questionnaires at 0, 7, 14, and 30 days. The primary outcome was efavirenz-related NPAEs during the first 2 weeks, and the secondary outcome was plasma HIV RNA level at 24 weeks. RESULTS: Compared with the stepped-dose group, the full-dose group had higher incidence and severity of dizziness (66.0% vs. 32.8%; P = 0.001), hangover (45.8% vs. 20.7%; P = 0.008), impaired concentration (22.9% vs. 8.9%; P = 0.038), and hallucinations (6.1% vs. 0%; P = 0.056) during the first week. From week 2, the incidence of efavirenz-related NPAEs was similar in both groups, although the severity was greater in the full-dose group. Virologic and immunologic efficacy seemed similar in both groups. LIMITATIONS: The sample size was calculated on the basis of a high absolute difference in rates of efavirenz-related NPAEs between the groups. A lower absolute difference and a larger sample size could have made the differences between groups reach statistical significance beyond the first week. In addition, the sample size does not allow confirmation of similar efficacy between treatment groups. CONCLUSION: Stepwise dose escalation of efavirenz over 2 weeks reduces the incidence and intensity of efavirenz-related NPAEs while maintaining efficacy. PRIMARY FUNDING SOURCE: Consejería de Salud, Junta de Andalucía, Spain.
Assuntos
Fármacos Anti-HIV/efeitos adversos , Benzoxazinas/efeitos adversos , Infecções por HIV/tratamento farmacológico , Transtornos Mentais/induzido quimicamente , Inibidores da Transcriptase Reversa/efeitos adversos , Transtornos do Sono-Vigília/induzido quimicamente , Adulto , Idoso , Alcinos , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/sangue , Benzoxazinas/administração & dosagem , Benzoxazinas/sangue , Contagem de Linfócito CD4 , Ciclopropanos , Método Duplo-Cego , Esquema de Medicação , Feminino , Infecções por HIV/imunologia , Infecções por HIV/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores da Transcriptase Reversa/administração & dosagem , Inibidores da Transcriptase Reversa/sangue , Tamanho da Amostra , Carga ViralRESUMO
The aim of this study was to assess whether hepatitis C virus (HCV) coinfection would affect the clinical and immunological outcome of HIV-infected patients following a simplification strategy. A prospective cohort of HIV-infected patients starting a ritonavir boosted darunavir monotherapy (mtDRV/rtv) was followed for 24 months. HCV infection was evaluated by HCV viremia and hepatic fibrosis. Immune activation was studied as HLA-DR CD38 coexpression on CD4(+) and CD8(+) T cells and also the quantification of plasma sCD14 levels. Microbial translocation was studied by the plasma levels of 16S rDNA and lipopolysaccharide (LPS). A total of 150 HIV-infected patients were enrolled in this study, including 46 individuals also infected with HCV (30.6%). HIV/HCV coinfection did not decrease mtDRV/rtv efficacy, since similar rates of HIV-1 intermittent viremia (HCV: 26.6% vs. no-HCV: 34.7%) and episodes of virological failure (HCV: 22.2% vs. no-HCV: 11.2%, p-value = 0.381) were found. No major differences were found between both groups at baseline, although higher HLA-DR(+)CD38(+)CD4(+) T cell counts were found in the coinfected group (HCV: 6.65% vs. no-HCV: 4.55%, p-value = 0.032); this difference was maintained in the 24 months of follow-up. After the 24-month follow-up, both groups, HIV-monoinfected patients and HIV/HCV-coinfected patients, presented similar immune activation and microbial translocation profiles. In conclusion, the use of a simplified mtDRV/rtv strategy compromises neither HIV nor HCV viremic control in coinfected patients, although a higher immune activation of CD4(+) T cells was found.
Assuntos
Antivirais/uso terapêutico , Darunavir/uso terapêutico , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Ritonavir/uso terapêutico , ADP-Ribosil Ciclase 1/genética , ADP-Ribosil Ciclase 1/imunologia , Adulto , Contagem de Linfócito CD4 , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/virologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/virologia , Coinfecção , Feminino , Expressão Gênica , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/fisiologia , Antígenos HLA-DR/genética , Antígenos HLA-DR/imunologia , Hepacivirus/efeitos dos fármacos , Hepacivirus/fisiologia , Hepatite C/imunologia , Hepatite C/virologia , Humanos , Ativação Linfocitária/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Carga Viral/efeitos dos fármacosRESUMO
The purpose of this article is to evaluate the evolution of microbial translocation (MT) and its role in CD4 and CD8 T cells immune activation (IA) in HIV-1-infected patients on ritonavir-boosted darunavir monotherapy (mtDRV/rtv).Prospective study of consecutive HIV-1-infected patients switched to mtDRV/rtv as a simplification regimen. Subjects were classified according to the virological behavior during a 24-month follow-up as continuous undetectable viral load, blips, intermittent viremia, and virological failure (VF). MT was evaluated by plasma LPS and 16S genomic rDNA (16S rDNA) levels, whereas IA was assessed by the coexpression of HLA-DR and CD38 in CD4 and CD8 T cells, and plasma sCD14 levels.Seventy-one patients were included in this substudy of the MonDar cohort (ClinicalTrials.gov: NCT01505722). At baseline, CD4 (ρâ=â-0.352, Pâ=â0.01) and CD8 T-cell activation (ρâ=â-0.468, Pâ<â0.001) were correlated with time with viral suppression, but not with MT markers. A significant decrease in plasma LPS levels was found only in patients without VF (baseline, 77.8 vs month 24, 60.4âpg/mL; Pâ<â0.001]. Both plasma 16S rDNA and sCD14 levels were unchanged irrespective of the viral behavior. The only variable independently associated with a decrease in CD4 and CD8 T cells activation was an undetectable HIV-1 viremia (ßâ=â4.78, Pâ<â0.001 and ßâ=â2.93, Pâ=â0.005, respectively).MT does not have a pivotal role in T-cell activation, at least in patients with long-term viral suppression. The viremic episodes and VF are the main factors related to CD4 and CD8 T-cells IA, even during mtDRV/rtv.
Assuntos
Translocação Bacteriana , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Inibidores da Protease de HIV/uso terapêutico , HIV-1 , Ativação Linfocitária , Ritonavir/uso terapêutico , Sulfonamidas/uso terapêutico , Viremia/tratamento farmacológico , Viremia/imunologia , Adulto , Biomarcadores/sangue , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Darunavir , Feminino , Infecções por HIV/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Carga ViralRESUMO
Administering raltegravir once daily would make adherence to antiretroviral treatment easier, especially if the concomitant drugs are also administered once daily. We report our experience on the use of raltegravir, both once- and twice-daily.Retrospective review of HIV-infected patients on treatment with raltegravir 800âmg once or 400âmg twice a day plus 2 analogs. Patients were classified as group A (subjects switched to raltegravir due to adverse events on a previous regimen or drug-drug interactions) and group B (subjects who restarted antiretroviral treatment after a previous drop-out). The primary clinical endpoint was the percentage of subjects with virological suppression after 96 weeks. Treatment's effectiveness (noncomplete/missing equals failure) was also evaluated. Pharmacokinetic study was performed in unselected patients. Plasma raltegravir concentrations were determined by high-performance liquid chromatography coupled with mass spectrometry.A total of 133 patients were included in the study (74 and 59 on raltegravir once- and twice-daily). There were only 4 virological failures in the entire cohort during the follow-up. Thus, the Kaplan-Meier estimation of efficacy by on-treatment analysis was 96.3% (CI95, 92.8-99.8) at week 96, independently of the dosing regimen and of the raltegravir concentrations. Similar exposures to raltegravir based on AUC0-τ, but higher Cmax and significantly lower Ctrough were observed when raltegravir was given once daily compared with 400âmg twice daily. In fact, 14 out of 56 Ctrough concentrations (25%) from patients taking raltegravir once daily were below the IC95 of wild-type HIV-1 clinical isolates while only 2 samples from patients receiving 400âmg twice a day were below this value, although no relationship between Ctrough and efficacy was found. The main limitations of the study are that the raltegravir dosing regimen was not randomized and more than 50% of the patients were virologically suppressed at baseline.Regimens comprising raltegravir 800âmg once daily plus 2 nucleos(t)ide reverse transcriptase inhibitors can be an efficacious and safe option, particularly in virologically suppressed patients and those with a viral load <100,000âcopies/mL.
Assuntos
Fármacos Anti-HIV/administração & dosagem , Infecções por HIV/tratamento farmacológico , Raltegravir Potássico/administração & dosagem , Inibidores da Transcriptase Reversa/uso terapêutico , Adulto , Fármacos Anti-HIV/farmacocinética , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Raltegravir Potássico/farmacocinética , Estudos RetrospectivosRESUMO
OBJECTIVE: To evaluate the pharmacokinetic interactions between efavirenz and rifampicin (rifampin) in patients with HIV infection and tuberculosis. DESIGN: Nonblind, randomised, pharmacokinetic study. PATIENTS: 24 patients (21 male, 3 female; mean age 37 years) with HIV infection and tuberculosis. INTERVENTIONS: Patients were randomised to one of the following treatments: group A (n = 16) received antituberculosis drugs without rifampicin, plus highly active antiretroviral therapy (HAART) including efavirenz 600 mg once daily, on days 1 to 7. Patients were then switched to rifampicin in bodyweight-adjusted fixed-dose combination plus HAART including efavirenz 600 mg once daily (group A-1; n = 8) or efavirenz 800 mg once daily (group A-2; n = 8). Group B (n = 8) received rifampicin in bodyweight-adjusted fixed-dose combination on days 1 to 7; on day 8, HAART including efavirenz 800 mg once daily was added. Blood samples were obtained on days 7 and 14. METHODS: Plasma concentrations of efavirenz and rifampicin were quantified by using validated high performance liquid chromatography assays, and pharmacokinetic parameter values were determined by noncompartmental methods. The differences between pharmacokinetic parameters on days 7 and 14 were used to assess interactions. RESULTS: There was a correlation between the pharmacokinetic parameters of efavirenz and the dose/kg administered. For efavirenz, mean (median) peak concentration, trough concentration and area under the concentration-time curve over the administration interval decreased 24% (24%), 25% (18%) and 22% (10%), respectively, in the presence of rifampicin. Large interpatient variability was observed, suggesting that plasma concentration monitoring of efavirenz may be advisable. Overall, the pharmacokinetics of efavirenz 800 mg plus rifampicin were similar to those of efavirenz 600 mg without rifampicin. The pharmacokinetics of rifampicin did not change substantially in the presence of efavirenz. Differences in patients' bodyweight appeared to cause further differences in exposure to efavirenz. Plasma concentrations of efavirenz in patients weighing <50 kg were similar to those previously described in HIV-infected patients without concomitant tuberculosis. However, plasma concentrations in patients weighing >or=50 kg were almost halved compared with those in patients weighing <50 kg. CONCLUSIONS: Although the minimal effective efavirenz plasma concentration that assures virological success is not currently known, it may be advisable to increase the dosage of efavirenz to 800 mg once daily when it is coadministered with rifampicin. Rifampicin can be used with efavirenz without dosage modification.
Assuntos
Infecções Oportunistas Relacionadas com a AIDS/tratamento farmacológico , Fármacos Anti-HIV/farmacocinética , Antituberculosos/farmacocinética , Oxazinas/farmacocinética , Rifampina/farmacocinética , Tuberculose/tratamento farmacológico , Infecções Oportunistas Relacionadas com a AIDS/sangue , Adulto , Alcinos , Fármacos Anti-HIV/sangue , Fármacos Anti-HIV/uso terapêutico , Antituberculosos/sangue , Antituberculosos/uso terapêutico , Área Sob a Curva , Benzoxazinas , Contagem de Linfócito CD4 , Ciclopropanos , Interações Medicamentosas , Feminino , Meia-Vida , Humanos , Masculino , Taxa de Depuração Metabólica , Oxazinas/sangue , Oxazinas/uso terapêutico , Rifampina/sangue , Rifampina/uso terapêutico , Tuberculose/sangueRESUMO
BACKGROUND: This study aimed to evaluate whether low darunavir (DRV) minimum plasma concentration (Cmin) values contribute to virological outcomes during DRV/ritonavir monotherapy (mtDRV/rtv). METHODS: This was a prospective observational single-arm 96-week efficacy study in virologically suppressed subjects on triple therapy switched to mtDRV/rtv (800/100 mg every 24 h). Previous virological failures (VF) on protease-inhibitor-based regimens were allowed if the historical resistance tests showed no major resistance mutation to DRV/rtv. VF was defined as two consecutive HIV RNA measurements of >200 copies/ml. Efficacy was analysed by per-protocol and by intention-to-treat analyses. Plasma DRV Cmin values were measured by LC-MS/MS. RESULTS: A total of 150 subjects were included. At week 96, the efficacy rate on treatment was 83.6% (95% CI 77.2%, 90.0%) by per-protocol analysis and 67.6% (95% CI 60.0%, 75.2%) by intention-to-treat. In the whole cohort the median (IQR) DRV Cmin was significantly higher during the periods of undetectable than of detectable viraemia (1.82 µg/ml [1.47-2.46] versus 1.56 µg/ml [0.93-2.32]; P=0.006) as well as in the subjects with blips and VF. However, a cutoff point sufficiently sensitive and specific could not be found. CONCLUSIONS: The DRV Cmin values are related to viral control during mtDRV/rtv, but therapeutic drug monitoring cannot be recommended routinely as a precise cutoff point is unknown. Adherence is a key success factor on this regimen.
Assuntos
Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1 , Ritonavir/uso terapêutico , Sulfonamidas/farmacocinética , Sulfonamidas/uso terapêutico , Adolescente , Adulto , Idoso , Terapia Antirretroviral de Alta Atividade , Darunavir , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Retratamento , Fatores de Risco , Falha de Tratamento , Resultado do Tratamento , Carga Viral , Adulto JovemRESUMO
OBJECTIVE: To assess the impact of blips and persistent viremia episodes on cell-associated HIV-DNA reservoir in extensively pretreated patients receiving ritonavir-boosted darunavir monotherapy (MtDRV/rtv) for 24 months. DESIGN AND METHODS: Patients from the MonDAR prospective study (NCT01606722) who received at least 6 months of MtDRV/rtv and had at least two available peripheral blood mononuclear cells (PBMCs) samples were selected and classified according to the viral outcome as continuous undetectable viremia (cUV; nâ=â40), blips (nâ=â31), intermittent viremia (IV; nâ=â23), and virological failure (VF, two consecutive viral loads >200âcopies/ml; nâ=â20). Proviral HIV-DNA was quantified by real-time PCR in PBMCs samples at baseline, and months 6, 12, 18 and 24. Additionally, HIV-DNA levels were exhaustively analyzed at virological failure and blip episodes. RESULTS: The HIV-DNA levels remained constant during the 24 months in every group. Neither blips nor intermittent viremia influenced the HIV-DNA levels at short-term or at middle term. By contrast, virological failure episodes gave rise to a significant increase in proviral DNA (2.15 vs. 2.32 log10 HIV-DNA copies/10 PBMCs; Pâ=â0.042). Basal proviral DNA levels more than 2 log10âcopies/10 PBMCs predicted the time to viral rebound at any given cut-off point (>20, >50, and >200âcopies/ml. HR: 3.02, 2.61, and 3.02, respectively; Pâ≤â0.03. Besides, an adherence less than 95% was also strongly associated with virological failure (HR, 3.17; Pâ=â0.021). CONCLUSION: Blip episodes and intermittent viremia did not affect the cellular HIV reservoir dynamic during MtDRV/rtv. Higher adherence and an HIV-DNA levels less than 2 log10âcopies/10 PBMCs at baseline were associated with a lower risk of virological failure.
Assuntos
DNA Viral/isolamento & purificação , Infecções por HIV/tratamento farmacológico , HIV/isolamento & purificação , Leucócitos Mononucleares/virologia , Provírus/isolamento & purificação , Ritonavir/uso terapêutico , Sulfonamidas/uso terapêutico , Adulto , Estudos de Coortes , DNA Viral/genética , Darunavir , Feminino , HIV/genética , Infecções por HIV/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Provírus/genética , Reação em Cadeia da Polimerase em Tempo Real , Carga Viral , ViremiaRESUMO
BACKGROUND: Optimizing HCV genotype 1 therapy in terms of response prediction and tailoring treatment is undoubtedly the cornerstone of treating HIV co-infected patients in clinical practice. Accordingly, our aim was to analyze the predictive value of HCV viral decline for sustained virological response (SVR), measured at a time point as early as week 2 of therapy with pegylated interferon alpha-2a plus ribavirin (Peg-IFN/RBV). METHODS: Previously untreated HIV/HCV genotype 1 co-infected patients were included in this study. The HCV RNA titer was measured at week 2 after starting treatment with Peg-IFN/RBV. The likelihood of reaching SVR when HCV RNA viral titers declined at week 2 was evaluated relative to predictive baseline factors. RESULTS: A total of 192 HIV/HCV genotype-1 co-infected patients were enrolled in the study and began therapy. One hundred and sixty-three patients completed a full course of Peg-IFN/RBV treatment for 2 weeks and 59 of these (36.2%) reached SVR. An HCV RNA viral load decline of ≥1.5 log IU/mL at week 2 had the maximum positive predictive value for SVR (83.3%; 95% CI: 68.5%-92.9%) and was identified as the strongest independent predictive factor for reaching SVR across all baseline predictive factors. CONCLUSIONS: HCV viral decline at week 2 had a high predictive value for identifying patients with a high and low likelihood of reaching SVR using dual therapy, regardless of strong predictive baseline factors. This finding may be useful for developing a predictive tool to help tailor HCV genotype 1 therapy in HIV co-infected patients.
Assuntos
Coinfecção/tratamento farmacológico , Infecções por HIV/tratamento farmacológico , Hepatite C/tratamento farmacológico , Interferon-alfa/administração & dosagem , Polietilenoglicóis/administração & dosagem , Ribavirina/administração & dosagem , Adulto , Antivirais/administração & dosagem , Coinfecção/virologia , Feminino , Genótipo , Infecções por HIV/patologia , Infecções por HIV/virologia , Hepacivirus/efeitos dos fármacos , Hepatite C/patologia , Hepatite C/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes/administração & dosagem , Resultado do Tratamento , Carga ViralRESUMO
OBJECTIVE: To evaluate the IL28B effect on hepatitis C virus (HCV) decline during first weeks of treatment according to HCV-1 subtypes. METHODS: Patients coinfected with HIV/HCV genotype 1 and naive to peginterferon-alpha-2a and ribavirin (Peg-IFN-alpha-2a/RBV) were included. Plasma HCV-RNA was measured at baseline, and then at weeks 1, 2, and 4. HCV-1 subtype (1a or 1b) was determined. HCV viral decline was analyzed according to HCV-1 subtype between baseline and week 1, week 2 and week 4 of treatment. Additionally, we analyzed the effect of the IL28B (rs12979860) genotype on HCV viral decline with HCV-1a and HCV-1b genotype patients (CC versus non-CC). RESULTS: Two hundred and six patients were included in the study, of whom 113 (54.8%) and 93 (45.2%) were infected by HCV-1a and 1b genotypes, respectively. No differences were found between HCV-1 subtypes in terms of HCV viral decline or rapid virological response rate. The effect of the IL28B-CC genotype on HCV viral decline was observed only among patients infected with HCV-1b at all time points analyzed (week 1: CC 1.53â±â0.33, non-CC 0.27â±â0.24, Pâ<0.001; week 2: CC 1.81â±â0.39, non-CC 0.74â±â0.39, Pâ=â0.002; week 4: CC 2.97â±â0.53, non-CC 1.2â±â0.61, Pâ<â0.001). CONCLUSION: Our study suggests that the effect associated with the impact of the IL28B-CC genotype on HCV decline during the first weeks of treatment with Peg-IFN-alpha-2a/RBV differs according to HCV-1 subtype and may be limited to HCV-1b patients.
Assuntos
Infecções por HIV/complicações , Hepacivirus/classificação , Hepatite C/complicações , Interferon-alfa/uso terapêutico , Interleucinas/genética , Polietilenoglicóis/uso terapêutico , Ribavirina/uso terapêutico , Carga Viral , Adulto , Antivirais/uso terapêutico , Feminino , Genótipo , Infecções por HIV/tratamento farmacológico , Hepacivirus/genética , Hepacivirus/isolamento & purificação , Hepatite C/tratamento farmacológico , Hepatite C/virologia , Humanos , Interferons , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes/uso terapêuticoRESUMO
BACKGROUND: Data on which to base definitive recommendations on the doses and duration of therapy for genotype 3 HCV/HIV-coinfected patients are scarce. We evaluated the efficacy of a lower peginterferon-α 2a dose and a shorter duration of therapy than the current standard of care in genotype 3 HCV/HIV-coinfected patients. METHODS AND FINDINGS: Pilot, open-label, single arm clinical trial which involved 58 Caucasian HCV/HIV-coinfected patients who received weekly 135 µg peginterferon-α 2a plus ribavirin 400 mg twice daily during 20 weeks after attaining undetectable viremia. The relationships between baseline patient-related variables, including IL28B genotype, plasma HCV-RNA, ribavirin dose/kg, peginterferon-α 2a and ribavirin levels with virological responses were analyzed. Only 4 patients showed lack of response and 5 patients dropped out due to adverse events related to the study medication. Overall, sustained virologic response (SVR) rates were 58.3% by intention-to-treat and 71.4% by per protocol analysis, respectively. Among patients with rapid virologic response (RVR), SVR and relapses rates were 92.6% and 7.4%, respectively. No relationships were observed between viral responses and ribavirin dose/kg, peginterferon-α 2a concentrations, ribavirin levels or rs129679860 genotype. CONCLUSIONS: Weekly 135 µg pegIFN-α 2a could be as effective as the standard 180 µg dose, with a very low incidence of severe adverse events. A 24-week treatment duration appears to be appropriate in patients achieving RVR, but extending treatment up to just 20 weeks beyond negativization of viremia is associated with a high relapse rate in those patients not achieving RVR. There was no influence of IL28B genotype on the virological responses. TRIAL REGISTRATION: ClinicalTrials.gov NCT00553930.
Assuntos
Genótipo , Infecções por HIV/complicações , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/genética , Interferon-alfa/uso terapêutico , Interleucinas/genética , Polietilenoglicóis/uso terapêutico , Polimorfismo de Nucleotídeo Único , Adulto , Relação Dose-Resposta a Droga , Feminino , Hepatite C Crônica/complicações , Hepatite C Crônica/metabolismo , Humanos , Interferon-alfa/efeitos adversos , Interferon-alfa/farmacocinética , Interferons , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis/efeitos adversos , Polietilenoglicóis/farmacocinética , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/farmacocinética , Proteínas Recombinantes/uso terapêutico , Ribavirina/farmacocinética , Ribavirina/uso terapêutico , Segurança , Resultado do TratamentoRESUMO
BACKGROUND: The aim of the study was to analyze the different impact of standard and low-dose Peg-IFN-α2a/RBV therapies on HCV viral decline in HIV/HCV genotype 3 co-infected patients during the first weeks of treatment. METHODS: Plasma HCV viral decline was analyzed between baseline and weeks 1, 2 and 4 in two groups of treatment-naïve HCV genotype 3 patients with HIV co-infection. The Standard Dose Group (SDG) included patients who received Peg-IFN at 180 µg/per week with a weight-adjusted dose of ribavirin; Low-Dose Group (LDG) patients received Peg-IFN at 135 µg/per week with 800 mg/day ribavirin. The effect of IL28B genotype on HCV viral decline was evaluated in both groups. HCV viral decline was analyzed using a multivariate linear regression model. RESULTS: One hundred and six patients were included: 48 patients in the SDG and 58 in the LDG. HCV viral decline for patients in the LDG was less than for those in the SDG (week 1:1.72±0.74 log(10) IU/mL versus 1.78±0.67 log(10) IU/mL, p = 0.827; week 2:2.3±0.89 log(10) IU/mL versus 3.01±1.02 log(10) IU/mL, p = 0.013; week 4:3.52±1.2 log(10) IU/mL versus 4.09±1.1 log(10) IU/mL, p = 0.005). The linear regression model identified the Peg-IFN/RBV dose as an independent factor for HCV viral decline at week 4. CONCLUSIONS: Our results showed that HCV viral decline was less for patients in the low-dose group compared to those receiving the standard dose. Until a randomized clinical trial is conducted, clinicians should be cautious about using lower doses of Peg-IFN/RBV in HIV/HCV genotype 3 co-infected patients.
Assuntos
Antivirais/uso terapêutico , Infecções por HIV/tratamento farmacológico , HIV/crescimento & desenvolvimento , Hepacivirus/crescimento & desenvolvimento , Hepatite C/tratamento farmacológico , Interferon-alfa/administração & dosagem , Polietilenoglicóis/administração & dosagem , Ribavirina/administração & dosagem , Adulto , Coinfecção/tratamento farmacológico , Coinfecção/genética , Relação Dose-Resposta a Droga , Quimioterapia Combinada/métodos , Feminino , Genótipo , HIV/genética , Infecções por HIV/sangue , Infecções por HIV/genética , Infecções por HIV/virologia , Hepacivirus/genética , Hepatite C/sangue , Hepatite C/genética , Hepatite C/virologia , Humanos , Masculino , Estudos Prospectivos , Proteínas Recombinantes/administração & dosagem , Resultado do Tratamento , Carga Viral/efeitos dos fármacosAssuntos
Infecções por HIV/tratamento farmacológico , Ritonavir/farmacocinética , Ritonavir/uso terapêutico , Saquinavir/farmacocinética , Saquinavir/uso terapêutico , Adulto , Contagem de Linfócito CD4 , Quimioterapia Combinada , Feminino , Humanos , Lactente , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , Gravidez , Ritonavir/administração & dosagem , Carga ViralRESUMO
We evaluated the plasma and intracellular pharmacokinetics, clinical efficacy, and safety of once-daily low-dose boosted saquinavir (SQVr; 1,200 of saquinavir [SQV] with 100 mg of ritonavir) plus two nucleotide reverse transcriptase inhibitors in treatment-naive or limited protease inhibitor (PI)-experienced human immunodeficiency virus (HIV)-infected patients. A prospective study without entry restrictions on the plasma HIV-RNA (VL) or CD4 cell count was carried out. Plasma and intracellular SQV levels were measured by high-performance liquid chromatography. Efficacy was evaluated by an intention-to-treat analysis; treatment failure was defined as virological failure (a VL of >50 copies/ml after 24 weeks or a confirmed rebound to >50 copies/ml) or interruption for any reason. A total of 151 patients were included in the study (106 of them either had never received PI or had no previous virological failure on PIs) and could be characterized as follows: previous C3 stage, 28.9%; injection-drug users, 69.1%; subjects with chronic viral hepatitis, 53%; and subjects with cirrhosis, 10%. The median baseline CD4 level was 184/mul, and the median VL was 4.8 log(10) copies/ml. Median C(max), area under the concentration-time curve from 0 to 24 h, and C(min) plasma and intracellular SQV levels were 3,672 and 10,105 ng/ml, 34,283 and 99,535 ng.h/ml, and 359 and 1,062 ng/ml, respectively. The efficacy as determined by intention to treat at 52 weeks was 69.7% (96% in the on-treatment analysis), with similar results regardless of the baseline VL and CD4 counts. Only five patients had virological failure despite adequate C(min) levels, but with a poor adherence (the only variable related to virological failure). Adverse events caused the withdrawal of the treatment in four patients (2.6%). In conclusion, given the pharmacokinetic profile, efficacy, and tolerability of this regimen, once-daily low-dose SQVr may be considered a treatment option in treatment-naive or limited PI-experienced HIV-infected patients, with the additional benefit of being currently the least-expensive PI-based regimen available.
Assuntos
Fármacos Anti-HIV , Infecções por HIV/tratamento farmacológico , Ritonavir , Saquinavir , Adulto , Idoso , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/uso terapêutico , Contagem de Linfócito CD4 , Quimioterapia Combinada , Feminino , HIV-1/efeitos dos fármacos , HIV-1/genética , HIV-1/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , RNA Viral/sangue , Inibidores da Transcriptase Reversa/administração & dosagem , Inibidores da Transcriptase Reversa/uso terapêutico , Ritonavir/administração & dosagem , Ritonavir/efeitos adversos , Ritonavir/farmacocinética , Ritonavir/uso terapêutico , Saquinavir/administração & dosagem , Saquinavir/efeitos adversos , Saquinavir/uso terapêutico , Resultado do TratamentoRESUMO
The efficacy of low-dose, ritonavir-boosted saquinavir (SQV/rtv) once daily plus 2 nucleoside retrotranscriptase inhibitors (NRTIs) in pregnant human immunodeficiency virus (HIV)-1-infected women was prospectively evaluated, ensuring a SQV minimum concentration (Cmin) >/=100 ng/mL with a therapeutic drug monitoring strategy. The primary clinical endpoint was the percentage of women with an HIV-RNA viral load (VL) of <50 copies/mL at the time of delivery. Forty-nine pregnancy episodes were included, with a median CD4 count and VL of 441/muL and 3710 copies/mL, respectively. Two patients were lost to follow-up and 1 patient discontinued treatment because of abdominal discomfort. SQV levels were in excess of the target Cmin in 43 of 46 episodes (93.4%) in which the end of pregnancy was reached on 1200/100 mg daily. The dosage was increased to 1600/100 mg in the remaining 3 episodes to achieve the target levels. By an intention-to-treat analysis, VL was undetectable at delivery in 43 episodes (87.7%; 95% confidence interval, 78.5-96.9) after a median of 18 weeks of treatment (range, 3-39). In the 3 episodes remaining, VLs of 110,400 copies/mL and no available data were observed after only 3 weeks of treatment. Mild adverse events attributable to SQV/rtv occurred in 6 of 49 pregnancies (12.2%). No cases of HIV vertical transmission were observed. The pharmacokinetics, efficacy, and tolerability of this regimen suggest that once-daily low-dose boosted SQV may be considered an appropriate option in PI-naive or limited-PI-experienced HIV-infected pregnant women. Nevertheless, therapeutic drug monitoring is advisable to maintain appropriate levels throughout pregnancy.